Brain regulation system and method

Abstract

Systems, devices, and methods are provided for delivering energy to a patient to treat a medical condition. A system for delivering energy to a patient includes a treatment device having one or more energy delivery elements. The treatment device may deliver energy, such as ultrasound energy, to a target location of the patient via the one or more energy delivery elements. Delivery of energy to a target location treats a medical condition of a patient.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 519,247 (Case No. SPI-003-PR1), filed August 12, 2023, entitled “Device for Multifocal Delivery of Ultrasound into Deep Brain Regions in Humans,” the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 519,256 (Case No. SPI-004-PR1), filed August 13, 2023, entitled “Remote Targeted Electrical Stimulation,” the contents of which are incorporated herein by reference in their entirety for all purposes.

[0003] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 519,436 (Case No. SPI-005-PR1), filed August 14, 2023, entitled “Durable Effects of Deep Brain Ultrasonic Neuromodulation on Major Depression,” the contents of which are incorporated herein by reference in their entirety for all purposes.

[0004] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 550,365 (Case No. SPI-006-PR1), filed February 6, 2024, entitled “Approach and Device for Targeted Neuromodulation Treatment of Chronic Pain,” the contents of which are incorporated herein by reference in their entirety for all purposes.

[0005] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 550,379 (Case No. SPI-007-PR1), filed February 6, 2024, entitled “Approach and Device for Controlled Targeted Neuromodulation Treatment of Depression,” the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0006] The present invention generally relates to systems, devices, and methods for applying and modulating ultrasound to specific targets in the human brain. Background Technology

[0007] Many patients exhibiting adverse mental and neurological symptoms are resistant to treatment. Current neuromodulation methods have limited effectiveness. Improved brain modulation systems and methods are needed. Summary of the Invention

[0008] According to one aspect of the invention, a system for delivering energy to a patient includes a treatment device comprising one or more energy delivery elements. The treatment device is configured to deliver energy to a target location of the patient via the one or more energy delivery elements. The energy delivery to the target location treats the patient's medical condition.

[0009] In some embodiments, the target location includes the location of the patient's brain.

[0010] In some embodiments, the treatment device is configured to deliver energy to an anatomical location of the patient selected from the group consisting of: brain; heart; liver; pancreas; spleen; dorsal root ganglion; spinal cord; peripheral nerves; and combinations thereof.

[0011] In some embodiments, the therapeutic device is configured to deliver ultrasonic energy. The therapeutic device may also be configured to further deliver magnetic field energy. The magnetic field may include a magnetic field of at least 0.5 T.

[0012] In some embodiments, the treatment device is configured to deliver one, two, or more types of energy selected from the group consisting of: acoustic energy, such as ultrasonic energy; optical energy, such as laser energy; thermal energy, such as thermal energy and / or cryogenic energy; electromagnetic energy, such as radio frequency energy, microwave energy, and / or electroporation energy; chemical energy; mechanical energy; and combinations thereof.

[0013] In some embodiments, the target location spans up to 10 mm, and the system is configured to deliver the energy precisely to the target location. The target location may span up to 5 mm.

[0014] In some embodiments, the therapeutic device is configured to deliver the energy with a spatial resolution of no more than 1.0 mm and a temporal accuracy of no more than 5 μs.

[0015] In some embodiments, the one or more energy delivery array elements comprise a plurality of energy delivery array elements arranged in one or more spherical focusing arrays. The one or more spherical focusing arrays may each comprise a radius of at least 10 mm, no more than 5,000 mm, or both.

[0016] In some embodiments, the treatment device includes a first treatment component and a second treatment component, the first treatment component being configured to deliver energy and positioned on the right side of the patient's head, and the second treatment component being configured to deliver energy and positioned on the left side of the patient's head. The system may further include a housing configured to position the first and second treatment components such that each of the treatment components delivers the energy through a temporal bone window of the patient's skull.

[0017] In some embodiments, the system is configured to deliver energy to multiple different target locations deep within the brain without moving the treatment device or the patient's head. The system can be configured to deliver energy sequentially to at least a first target location and a second target location.

[0018] In some embodiments, the system includes a housing and a patient mask that are configured together to reproducibly position the patient’s head in a desired arrangement for energy delivery without the use of MRI guidance.

[0019] In some embodiments, the system is configured to verify the targeting of energy delivery via MRI oxygen-dependent imaging. The images may provide target location guidance information, dosimetry information, or both.

[0020] In some embodiments, the system further includes an algorithm configured to determine energy delivery drive signals that compensate for one or more obstacles present in the energy delivery path from the treatment device to the target location. The one or more obstacles may include obstacles selected from the group consisting of: the skull; the scalp; hair; components of the system; and combinations thereof. The treated medical condition may include depression. The treated medical condition may include pain, such as chronic pain. The treated medical condition may include addiction, anxiety, and / or other mental disorders. The treated medical condition may include cognitive decline, such as mild cognitive decline. The treated medical condition may include Alzheimer's disease.

[0021] According to another aspect of the present invention, a method of treating a patient suffering from a medical condition includes: selecting a patient for treatment; selecting a system for delivering energy to the patient, the system including a treatment device for delivering the energy to a target location of the patient; and delivering the energy to the target location of the patient via the treatment device. The energy delivery treats the patient's medical condition.

[0022] In some embodiments, the delivered energy includes ultrasonic energy.

[0023] In some embodiments, the delivered energy further includes magnetic field energy.

[0024] In some embodiments, the medical condition being treated includes pain. The selected patients may have a mean 24-hour visual analog scale (VAS) pain score of at least 1. The selected patients may have a mean 24-hour VAS pain score of at least 3. The selected patients may have experienced at least 3 months of moderate pain. The target location may include the anterior cingulate cortex. The target location may include at least two target locations within the anterior cingulate cortex. The target location may include at least four target locations within the anterior cingulate cortex. The at least four target locations include four locations selected from the group consisting of: the infrakal ACC (Brodman area 2565) and six target locations from within the pACC to the aMCC (Brodman area s24, p24, a24, 33). The at least four target locations may include eight target locations within the anterior cingulate cortex. Each target location may be at least 2 mm, no more than 6 mm, or both of these conditions may be separated from adjacent target locations. Each target location may be approximately 4 mm separated from adjacent target locations. The energy delivery may include energy delivery with a peak intensity not exceeding 300 W / cm². The energy delivery may include energy delivery with a peak intensity not exceeding 225 W / cm² and / or not exceeding 190 W / cm². The energy delivery may include energy delivery lasting no more than 3 hours, no more than 2 hours, and / or no more than 1 hour. The energy delivery may include energy delivery lasting at least 30 minutes, no more than 120 minutes, or both. The energy delivery may include energy delivery lasting approximately 40 minutes. The energy delivery may include energy delivery with a field size less than 5 mm × 5 mm × 40 mm. The energy delivery may include energy delivery with a field size of approximately 2.4 mm × 3.6 mm × 20.4 mm. The energy delivery may include multiple test energy deliveries configured to test symptom relief. Each test energy delivery may include an energy delivery lasting no more than 60 seconds. The energy delivery may include multiple energy deliveries configured to provide therapeutic benefit to the medical condition. The multiple energy deliveries may include at least four energy deliveries lasting at least one minute. The multiple energy deliveries may include approximately 12 energy deliveries, each lasting three minutes. The energy delivery may include an energy delivery with an amplitude of at least 0.5 MPa. The energy delivery may include an energy delivery with an amplitude of approximately 1 MPa. The energy delivery may include an energy delivery comprising pulse trains with a duration of at least 10 msec, delivered at a duty cycle of less than 90%. The interval between these pulse trains may not exceed 20 seconds. The energy delivery may include an energy delivery comprising pulse trains with a duration of approximately 30 msec, a duty cycle of 50%, and an interval of 0.7 seconds.This treatment can achieve efficacy including one or more of the following: immediate pain reduction of at least 30% after energy delivery; pain reduction of at least 21.5% one day after energy delivery; and / or pain reduction of at least 16.5% seven days after energy delivery. This treatment can reduce the absolute VAS pain score by at least one point. This treatment can reduce the absolute VAS pain score by 2.7 ± 1.4 points. This treatment has at least a 50% expected rate of achieving a 33% pain reduction immediately after energy delivery. This treatment has approximately a 75% expected rate of achieving a 33% pain reduction immediately after energy delivery. This treatment has at least a 30% expected rate of achieving a 33% pain reduction 24 hours after energy delivery. This treatment has approximately a 60% expected rate of achieving a 33% pain reduction 24 hours after energy delivery. This treatment can reduce the PROMIS pain intensity score by at least 10%. This treatment can reduce the PROMIS pain intensity score by a mean ± SD of 5.68 ± 7.2 points. This treatment can reduce the PROMIS depression score by at least 10%. This treatment can reduce the PROMIS depression score by 2.27 ± 3.75 points. This treatment can reduce the PROMIS anxiety score by at least 10%. This treatment can reduce the PROMIS anxiety score by 2.87 ± 6.21 points.

[0025] In some embodiments, the medical condition being treated includes depression. The selected patient may have treatment-resistant depression. The initial DSM-5 diagnosis of the selected patient may be major depressive disorder or bipolar disorder. The selected patient may currently have a moderate to severe depressive episode lasting at least 1 month without psychotic features. The selected patient may currently have a moderate to severe depressive episode lasting at least 2 months without psychotic features. The selected patient's QIDS score may be at least 6. The selected patient's QIDS score may be at least 10. The target location may include a location in the subcallosal cingulate cortex. The target location may include at least two target locations within the subcallosal cingulate cortex. The target location may include at least three target locations within the subcallosal cingulate cortex. The at least two target locations may include midline target locations in the subcallosal cingulate cortex. The at least two target locations may be stimulated sequentially. The at least two target locations may include a first target location, a second target location, and a third target location, wherein the first target location may be at least 2 mm and / or no more than 6 mm in front of the second target location, and the third target location may be at least 2 mm and / or no more than 6 mm behind the second target location. The first target location may be approximately 4 mm in front of the second target location, and the third target location may be approximately 4 mm behind the second target location. The energy delivery may include energy delivery with a peak intensity not exceeding 300 W / cm². The energy delivery may include energy delivery with a peak intensity not exceeding 225 W / cm² and / or not exceeding 190 W / cm². The energy delivery may include energy delivery for no more than 3 hours, no more than 2 hours, and / or no more than 1 hour. The energy delivery may include energy delivery with an amplitude of at least 0.5 MPa. The energy delivery may include energy delivery with an amplitude of approximately 1 MPa. The energy delivery may include energy delivery with a field size less than 5 mm × 5 mm × 40 mm. The energy delivery may include energy delivery with a field size of approximately 2.4 mm × 3.6 mm × 20.4 mm. The energy delivery may include energy delivery comprising pulse trains with a duration of at least 10 ms, delivered at a duty cycle of less than 90%. The interval between these pulse trains may not exceed 20 seconds. The energy delivery may include energy delivery comprising pulse trains with a duration of approximately 30 ms, a duty cycle of 50%, and a pulse train interval of 0.7 seconds. The energy delivery may include energy delivery comprising pulse trains with a duration of approximately 30 ms, a duty cycle of 50%, and a pulse train interval of 1.4 seconds. The energy delivery may include energy delivery lasting at least 30 seconds. The energy delivery may include energy delivery lasting approximately 60 seconds.The energy delivery may include energy deliveries in blocks, which include resting periods and effective ultrasound treatment periods. These resting and effective periods may be staggered. These effective and / or resting periods may include a duration of at least 30 seconds. These effective and / or resting periods may include a duration of approximately 1 minute. These effective and / or resting periods may include a duration of approximately 3 minutes. Each block may include at least six total periods. Each block may include approximately 10 total periods. At least two energy blocks may be delivered. Energy delivery parameters may vary between different blocks. Energy delivery durations may vary between different blocks. At least three energy blocks may be delivered. Each block may include at least three test energy deliveries with a duration of at least one minute. Each block may approximately include: three to five ultrasound treatments, each lasting one minute, performed at 1.5-second pulse train intervals, such as for testing tolerance at each target site. Each block may include at least six energy deliveries with a duration of at least two minutes. Each block may comprise approximately: six ultrasound treatments of three minutes each at 1.4-second pulse intervals, and / or six ultrasound treatments of three minutes each at 0.7-second pulse intervals. This treatment can achieve at least a 50% change in grief level. This treatment can achieve approximately a 63% change in grief level. This treatment can achieve at least a 25% change in HRDS-6 on day 1 after energy delivery. This treatment can achieve approximately a 55% change in HRDS-6 on day 1 after energy delivery. This treatment can achieve at least a 20% change in HRDS-6 on day 7 after energy delivery. This treatment can achieve approximately a 52% change in HRDS-6 on day 7 after energy delivery.

[0026] In some embodiments, the medical condition being treated includes: addiction; anxiety; and / or other mental disorders. The target location may include one, two, or more locations selected from the group consisting of: the subcallosal cingulate cortex; the nucleus accumbens; the cingulate cortex; and combinations thereof. The medical condition being treated may include cognitive decline. The medical condition being treated may include mild cognitive decline. The selected patient's Montreal Cognitive Assessment score may not exceed 25. The target location may include one, two, or more locations selected from the group consisting of: the hippocampus; the amygdala; the entorhinal cortex; the cingulate cortex; the fornix; and combinations thereof. The medical condition being treated may include Alzheimer's disease. The selected patient's Montreal Cognitive Assessment score may not exceed 15. The target location may include one, two, or more locations selected from the group consisting of: the hippocampus; the amygdala; the entorhinal cortex; the cingulate cortex; the fornix; and combinations thereof.

[0027] The techniques described herein, their properties and incidental advantages, will be best appreciated and understood in light of the following detailed description taken in conjunction with the accompanying drawings, in which representative embodiments are described by way of example. By incorporating references

[0028] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if specifically and individually indicated that each individual publication, patent, or patent application is incorporated herein by reference in its entirety. The contents of all publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for all purposes. Attached Figure Description

[0029] Figure 1 A block diagram illustrating an embodiment of a system for performing medical procedures on a patient, according to a concept conceived in accordance with the present invention, is shown.

[0030] Figure 1A A block diagram illustrating another embodiment of a system for performing medical procedures on a patient, conceived according to the present invention, is shown.

[0031] Figure 1B A block diagram illustrating another embodiment of a system for performing medical procedures on a patient, conceived according to the present invention, is shown.

[0032] Figures 2A to 2B Anatomical diagrams and photographs of a portion of a system conceived according to the present invention for delivering energy to a patient's brain are shown.

[0033] Figures 2C to 2D Coronal and sagittal views of patient-specific brain anatomy structures conceived according to the present invention are shown respectively.

[0034] Figure 3A An example pressure field, conceived according to the present invention, is measured in three dimensions using an isolated human skull.

[0035] Figure 3B The electronic targeting range, as conceived according to the present invention, is measured using four ex vivo skulls.

[0036] Figures 4A to 4B This is a bar graph relating the relative distances of the energy delivery array elements and markers of five patients, as conceived according to the present invention.

[0037] Figure 5 The diagram includes two bar graphs that demonstrate the positive effects of SCC regulation based on the present invention.

[0038] Figures 6A to 6C These are, respectively, brain images, graphs, and another brain image related to the study of S2, as conceived according to the present invention.

[0039] Figure 7 This is a graph illustrating the changes in Hamilton Depression Rating Scale scores induced by ultrasound therapy, based on the concept of the present invention.

[0040] Figure 8 This is a table of adverse reactions encountered in the study of S2 according to the present invention.

[0041] Figures 9A to 9B These are, respectively, the vector representation and the graph representing the electric field properties according to the present invention.

[0042] Figures 10A to 10D It is a first vector representation, a second vector representation, a first pair of curves, and a second pair of curves related to electric field measurement and properties, as conceived according to the present invention.

[0043] Figures 11A to 11C These are, respectively, a first bar graph, a curve graph, and a second bar graph relating to the response amplitude of the combination of ultrasonic delivery and magnetic field delivery, as conceived according to the present invention.

[0044] Figures 12A to 12C These are, respectively, an anatomical diagram based on the concept of the present invention, two brain temperature measurement images, and a gamma activity curve.

[0045] Figures 13A to 13C These are a flowchart, an anatomical diagram, and two brain images, respectively, based on the concept of the present invention.

[0046] Figure 14 This is a bar graph based on the present invention, showing the percentage change in pain intensity of ACC under sham and effective stimuli.

[0047] Figure 15 This is a graph showing the change in pain intensity over time under sham and effective stimuli in the ACC according to the present invention.

[0048] Figures 16A to 16B These are two bar graphs representing the response rates to effective stimuli and sham stimuli, based on the concept of the present invention.

[0049] Figure 17 This is a bar graph representing the changes in PROMIS pain intensity in comparison to spurious stimuli and effective stimuli, based on the concept of the present invention.

[0050] Figures 18A to 18B These are MRI images of the infrakal cingulate cortex and anterior dorsal cingulate cortex of a patient in S4, based on the concept of this invention.

[0051] Figures 19A to 19C These are, respectively, a first brain image, a second brain image, and a target regulation curve from study S5, based on the concept of this invention.

[0052] Figure 20 Three MRI images of a patient’s brain, based on a concept conceived in this invention, are shown, demonstrating selective inactivation of the SCC.

[0053] Figure 21 This is a bar graph, based on the concept of the present invention, showing the changes in the degree of sadness under sham stimuli and effective stimuli.

[0054] Figures 22A to 22C These are, respectively, a first graph showing the change in HDRS-6 score under sham and effective stimuli, a second graph showing the percentage change in HDRS-6 score, and a bar graph showing the response rate, all based on the concept of the present invention.

[0055] Figure 23 This is a flowchart illustrating the research design of research S5 according to the present invention.

[0056] Figure 24 This is a set of brain images illustrating various SCC ultrasound targets according to the present invention.

[0057] Figure 25 This is a flowchart illustrating the participation of research participants in research S5 according to the present invention.

[0058] Figure 26 This is a set of brain images representing distributed neural modulation during SCC stimulation, based on the concept of the present invention.

[0059] Figure 27 This is a table representing the rating changes of an extended version of the positive and negative emotion scale S5, based on the concept of this invention.

[0060] Figures 28A to 28C The bar charts, based on the present invention, represent changes in sadness level, HDRS-6 score, and HDRS-6 percentage under sham and effective stimuli, respectively. Detailed Implementation

[0061] Reference will now be made in detail to existing embodiments of the present technology, examples of which are illustrated in the accompanying drawings. Similar reference numerals may be used to refer to similar components. However, this specification is not intended to limit the disclosure to the particular embodiments, and it should be construed as including various modifications, equivalents, and / or alternatives to the embodiments described herein.

[0062] It should be understood that, when used herein, the words “comprising” (and any of its forms, such as “comprise” and “comprises”), “having” (and any of its forms, such as “have” and “has”), “including” (and any of its forms, such as “includes” and “include”), or “containing” (and any of its forms, such as “contains” and “contain”) specify the presence of the stated feature, whole, step, operation, element, and / or component, but do not preclude the presence or addition of one or more other features, wholes, steps, operations, elements, components, and / or groups thereof.

[0063] It should be further understood that although the terms first, second, third, etc., may be used herein to describe various restrictions, array elements, components, regions, layers, and / or portions, these restrictions, array elements, components, regions, layers, and / or portions should not be limited by these terms. These terms are used only to distinguish one restriction, array element, component, region, layer, or portion from another. Therefore, without departing from the teachings of this application, the first restriction, array element, component, region, layer, or portion discussed below may be referred to as the second restriction, array element, component, region, layer, or portion.

[0064] It should be further understood that when an element (also referred to herein as a “component”) is described as being “on another element,” “attached,” “connected,” or “coupled” to another element, it can be directly on or above that other element, or connected to or coupled to that other element, or one or more intermediate elements may exist. In contrast, when an element is described as being “directly on another element,” “directly attached,” “directly connected,” or “directly coupled” to another element, no intermediate elements exist. Other terms used to describe relationships between elements should be interpreted in a similar manner (e.g., “between” vs. “directly between,” “adjacent” vs. “directly adjacent,” etc.).

[0065] As used herein, the terms “operably attached,” “operably connected,” “operably coupled,” and similar terms related to the attachment of components shall refer to the attachment of two or more components that achieve one, two, or more of the following effects: electrical attachment; fluid attachment; magnetic attachment; mechanical attachment; optical attachment; acoustic attachment; and / or other operable attachment arrangements. Operable attachment of two or more components can facilitate the transmission of the following between the two or more components: power; signals; electrical energy; fluids or other flowable materials; magnetism; mechanical linkage; light; sound, such as ultrasound; and / or other materials and / or components.

[0066] It should be further understood that when the first array element is referred to as "in the second array element", "on the second array element" and / or "within the second array element", the first array element can be located as: within the internal space of the second array element, within a portion of the second array element (e.g., within the wall of the second array element); located on the outer surface and / or inner surface of the second array element; and one or more combinations thereof.

[0067] As used herein, the term "proximate" when used to describe the proximity of a first component or location to a second component or location should be understood to include one or more locations close to the second component or location, as well as locations within, on, and / or within the second component or location. For example, a component located near an anatomical site (e.g., a blood or other fluid delivery site) should include components located close to the anatomical site, as well as components located within, on, and / or within the anatomical site.

[0068] Spatial relative terms such as “below,” “under,” “lower,” “above,” “upper,” and “under” can be used to describe the relationship between an element and / or feature and another element (or feature), as illustrated, for example, in the accompanying drawings. It should be further understood that these spatial relative terms are intended to cover different orientations of the device in use and / or operation other than those depicted in the drawings. For example, if the device in the figures is flipped, elements described as “below” and / or “under” other elements or features will be oriented “above” those other elements or features. The device may be oriented in other ways (e.g., rotated 90 degrees or in other orientations), and the spatial relative descriptors used herein will be interpreted accordingly.

[0069] The term “reduce (reducing, reduction, reduction, etc.)” as used herein is intended to include a reduction in quantity, including a reduction to zero. The likelihood of a reduction occurring should include prevention of its occurrence. Accordingly, the terms “prevent (preventing, prevention, and prevention)” and “avoid (avoiding, avoiding)” should respectively include the actions of “reduce (reducing, reduction, reduction)”.

[0070] The term “and / or” as used herein shall be understood as a specific disclosure of each of the two specified features or components in the presence or absence of the other. For example, “A and / or B” shall be understood as a specific disclosure of each of (i) A, (ii) B, and (iii) A and B, as if each were listed separately herein.

[0071] The term “one or more” as used in this document may mean one, two, three, four, five, six, seven, eight, nine, ten, or more, up to any number.

[0072] The terms “and combinations thereof” and “and combinations thereof” may each be used in this document after a list of items to be included individually or collectively. For example, a component, process, and / or other item selected from the group consisting of: A; B; C; and combinations thereof, should include a combination of one or more components, including: one, two, three, or more items of item A; one, two, three, or more items of item B; and / or one, two, three, or more items of item C.

[0073] In this specification, unless otherwise expressly stated, “and” may mean “or”, and “or” may mean “and”. For example, if a feature is described as having A, B, or C, then the feature may have A, B, and C, or any combination of A, B, and C. Similarly, if a feature is described as having A, B, and C, then the feature may have only one or both of A, B, or C.

[0074] As used herein, when a quantifiable parameter is described as having a value "between a first value X and a second value Y", it should include a parameter having the following values: at least X, not exceeding Y, and / or at least X and not exceeding Y. For example, a length between 1 and 10 should include a length of at least 1 (including values ​​greater than 10), a length of less than 10 (including values ​​less than 1), and / or a value greater than 1 and less than 10.

[0075] The expression “configured as (or set as)” as used in this disclosure may be used interchangeably with expressions such as “suitable for,” “capable of,” “designed to,” “adapted to,” “manufactured as,” and “capable”, depending on the context. The expression “configured as (or set as)” does not mean that it is “specifically designed for” only in hardware. Alternatively, in some cases, the expression “device configured as…” may mean that the device “can” operate with another device or component.

[0076] As used herein, the terms “about” or “approximately” shall refer to ±20% of the stated value.

[0077] As used herein, the term "threshold" refers to a maximum level, minimum level, and / or range of values ​​associated with a desired or undesirable state. In some embodiments, system parameters are maintained above a minimum threshold, below a maximum threshold, within a threshold range of values, and / or outside a threshold range of values, for example, to induce desired effects (e.g., effective treatment) and / or to prevent and / or otherwise reduce (hereinafter "prevent") undesirable events (e.g., device and / or clinical adverse events). In some embodiments, thresholds are determined to include safety margins, such as to account for patient, user, and / or operator variability, system variability, tolerances, etc. As used herein, "exceeding a threshold" refers to a parameter being above a maximum threshold, below a minimum threshold, within a threshold range, and / or outside a threshold range.

[0078] As described herein, “room pressure” should be understood to mean the pressure of the environment surrounding the systems and devices of this invention. Positive pressure includes pressures above room pressure or simply pressures greater than another pressure, such as a positive pressure difference across a fluid passageway (e.g., a valve). Negative pressure includes pressures below room pressure or pressures less than another pressure, such as a negative pressure difference across a fluid passageway (e.g., a valve). Negative pressure can include a vacuum, but does not imply pressures below a vacuum. As used herein, the term “vacuum” can be used to refer to a complete or partial vacuum, or any negative pressure as described above.

[0079] In this document, the term "diameter" used to describe non-circular geometries should be understood as the diameter of an imaginary circle that approximates the geometry being described. For example, when describing a cross-section (such as the cross-section of a component), the term "diameter" should be understood as representing the diameter of an imaginary circle having the same cross-sectional area as the cross-section of the component being described.

[0080] In this document, the terms “major axis” and “minor axis” of a component refer to the length and diameter, respectively, of the smallest imaginary cylinder that can completely enclose the component.

[0081] As used herein, the term "functional element" should be understood to include one or more elements configured and arranged to perform a function. A functional element may include sensors and / or transducers. In some embodiments, a functional element is configured to deliver energy. In some embodiments, a functional element is configured to treat tissue (e.g., a functional element configured as a treatment element). Alternatively or additionally, a functional element (e.g., a functional element including sensors) may be configured to record one or more parameters, such as patient physiological parameters; patient anatomical parameters (e.g., tissue geometry parameters); patient environmental parameters; and / or system parameters. In some embodiments, sensors or other functional elements are configured to perform diagnostic functions (e.g., acquiring data for performing a diagnosis). In some embodiments, a functional element is configured to perform therapeutic functions (e.g., delivering therapeutic energy and / or therapeutic agents). In some embodiments, a functional element includes one or more elements configured and arranged to perform functions selected from the group consisting of: delivering energy; extracting energy (e.g., cooling a component); delivering a drug or other agent; manipulating system components or patient tissue; recording and / or otherwise sensing parameters, such as patient physiological parameters or system parameters; and combinations of one or more of these. Functional elements may include fluid and / or fluid delivery systems. Functional elements may include reservoirs, such as expandable balloons or other fluid sustaining reservoirs. A "functional component" may include components configured and arranged to perform functions, such as diagnostic and / or therapeutic functions. A functional component may include expandable components. A functional component may include one or more functional elements.

[0082] As used herein, the term "transducer" should be understood to include any component or combination of components that receives energy or any input and produces an output. For example, a transducer may include electrodes that receive electrical energy and distribute it to tissue (e.g., based on electrode size). In some configurations, a transducer converts an electrical signal into any output, such as: light (e.g., a transducer including a light-emitting diode or a light bulb), sound (e.g., a transducer including a piezoelectric crystal configured to deliver ultrasonic energy); pressure (e.g., applied pressure or force); thermal energy; cryogenic energy; chemical energy; mechanical energy (e.g., a transducer including a motor or solenoid); magnetic energy; and / or different electrical signals (e.g., input signals different from those of the transducer). Alternatively or additionally, a transducer may convert a physical quantity (e.g., a change in a physical quantity) into an electrical signal. A transducer may include any component that delivers energy and / or agents to tissue, such as a transducer configured to deliver one or more of the following: delivering electrical energy to tissue (e.g., a transducer including one or more electrodes); delivering optical energy to tissue (e.g., a transducer including a laser, a light-emitting diode, and / or optical components such as lenses or prisms); delivering mechanical energy to tissue (e.g., a transducer including tissue manipulation elements); delivering ultrasonic energy and / or other acoustic energy to tissue (e.g., a transducer including piezoelectric crystals); chemical energy; electromagnetic energy; magnetic energy; and combinations of one or more of these.

[0083] As used herein, the term "fluid" can refer to a liquid, gas, gel, or any flowable material, such as a material that can be propelled through cavities and / or openings.

[0084] As used herein, the term "material" can refer to a single material or a combination of two, three, four or more materials.

[0085] As used herein, the term "user interface" can include one or more interfaces, each including one or more components configured to receive input from a user (referred to herein as "user input devices") and / or one or more components configured to provide output to a user (referred to herein as "user output devices"). Input devices can include one, two, three, or more components selected from the group consisting of: a keyboard; a mouse; buttons; switches; joysticks; keypads, such as membrane keyboards; joysticks; touchscreen displays; microphones; brain-computer interfaces (e.g., thought control devices); cameras, such as cameras with eye tracking, motion tracking, gesture recognition, and / or other image processing capabilities configured to recognize user input; motion capture devices, such as cameras and / or devices including one or more accelerometers; virtual input devices, such as virtual devices including ultrasound-based, image capture, and / or motion sensing of user input; physiological input sensors, such as sensors configured to provide input signals based on user actions (e.g., flexion of muscles near the sensor); odor detectors, such as detectors configured to recognize pheromones or other odors generated by the user; other input components; and combinations thereof. Output devices may include one, two, three, or more components selected from the group consisting of: visual output components, such as lamps and / or displays, such as touchscreen displays; auditory output components, such as buzzers and / or speakers; tactile output components, such as vibration transducers and / or ultrasound devices configured to generate tactile output; brain-computer interfaces; augmented reality (AR) and / or virtual reality (VR) output devices, such as glasses or head-mounted devices including opaque displays, transparent displays, and / or “head-up” displays, wherein information is presented to the user in an overlay manner; odor output devices configured to generate aroma output, such as computerized odor output; other output components; and combinations thereof.

[0086] The terms “data” and “information” are used interchangeably in this document.

[0087] As used herein, the term “access” can refer to providing access to a location within a patient’s body for the delivery of fluids or other materials, and / or the removal of fluids or other materials.

[0088] As used herein, "treatment planning," "treatment program," etc., can include one or more medical procedures (e.g., diagnostic and / or therapeutic procedures) to be performed using the systems, devices, and methods of the present invention. A treatment program can include: the anatomical location of one or more tissue portions to be treated, and / or one or more anatomical locations of one or more tissue portions to be avoided; the setup of energy delivery (e.g., ultrasound delivery) to be used in diagnostic procedures (e.g., imaging procedures or other diagnostic procedures); the setup of energy delivery (e.g., ultrasound delivery) to be used in therapeutic procedures (e.g., ablation procedures, stimulation procedures, and / or other therapeutic procedures); the identity of one or more clinicians to perform the medical procedures; and combinations thereof.

[0089] As used in this article, "acoustic path" can refer to the path in a tissue volume through which energy (e.g., ultrasonic energy) propagates.

[0090] It should be understood that, for clarity, certain features of the inventive concept described in the context of a single embodiment may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the inventive concept described in the context of a single embodiment may also be provided individually or in any suitable sub-combination. For example, it should be understood that all features set forth in any claim (whether an independent claim or a dependent claim) may be combined in any given manner.

[0091] It should be understood that at least some of the figures and descriptions in this invention have been simplified to focus on the array elements relevant to a clear understanding of the inventive concept, while other array elements that would be understood by one of ordinary skill in the art to also constitute part of the inventive concept have been omitted for clarity. However, because such array elements are well known in the art, and because they do not necessarily contribute to a better understanding of the inventive concept, descriptions of such array elements are not provided herein.

[0092] The terminology defined in this disclosure is used only to describe specific embodiments of this disclosure and is not intended to limit the scope of this disclosure. Terms provided in the singular are intended to include the plural form as well, unless the context clearly indicates otherwise. Unless otherwise defined herein, all terms used herein (including technical or scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art. Terms defined in general dictionaries should be interpreted as having the same or similar meaning as in the context of the relevant art and should not be interpreted as having an ideal or exaggerated meaning unless expressly so defined herein. In some cases, the terms defined in this disclosure should not be construed as excluding embodiments of this disclosure.

