Neuromodulation Energy Application Technology

Abstract

Embodiments of this disclosure relate to techniques for the precise positioning of an energy application device for neuromodulation therapy protocols. In one embodiment, a neuromodulation positioning patch is applied to a patient's skin. The energy application device is configured to be coupled to a frame of the neuromodulation positioning patch to position the transducer of the energy application device within an opening at a treatment location. In one embodiment, the frame is further configured to be coupled to a removable docking part of an imaging probe, which, when coupled to the removable docking part and, consequently, the frame of the neuromodulation positioning patch, is configured to acquire image data through the opening to identify or verify the treatment location.

Description

Technical Field

[0001] The subject matter disclosed herein relates to techniques for supporting the application of neuromodulation energy dosages in subjects via application of neuromodulation energy to induce a target physiological outcome. Specifically, the disclosed techniques can be part of a repeated dosage regimen, a self-application regimen, and / or a home neuromodulation treatment regimen. Background Art

[0002] Neuromodulation has been used to treat a variety of clinical conditions. For example, electrical stimulation at different locations along the spinal cord has been used to treat chronic back pain. However, it is challenging to position electrodes at or near the target nerve. For example, such technology may involve surgical placement of electrodes that deliver energy. In addition, specific tissue targeting via neuromodulation is challenging. Electrodes positioned at or near certain target nerves mediate neuromodulation by triggering action potentials in nerve fibers, which in turn leads to neurotransmitter release at the synapses and synaptic communication with the underlying nerves. This propagation can lead to relatively larger or more diffuse physiological effects than expected because the current implementation of implanted electrodes stimulates many nerves or axons at the same time. Because neural pathways are complex and interconnected, more selective and targeted regulatory effects may be more useful clinically. However, the effectiveness of selectively targeting specific nerves may depend on the accurate positioning of the energy application device. Summary of the invention

[0003] The following summarizes certain embodiments commensurate with the scope of the claimed subject matter. These embodiments are not intended to limit the scope of the claimed subject matter, but these embodiments are only intended to provide a brief overview of possible embodiments. In fact, the present disclosure can encompass various forms that may be similar or different from the embodiments set forth below.

[0004] In one embodiment, a neuromodulation energy application system including a neuromodulation positioning patch is provided. The neuromodulation positioning patch includes a conformable substrate including an application surface configured to be applied to the subject's skin, the application surface including an adhesive portion, wherein the conformable substrate forms a first opening, and when the conformable substrate is applied, the first opening allows a portion of the subject's skin to be observed through the first opening. The neuromodulation positioning patch also includes a resilient frame, which is disposed on the conformable layer to surround the first opening and protrude from the top surface of the conformable layer, the top surface being opposite to the adhesive surface. The neuromodulation positioning patch also includes a dock configured to removably cooperate with the elastic frame, wherein the dock forms a shaped channel terminating in a second opening, wherein when the dock cooperates with the elastic frame, the second opening is located within the first opening. The neuromodulation energy application system also includes an ultrasonic treatment probe configured to be assembled within the frame or coupled to the frame to apply neuromodulation energy to an area of ​​interest of the internal tissue through a portion of the subject's skin.

[0005] In another embodiment, a method is provided, the method comprising the following steps: acquiring image data of a subject; identifying or verifying a region of interest based on the acquired image data; determining a treatment location on the subject's skin based on the region of interest; positioning a neuromodulation positioning patch on the subject's skin so that an opening formed in the neuromodulation positioning patch is positioned on or above the treatment location; connecting an ultrasonic treatment probe to the neuromodulation positioning patch to pass through the opening and position a treatment transducer of the ultrasonic treatment probe at the treatment location; and applying ultrasonic energy from the ultrasonic treatment probe to the treatment location area of ​​interest through the treatment location.

[0006] In another embodiment, a neuromodulation positioning patch is provided, which includes a conformable substrate, the conformable substrate including an opening extending through the conformable substrate; an adhesive disposed on an application surface of the conformable substrate; an elastic frame connected to the substrate around the periphery of the opening and protruding from the top surface of the conformable substrate, the elastic frame including one or more mating features; and at least one docking piece for an ultrasound imaging probe, the at least one docking piece being configured to removably engage with the elastic frame via one or more complementary mating features that engage with the one or more mating features, wherein the docking piece forms a shaped channel terminating in a second opening, wherein when the docking piece engages with the elastic frame, the second opening is located within the first opening. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] These and other features, aspects and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings, in which like characters refer to like parts throughout the drawings, and in which:

[0008] Figure 1 is a schematic diagram of a neuromodulation system using a pulse generator and a neuromodulation localization patch according to an embodiment of the present disclosure;

[0009] Figure 2 is a schematic diagram of a neuromodulation positioning patch and docking piece and an ultrasound imaging probe in an uncoupled configuration according to an embodiment of the present disclosure;

[0010] Figure 3 is a schematic diagram of a neuromodulation positioning patch and a docking piece according to an embodiment of the present disclosure;

[0011] Figure 4 is a schematic diagram of a neuromodulation localization patch and a docking piece coupled to a probe according to an embodiment of the present disclosure;

[0012] Figure 5 is a schematic diagram of a neuromodulation localization patch kit including different docking pieces for various configurations according to embodiments of the present disclosure;

[0013] Figure 6 is a schematic diagram of a neuromodulation localization patch coupled to an ultrasound imaging probe via a docking piece according to an embodiment of the present disclosure;

[0014] Figure 7 is a schematic diagram of an empty or unconnected neuromodulation localization patch worn by a subject;

[0015] Figure 8 is a schematic diagram of a neuromodulation localization patch and an ultrasound therapy probe configured to be coupled to a frame of the neuromodulation localization patch in an uncoupled configuration according to an embodiment of the present disclosure;

[0016] Fig. 9 is connected to Figure 8 A bottom view of a neuromodulation positioning patch of an ultrasound therapy probe;

[0017] Fig.10 is connected to Figure 8 A bottom view of a frame of a neuromodulation positioning patch of an ultrasound therapy probe;

[0018] Fig.11 is a component view of a neuromodulation localization patch and an ultrasound therapy probe configured to couple to a frame of the neuromodulation localization patch using a locking feature according to an embodiment of the present disclosure;

[0019] Fig.12 is a bottom view of a neuromodulation localization patch with an integrally combined ultrasound therapy and imaging probe according to an embodiment of the present disclosure;

[0020] Fig.13 is a flow chart of a neuromodulation technique using a neuromodulation localization patch according to an embodiment of the present disclosure; and

[0021] Fig.14 is a block diagram of a neuromodulation system according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0022] One or more specific embodiments will be described below. In order to provide a concise description of these embodiments, not all features of actual implementations are described in this specification. It should be understood that in the development of any such actual implementation, as in any engineering or design project, many implementation-specific decisions must be made to achieve the developer's specific goals, such as complying with system-related and business-related constraints, which may vary from implementation to implementation. In addition, it should be understood that such development efforts may be complex and time-consuming, but are still routine tasks for design, fabrication, and manufacturing for those of ordinary skill who benefit from this disclosure.