[0093] This document provides systems, apparatus, and methods for performing medical procedures (also referred to herein as “clinical procedures”) on patients, such as diagnostic procedures, therapeutic procedures (also referred to herein as “treatment procedures”), and / or other medical procedures. In some embodiments, at least ultrasonic energy is delivered to the patient (e.g., through the patient’s skull) to treat the patient’s medical condition. In some embodiments, ultrasonic energy and magnetic energy (e.g., through the patient’s skull) are delivered to the patient (e.g., simultaneously) to treat the patient’s medical condition. Typical medical conditions treated by the systems, apparatus, and methods of the present invention include, but are not limited to: pain; depression, anxiety; addiction, and / or other mental disorders, cognitive impairment, such as mild cognitive impairment; Alzheimer’s disease; other medical conditions; and combinations of one, two, or more of these.

[0094] Now for reference Figure 1 The present invention illustrates a system for performing medical procedures on a patient. System 10 can be configured and / or adapted (referred to herein as "configured" or "adapted") to perform medical procedures on a patient, including diagnostic procedures, therapeutic procedures, or both. Patients may include human patients and / or other mammalian patients, referred to herein as "patients". System 10 can be configured to modulate, stimulate, and / or otherwise treat one or more brain locations, such as when configured to modulate, stimulate, and / or otherwise treat deep brain circuits of a patient. Alternatively or additionally, system 10 can be configured to generate images and / or other diagnostic data associated with one or more brain locations, such as when configured to generate diagnostic data associated with deep brain circuits of a patient.

[0095] System 10 includes one, two, or more treatment devices, such as treatment device 100 as shown in the figure. Treatment device 100 may include devices selected from the group consisting of: devices configured to be mounted (e.g., fixedly and / or removably mounted) to a tabletop or other surface; head-mounted devices; devices attached to manipulatory arms; and combinations thereof. As used herein, “user,” “operator,” and / or “clinician” of system 10 may refer to physicians, nurses, clinicians, and / or other healthcare professionals who use treatment device 100 and / or other components of system 10. System 10, treatment device 100, and / or Figure 1 Other components of system 10 may have the same characteristics as the reference. Figure 1A Similar construction and arrangement to similar components described elsewhere in this document.

[0096] The treatment device 100 may include one, two, or more components for treating tissue, such as treatment component 150 as shown herein. Each treatment component 150 may include one, two, or more energy delivery transducers, such as energy delivery array element 155 as shown herein (e.g., one, two, or more ultrasound transducers). Treatment component 150 may be configured to deliver one, two, or more forms of energy as described herein. In some embodiments, treatment component 150 is configured to perform diagnostics (e.g., in addition to or alternative to treatment), such as diagnosing a patient's medical condition, diagnosing a procedure performed by system 10 (e.g., evaluation), and / or other diagnostics. In some embodiments, treatment component 150 includes components of one or more ultrasound transducers, such as when treatment component 150 is configured to deliver ultrasound energy to tissue for, for example, to modulate, stimulate, and / or otherwise treat the tissue (referred to herein as "modulation," "stimulation," or "treatment") and / or to deliver ultrasound energy to create image data and / or other diagnostic data (e.g., when treatment component 150 is configured to both deliver and receive ultrasound energy). Treatment component 150 may include a component comprising one or more arrays of ultrasonic transducers, wherein each array may include one or more ultrasonic transducers. In some embodiments, treatment component 150 includes a first portion (i.e., treatment component 150a) and a second portion (i.e., treatment component 150b), each as shown in the figures. In some embodiments, during a medical procedure performed using system 10, treatment component 150a is positioned on one side of the patient's head, and treatment component 150b is positioned on the opposite side of the patient's head, as described herein. Treatment component 150 may have a reference... Figure 1A Similar construction and arrangement to component 150 described elsewhere in this document.

[0097] System 10 may include one, two, or more consoles and / or other modular components, such as console 200 as shown. Console 200 may be configured to be operatively connected to treatment device 100 and / or another component of system 10, for example when the attachment includes electrical attachment (e.g., for transmitting power, data, and / or other signals), fluid attachment (e.g., for transmitting cooling fluid, hydraulic fluid, pneumatic fluid, and / or other fluids), optical attachment (e.g., for transmitting laser and / or other light); mechanical attachment (e.g., for operating mechanical linkages); acoustic attachment (e.g., for transmitting sound); and / or other attachments. Console 200 may be configured to be operatively connected to treatment device 100 and / or another component of system 10, for example, to send power and / or signals to and / or receive signals from the connected component. Console 200 may provide a user interface (e.g., as described herein) for inputting commands and / or other information from a user of system 10, and / or for outputting information from system 10 to a user. Console 200 may include one or more discrete components. The console 200 may include a trolley or other freestanding component, and / or other components designed to be placed on a table, countertop, or off-ground surface. The console 200 may include one, two, or more components selected from the group consisting of: laptop computers, tablet computers, and / or other computers. In some embodiments, all or a portion of the console 200 includes a handheld device. In some embodiments, the treatment device 100 includes all or at least a portion of the console 200. The console 200 may have a design similar to that of a reference device. Figure 1A Similar construction and arrangement to the console 200 described elsewhere in this document.

[0098] System 10 may include one, two, or more modules configured to perform functions, such as processing unit 50 as shown. Treatment device 100, console 200, and / or another component of system 10 may include all or part of processing unit 50. Processing unit 50 may have the same characteristics as referenced... Figure 1A It has a similar construction and arrangement to the processing unit 50 described elsewhere in this document.

[0099] System 10 may include one, two, or more modules configured to provide a user interface, such as user interface 60 as shown in the figure. Treatment device 100, console 200, and / or another component of system 10 may include all or part of user interface 60. User interface 60 may have a similar design to reference [reference / ... Figure 1A It has a similar construction and layout to the user interface 60 described elsewhere in this document.

[0100] System 10 (e.g., any component of system 10) may include one, two, or more elements, components, and / or other parts configured to perform functions, such as functional element 99 as shown. Treatment device 100, console 200, and / or another component of system 10 may include all or part of one or more functional elements 99. Functional element 99 may have the same characteristics as referenced... Figure 1A Similar construction and arrangement to the functional array element 99 described elsewhere in this document.

[0101] In some embodiments, system 10 is configured to perform an imaging procedure and / or otherwise collect image data, i.e., image data IDs, such as when one or more ultrasound transducers of treatment component 150 (e.g., energy delivery array 155 including ultrasound transducers, referred to herein as UST 155U) deliver ultrasound to tissue, and one or more ultrasound transducers of treatment component 150 (e.g., similar and / or dissimilar transducers in energy delivery array 155) receive the delivered ultrasound (e.g., receive reflections of the delivered ultrasound), such that system 10 can generate one or more images of tissue (e.g., target tissue as described herein) based on the timing and / or other parameters of the delivered and received ultrasound. System 10 may be configured to generate two-dimensional (2D) and / or three-dimensional (3D) images based on the collected image data IDs.

[0102] In alternative and / or additional embodiments, system 10 is configured to perform a “treatment procedure,” such as a treatment procedure that includes delivering ultrasound energy. System 10 may be configured to perform treatment procedures that include tissue treatment procedures, such as tissue modulation and / or other tissue treatment procedures that include delivering energy (e.g., ultrasound energy, radio frequency energy, magnetic energy, and / or one or more other forms of energy as described herein) to tissue. In some embodiments, the delivered energy may include ultrasound energy delivered to tissue by one or more transducers of energy delivery array 155, such as ultrasound energy delivered to a “target tissue” (also referred to as a “target site”) to be modulated and / or otherwise treated. In some embodiments, system 10 is configured to deliver ultrasound energy to activate drugs and / or other agents; and / or to enhance the efficacy of drugs and / or other agents.

[0103] In some embodiments, system 10 is configured to perform a “combined imaging and treatment procedure” that includes performing one or more imaging procedures and one or more tissue modulation and / or other tissue treatment procedures. In these embodiments, system 10 may be configured to simultaneously generate image data IDs (e.g., images for creating tissues, agents, and / or implants within a patient) and deliver treatments (e.g., treatments for modulating and / or otherwise treating tissues, and / or treatments for modifying implants and / or agents). Alternatively or additionally, system 10 may be configured to sequentially (e.g., in a repetitive manner) generate image data IDs (e.g., images for creating tissues, agents, and / or implants within a patient) and deliver treatments (e.g., treatments for modulating and / or otherwise treating tissues, and / or treatments for modifying implants and / or agents). In the combined imaging and treatment procedure, energy delivery and / or other parameters of the treatment procedure (e.g., a tissue treatment procedure) may be determined (e.g., automatically determined by system 10) based on image data IDs collected concurrently with and / or prior to the performance of the treatment.

[0104] In some embodiments, system 10 is configured to perform: imaging the brain (e.g., imaging one or more parts of the brain), such as to identify the location of one or more target tissue sites to be treated, such as to perform modulation of one or more deep brain circuits, as described herein. In some embodiments, the location of one or more target sites to be treated (e.g., receiving ultrasound and / or other forms of energy) is based on data collected during a procedure of imaging the patient's brain. The brain imaging procedure may be performed using ultrasound energy (e.g., as delivered and received by treatment device 100), using MRI (e.g., via imaging device 800 including MRI), or using both.

[0105] In some embodiments, system 10 is configured to perform: imaging (e.g., for performing diagnostic analysis, such as for determining the location of target tissue to be treated); treatment (e.g., modulation and / or other tissue treatment); or both, such as when performing one or both procedures at an anatomical location selected from the group consisting of: brain; heart; liver; pancreas; spleen; dorsal root ganglion; spinal cord; peripheral nerves; and combinations thereof.

[0106] In some embodiments, system 10 is configured to perform: imaging (e.g., for performing diagnostic analysis, such as for determining the location of target tissue to be treated); treatment (e.g., modulation and / or other tissue treatment); or both, such as when performing one or both procedures to diagnose and / or treat tissue types selected from the group consisting of: brain tissue; heart tissue; liver tissue; pancreatic tissue; spleen tissue; dorsal root ganglion tissue; spinal cord tissue; peripheral nerve tissue; and combinations thereof.

[0107] System 10 can be configured to avoid affecting certain tissue volumes, i.e., “non-target tissue,” also referred to herein as “non-target locations.” In some embodiments, system 10 is configured to perform diagnostic procedures in which damage and / or other undesirable effects on non-target tissue are prevented or at least reduced (referred to herein as “reduced,” “prevented,” or “avoided”). In some embodiments, tissue immediately adjacent to the target tissue includes “safety margin tissue” (also referred to herein as “safety margin location”), and tissue outside the safety margin tissue includes non-target tissue. In these embodiments, safety margin tissue may include tissue that is not particularly desired to be treated (e.g., modulated or otherwise treated) but does not need to be avoided.

[0108] As described herein, system 10 can be configured to perform both diagnostic procedures (e.g., procedures that generate one or more images of tissues or other materials on and / or inside a patient) and therapeutic procedures (e.g., procedures that modulate and / or otherwise treat target tissue). In these embodiments, diagnostic procedures (e.g., imaging) and therapeutic procedures can be performed simultaneously, sequentially, or both. In some embodiments, imaging and tissue treatment (e.g., modulation) are performed in an alternating manner, such as when tissue treatment (e.g., adjusting one or more ultrasound delivery parameters and / or other therapeutic parameters) is adjusted based on analysis of one or more images (also referred to herein as “image data IDs”). Adjustments to therapeutic parameters can be performed by system 10 (e.g., via algorithms of system 10 as described herein), by a clinician (e.g., based on information provided by system 10), or via a combination of system 10 and a clinician (e.g., when a clinician needs to confirm the acceptability of parameters “recommended” by system 10 or parameter changes).

[0109] In some embodiments, the system 10 is configured to perform diagnostic and / or therapeutic procedures, which include delivering ultrasound energy to activate drugs and / or other agents; and / or to enhance the efficacy of drugs and / or other agents.

[0110] In some embodiments, the system 10 is configured to perform a medical procedure that includes delivering ultrasound energy to an implant and / or a drug, such as for supplying power to the implant and / or a drug and / or otherwise modifying the implant and / or the drug.

[0111] The target tissue treated using system 10 may include two, three, four, or more target tissue volumes. Each target tissue volume may be adjacent to another target tissue volume, and any pair of target tissue volumes may not be adjacent. In some embodiments, the two or more target tissue volumes may include two or more brain tissue volumes.

[0112] In some embodiments, the treatment component 150 includes a first portion (i.e., component 150a) configured to be positioned on one side of the patient’s head and a second portion (i.e., component 150b) configured to be positioned on the opposite side of the patient’s head, as described herein.

[0113] In some embodiments, system 10 and / or one or more of its components have a similar construction and arrangement to the systems and components described in U.S. Patent Application US20230210493A1 (Serial No. 18 / 093,220), filed January 4, 2023, entitled “System and Methods for Modulation of Deep Brain Circuits,” and / or in International PCT Application WO 2023211898 (Serial No. PCT / US2023 / 019759), filed April 25, 2023, entitled “System and Method for Sharpening the Focal Volume of Therapeutic and Imaging Systems,” the contents of each of these applications are incorporated herein by reference for all purposes.

[0114] For further reference Figure 1A This illustrates another embodiment of a system for performing medical procedures conceived according to the present invention. Figure 1A System 10 can have the same Figure 1 Similar construction and arrangement to System 10 described elsewhere in this document. For example, Figure 1A The system 10 may include a treatment device 100, a treatment component 150, an energy delivery module 250 (each shown in the figure), a processing unit 50, a user interface 60, a functional array 99, and a console 200 (also shown in the figure).

[0115] In some embodiments, system 10 further includes one or more additional imaging devices, namely imaging devices 800 as shown, wherein each device is configured to generate image data ID. Treatment device 100 may include all or part of imaging device 800. Imaging device 800 may include one, two, or more devices selected from the group consisting of: a fluorescence microscope or other imaging device; a CT scanner; a magnetic resonance imaging (MRI) scanner; a positron emission tomography (PET) scanner; an ultrasound imager; optical coherence tomography (OCT) and / or other light-based imaging devices; and combinations thereof. Imaging device 800 may include an MRI configured to identify target tissue for treatment (e.g., identifying one or more brain tissue volumes for modulation and / or other treatments).

[0116] As described herein, the treatment component 150, the imaging device 800, and / or one or more other components of the system 10 may be configured to generate (also referred to as “record,” “acquire,” “collect,” etc.) image data, referred to herein as image data ID.

[0117] Processing unit 50 may include one or more modules, each of which may be configured to perform, control, and / or monitor one or more functions of system 10 (e.g., as described herein). One or more devices or other components of system 10 may include all or part of processing unit 50, such as when all or part of processing unit 50 is integrated with treatment device 100, console 200, imaging device 800, and / or another component of system 10. For example, processing unit 50 may be configured to perform and / or facilitate one or more processes, data collection, data analysis, data transmission, signal processing functions, drug delivery, location of access elements, flow monitoring, monitoring of one or more patient parameters, and / or other functions of system 10 (referred to herein as "functions of system 10", "system 10 functions", or simply "system functions"). Processing unit 50 may include one or more electronic elements, electronic components, and / or other electronic parts, such as parts selected from the group consisting of: microprocessors; microcontrollers; state machines; memory storage units; analog-to-digital converters; rectifier circuit systems; filters and other signal conditioners; sensor interface circuit systems; transducer interface circuit systems; and combinations of one, two, or more of these. For example, processing unit 50 may include at least one processor and at least one memory storage unit, such as processor 51 and memory 52, each as shown in the figure. Memory 52 may include local memory, external storage devices, and / or remote or cloud-based memory systems. Memory 52 may be coupled to processor 51, and memory 52 may store one or more sets of computer instructions, namely instruction 53 as shown in the figure. Instruction 53 may include executable instructions for performing energy delivery compensation (e.g., as described herein) and other functions of system 10. Instruction 53 may include instructions used by processor 51 to execute one or more algorithms of system 10. For example, system 10 may include one or more algorithms executed by processor 51, namely algorithm 55 as shown in the figure. Additionally or alternatively, instruction 53 may include instructions for running one or more applications of system 10 (e.g., application 56 as shown). Processing unit 50 may be configured to "run" application 56, such that application 56 can initiate, modify, stop, and / or otherwise control the execution of various functions of therapeutic device 100 and / or another component system 10. In some embodiments, application 56 is configured to receive input from a user of system 10, for example, via a user interface (e.g., user interface 60 described herein). In some embodiments, algorithm 55 may include one or more machine learning algorithms, neural network algorithms, and / or other artificial intelligence algorithms (referred to herein as "AI algorithms").As described herein, all or part of one or more processing units 50 may be integrated into one, two or more of the various components of system 10, such as treatment device 100, console 200, server (e.g., server 80 described herein), and / or other components of system 10. The execution of the functions of system 10 is described above as being performed by processing unit 50. Alternatively or additionally, the execution of the functions of system 10 may be interchangeably described herein as being performed by algorithm 55 and / or system 10. For example, “algorithm 55 configured to perform an action, routine, and / or another function” can be interpreted as processing unit 50 and / or system 10 being configured to perform that action, routine, and / or other function, and vice versa.

[0118] As described herein, processing unit 50 (e.g., processing unit 105 of treatment device 100, processing unit 205 of console 200, and / or processing unit of another system 10 component) may be configured to execute one or more algorithms, namely algorithm 55. Each algorithm 55 may include an artificial intelligence algorithm or other algorithms. In some embodiments, system 10 is configured to generate a volumetric multidimensional image of tissue (e.g., as described herein), and algorithm 55 includes an artificial intelligence algorithm or other algorithms configured to perform the following functions: characterize one or more tissue types; identify tissue areas to avoid treatment; and / or suggest tissue areas to be treated.

[0119] Algorithm 55 may include artificial intelligence algorithms or other algorithms configured to evaluate image data IDs to maintain focus (e.g., a specific field of view) for delivering energy (e.g., delivering ultrasound energy to modulate tissue).

[0120] User interface 60 may include one or more user interfaces configured to provide information to and / or receive information from a user of the system (e.g., a clinician and / or other users of system 10). One or more devices or other components of system 10 may include all or part of user interface 60, such as when all or part of user interface 60 is integrated with treatment device 100, console 200, imaging device 800, and / or another component of system 10. User interface 60 may include one or more user input and / or output components as described herein. For example, user interface 60 may include a keyboard, mouse, touchscreen, and / or other human-machine interface and / or other input components, namely user input device 61. In some embodiments, user interface 60 includes a speaker, indicator lights, haptic transducers, and / or other human-machine interface and / or other output components, namely user output device 62. In some embodiments, user output device 62 includes a video output component, such as display 63 as shown. Display 63 may include a touchscreen display, for example when user input device 61 and user output device 62 jointly include display 63. In some embodiments, processing unit 50 is configured to provide an interactive graphical interface GUI 65, such as a graphical user interface provided by application 56. GUI 65 may be displayed via display 63 (e.g., displayed to a user of system 10). In some embodiments, user interface 60 and / or GUI 65 include virtual reality and / or augmented reality interfaces. One or more components of system 10 may include one or more portions of user interface 60, such as therapeutic device 100, console 200, and / or other components of system 10 described herein.

[0121] Communication module 70 may include one or more communication modules configured to send and / or receive data. One or more devices or other components of system 10 may include all or part of communication module 70, such as when all or part of communication module 70 is integrated with treatment device 100, console 200, and / or another component of system 10. Communication module 70 may be configured to provide communication between two or more components of system 10 (e.g., transmitting commands, delivery information, patient information, and / or other data therebetween) via wired and / or wireless communication. For example, communication module 70 may include one or more transmitters and / or receivers, i.e., transceivers 71 as shown. Transceiver 71 may include wireless transceivers, such as Bluetooth transceivers, near field communication (NFC) transceivers, Wi-Fi transceivers, cellular transceivers, satellite-connected transceivers, and / or other short-range and / or long-range wireless transceivers. Wireless connectivity may include short-range wireless connectivity, such as NFC connectivity and / or Bluetooth Low Energy (BLE) connectivity. In some embodiments, the communication module 70 is configured to transmit data via acoustic signals (such as acoustic signals outside the user's hearing range). In some embodiments, the communication module 70 is configured to communicate via one or more wired and / or wireless networks (such as network 75 as shown). Network 75 may include wireless networks such as cellular networks, LANs, WANs, VPNs, the Internet, and / or other wireless networks connecting two or more devices. In some embodiments, network 75 includes wired networks and / or includes networks containing wired and wireless devices.

[0122] The communication module 70 can be configured to transmit data between at least a first component and at least a second component of the system 10, as described herein. In some embodiments, the first component of the system 10 includes the treatment device 100. The second component may include another component of the system 10, such as the console 200 and / or the imaging device 800.

[0123] The treatment device 100 may include one or more housings, namely housing 110 as shown. In some embodiments, housing 110 is configured to position and orient a first treatment component 150a relative to a second treatment component 150b. In some embodiments, the position, orientation, or both are adjustable (e.g., automatically adjusted by the system, manually adjusted by an operator, or both). In some embodiments, housing 110 surrounds all or part of the treatment component 150.

[0124] Treatment device 100 may include one or more markers, namely marker 115 as shown. Marker 115 may include one or more markers of device 100 that are used during registration procedures (e.g., as described herein) and / or subsequent treatment procedures using registration information to locate device 100. Marker 115 may include one, two or more markers selected from the group consisting of (e.g., reference markers): MRI visualization markers; radiographic markers; ultrasound visible markers; electrically identifiable markers; electromagnetic markers; visible markers; and combinations thereof. Housing 110 may include one or more markers 115. Treatment assembly 150 may include one or more markers 115.

[0125] System 10 may include one or more markers, namely marker 95 as shown, which are configured to be placed on a patient, such as patient-on-patient markers used during registration procedures (e.g., as described herein) and / or subsequent treatment procedures using registration information to locate treatment device 100, the patient, and / or another component of system 10. Marker 95 may include one, two, or more markers selected from the group consisting of (e.g., reference markers): MRI visualization markers; radiographic markers; ultrasound-visible markers; electrically identifiable markers; electromagnetic markers; visible markers; and combinations thereof.

[0126] In some embodiments, the treatment device 100 includes a user interface 106, which includes at least a portion of the user interface 60 of the system 10. The user interface 106 of the treatment device 100 may be located on a housing 110. The user interface 106 may include alarm elements (e.g., alarm elements 49 of the alarm assembly 40 located on and / or within the housing 110).

[0127] In some embodiments, the treatment device 100 includes at least a portion of a processing unit 50, at least a portion of a user interface 60, and / or at least a portion of a communication module 70, for example, when the treatment device 100 includes a processing unit 105, a user interface 106, and / or a communication module 107, as shown in the figures.

[0128] In some embodiments, the treatment device 100 includes one or more sensing modules, namely sensor modules 120, which may include one or more sensors, namely sensors 125, each as shown in the figure. In some embodiments, sensor 125 includes one or more thermocouples and / or other temperature sensors, such as temperature sensors for monitoring the temperature of one or more portions of the treatment assembly 150 and / or another portion of the treatment device 100. Sensor 125 may include one, two, three or more sensors selected from the group consisting of: temperature sensors; pressure sensors; strain gauges; accelerometers; physiological sensors; GPS sensors; and combinations thereof.

[0129] The treatment device 100 includes a treatment assembly 150, which includes an energy delivery array 155. The energy delivery array 155 may include one or more portions, each portion including one, two or more ultrasonic transducers UST 155U, such as: one, two or more piezoelectric-based ultrasonic transducers (e.g., piezoelectric micromachining ultrasonic transducers PMUT); one, two or more capacitive micromachining ultrasonic transducers (CMUT); and / or one, two or more other forms of ultrasonic transducers.

[0130] The energy delivery array element 155 may include one, two or more energy delivery transducer arrays (e.g., one, two or more ultrasonic transducer arrays configured as a phased array that allows for electronic focusing of ultrasonic energy delivery).

[0131] In some embodiments, one or more energy delivery transducers (e.g., ultrasound-based energy delivery transducers) of the energy delivery array 155 may be configured to switch between an “imaging mode” and a “treatment mode,” such as when switching between an imaging mode that delivers imaging-grade ultrasound energy to and receives reflected ultrasound energy from tissue and a treatment mode that delivers tissue-modulating and / or other therapeutic-grade ultrasound energy to modulate and / or otherwise treat tissue. Another component of the treatment device 100, console 200, and / or system 10 may include a switching component configured to perform switching of the transducers of the energy delivery array 155 between imaging and treatment modes.

[0132] The console 200 may include one or more consoles configured to be operatively attached to one or more other components of the treatment device 100, the imaging device 800, and / or the system 10. In some embodiments, the console 200 includes at least a portion of a processing unit 50, at least a portion of a user interface 60, and / or at least a portion of a communication module 70, such as when the console 200 includes a processing unit 205, a user interface 206, and / or a communication module 207, as each is shown in the figures.

[0133] The console 200 can be operatively connected to the treatment device 100, imaging device 800, and / or another component of the system 10 via a wired and / or wireless connection (e.g., via a connection provided between the communication module 107 of the treatment device 100 and the communication module 207 of the console 200). The console 200 can be configured to receive data, such as data 85 (e.g., for “uploading” data 85), from the treatment device 100, from the user interface 206, from the communication module 207, from the imaging device 800, and / or from another component of the system 10. In some embodiments, the console 200 is configured to adjust one or more parameters of the operation of the treatment device 100 and / or the imaging device 800, for example, based on analysis of the data 85.

[0134] Console 200 may include one or more consoles, such as one or more similar and / or different consoles 200.

[0135] The console 200 may include an energy delivery module 250 as shown in the figure. This energy delivery module may include one or more modules (e.g., electronic modules) configured to: provide drive signals to the energy delivery array element 155; receive signals from the energy delivery array element 155 (e.g., from recorded reflections, such as ultrasonic reflections); or both. The energy delivery module 250 may be configured to drive one, two, or more phased arrays of energy delivery array elements 155 including ultrasonic transducers, for example, when drive signals as described in studies S1, S2, S3, S4, and / or S5 as described herein are provided.

[0136] The energy delivery module 250 may include one or more therapy-based drive signal circuitry components, namely, a therapy signal generator 255 as shown, which may include one or more transmission channels (e.g., drive channels configured to drive the energy delivery array 155 to deliver energy, such as ultrasound energy and / or other energy). The therapy signal generator 255 may include multiple transmission channels. The therapy signal generator 255 may be configured to independently control the phase, amplitude, and / or both phase and amplitude of each transmission channel. Each channel of the therapy signal generator 255 may be controlled by a processing unit 50 (e.g., computer-controlled, such as when the processing unit 50 includes a microcontroller and / or an FPGA). The processing unit 50 may be configured to change (e.g., dynamically change, such as when therapy energy is delivered by the energy delivery array 155) the focusing parameters of the energy being delivered (e.g., an ultrasound beam), such as for dynamically focusing (or refocusing) the therapy energy delivery. Focusing parameters may include depth of focus, aperture size, power output, and / or focus angle. The focal point of the therapeutic energy delivery can be dynamically adjusted within the field of view of the energy delivery array element 155.

[0137] The energy delivery module 250 may include one or more imaging (e.g., ultrasound imaging) drive circuitry components and / or signal recording components, namely, the imaging signal generator 256 as shown. The imaging signal generator 256 may include multiple transmit channels (e.g., drive channels configured to drive the energy delivery array 155 to transmit energy (e.g., ultrasound energy and / or other energy), and / or the imaging signal generator 256 may include multiple receive channels (e.g., channels configured to record reflected energy signals (e.g., ultrasound signals) sensed by the energy delivery array 155). In some embodiments, the treatment signal generator 255 and the imaging signal generator 256 include one or more of the same components, such as when the transmit channel of the treatment signal generator 255 is configured to transmit energy (e.g., ultrasound energy) for both treatment energy delivery and tissue imaging (e.g., delivering treatment energy during a treatment portion and imaging energy during an imaging portion of the treatment procedure, as described herein). In some embodiments, the treatment signal generator 255 includes an imaging signal generator 256, for example when the energy delivery module 250 does not include a separate transmit channel for delivering treatment and imaging energy, and / or when the treatment signal generator 255 also includes one or more receive channels.

[0138] In some embodiments, system 10 includes one or more servers, namely server 80 as shown, wherein each server 80 may be configured to provide data storage and / or data processing, such as providing data processing for providers of system 10 (e.g., manufacturers and / or distributors of system 10) and / or users of system 10. As used herein, data processing may refer to: receiving data; filtering, classifying, analyzing and / or otherwise processing data; sending data (e.g., sending the results of data processing); and / or storing data, such as data received from multiple consoles 200, multiple therapeutic devices 100, multiple imaging devices 800, and / or multiple other components of system 10 located at various clinical sites. Server 80 may include one or more processing units 50. Additionally or alternatively, server 80 may include one or more data storage units for storing data collected by system 10 (i.e., data 85 as shown). In some embodiments, server 80 is configured to process data from various users of system 10, such as when the provider of system 10 maintains one or more servers 80, which are configured to process data for each user (and / or a subset thereof) of system 10 (e.g., each patient and / or clinician of system 10). Server 80 may include “off-site” servers (e.g., located away from the user's location in system 10), such as servers owned, maintained, and / or otherwise provided by the provider of system 10. Alternatively or additionally, server 80 may include a cloud-based server.

[0139] In some embodiments, data 85 includes data recorded during a medical procedure (e.g., a medical procedure performed using system 10), such as data relating to one or more energy delivery parameters and / or one or more patient parameters (e.g., the location of the tissue receiving the energy delivery and / or one or more patient physiological parameters present at the time of energy delivery).

[0140] In some embodiments, server 80 is configured to communicate with one or more treatment devices 100, such as through communication provided between communication module 107 and server 80 and / or between communication module 107 and communication module 207 of console 200 via network 75, wherein console 200 is configured to communicate with one or more treatment devices 100, and server 80 is configured to communicate with one or more consoles 200 (e.g., via network 75). In some embodiments, server 80 is configured to collect data 85, including data 85 containing usage information (e.g., usage information of treatment device 100 and / or imaging device 800).

[0141] As described herein, one or more components of system 10 may include all or part of processing unit 50, such as processing unit 50 including processor 51 and memory 52 coupled to processor 51, wherein memory 52 stores instructions 53 for processor 51 to execute algorithm 55. In some embodiments, algorithm 55 includes AI algorithm, such as when AI algorithm is trained based on usage data collected by server 80.

[0142] System 10 may include one or more components configured to issue alerts to users of system 10, namely, alarm component 40 as shown. One or more devices or other components of system 10 may include all or part of alarm component 40, such as when all or part of alarm component 40 is integrated with treatment device 100, console 200, imaging device 800 and / or another component of system 10. Alarm component 40 may include one or more alarm elements, namely alarm element 49 as shown, that provide visible signals, audible signals, tactile signals and / or other signals to the user. In some embodiments, alarm component 40 is configured to provide alerts to the user via alarm element 49 indicating a warning or other alarm condition (e.g., an unexpected or other event or condition has occurred and / or exists). All or part of one or more alarm components 40 may be integrated into one, two or more of the various components of system 10, such as when integrated into treatment device 100, imaging device 800 and / or other components of system 10.

[0143] In some embodiments, system 10 is configured to allow a user (e.g., a clinician) to set one or more alarm thresholds for a set of one or more parameters monitored by the system (e.g., one or more parameters monitored by treatment device 100, console 200, imaging device 800, and / or other components of system 10). In these embodiments, alarm component 40 may be configured to issue an alarm to one or more users of system 10 (e.g., a clinician using treatment device 100) when a threshold of a monitored parameter is exceeded. In some embodiments, the threshold represents the maximum energy to be applied to tissue, the maximum time for energy delivery, and / or the maximum tissue temperature.

[0144] As described herein, one or more components of system 10 may include at least a portion of processing unit 50, such as processing units 105 and / or 205 of treatment device 100 and console 200, respectively, each processing unit including at least a portion of processing unit 50. The various processing units of system 10 may be referred to individually or collectively herein as processing unit 50. Processing unit 50 (e.g., by executing algorithm 55 via processor 51) may be configured to detect target tissue (e.g., target location) and / or non-target tissue (e.g., non-target location) to be imaged, treated (e.g., modulated), or both.

[0145] In some embodiments, system 10 is configured to distinguish between a first tissue type and a second tissue type. For example, processing unit 50 may use image data IDs collected using energy delivery array 155 and / or imaging device 800 (e.g., MRI or other imaging device) to distinguish tissue types. In some embodiments, processing unit 50 is configured to distinguish between healthy tissue and diseased tissue, between regulated tissue and unregulated tissue, and / or to perform another type of distinction within the tissue.

[0146] In some embodiments, one or more components of system 10 are configured to be calibrated. For example, one or more components of treatment device 100 and / or imaging device 800 may be configured to be calibrated.

[0147] In some embodiments, system 10 includes one or more drugs and / or other agents, namely agent 30 as shown in the figure, such as one or more agents that can be applied before, during and / or after using treatment device 100 and / or imaging device 800.

[0148] In some embodiments, system 10 includes one or more auxiliary devices, namely auxiliary device 700 as shown. Auxiliary device 700 may include a drug delivery system, such as an intravenous drug delivery system or other drug delivery system configured to deliver drug 30 to a patient (e.g., before, during, and / or after an energy delivery procedure performed using treatment device 100).

[0149] As described herein, system 10 may include one or more functional elements, such as functional elements 99, 199, 299, 899, and / or 999 as shown in the figures. Each functional element may include one or more sensors, one or more transducers, and / or one or more other functional elements. Functional elements 99, 199, 299, 899, and / or 999 may include heating and / or cooling elements, such as thermal elements configured to heat or cool a patient (e.g., heat or cool a patient's head or other tissue to which energy is to be delivered). Functional elements 99, 199, 299, 899, and / or 999 may include manipulation elements, such as manipulation elements configured to manipulate (e.g., robotically manipulate) components of system 10. Functional elements 99, 199, 299, 899 and / or 999 may include vacuum application elements, such as vacuum application elements configured to maintain system components (e.g., treatment component 150 of treatment device 100) releasably attached to a patient (e.g., patient head) or a surface (e.g., tabletop).

[0150] In some embodiments, system 10 (e.g., via algorithm 55) is configured to perform a "system diagnostic procedure". For example, system 10 may be configured to evaluate the functionality of one or more components of the treatment device 100. When one or more faulty components of the treatment device 100 are identified (e.g., confirmed via a system diagnostic procedure), system 10 may: enter an alarm status; disable the functionality of the treatment device 100 or another component of system 10; and / or execute another alarm function and / or compensation function. System 10 may be configured to perform various system diagnostic procedures.

[0151] In some embodiments, system 10 is configured to determine the “orientation angle” of the treatment component 150 of treatment device 100 (e.g., the orientation angle of all or part of the energy delivery array element 155). System 10 may be configured to generate two-dimensional (2D) and / or three-dimensional (3D) images, and system 10 may enhance (e.g., correct, adjust, and / or otherwise enhance) the 2D or 3D images based on the determined orientation angle.

[0152] System 10 can be configured to: automatically identify (e.g., via algorithm 55) one or more tissue landmarks; and / or allow an operator to manually identify one or more tissue landmarks. Landmark identification can be used to: automatically locate and / or relocate treatment component 150; and / or allow an operator to manually locate and / or relocate treatment component 150. System 10 (e.g., via algorithm 55, such as an AI algorithm) can be configured to continuously and / or intermittently image tissue during treatment performed using treatment device 100, for example, to track treatment progress. System 10 can be configured to continuously or at least repeatedly confirm the correct positioning of treatment component 150 (e.g., of energy delivery element 155) and / or another component of system 10 during modulation and / or other tissue treatment, for example, by monitoring changes in the target tissue being treated and / or changes in other physiological parameters of the patient. In some embodiments, functional elements 99, 199, 299, 899, and / or 999 include a manipulation component configured to automatically manipulate (e.g., robotically manipulate) the treatment component 150 if changes in the target tissue exceed a threshold.

[0153] As described herein, other energy delivery components of the treatment device 100 and / or system 10 may be configured to deliver energy (e.g., ultrasound) to treat a patient (e.g., modulate and / or otherwise treat the patient's target tissue), and system 10 may be configured (e.g., via algorithm 55) to monitor the progress of treatment. In some embodiments, algorithm 55 is configured to automatically adjust one or more energy delivery settings (e.g., amplitude, frequency, pulse width, and / or duty cycle) if the progress of treatment exceeds a threshold (e.g., to avoid understimulation and / or overstimulation).

[0154] System 10 can be configured to: collect a first set of image data IDs and perform a first tissue treatment procedure to treat a first target tissue volume. System 10 can be further configured to subsequently collect a second set of image data IDs and then perform a second tissue treatment procedure on a second target tissue volume (e.g., where the second target tissue volume includes at least a portion of the first target tissue volume, or when the entire second target tissue volume differs from the first target tissue volume). The first set of image data IDs and / or the second set of image data IDs can be generated using energy delivery array 155, imaging device 800, and / or another imaging device. The second set of image data may include identification of untreated tissue that would otherwise be intended to be treated in the first tissue treatment procedure.

[0155] As described herein, system 10 may include one or more devices for delivering energy to treat tissue. For example, a treatment component 150 of treatment device 100 may be configured to deliver energy to tissue to treat tissue. In some embodiments, treatment component 150 and / or another component of the system are configured to deliver ultrasonic energy to treat tissue. Alternatively or additionally, energy delivery performed by one or more of these components may include one, two or more forms of energy selected from the group consisting of: acoustic energy, such as ultrasonic energy; optical energy, such as laser energy; thermal energy, such as thermal energy and / or cryogenic energy; electromagnetic energy, such as radio frequency energy, microwave energy and / or electroporation energy; chemical energy; mechanical energy; and combinations of one, two or more of these.

[0156] The treatment component 150 can be configured to treat tissue (e.g., target tissue) via the delivery of ultrasonic energy, as described herein. In some embodiments, system 10 (e.g., energy delivery element 155 via one or more algorithms 55) is configured to adjust the frequency of ultrasonic energy delivered by energy delivery element 155 (e.g., ultrasonic energy configured to modulate the brain or other tissue) based on one or more of the following: distance to the target tissue; tissue type of the target tissue; and / or tissue characteristics between the ultrasonic transducer and the target tissue. System 10 can be configured to deliver energy (e.g., ultrasonic energy, magnetic field energy, or both) to multiple targets simultaneously, sequentially, or both. In some embodiments, energy delivered to a first target is delivered using a first set of energy delivery parameters, and energy delivered to a second target is delivered using a second set of energy delivery parameters. The first set of energy delivery parameters and the second set of energy delivery parameters (e.g., amplitude, frequency, pulse width, and / or duty cycle) can be a set of similar parameters (e.g., the same values) or a set of different parameters (e.g., differences in one or more aspects of amplitude, frequency, pulse width, and / or duty cycle).

[0157] System 10 (e.g., via algorithm 55) can be configured to dynamically adjust the imaging time, treatment time, or both. Alternatively or additionally, system 10 can be configured to dynamically adjust the focus of energy delivery (e.g., ultrasound energy delivery) for imaging, treatment, or both.

[0158] Target tissue to be treated by treatment device 100 may include multiple tissue volumes, such as multiple adjacent tissue volumes and / or multiple non-adjacent tissue volumes. In some embodiments, multiple tissue volumes are treated via a procedure (e.g., via one or more sets of energy delivery transducers of energy delivery array 155) in which one target tissue volume is treated by energy delivery (e.g., ultrasound energy delivery), then the energy focus is adjusted (e.g., to change the field of view to include a second tissue volume), and then the second target tissue volume is treated. In these embodiments, two tissue volumes can be treated without translation, rotation, and / or otherwise moving treatment component 150 (e.g., by simply changing the field of view electronically). This avoidance of moving treatment component 150 can improve safety, reduce procedure time, and / or provide other benefits. In some embodiments, changing the electronic focus of one, two, or more treatment components 150, combined with translation, rotation, and / or otherwise moving treatment component 150, is used to treat one, two, or more target tissue volumes.

[0159] Electronic and / or motion-based adjustments can be made to the field of view of one, two or more treatment components 150 to compensate for patient movement, such as keeping the field of view of the treatment component 150 pointing to a specific tissue volume during tissue volume movement (e.g., during breathing or other causes of tissue movement).

[0160] The treatment component 150 of the treatment device 100 may include one or more sets of energy delivery transducers of energy delivery array elements 155, which are configured to deliver ultrasound energy to: generate image data ID; modulate and / or otherwise treat tissue; or both. In some embodiments, a first set of energy delivery array elements 155a is configured to at least generate image data ID, and a second set of energy delivery array elements 155b is configured to at least treat tissue.

[0161] As described herein, console 200 and / or another system component 10 may collectively include one or more algorithms, namely algorithm 55 as shown in the figure, which are stored as instructions 53 in memory 52 for execution by processor 51. Algorithm 55 may include artificial intelligence (AI) algorithms, also as described herein. In some embodiments, algorithm 55 is configured to generate an anatomical model based at least on image data IDs. The anatomical model may include two or more sets of image data “stitched together” by algorithm 55. Algorithm 55 may be configured to generate the anatomical model based on one or more landmarks identified in the image data IDs. Algorithm 55 may be configured to identify one or more features of interest in the anatomical model. The one or more features of interest may include one or more features selected from the group consisting of: tumor tissue; marginal tissue; blood vessels; ducts; target tissue; safety margin tissue; non-target tissue; and combinations thereof.

[0162] Algorithm 55 can be configured to identify non-target tissues in the anatomical model generated by system 10, and system 10 can be configured to use the anatomical model to limit energy delivery to non-target tissues (e.g., via treatment device 100).

[0163] Algorithm 55 can be configured to compensate for tissue movement during the creation of an anatomical model. The image data ID may include image data collected prior to tissue movement. Algorithm 55 can be configured to adjust the "trajectory" (e.g., 2D or 3D movement path) of components of system 10 based on an assessment of tissue movement. Algorithm 55 can be configured to predict patient movement and / or other tissue movement. System 10 may include a second imaging device (e.g., imaging device 800), and algorithm 55 can be configured to create the image data ID by combining first image data received from energy delivery element 155 and second image data (e.g., MRI) received from imaging device 800.

[0164] Algorithm 55 may include an AI algorithm or other algorithm configured to identify one or more target tissue volumes to be modulated and / or otherwise treated by system 10. System 10 may be configured to acquire image data IDs from imaging device 800 (e.g., MRI), and algorithm 55 may be configured to generate anatomical patterns based on the image data IDs from imaging device 800.

[0165] Algorithm 55 may include a bias. For example, Algorithm 55 may be configured to determine one or more energy delivery parameters (e.g., amplitude, frequency, pulse width, and / or duty cycle), and the bias may cause energy delivery to tend towards understimulation or overstimulation. Alternatively or additionally, Algorithm 55 may be configured to “steer” energy delivery (e.g., mechanically, electronically, or both), and the bias of Algorithm 55 may be configured to cause the delivered energy to avoid certain non-target tissues to which energy delivery may lead to adverse events.

[0166] The housing 110, treatment assembly 150, and other components of the treatment device 100 may be configured to be "MRI-compatible," meaning they are constructed of materials that allow the device 100 to be placed within the MRI imaging field of view during a magnetic resonance imaging procedure without adverse effects (e.g., no undesirable heating of components, no MRI image distortion, etc.). In some embodiments, one or more portions of the console 200 and / or other system 10 components are MRI-compatible.

[0167] System 10 can be configured to provide high-precision energy delivery (e.g., ultrasound energy delivery) for use in clinical treatments such as mental health or neurology. In some embodiments, system 10 provides mechanisms for controlling the delivery dose of energy across a target region (e.g., through the skull or other bones) to produce a predictable effect in the target region. In some embodiments, system 10 provides multifocal energy delivery that predictably modulates specific target regions (e.g., brain regions) based on the patient's specific needs.

[0168] System 10 can be configured to deliver focused ultrasound energy, such as transcranial focused ultrasound energy, which provides non-invasive and reversible treatment of medical barriers through precise and personalized manipulation of one or more brain circuits or other target sites. System 10 can be configured to deliver focused ultrasound (e.g., low-intensity focused ultrasound), such as non-invasively stimulating target sites in the brain (e.g., deep brain target sites). Alternatively or additionally, system 10 can be configured to deliver focused ultrasound (e.g., low-intensity focused ultrasound) to induce the effective delivery of one or more agents (e.g., one or more agents 30 containing pharmaceutical reagents), such as delivering one or more agents across a complete and temporarily open blood-brain barrier. System 10 can deliver focused ultrasound through the entire skull and scalp and into a designated deep brain region (e.g., when high precision is desired, the region spans a diameter less than or equal to 10 mm, 5 mm, 4 mm, or 3 mm, or when high precision is not desired, the region is greater than 3 mm, 4 mm, and / or 5 mm). The treatment component 150 may include energy delivery arrays 155 comprising one, two, or more arrays of ultrasound transducers, which may sequentially (e.g., in a fine time sequence), simultaneously, or both, stimulate multiple distinct target locations (e.g., brain locations). These arrays may deliver focused ultrasound with high spatiotemporal resolution (e.g., spatial accuracy not exceeding 1.0 mm, 0.7 mm, and / or 0.5 mm, and temporal accuracy not exceeding 0.05 μs, 0.03 μs, and / or 0.01 μs, or both). The location where the ultrasound energy is focused may be manually altered (e.g., by patient movement and / or by movement of one or more portions of the energy delivery array 155), and / or may be programmably altered by the system 10 (e.g., via electronic focusing performed by the processing unit 50).

[0169] The treatment component 150 may include energy delivery array elements 155, which comprise one or more arrays of one or more energy delivery transducers (e.g., ultrasound transducers) that can provide an energy delivery path that can be electronically guided and controlled (also referred to herein as “focused”). The system 10 may include an imaging device 800 (e.g., MRI) configured to enhance the energy delivery of the treatment component 150. In some embodiments, the treatment device 100 and other components of the system 10 are configured to minimize the use of the imaging device 800 (e.g., minimize the use of MRI).

[0170] System 10 can be configured to deliver energy (e.g., ultrasound energy) to a target location (e.g., one or more brain locations) and compensate for attenuation, phase shifts, and / or other variations in the delivered energy that may occur along the energy delivery path to the target location. For example, the energy delivery path may include the skull or other bones, scalp, hair, and / or other “obstacles” that may affect the delivered energy. Compensation for potentially beneficial obstacles may also include the coupling between the treatment module 150 and the patient’s head, and any bubbles that may be present in the coupling interface. Compensation performed by system 10 may include determining amplitude, timing (e.g., frequency, pulse width, phase, and / or other timing parameters) and / or other energy delivery parameters (e.g., ultrasound energy delivery parameters) such that the delivered energy arrives at the selected target location with the desired intensity (e.g., an intensity that provides therapeutic benefit without adverse effects). Compensation performed by system 10 may include test measurements (e.g., not estimates) performed using the skull and other obstacles of the patient to be treated, using a form similar to the expected therapeutic energy to be delivered subsequently (e.g., a similar frequency).

[0171] As described herein, treatment component 150 may include multiple parts, such as a first part (i.e., component 150a) and a second part 150b. Treatment component 150a may include a first energy delivery element 155a, which includes one or more energy delivery transducers (e.g., one or more ultrasound transducers), and treatment component 150b may include a second energy delivery element 155b, which includes one or more energy delivery transducers (e.g., one or more ultrasound transducers). Each of energy delivery modules 155a and 155b may include one or more transducers configured to deliver energy (e.g., deliver ultrasound energy), receive energy (e.g., receive ultrasound energy), or both. Treatment component 150a may be positioned on one side of the target location to be treated, and the second part 150b may be positioned on the opposite side of the target location. In some embodiments, the compensation provided by system 10 may be based on relative transmission (RTT) measurements performed between components 150a and 150b, which directly measure attenuation and distortion of a given energy delivery path (e.g., a path through the skull and scalp of the same patient to receive treatment). System 10 then acquires the attenuation and phase values ​​of these measurements and compensates for these attenuation and phase values ​​by adjusting the amplitude and phase of the transducer of the energy delivery array 155 that will deliver therapeutic energy. Measurements of skull aberrations of energy delivery (e.g., ultrasound energy delivery) using the expected energy delivery itself provide accurate compensation for the energy intensity delivered to a designated target location (e.g., a brain target), sharpening the energy delivery focus and thus enabling more precise, safer, and more effective treatment for the patient. This compensation may be implemented via the electronic hardware of controller 50, and the compensation may accurately achieve the expected intensity of energy delivery to the target location (e.g., one or more locations in the patient's brain) (e.g., as determined by the patient's clinician).

[0172] As described herein, the treatment device 100 may include a first treatment component 150a and a second treatment component 150b, the first treatment component being configured to be positioned on one side of the patient's head and the second treatment component being configured to be positioned on the opposite side of the patient's head, for example, as described in Reference Figure 2A , Figure 2B and / or Figure 13BAnd / or refer to the descriptions in studies S1, S2, S3, S4 and / or S5. In these embodiments, the treatment device 100 can be configured as an energy delivery device to deliver ultrasound energy to a patient's brain, such as when the energy delivery array 155 includes 64 to 1,024 ultrasound transducers (e.g., approximately 256 ultrasound transducers) positioned within the housing 110. The placement of the transducers for delivering ultrasound energy can be optimized for a specific multifocal operation for a particular patient. Because brain tissue attenuates ultrasound minimally, ultrasound can be delivered to deep brain targets. However, the head, particularly the skull, causes phase shifts and attenuation of ultrasound waves. Accordingly, the system 10 can use ultrasound itself to correct (also known as "compensate") ultrasound aberrations caused by the skull and other obstructions to the head, as described herein. In this configuration, head aberrations are measured directly and accurately, and no additional head scans, such as CT or MRI, are required. As described herein, system 10 can perform ultrasound RTT measurements over each corresponding segment of a given head, providing phase and amplitude values ​​that can be used to correct for aberrations in each intended energy delivery path for a particular patient's head. The amplitude of the drive signal provided by energy delivery module 250 to the corresponding ultrasound transducer of energy delivery array 155 is scaled and the phase is shifted to deliver distortion-free deterministic intensity to the therapeutic target as part of the patient's treatment. In some embodiments, specific characteristics of the RTT waveform can be optimized to maximize the accuracy of detection of ultrasound energy delivered across the head, and thus maximize the accuracy of compensation for therapeutic delivery into the head.

[0173] Compensation performed by system 10 may include driving (e.g., via energy delivery module 250) at least one ultrasonic transducer of the first treatment component 150a to generate ultrasonic waves that achieve the desired ultrasonic energy at a target location in a “free field volume” corresponding to the target location of energy delivery (e.g., a brain target location). Ultrasonic waves exiting the free field volume are measured by at least one receiving ultrasonic transducer of a second treatment component 150b, which is positioned at a fixed distance and orientation on the opposite side of the free field volume relative to the first treatment component 150a (e.g., relative to at least one transmitting ultrasonic transducer of the first treatment component 150a). Treatment components 150a and 150b may be part of a treatment device 100, which includes devices mounted to a surface (e.g., a countertop, bed, table, or other surface-containing component). A portion of the patient's body (such as the patient's head in a brain stimulation procedure) can be positioned between the first treatment component 150a and the second treatment component 150b, and the transmitting ultrasound transducer of the energy delivery array 155a is again driven to generate the same ultrasound waves toward the head, while the receiving ultrasound transducer of the energy delivery array 155b measures the ultrasound waves exiting the head, which have been altered at least in part due to the presence of the head in the ultrasound path between the transmitting and receiving ultrasound transducers of the energy delivery array 155a and the energy delivery array 155b. One or more adjusted ultrasound shapes are then determined (e.g., by algorithm 55) based on the difference between the ultrasound waves measured by the free-field volume and the altered ultrasound waves measured by the head, wherein attenuation and phase shift are compensated by the adjusted ultrasound drive signal provided by the energy delivery module 250 to deliver the desired ultrasound stimulation energy at the target location. The transmitting ultrasound transducer of the energy delivery array 155a of the treatment component 150a is then driven by the adjusted drive signal provided by the energy delivery module 250 to generate adjusted ultrasound waves toward the head.

[0174] In some embodiments, system 10 can be configured to treat anxiety and depression-related disorders, including post-traumatic stress disorder. In these embodiments, target sites for energy delivery may include one, two, or more anatomical locations selected from the group consisting of: the nucleus accumbens; the cingulate cortex; other brain locations; and combinations thereof. These disorders involve abnormal connectivity between two deep brain regions: the infragenual cingulate and amygdala, and adjacent loops. For these and other medical conditions (e.g., addiction and / or other medical conditions), system 10 can be configured to deliver low-intensity ultrasound (e.g., peak intensity less than or equal to 300 W / cm²). 2 225 W / cm 2 and / or 190 W / cm 2For a sustained desired time period (e.g., not exceeding 3 hours, 2 hours, and / or 1 hour), energy (e.g., ultrasound energy) is delivered to a target location including the cingulate gyrus and amygdala. The energy delivery is configured to induce persistent changes in the associated circuitry.

[0175] In some embodiments, system 10 can be configured to treat pain. For example, system 10 can be configured to treat thalamic nuclei, such as those involved in pain. Pain disorders may involve abnormal connectivity of the thalamic insular cortex, cingulate cortex, nucleus accumbens, and / or ventral tegmental region. For these medical conditions, system 10 can be configured to provide low-intensity ultrasound (e.g., peak intensity less than or equal to 300 W / cm²). 2 225 W / cm 2 and / or 190 W / cm 2 For a sustained desired time period (e.g., no more than 3 hours, 2 hours, and / or 1 hour), energy (e.g., ultrasound energy) is delivered to target locations that include these brain circuits, such as to modulate the pain threshold.

[0176] In some embodiments, fMRI BOLD (blood oxygen level dependent imaging), MRI thermometry, or MRI acoustic radiation force imaging (e.g., when imaging device 800 includes MRI) can be used to confirm (e.g., in a closed-loop arrangement) the targeting of target regions (e.g., one or more target regions of the brain). These imaging sequences visualize regions affected by energy delivery (e.g., ultrasound energy delivery) and can therefore increase the reproducibility of the treatment provided by system 10 and minimize potential off-target effects. In some embodiments, imaging device 800 including MRI can be used to establish patient-specific anatomy (e.g., patient-specific anatomy of the head and brain).

[0177] System 10 can be configured to allow an operator (e.g., a clinician) to select that energy (e.g., ultrasound energy) will be delivered to one or more target locations (e.g., deep brain locations), such as to deliver therapeutic energy to the target locations, to image the target locations, or both. In some embodiments, system 10 is configured to automatically or semi-automatically (referred to herein as "automatically") generate a treatment plan for the treatment of a patient, such as a treatment plan that includes one or more target locations for treatment.

[0178] In some embodiments, system 10 performs treatment via treatment device 100, the treatment including the delivery of energy (e.g., ultrasound energy) by one or more treatment components 150, wherein tissue is ablated. In some embodiments, the tissue ablation procedure is performed based on data collected during a compensation procedure (e.g., as described herein) performed prior to and / or during the ablation procedure.

[0179] In some embodiments, system 10 is configured to provide diagnostic information that can be used to guide the implantation of an accessory device 700, including an implant (such as an implant including a deep brain stimulator).

[0180] In some embodiments, system 10 is constructed and arranged as described in U.S. Patent Application US20230210493A1 (Serial No. 18 / 093,220), filed January 4, 2023, entitled “System and Methods for Modulation of Deep Brain Circuits,” and / or in International PCT Application WO2023211898 (Serial No. PCT / US2023 / 019759), filed April 25, 2023, entitled “System and Method for Sharpening the Focal Volume of Therapeutic and Imaging Systems,” the contents of each of these applications are incorporated herein by reference for all purposes.

[0181] Now for reference Figure 1B This illustrates another embodiment of a system for performing medical procedures conceived according to the present invention. Figure 1B System 10 can have the same Figure 1 , Figure 1A Similar construction and arrangement to System 10 described elsewhere in this document. Figure 1B In one embodiment, system 10 includes a treatment device 100, and Figure 1AThe system 10 includes one or more other components, and a second treatment device 900 as shown. Treatment device 100 may be configured to deliver ultrasound energy (e.g., to deliver stimulating ultrasound energy to a patient's tissue, as described herein), and the second treatment device 900 may be configured to deliver another (e.g., different) form of energy, such as magnetic field energy (e.g., device 900 includes a device configured to generate a strong magnetic field within the patient's tissue). The second treatment device 900 includes a treatment component 950 for delivering the second form of energy (e.g., magnetic field energy). The second treatment device 900 may include functional elements 999, i.e., functional elements comprising one or more sensors, one or more transducers, and / or one or more other functional elements as described herein. In some embodiments, the second treatment device 900 includes MRI and / or other magnetic field generating devices. In some embodiments, the second treatment device 900 includes one or more of the following: a magnetic field generating component; a permanent magnet; a magnetic coil; and / or one, two, or more of these / combinations. In some embodiments, the treatment device 100, the second treatment device 900, and / or another component of the system 10 are constructed and arranged as described with reference to Study S3 described herein.

[0182] In some embodiments, the treatment device 100 includes a second treatment device 900, such as a single device that may be configured to deliver two forms of energy when performing medical procedures on a patient (e.g., treatment to stimulate brain tissue or other tissues), such as a single device being configured to deliver ultrasonic energy and magnetic field energy.

[0183] Figure 1B System 10 can be configured to generate an electric field (e.g., a focused electric field) by combining two energy deliveries (magnetic field delivery by device 900 and ultrasonic field delivery by device 100). For example, system 10 can be configured to combine two orthogonal, remotely applied energies, including a magnetic field and a focused ultrasonic field. The effect of this energy delivery derives from the Lorentz force equation applied to the magnetic and ultrasonic fields. In ongoing studies (reference study S3 described herein), system 10 was used to elicit this effect, and the generated electric field was confirmed to conform to the Lorentz equation. In various studies, this effect has significantly and safely modulated the peripheral nerves of human subjects and deep brain regions of non-human primates. This configuration of system 10 opens up a new set of applications in which electric fields are generated within intact biological tissues or materials with high spatiotemporal resolution, thereby circumventing the limitations of traditional electrode-based procedures.

[0184] Electromagnetic waves delivered by previous devices cannot be used to target deep brain regions in a focused manner. At high frequencies (light or infrared), electromagnetic waves are severely attenuated by the skull or superficial tissue layers. At lower frequencies, waves (microwaves) can penetrate deep, but at relevant neuromodulation doses, microwaves can damage mitochondria and potentially other cellular structures. At even lower frequencies (radio range), the wavelengths are too broad (tens of centimeters or meters) for focused stimulation to be achieved.

[0185] The ultrasound delivered by System 10 provides both deep penetration and safe application. Ultrasound delivered by System 10 can effectively modulate excitable cells at high frequencies (e.g., at least 10 MHz), where strong radiative forces exist that cause mechanical displacement of the membrane and activate ion channels. However, such high-frequency ultrasound is severely attenuated by the human skull; for this reason, frequencies below 1 MHz can be used for transcranial therapy. Ultrasound delivered by System 10 can also modulate excitable structures at lower frequencies, but the powerful effects based on established biophysical principles remain difficult to achieve.

[0186] Figure 1B System 10 can be configured, for example, to generate strong magnetic fields by combining focused ultrasound and magnetic fields, which are used to non-invasively generate localized electric fields. Specifically, when charged molecules q are in a magnetic field... China-Israel speed As it moves, the molecule experiences an intensity of Lorentz force In order to generate a local electric field, molecular motion... It should only occur at the target site of interest. System 10 can achieve this targeting using focused ultrasound. The ultrasound (mechanical pressure wave) causes the molecules at the target site to move at a speed... Displacement occurs, where Z is a constant of the medium, i.e., the "acoustic impedance". Therefore, the sound wave delivered by system 10 to the target point perpendicular to the magnetic field generates an electric field intensity at that target point. The intensity points in a direction perpendicular to both components (reference). Figure 9A Due to this electric field, positively and negatively charged molecules are pulled in opposite directions, thus inducing an electric current. Sound waves alone will displace positively and negatively charged molecules in the same direction, therefore no charge gradient is generated and thus no electric field is produced; a magnetic field is the crucial complement. Induced Field The time characteristic curve corresponds to Therefore, the induced waveform can be controlled by the time characteristic curves of an ultrasonic field, a magnetic field, or both (see reference). Figure 9B ).

[0187] System 10 of the present invention (for example, reference) Figure 1 , Figure 1A, Figure 1B System 10, and / or system 10 described elsewhere herein, may be configured to treat one, two, or more medical conditions in a patient, including but not limited to: pain; depression, anxiety, addiction, and / or other mental disorders; Alzheimer's disease; and / or other medical conditions. The treatment device 100 of System 10 may include a treatment component 150 comprising one or more energy delivery elements 155. Energy delivery elements 155 may include ultrasound transducers and / or other energy delivery elements employed in a phased array or other arrangement, for example, to treat the patient's (multiple) medical conditions by delivering ultrasound energy and / or other energy to one, two, or more target locations (such as one, two, or more target locations in the patient's brain) (e.g., sequentially or simultaneously).

[0188] In some embodiments, the treatment device 100 is configured to deliver ultrasonic energy. The treatment device 100 may be further configured to deliver magnetic field energy. Alternatively or additionally, components of the system 10 (e.g., a second treatment device 100) may be configured to deliver magnetic field energy. The provided magnetic field may include a magnetic field of at least 0.5 T.

[0189] In some embodiments, the treatment device 100 includes a first treatment component 150a and a second treatment component 150b, the first treatment component being configured to deliver energy and positioned on the right side of the patient's head, and the second treatment component being configured to deliver energy and positioned on the left side of the patient's head. The system 10 (e.g., the treatment device 100) may further include a housing 110 configured to position the first treatment component 150a and the second treatment component 150b such that each of these treatment components delivers energy through a temporal bone window of the patient's skull.

[0190] In some embodiments, system 10 is configured to deliver energy to multiple different target locations deep in the brain without moving the treatment device 100, without moving the patient's head, or without moving either the head or the device 100. System 10 may be configured to deliver energy sequentially, simultaneously, or both to at least a first target location and a second target location.

[0191] In some embodiments, system 10 includes a housing 110 and a patient mask 700a, which together are configured to reproducibly position the patient’s head in a desired arrangement to deliver energy, such as to avoid the need for MRI-based guidance (e.g., MRI is used only for the initial data acquisition procedure, or is not used at all).

[0192] In some embodiments, system 10 is configured to verify the targeting of energy delivery (e.g., verifying whether treatment device 100 can accurately deliver energy to one or more target sites) via MRI blood oxygen-dependent (BOLD) imaging. BOLD images can provide target location guidance information, dosimetry information, or both.

[0193] In some embodiments, system 10 further includes algorithm 55 configured to determine energy delivery drive signals that compensate for one or more obstacles present in the energy delivery path from the treatment device to the target location. The one or more obstacles may include obstacles selected from the group consisting of: skull; scalp; hair; components of system 10; and combinations thereof.

[0194] Methods of using System 10 to treat medical conditions may include: selecting a patient for treatment; selecting a system of the present invention; and delivering energy (e.g., ultrasound energy, or ultrasound energy and magnetic field energy) to one or more target locations on the patient via treatment device 100 to treat the patient's medical condition. Medical conditions treated using System 10 may include depression, such as when the target locations receiving energy include anatomical locations selected from the group consisting of: the subcallosal cingulate cortex; the nucleus accumbens; the cingulate cortex; other brain locations; and one or more combinations thereof. Medical conditions treated using System 10 may include pain, such as chronic pain, such as when the target locations receiving energy include anatomical locations selected from the group consisting of: the anterior cingulate cortex; other brain locations; and combinations thereof. Medical conditions treated using System 10 may include addiction, anxiety, and / or another mental disorder, such as when the target locations receiving energy include anatomical locations selected from the group consisting of: the subcallosal cingulate cortex; the nucleus accumbens; the cingulate cortex; other brain locations; and combinations thereof. Medical conditions treated with System 10 may include cognitive decline, such as mild cognitive decline. Patients selected for treatment of cognitive decline may have a Montreal Cognitive Assessment score not exceeding 25. Patients selected for treatment of cognitive decline may receive energy deliveries to one, two, or more locations selected from groups of the following: hippocampus; amygdala; entorhinal cortex; cingulate cortex; fornix; other brain locations; and combinations thereof. Medical conditions treated may include Alzheimer's disease. Patients selected for treatment of Alzheimer's disease may have a Montreal Cognitive Assessment score not exceeding 15. Patients selected for treatment of Alzheimer's disease may receive energy deliveries to one, two, or more locations selected from groups of the following: hippocampus; amygdala; entorhinal cortex; cingulate cortex; fornix; other brain locations; and combinations thereof.