[0023] Any embodiment or explanation given herein should not be regarded as the constraint, restriction or expression definition of any term or multiple terms utilized by them in any way.On the contrary, these embodiments or explanations should be regarded as being described with respect to different specific embodiments and only as illustrative.It will be understood by those of ordinary skill in the art that any term or multiple terms using these embodiments or explanations will cover other embodiments that may or may not be provided with them or provided elsewhere in this specification, and all these embodiments are intended to be included in the scope of that term or multiple terms.The language specifying this non-limiting embodiment and explanation includes but is not limited to: "for example", "such as", "such as", "for example", "including", "in certain embodiments", "in some embodiments" and "in one (the) embodiment".

[0024] Provided herein is a technique for non-invasive neuromodulation of a target region of interest as part of a treatment regimen, which allows reproducible and reliable application of energy to a specific region or region of interest during a treatment regimen. Non-invasive neuromodulation can be applied via an energy application device (e.g., a treatment probe, an ultrasound treatment probe), which is positioned on the patient's skin and delivers neuromodulation energy through the skin and to the region of interest. For some patients, a treatment regimen may include applying energy (e.g., non-invasive ultrasound or mechanical energy application) to the patient's region of interest at intervals according to the patient's specific clinical needs and at a dose associated with a target physiological outcome. Depending on the length of the interval between energy applications (e.g., an interval of hours, days, or weeks), it may be inconvenient and cumbersome for a patient to receive neuromodulation energy in a doctor's office or hospital at each treatment time. Therefore, it would be beneficial to allow a patient to receive neuromodulation energy at home or in a convenient outpatient setting according to a treatment regimen via self-directed delivery or with the help of a family member or caregiver. However, because patients generally do not have skills or training in medical device operation, it may be challenging to train patients to manage their own neuromodulation treatment. In addition, the treatment regimen for each patient can be personalized and vary from patient to patient based on variations in anatomy, the patient's clinical condition, and the patient's responsiveness to energy to produce a target physiological outcome. For example, a treatment regimen for treating a specific condition can target a specific region of interest (e.g., a region of the liver, pancreas, or other tissue). The effective energy application site associated with the neuromodulation energy targeted to the region of interest may be at a site in one patient, and at a slightly different site in another patient due to differences in the patient's anatomical structure. These sites may also include areas on the patient's back or side that are difficult to reach while maintaining a treatment probe, and even if reached, it is difficult for the patient to target accurately with repeated doses. In addition, identifying the desired region of interest and the associated treatment location on the skin to achieve energy delivery to the region of interest may involve complex imaging devices that are not widely available and increase time for each dose of a multi-dose treatment regimen.

[0025] The neuromodulation technology disclosed herein facilitates identification of treatment locations on a patient's skin for an energy application device, and positioning a neuromodulation positioning patch at or around the treatment location. For example, if a patient is prescribed a multi-dose treatment regimen that occurs over a period of days or weeks, a neuromodulation positioning patch may be applied to the patient at the beginning of the treatment regimen, and may remain in place until the treatment regimen is completed to facilitate the correct positioning of the energy application device. The neuromodulation positioning patch includes a support structure that reversibly matches or cooperates with an energy application device (e.g., a treatment probe), and positions the energy application device at a treatment location for accurate targeting of an area of ​​interest via the application of neuromodulation energy. A treatment location is a location on a patient's body where, when an energy application device is positioned at a treatment location as provided herein, the energy applied at (and through) the treatment site affects a desired area of ​​interest in the patient's body to achieve a target physiological outcome. Such technology can guide patients and / or their caregivers to accurately administer their own treatment.

[0026] In one embodiment, the neuromodulation positioning patch can at least partially support and orient the treatment probe so that the patient or caregiver does not need to apply pressure, or in some embodiments, hold the treatment probe to maintain the treatment probe in the correct position. This can reduce the variability of dose application, which may be the result of different caregivers orienting and / or positioning the treatment probe at slightly different positions that are not aligned or partially aligned with the treatment position. In addition, different pressures of the probe on the skin at the treatment position may also lead to undesirable variability in the applied dose. Other benefits of the disclosed technology are that the neuromodulation positioning patch allows one-time identification of the area of ​​interest and the treatment position on the patient's skin. Once identified, the neuromodulation positioning patch is positioned in the appropriate position. In subsequent dose applications, there is no need to perform complex imaging associated with the identification of the area of ​​interest. Therefore, dose application is faster and can occur at home or in an outpatient environment without complex imaging devices, resulting in greater flexibility in receiving neuromodulation energy according to the treatment plan. The neuromodulation positioning patch can be multifunctional and configured to be connected to the treatment probe and the imaging probe via an adapter structure.

[0027] To this end, the disclosed neuromodulation techniques may be used with a neuromodulation system configured to deliver neuromodulation energy as part of a treatment regimen. Figure 1is a schematic diagram of a system 10 that uses a neuromodulation localization patch supporting an energy application device to achieve a neuromodulation effect, such as neurotransmitter release and / or activation of components of a synapse (e.g., presynaptic cells, postsynaptic cells) in response to energy application. The depicted system includes a pulse generator 14 coupled to an energy application device 12 (e.g., an ultrasonic treatment probe). The energy application device is coupled to a neuromodulation localization patch 16 that is in position on the subject's skin and holds or supports the energy application device 12 at a treatment location during the application of neuromodulation energy. The energy application device 12 is configured to receive energy pulses, for example via a lead or wireless connection, which are directed to an area of ​​interest 18 of an internal tissue or organ (e.g., peripheral tissue) of the subject during use, which in turn results in a target physiological outcome. In the depicted embodiment, the neuromodulation localization patch 16 is positioned in a difficult-to-reach location on the patient's back. However, it should be understood that the neuromodulation localization patch 16 may be applied to align with a suitable treatment site, depending on the clinical needs of the subject.

[0028] In some embodiments, the energy application device 12 and / or the pulse generator 14 can communicate wirelessly, such as with a controller 20, which in turn can provide instructions to the pulse generator 14. In other embodiments, the pulse generator 14 can be integrated within the controller 20. The energy application device 12 can be operated by a caregiver and positioned on or above the skin of the subject via a neuromodulation positioning patch 16 so that energy pulses are delivered transcutaneously to desired internal tissues (e.g., peripheral tissues including one or more peripheral axon terminals). Once positioned to apply energy pulses to a desired treatment location via connection to the neuromodulation positioning patch 16, the system 10 can initiate neuromodulation of one or more neural pathways to achieve a target physiological outcome or clinical effect.

[0029] In certain embodiments, the system 10 may include an evaluation device 22 that is coupled to the controller 20 and evaluates a feature that indicates whether a target physiological outcome of the modulation has been achieved. In one embodiment, the target physiological outcome may be local. For example, modulation of one or more neural pathways may result in local tissue or functional changes, such as changes in tissue structure, local changes in the concentration of certain molecules, tissue displacement, increased fluid movement, etc., as disclosed herein. The target physiological outcome may be a goal of a treatment regimen. For example, the target physiological outcome may include hormone secretion (such as secretion of insulin from the pancreas or ghrelin from the GI), cell viability, and / or cell or hormone stability.