[0195] Now for reference Figures 2A to 2BThe figures show anatomical diagrams and photographs of a portion of a system conceived according to the present invention for delivering energy to a patient's brain. See also: Figures 2C to 2D The system displays coronal and sagittal views of the patient-specific brain anatomy. System 10 can be configured to determine calculated fields shown as superimposed on the patient-specific brain anatomy, for example, to mark target locations for treatment for clinicians. Figures 2C to 2D The system 10 can be configured to compensate for the skull and other obstacles present in the energy delivery path to the target location in the brain, such as delivering energy (e.g., ultrasound energy) via a specific path with limited obstacles, and / or by compensating for the effects of obstacles in the path, each as described herein. The human skull constitutes a significant barrier to ultrasound. For example, the human skull alone can attenuate the intensity of neuromodulated ultrasound by 4.5 to 64 times, depending on the skull segment and the individual patient. The system 10 may include a treatment device 100 configured to be positioned around the head of the patient P (e.g., the genu cingulate cortex in the view). Figures 2A to 2B As shown), the treatment component 150 can deliver energy (e.g., ultrasound energy) through the temporal and parietal cranial windows, for example, to minimize the severity of aberrations, both in terms of ultrasound phase shift caused by crossing the skull and in terms of ultrasound attenuation. Figure 2B As shown, the housing 110 may include a frame (e.g., an MRI-compatible frame) that positions the treatment components 150a and 150b, particularly along the anterior-posterior and superior-inferior axes, to achieve a desired energy delivery path. In some embodiments, the system 10 includes auxiliary devices, such as... Figure 2B The mask 700a shown includes a mask, such as a radiation mask or other mask including lateral windows (not shown) that allow ultrasound waves to be transmitted unimpeded from the energy delivery module 250 to the patient. The mask 700a can be used to immobilize the patient during procedures performed using the system 10. In some embodiments, the mask 700a is configured to be attached (e.g., fixedly and / or adjustably attached) to the housing 110 such that the relative position between the housing 110 and the treatment assembly 150 can be maintained (e.g., when the mask 700a is applied to the patient, the relative position between the patient and the treatment assembly 150 can be maintained, for example, to perform a registration procedure as described herein). In some embodiments, the treatment device 100 includes one or more energy coupling elements, i.e., such as... Figure 2BThe couplers 156a and 156b shown, the one or more energy coupling elements, can be configured to provide an efficient energy delivery path (e.g., an ultrasound energy delivery path) between the treatment component 150 and the patient. Couplers 156a and 156b may include poly(vinyl alcohol) cryogel, other hydrogels, and / or another material that provides an efficient energy delivery path.

[0196] The treatment assembly 150 may include energy delivery elements 155 comprising a plurality of independently controllable energy delivery transducers. In some embodiments, the energy delivery element 155 includes an ultrasound transducer UST 155U, such as at least two, six, and / or ten ultrasound transducers, and / or no more than 10,000, 1,000, and / or 252 ultrasound transducers (e.g., two groups of 126 independently controllable ultrasound transducers). The UST 155U may include two or more ultrasound transducer arrays (e.g., at least two phased arrays) that maximize the volume of the target location to which ultrasound energy can be refocused. This configuration allows an operator (e.g., a clinician) to rapidly and precisely treat multiple brain locations without moving the patient or the treatment device 100. The UST 155U may include a first set of ultrasonic transducers 155Ua and a second set of ultrasonic transducers 155Ub, the first set of ultrasonic transducers including a first spherical phase array of ultrasonic transducers and the second set of ultrasonic transducers including a second spherical array of ultrasonic transducers.

[0197] Treatment components 150a and 150b may be separated by a distance of at least 10 mm, 25 mm, and / or 50 mm, and / or by a spacing not exceeding 10,000 mm, 2,500 mm, and / or 1,000 mm, such as a spacing of approximately 187 mm. All or part of the transducer of the UST 155U may include at least 0.04 mm... 2 0.35 mm 2 and / or 1 mm 2 The surface area (e.g., a 1 mm × 1 mm transducer), and / or all or part of the transducer of the UST 155U may include no more than 3600 mm². 2 2025 mm 2 and / or 900 mm 2The surface area (e.g., a 30 mm × 30 mm transducer), such as a transducer with a 6 mm × 6 mm square surface geometry. UST 155U may include PZT material. All or part of the transducer of UST 155U can be driven at frequencies of at least 10 kHz, 25 kHz and / or 50 kHz, and / or not exceeding 10,000 kHz, 4,000 kHz and / or 2,000 kHz (e.g., a frequency of approximately 650 kHz). All or part of UST 155U may be rated at at least 0.01 W / cm². 2 0.05 W / cm 2 and / or 0.1 W / cm 2 The sound power, for example, is approximately 3 W / cm². 2 The rated acoustic power. The UST 155U may include one or more spherical focusing arrays (e.g., two spherical focusing arrays) with radii of at least 10 mm, 25 mm and / or 50 mm, and / or no more than 5,000 mm, 2,500 mm and / or 1,000 mm (e.g., a radius of approximately 165 mm). In some embodiments, the UST 155U array includes 126 ultrasonic transducers arranged in a 9 × 14 grid, with a transducer spacing of 0.5 mm. In other embodiments, the UST 155U array includes 130 ultrasonic transducers arranged in a 10 × 13 grid, with a transducer spacing of 0.5 mm. One or more UST 155U arrays may include one or more dimensional parameters selected from the group consisting of: a height of 55 mm, a width of 86 mm, and a span surface area of ​​47.3 cm². 2 And combinations of two or three of these. The UST 155U can be connected to a conductor (e.g., approximately 38 gauge insulated copper wire), one end of which is connected to an impedance matching network (e.g., the impedance matching network of the power delivery module 250) that is matched at the drive frequency of the UST 155U (e.g., at a drive frequency of 650 kHz).

[0198] The power delivery module 250 may include 256 output channels and may include a 600 W high-voltage dual DC power supply. The UST 155U may be connected to the delivery module 250 via a cable (e.g., a cable of at least 3 m, 6 m, or 9 m) that may be detached from the module 250 (e.g., such that the cable may pass through an MRI waveguide).

[0199] Coupling the treatment component 150 to the patient may include using Figure 2BNeutralize the coupler 156 described herein. In some embodiments, an auxiliary device (i.e., coupling gel 700b including ultrasound coupling gel) may be applied between the patient and one or more components of the system 10 (e.g., between the patient and the coupler 156) and / or between two or more components of the system 10 (e.g., between the coupler 156 and the treatment component 150).

[0200] System 10 can be configured to mechanically register treatment device 100 to a patient, such as mechanically registering treatment device 100 to the patient's brain anatomy. For example, mask 700a may include a thermoplastic mask (e.g., an Aquaplast U-frame, QFix, or the like) including lateral windows for unobstructed ultrasound propagation. Once the patient's head is secured with mask 700a, a single T1 MRI image can be generated, in which treatment components 150a and 150b are mounted on the patient, above the target brain site of interest. The MRI field of view may include the patient's brain anatomy and components 150a and 150b (e.g., component 150 including marker 115, which includes a reference marker visible on the MRI image). Using the reference marker, the geometry of UST 155U of treatment components 150a and 150b can be registered within the MRI image of the patient's brain. Housing 110 may include horizontal and vertical tracks, and housing 110 may be locked in specific discrete positions. This adjustable, lockable configuration allows the treatment component 150 and the associated UST 155U to be repeatedly placed on any part of the left and right sides of the patient's head to target virtually the entire deep brain volume. In subsequent treatment sessions (e.g., repeated and similar treatment sessions), a clinical setting other than an MRI setting can be used, in which the treatment component 150 is locked (e.g., manually and / or automatically) in the same position used during the initial procedure performed in the MRI setting (e.g., where the patient's head is positioned relative to treatment components 150a and 150b using a similar mask 700a). This setup procedure reproduces the position of treatment components 150a and 150b and the subject's head in the same configuration initially performed (e.g., and imaged within MRI). Anatomical MRI data with this configuration of the registered treatment component 150 can be used for all subsequent "repeated" treatment sessions for this patient without the need for an MRI, and also enables precise patient-specific stimulation of one or more brain target locations for energy delivery.

[0201] System 10 (e.g., energy delivery module 250) can be configured to perform beamforming using the ultrasonic phased array of the UST 155U by emitting ultrasound from each transducer of the UST 155U, wherein the emission delay causes the wavefronts to arrive at the intended target location simultaneously, resulting in constructive interference of the wavefronts. System 10 can calculate these delay values ​​by dividing the distance from each transducer to the target location by the velocity of sound along the associated acoustic path. The distance from each transducer to the brain target is known from MRI images generated when the treatment component 150 is mounted on a patient, wherein both the UST 155U and the subject's brain are in the same image space. System 10 can use the velocity of sound in water to set an initial delay for focusing to the target location, and add an estimated phase shift based on any cranial compensation performed (e.g., as described herein) to account for phase shifts caused by coupling, hair, scalp, skull, and brain. These delays (including the sum of focusing in water and the estimated phase shift) can be applied to focus on the target location in the brain.

[0202] In some embodiments, the treatment device 100 may include a treatment component 150 having a dual UST 155a array. RTT measurements (e.g., as described herein) can be performed to assess how the patient's skull and other obstructions distort ultrasound transmission to a target location in the brain, and to compensate for these distortions. Each individual transducer of the UST 155Ua of the treatment component 150a (e.g., each of 126 transducers) can emit pulses (e.g., 10-cycle, 650 kHz pulses) while recording responses from all other non-transmitting transducers UST 155U on the contralateral treatment component 150b. During the transmission scan, the peak pressure amplitude of each transmitting transducer can be 80 kPa. The entire process of such a scan may take less than one second to complete. The pulse frequency (e.g., a 650 kHz pulse frequency) is the same as the pulse frequency to be used in subsequent therapeutic neuromodulation procedures. This transmission measurement is relative: it is performed in the presence and absence of the patient. When the patient is absent, the measurement can be performed with a liquid (e.g., water). This patient-absent measurement does not require prior information about the patient's anatomy; for example, it does not require any CT or MRI images of the patient's head. This can be represented by the transducer of the treatment component 150a. After emitting a brief 10-cycle pulse, the transducer of the treatment component 150b... The signals received are denoted as follows: Signals received in a free field and signals received through sound barriers (skull, hair, coupling, and other barriers) are respectively represented as... and .

[0203] The compensation performed by system 10 can measure the transmission value in the water. Compared with the measurement values ​​obtained through subjects Comparisons were made to estimate the subject's head position relative to each transducer. Introduced phase shift and amplitude Distortion. When there are no transmission barriers, the amplitude of the transmitted waveform passing through the subject can be measured by dividing the peak amplitude of the transmitted waveform passing through the water. to transducer Transmission attenuation :

[0204] (1)

[0205] The attenuation across both sides of the skull is a product relationship, therefore ,in, It is a transducer The attenuation factor is estimated to compensate for the skull and other barriers in front of the transducer. To estimate the transducer... This value can first be selected by choosing the transmission pair, where the transmitting transducer... Between the target location and the transmitting transducer The angle between the transducer and the receiver is less than or equal to 7 degrees. Then, Estimated as The square root of the median transmission value between the selected receiving transducer and the target transducer. The estimation method for phase correction is similar, i.e., finding the value that makes the waveform... With waveform Phase shift that minimizes the cross-correlation between them .

[0206] Once the phase and amplitude values ​​are estimated, the stimulation parameters can be adjusted (e.g., system 10 can automatically adjust the stimulation parameters) to compensate for distortion. This is achieved by estimating the attenuation value of each transducer. It can be applied to the transducer voltage according to Scaling is applied to compensate for this attenuation. If If the value is less than a threshold of 0.1, the transducer can be shut off (e.g., to prevent transducer overdrive). Similarly, by estimating the velocity through the skull as... The transducer's emission time can be delayed for the same duration, thereby compensating for this waveform distortion. In some embodiments, compensation can be performed in less than five minutes, such as less than three minutes and / or approximately two minutes.

[0207] System 10 can be configured to deliver energy (e.g., ultrasound energy) to the subcallosal cingulate cortex and / or associated circuits (note that major depressive disorder is known to be associated with overactivity of the subcallosal cingulate cortex).

[0208] The applicant has used the systems, devices and methods of this invention in various human clinical studies, non-human mammalian clinical studies and other studies.

[0209] Study S1

[0210] Human subjects: In a study (Study S1), participants (also referred to as “patients” or “subjects” in this text) were selected who had a preliminary diagnosis of major depressive disorder or bipolar disorder and a total score greater than 10 on the 16-item Rapid Self-Rating Depression Scale (QIDS). Two patients were recruited for the study: patient PS1-1, aged 32, and patient PS1-2, aged 35, both with a history of severe treatment-resistant depression.

[0211] Neural modulation parameters: The emotion-related effects reported in this study were measured via an ultrasound treatment procedure (using ultrasound delivery as described herein, system 10) performed under non-MRI conditions. The UST 155U of the treatment component 150a delivered ultrasound (650 kHz, 1.0 MPa peak pressure, estimated using the transcranial bone transmission relative correction method described herein, MI = 1.2, I) to each target site during a 30 ms ON period. SPPA = 31W / cm 2 ), followed by a 4s off period (0.75% duty cycle, I SPTA = 0.233W / cm 2 The duration of ultrasound treatment varied from 60s to 180s.

[0212] Active sham stimulation (SHAM): Potential artifacts related to transceiver ultrasound application were controlled. Specifically, an active sham stimulation control was set up, using the same waveform and emission voltage, but not focused on a specific target. The ultrasound emission time was set so that each transducer of the UST 155U emitted an unfocused plane wave axially from the transducer surface. The power applied to the transducers and the emission pressure of each transducer were consistent with those during verum stimulation. With this setting, the energy and waveform received by the patient's head were the same under both verum and active sham stimulation conditions, but the peak spatial pressure of the plane wave in the brain was 0.098 MPa, 0.30 W / cm². 2 Compared to focusing conditions (1MPa, 31.1W / cm) 2 It is an order of magnitude lower.

[0213] Emotional effects and adverse reactions were assessed using a seven (7) subscale: depression and anxiety. For example, the depression scale ranged from -3 (significantly reduced depression) to +3 (significantly increased depression), with 0 indicating no change. Immediately after each ultrasound treatment, a psychiatrist asked the patient to rate their mood. In addition, patients were required to complete the General Assessment of Adverse Reactions (GASE) questionnaire before enrollment in the trial and at the end of each ultrasound treatment session. Patients were asked to rate each of the 36 different symptoms: 0 (absent), 1 (mild), 2 (moderate), 3 (severe), and indicate whether the symptom was related to the treatment.

[0214] Study Protocol: In Study S1, the initial patient visit was conducted in an MRI room (Magnetom VIDA, 3T, Siemens AG). Prior to imaging, a mask 700a containing a thermoplastic face mask was shaped and secured to the patient's face, and the treatment device 100 (including treatment components 150a and 150b described herein) was coupled to the patient's head. Structural MRI images were recorded for the previously described registration. The second visit included a non-MRI visit, during which the patient's head was secured in the same type of mask 700a containing a thermoplastic face mask; and the treatment components 150a and 150b of the treatment device 100 were locked in the same positions as during the first visit. Ultrasound stimulation was delivered to the subgenual cingulate cortex and ventral striatum. During the 1.5-hour neuromodulation session, brain target locations were presented randomly and blinded, alternating with the aforementioned active sham stimulation (plane wave).

[0215] MRI: Imaging data were recorded using a 3T MRI scanner (MagnetomVida, Siemens AG). A Siemens AG flexible coil (small size) was positioned in front of and above the patient's head to maximize the signal-to-noise ratio of the acquired signals.

[0216] Anatomical collection: Anatomical images were acquired using a magnetized preparation radiofrequency pulsed rapid gradient echo (MPRAGE) sequence. 192 sagittal slices, 1.3 mm thick, were acquired from anterior to posterior, ascending direction. The repetition time (TR) was 2400 ms; the echo time (TE) was 2.26 ms; the reversal time (TI) was 1060 ms; and the echo interval was 6.84 ms. The field of view (FOV) was 256 mm, the bandwidth was 200 Hz / pixel, and the flip angle was 8 degrees.

[0217] Deflection range and focusing volume measurement: The study of S1 includes the measurement of deflection range and focusing volume.

[0218] Skulls: Study S1 used four complete ex vivo human skulls. Each skull had a large opening at its base to allow for acoustic field measurements inside the skull. Each skull was degassed overnight in deionized water at approximately -25 mmHg. After degassed, the skulls were transferred in degassed water to an experimental water tank with a continuous flow of degassed water (AIMS III system, equipped with an AQUAS-10 water conditioner, Onda).

[0219] Deflection Range: Beamforming range within four excised skulls was measured using hydrophone acoustic field scanning. At each scan location, the transducer of the UST 155U was individually excited, and the received signal was recorded. The total pressure at each point was the sum of these individual waveforms, assuming perfect penetration and focusing of the acoustic waves through the skull. Perfect focusing required delay adjustments to the received signals of each array element so that they arrived at the hydrophone simultaneously and in phase. The delay was determined by maximizing the cross-correlation between all waveforms. Scans were performed in two-dimensional planes (XY, XZ, and YZ), with scan ranges of 80 mm, 60 mm, and 56 mm in the X (axial), Y (lateral), and Z (thickness) dimensions, respectively, and a step size of 1.5 mm for all dimensions. These two-dimensional scan data were then interpolated to a resolution of 0.2 mm, and the half-value full width (FWHM) distance at each dimension was calculated with the geometric center of the two arrays as the origin. In the X dimension, the FWHM value exceeded the ±40 mm scan range limited by the width of the excised skull. To estimate the complete FWHM at this size, a quadratic polynomial is fitted to the sound field measured at the X-axis centered at the origin, and the sound field distribution is extrapolated to ±100 mm. The FWHM is calculated as the difference in X coordinates at which the extrapolated sound field distribution first drops below 50% of its peak value.

[0220] Pressure Field Hydrophone Scanning: A capsule-type hydrophone (HGL-0200, Onda) fixed to a three-degree-of-freedom programmable displacement system (Aims III, Onda) was used to record the ultrasonic field emitted by each transducer of the UST 155U. The hydrophone used had a sensitivity of approximately -266 dB relative to 1 V / μPa and an aperture size of 200 μm. This aperture size was within the length of the ultrasonic wave used (2.3 mm). The 3D acoustic field was measured in 0.2 mm steps to characterize the contribution of each element to the total acoustic field with high spatial resolution. The hydrophone scan was performed in a 40 mm x 40 mm plane across all three dimensions (XY, XZ, and YZ).

[0221] Scans were performed underwater and while penetrating a detached human skull, at the geometric center of two ultrasound arrays. At each scan location, the transducer of the UST 155U was individually excited, and the received signal was recorded. Due to the superposition of ultrasound pressures, the total pressure was calculated as the sum of the individual pressure components.

[0222] Focusing volume: The focusing volume of the array is quantified by measuring the total magnitude of the intensity field above the half-maximum. Specifically, the voxel convex hull method is used, just above the half-maximum intensity in the XY and XZ planes. At each position on the x-axis, the full width at the half-maximum intensity (the width of the focusing volume at the half-maximum intensity) on the Y and Z dimensions is calculated. These products are then integrated along the x-axis to obtain the total volume. Function and Let x and z represent the half-widths of the Y and Z dimensions at position x, respectively. Then the focusing volume equals... .

[0223] Measurement of Position Reproducibility: The registration error across treatment sessions was quantified in five human patients by measuring the positional variability between the treatment device 100 and the patient. Specifically, the positions of six reference markers (marker 115) on treatment components 150a and 150b and four anatomical landmarks on the patient (nose tip, left and right corners of the eyes, and left temple marker) were recorded using an optical tracking probe (Brainsight, Rogue Resolutions Ltd.). These measurements were performed on each patient in 10 trials. Before each treatment session, the system 10 (e.g., treatment device 100) and the patient were rearranged to simulate a new treatment session. After each treatment session, the patient was removed from the mask 700a (e.g., a thermoplastic mask) and allowed to stand up from the treatment bed where the procedure was performed. The treatment device 100 was unscrewed from its locked position and returned to its reference position. Each reference marker and anatomical landmark was measured three times using the probe. The median of these three measurements was used as the reference position.

[0224] The positional variability between the treatment device 100 and the patient is measured by calculating the average position of each reference marker (markers 95 and 115) across all trials for each patient and subtracting this number from the reference position. Next, the joint positional variability between the patient and the device 100 is calculated by taking the differences between each reference on the device 100 (each mark 115) and each reference on the patient (such as mark 95). The mean deviation of distance for each pair across multiple trials is measured. Targeting accuracy is determined by the average relative positional variability between all reference pairs.

[0225] Results: The system 10 of this invention was configured to neuromodulate specific deep brain regions in mammalian patients. In study S1, the treatment device 100 comprised two treatment components: treatment components 150a and 150b, each containing a phased array transducer UST 155U, which were positioned on the opposite side of the patient's head (e.g., Figure 2A (As shown). The dual phased array enables the device 100 to focus ultrasound electrons onto a designated deep brain target and to specifically penetrate areas of the skull with relatively good acoustic permeability: the parietal and temporal bones.

[0226] Prior to the procedure, the patient's head was secured using a 700a mask, which includes components such as... Figure 2B The standard radiographic mask with individualized fit is shown. Lateral windows in mask 700a allow ultrasound to be delivered to the head via a coupling medium (e.g., coupler 156, coupling gel 700b, or both). An imaging device 800 incorporating MRI provides a means for precise registration of treatment device 100 relative to the patient's brain anatomy. Mask 700a is attached to the same housing 110 as the housing housing housing treatment components 150a and 150b, thus requiring only one MRI scan for the MRI-based registration process. Subsequent treatments using treatment device 100 (e.g., delivering ultrasound energy to the patient's brain) can be repeated without MRI.

[0227] Figure 2C -D shows the intensity field generated by the treatment device 100, superimposed on the patient's brain anatomy. For a designated target point in the subgenual cingulate cortex (SGC), the lateral x-thickness x-axial dimensions of this intensity field are 2.4 mm x 3.6 mm x 20.4 mm (y, z, and x dimensions in the Montreal Neurological Institute coordinate system). The total sound field volume is 0.142 cm³. 3 This is equivalent to a sphere with a radius of 3.24 mm.

[0228] The phased array configuration of the treatment device 100 enables electronic focusing of ultrasound energy onto a designated target point without moving the patient or the device 100. Figure 3A The image shows an example pressure field measured three-dimensionally using an ex vivo human skull. The middle and right subplots show that the two ultrasound transducer arrays UST 155U of the treatment component 150 produced a significant standing wave as expected. Figure 3B In this study, the electronic targeting range (tissue within the dashed lines) was measured using four excised human skulls. The white boundaries delineate the area where the treatment device 100 can deliver 50% of its maximum pressure output. The sound field was measured inside the excised human skull and superimposed on anatomical MRI for comparison. Any target point within this region can be reached within tens of microseconds. Figure 3B As shown, the treatment device 100 is configured to achieve focus deflection via beamforming to modulate single or multiple targets within a relatively wide treatment envelope. The treatment device 100 is capable of delivering at least half of its maximum pressure addressable space, measured by hydrophones within four isolated skull fragments, with axial, lateral, and thickness dimensions of 110.8 mm ± 5.69 mm, 46.1 mm ± 3.4 mm, and 44.8 mm ± 2.7 mm (mean ± sd), respectively. Figure 3BTo target additional parts of the brain, the housing 110 is adjustablely attached to the treatment components 150a and 150b, allowing these components 150 to be physically translated along the patient's anterior-posterior and superior-inferior dimensions to target specific target areas.

[0229] The registration error between the patient's head and the treatment component 150 was evaluated over ten treatment sessions in five patients. In all treatment sessions (n ​​= 10 patients per session), the mean offset of the ultrasonic transducer UST 155U position relative to its initial position was 0.89 mm ± 0.64 mm (mean ± sd). In each dimension (x, y, z), the transducer USD 155U offsets were 0.45 mm ± 0.32 mm, 0.43 mm ± 0.14 mm, and 0.44 mm ± 0.17 mm, respectively. Head positioning error was also within acceptable limits. Using a reference marker (marker 95) located on the subject's head, the mean error measured across all subjects and treatment sessions was 1.28 mm ± 0.66 mm, with errors of 0.53 mm ± 0.19 mm, 0.68 mm ± 0.27 mm, and 0.71 mm ± 0.31 mm in the x, y, and z dimensions, respectively. The relative error between the transducer USD 155U and the patient's head is calculated, which is the ultimate indicator reflecting targeting accuracy. For example... Figure 4A As shown in -B, the relative error for all subjects was 1.64 mm ± 0.66 mm, and the relative errors for the x, y, and z dimensions were 0.77 mm ± 0.50 mm, 0.93 mm ± 0.41 mm, and 0.99 mm ± 0.49 mm, respectively. Figure 4A The bar graph shows the mean ± standard deviation of the difference between the relative distances of the transducer UST 155U and the marker 95 in the heads of the above five patients. Figure 4B Bar graph showing the differences in the average values ​​of each size for 5 patients.

[0230] Treatment device 100 was used to modulate the scleral tract (SGC) in two patients (patients PS1-1 and PS1-2), both of whom had treatment-resistant depression (trial NCT05301036). Major depressive disorder is often associated with hyperactive SGC activity, and treatment device 100 and other components of system 10 can be used to achieve transient inhibition of the SGC, thereby improving subjective mood. To inhibit neural activity, treatment device 100 delivers ultrasound to brain targets at a low duty cycle, a method that tends to inhibit neuronal activity. Modulation of the SGC had a positive effect on depression and anxiety indicators in both patients. Figure 5Two bar graphs illustrate the positive effect. The graph shows the patient's overall self-reported mood score after each stimulation procedure. Psychiatrists assessed patient mood changes immediately after each ultrasound delivery procedure, measuring changes in depression using a seven-point scale (from -3 (indicating significant reduction in depression) to +3 (indicating significant worsening of depression), where 0 indicates no change). The sham stimulation delivered to the brain had the same energy and waveform but was not focused. A sham stimulation control was used to address potential general auditory and tactile artifacts that might be associated with transcranial ultrasound treatment. Patients were blinded for each stimulation. A positive mood effect was observed after at least 60 seconds of SGC modulation, while this effect was not observed in other cases including sham stimulation. SGC stimulation lasting 60 seconds or longer reduced depression (t... 18 =3.54, p=0.0012, two-tailed t-test) and anxiety (t 18 = 2.87, p = 0.0051, two-tailed t-test) The indicators showed significant improvement. The sham stimulation had no significant effect on the depression (t7 = 1.53, p = 0.17) or anxiety (t7 = 0, p = 1) indicators.

[0231] The safety of the stimulus was evaluated at both behavioral and anatomical levels. At the behavioral level, the patient completed a standard clinical adverse reaction questionnaire. No adverse effects were observed by either the patient or the attending psychiatrist. At the anatomical level, structural T1-w and T2-w MRI scans of the brain were collected. No significant changes were observed.

[0232] Discussion: System 10 is configured to: minimize distortions caused by ultrasound as it travels through the skull; provide flexible electronic targeting of deep brain regions; and employ mechanical registration for practical and low-cost registration both inside and outside MRI.

[0233] System 10, via housing 110 and other components of system 10, can be configured to deliver energy (such as ultrasound energy) through the temporoparietal window of the skull, thereby enhancing energy delivery to the patient's brain. System 10 can be further configured to correct for all energy delivery aberrations caused by the skull and other obstructions, as described herein. All energy delivery transducers of treatment assembly 150 (e.g., a phased array of ultrasound transducers UST 155U) are independently controllable. In this configuration, the emission time and amplitude of each energy delivery element of treatment assembly 150 can be adjusted individually to optimize energy delivery.

[0234] The phased array of energy delivery elements 155 in the treatment component 150 has the ability to target multiple regions deep in the brain. For example, when modulating the SGC of a patient (patient S1A), the focal point needs to be deflected 17 mm laterally and 9 mm thickly from the geometric center of the array. Electron beamforming can also deliver ultrasound to the upper and lower regions of the infragenual cingulate cortex and the ventral striatum. The treatment device 100 can electronically and rapidly direct ultrasound delivery to different targets (e.g., within less than 1 millisecond), thereby enabling rapid stimulation sequences to modulate neural networks in a precise spatiotemporal pattern. This capability provides effective treatment for psychiatric and neurological disorders that require both high targeting accuracy and the flexibility to target distal nodes of neural networks.

[0235] The repositioning of the patient's head and the transducer of the treatment assembly 150 based on a single MRI registration procedure was found to be reproducible across treatment sessions, with an average relative positioning error of 1.64 mm between the patient marker 95 and the marker 115 on the treatment device 100 (see [link to relevant documentation]). Figure 4A -B). This mechanical registration method enables accurate targeting of deep brain regions both inside and outside the MRI scanner. For non-MRI operations, the mask 700a (such as a thermoplastic mask) offers a convenient solution for cost reduction, decreasing costs associated with systems such as optical neuronavigation.

[0236] System 10 can be used to perform various medical procedures, such as diagnostic procedures, treatment procedures, or both. Its ability to flexibly modulate specific deep brain targets provides a unique guiding tool for invasive methods such as deep brain stimulation or brain tissue ablation. By precisely modulating candidate targets sequentially, System 10 can be used to identify brain regions that maximize the improvement of signs or symptoms in each individual patient. This brain region can then serve as a target for subsequent invasive treatments. The flexible neuromodulation provided by System 10 also offers a unique tool for manipulating deep brain structures, contributing to a better understanding of the causal relationships between human brain function. By using System 10 to systematically modulate specific brain regions, operators can clarify the causal relationships between these regions and given behaviors.

[0237] System 10 can be configured to deliver low-intensity ultrasound to one or more targets in the brain for a sufficient duration (e.g., approximately 150 s) to induce persistent effects in the stimulated structures. These neuroplastic effects are believed to be mediated at least in part by the activation of glial cells and their subsequent effects on synaptic processes. These effects provide a unique opportunity for achieving persistent circuit resetting, similar to repeated applications of electroconvulsive therapy or TMS, but with far greater targeting capabilities using System 10. This targeted nature of stimulation promises to improve the efficacy and safety of treatment and provide a treatment option for patients who do not respond well to existing therapies.

[0238] Study S2

[0239] In a study (Study S2), a 30-year-old white female patient (PS2-1) with severe, treatment-resistant nonpsychotic depression was recruited to Study S2. The patient had a history of electroconvulsive therapy (ECT) with complete remission but no sustained efficacy. The treatment device 100 was co-registered with the patient's brain anatomy using magnetic resonance imaging (MRI), and the neural response to stimulation was evaluated using the system 10 of the present invention. A short 30-millisecond pulse of low-intensity ultrasound delivered every 4 seconds to the patient's target region (including the subcingulate cortex (SCC)) resulted in a significant reduction in oxygenation-dependent activity on MRI within the target region. Following repeated stimulation of three anterior cingulate cortex targets, the patient's depressive symptoms resolved within 24 hours post-stimulation. The remission persisted for at least 44 days thereafter.

[0240] The system 10 of this invention is configured to overcome many limitations of existing stimulation methods. System 10 is configured to directly measure and compensate for ultrasound attenuation caused by the head, hair, and other obstacles described herein, thereby safely and effectively delivering deterministic ultrasound intensity to one or more deep brain targets. Under MRI guidance, the treatment device 100 can be applied to the spinal cord (SCC) and related circuits in patients with treatment-resistant depression. Notably, after a single ultrasound stimulation of three SCC-related targets in patient PS2-1, depressive symptoms rapidly improved. At the final assessment 44 days after treatment, patient PS2-1 remained in remission.

[0241] Case Report: Patient PS2-1 was a 30-year-old white female with severe treatment-resistant depression. The diagnosis was established as unresponsiveness to two or more adequate doses of first-line medications. Recurrent major depressive disorder was confirmed using a structured Mini-International Neuropsychiatric Interview (MINI) (7.0.0). There was a family history of mood disorders, including major depressive disorder, bipolar disorder, and a history of suicide. She experienced depressive and anxiety episodes at age 13. Between the ages of 14 and 29, patient PS2-1 received psychotherapy and underwent trials with the following medications: sertraline, bupropion, citalopram, fluoxetine, duloxetine, trazodone, aripiprazole, quetiapine, clonazepam, lorazepam, lamotrigine, and lithium. Patient PS2-1 reported initial effectiveness with most of these medications, but diminishing efficacy over time; fluoxetine, in particular, was significantly associated with an increased suicidal ideation, leading to her first psychiatric hospitalization. Patient PS2-1 experienced exacerbations of perinatal depression, associated with two full-term deliveries and one miscarriage. Patient PS2-1 was hospitalized three times for suicidal ideation. There was no history of suicide attempts, mania, substance use disorder, or psychosis, nor any significant medical comorbidities. Patient PS2-1's depressive episodes reached severe level at age 29 [QIDS-SR score of 16, severe]. Patient PS2-1 received a course of bifrontal electroconvulsive therapy (ECT), which significantly improved after an acute eight-course series: one week after the acute series, the QIDS-SR score decreased to 4 (remission). Patient PS2-1 received 30 maintenance ECT sessions over the following year. Attempts to reduce the frequency of treatment resulted in symptom relapse. ECT was discontinued due to cognitive and memory problems. At this point, Patient PS2-1 was evaluated and enrolled in Study S2, with a six-item Hamilton Depression Rating Scale (HDRS-6) score of 11 and a QIDS-SR score of 16. At enrollment and throughout the study, patients with PS2-1 received combination therapy: bupropion (XL) 450 mg daily, duloxetine 90 mg daily, and lithium (ER) 450 mg twice daily. The medication regimen remained unchanged during the study. There was no evidence of developmental or cognitive impairment.

[0242] During registration and subsequent therapeutic procedures (as described herein), the treatment device 100, such as Figure 2B The patient is shown being placed in a treatment device 100 with a mask 700a containing a radiation mask with a lateral window, and couplers 156a and 156b. A compensation procedure (as described herein) is performed, and therapeutic ultrasound delivery is performed through the treatment device 100 using a compensated drive signal. The treatment device 100 used in Study S2 includes a first treatment component 150a (containing 126 UST 155U units) and a second treatment component 150b (also containing 126 UST 155U units). The binding of the modulating target SCC was validated using functional MRI (see [link to study]). Figure 6A -C). A standard Siemens AG flexible coil was placed above the patient (0.8% duty cycle). On and off periods were performed in a non-ultrasound manner, with one-minute ON blocks followed by one-minute OFF blocks delivered ultrasound, for a total of 10 minutes. An MRI scanner (including an MRI imaging device 800) acquired fMRI BOLD signals during stimulation. Figure 6A In the diagram, color bars display the t-statistic related to the BOLD difference between the on and off blocks. White circles outline the approximate location of the SCC. Figure 6B The diagram illustrates the modulation of hemodynamic responses. Figure 6C The image shows a control stimulus used to control for potential general artifacts associated with ultrasound, wherein the waveform and pressure amplitude of the delivered stimulus are consistent with those of the stimulus focused on the SCC, but are unfocused (e.g., a plane wave emitted by a transducer UST 155U).

[0243] By placing the treatment components 150a and 150b on the opposite side of the patient's head, the ultrasound can be electronically focused onto a designated deep brain target, while compensation (e.g., through the compensation methods described herein) can be implemented to correct for ultrasound attenuation caused by the skull, hair, coupling medium, and other obstacles.

[0244] To evaluate the immediate effects of stimulation on emotional state, System 10 was used to modulate three different regions of the cingulate cortex of the patient's PS2-1 during a 2-hour stimulation session. The intensity field delivered to the brain had dimensions of 2.4 mm × 3.6 mm × 20.4 mm in the lateral × thickness × axial direction (y, z, and x dimensions in the Montreal Institute for Neurology (MNI) coordinate system). The centers of each target were located at: posterior SCC [MNI coordinates (0, 26.21, -8.11) (x, y, z are MNI center coordinates)], anterior SCC [MNI coordinates (0, 34.21, -6.11)], and anterior genicular cingulate cortex [MNI coordinates (0, 34.21, 3.11)]. These targets were selected to maximize the potential for modulating white matter tracts within the SCC. Each target site was subjected to 650 kHz continuous wave ultrasound, with an on-time of 30 ms followed by an off-time of 4 seconds (0.8% duty cycle), for an average duration of 2 minutes (range 20–180 seconds). After compensation for ultrasound attenuation caused by the head, hair, and other obstructions (performed by System 10), the estimated peak pressure at the target site was 1.0 MPa. Each target site received ten ultrasound treatments, with the order of the three target sites randomized, for a total of 30 stimulation sessions, resulting in a total effective stimulation duration of 64 minutes. The stimulation intensity was maintained below the FDA 510(k) Category 3 guidelines (peak intensity below 190 W / cm²). 2The time-averaged intensity is below 720 mW / cm. 2 ).

[0245] To evaluate any persistent effects of the stimulus, HDRS-6 scores were collected before and after the stimulus. Figure 7 The study demonstrated that the non-invasive deep brain stimulation provided by System 10 can improve the mood state of patients with major depressive disorder. Effective stimulation of three different targets in the SCC during a single 64-minute treatment session resulted in, for example... Figure 7 As shown, patient PS2-1's HDRS-6 score decreased from 11 to 0, indicating effective remission. The day after treatment, patient PS2-1 reported: "This is the first time in three years I feel like I've found myself again; I feel like my brain has been awakened." This effect was durable, with the patient remaining in remission (HDRS-6 = 0) for at least 44 days after ultrasound treatment (at the time of the last assessment). Approximately five months after the stimulation, she began to experience a relapse of depression; during this five-month period, her medication remained unchanged.

[0246] In study S2, the safety of the stimuli provided by System 10 was evaluated from both behavioral and anatomical perspectives. At the behavioral level, patient PS2-1 completed the standard clinical questionnaire on adverse stimulus reactions. No adverse effects were observed by the patient or the attending psychiatrist. Patient PS2-1 completed the General Assessment of Adverse Reactions (GASE) survey and reported no treatment-related adverse reactions (see [link to study S2-1]). Figure 8 (Table). Furthermore, no abnormalities were observed on either T1-weighted or T2-weighted MRI of the subjects' brains.

[0247] Discussion and Conclusion: Study S2 confirmed that direct ultrasound modulation of deep brain targets associated with SCC using System 10 resulted in rapid and sustained improvement in depression. Relief after stimulation lasted at least 6 weeks. No safety issues or adverse reactions were observed. Compared to existing neuromodulation devices, this method has three significant advantages: (1) it can deliver stimulation to deep brain targets non-invasively; (2) it provides precise and flexible electronic targeting; and (3) it delivers controllable stimulation intensity to the targets.

[0248] Functional MRI (fMRI) confirmed that the treatment device 100 significantly and reliably targeted the specified deep brain cerebrospinal discoid (SCC) and its associated circuits. This stimulation resulted in a significant decrease in fMRI BOLD activity at the target site, suggesting SCC inhibition. This effect occurred only during effective stimulation; it was not observed during sham stimulation.

[0249] The therapies provided by system 10 are not limited to the modulation of the SCC; the ultrasound array configuration of treatment device 100 can modulate targets throughout the deep brain. For example, device 100 can deliver stimulation energy to the ventroposteromedial nucleus or ventroposterolateral nucleus of the thalamus to treat patients with chronic pain.

[0250] Transcranial low-intensity ultrasound (TAI) has been safely used in human subjects in previous studies, but the strong distortion characteristics of the skull severely limit the predictability of the delivered intensity. Existing uncertainties associated with TAI delivery may raise safety concerns, as overcompensation for skull ultrasound attenuation could lead to mechanical or thermal tissue damage. Treatment device 100 and other components of system 10 use transmission scanning to measure the acoustic properties of the patient's skull, hair, and other obstructions to determine adjustment parameters for therapeutic ultrasound delivery, thereby effectively delivering stimulation within established safety limits. The ultrasound intensity delivered in Study S2 was limited by the FDA 510(k) Class 3 safety guidelines for ultrasound imaging: spatial peak time mean intensity less than 0.72 W / cm². 2 The average intensity of the spatial peak pulse is less than 190 W / cm². 2 .

[0251] System 10 provides ultrasound of sufficient duration and intensity to induce persistent neuroplasticity effects in the target circuitry. These effects are believed to be mediated at least in part by glial cell activation and its subsequent effects on synaptic processes. This molecular pathway and related pathways offer a unique opportunity for persistent circuit resetting, similar to electroconvulsive therapy or repetitive transcranial magnetic stimulation, but this method allows for targeted, direct action on the affected deep brain circuitry. This approach will enhance the effectiveness and safety of neuromodulation therapy, achieving targeted, patient-specific resetting of dysfunctional deep brain circuitry.

[0252] As demonstrated in clinical studies, the treatment device 100 and other components of the system 10 can be configured (e.g., in a holistic configuration) for treating patients with depression. This includes patients with major depressive disorder, as well as patients with depression who may also have comorbid anxiety, chronic pain, Alzheimer's disease, and / or post-traumatic stress disorder.

[0253] Study S3

[0254] System 10 is used for another item Research This refers to Study S3, as described in this paper; in this study, ultrasound and magnetic fields were delivered in combination via System 10 to stimulate the peripheral nerves of mammalian patients. As used herein, “L-field” refers to the generated electric field, and “L-stimulation” refers to the generated stimulation effect; both names derive from their origins in the Lorentz equation and their electrical and local properties.

[0255] Ultrasound Device: Ultrasound stimulation for field assessment and peripheral nerve stimulation is generated by a focused MRI-compatible ultrasound transducer with a diameter of 64 mm and a focal length of 52 mm. The transducer operates at a frequency of 258 kHz. A water-filled coupling cone made of 1 mm thick plastic is used to focus the ultrasound onto the target point (see Figure 10). The coupling cone has a height of 52 mm and a diameter of 70 mm. The diameter of the coupling cone aperture at the ultrasound target point is 16 mm. The system 10 generates stimulation through its programmable function generator section, thereby producing a stimulation waveform. The signal is amplified by a 55 dB, 250 kHz–30 MHz power amplifier in the system 10.

[0256] Ultrasonic field measurement: The pressure field was measured at the ultrasonic target location in a free field within the water tank. A capsule-type hydrophone (HGL-0200, Onda) was used to measure the pressure. This hydrophone was calibrated between 250 kHz and 40 MHz and mounted on a three-degree-of-freedom programmable displacement system (Aims III, Onda). The spatial distribution of the generated ultrasonic pressure is shown below. Figure 10C The peak-normalized ultrasonic pressure field is shown. The pressure curves are averaged over the x and y dimensions. The dashed line represents the 0.707 (0.5) pressure (intensity) level, used to characterize the sound field using the half-width at half-maximum (FWHM). The FWHM has a diameter of 6.5 mm in the xy dimension and a focal length (z dimension) of 3.3 mm. Hydrophone measurements have an error of approximately 1 dB (HGL-0200, Onda). This may cause a discrepancy between the theoretical and measured sound fields (see [link to relevant documentation]). Figure 9B ).

[0257] Magnetic field: Peripheral nerve stimulation and related measurements performed by System 10 were all performed within a 7T MRI scanner (Bruker BioSpec). The ultrasound transducer assembly of System 10 was placed inside the aperture, 20 cm from the aperture exit surface. The static magnetic field inside the aperture was considered relatively uniform. The direction of the magnetic field was perpendicular to the direction of the ultrasound field (see Figure 10).

[0258] Measurement of the generated electric field: The electric field generated by the system 10, which uses a pair of copper electrodes placed at the ultrasonic target point, is measured (see [reference]). Figure 10A Measurements were performed under specified geometry and after the device was rotated 90 degrees relative to the magnetic field. The electrode spacing was 3 mm. The coupling cone was filled with saline solution. The electrodes were insulated, with only the electrode tips exposed to the medium. One hundred repetitions of a continuous 258 kHz tone burst, lasting 50 ms, were acquired at pressure amplitudes of 0.1 MPa, 0.3 MPa, and 0.5 MPa. For each repetition, the peak amplitude of the inter-electrode induced voltage was measured, and the 100 values ​​at each pressure were averaged. The L-field was compared with that under the default geometry (see...). Figure 10A ) and rotate 90 oThe L-field effect after the measurement is reduced, and the respective voltage amplitudes are subtracted to ensure that the measurement is not affected by potential ultrasound-related artifacts.

[0259] Calculation of the generated electric field: The generated electric field follows the Lorentz equation. The acoustic impedance Z = 1.58 MRayleigh is used in this equation. To ensure the determinism of the measurement results, the electrode is inserted into the salt water to a depth of 1.5 mm. This depth corresponds to a quarter wavelength. This depth allows the electrode tip to be positioned at a specific location at the antinode of the reflected wave at the water-air interface. The pressure at the antinode is doubled, thus forming... (See) Figure 9B ).

[0260] Nerve stimulation: In study S3, eighteen participants (6 women and 12 men, aged 21–38 years) were involved. Participants were asked to gently place their right thumb on a plastic coupling cone filled with degassed water (see [link to study S3]). Figure 10B Subjects closed their eyes and wore noise-canceling earmuffs (X4A, 3 M; 27dB noise reduction) to fully focus on the stimulus. Subjects could neither hear nor see the stimulus or its production.

[0261] Stimulation: Stimulation was administered within the aperture of a 7T MRI scanner or at a distance of 3 meters. The stimulation sequence was randomized and without replacement, such that half of the subjects received stimulation inside the scanner first, and the other half received stimulation outside the scanner first. Subjects were instructed to place their fingers on the aperture, perpendicular to the ultrasonic and magnetic fields (see [link to relevant documentation]). Figure 10B ), in order to maximize the L-stimulation effect.

[0262] In study S3, nine different stimuli were used, including three pressure levels and three different waveforms (see [link]). Figure 10D The tenth stimulus is a sham stimulus, delivering negligible pressure (5 kPa, corresponding to the noise level of the amplifier-transducer output) under the same conditions. The selected parameters ensure safe and effective stimulation. The fundamental carrier frequency of the system's 10 transducers is 258 kHz. The duration of each stimulus (200 ms) was chosen to provide sufficient time for potential integration effects. The peak ultrasonic pressure amplitudes measured at the aperture center were 0.35 MPa, 0.53 MPa, and 0.7 MPa. This peak pressure was chosen to generate a considerable electric field strength (up to 3.1 V / m) at the target site, while being low enough to match the Ip per pulse. SPPA Category 3 510(k) recommendations, and meeting the requirements throughout the study period. SPTARecommended, and sufficiently low, to avoid triggering unpleasant nociceptive responses. Stimuli were either continuous (200 ms acoustic pulse trains) or pulsed at 500 Hz or 10 kHz, both with a 50% duty cycle. The pulsed stimulation was based on the assumption that it would generate multiple initiation responses, thereby enhancing the stimulus. The L-stimulation effect was observed regardless of whether the stimulus was continuous or pulsed; only a weak interaction existed between the stimulus waveform and the magnetic field (see Table 1).

[0263]

[0264] Table 1

[0265] Table 1 shows the effects of magnetic field (M), ultrasonic pressure (P), and stimulus waveform (W; continuous or pulsed) on the frequencies of nociceptive and tactile responses (left column) and the frequencies of tactile responses (right column). These effects were assessed using a three-way ANOVA, involving the three main effects and all possible interactions. Items in bold are considered statistically significant (p < 0.05).

[0266] In study S3, ten stimuli were repeated ten times. Each subject completed a total of 100 stimulus trials inside the scanner and 100 trials outside the scanner. Stimuli were delivered every 8–12 seconds. Stimuli were randomly drawn without replacement from 100 stimulus combinations. This method avoids the influence of stimulus order on the results.

[0267] Response and Assessment: Participants were instructed to verbally report sensations in any combination of the following: pain, vibration, and tapping; and to report an intensity rating: 1: low, 2: moderate, 3: high. After each stimulus, the data collectors in Study 3 were prompted to enter the reported sensation (or no sensation) and its intensity into the data recording program. The data collectors were blinded to the stimuli. After the experiment, for each stimulus type, the response amplitude was calculated as the percentage of the trial in which the participant recorded the response, and weighted according to the reported intensity. Regardless of whether the sensory results were weighted by intensity or simply classified binary, the primary results were consistent (see Results section below). Vibration and tapping responses were combined into a tactile response.

[0268] Acoustic continuum: Water and skin (including soft tissue) have highly matched acoustic impedances (1.48 MRayleli and 1.68 MRayleli, respectively). In this way, approximately 99.6% of the energy... It is delivered into the finger. Therefore, the water-finger interface is essentially acoustically permeable and can be considered a continuous medium from an ultrasonic perspective.

[0269] Stimulation safety: The safety of the ultrasound stimulation used in this study is below the FDA 510(k) Category 3 recommendation (FDA 2023). Specifically, the highest peak pressure used in the study was 0.7 MPa, corresponding to a peak intensity of 15.3 W / cm². 2 Far below the FDA-recommended I SPPA = 190W / cm 2 (See Table 2). Furthermore, the temporally averaged spatial peak intensity is I. SPTA = 150mW / cm 2 It is also lower than the FDA-recommended level. SPTA = 720mW / cm 2 The charge density calculation (see Table 2) used an EEG conductivity of 0.26 S / m. Therefore, from the perspectives of both ultrasound and electrical stimulation safety, a much higher level of stimulation can be used. A maximum stimulation of 0.7 MPa was tolerable for all subjects. After the experiment, thumb function was normal in all subjects, and sensation was unaffected.

[0270]

[0271] Table 2

[0272] Table 2 shows the compliance with safety criteria. This study used nine different stimuli: three pressure levels and three different waveforms, one continuous (100% duty cycle) and two pulsed (both 50% duty cycle). All stimuli lasted 200 ms and were delivered on average every 10 s. E represents the peak intensity of the L-stimulation induced in a 7T magnetic field. The charge density calculation used an EEG conductivity of 0.26 S / m. Ideally, the charge density of electrical stimulation should not exceed 30 μC / cm³. 2 All stimuli were within the recommended safety range. No adverse acute or long-term effects were reported by the subjects.

[0273] Nonhuman Primate Brain Stimulation: Two adult male rhesus monkeys (rhesus monkeys M1 and M2) were used in the brain stimulation portion of the S3 study. System 10 delivered ultrasound via a 256-element, MRI-compatible phased array of ultrasound transducers (e.g., UST 155u). Briefly, the transducer array was placed within a frame (e.g., housing 110), which was mounted within four titanium pins fixed to the monkey skull. This mounting system ensured reproducible targeting of energy delivery to the brain. Coupling to the head was mediated using a cryogel (e.g., coupling gel 700b). Coupling quality was verified using ultrasound imaging sequences prior to each treatment session. The monkeys were positioned within the MRI scanner in the standard sphinx position. The monkeys were anesthetized with isoflurane (1.0% - 1.25% + 1-2 l min). -1Medical-grade oxygen was used. System 10 delivered ultrasound to two deep brain targets: the left and right lateral geniculate nuclei (LGNs). MRI thermometry was used to verify LGN targeting. Ultrasound stimulation (100 ms duration, 480 kHz carrier frequency, 2 MPa amplitude) was applied to each LGN (left LGN, right LGN, etc., every 4 seconds) in a strictly alternating manner. Stimulation was either continuous or pulsed at a 200 Hz pulse repetition frequency with a 50% duty cycle. Data acquisition was performed under two conditions: the monkey was fully immersed in a 3T MRI (Siemens AG TRIO and VIDA), or its head was moved 2 m outside the aperture plane. The magnetic field at this distance contained approximately 20 mT. Each monkey received two stimulation cycles. In monkey M1, the pulse stimulation sequence for both cycles was medial-lateral. For CW ultrasound treatment, the sequence for the first cycle was medial-lateral, and the sequence for the second cycle was reversed. In monkey M2, the pulse stimulation sequence for the first cycle was medial-lateral, and the sequence for the second cycle was reversed. In monkey M2, only one CW phase was recorded, in the order of external to internal. There was at least a 2-minute interval between internal and external stimuli. A total of 40 stimuli were delivered per phase. This number was set to provide sufficient statistical power without potentially harmful effects on the stimulated tissue. A total of seven phases were recorded (monkey M1: two phases of pulsed stimulation, two phases of continuous stimulation; monkey M2: two phases of pulsed stimulation, one phase of continuous stimulation), each comparing the presence and absence of a magnetic field. The ultrasound pressure amplitude was 2.0 MPa, corresponding to I... SPPA = 129.0W / cm 2 It complies with FDA 510k guidelines. SPPA = 190W / cm 2 Recommendation (FDA 2023).

[0274] The recording and quantification of gamma activity were similar to previous studies (Webb et al. 2023). Activity was assessed within a 400 ms time window, with 100 ms overlaps. Gamma activity was normalized to the mean gamma activity within the 1 s time window preceding each stimulus, providing a baseline for assessing ultrasound and L-stimulation-induced changes. The activity induced by the rear electrode and by left and right LGN stimulation was averaged.

[0275] Result: The equation for the generation of the electric field is determined by the ultrasonic field and the magnetic field. Prediction: The generated electric field strength should increase with ultrasonic pressure according to... The rate changes proportionally (see Figure 9B (solid line). Consistent with this prediction, the measured induced field strength increased significantly with ultrasonic pressure (see [reference]). Figure 9B (Dashed line; p=0.037, linear regression F-test). The slope of the measured field is... 5.5 Vm -1 1MPa -1The slope (4.4 V m) calculated using the Lorentz equation under the applicable magnetic field strength (7 T) is different from that calculated using the Lorentz equation. -1 MPa -1 The results are highly consistent. Therefore, when a magnetic field is applied perpendicularly to an ultrasonic field, an electric field is indeed generated as predicted by the Lorentz equation, thus directly verifying the concept.

[0276] Figure 9A and 9B The system 10 demonstrates its ability to generate L-field strength relevant to biological applications. A stimulus of 0.5 MPa fully complies with FDA 510(k) safety criteria (FDA 2023), and it induces a peak electric field strength of 2.81 V / m within a 7T magnetic field (see [link to relevant documentation]). Figure 9B This field strength can significantly modulate neural activity. The electric field generated by System 10, as low as 0.3 V / m, can modulate neuronal firing. Clinically relevant transcranial electrical stimulation at the accepted maximum current of 2 mA can produce an electric field strength of approximately 0.28 V / m (95th percentile) in the human brain.

[0277] System 10 was also used to examine whether L-stimulation could modulate bioelectrical signals. Specifically, ultrasound delivery was focused from a distance of 52 mm onto a target with intact nerves and receptors, namely the human thumb (see [link to documentation]). Figure 10B Focused ultrasound stimulation (see) Figure 10C and 10D Delivered to the target site every 8-12 seconds. Subjects (n=18) were asked to report any nociceptive or tactile sensations. Nociceptive sensations originate from the activation of free nerve endings in the skin and can therefore serve as an indicator of neural activation.

[0278] like Figure 11AAs shown, the magnetic field significantly enhanced the amplitude of the nociceptive response. The figures show the mean ± SEM of the response amplitude under ultrasound alone and ultrasound combined with a 7T magnetic field, with the left side representing the nociceptive response and the right side representing the tactile response. The data are the summative results for all tested stimuli. Double asterisks indicate significant effects (p<0.01). Across all pressure levels and waveforms, the L stimulus increased the amplitude of the nociceptive response by 74%. In contrast to the nociceptive response, the tactile response was inhibited; there was a double separation of the effect between the magnetic field and sensory type (two-way ANOVA, magnetic field × sensory interaction, p<0.001; F(1, 644) = 13.20). This effect was similar if the subject's response was not scaled according to response intensity (p<0.001; F(1, 644) = 13.93). Paired post-hoc tests showed that the increase in nociceptive response (p=0.0059; t(17)=3.14, paired two-sided t-test) and the decrease in tactile response (p=0.0033; t(17)=-3.41) were significant. These effects were similar when the responses were not scaled according to response intensity (p=0.0037; t(17)=3.36 and p=0.0029; t(17)=-3.47, respectively).

[0279] Analysis of nociceptive responses reveals that these responses reflect the activation of nerves or nerve endings. Figure 11B The dependence of all stimuli on the presence or absence of a magnetic field is shown, displayed separately for each ultrasonic pressure. The nociceptive response induced by the L stimulus increases with ultrasonic pressure. Figure 11B The data show the mean ± SEM amplitude of the nociceptive response at the target site as a function of ultrasound pressure, and the presence (green) and absence (gray) of a magnetic field. The data are a summary of all stimuli. Figure 11B The data confirmed Figure 11A The results showed that the magnetic field amplifies the nociceptive response. A complete three-way ANOVA model was used to assess the effect, incorporating the magnetic field, ultrasonic pressure, stimulus waveform, and all possible interactions (see Table 1). In this comprehensive analysis, the magnetic field effect was also significant (p < 0.001, F(1, 408) = 18.55).

[0280] L stimulus based on A focused electric field is generated at the ultrasound target site. In this equation, the effect increases with ultrasound pressure P. Therefore, the higher the ultrasound pressure, the stronger the induced electric field, and the more significant the nociceptive response; this effect is independent of any neuromodulation of ultrasound alone. Consistent with this expectation, a significant interaction between the magnetic field and ultrasound pressure was found (see [link to relevant documentation]). Figure 11B ;p=0.0012, F(3, 408) = 5.41).

[0281] The effects of all factors and their interactions are summarized in Table 1. A significant interaction was found between the magnetic field and the stimulation waveform in terms of neural activation assessed by nociceptive response (p = 0.043, F(2, 408) = 3.16). The contrast between L-stimulation and ultrasound alone was more pronounced when pulsed ultrasound stimulation was performed via System 10. Specifically, averaging across all pressures, the response frequency ratio (7T vs. 0T) for continuous waveforms was 1.61, while the ratios for pulsed 500 Hz and 10 kHz waveforms were 1.85 and 3.85, respectively.

[0282] The reported effect stems from the induction of a local electric field, a process that follows the Lorentz electromotive force equation, and the effect depends on the orientation of the nerve relative to the applied electric field. In particular, the electric field can effectively stimulate the nerve if the electric field gradient is along the nerve pathway rather than across it. To test this, four subjects were asked to place their thumbs at the aperture in (1) perpendicular to the magnetic field (currently the default) and (2) parallel to the magnetic field. Figure 11C This demonstrates that L stimulation activates neurons in an orientation-specific manner. Figure 11C The mean ± SEM of the nociceptive response amplitude is shown as a function of the orientation of the induced electric field relative to the subject's nerve. The neural modulation effect is maximized when the nerve is aligned with the induced electric field (green). Data are summative results for all stimuli. An asterisk indicates that the modulation produced by the magnetic field and its orientation is significant (p < 0.05).

[0283] like Figure 11C As shown, these conditions significantly modulated the response (p=0.041, F(2, 33) = 3.50). Consistent with expectations, the effect was specific for perpendicular geometry; no effect was observed for parallel geometry (p=0.88, t(3) = 0.17, paired two-tailed t-test).

[0284] Study S3 evaluated the effects of L stimulation on deep brain regions in non-human primates. Figure 12A System 10 is shown, comprising a 256-element MRI-compatible phased array of ultrasound transducers inserted into a frame mounted on four titanium pillars attached to the skulls of two non-human primates (monkeys M1 and M2, described herein). Each monkey was positioned in a standard Sphinx pose. In this pose, the scanner's magnetic field (see arrow) is oriented towards the observer. Because ultrasound is delivered from above, the induced L-stimulation field is distributed along the monkey's left-right axis. It specifically targets the lateral geniculate nucleus (LGN), a deep brain region that transmits visual information to the visual cortex; see [link to relevant documentation]. Figure 12BThis study provides MRI thermometry images validating LGN targeting. The images show selective targeting of the left and right LGNs. Previous studies have shown that ultrasound neuromodulation of the LGN can increase gamma activity in the visual cortex. In study S3, the same apparatus and recordings were used to assess the effects of L-stimulation. Reference Figure 12C The image shows the mean ± SEM of high gamma activity recorded from the two posterior pins, in response to 100ms stimulation (480kHz carrier frequency, 2MPa amplitude) applied strictly alternately to each LGN every 4s. Stimulations were either continuous or pulsed at a 200Hz pulse repetition frequency. Data were pooled for both conditions due to no statistically significant difference. Data are shown for monkeys located inside the MRI (green) and 2m outside the MRI aperture (black), respectively. The response is aligned with the offset of each ultrasound stimulation (blue bar) and includes seven phases of data recorded in two monkeys, M1 and M2. As described above, stimulation was delivered every 4s inside and outside the static magnetic field of a 3T MRI magnet by System 10. The ultrasound stimulation amplitude was 2MPa, lasted 100ms, and was either continuous or pulsed at a 200Hz pulse repetition frequency. Consistent with previous findings, a significant increase in visual cortical gamma activity was observed after ultrasound stimulation (see [link to previous study]). Figure 12C (Black). Crucially, the presence of a strong magnetic field significantly affects induced gamma activity (see...). Figure 12C (Green). Specifically, the presence of the magnetic field suppressed the gamma response and made the rise after the stimulus onset more gradual. These effects were assessed using a two-way ANOVA, with the factors being magnetic field and stimulus type (continuous or pulsed). Gamma activity was measured within a time window (100 ms) immediately after the ultrasound termination and continued until the end of each trial (4 s). A significant magnetic field effect was observed (F(1, 981) = 5.64, p = 0.018). Neither the stimulus type nor the interaction between the two factors was significant (F(1, 981) = 1.27, p = 0.26 and F(1, 981) = 1.06, p = 0.30, respectively). Within the considered time window, gamma activity in monkeys M1 and M2 increased by an average of 6.1% and 5.4% at 0T, respectively, and by 2.0% and 2.5% at 3T. No detrimental effects were observed during or after the stimulus. The monkeys exhibited normal behavior after the procedure.

[0285] Discussion: Study S3 demonstrates that a system 10 configured to generate a combination of a magnetic field and a focused ultrasound field can remotely and noninvasively generate a local electric field. The resulting stimulation (L-stimulation) produces significant neuromodulation effects, and Study S3 has confirmed these effects in both the human peripheral nervous system and the central nervous system of non-human primates. Therefore, this method can be used for electrodeless modulation of neural activity and other processes that depend on electrical signal transmission.

[0286] Compared to traditional electrode-based stimulation, System 10 is configured to provide L-stimulation with three main advantages. First, a key advantage is that L-stimulation generates a localized electric field without requiring electrode insertion into the target site. Its localization is achieved through ultrasonic focusing. For high-frequency ultrasound, the focusing precision of the stimulation delivered by System 10 can reach the tens of micrometers level (e.g., less than 100 μm, or less than 50 μm). Second, the L-field can generate a steeper gradient, thus possessing a significantly higher potential for triggering biological effects compared to the electric field generated by a pair of electrodes. Specifically, the Lorentz equation… This indicates the spatial distribution of electric field intensity. Distribution of ultrasonic pressure waves Consistent. Therefore, the propagating sinusoidal ultrasonic pressure wave will generate an E gradient, with its positive and negative peaks spaced apart by E values. At 258 kHz, this equates to approximately 2.9 mm. In contrast, conventional electromagnetic fields, due to their much faster propagation speed, have a velocity of approximately 231 m at the same frequency. Therefore, thanks to the ultrasound component, the electric field gradient generated at the target site by L stimulation is five orders of magnitude stronger than that of a conventional electromagnetic field. This difference is crucial for neural stimulation because the effect of neural stimulation is known to vary with the activation function. It changes proportionally, among which The electric field gradient is along the excitable structure. The L-field gradient can be modulated using specific frequencies and waveforms of ultrasonic pressure waves. Third, L-stimulation can circumvent barriers associated with biological membranes. Membranes are permeable to L-stimulation because they are also permeable to magnetic and ultrasonic fields. This membrane-free nature of L-stimulation opens up a range of new clinical applications, enabling remote modulation of intracellular processes with greater effectiveness than previously understood.