[0030] The neuromodulation positioning patch 16 can be used in combination with the neuromodulation treatment scheme as provided herein. Neuromodulation of one or more neural pathways to achieve the target physiological result can cause systemic or non-local changes, and the target physiological result can be related to the change in the concentration of circulating molecules or the change in the characteristics of the tissue of the area of ​​interest that does not include direct application of energy. In one embodiment, the displacement can be a proxy measurement (proxy measurement, alternative measurement) for the desired adjustment, and the displacement measurement below the expected displacement value can cause the modification of the adjustment parameter until the expected displacement value is caused. Therefore, in some embodiments, the assessment device 22 can be configured to assess the concentration change. In some embodiments, the assessment device 22 can be an imaging device configured to assess the change in organ size position and / or tissue characteristics. In some embodiments, the assessment device 22 monitors the change in blood pressure, indicating the change in arterial resistivity associated with the treatment. In another embodiment, the assessment device 22 can be a circulating glucose monitor. Although the depicted elements of the system 10 are shown separately, it should be understood that some or all of the elements can be combined with each other. In another embodiment, the assessment device may assess the local temperature rise of the tissue, which may be detected using a separate temperature sensor or ultrasound imaging data from the energy application device 12 when configured for ultrasound energy application. The assessment of the differential velocity of sound may be detected by pre / during / post-treatment differential imaging techniques.

[0031] Based on this assessment, the modulation parameters of the controller 20 may be changed so that an effective amount of energy is applied. For example, if the desired modulation is associated with a concentration change (circulating concentration or tissue concentration of one or more molecules) within a defined time window (e.g., 5 minutes, 30 minutes after the start of the energy application procedure) or relative to a baseline at the start of the procedure, then a change in the modulation parameters (such as pulse frequency or other parameters) may be desired, which in turn may be provided to the controller 20 by the operator or via an automatic feedback loop for defining or adjusting the energy application parameters or modulation parameters of the pulse generator 14 until the modulation parameters result in the application of an effective amount of energy.

[0032] As provided herein, the system 10 can provide energy pulses to apply an effective amount of energy according to various adjustment parameters as part of the treatment regimen. For example, the adjustment parameters may include different stimulation time modes ranging from continuous to intermittent. Through intermittent stimulation, energy is delivered for a period of time at a specific frequency during the signal on time. After the signal on time is a time period without energy delivery, referred to as the signal off time. The adjustment parameters may also include the frequency and duration of stimulation application. The application frequency may be continuous or delivered in different time periods (e.g., within a day or a week). In addition, the treatment regimen may specify the time of applying energy in a day or relative to the time of eating or other activities. The treatment duration causing the target physiological result may last for different time periods, including but not limited to from a few minutes to a few hours. In some embodiments, the treatment duration with a specified stimulation mode may last for one hour, repeated at intervals of, for example, 72 hours. In some embodiments, energy may be delivered at a higher frequency, for example, every three hours, for a shorter duration, for example, 30 minutes. The energy application according to the adjustment parameters (such as treatment duration, frequency, and amplitude) may be adjustably controlled to achieve the desired result.

[0033] The energy application device 12 can be configured as an in vitro non-invasive device. The energy application device 12 can be an in vitro non-invasive ultrasound treatment probe including an ultrasonic transducer or a mechanical actuator. For example, the energy application device 12 can be configured as a handheld ultrasound probe. In addition, in addition to the handheld configuration, the energy application device 12 can include a steering mechanism that responds to instructions from the controller 20. The steering mechanism can direct or guide the energy application device 12 toward the region of interest 18, and then the controller 20 can focus the energy application on the region of interest 18.

[0034] In operation, the neuromodulation localization patch 16 can be configured to hold or support the energy application device 12 during dose delivery. In addition, the neuromodulation localization patch 16 is configured to hold or support an imaging probe to acquire images to identify or verify the desired treatment site. As provided herein, the imaging probe can be part of the system 10 and can also be operated using the same or similar components that control energy application via the energy application device 12. That is, the imaging probe can use the pulse generator 14 under the control of the controller 20. In one embodiment, the ultrasonic treatment transducer and / or imaging transducer disclosed herein includes a MEMS transducer, such as a capacitive micromachined ultrasonic transducer. In one embodiment, the treatment transducer and the imaging transducer can be integrated into a single energy application device 12. However, in other embodiments, the energy application device 12 and the imaging probe are separate devices.

[0035] Because the energy-applying device 12 and the imaging probe may have different configurations, the neuromodulation localization patch 16 includes features that make the neuromodulation localization patch 16 suitable for coupling to both types of devices. Figure 2 2 is a schematic diagram of a neuromodulation localization patch 16 applied to a subject and configured to receive an imaging probe 28. The neuromodulation localization patch 16 includes a conformable substrate 30 that forms a hole or opening 32 through the conformable substrate to allow observation of the patient's skin through the opening 32 when the neuromodulation localization patch 16 is applied (e.g., adhered) in place. The conformable substrate 30 can be formed of fabric, paper, or a conformable polymer. The opening 32 is surrounded by an elastic frame 34 protruding from a top surface 36 of the conformable substrate 30. The top surface 36 is opposite to the surface of the conformable substrate 32 applied to the patient's skin.

[0036] In some embodiments, the neuromodulation positioning patch 16 is worn for several days. Therefore, the conformable base 32 can be more comfortable for the subject than a rigid base. However, in some embodiments, portions of the conformable base 32 can be replaced or reinforced with rigid elements to help support larger or heavier connection probes.

[0037] In the operation of the imaging configuration, the elastic frame 34 is configured to be coupled to the removable docking member 40. The removable docking member 40 forms a passageway that terminates in the distal opening 42 that accommodates the imaging probe 28. The elastic frame 34 is coupled to the removable docking member 40 so that the distal opening 42 of the docking member 40 is positioned within the opening 32. In this way, when coupled to the docking member 40, the imaging transducer 46 of the imaging probe 28 is correctly positioned at the treatment site 50. In one embodiment, the docking member 40 is configured to directly contact the patient's skin at the distal opening when coupled to the elastic frame 34. The elastic frame 34, the docking member 40, and / or the imaging transducer 46 of the imaging probe 28 may include one or more mating features that facilitate their respective coupling. For example, the inner wall 52 of the elastic frame 34 may include one or more grooves or protrusions 54 that are configured to cooperate with the complementary features 56 on the outer wall 68 of the docking member 40. Similarly, the outer wall 58 of the housing 59 of the imaging probe may also include one or more mating features 60 that are configured to mate with complementary features 62 on the inner wall 64 of the dock 40. The resilient frame 34, dock 40, and / or imaging transducer 28 may be formed of a rigid or semi-rigid material, such as a polymer having a Shore D hardness of 10-50.

[0038] As disclosed herein, mating features (e.g., mating features 54, 56, 60, 62) may be configured as grooves, recesses, protrusions, locking features, threaded features, snaps, etc. In addition, certain components may be additionally or alternatively configured for interference fit. The mating features may also include one or more signal generators or indicators (e.g., RFID chips 57) that generate or provide signals to indicate successful mating when mated with their complementary features. The mating features may be configured to only allow the components to mate in one orientation relative to each other. For example, the elastic frame 34 and the docking piece 40 may mate with each other in only one direction. In addition, the docking piece 40 may also accommodate the imaging probe 28 in only one direction. Such an arrangement may facilitate the correct orientation of the imaging probe 28 within the neuromodulation positioning patch 16 and relative to the treatment site 50.