[0287] When the ultrasound pressure is approximately one-third of the current FDA 510(k) guideline allowable value (0.7 MPa in soft tissue, compared to a guideline allowable value of 2.4 MPa, or below 190 W / cm²), 2 (FDA 2023), which detected significant effects on human peripheral nerves. At 2.4 MPa, which is still considered safe, the effect intensity of L stimulation is more than three times that reported in Study S3. Furthermore, for the relatively low frequencies used in Study S3, System 10 can apply ultrasound amplitudes higher than 2.4 MPa with short pulses without the risk of harmful thermal effects. If a stronger effect is required for certain clinical applications, stimulation can be performed in a stronger magnetic field. Magnetic fields exceeding 30 T are currently readily available.

[0288] Study S3 shows that L-stimulation delivered by System 10 enhances nociceptive responses and reduces tactile responses. Its preferential action on nociceptive fibers may be due to the generation of steep gradient fields on the millimeter scale induced by L-stimulation. These gradients may preferentially act on neural structures with this scale geometry (i.e., nociceptive fibers), while their effects may be averaged out for geometries exceeding wavelength (i.e., tactile receptors and fibers). Furthermore, this dual separation suggests that the L-field delivered by System 10 modulates the electrical signals generated by ultrasound in the skin receptors. This modulation could be applied to clinical applications of blocking abnormal signal transduction, such as in pain management.

[0289] In study S3, System 10 was used to deliver a pressure of 2.0 MPa to deep brain targets in non-human primates to induce reliable changes in gamma activity in the visual cortex. The presence of a 3T magnetic field was found to significantly attenuate and delay the gamma response to ultrasound. This effect lasted for at least 4 seconds, the duration of the stimulation interval. Previous studies have used high-frequency continuous electrical waveforms to achieve neural inhibition or conduction block. The ultrasound delivered by System 10 has a relatively high carrier frequency, producing a high-frequency waveform, thus this effect is consistent with those studies. The relatively high pressure amplitude of 2.0 MPa generated by System 10 further amplifies this effect. The response of peripheral nerves and LGN neurons to this novel stimulation pattern that induces steep gradients may also differ fundamentally.

[0290] System 10 can deliver continuous stimulation, such as stimulation containing a high-frequency carrier wave that inhibits neural activity. Alternatively or additionally, system 10 can deliver pulsed stimulation, such as pulsed stimulation that produces an “initiation response,” wherein neural activity transiently increases after the initiation of the high-frequency stimulation. Neither human peripheral nerve stimulation nor monkey central nervous system stimulation differentiates between stimulation types. Inducing significant neural excitation using L stimulation may require a pulse repetition frequency much higher than that used in this study. In some embodiments, the pulse repetition frequency includes a rate of at least 0.1 Hz, a rate not exceeding 100 kHz, or both.

[0291] The L-stimuli delivered by System 10 are non-invasive and targeted, providing a new means for systematically modulating specific neural targets in each patient, potentially achieving the goals of precision medicine. System 10 may include a transducer array that can be programmed to focus ultrasound onto neural targets. This array can be as small as tens of micrometers when applied to soft tissue and approximately 3 mm in diameter when applied through the human skull. Combined with the microsecond-level temporal resolution of ultrasound, the L-stimuli delivered by System 10 can sequentially or synergistically activate multiple circuits. In summary, the high spatiotemporal resolution of energy delivery by System 10 provides a means for systematically modulating specific neural targets. For example, System 10 can be used to deliver L-stimuli to identify (e.g., and subsequently treat) neural circuits involved in chronic pain in a specific patient. Furthermore, the ability to systematically manipulate specific brain circuits is expected to change current understanding of basic brain function.

[0292] For a static magnetic field, the L-stimulus delivered by system 10 produces a stimulation frequency that is the same as the frequency of the applied ultrasound. This determined ultrasound frequency ensures that delivery is unaffected by potential external sources unless they operate at the same frequency as the ultrasound.

[0293] In some embodiments, system 10 includes MRI to deliver a magnetic field during L-stimulus delivery. Alternatively, system 10 may include a set of one, two, or more coils to generate the magnetic field (e.g., functional elements 99 and / or 199, including one, two, or more coils configured to deliver the magnetic field). Since no gradient and imaging are required, the production of such a system can be far more economical than system 10, which includes MRI.

[0294] The L-stimulus delivered by System 10 induces an electric field without the need to insert electrodes into the target site, thus maintaining its integrity and sterility. This delivery configuration can provide clinical and other applications beyond neuromodulation, such as remote stimulation of tissue or cell cultures, food processing, or catalysis of certain chemical reactions.

[0295] In summary, Study S3 demonstrates that electrical stimulation generated by remotely applying magnetic and ultrasonic fields via System 10 is both effective and safe. The high spatiotemporal resolution stimulation achieved by the ultrasonic phased array of System 10 provides a new means for the flexible and systematic modulation of biological processes. This systematic tool can non-invasively modulate spatially specific biological processes (including those within the nervous system) in mammalian patients.

[0296] Study S4

[0297] As described herein, the system 10 of this invention can be used to treat pain experienced by patients (e.g., chronic pain) by directly intervening in deep brain circuits. Cingulate-GV troponinosis targeting the anterior cingulate cortex and deep brain stimulation have shown significant improvements in pain discomfort, but these interventions require brain surgery. In Study S4 described herein, System 10 was used for completely non-invasive modulation of this deep emotional center of the brain, using low-intensity transcranial focused ultrasound delivered via treatment device 100. In a randomized crossover trial, twenty patients with chronic pain received either 40 minutes of effective stimulation or sham stimulation and were monitored for one week. 60% of patients experienced clinically significant pain relief on days 1 and 7 after effective stimulation, while sham stimulation resulted in such benefits in only 15% and 20% of subjects, respectively. On average, effective stimulation reduced pain by 60.0% immediately after intervention, and by 43.0% and 33.0% on days 1 and 7, respectively. The corresponding sham stimulation levels were 14.4%, 12.3%, and 6.6%. Stimulation was well tolerated, and no adverse events were detected. Adverse reactions were generally mild and subsided within 24 hours. In summary, direct ultrasound stimulation of the anterior cingulate cortex of System 10 provides rapid, clinically significant, and durable improvement in pain severity.

[0298] Introduction: It is estimated that 20% to 30% of the population suffers from chronic pain, which persists even after the initial injury has healed. Chronic pain is often difficult to cure, significantly reduces quality of life, frequently triggers mental disorders, and in some cases even leads to suicide. Imaging and interventional studies provide strong evidence that the anterior cingulate cortex (ACC), a deep neural center in the limbic system, is involved in the unpleasant and aversive components of pain.

[0299] The ACC exhibits structural and functional heterogeneity. Three subregions of the ACC—the anterior-middle cingulate cortex (aMCC), the anterior genicular ACC (pACC), and the inferior genicular ACC (sACC)—are all involved in the emotional regulation of chronic pain. Anatomically, the pACC is closely connected to the prefrontal cortex, while the sACC is connected to the amygdala. These areas show functional separation in terms of emotional valence: the sACC and pACC are regulated by negative and positive emotions, respectively. The aMCC plays a role in the cognition / appraisal of chronic pain. Actual pain experience and pain-related situational cues activate the aMCC. Furthermore, activity in this area is modulated by attentional orientation or shifting of attention to painful stimuli.

[0300] Therefore, the ACC has a unique function in integrating affective-cognitive parameters in pain perception. In fact, preclinical models of neuropathic pain suggest that the ACC plays an important role in linking pain with depressive behaviors. Furthermore, ACC hyperactivity exacerbates the aversive component of chronic pain. The ACC also appears to integrate situational affective valence into the subjective experience of pain. For example, individuals receiving noxious stimuli while seeing sad faces showed significantly stronger ACC activation compared to individuals presenting happy faces. Post-pathological ACC reduction can lead to defective response selection to noxious stimuli, motor mutism, motor neglect, impaired motor priming, and abnormal social behaviors.

[0301] Surgical intervention of the ACC using cingulate gyrus transection is known to improve pain symptoms, supporting a causal role for this brain region in pain management. Specifically, a systematic review evaluating patients in 11 studies showed that this well-tolerated procedure provided pain relief in over 60% of cases. Deep brain stimulation (DBS) implantation targeting the ACC reduced pain intensity by an average of 35% to 48%. Despite the effectiveness of these treatment options, both cingulate gyrus transection and DBS require surgical intervention, which significantly limits their potential for wider application to benefit a broader patient population.

[0302] To address this issue, the system 10 conceived in this invention can be used for completely non-invasive modulation of the ACC and related circuits. System 10 can focus ultrasound waves through the intact skull and scalp to deep brain targets. Crucially, system 10 measures and compensates for the severe aberrations caused by ultrasound in the human head, thereby delivering controlled and defined ultrasound intensity to each target. In Study S4, system 10 was used to modulate the ACC in 23 patients with chronic pain. The primary objective of Study S4 was to evaluate its effect on pain using a randomized, crossover, sham-controlled study design. In addition to clinical outcomes, we also validated target binding using functional MRI (fMRI) in a subset of patients.

[0303] Methods - Trial Design: Study S4 was a pilot double-blind, randomized, controlled crossover trial to evaluate the efficacy and safety of System 10 for focused ultrasound (FUS) stimulation of the ACC in participants experiencing extensive chronic pain (also referred to as “patients” or “subjects” in this article).

[0304] Participants meeting the study criteria completed baseline measurements of chronic pain, including the Brief Pain Scale, the Patient-Reported Outcomes Measurement Information System (PROMIS) pain intensity, PROMIS depression, and PROMIS anxiety indices. After baseline, participants were randomly assigned to either an effective stimulation group or a sham stimulation group. Both groups underwent an MRI scan (approximately 1 hour) primarily to register the treatment device 100 with the patient's brain anatomy. This scan also measured fMRI activation in response to ultrasound stimulation (via an MRI-integrated imaging device 800). Subsequently, participants underwent a treatment session outside of MRI (40 minutes of stimulation, approximately 1 hour total), using either fully effective or sham stimulation. Participants were monitored for 7 days post-treatment, and those still meeting the inclusion criteria were crossovered to the corresponding group. Participants were required to have a 24-hour mean Visual Analogue Scale (VAS) pain score of at least 3 to be eligible for a second treatment, and treatment was delayed after either effective or sham stimulation until this threshold was reached. At crossover, participants repeated the treatment procedure from the corresponding group, and were monitored again for 7 days post-intervention.

[0305] Methods - Participants: Study S4 recruited participants aged 18 to 65 years with a primary diagnosis of chronic pain. The pain had to have lasted for at least 3 months and be of moderate to severe severity.

[0306] Exclusion criteria include any of the following patients: a lifelong history of severe suicide attempts; a history of severe brain injury or other neurological disorders; brain stimulation (such as electroconvulsive therapy, transcranial magnetic stimulation [TMS] and / or vagus nerve stimulation) within the past month; intolerance or contraindication to MRI; and / or implanted devices in the head or neck.

[0307]

[0308] Table 3

[0309] Table 3 lists the following for the true stimulus group (left) and the sham stimulus group (right): number of female (male) subjects, mean age ± SD, mean pain ± SD baseline visual analog scale score, and PROMIS pain intensity, mean depression and anxiety ± SD baseline score for each group.

[0310] Table 3 summarizes the characteristics of the participant sample. The study cohort consisted of 60% women with a mean age of 46.6 years. The 24-hour mean pain score on the Brief Pain Inventory (BPI) ranged from 3 to 8, with a mean of 5.35 in the effective stimulus group and 5.21 in the sham stimulus group. The pain intensity score on the Patient Reported Outcomes Measurement Information System ranged from 54.2 to 74.4, with a mean of 65.02 in the effective stimulus group and 63.60 in the sham stimulus group. This study cohort corresponds to participants with moderate to severe pain. Subjects had a single or multiple sources of chronic pain, ranging from fibromyalgia (10), myofascial pain syndrome (4), generalized pain syndrome (4), migraine (3), back pain (3), neuropathy (3), arthritis (3), chronic fatigue syndrome (2), complex pain syndrome, piriformis syndrome, atypical trigeminal neuralgia, cervical spondylosis with myelopathy, shoulder pain, foot pain, joint pain, endometriosis, scleroderma, autonomic dysfunction, common variant immunodeficiency disease, temporomandibular joint disorder, Guillain-Barré syndrome, Crohn's disease, and post-cancer pain.

[0311] Figure 13A -C respectively displays the flowchart, anatomical diagram, and MRI image. Figure 13A The experimental design flowchart shows that participants were randomly assigned to MRI T1 and 10-minute fMRI measurements for effective or sham stimulation. This was followed by an initial 40-minute ultrasound treatment session outside the MRI scanner, with 7 days of monitoring, a washout period, a second treatment session outside the MRI scanner, and 7 days of monitoring. Twenty usable data points were available under both effective and sham stimulation conditions. Figure 13B The diagram illustrates how treatment device 100 delivers transcranial low-intensity focused ultrasound to the ACC target point. Figure 13C The image shown is an MRI image used to validate ACC targeting. Because the ACC is a relatively large structure relative to the ultrasound focal point (2.4 mm × 3.6 mm × 20.4 mm), eight ACC subregions were targeted, as indicated by the white crosshairs. The green crosshairs illustrate the targeting of one of these subregions. The pink areas delineate the ultrasound focusing volume corresponding to a peak intensity greater than 50%.

[0312] Methods - Intervention: Study S4 evaluated FUS stimulation of the ACC in a single 1-hour session, including 40 minutes of effective ultrasound treatment. Ultrasound was focused onto the target site using a treatment device 100, which included two phased-array transducers positioned above the left and right parietal bones. All treatments were performed outside of MRI (see [link to MRI]). Figure 13A ).

[0313] Methods - Registration: Prior to treatment, subjects underwent standard anatomical (T1-weighted) MRI for treatment guidance. These scans enabled co-registration of the treatment device 100 location with specific brain anatomy structures of the subject, such as via the housing 110 and / or other components of the system 10 as described herein. Treatment was performed outside of the MRI. The patient's head was secured in a radiographic mask (e.g., mask 700a as described herein) and positioned as during the previous MRI scan to ensure reproducibility of the target (see [link to relevant documentation]). Figure 13B ).

[0314] Methods - Targeting: After registration, eight target points were selected within the ACC: two target points within the infrakal ACC (Brodman region 2565), and six target points within the pACC to aMCC (Brodman regions s24, p24, a24, 33). The array generated a 26 dB intensity field with lateral, thickness, and axial dimensions of 2.4 mm × 3.6 mm × 20.4 mm (y, z, and x dimensions in the Montreal Institute of Neurology [MNI] coordinate system) (see [link to relevant documentation]). Figure 13C Each of the eight target sites is centered on the subject's midline in the x-axis and on the bilateral hemispherical white matter tracts in the y-z-axis. Each target site is spaced 4 mm apart from adjacent target sites in the sagittal plane (y-z dimension) to form a continuous region while avoiding overlap of stimulation subregions (see [link to relevant documentation]). Figure 13A -C). Within this plane, the target point is also positioned at least 4 mm from the outer edge of the callus to minimize direct stimulation of this highly connected region. The focal shape enables bilateral stimulation of the ACC. The average target point location and distribution are as follows. Figure 13C As shown.

[0315] Methods - Treatment: The treatment procedure, performed outside the scanner, consisted of two stimulation blocks. Block A contained sixteen 30-second stimulations to detect immediate symptom relief. Symptoms were verbally assessed after each ultrasound treatment, with the subject reporting any positive or negative changes in pain. Targets were randomly ordered without replacement, ensuring each target was stimulated twice. Verbal reports between ultrasound treatments typically took 15 to 60 seconds. The four targets with the most significant pain symptom relief were selected. Block B delivered twelve 3-minute ultrasound treatments to these four targets in a randomized, staggered manner. A 15 to 60-second interval remained between each individual stimulation as the operator selected the next target and the subject reported any positive or negative changes from the previous stimulation. Sham stimulation followed the same protocol but only provided auditory masking to the subject; no voltage was applied to the transducer of the treatment device 100.

[0316] Methods - Stimulation parameters: Ultrasound was delivered to each target site at an amplitude of 1 MPa (estimated by relative transmission to the skull; spatial peak pulse mean intensity (ISPPA) was 31.0 W / cm²). 2Mechanical index (MI) = 1.2, thermal index (TI) = up to 0.64), pulse train duration 30 ms, consisting of 5 ms on and 5 ms off pulses (duty cycle = 50%), pulse train interval 0.7 s, pulse repetition frequency (PRF) = 1.42 Hz, spatial peak time average intensity (ISPTA) = 0.66 W / cm². 2 The target thermal index is expressed in W / W. deg Calculate, where W = 310,000 W / m 2 And W deg = ΔTρC / (2αf) = 480,000W / m 2 In the formula, ΔT represents a temperature change of 1 degree Celsius, and ρ represents the density of brain tissue (1030 kg / m³). 3 C represents the specific heat of brain tissue (3630 J / (kgK), and α represents the absorption rate of brain tissue at 6MHz. -1 m -1 f represents the frequency of 0.65 MHz. Previous studies have evaluated the potential for skull heating through simulation and measurements inside the ex vivo human skull, showing that a 30-millisecond pulse can raise the temperature by up to 0.047°C.

[0317] Methods - Relative Transmission Cranial Correction: As described herein, System 10 provides the ability to directly measure and compensate for the attenuation of ultrasound by the patient's head and hair. In short, in the method employed in Study S4, the transducer (energy delivery element 155) of Treatment Device 100 sequentially emits 10 cycles of low-intensity, 650 kHz pulses from each individual element, while simultaneously recording the responses of all other non-emitting elements. This transmission procedure allows for the direct measurement of ultrasound attenuation and phase shift through the skull and other obstacles (including acoustic coupling between hair and System 10) in the transmission path. This transmission method is a relative measurement, performed by comparing the results with reference measurements of a transducer with the same fixed geometry in water. The relative difference in the received ultrasound waveform between the two conditions allows for the calculation of the attenuation and phase shift experienced by the ultrasound from each element to the target. These values ​​are then used to adjust the amplitude of each beam by estimating the reciprocal of the attenuation and delaying the transmission time according to the estimated phase shift. This method restores the amplitude and sound field at the target.

[0318] Methods - Sham Stimulation: Sham stimulation employed auditory masking. During the intervention, subjects in both the sham stimulation and effective stimulation groups wore headphones. White noise and pre-recorded ultrasound transmission pulses were played through the headphones. These auditory stimuli were timed to the ultrasound stimulation during the effective stimulation period to mask any sounds associated with ultrasound delivery. No ultrasound was delivered during the sham stimulation period while auditory masking was in place.

[0319] Methods - MRI Acquisition: MRI acquisition was performed using a Siemens VIDA 3T system. Acquired data included fMRI BOLD, high-resolution anatomical magnetization preparation fast gradient echo (MPRAGE), and two sets of opposite-phase encoded spin echo field maps. Data acquisition included the following sequences: fMRI BOLD (T2... -Weighted): Interleaved series, back-to-front (PA) phase encoding, repetition time (TR) 2.0 s, echo time (TE) 33 ms, flip angle (FA) 80°, field of view (FOV) 207 mm, 52 slices, slice thickness 2.4 mm, bandwidth 2004 Hz / pixel, echo interval 0.62 ms, 300 volumes per 10 minutes; MPRAGE Anatomy: Ascending series, AP phase encoding, TR 2.4 s, TE 2.26 ms, FA 8°, 192 slices, slice thickness 1.3 mm, bandwidth 200 Hz / pixel, echo interval 6.84 ms; Spin echo field map: Interleaved series, AP and PA phase encoding, TR 9.5 s, TE 66 ms, FOV 207 mm, 52 slices, slice thickness 2.4 mm, bandwidth 1162 Hz / pixel, echo interval 0.96, echo plane imaging (EPI) factor 86.

[0320] MRI visits are primarily used to acquire anatomical MRI of the patient for device-patient registration. A secondary objective of this step is to investigate fMRI BOLD activity during simultaneous ultrasound stimulation of the ACC.

[0321] Methods - MRI Processing: A simplified fMRI processing workflow was employed to enable individualized analysis within the patient-specific raw MRI space. Functional MRI processing was performed using the Functional Neuroimaging Analysis Software (AFNI 24.0.04), ANIMA (3.0), and Statistical Parametric Mapping 12 (SPM12 r7219) software package. Processing was performed in five steps: removal of abnormal voxel signals from BOLD (de-spiking) (AFNI), EPI BOLD distortion correction using inverse phase-encoded spin echo field maps (AN-IMA), spatial realignment of the BOLD time series relative to the 10th volume (SPM12), layer-time correction of the BOLD time series (SPM12), and spatial smoothing of the time series BOLD using an 8-mm Gaussian kernel (SPM12).

[0322] Because ultrasound transducers and water-based hydrogel coupling (PVA hydrogel, UltrasoundCoupling.com) within MRI can produce artifacts and MRI distortion, special preprocessing considerations were taken into account. Based on these considerations, a multi-software combined processing workflow was constructed specifically for this study. In particular, AFNI peak removal was found to most accurately and consistently identify and remove aberrant gel coupling signals in EPI BOLD images. After peak removal, all data underwent visual quality checks to ensure gel coupling signals were removed before further preprocessing was performed.

[0323] Methods – Functional MRI Analysis: Individual analyses of functional MRI BOLD activation were performed on SPM12 using a general linear model of the whole brain (GLM). The design compared five staggered 1-minute stimulation intervals with five 1-minute resting intervals within a 10-minute BOLD scan time. Stimulated blocks followed parameters used in out-of-scan therapy procedures, but the total duration of the ultrasound-processed blocks was 1 minute. Two directional t-tests were used to analyze effective and sham stimulation data, comparing stimulated and non-stimulated blocks. Significance of BOLD was determined by cluster analysis including uncorrected signal values ​​(P < 0.001) and subsequent P < 0.05. Head movements were minimized by the system itself using stereotactic radiotherapy thermoplastic masks described herein (e.g., Aquaplast RT Open Eye and Mouth Slimline U-Frame; QFix). Steps were taken to maximize the sensitivity of fMRI data processing. First, individuals were analyzed within the original subject space to reduce spatial distortion caused by normalization relative to the standard MNI space. Second, motion parameters were not included in the first-level subject-space GLM. This is because, in block-design fMRI experiments, including motion parameters in the subject-level GLM analysis would reduce the sensitivity of GLM in detecting BOLD modulation.

[0324] Methods - Functional MRI whole-brain cohort analysis: Whole-brain and voxel-level analyses were performed to identify changes in brain activity associated with ultrasound neuromodulation. To achieve cohort-level activation analysis, in addition to the first-level individual analysis steps, the following fMRI processing steps were performed after slice time correction: co-registration of high-resolution T1 and realigned time series means (SPM12), normalization of co-registered T1 against MNI space using the Advanced Normalization Tool (ANT), normalization of time series BOLD by applying T1-normalized deformation field (ANT), and spatial smoothing of time series BOLD using an 8-mm Gaussian kernel (SPM12). Two whole-brain directional t-tests were performed to compare resting blocks with ultrasound-processed blocks (off > on and on > off t-tests) to reveal the decrease and increase in brain activation corresponding to effective ultrasound processing.

[0325] Methods - Clinical Assessment: The primary therapeutic efficacy outcome was the difference between effective and sham stimuli (FUS) measured by the mean 24-hour pain intensity score of the BPI before and after the intervention. The Brief Pain Scale (BPS) was completed daily for 7 days post-intervention. Secondary outcomes were measured by PROMIS pain intensity, PROMIS depression, and PROMIS anxiety. Mean verbal VAS pain scores were recorded throughout the treatment course to assess the immediate effects of the stimuli provided by System 10.

[0326] The safety of focused ultrasound (FUS) delivered by System 10 in the S4 study was assessed using a series of spontaneously reported adverse events and adverse reactions general assessments, which were recorded at baseline and 24 hours after effective stimulation and sham stimulation treatments.

[0327] Methods - Statistical Analysis: Repeated measures ANOVA was used to compare the primary outcome, mean 24-hour pain intensity (BPI), between the sham stimulation group and the effective stimulation group during the 7-day monitoring period. Multiple comparisons were performed using Greenhouse-Geisser adjusted p-values. Two-sample t-tests corrected for Bonferroni-Holm were used for multiple comparisons to compare daily data after treatment between groups. Secondary outcomes, such as immediate pain relief, PROMIS pain intensity, PROMIS depression, and PROMIS anxiety, were compared between groups using Wilcoxon signed-rank tests to handle non-normal distributions of scores.

[0328] Methods - Randomization: Randomization was performed by volunteers who were not involved in data collection. These volunteers prepared envelopes before the trial, sealing a strip of paper labeled "effective stimulus" or "sham stimulus" inside. Before each treatment session, the envelopes containing the random labels were given to personnel in Operating System 10 and were not shared with any other personnel who had contact with the patients. Patients were not informed of their group assignments. Clinicians, research coordinators, and researchers operating equipment for patients during MRI and treatment were all blinded.

[0329] Results - Study Design: This study involved a randomized sham-stimulation controlled crossover design, in which patients were randomly assigned to either the effective stimulation or sham stimulation treatment group, and crossed over to the control group after 1 week. Figure 13A This study recruited twenty-three patients with chronic pain (see Table 3). Two patients initially enrolled in the sham stimulation group completed the sham stimulation phase and subsequently refused follow-up contact, without crossing over to the second group. Neither participant experienced any adverse events related to sham stimulation treatment. Their results and safety data were included in the analysis.

[0330] None of the patients initially admitted to the effective stimulation group dropped out, although one patient who experienced pain relief did not complete the crossover to the sham stimulation group. Overall, 20 effective stimulation data points and 20 sham stimulation data points were available for clinical effect analysis.

[0331] Results - Targeting: As described in this article, ultrasound delivery during the treatment process using system 10 was performed outside of MRI, using a patient-aligned T1 MRI scan and the transducer of treatment device 100.

[0332] Figure 14 This is a bar chart showing the percentage change in pain intensity in the ACC under sham and effective stimuli. (Example) Figure 14 As shown, pain intensity changed rapidly after ultrasound modulation of the ACC. The mean ± SEM change in VAS scores in response to sham stimulation (orange) and effective stimulation (blue) at the ACC is displayed relative to the pre-intervention VAS scores. Individual data points are indicated by shaded circles. Figure 14 middle, The result indicates P = 0.00013, and the Wilcoxon signed-rank test is used.

[0333] Figure 15 This is a graph showing the change in pain intensity over time in the ACC under sham and effective stimuli. It displays the persistent changes in pain intensity after ultrasound modulation of the ACC using System 10, including the mean VAS score ± SEM change relative to the baseline VAS score before each intervention. Effect measurements were taken up to 7 days (x-axis). Data are presented separately for effective stimuli (blue) and sham stimuli (orange). Dashed lines represent levels of pain relief considered clinically significant. Asterisks indicate significant differences between the effects of effective and sham stimuli. P < 0.05, P < 0.01; Bombferroni-Holm correction was used for multiple comparisons.

[0334] Figure 16A -B is a two-bar graph representing the response rates to a valid stimulus and a sham stimulus. Figure 16 uses a method similar to... Figure 15 Similar format, showing pain intensity relief of more than 33% ( Figure 16A ) and more than 50% Figure 16B The proportion of subjects.

[0335] Figure 17This is a bar graph comparing changes in PROMIS pain intensity between sham and effective stimuli, including changes in PROMIS pain intensity scores on day 7 after ultrasound modulation using System 10 of the ACC. It shows the mean ± SEM change of the PROMIS score on day 7 after stimulation relative to the pre-stimulation PROMIS score. Dashed lines indicate clinically significant levels of pain relief. Figure 17 As shown, P = 0.0014, using the Wilcoxon signed-rank test.

[0336] Results – Pain Modulation: Ultrasound was delivered to all ACC subregions within 40 minutes. Standardized VAS and PROMIS scores were measured up to 7 days after a single intervention. Immediately after effective stimulation, patients reported a VAS pain relief score of 60.0 ± 33.1% (mean ± SD; see [link to relevant documentation]). Figure 14 This corresponds to an absolute VAS change of -2.7 ± 1.4. In contrast, the sham stimulation group, which only delivered auditory masking sounds (see Methods) without ultrasound, achieved a relief rate of 14.39 ± 32.15%. This difference was highly significant (P = 0.00013, z = 3.83, Wilcoxon signed-rank test). Following effective stimulation treatment, 75% (15 of 20) of patients reported clinically significant (33%) pain relief, with 60% (12 of 20) reporting greater than 50% relief. In contrast, following sham stimulation treatment, 15% of subjects achieved clinically significant pain relief, and 10% (2 of 20) achieved greater than 50% relief. In summary, these data suggest that ultrasound ACC treatment provided by System 10 can significantly reduce pain levels after a single treatment session.

[0337] The persistence of pain relief after a single treatment course was evaluated. Figure 15 Pain relief following effective stimulation (rather than sham stimulation) was particularly significant within days after intervention and remained statistically and clinically significant throughout the 7-day follow-up period. Figure 15 Repeated measures ANOVA confirmed that the effective stimulation treatment group was significantly more effective than the sham stimulation treatment group (group effect: effective stimulation or sham stimulation; F7 = 3.21, P = 0.0086, Greenhouse-Geisser adjusted). Following effective stimulation treatment, 60% (12 of 20) of patients reported clinically significant pain relief at 24 hours and 7 days, with 55% and 30% reporting pain relief exceeding 50% at these time points, respectively. In contrast, following sham stimulation treatment, 15% (3 of 20) and 20% of patients achieved clinically significant pain relief at 24 hours and 7 days, respectively, with 10% reporting pain relief exceeding 50% (see [link to relevant documentation]). Figure 16A -B).

[0338] The beneficial effects of ACC neural modulation provided by System 10 in Study S4 are also reflected in the PROMIS pain intensity score (see Figure 17 Effective stimulation resulted in a mean ± SD decrease of 5.68 ± 7.2 points in the PROMIS pain intensity score, a significant effect compared to sham stimulation (P = 0.0014, z = 3.20, Wilcoxon signed-rank test). In the effective stimulation group, 55% (11 out of 20) of subjects showed at least a clinically significant change of 2.5 in their pain scores, compared to 17% (3 out of 19). The effective stimulation group resulted in a 2.27 ± 3.75 decrease in PROMIS depression scores, compared to a 0.23 ± 6.16 decrease in the sham stimulation group (P = 0.14, z = 1.48, Wilcoxon signed-rank test). The effective stimulation group resulted in a 2.87 ± 6.21 decrease in PROMIS anxiety scores, compared to a 0.65 ± 5.36 decrease in the sham stimulation group (P = 0.20, z = 1.29, Wilcoxon signed-rank test).

[0339] Results - Safety: Stimulus was well tolerated, and no adverse events were detected. There were no significant differences between effective and sham stimulation in any measure of symptoms (see Table 4 below). All treatment-related adverse reactions resolved before the end of the study. There was no significant difference in withdrawal rates between effective and sham stimulation conditions (P = 0.49, Fisher's exact test). No significant increase in pain as measured by the Short Form Pain Scale was observed in either the sham or effective stimulation treatment groups.

[0340]

[0341] Table 4

[0342] After stimulation with S4, patients were asked to complete a standard clinical questionnaire to assess potential adverse reactions. Table 4 shows the data for the effective stimulus (left side) and the sham stimulus (right side).

[0343] Figure 18A -B represents MRI images of the infragenic cingulate cortex (subjects 17, 2, 21, and 5) and the dorsal anterior cingulate cortex (subjects 19, 4, 8, 7, and 9), respectively. Infragenic ACC data for all subjects who received effective stimulation: Subject 17 (cluster level P < 0.0001; error discovery rate corrected, k E = 369 voxels), Subject 2 (cluster level P < 0001; false discovery rate corrected, k E= 414), Subject 21 (cluster level P < 0.0001; false discovery rate corrected, k E = 5791 voxels), Subject 5 (signal inclusion P < 0.005; cluster level P < 0.016; false discovery rate corrected, k E = 183 voxels). For aMCC: 19 subjects (cluster level P < 0.0001; false discovery rate corrected, k E = 1344 voxels), 4 subjects (cluster level P < 0.0001; false discovery rate corrected, k E = 1992 voxels), 8 subjects (cluster level P = 0.034; uncorrected, k E = 47 voxels). Subjects 7 and 9 did not show significant activation in the target region. Group analyses of both targets showed no significant differences.

[0344] Results - Functional MRI Target Cohesion: Before the start of the treatment procedure outside of MRI, sham and real stimuli were delivered within MRI, and the ultrasound focal point was verified using a target cohesion procedure. Parameter validation was performed to confirm that System 10 could effectively target the ventral (below the knee) and dorsal portions of the ACC.

[0345] Of the four patients who underwent the infrakal ACC engagement test, three showed a significant effect at the target site; of the five patients who underwent the dorsal ACC engagement test, three showed a significant effect (see [link to relevant documentation]). Figure 18A -B). Among patients with significant effects, all patients with infrakal ACC showed target inactivation, while 2 patients with aMCC showed target activation and 1 patient with aMCC showed target inactivation. Secondary group analysis showed no significant clustering among the 4 patients who received infrakal ACC, the 5 patients who received aMCC, or the 10 patients who received sham stimulation.

[0346] Discussion: Study S4 supports a novel treatment for chronic pain using non-invasive FUS stimulation of deep brain targets known to reflect pain experience. Results show that the system 10 conceived in this invention can precisely, non-invasively, and controllably modulate deep brain structures. In this method, a treatment device 100 including a phased array device delivers ultrasound to designated deep brain targets while simultaneously measuring and compensating for severe aberrations incurred by the ultrasound across the head, as described herein. Low-intensity ultrasound was applied to the ACC of patients with chronic pain using this method. A randomized, crossover, sham-stimulation controlled evaluation showed that this intervention provides rapid, clinically significant, and durable relief from chronic pain.

[0347] Rapid improvement in chronic pain can be achieved through pharmacological treatment or surgical interventions, including cingulate gyrus incision and deep brain stimulation (DBS). However, pharmacological treatment requires frequent re-administration, is often accompanied by significant adverse reactions, and can be addictive. On the other hand, surgical treatment carries significant risks, including brain hemorrhage and infection. The ultrasound emitted by System 10 provides an alternative, non-pharmacological, and non-invasive treatment option for chronic pain.

[0348] System 10 provides ultrasound with a unique triple characteristic: non-invasiveness, deep penetration, and precise focusing. Because sound waves travel much slower than electromagnetic waves, they have relatively short wavelengths. Thanks to diffraction, short wavelengths allow for relatively precise focusing at deep sites. Nevertheless, this technology has been limited by significant obstacles: the skull and hair severely and unpredictably attenuate and distort ultrasound waves. The method proposed in Study S4 and provided by System 10 directly measures and compensates for these barriers in each individual, thereby delivering a controlled, deterministic amount of ultrasound intensity to a designated target. In this way, low-intensity ultrasound can effectively and safely achieve targeted, non-invasive neuromodulation.

[0349] At the mechanistic level, ultrasound energy delivered via System 10 mechanically activates ion channels and directly induces action potentials. When ultrasound is delivered to neural tissue for tens of seconds or longer, it can also induce neural plasticity effects. These effects are at least partially attributable to the activation of glial cells. Furthermore, these effects depend on the ultrasound parameters provided by System 10. Detailed modeling studies have shown that low-energy ultrasound irradiation produces an overall inhibitory effect, while higher-energy ultrasound irradiation tends to produce an excitatory effect. Ultrasound-induced neural plasticity offers a unique opportunity for non-invasive resetting of dysfunctional circuits. Persistent resetting based on induced neural plasticity is the primary hypothetical mechanism behind the persistent effects reported in S4.

[0350] In study S4, bidirectional polarity of the modulated fMRI BOLD signal was observed despite the use of low-energy ultrasound irradiation. This bidirectionality between target activation and inactivation may stem from biological differences between the infrakal ACC and aMCC. In patients with statistical significance, ultrasound of the infrakal ACC resulted in target inactivation. Similarly, this inactivation was largely confined to the ultrasound target area. In contrast, two of the three patients with significant modulation of the aMCC showed activation in the target area. Furthermore, regardless of whether the target was activated or inactivated, this aMCC modulation was accompanied by changes in activity above the target in the dorsomedial prefrontal cortex. In summary, the data from study S4 suggest that the neuromodulation effects of ultrasound may depend not only on parameters but also on brain regions. Indeed, the infrakal ACC and aMCC have unique cellular structures, with the aMCC containing both larger cell bodies and a higher glial cell-to-neuron ratio. As previously mentioned, ultrasound-induced neuroplasticity is partly due to glial cell activation.

[0351] Three pieces of evidence support the view that the ACC modulatory effect in study S4 originated from the stimulus rather than a general artifact. First, there was a significant and substantial difference between effective and sham stimuli in the relief of pain intensity levels. This difference persisted even though the sham stimulus was controlled for placebo using an active auditory protocol. Second, effective stimuli induced local effects and did not cause congruent activation of the auditory or somatosensory cortex (see [link to study S4]). Figure 18A -B). Finally, no MRI BOLD activation was observed at the target site in some patients, providing negative control data suggesting that the modulation observed in other patients was not due to general artifacts.

[0352] System 10 in study S4 includes an imaging device 800, including an MRI, for registering the treatment device 100. In some embodiments, system 10 is configured to register the treatment device 100 without using an MRI.

[0353] In some embodiments, as described herein, system 10 is configured to deliver transcranial ultrasound stimulation and transcranial magnetic stimulation simultaneously. The effects of the two modes may be complementary, and combined application may produce a stronger effect than either method alone.

[0354] In summary, Study S4 demonstrates a successful non-invasive targeting approach that modulates deep brain circuits involved in chronic pain. Using this method, System 10 provides effective, rapid, and lasting relief from chronic pain. The procedure is incision-free, drug-free, and can be administered to patients within minutes. Therefore, this method can be applied to a wide range of patients and may help reduce the use of opioids or other medications that cause systemic adverse reactions.

[0355]

[0356] Table S1: Data of all subjects included in the analysis

[0357] System 10 and its components can be configured and used as described in Study S4 and other parts of this document, for example, to treat a patient as described in Study S4 and other parts of this document, to achieve the beneficial effects obtained by using System 10 for treatment as described in Study S4 and other parts of this document.

[0358] Patients eligible for treatment may include those with a 24-hour mean visual analog scale pain score of at least 1 (e.g., at least 3). Enrolled patients may have experienced moderate-level pain for at least 3 months. Target locations (e.g., one or more anatomical locations to which energy delivery is made) may include the anterior cingulate cortex (ACC). Target locations may include at least two or at least four target locations within the ACC. At least four target locations may include four locations selected from the following groups: the infrakal ACC (Brodman area 2565) and six target locations from the pACC to the aMCC (Brodman area s24, p24, a24, 33). At least four target locations may include eight target locations within the ACC. Each target location may be at least 2 mm, no more than 6 mm, or both of these distances from adjacent target locations (e.g., to achieve continuous tissue stimulation while avoiding overlap of stimulated subregions). Each target location may be approximately 4 mm from adjacent target locations. Energy delivery may include a peak intensity not exceeding 300 W / cm². 2 Energy delivery. Energy delivery may include peak intensity not exceeding 225 W / cm². 2 and / or not exceeding 190W / cm 2Energy delivery. Energy delivery may include energy deliveries lasting no more than 3 hours, no more than 2 hours, and / or no more than 1 hour. Energy delivery may include energy deliveries lasting at least 30 minutes, no more than 120 minutes, or both. Energy delivery may include energy deliveries lasting approximately 40 minutes. Energy delivery may include energy deliveries with a field size less than 5 mm × 5 mm × 40 mm. Energy delivery may include energy deliveries with a field size of approximately 2.4 mm × 3.6 mm × 20.4 mm. Energy delivery may include multiple test energy deliveries configured to test symptom relief (e.g., to determine suitable targets for energy reception). Each test energy delivery may include an energy delivery lasting no more than 60 seconds. Energy delivery may include multiple energy deliveries configured to provide therapeutic benefit to a medical condition. The multiple energy deliveries may include at least four energy deliveries lasting at least one minute. The multiple energy deliveries may include approximately 12 energy deliveries, each lasting three minutes. Energy delivery may include energy deliveries with an amplitude of at least 0.5 MPa. Energy delivery may include energy deliveries with an amplitude of approximately 1 MPa. Energy delivery may include energy delivery comprising pulses of at least 10 msec, delivered at a duty cycle of less than 90%. The interval between pulses may not exceed 20 seconds. Energy delivery may include energy delivery comprising pulses of approximately 30 msec, a duty cycle of 50%, and an interval of 0.7 seconds. The treatment provided by System 10 may achieve efficacy including one or more of the following: immediate pain reduction of at least 30% after energy delivery; pain reduction of at least 21.5% one day after energy delivery; and / or pain reduction of at least 16.5% seven days after energy delivery. The treatment provided by System 10 may reduce the absolute VAS pain score by at least one point. The treatment provided by System 10 may reduce the absolute VAS pain score by 2.7 ± 1.4 points. The treatment provided by System 10 may have at least a 50% expectation of achieving 33% pain reduction immediately after the energy delivery. The treatment provided by System 10 may have approximately a 75% expectation of achieving 33% pain reduction immediately after the energy delivery. The treatment provided by System 10 has an expected pain reduction of at least 30% within 24 hours following energy delivery (33%). The treatment provided by System 10 has an expected pain reduction of approximately 60% within 24 hours following energy delivery (33%). The treatment provided by System 10 can reduce the PROMIS pain intensity score by at least 10%. The treatment provided by System 10 can reduce the PROMIS pain intensity score by a mean ± SD of 5.68 ± 7.2 points. The treatment provided by System 10 can reduce the PROMIS depression score by at least 10%.The treatment provided by System 10 reduced the PROMIS depression score by 2.27 ± 3.75 points. The treatment provided by System 10 reduced the PROMIS anxiety score by at least 10%. The treatment provided by System 10 reduced the PROMIS anxiety score by 2.87 ± 6.21 points.

[0359] Research S5

[0360] As described herein, the system 10 conceived in this invention can be used to treat patients with depression. Major depressive disorder is associated with excessive activity of the subcingulate gyrus (SCC) of the corpus callosum. Stimulation of the SCC by surgically implanted electrodes can alleviate depression, but existing non-invasive techniques cannot directly and selectively modulate deep targets. The use of system 10 provides a novel non-invasive neuromodulation method for delivering low-intensity focused ultrasound to the SCC. In a study (Study S5), twenty-two patients with treatment-resistant depression participated in a randomized, double-blind, sham-stimulation controlled study. During concurrent functional MRI (e.g., via an imaging device 800 including MRI), system 10 was used to deliver ultrasound stimulation to the bilateral SCCs of each patient's brain to quantify target engagement. In some embodiments, system 10 can be configured to deliver ultrasound without concurrent functional MRI. In Study S5, emotional state was measured using the sadness subscale of the Positive and Negative Affect Scale before and after 40 minutes of real stimulation (also referred to as "effective stimulation") or sham stimulation of the SCC. Changes in depression severity were measured using the six-item Hamilton Depression Rating Scale-6 (HDRS-6) at 24 hours and 7 days. Results: Functional MRI showed target-specific reductions in SCC activity during stimulation (p=0.028, n=16). SCC neural modulation was detectable at the individual subject level in 8 out of 16 participants with a single 10-minute scan (p<0.05, small volume correction). Real stimulation resulted in greater improvement in mood and depression scores than sham stimulation. In the protocol-compliant sample (n=19), real stimulation was superior to sham stimulation in 24-hour HDRS-6 and grief scores (both p<0.05, d>1). A non-significant trend was observed in the intention-to-treat sample. In Study S5, ultrasound stimulation using System 10 was demonstrated to modulate SCC activity and rapidly reduce depressive symptoms.

[0361] Deep neural circuits are involved in the pathophysiological processes of various mental illnesses, including mood disorders, anxiety disorders, and addictions. Current treatments for these conditions are often ineffective, but specific and precise modulation of deep neural target activity holds promise for better treatment options. For example, major depressive disorder is associated with excessive activity in the subcallosal cortex (SCC), a peripheral region located on the ventral side of the corpus callosum. Functional imaging studies have shown that individuals with depression exhibit hyperactivity in the SCC, and interventional studies have demonstrated that disrupting SCC activity through deep brain stimulation can alleviate depressive symptoms.

[0362] However, existing deep brain stimulation methods require surgical implantation of stimulating electrodes, which carries significant risks. The high risk-benefit ratio and cost of surgical intervention limit the range of individuals who can benefit from invasive methods. On the other hand, existing non-invasive neuromodulation modalities have other limitations. Due to the fundamental physical properties of electromagnetic fields, transcranial magnetic stimulation and transcranial electrical stimulation cannot directly and selectively modulate deep structures such as the spinal cord (SCC). This lack of selectivity leads to limited effectiveness and numerous adverse effects.

[0363] System 10 overcomes these limitations. As described herein, System 10 can be used for non-invasive and controllable modulation of SCC and other deep brain targets. Also as described herein, the treatment device 100 of System 10 may include an array of ultrasound transducers (e.g., an array of energy delivery elements 155 including ultrasound transducers) configured to focus low-intensity ultrasound waves onto deep brain targets through the intact skull and scalp. Crucially, System 10 can be configured to measure and compensate for significant aberrations in ultrasound waves passing through the human head and / or other obstacles, thereby delivering controllable, deterministic, and safe ultrasound intensity to the target.

[0364] In study S5, a randomized, blinded, sham-controlled study design was employed, using System 10 to treat a cohort of participants with treatment-resistant depression (referred to herein as “patients” or “subjects”). Ultrasonic stimulation was delivered to the SCC under individualized MRI guidance via System 10, and the neural effects of the stimulation were quantified using concurrent functional MRI. The two parallel objectives of this study were (1) to demonstrate that ultrasound stimulation can act on the SCC target, and (2) to characterize the immediate emotional effects and tolerance of the stimulation. System 10 was used to “inactivate” the SCC (e.g., reduce activation) in patients receiving effective stimulation therapy, and to improve mood and depressive symptoms.

[0365] Figures 19 to 28 are related to study S5.

[0366] Figure 19A -B shows two brain images demonstrating ultrasound targeting and neuromodulation using System 10. Figure 19C This is a target adjustment diagram. Figure 19A The image shows the ultrasound field generated at the focal point superimposed on sagittal and coronal images. The focal point size is 20.4 mm × 2.4 mm × 3.6 mm (MNI space). Figure 19B The image shows target engagement in individual subjects assessed using concurrent BOLD imaging. Selective inactivation of SCC was observed: peak coordinates = [4, 20, -6], whole-brain FWE corrected p < 0.001. Display thresholds were: t < -4, t > 4, cluster size > 50 voxels. Figure 19CTable 7 shows the modulation of the target SCC region in the cohort (n = 16). Each symbol represents the BOLD response extracted from the SCC by an individual subject. The bars represent the mean ± SEM response: t(15) = -2.43, p = 0.028, one-sample two-tailed t-test. The symbol color indicates the individual subject results of the small volume correction analysis (see Table 7). Six subjects showed statistically significant inactivation at the individual subject level (green). Two subjects showed significant activation (red). Eight subjects (blue) showed no significant modulation at the individual subject level.

[0367] Figure 20 Three brain images are shown, demonstrating selective SCC inactivation implemented using System 10. A group analysis of 12 subjects with SCC inactivation during stimulation is presented. The corresponding negative β weights are shown in... Figure 19C No significant inactivation was observed in other brain regions.

[0368] Figure 21 The bar graph shows the improvement in mood after using System 10 to sonicate SCC. Figure 21 This figure shows the immediate changes in PANAS-X grief scores after treatment with sham stimuli (n = 10) and effective stimuli (n = 8) in a sample meeting the protocol requirements. The mean percentage change in grief scores was -63% in the effective stimulus group and -47% in the sham stimulus group. The standardized effect size between groups is d = -1.15 (95% confidence interval = [-2.24, -0.07]). (See figure...) This indicates p < 0.05, and the error bars represent SEM.

[0369] Figure 22A -C consists of two curve graphs and one bar graph, showing the improvement of depressive symptoms after ultrasound stimulation of the SCC using System 10. Figure 22A The changes in the six Hamilton Depression Rating Scale (HDRS-6) scores of the eligible participants were shown at 24 hours and 7 days post-treatment. The standardized effect sizes between groups were also shown: d = -1.078 at 24 hours (95% confidence interval = [-2.11, -0.04]) and d = -0.59 at 7 days (95% confidence interval = [-1.59, 0.40]). Figure 22B The average percentage change in HDRS-6 scores over 1 day and 7 days is shown: -55% and -52% in the effective stimulation group, and -22% and -29% in the sham stimulation group. Figure 22C The study showed the proportion of subjects in the effective stimulation group (n = 9) and the sham stimulation group (n = 10) who had a reduction of at least 50% in their HDRS-6 scores at 24 hours and 7 days.

[0370] Figure 23This is a flowchart illustrating the clinical trial design of Study S5. As described above, Study S5 was a double-blind, randomized, sham-stimulus controlled, crossover design. Clinical evaluation was conducted at the baseline visit (not shown). Approximately one week later, participants returned for their first stimulation visit (Day 0), and were randomly assigned 1:1 to the real stimulation group or the sham stimulation group. Pretreatment scale data were collected: the six-item Hamilton Depression Rating Scale (HDRS-6) and the Extended Positive and Negative Affect Scale (PANAS-X). Each participant then underwent a one-hour MRI examination, followed immediately by a one-hour treatment session. The post-treatment PANAS-X was completed immediately after the treatment session. The HDRS-6 was repeated 24 hours later (Day 1). Participants returned 6 days later (Day 7), at which point the treatment assignments were crossovered to sham or real stimulation, and the Day 0 procedure was repeated. The HDRS-6 was repeated 24 hours later and 7 days later (Day 8 and Day 14). The main efficacy outcomes shown at the bottom of the chart are: changes in PANAS-X grief score on day 0, changes in HDRS-6 score from day 0 to day 1, and changes in HDRS-6 score from day 0 to day 7.

[0371] Figure 24 This is a set of brain images showing the ultrasound target points in the inferior cingulate gyrus of the corpus callosum. In the 16 images shown, green crosshairs are superimposed on the sagittal T1-weighted images of each subject. The ultrasound focus provided by System 10 is centered on the midline and extends to the bilateral inferior cingulate gyrus cortex.

[0372] Figure 25 This is a flowchart illustrating participant participation in study S5. The intention-to-treat sample included all randomized participants. Before crossover, the protocol-compliant sample excluded two participants who received real stimulation during MRI at the sham stimulation visit, and one participant who had already received real stimulation before randomization. After crossover, the protocol-compliant sample further excluded three participants who received real stimulation during MRI at the sham stimulation visit.

[0373] Figure 26 This is a set of brain images illustrating distributed neuromodulation during ultrasound treatment of the inferior cingulate gyrus of the corpus callosum using System 10. It shows that ultrasound treatment of the SCC evoked multiple activation and inactivation patterns in distributed brain regions. The upper right inset shows the SCC target. Each sub-image represents an individual patient. The direction and significance of individual-level SCC neuromodulation are indicated at the top of each sub-image (see Table 7). [Image description continues...] Significance at the individual subject level (p < 0.05). Activated regions (red) and inactivated regions (blue) are superimposed on the sagittal image. Display thresholds: t < -2 and t > 2.

[0374] Figure 27This table represents the rating changes of the extended positive and negative emotion scale S5. Values ​​are expressed as mean and standard error of the mean. A two-sample t-test was used. Data for one participant who received the valid stimulus is missing. Sadness was a pre-specified primary outcome measure.

[0375] Figure 28A -C represents three bar charts, which show the percentage changes in PANAS-X grief score, HRRS-6 score, and HDRS-6 score for individual subjects who met the treatment protocol. Figure 28A It shows the immediate changes in the PANAS-X grief score. Figure 28B It shows the changes in HDRS-6 scores over 24 hours and 7 days. Figure 28C It shows the percentage change in HDRS-6 rating.

[0376] Table 5 includes a list of inclusion and exclusion criteria for study S5.

[0377]

[0378] Table 5

[0379] Table 6 includes the baseline demographic and clinical characteristics of the intention-to-treat sample in study S5. Diagnosis was based on the Brief International Neuropsychiatric Interview 7.0. Two participants with bipolar disorder had subthreshold manic symptoms but did not meet the criteria for bipolar I or II disorder. Only cases with documented failure of antidepressant trials within the past two years were included. No significant differences were found between the true stimulation group and the sham stimulation group (all p > 0.05).

[0380]

[0381] Table 6

[0382] Methods and Materials - Study Design and Participants: Eligible individuals were adults (aged 18-65 years) diagnosed with major depressive disorder or bipolar disorder according to DSM-5, currently experiencing a moderate to severe depressive episode, without psychotic features, and with a duration of illness of at least 2 months (see Table 5 for complete inclusion / exclusion criteria). Study S5 employed a double-blind, randomized, sham-controlled, crossover design (see [link to study design]). Figure 23Clinical evaluation was performed at the baseline visit. Patients returned approximately one week later for their first stimulation visit, randomly assigned 1:1 to either the true stimulation group or the sham stimulation group. At the first stimulation visit, each patient underwent a 1-hour MRI examination, followed by a 1-hour treatment session. Seven days later, each patient returned for a second stimulation visit, during which patients underwent crossover treatment (true stimulation changed to sham stimulation, or sham stimulation changed to true stimulation). At the second stimulation visit, the 1-hour MRI examination and 1-hour treatment session were repeated. Symptom assessments were performed at the beginning and end of each stimulation visit, and at 24 hours and 7 days after each stimulation visit.

[0383] Methods and Materials - System 10: In Study S4, the treatment device 100 of System 10 comprises two phased arrays of ultrasound transducers positioned on either side of the patient's head via a frame, such as via the housing 110 described herein and / or other components of System 10. An acoustic coupling gel is placed between each array and the head, and a thermoplastic mask (e.g., mask 700a described herein) is individually fitted to the patient's head to minimize movement relative to the frame and transducer arrays. Transceiver scans are performed between the two arrays to measure acoustic distortion caused by the head and coupling, and phase and amplitude adjustments for each transducer element are calculated using an algorithm to compensate for this distortion. MRI is performed with the ultrasound transducer arrays fixed (e.g., via imaging device 800), and the arrays are co-registered with individual brain anatomy using reference markers visible on the MRI device. The ultrasound focal point formed by the treatment device 100 has dimensions of 20.4 mm × 2.4 mm × 3.6 mm (Montreal Institute of Neurology (MNI) spatial x, y, z dimensions). The focal point can be moved to the target point via programmatic control without moving the treatment device or the patient. To ensure safety, the ultrasound intensity is always kept below the FDA 510(k) Class 3 diagnostic ultrasound guidelines (peak intensity below 190 W / cm²). 2 The time-averaged intensity is below 720 mW / cm. 2 The mechanical index is below 1.9.

[0384] Methods and Materials - Target and Target Engagement Measurement: Individual T1-weighted imaging guided ultrasound targeting. Target engagement was measured using blood oxygen level-dependent (BOLD) imaging. MRI acquisition details are provided in the Supplementary Methods section below. The ultrasound processing focus was centered on the midline, covering both left and right SCCs to match the previously described bilateral targets for invasive DBS. Individual targets are shown in... Figure 24 The target ultrasound delivery amplitude was 1 MPa (31.1 W / cm²). 2(After cranial correction), the pulse train duration was 30 ms, consisting of 5 ms on and 5 ms off pulses, with a pulse train interval of 1.4 seconds and a duration of 60 seconds. These stimulation parameters were expected to produce a net inhibitory effect. Neuromodulation was quantified using simultaneous (online) BOLD imaging, employing a 10-minute block design paradigm, alternating between five 1-minute resting periods (without ultrasound treatment) and five 1-minute effective ultrasound treatment periods. White noise was continuously played through earplugs during the 10-minute examination to mask any auditory effects that ultrasound might produce. Due to technical malfunctions during some BOLD imaging examinations, several cases required deviations from the protocol; even if the treatment allocation had been changed from true stimulation to sham stimulation, true stimulation was repeated during the functional MRI of the second stimulation session (see Supplementary Methods below). Of the 21 participants who received ultrasound treatment during MRI, 5 were unable to obtain usable BOLD data due to technical issues; therefore, the final dataset reported in this paper includes 16 subjects.

[0385] Methods and Materials - Randomization and Blinding: Participants were randomly assigned to either the true stimulus (effective) group or the sham stimulus (placebo) group at the first stimulation visit. The assignment sequence was generated using a random number generator with a block size of 6. A series of envelopes containing a slip of paper labeled "effective stimulus" or "sham stimulus" were prepared before the trial, and the contents of the series were unknown to anyone. The System 10 operator was required to know the assignments at the first stimulation visit. All other staff, participants, and clinical assessors remained blinded. The treatment assignments were disclosed to participants after an HDRS-6 assessment seven days after the second stimulation visit.

[0386] The effectiveness of blinding was assessed by asking a subgroup of 13 participants about their best guess at the intervention received using a 0-100 scale: 0 represented a spurious stimulus, 100 represented a true stimulus, and 50 represented no uncertainty. Assessments were collected at the end of the first stimulus visit.

[0387] Methods and Materials - True and Sham Stimulation Treatment Course: Following MRI imaging, stimulation was delivered outside the MRI scanner during a single 1-hour treatment session, comprising 39–41 minutes (cumulative) of true or sham stimulation ultrasound treatment. Three midline targets within the SCC region were stimulated sequentially to maximize changes in emotional symptoms. In addition to the original targets stimulated during concurrent functional MRI, two additional targets were established on the individual MRI, approximately 4 mm anterior and 4 mm posterior. These targets were then stimulated for equal durations in a randomized order during the 1-hour session. The ultrasound amplitude delivered to each target was 1 MPa (31.1 W / cm²). 2(After skull correction), the pulse train duration is 30ms, consisting of 5ms on and 5ms off pulses, with a pulse train interval of 1.4 seconds or 0.7 seconds. The entire treatment course consists of three stimulation blocks (A, B, and C). Block A contains 3-5 one-minute ultrasound treatments with a 1.4-second pulse train interval to test the tolerance of each target point. Block B contains 6 three-minute ultrasound treatments with a 1.4-second pulse train interval. Block C contains 6 three-minute ultrasound treatments with a 0.7-second pulse train interval.

[0388] To mask the occasional slight vibrations during ultrasound stimulation delivery, patients wore earplugs and received the same auditory stimulation during both effective and sham stimulation interventions. Audio recordings of white noise and array ultrasound pulses were combined, synchronizing the timing of the auditory stimulation with the ultrasound stimulation delivery.

[0389] Methods and Materials - Clinical Outcome Measures: Two common primary efficacy measures were pre-specified. Immediate changes in mood state were quantified using the grief subscale of the Extended Positive and Negative Affect Scale (PANAS-X), and changes in the severity of depressive symptoms over 24 hours and 7 days were measured using the HDRS-6 (see [link to relevant documentation]). Figure 23 PANAS-X is a reliable, validated 60-item self-report mood scale. It was administered at the beginning and end of each stimulus visit, using a "present" timeframe. The sadness subscale contains 5 items (sadness, melancholy, depression, loneliness, and isolation), each rated on a 5-point scale. The PANAS-X subscales were recalculated to a 0-100 range, and changes were calculated (post-stimulus minus pre-stimulus). HDRS-6 is a simplified version of the original 17-item scale, including core symptoms of depression (depressive mood, guilt, work and activity, retardation, psychotic anxiety, and generalized somatic symptoms). This scale is highly correlated with the longer HDRS, sensitive to changes, suitable for short timeframes, and measures rapid effects. HDRS-6 was administered by a blinded psychiatrist or senior psychiatric resident at the beginning of each stimulus visit (e.g., before the stimulus), using a 7-day timeframe, and repeated at 24 hours and 7 days post-visit, using 24-hour and 7-day timeframes respectively. Tolerability and safety were assessed at each visit using spontaneously reported adverse events, the General Adverse Events Assessment (GASE) scale, the YMRS, and the C-SSRS. Secondary outcomes are described in the supplementary material below.

[0390] Methods and Materials – Functional MRI Analysis: The functional MRI processing workflow is described in the Supplementary Methods section. The primary analysis of target engagement employed the region of interest (ROI) corresponding to the ultrasound-delivered SCC volume. The ROI was constructed by horizontally stitching together three spheres with a radius of 4 mm around the MNI coordinates [0, 20, -8], forming an ellipsoid with a radius of 4 mm (y and z dimensions) and a length of 12 mm (x dimension). Therefore, the ROI volume was confined to the gray matter range and approximately four times larger than the ultrasound processing focal point volume to accommodate individual differences in targeting and shifts in peak values ​​in the statistical parametric plots. Target engagement for each patient was evaluated using subject-level GLM family error small volume correction (FWE-SVC) analysis limited to the SCC ROI. Furthermore, pooled GLM β weights for each participant's ROI were extracted from the secondary group model and compared between effective and resting blocks (on > off t-test). One-sample t-tests were used to evaluate group-level target engagement for these extracted β weights. Whole-brain voxel analysis was used to evaluate neural responses in brain regions outside the SCC (off-target effects). Two whole-brain directional t-tests were used to compare the resting block and the ultrasound-treated block (off > on, on > off t-tests) to reveal the brain regions activated or inactivated during ultrasound treatment.

[0391] Methods and Materials - Clinical Outcome Analysis: PANAS-X sadness changes (before and after stimulation) were calculated for each patient at the first stimulation visit, and a two-sample t-test was used to evaluate differences between treatment groups (true stimulation vs. sham stimulation). Similarly, changes in HDRS-6 scores at 24 hours and 7 days after the first stimulation visit were calculated, and a two-sample t-test was used to test differences between groups at each time point.

[0392] The intention-to-treat sample included all 22 randomized participants. The protocol-compliant sample (n = 19) excluded 3 patients who did not receive stimulation according to the pre-specified protocol. One patient had received effective stimulation during MRI according to a different protocol before being randomized to the true stimulation group; one patient was randomized to the sham stimulation group but received effective stimulation during MRI; and one patient unexpectedly received several minutes of effective stimulation during the sham stimulation treatment session.

[0393] Results - Participant Characteristics: Twenty-nine adults with treatment-resistant depression were enrolled in this study, of whom 22 were randomized (see participation flowchart). Figure 25 Ten participants were assigned to the true stimulation group and 12 to the sham stimulation group during the first treatment session. The demographic and clinical characteristics of the true stimulation and sham stimulation groups were comparable (all p > 0.05, see Table 6). Twenty participants returned for a second stimulation visit, crossover to receive either the sham or true stimulation intervention.

[0394] Table 7 presents information related to the individual subject analysis of target binding. A generalized linear model of SPM12 with small volume correction (SVC) was used to analyze the target region for each participant. The target volume was the area within the inferior cingulate gyrus of the corpus callosum that received ultrasound treatment. In Table 7, asterisks indicate statistically significant modulation of the target at the individual level.

[0395]

[0396] Table 7

[0397] Results - Target Energization: Individual-level analysis showed that, based on a single 10-minute BOLD imaging session, statistically significant neural modulation was observed in the target SCC region in 8 out of 16 subjects (p < 0.05, FWE-SVC) (see Table 7). The expected reduction in BOLD signal (i.e., inactivation) was detected in 6 subjects. Examples of SCC inactivation are shown in... Figure 19A -B. No significant modulation was observed in eight participants, while significant SCC activation was observed in two subjects. At the group level, the mean effect of SCC modulation was inactivation: β-weighted data extracted from the target SCC region (see [link to relevant documentation]). Figure 19C The result was significantly less than zero in the cohort (t(15) = -2.43, p = 0.028, one-sample two-tailed t-test).

[0398] Results - Whole-brain effects: To evaluate the broad effects of SCC modulation on brain networks, whole-brain effects were assessed for each subject. Multiple activation and inactivation patterns were observed in distributed brain regions (see [link to study]). Figure 26 Whole-brain analysis at the group level revealed no consistent inactivation except for SCC (p > 0.05, corrected for false discovery rate). However, at the group level, activation (i.e., increased activity) was detected in the left ventrolateral prefrontal cortex and the right superior temporal gyrus (see Table 8).

[0399] The response of distributed brain regions may depend on the polarity of SCC regulation. Therefore, a subgroup of 12 subjects whose SCCs were inactivated after ultrasound treatment was also analyzed. Significant inactivation was found only in the SCCs (see [link to analysis]). Figure 20 Activation was detected in the left ventrolateral prefrontal cortex and bilateral temporal cortex (see Table 8), consistent with the findings of the entire cohort study.