[0039] In the depicted configuration, the elastic frame 34 extends a distance 70 (e.g., less than 3 cm, less than 1 cm) from the top surface 36. The protrusion is in a direction away from the subject. In some embodiments, it is desirable that the elastic frame 34 has a relatively low profile so as to cause less discomfort to the subject over time. In addition, by configuring the docking piece 40, which may have a relatively large profile, to be removable, the neuromodulation positioning patch 16 can be only temporarily configured in a higher profile (greater protrusion from the skin) imaging configuration. In other embodiments, the elastic frame 34 can be configured to have a retractable or adjustable height wall 52 so that the elastic frame 34 can be switched between an undocked or empty configuration, which has a lower profile relative to the docked or operating configuration.

[0040] The initial positioning of the neuromodulation positioning patch 16 on the patient can be performed by an imaging technician or physician. The operator acquires images until an image including the region of interest 18 is acquired. The position of the imaging probe 28 on the skin when acquiring the image of the region of interest 18 can correspond to the treatment position 50. In one embodiment, an indicator 74 (such as a marker, a temporary tattoo or a sticker) can be applied to the skin of the treatment position 50 to guide the correct positioning of the opening 32 to align with the treatment position 50, that is, to be positioned on or above the treatment position 50. In addition, the indicator 74 can be shaped to align with the opening 32 to assist in the correct positioning of the neuromodulation positioning patch 16. In one embodiment, the neuromodulation positioning patch 16 can be configured to apply and / or refresh the indicator 74. For example, the conformable substrate 30, the elastic frame 34 and / or the removable docking piece 40 may include ink or other transferable materials that are configured to mark the subject when the neuromodulation positioning patch 16 is applied. Because the neuromodulation positioning patch 16 can be moved along the subject to try several positions before finally adhering to the appropriate position, the transferable material can be actuated or triggered via a user action. For example, the transferable material can be pressure-sensitive and can be applied when sufficient pressure is applied. In another embodiment, the successful cooperation of the removable docking piece 40 and the elastic frame 34 opens a reservoir containing transferable materials in the removable docking piece 40 and the elastic frame 34 and open to the patient contact side of the neuromodulation positioning patch 16. In another embodiment, the user presses a button or actuator to release the transferable material. In this way, the desired position of the neuromodulation positioning patch 16 can be marked so that when the previous device is due for replacement, a new neuromodulation positioning patch 16 can be applied to the subject.

[0041] After identifying the desired treatment site 50, an indicator 74 is applied to mark the preferred position of the neuromodulation positioning patch 16. This identification may constitute a first pass positioning that allows the subject or operator to adhere the neuromodulation positioning patch 16 to the correct position based on the imaging data. However, additional imaging data may be required to verify the treatment position 50 and / or obtain information for fine manipulation of the treatment probe. That is, the imaging probe 28 supported by the neuromodulation positioning patch 16 at the treatment site 50 may additionally or alternatively acquire imaging data to verify the treatment site 50 and / or provide it to the treatment probe for the controller 20 to manipulate the ultrasonic treatment beam. It should be understood that the treatment position 50 as provided herein may include the angle, orientation and / or posture of the energy application device 12. Position information may also include an assessment of contact or pressure on the subject.

[0042] In certain embodiments, the ultrasound imaging probe 28 can be any suitable probe capable of acquiring image data of internal tissues near and around the target tissue including the region of interest 18. If the first pass of image acquisition for initial positioning of the neuromodulation positioning patch 16 is successful, a lower complexity ultrasound imaging probe 28 can be used to acquire additional verification or beam steering image data. For example, images from a high resolution first pass can be accessed and used to supplement additional lower quality image data. Thus, a caregiver can have flexibility in image resolution capabilities when selecting an available ultrasound image probe 28 to acquire additional image data. Thus, a more commonly available lower complexity ultrasound image probe 28 may be appropriate.

[0043] Figure 3 The neuromodulation localization patch 16 is shown with a mating removable docking piece 40 that is ready to receive a probe, such as an imaging probe 28, as shown in FIG. Figure 4 The probe is inserted through the proximal opening 80 of the removable docking member 28. Figure 4 The embodiment depicted in the figure shows a mating imaging probe 28, but it should be understood that in embodiments, the removable docking piece 40 can also be configured to receive a therapeutic probe. In addition, in embodiments where the imaging probe 28 and the therapeutic probe are implemented as an integral device, the removable docking piece 40 or a different removable docking piece 40 can receive the integral device.

[0044] The removable docking piece 40 provides elastic support to the matching probe (e.g., imaging probe 28) to maintain the desired direction of the probe relative to the subject. The inner wall 64 directly contacts and supports the probe housing 59 to maintain the orientation along the desired axis, such as the axis 82 passing through the housing 59, and is aligned with the direction of the applied energy 84. The probe can be maintained to avoid tilting (e.g., along arrow 86) so that the energy applied during the activation of the probe is generally along the stable axis. In addition, the matching feature 62 of the docking piece can also be used to facilitate the positioning of the probe. The outer wall 68 of the docking piece 40 is defined by a height 81, which increases the profile of the neuromodulation positioning patch 16 beyond the distance 70 that the frame 34 extends from the conformable base. In one embodiment, the docking piece 40 has a distal recess or groove that cooperates with the elastic frame 34. In such an embodiment, the matching docking piece 40 overlaps the elastic frame 34. The distance 81 is greater than the distance 70 that the frame 34 extends from the conformable base 30. In one embodiment, the height 81 of the dock 40 is at least 2, 2.5, or 3 times the distance 70. As discussed herein, the increase in the profile of the neuromodulation locating patch 16 with the mating dock 40 is temporary.

[0045] The positioning and adhesion of the patch 16 on the patient sets the xy position and the rotation of the probe (e.g., the energy application device 12 and / or the imaging probe 28). In another embodiment, the docking piece 40 or the frame 34 can allow fine adjustment of the tilt, shake and / or compression (pressure on the skin) of the probe. For example, the docking piece 40 or the frame 34 can include a compressible foam or putty disposed on the inner wall 64, which allows the probe to be turned (e.g., along arrow 86) until the desired direction is achieved. The desired direction can be associated with improved image data obtained and / or improved contact with the subject's skin or pressure applied to the subject's skin. The putty or foam keeps the probe in the desired direction. In other embodiments, the docking piece 40 or the frame 34 can include other features that allow the probe direction to be adjusted, such as compressible or memory metal walls. In another embodiment, the direction can be adjusted by locking an adjustable mechanical linkage on each adjustable dimension-specifically, tilt, shake and compression. For compression, the Z position (for example, along axis 82) of probe is set and can be adjusted so that when probe is locked in docking piece, the probe face can push past the framework 34 of wearable patch 16 into the skin to ensure good contact or realize specific target contact force. The positioning of probe relative to framework 34 can allow several different position grooves along axis 82. In one embodiment, framework 34 and / or docking piece 40 can include two or more internal matching features 54,56, such as groove, at different positions along Z axis. Groove can be configured to be at least partially conformable (formed with flexible edge) so that the user can push through continuous matching features 54,56 with appropriate force until the desired position of probe along axis 82 is realized. In another embodiment, probe, framework 34 and / or docking piece 40 can include deployable locking features. For example, probe can be adjusted in docking piece 40 or framework 34 (in the embodiment without docking piece 40), until the desired position is reached. The user may then press a button on the dock 40 or frame 34 which causes actuation of a locking feature of the probe toward contact with the probe housing or a mating feature on the probe to lock the probe in place.

[0046] Figure 5Schematic diagram of a neuromodulation positioning patch kit, which includes different docking pieces 40 that cooperate with ultrasound imaging probes 28 of different shapes to facilitate the use of multiple types and / or configurations. In one embodiment, the neuromodulation positioning patch 16 can be provided as a kit with different types of docking pieces 40, which can be selected based on the available imaging mode. The caregiver may wish to use an available or familiar imaging device to obtain image data that allows the initial positioning of the neuromodulation positioning patch 16 and / or the verification of the position after positioning. By providing an interchangeable docking piece 40 including a channel 87 of different shapes, a variety of available imaging probes can be used. In the depicted embodiment, different docking pieces 40a, 40b, 40c, 40d can be shaped so that their outer walls 68 are substantially the same to allow each of the different docking pieces 40a, 40b, 40c to cooperate with the elastic frame 34. In one embodiment, the unmatched portion of the outer wall 68 can vary between different docking pieces 40 in size and shape. Additionally, each of the different docking components 40a, 40b, 40c, 40d may include the same mating features on their outer walls 68. In an alternative embodiment, each of the different docking components 40a, 40b, 40c, 40d may include a unique mating feature 56 that, when mated with the resilient frame, triggers activation of an identification signal for the particular type of docking component 40, which in turn may be provided by the ultrasound imaging probe 28 to its controller (e.g., controller 20) as an authentication procedure.

[0047] The internal shaping channels 87a, 87b, 87c, 87d are configured so that only certain or specific types of ultrasound imaging probes 28 will be assembled in each individual docking piece 40, and in one embodiment, will only be assembled in a specific direction. The internal shaping channel 87 may include grooves, notches or other shaping features associated with a specific type of ultrasound imaging probe 28. In one embodiment, the kit may also include a universal docking piece 40 having a larger or generally annular channel 87 that allows insertion of multiple types of ultrasound imaging probes 28. The shaped channel terminates in a corresponding distal opening 42 that positions the transducer 46 at a desired treatment (or imaging) position. The individual docking pieces 40 may also be sized and shaped to allow the operator to try different probe angles or directions. For example, some internal channels 87 may be oriented at different angles relative to each other (e.g., internal channel 87a and internal channel 87d) so that the retained probes are kept at different angles accordingly. In addition, the kit may include one or more adjustable docking pieces 40 that allow the probe to move within the internal channel 87 until the desired position is reached. For example, a docking piece 40 having an oversized or universally sized internal passage 87 may be equipped with a gasket, foam, gel, locking mechanical connection, or other temporary stabilizing material that may be inserted into the internal passage 87 to fill any gaps between the inner wall 64 and the housing 59 of the probe and to maintain the probe in a desired orientation.

[0048] The kit may also include a plurality of neuromodulation locating patches 16, for example, with different sizes and shapes for application to different treatment sites. In addition, it should be understood that some components of the kit may be disposable (neuromodulation locating patches 16), while other components may be reusable (docking piece 40).

[0049] Figure 6 is a schematic diagram of a neuromodulation positioning patch 16 connected to an ultrasound imaging probe 28 via a docking piece 40 in a connection or imaging configuration. In the connection configuration, the imaging transducer 46 of the ultrasound imaging probe 28 is aligned with a treatment location 50 on the patient's skin, and imaging energy can be applied. As shown, when in conjunction with the elastic frame 34, the docking piece 40 can also provide support to the ultrasound imaging probe 28 to maintain the ultrasound imaging probe 28 at a desired pressure and in a desired position and orientation relative to the treatment site 50 during the acquisition of image data. After the acquisition of image data is completed, the docking piece 40 and the ultrasound imaging probe 28 can be removed from the neuromodulation positioning patch 16, so that the subject can continue to wear only the less complex and less expensive components of the system 10, which can be easily replaced if damaged.

[0050] Figure 7Schematic diagram of an empty or unconnected neuromodulation positioning patch 16 worn by a subject. In an unconnected configuration, the neuromodulation positioning patch 16 may include only a conformable substrate 30 and an elastic frame 34. As discussed herein, the conformable substrate 30 may be enhanced by one or more rigid or semi-rigid layers or structures to maintain the integrity of the position of the neuromodulation positioning patch 16 on the subject's skin and support any matching structure. For comfort, the elastic frame 34 may be a relatively low profile, and may be round or may include a cushioning layer or buffer to prevent discomfort when pressed. As described above, in an unconnected configuration, the neuromodulation positioning patch 16 is ready to receive an ultrasound imaging probe 28 or an energy application device, depending on the next step in the treatment regimen. It should be understood that the patch 16 can be used in conjunction with various treatment regimens, such as those that occur in days, weeks, months or even years. The patch 16 can be configured to be replaced as needed, and the new patch 16 can be applied to the subject according to the technology provided herein. In addition, additional image acquisition during the treatment process can be used to check the initial placement of the patch 16. Still further, additional images may be acquired so that patch placement may be responsive to changes in the subject's physiology over time. For example, ultrasound treatment for metabolic disorders according to the techniques herein may result in weight loss, which may affect proper patch positioning by changing the depth of the region of interest relative to the skin.

[0051] Although the conformable substrate 30 is depicted as having a generally annular configuration, it should be understood that other shapes are contemplated, including elongated shapes, rectangular shapes, irregular shapes, etc. For example, a particular treatment site 50 may be associated with a particular shape of the conformable substrate 30 to achieve a desired adhesion. In addition, the opening 32 and the elastic frame 34 are depicted as being generally rectangular. However, depending on the size of the treatment site 50 and the size and shape of the energy application device 12 and the ultrasound imaging probe 28, the opening 32 and the elastic frame 34 may be configured as an annular shape, an elongated shape, a rectangular shape, an irregular shape, etc.

[0052] In addition, the perimeter of the opening 32 can be completely defined by the elastic frame 34, or can be largely defined (e.g., at least 75% defined). In one embodiment, the conformable substrate 30 and the elastic frame 34 can form a U-shape that allows a sliding action to couple the energy application device 12 and / or the ultrasound imaging probe 28 to the neuromodulation positioning patch 16.