[0400]

[0401] Table 8

[0402] Table 8 presents data related to the brain regions activated by ultrasound treatment of the subcallosal cingulate gyrus in Study S5. It shows the results of the SPM12 general linear model under on > off conditions.

[0403] Results - Mood and Depression Changes: The primary efficacy endpoint was the immediate PANAS-X change in sadness following stimulation, and the changes in HDRS-6 scores at 24 hours and 7 days after stimulation visits.

[0404] In the protocol-compliant sample (n = 19), the intergroup differences in grief and 24-hour HDRS-6 scores were statistically significant (grief: p = 0.027, t(16) = -2.43, d = -1.15; 24-hour HDRS-6: p = 0.031, t(17) = -2.35, d = -1.08; 7-day HDRS-6: p = 0.22, t(17) = -1.29, d = -0.59), as Figure 21 , 22A -C and 28 are shown. The response rates (improvement ≥ 50%) for sham stimuli and effective stimuli were 20% and 67% at 24 hours, and 30% and 67% at 7 days, respectively (see Figure 28). Figure 22A -C).

[0405] For the intention-to-treat sample (n = 22), the scores of the true stimulation group decreased more significantly than those of the sham stimulation group, but the difference between the groups did not reach the significance level of p < 0.05 (sadness: p = 0.064, t(19) = -1.96, Cohen's d = -0.87; 24-hour HDRS-6: p = 0.18, t(20) = -1.38, d = -0.59; or 7-day HDRS-6: p = 0.45, t(20) = -0.77, d = -0.33).

[0406] Results - Tolerability and Safety: During this crossover study, 21 participants received real stimuli and 21 received sham stimuli. No serious adverse events (SAEs) occurred during the study. No SAEs occurred during or immediately after the stimulation. No participants developed mania or hypomania.

[0407] During the 24-hour follow-up visits following each stimulus visit, self-reported adverse reactions were collected using a standardized questionnaire (see Table 9). The most frequently reported symptoms were depressive mood (62% for real stimulus; 67% for sham stimulus), headache (57% for real stimulus; 67% for sham stimulus), and anxiety (57% for real stimulus; 52% for sham stimulus). 29% of participants reported suicidal thoughts after real stimulus, compared to 24% after sham stimulus.

[0408] Two participants experienced severe adverse psychological events following a 24-hour follow-up visit, both occurring after the actual stimulus. The first participant developed acute depression with suicidal ideation three days after the stimulus and intentionally overdosed on medication, requiring no medical intervention. The other participant experienced a rapid worsening of depression and suicidal ideation within hours of the 24-hour follow-up visit. Both participants had a history of similar mood swings. Over the next two weeks, both participants' depression improved, and their suicidal ideation subsided.

[0409]

[0410] Table 9

[0411] Table 9 summarizes the stimulation safety data. Twenty-four hours after ultrasound stimulation via System 10, participants completed a standard clinical questionnaire to assess a range of potential adverse reactions. Data for effective stimulation (left) and sham stimulation (right) are shown separately.

[0412] Results – Blinding Effectiveness: At the end of the first stimulation visit, 13 participants were asked to guess the intervention they received on a scale of 0-100, with 50 representing complete uncertainty. The mean (SD) score was 48 (32) in the sham stimulation group and 64 (26) in the effective stimulation group. There were no significant differences between the scores and 50 in either group (p = 0.87 and p = 0.30, one-sample two-tailed t-test), nor were there any differences between the means in either group (p = 0.35, two-sample two-tailed t-test). This indicates that the blinding procedure used in this study was effective.

[0413] Discussion: Study S5 included a cohort of individuals with treatment-resistant depression using System 10. In this study, System 10 included a treatment device 100 containing a phased array device that delivers ultrasound to a designated deep brain target while simultaneously measuring and compensating for severe aberrations in the ultrasound transcranially. It was found that transcranial delivery of low-intensity focused ultrasound to the SCC using System 10 safely reduced SCC activity, resulting in immediate mood improvement and rapid relief of depressive symptoms. This proof-of-principle study demonstrates that this application of System 10 can be used not only for depression but also for a variety of other neuropsychiatric disorders.

[0414] As described in this article, ultrasound possesses a unique triple characteristic: non-invasiveness, deep penetration, and precise focusing. Compared to electromagnetic waves, sound waves have shorter wavelengths. Thanks to diffraction effects, shorter wavelengths allow for relatively precise focusing into deeper areas. Nevertheless, ultrasound technology has long been limited by significant obstacles: the skull and hair severely and unpredictably attenuate and distort ultrasound waves. The method employed in Study S5 directly measures and compensates for these obstacles within each individual, thereby delivering controlled, deterministic ultrasound intensity to designated targets in the patient's brain for safe and effective neuromodulation.

[0415] In study S5, target activity was reduced across the entire patient group after SCC ultrasound treatment, and statistically significant inactivation was observed in 6 subjects at the individual level (see [link to study S5]). Figure 19C In some embodiments, system 10 can be configured to achieve individualized target optimization, such as obtaining highly consistent effects among different subjects. A key advantage of system 10 over surgical methods is that it allows for easy focusing of ultrasound onto one or more different targets without moving the treatment device 100 or the patient. Furthermore, system 10 can be used to set multiple targets and irradiate them sequentially or nearly simultaneously. This flexibility, combined with the safety of repetitive stimulation, makes it well-suited for individualized optimization. This flexible approach can also be applied to other targets in surgical deep brain stimulation studies, such as the medial anterior tract and ventral striatum.

[0416] The transcranial ultrasound system 10, based on the concept of this invention, achieves SCC inactivation, which can immediately alleviate sadness and rapidly improve depressive symptoms in individuals with moderate to severe treatment-resistant depression. The difference between the effective stimulation and sham stimulation treatment groups was most significant in participants who adhered to the treatment protocol, and the greatest difference was observed in immediate and 24-hour assessments; a subset of participants observed a durable antidepressant effect lasting for one week or longer.

[0417] In summary, Study S5 employed a non-invasive, targeted approach using System 10 to modulate deep limbic circuits (SCCs) involved in treatment-resistant depression. Data indicate that System 10 can be used to deliver ultrasound to non-invasively modulate SCCs and rapidly improve mood and depressive symptoms. Due to its non-invasive nature, System 10 holds promise for benefiting a wide range of patients with depression.

[0418] The following is additional information related to the study of S5.

[0419] Supplementary Methods - Participants: Inclusion and exclusion criteria are shown in Table 5. Eligibility was confirmed through a complete psychiatric and medical history, as well as physical and neurological examinations. Participants underwent the Brief International Neuropsychiatric Interview (version 7.0), the Hamilton Depression Rating Scale-6 (HDRS-6), and the Young Mania Rating Scale (YMRS) administered by psychiatrists. Participants also completed the Symptom Checklist-SR (IDS-SR), the Generalized Anxiety Disorder-7 (GAD-7), the Columbia Suicide Severity Rating Scale (C-SSRS), and MRI safety screening.

[0420] Supplementary Methods - MRI Acquisition: MRI acquisition was performed using a Siemens VIDA 3-T system with a large flexible coil. For target guidance, T1-weighted structural images were acquired using magnetization preparation radiofrequency pulses and rapid gradient echo (MPRAGE) (ascending sequence, AP phase encoding, TR 2.4s, TE 2.26ms, FA 8 degrees, FOV 256mm, acquisition matrix 256, reconstruction matrix 256, in-plane resolution 1.0mm × 1.0mm, 192 slices, slice thickness 1.3mm, bandwidth 200Hz / pixel, echo interval 6.84ms). For measuring target adhesion, T2... - Weighted functional imaging was used to measure oxygen level dependent (BOLD) signals (interleaved series, PA phase encoding, TR 2.0s, TE 33ms, FA 80 degrees, FOV 207mm, acquisition matrix 86, reconstruction matrix 86, in-plane resolution 2.41mm × 2.41mm, 52 slices, slice thickness 2.4mm, bandwidth 2004Hz / pixel, echo interval 0.62ms, 300 volumes per 10 minutes). Two sets of inverse phase-encoded spin echo field maps were also acquired for distortion correction (interleaved series, AP and PA phase encoding, TR 9.5s, TE 66ms, FOV 207mm, acquisition matrix 86, reconstruction matrix 86, in-plane resolution 2.41mm × 2.41mm, 52 slices, slice thickness 2.4mm, bandwidth 1162Hz / pixel, echo interval 0.96, EPI factor 86).

[0421] Supplemental Methods - Functional MRI Processing: The functional MRI processing workflow uses the AFNI (24.0.04), ANIMA (3.0), ANTS (2.3.1), FreeSurfer (6.0.3), and SPM12 (r7219) software packages. The processing was performed in nine steps: reducing abnormal voxel signals in the BOLD sequence (AFNI despiking); echo-planar imaging BOLD image distortion correction using inverse phase-coded spin echo field maps (ANIMA); spatial realignment of the BOLD time series relative to the 10th volume (SPM12); layer-time correction of the BOLD time series (SPM12); removal of ultrasound equipment and brain extraction from high-resolution anatomical T1 images (FreeSurfer); co-registration of high-resolution T1 images with the mean of the realigned time series (SPM12); spatial normalization of the co-registered T1 images relative to the MNI (ANTS); normalization of the BOLD time series by normalizing the deformation field of the T1 images (ANTS); spatial smoothing of the BOLD time series using an 8-mm Gaussian kernel (SPM12). First-level individual analysis was performed using SPM12, employing a generalized linear model of the whole brain (GLM) and classical hemodynamic response functions. Individual block design analysis was performed using two directional t-tests, comparing five staggered stimulation periods and five resting periods in a 10-minute scan. Because the patient's head was fixed with an individualized fitted mask during the scan, motion parameters were not included in the first horizontal block design model to improve the model's sensitivity to ultrasound-induced activation changes.

[0422] Supplementary Methods - Target Engagement Measurements: Due to experimental malfunctions, only 16 out of 21 participants who received effective ultrasound treatment during functional MRI had valid functional imaging data obtained. Ten scans were from the second treatment visit, three from the first, and three from an optional third visit. These discrepancies stemmed from attempts to optimize the signal-to-noise ratio of the fMRI experiment at two different time points during the study. These unsuccessful experimental changes aimed to mitigate potential confounding factors from ultrasound equipment cables and currents near the MRI. Consequently, five participants were excluded from the MRI analysis due to changes in the MRI experimental design. Data from the 16 included participants were processed using the same experimental procedure.

[0423] Supplemental Results - Secondary Clinical Outcomes: Mood changes were measured using the PANAS-X method before and after each ultrasound treatment session. Each PANAS-X subscale was recalculated to the 0-100 range, and changes in each subscale were calculated. Figure 27 The changes in each subscale of the effective stimulation treatment group and the sham stimulation treatment group were shown during the first treatment visit.

[0424] Secondary efficacy outcomes were IDS-SR (including QIDS-SR) and GAD-7, measured immediately before each stimulation session and 7 days later. Changes in IDS-SR, QIDS-SR, and GAD-7 at 7 days were calculated, and two-sample t-tests were used to assess inter-group differences at each time point. In the intention-to-treat sample, no statistically significant differences were found between the effective stimulation group and the sham stimulation group in QIDS-SR (p = 0.84, t(20) = -0.20, d = -0.08) or GAD-7 (p = 0.52, t(20) = -0.66, d = 0.28). Similarly, the intergroup differences in the samples conforming to the protocol were not significant (QIDS-SR: p = 0.55, t(17) = -0.61, d = -0.28; GAD-7: p = 0.29, t(17) = 0.29, d = 0.14).

[0425]

[0426] Table 10

[0427] Table 10 shows the grief rating scale at various time points. The Extended Positive and Negative Affect Scale (PANAS-X) was assessed before and after the first stimulus visit (Day 0) and the second stimulus visit (Day 7). Figure 23 As shown. The values ​​represent the mean (SD) of the grief subscale.

[0428]

[0429] Table 11

[0430] Table 11 shows the depression rating scale at various time points. The six items of the Hamilton Depression Rating Scale (HDRS-6) were administered before the first stimulation visit (day 0), 24 hours after the first stimulation (day 1), before the second stimulation visit (day 7), 24 hours after the second stimulation (day 8), and 7 days after the second stimulation (day 14). Figure 23 As shown. The value represents the average (SD) of the overall HDRS-6 score.

[0431] Supplementary Results - Post-Crossover Outcomes: A randomized crossover design was chosen, ensuring that each participant received both real and sham stimuli, thereby maximizing the amount of efficacy, tolerability, and safety information collected from a limited pool of participants. PANAS-X grief scores and HDRS-6 scores at each time point before and after the crossover are shown in Tables 10 and 11.

[0432] System 10 and its components can be configured and used as described in Study S5 and other parts of this document, for example, to treat a patient as described in Study S5 and other parts of this document, to achieve the beneficial effects obtained by using System 10 for treatment as described in Study S5 and other parts of this document.

[0433] Patients selected for System 10 treatment may include those diagnosed with treatment-resistant depression. The initial DSM-5 diagnosis for patients selected for System 10 treatment may be major depressive disorder or bipolar disorder. Patients selected for System 10 treatment may currently have a moderate to major depressive episode lasting at least 1 month or at least 2 months without psychotic features. Patients selected for System 10 treatment may have a QIDS score of at least 6 or at least 10. Target locations (e.g., for ultrasound delivery and / or ultrasound combined with magnetic field energy delivery) may include locations in the subcingulate cortex (SCC) of the corpus callosum. Target locations may include at least two or at least three target locations within the SCC. At least two target locations may include a midline target location within the SCC. At least tw...

Claims

1. A system for delivering energy to a patient, the system comprising: A treatment device comprising one or more energy delivery elements, wherein the treatment device is configured to deliver energy to a target location of the patient via the one or more energy delivery elements. The energy delivered to the target site is used to treat the patient's medical condition.

2. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The target location includes the patient's brain.

3. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The treatment device is configured to deliver energy to the patient’s anatomical location, which is selected from the group consisting of: brain; heart; liver; pancreas; spleen; dorsal root ganglion; spinal cord; peripheral nerves; and combinations thereof.

4. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The treatment device is configured to deliver ultrasonic energy.

5. The system according to claim 4 and / or any one or more of the other claims herein, wherein, The treatment device is configured to further deliver magnetic field energy.

6. The system according to claim 5 and / or any one or more of the other claims herein, wherein, The magnetic field includes a magnetic field of at least 0.5 T.

7. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The treatment device is configured to deliver one, two, or more types of energy selected from the group consisting of: acoustic energy, such as ultrasonic energy; Light energy, such as laser energy; thermal energy, such as thermal energy and / or cryogenic energy; electromagnetic energy, such as radio frequency energy, microwave energy and / or electroporation energy; chemical energy; mechanical energy; and combinations thereof.

8. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The target location spans up to 10 mm, and the system is configured to deliver the energy precisely to the target location.

9. The system according to claim 8 and / or any one or more of the other claims herein, wherein, The target location spans up to 5 mm.

10. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The treatment device is configured to deliver the energy with a spatial resolution of no more than 1.0 mm and a temporal accuracy of no more than 5 μs.

11. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The one or more energy delivery elements include multiple energy delivery elements arranged in one or more spherical focusing arrays.

12. The system according to claim 11 and / or any one or more of the other claims herein, wherein, Each of the one or more spherical focusing arrays includes a radius of at least 10 mm, not exceeding 5,000 mm, or both.

13. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The treatment device includes a first treatment component and a second treatment component, the first treatment component being configured to deliver energy and positioned on the right side of the patient's head, and the second treatment component being configured to deliver energy and positioned on the left side of the patient's head.

14. The system according to claim 13 and / or any one or more other claims herein, further comprising a housing configured to position the first treatment component and the second treatment component such that the treatment components each deliver the energy through a temporal window of the patient's skull.

15. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The system is configured to deliver energy to multiple different target locations deep within the brain without moving the treatment device or the patient's head.

16. The system according to claim 15 and / or any one or more of the other claims herein, wherein, The system is configured to deliver energy to at least a first target location and a second target location in a sequential manner.

17. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The system includes a housing and a patient mask, which are configured together to reproducibly position the patient's head in a desired arrangement for energy delivery without the use of MRI guidance.

18. The system according to claim 1 and / or any one or more of the other claims herein, wherein, The system was configured to verify the targeting of energy delivery by using MRI blood oxygen-dependent imaging.

19. The system according to claim 18 and / or any one or more of the other claims herein, wherein, The image provides target location guidance information, dosing information, or both.

20. The system according to claim 1 and / or any one or more of the other claims herein, further comprising an algorithm configured to determine energy delivery drive signals that compensate for one or more obstacles present in the energy delivery path from the treatment device to the target location.

21. The system according to claim 20 and / or any one or more of the other claims herein, wherein, The one or more obstacles include obstacles selected from the group consisting of: the skull; the scalp; the hair; the components of the system; and combinations thereof.

22. The system according to claim 21 and / or any one or more of the other claims herein, wherein, The medical conditions treated include depression.

23. The system according to claim 21 and / or any one or more of the other claims herein, wherein, The medical conditions treated include pain, such as chronic pain.

24. The system according to claim 21 and / or any one or more of the other claims herein, wherein, The medical conditions treated include addiction, anxiety, and / or other psychological disorders.

25. The system according to claim 21 and / or any one or more of the other claims herein, wherein, The medical conditions treated include cognitive decline, such as mild cognitive decline.

26. The system according to claim 21 and / or any one or more of the other claims herein, wherein, The medical conditions treated include Alzheimer's disease.

27. A method for treating a patient suffering from a medical condition, the method comprising: Select patients for treatment; Select a system for delivering energy to the patient, the system including a therapeutic device for delivering the energy to a target location on the patient; as well as Energy is delivered to the patient's target location via the treatment device; The energy delivery was used to treat the patient's medical condition.

28. The method according to claim 27 and / or any one or more of the other claims herein, wherein, The system includes the system as described in any one or more of claims 1 to 26.

29. The method according to claim 27 and / or any one or more of the other claims herein, wherein, The delivered energy includes ultrasonic energy.

30. The method according to claim 27 and / or any one or more of the other claims herein, wherein, The delivered energy further includes magnetic field energy.

31. The method according to claim 27 and / or any one or more other claims herein, wherein, The medical conditions treated include pain.

32. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The selected patients had an average 24-hour visual analog scale pain score of at least 1.

33. The method according to claim 32 and / or any one or more other claims herein, wherein, The selected patients had an average 24-hour visual analog scale pain score of at least 3.

34. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The selected patients had experienced at least 3 months of moderate pain.

35. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The target location includes the anterior cingulate cortex.

36. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The target location includes at least two target locations within the anterior cingulate cortex.

37. The method according to claim 36 and / or any one or more other claims herein, wherein, The target locations include at least four target locations within the anterior cingulate cortex.

38. The method according to claim 37 and / or any one or more of the other claims herein, wherein, The at least four target locations include four locations selected from the group consisting of: the infrakal ACC (Brodman region 2565) and six target locations from within the pACC to the aMCC (Brodman region s24, p24, a24, 33).

39. The method according to claim 38 and / or any one or more of the other claims herein, wherein, The at least four target locations include eight target locations within the anterior cingulate cortex.

40. The method according to claim 36 and / or any one or more other claims herein, wherein, Each target location must be at least 2 mm away from the adjacent target location, and no more than 6 mm away, or both of these conditions must be met.

41. The method according to claim 40 and / or any one or more of the other claims herein, wherein, Each target point is approximately 4 mm apart from the adjacent target point.

42. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This energy delivery includes peak intensity not exceeding 300 W / cm². 2 Energy delivery.

43. The method according to claim 42 and / or any one or more other claims herein, wherein, This energy delivery includes a peak intensity not exceeding 225 W / cm². 2 and / or not exceeding 190 W / cm 2 Energy delivery.

44. The method according to claim 42 and / or any one or more other claims herein, wherein, This energy delivery includes energy deliveries of no more than 3 hours, no more than 2 hours, and / or no more than 1 hour.

45. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The energy delivery includes energy delivery that lasts for at least 30 minutes, no more than 120 minutes, or both.

46. ​​The method according to claim 45 and / or any one or more of the other claims herein, wherein, This energy delivery consists of an energy delivery that lasts for approximately 40 minutes.

47. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This energy delivery includes energy delivery with a field size of less than 5 mm × 5 mm × 40 mm.

48. The method according to claim 47 and / or any one or more of the other claims herein, wherein, The energy delivery includes energy delivery with a field size of approximately 2.4 mm × 3.6 mm × 20.4 mm.

49. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This energy delivery includes multiple test energy deliveries configured to test symptom relief.

50. The method according to claim 49 and / or any one or more of the other claims herein, wherein, Each test energy delivery consists of no more than 60 seconds of energy delivery.

51. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This energy delivery includes multiple energy deliveries configured to provide therapeutic benefits to the medical condition.

52. The method according to claim 51 and / or any one or more of the other claims herein, wherein, The multiple energy deliveries consist of at least four energy deliveries, each lasting at least one minute.

53. The method according to claim 52 and / or any one or more of the other claims herein, wherein, This multiple energy delivery consists of approximately 12 energy deliveries, each lasting three minutes.

54. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The energy delivery includes energy delivery with an amplitude of at least 0.5 MPa.

55. The method according to claim 54 and / or any one or more of the other claims herein, wherein, This energy delivery includes an energy delivery amplitude of approximately 1 MPa.

56. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The energy delivery includes energy delivery comprising a pulse train with a duration of at least 10 msec delivered at a duty cycle of less than 90%.

57. The method according to claim 56 and / or any one or more of the other claims herein, wherein, The interval between these pulse trains does not exceed 20 seconds.

58. The method according to claim 56 and / or any one or more of the other claims herein, wherein, This energy delivery includes a duration of approximately 30 msec; The duty cycle is 50%; and the energy delivery of pulse trains with a pulse train interval of 0.7 seconds.

59. The method according to claim 31 and / or any one or more of the other claims herein, wherein, The treatment achieves one or more of the following effects: immediate pain reduction of at least 30% after energy delivery; pain reduction of at least 21.5% one day after energy delivery; and / or pain reduction of at least 16.5% seven days after energy delivery.

60. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This treatment reduced the absolute VAS pain score by at least one point.

61. The method according to claim 60 and / or any one or more other claims herein, wherein, This treatment reduced the absolute VAS pain score by 2.7 ± 1.4 points.

62. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This treatment has at least a 50% expectation of achieving 33% pain relief immediately after the energy delivery.

63. The method according to claim 62 and / or any one or more other claims herein, wherein, This treatment has an expected 75% chance of achieving 33% pain relief immediately after the energy delivery.

64. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This treatment has an expected rate of at least 30% to achieve 33% pain relief within 24 hours after the energy delivery.

65. The method according to claim 64 and / or any one or more of the other claims herein, wherein, This treatment has an expected 60% chance of achieving 33% pain relief within 24 hours after the energy delivery.

66. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This treatment reduced the PROMIS pain intensity score by at least 10%.

67. The method according to claim 66 and / or any one or more of the other claims herein, wherein, The treatment resulted in a mean ± SD reduction of 5.68 ± 7.2 points in the PROMIS pain intensity score.

68. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This treatment reduced the PROMIS depression score by at least 10%.

69. The method according to claim 68 and / or any one or more of the other claims herein, wherein, This treatment reduced the PROMIS depression score by 2.27 ± 3.75 points.

70. The method according to claim 31 and / or any one or more of the other claims herein, wherein, This treatment reduced the PROMIS anxiety score by at least 10%.

71. The method according to claim 70 and / or any one or more other claims herein, wherein, This treatment reduced the PROMIS anxiety score by 2.87 ± 6.21 points.

72. The method according to claim 27 and / or any one or more of the other claims herein, wherein, The medical conditions treated include depression.

73. The method according to claim 72 and / or any one or more other claims herein, wherein, The selected patients suffered from treatment-resistant depression.

74. The method according to claim 72 and / or any one or more other claims herein, wherein, The selected patients were initially diagnosed with major depressive disorder or bipolar disorder according to the DSM-5 standard.

75. The method according to claim 72 and / or any one or more other claims herein, wherein, The selected patients currently have a moderate to severe depressive episode lasting at least one month and have no psychotic features.

76. The method according to claim 75 and / or any one or more of the other claims herein, wherein, The selected patients currently have a moderate to severe depressive episode lasting at least 2 months and have no psychotic features.

77. The method according to claim 72 and / or any one or more other claims herein, wherein, The selected patients had a QIDS score of at least 6.

78. The method according to claim 77 and / or any one or more other claims herein, wherein, The selected patients had a QIDS score of at least 10.

79. The method according to claim 72 and / or any one or more other claims herein, wherein, The target location includes the area of ​​the inferior cingulate cortex of the corpus callosum.

80. The method according to claim 72 and / or any one or more other claims herein, wherein, The target locations include at least two target locations within the inferior cingulate cortex of the corpus callosum.

81. The method according to claim 80 and / or any one or more other claims herein, wherein, The target locations include at least three target locations within the inferior cingulate cortex of the corpus callosum.

82. The method according to claim 80 and / or any one or more other claims herein, wherein, The at least two target locations include the midline target location of the inferior cingulate cortex of the corpus callosum.

83. The method according to claim 80 and / or any one or more other claims herein, wherein, Stimulate at least two target sites sequentially.

84. The method according to claim 80 and / or any one or more other claims herein, wherein, The at least two target locations include a first target location, a second target location, and a third target location, wherein the first target location is at least 2 mm and / or no more than 6 mm in front of the second target location, and wherein the third target location is at least 2 mm and / or no more than 6 mm behind the second target location.

85. The method according to claim 84 and / or any one or more other claims herein, wherein, The first target point is located approximately 4 mm in front of the second target point, and the third target point is located approximately 4 mm behind the second target point.

86. The method according to claim 72 and / or any one or more other claims herein, wherein, This energy delivery includes energy delivery with a peak intensity not exceeding 300 W / cm2.

87. The method according to claim 86 and / or any one or more other claims herein, wherein, This energy delivery includes a peak intensity not exceeding 225 W / cm². 2 and / or not exceeding 190 W / cm 2 Energy delivery.

88. The method according to claim 86 and / or any one or more other claims herein, wherein, This energy delivery includes energy deliveries of no more than 3 hours, no more than 2 hours, and / or no more than 1 hour.

89. The method according to claim 72 and / or any one or more other claims herein, wherein, The energy delivery includes energy delivery with an amplitude of at least 0.5 MPa.

90. The method according to claim 89 and / or any one or more other claims herein, wherein, This energy delivery includes an energy delivery amplitude of approximately 1 MPa.

91. The method according to claim 72 and / or any one or more other claims herein, wherein, This energy delivery includes energy delivery with a field size of less than 5 mm × 5 mm × 40 mm.

92. The method according to claim 91 and / or any one or more of the other claims herein, wherein, The energy delivery includes energy delivery with a field size of approximately 2.4 mm × 3.6 mm × 20.4 mm.

93. The method according to claim 72 and / or any one or more other claims herein, wherein, The energy delivery includes energy delivery comprising a pulse train with a duration of at least 10 msec delivered at a duty cycle of less than 90%.

94. The method according to claim 93 and / or any one or more of the other claims herein, wherein, The interval between these pulse trains does not exceed 20 seconds.

95. The method according to claim 93 and / or any one or more of the other claims herein, wherein, This energy delivery includes a duration of approximately 30 msec; The duty cycle is 50%; and the energy delivery of pulse trains with a pulse train interval of 0.7 seconds.

96. The method according to claim 93 and / or any one or more of the other claims herein, wherein, This energy delivery includes a duration of approximately 30 msec; The duty cycle is 50%; and the energy delivery of pulse trains with a pulse train interval of 1.4 seconds.

97. The method according to claim 72 and / or any one or more other claims herein, wherein, This energy delivery includes an energy delivery that lasts for at least 30 seconds.

98. The method according to claim 97 and / or any one or more of the other claims herein, wherein, This energy delivery consists of an energy delivery that lasts approximately 60 seconds.

99. The method according to claim 72 and / or any one or more other claims herein, wherein, The energy delivery consists of energy delivery in blocks, which include resting periods and effective ultrasound treatment periods.

100. The method according to claim 99 and / or any one or more other claims herein, wherein, These rest periods and effective periods are interleaved.

101. The method according to claim 100 and / or any one or more other claims herein, wherein, These valid periods and / or these resting periods include a duration of at least 30 seconds.

102. The method according to claim 101 and / or any one or more other claims herein, wherein, These effective periods and / or these resting periods include a duration of approximately 1 minute.

103. The method according to claim 101 and / or any one or more of the other claims herein, wherein, These effective periods and / or these resting periods include a duration of approximately 3 minutes.

104. The method according to claim 100 and / or any one or more other claims herein, wherein, Each block includes at least six total time periods.

105. The method according to claim 105 and / or any one or more other claims herein, wherein, Each block comprises approximately 10 total time periods.

106. The method according to claim 99 and / or any one or more of the other claims herein, wherein, Deliver at least two energy blocks.

107. The method according to claim 106 and / or any one or more other claims herein, wherein, Energy delivery parameters differ between different blocks.

108. The method according to claim 106 and / or any one or more other claims herein, wherein, The duration of energy delivery varies between different blocks.

109. The method according to claim 106 and / or any one or more of the other claims herein, wherein, Deliver at least three energy blocks.

110. The method according to claim 106 and / or any one or more other claims herein, wherein, Each block includes at least three test energy deliveries with a duration of at least one minute.

111. The method according to claim 110 and / or any one or more other claims herein, wherein, Each block typically consists of three to five one-minute ultrasound treatments performed at 1.5-second pulse intervals, for example, to test the tolerance of each target site.

112. The method according to claim 106 and / or any one or more other claims herein, wherein, Each block consists of at least six energy deliveries lasting at least two minutes.

113. The method according to claim 112 and / or any one or more other claims herein, wherein, Each block comprises approximately: six ultrasonic treatments of three minutes each, performed at 1.4-second pulse intervals, and / or six ultrasonic treatments of three minutes each, performed at 0.7-second pulse intervals.

114. The method according to claim 99 and / or any one or more of the other claims herein, wherein, This treatment resulted in at least a 50% change in the level of grief.

115. The method according to claim 114 and / or any one or more of the other claims herein, wherein, The treatment resulted in a change of approximately 63% in the level of grief.

116. The method according to claim 99 and / or any one or more of the other claims herein, wherein, The treatment achieved at least a 25% change in HRDS-6 on day 1 after the energy delivery.

117. The method according to claim 116 and / or any one or more other claims herein, wherein, The treatment achieved approximately 55% HRDS-6 change on day 1 after the energy delivery.

118. The method according to claim 99 and / or any one or more other claims herein, wherein, The treatment achieved at least a 20% change in HRDS-6 by day 7 after the energy delivery.

119. The method according to claim 118 and / or any one or more other claims herein, wherein, The treatment achieved approximately 52% HRDS-6 change by day 7 following the energy delivery.

120. The method according to claim 27 and / or any one or more other claims herein, wherein, The medical conditions treated include: addiction; anxiety; and / or other mental disorders.

121. The method according to claim 120 and / or any one or more other claims herein, wherein, The target location includes one, two or more locations selected from the group consisting of: the subcallosal cortex; the nucleus accumbens; the cingulate cortex; and combinations thereof.

122. The method according to claim 27 and / or any one or more other claims herein, wherein, The institute treats medical conditions including cognitive decline.

123. The method according to claim 122 and / or any one or more other claims herein, wherein, The institute treats medical conditions including mild cognitive decline.

124. The method according to claim 122 and / or any one or more other claims herein, wherein, The selected patients had a Montreal Cognitive Assessment score of no more than 25.

125. The method according to claim 122 and / or any one or more other claims herein, wherein, The target location includes one, two or more locations selected from the group consisting of: hippocampus; amygdala; entorhinal cortex; cingulate cortex; fornix and combinations thereof.

126. The method according to claim 27 and / or any one or more other claims herein, wherein, The medical conditions treated include Alzheimer's disease.

127. The method according to claim 126 and / or any one or more other claims herein, wherein, The selected patients had a Montreal Cognitive Assessment score of no more than 15.

128. The method according to claim 126 and / or any one or more other claims herein, wherein, The target location includes one, two or more locations selected from the group consisting of: hippocampus; amygdala; entorhinal cortex; cingulate cortex; fornix; and combinations thereof.

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