[0053] Figure 8 is a schematic diagram of a neuromodulation localization patch and an energy application device 12 configured as an ultrasound therapy probe configured to be coupled to a flexible frame 34 of the neuromodulation localization patch 16 in an uncoupled configuration. Fig. 9 is connected to Figure 8A bottom view of the neuromodulation positioning patch 16 with the energy application device 12 (ie, in the coupled configuration). Fig.10 34 is a bottom view of the positioning of the transducer 95 of the energy application device 12 within the flexible frame 34, wherein the energy application device 12 is matched to fill the opening 32 formed by the frame 34. The connection can be via a mating feature 54 of the flexible frame 34, which is also connected to the docking member 40, so that the mating feature 54 receives and is connected to the docking member 40, and is configured to be connected to a complementary mating feature 90 formed in or disposed on the housing 91 of the energy application device 12. The connection can also be via a separate dedicated mating feature, which is distinguishable from the docking mating feature of the flexible frame 34 (for example, in a different position, different size or shape) and is configured to be connected to the complementary mating feature 90. One or both of the mating features of the energy application device 12 and the flexible frame 34 may include a signal element (such as a connector 92 and a connector 94) that is activated by the connection and sends a signal indicating a successful connection. For example, the connectors 92, 94 can be in direct contact when connected to complete the circuit, and the circuit is activated to send a signal when completed. When coupled, the energy application device 12 may be at least partially supported by the resilient frame 34 and the conformable base 30 to remain in place within the opening 32 during energy application and to position the therapy transducer 95 so that a bottom surface 96 of the therapy transducer 95 contacts the patient's skin.

[0054] The application layer 97 of the neuromodulation positioning patch 16 includes an adhesive 99 that can at least partially cover the application layer 97 and is used to adhere the neuromodulation positioning patch 16 to the patient's skin. In one embodiment, the adhesive is disposed on at least 50% of the surface area of ​​the application layer 97. In one embodiment, the application layer 97 includes a coupling gel area 98 that includes an ultrasound gel disposed on the application layer. When the neuromodulation positioning patch 16 is applied, the ultrasound gel can be pushed into the opening 32. Therefore, in some embodiments, the energy application device 12 and / or the imaging probe 28 can directly contact the patient's skin. It should be understood that, as provided herein, direct contact can include connecting the skin to the probe head via a thin layer of ultrasound gel. The neuromodulation positioning patch 16 may also include a release layer (not shown) that covers the application layer 97 during storage to maintain the adhesive 99 and the coupling gel 98. When a release layer is present, the release layer is removed before applying the neuromodulation positioning patch 16.

[0055] Fig.11is an exploded view of an embodiment of a neuromodulation locating patch 16 configured to reversibly couple to an energy application device 12 including an ultrasonic therapy transducer 95. The housing 91 of the energy application device 12 holds both the ultrasonic therapy transducer 95 and a tension spring 100, wherein the tension spring 100 is positioned between a top surface 102 of the ultrasonic therapy transducer 95 and an inner surface 103 of the housing 91. In this manner, when the energy application device is coupled to the frame 34 of the neuromodulation locating patch 16, the bottom surface 96 of the therapy transducer 95 can be held against the patient's skin with tension (e.g., light pressure).

[0056] The connection may be between a mating feature 90 (such as a protrusion) of the housing 91 of the energy application device 12 and a complementary feature 54 (such as a shaped channel 104) of the frame 34, the mating feature 90 being configured to lock with the complementary feature 54 of the frame 34. In the depicted embodiment, the connection may be a twist-lock arrangement so that the energy application device 12 is placed within the opening 32 of the frame 34 and the protrusion is positioned within a locking area 105 extending away from the channel opening of the shaped channel 104. However, other connection arrangements (e.g., threaded connection, snap fit, etc.) are also contemplated. The frame 34 may also include an opening configured to accommodate a cable 108 of the ultrasonic therapy transducer 95. In this way, when the cable 108 is placed within the opening 106 and the complementary mating features 54, 90 are connected, the ultrasonic therapy transducer 95 can be properly aligned with the frame 34.

[0057] Fig.12 4 is a bottom view of a neuromodulation localization patch 16 showing an applied layer 97 and having an integrally combined ultrasound therapy transducer 95 and imaging transducer 46 according to an embodiment of the present disclosure. Although certain embodiments of the present disclosure are discussed in the context of removable or exchangeable components of the neuromodulation localization patch 16, the neuromodulation localization patch 16 may also be implemented as a multifunctional, one-piece device. The imaging transducer 46 may be used for spatial selection of a region of interest 18 within the target tissue and verification of the location of the therapy transducer 95 applying neuromodulation energy.

[0058] Fig.131 is a flowchart of a neuromodulation method 110 using a neuromodulation positioning patch 16 according to an embodiment of the present disclosure. The method 100 may include a step of acquiring image data for identifying a treatment site 50. In one embodiment, the image data is acquired in conjunction with the neuromodulation positioning patch 16. However, in other embodiments, the image data is previously acquired or acquired during a separate procedure. For example, the method 100 may include a step (box 112) of applying the neuromodulation positioning patch 16 to the patient's skin at the treatment location 50. As provided herein, the applying step may include a pre-positioning step, wherein the neuromodulation positioning patch 16 is in a temporary or non-adherent position. Although the neuromodulation positioning patch 16 may be configured to be applied directly to the skin, it is also contemplated that in certain embodiments, there may be an intermediate structure (e.g., a thin fabric layer) between the neuromodulation positioning patch 16 and the skin. As discussed herein, the initial positioning and application of the skin may be based on previously acquired image data. In another embodiment, the neuromodulation positioning patch 16 may be temporarily positioned on the skin (i.e., not adhered in place) until the correct treatment location 50 is identified via the acquired image data. After identification, the neuromodulation positioning patch 16 can then be bonded in place. During identification of the treatment location and / or during the acquisition of other image data that occurs throughout the treatment process, the docking piece 40 can be coupled to or cooperate with the elastic frame 34 (frame 114), and the ultrasound imaging probe 28 can be inserted into the docking piece (frame 116) to acquire image data at the treatment location or at a potential treatment location (frame 118), thereby evaluating the acquired image data to determine whether the potential treatment location is the treatment location 50. In one embodiment, the neuromodulation positioning patch 16 is in a non-adherent configuration, and the imaging probe 28 is docked in the neuromodulation positioning patch 16 and activated to acquire image data. The neuromodulation positioning patch 16 is adjusted to change the position on the subject's skin, thereby moving the docked imaging probe 28 until the treatment site 50 is confirmed. Once the neuromodulation positioning patch 16 is in place, the release liner covering the adhesive 99 can be removed to secure the neuromodulation positioning patch 16 in place.

[0059] In another embodiment, the imaging probe 28 may be used without the neuromodulation localization patch 16 for a first period of time to facilitate coarse position adjustment. Once the imaging probe is proximate the treatment site 50 , the imaging probe 28 may be coupled to the removable dock 48 and the neuromodulation localization patch 16 .

[0060] Subsequently, the imaging probe 28 and the docking member 40 are removed from the flexible frame 34 (block 120), for example, by disconnecting complementary mating features or applying force to overcome an interference fit. The empty flexible frame 34 is then mated to the energy application device 12 (e.g., an ultrasound therapy probe) to position the therapy transducer at the therapy location 50 (block 122). Once mated, ultrasound therapy energy (neuromodulation energy) is applied (block 124).

[0061] Fig.14 is a block diagram of certain components of the system 10. As provided herein, the system 10 for neuromodulation may include a pulse generator 14 suitable for generating multiple energy pulses for application to tissue of a subject. The pulse generator 14 may be separate or may be integrated into an external device (such as a controller 20). The controller 20 includes a processor 130 for controlling the device. Software code or instructions are stored in a memory 132 of the controller 20 for execution by the processor 130 to control multiple components of the device. The controller 20 and / or the pulse generator 14 may be connected to the energy application device 12 via one or more leads 133 or wirelessly. As disclosed herein, the control of the energy application device 12 may further use input from one or more mating features 92 to detect successful mating of the energy application device 12 and the neuromodulation positioning patch 16.

[0062] The controller 20 also includes a user interface having an input / output circuit 134 and a display 136, which is adapted to allow a clinician to provide a selection input or adjustment parameter to the adjustment program. Each adjustment program may include one or more groups of adjustment parameters, including pulse amplitude, pulse width, pulse frequency, etc. The pulse generator 14 modifies its internal parameters in response to a control signal from the controller device 20 to change the stimulation characteristics of the energy pulses emitted to the subject applied by the energy application device 12 through the lead 133. Any suitable type of pulse generating circuit can be used, including but not limited to constant current, constant voltage, multiple independent current or voltage sources, etc. The energy applied depends on the current amplitude and pulse width duration. The controller 20 allows the energy to be adjusted by changing the adjustment parameters and / or starting the energy application at a specific time or canceling / suppressing the energy application at a specific time. In one embodiment, the adjustable control of the energy application device applying an effective amount of energy is based on information about the concentration of one or more molecules (e.g., circulating molecules) in the subject. If the information comes from the evaluation device 22, the feedback loop can drive the adjustable control. For example, a diagnosis can be made in response to neuromodulation based on the circulating glucose concentration measured by the evaluation device 22. When the concentration is above a predetermined threshold or range, the controller 20 can initiate a treatment regimen of energy application to the region of interest (e.g., liver) and having regulation parameters associated with a reduction in circulating glucose. The treatment regimen can use different regulation parameters (e.g., higher energy levels, more frequent applications) than those used in the diagnostic regimen.

[0063] In one embodiment, the memory 132 stores different operating modes that can be selected by the operator. For example, the stored operating modes may include instructions for executing a set of adjustment parameters associated with a specific treatment site (such as an area of ​​interest in the liver, pancreas, gastrointestinal tract, spleen). Different sites may have different associated adjustment parameters. The controller 20 may be configured to execute appropriate instructions based on selection, rather than having the operator manually enter the mode. In another embodiment, the memory 132 stores operating modes for different types of processes. For example, activation can be associated with different stimulation pressures or frequency ranges relative to stimulation pressures or frequency ranges associated with inhibiting or blocking tissue function.

[0064] In one specific embodiment, when the energy application device 12 is an ultrasonic transducer, the effective amount of energy may involve a predetermined time-averaged intensity applied to the region of interest. For example, the effective amount of energy may include a time-averaged power (time-averaged intensity) and a peak positive pressure in the range of 1mW / cm2–30,000mW / cm2 (time-averaged intensity) and 0.1MPa to 7MPa (peak pressure). In one embodiment, the time-averaged intensity is less than 35W / cm2 in the region of interest to avoid levels associated with thermal damage & ablation / cavitation. In another specific embodiment, when the energy application device is a mechanical actuator, the vibration amplitude is in the range of 0.1 to 10mm. The selected frequency may depend on the mode of energy application, such as ultrasound or mechanical actuator. The controller 20 may be able to operate in a verification mode to obtain a treatment position, and the treatment position may be implemented as part of a treatment operation mode that is configured to execute a treatment regimen when the energy application device 12 is positioned at the treatment position.

[0065] The system may also include an imaging device (e.g., an ultrasound imaging probe 28) that assists in focusing the energy application device 12. In one embodiment, the imaging device may be integrated with the energy application device 12 or be the same device as the energy application device 12 so that different ultrasound parameters (frequency, aperture, or energy) are applied for selecting (e.g., spatially selecting) a region of interest and for focusing energy to the selected region of interest for targeting and subsequent neuromodulation. In another embodiment, the memory 132 stores one or more targeting or focusing modes for spatially selecting a region of interest within an organ or tissue structure. The spatial selection may include selecting a subregion of an organ to identify a volume of the organ corresponding to the region of interest. The spatial selection may rely on image data as provided herein. Based on the spatial selection, the energy application device 12 may focus on a selected volume corresponding to the region of interest. For example, the energy application device 12 may be configured to first operate in a verification mode in order to acquire a treatment position by acquiring image data that is used to identify a treatment position associated with acquiring the region of interest. The verification mode energy is not applied at a level suitable for neuromodulation therapy and / or is not applied using modulation parameters suitable for neuromodulation therapy. However, once the region of interest is identified, the controller 20 may be operated in a therapeutic mode according to adjustment parameters associated with achieving a target physiological outcome.

[0066] The controller 20 may also be configured to receive input related to a target physiological outcome as input for selection of an adjustment parameter. For example, when an imaging modality is used to assess a tissue feature, the controller 20 may be configured to receive a calculated index or parameter of the feature. Based on whether the index or parameter is above or below a predefined threshold, a diagnosis may be made, and an indication of the diagnosis may be provided (e.g., via a display). In one embodiment, the parameter may be a measurement of tissue displacement of the affected tissue or a measurement of the depth of the affected tissue. Other parameters may include assessing the concentration of one or more molecules of interest (e.g., assessing one or more changes in concentration relative to a threshold or baseline / control, rate of change, determining whether the concentration is within a desired range). In addition, the energy application device 12 (e.g., an ultrasonic transducer) may be operated under the control of the controller 20 to a) acquire image data of the tissue, which may be used to spatially select an area of ​​interest within the target tissue; b) apply adjustment energy to the area of ​​interest; and c) acquire images to determine the target physiological outcome that has occurred (e.g., via displacement measurement). In such an embodiment, the imaging device, the assessment device 22, and the energy application device 12 may be the same device.

[0067] Includes region of interest 18 (see Figure 1 ) can be an internal tissue or organ including synapses of axon terminals and non-neuronal cells. Synapses can be stimulated by applying energy directly to axon terminals within a focal field or focal band of an ultrasonic therapeutic transducer 95 (the focal field or focal band is focused on a region of interest 18 of the target tissue) to cause the release of molecules into the synaptic cleft, for example, the release of neurotransmitters and / or changes in ion channel activity to cause downstream effects. The region of interest 18 can be selected to include a certain type of axon terminal, such as axon terminals of a specific neuronal type and / or axon terminals that form synapses with a certain type of non-neuronal cells. Therefore, the region of interest 18 can be selected to correspond to a portion of the target tissue having a desired axon terminal (and associated non-neuronal cells). The application of energy can be selected to preferentially trigger the release of one or more molecules (such as neurotransmitters) from the nerve within the synapse, or directly activate the non-neuronal cell itself by direct energy transduction (i.e., mechanical transduction or voltage-activated proteins within the non-neuronal cell), or cause activation of the nerve and non-neuronal cell to cause a desired physiological effect. The region of interest 18 may be selected as a neural site of access to the organ. In one embodiment, liver stimulation or modulation may refer to modulation of the region of interest 18 at or near the porta hepatis. Acquisition of the treatment location 50 may include selection of the region of interest 18, whereby the location of the region of interest 18 on the patient's body within the focal zone of the energy application device 12 during operation is the treatment location 50.

[0068] Energy can be focused or substantially concentrated on the region of interest 18 and only on a portion of the internal tissue, such as less than about 50%, 25%, 10%, or 5% of the total volume of the tissue. That is, the region of interest 18 can be a sub-region of the internal tissue. In one embodiment, energy can be applied to two or more regions of interest 18 in the target tissue, and the total volume of the two or more regions of interest 18 can be less than about 90%, 50%, 25%, 10%, or 5% of the total volume of the tissue. In one embodiment, the energy is applied to only about 1%-50% of the total volume of the tissue, only about 1%-25% of the total volume of the tissue, only about 1%-10% of the total volume of the tissue, or only about 1%-5% of the total volume of the tissue. In some embodiments, only the axon terminals in the region of interest 18 of the target tissue will directly receive the applied energy and release neurotransmitters, while the unstimulated axon terminals outside the region of interest 18 do not receive a large amount of energy and are therefore not activated / stimulated in the same manner. In some embodiments, axon terminals in the tissue portion that directly receives energy will induce altered neurotransmitter release. In this way, tissue subregions can be targeted for neuromodulation in a granular manner, for example, one or more subregions can be selected. In some embodiments, energy application parameters can be selected to induce preferential activation of neural or non-neuronal components within the tissue that directly receives energy to induce the desired combined physiological effect. In certain embodiments, energy can be focused or concentrated in an area less than about 25 mm 3 In some embodiments, the energy may be focused or concentrated within a volume of about 0.5 mm. 3 -50mm 3 However, other focal volumes are also contemplated based on the desired physiological outcome. The focal volume and focal depth used to focus or concentrate energy within region of interest 18 may be affected by the size / configuration of energy application device 12. The focal volume of energy application may be defined by a focal field or focal zone of energy application device 12.

[0069] As provided herein, energy can be applied substantially only to a region of interest or regions of interest 18 in order to preferentially activate synapses in a targeted manner to achieve a target physiological outcome. Thus, in certain embodiments, only a subset of a plurality of different types of axon terminals in a tissue are exposed to direct energy application.

[0070] In certain embodiments, the target tissue comprising the region of interest 18 is an internal tissue or organ including peripheral nerve endings or peripheral axon terminals. Contemplated tissue targets include gastrointestinal (GI) tissue (stomach, intestine), muscle tissue (cardiac, smooth and bone), epidermal tissue (epidermis, organ / GI lining), connective tissue, glandular tissue (exocrine / endocrine), etc. In one embodiment, concentrated application of energy at the neuromuscular junction promotes the release of neurotransmitters at the neuromuscular junction without upstream action potentials. In one embodiment, the contemplated regulatory targets may include portions of the pancreas responsible for controlling insulin release or portions of the liver responsible for sensing glucose / metabolites and / or regulating their circulating concentrations.

[0071] While certain embodiments are disclosed in the context of ultrasound energy application, it should be understood that other energy types are contemplated, such as mechanical energy. Thus, energy application device 12 may be configured as a mechanical vibrator to apply neuromodulation energy. Furthermore, while certain embodiments of the present disclosure are discussed in the context of ultrasound imaging data, system 10 may be implemented to acquire alternative or additional types of imaging data to guide energy application to region of interest 18.

[0072] This written description uses examples to disclose certain implementations, including the best mode, and also to enable any person skilled in the art to practice the disclosed implementations, including making and using any devices or systems and performing any incorporated methods. The scope of the patent is defined by the claims, and may include other implementations that occur to those skilled in the art. Such other implementations are intended to fall within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

Claims

1. A neuromodulation energy application system, comprising: Neuromodulation targeting patch, including: a conformable substrate comprising an application surface configured to be applied to the skin of a subject, the application surface comprising an adhesive portion, wherein the conformable substrate forms a first opening that allows a portion of the subject's skin to be viewed through the first opening when the conformable substrate is applied; an elastic frame disposed on the compliant substrate to surround the first opening and protrude from a top surface of the compliant substrate, the top surface being opposite to the adhesive surface; an abutment configured to removably mate with the resilient frame, wherein the abutment defines a shaped channel terminating in a second opening, wherein the second opening is located within the first opening when the abutment is mated with the resilient frame; and an ultrasound therapy probe configured to fit within or be coupled to the frame to apply neuromodulation energy to a region of interest of internal tissue through a portion of the subject's skin, The frame includes one or more mating features, which are configured to reversibly mate with one or more complementary features of the docking piece or the ultrasonic therapeutic probe, and the ultrasonic therapeutic probe is configured to detect connection with the one or more complementary features of the frame and provide a signal indicative of the connection.

2. The system according to claim 1, wherein: The shaped channel is configured to receive an ultrasound imaging probe configured to acquire ultrasound image data to identify the region of interest when positioned within the shaped channel.

3. The system according to claim 1, wherein: Wherein the docking piece is one of a plurality of docking pieces, each individual docking piece of the plurality of docking pieces has a differently shaped channel configured to accommodate a correspondingly different type of ultrasound imaging probe.

4. The system according to claim 1, wherein: The application layer includes an ultrasound gel portion.

5. The system according to claim 1, wherein: The ultrasonic therapy probe includes a shell supporting an ultrasonic therapy transducer and having the one or more complementary features, wherein the shell is configured to reversibly mate with the frame via the one or more complementary features to cover the opening and orient the ultrasonic therapy transducer toward the patient's skin.

6. The system according to claim 5, wherein: The one or more mating features of the frame are configured to mate with the one or more complementary features of the housing in only one orientation.

7. The system according to claim 6, wherein: The only one orientation positions the ultrasound therapy transducer within the frame at the same location as an imaging transducer of an ultrasound imaging probe when coupled to the dock that mates with the frame.

8. The system according to claim 5, wherein: The ultrasound therapy probe is a wireless probe and wherein one or more batteries are positioned on or in the housing.

9. The system according to claim 5, wherein: The ultrasound therapy probe is a wired probe that is coupled to a power source via a cable extending from the housing.

10. The system according to claim 1, wherein: The ultrasound therapy probe is configured to cease applying neuromodulation energy when the coupling is not detected.

11. The system according to claim 1, wherein: The frame or the dock includes a mechanical lock that, when activated, holds the probe's transducer at a fixed contact pressure against the subject.

12. The system of claim 1, wherein: The frame or the docking piece includes a mechanical lock that, when activated, holds the probe in a fixed orientation relative to the subject and / or relative to the neuromodulation positioning patch.

13. A system for neuromodulation, comprising: an ultrasound imaging probe configured to acquire image data of a subject; The controller is configured as: identifying or verifying a region of interest based on the acquired image data; determining a treatment location on the subject's skin based on the region of interest; as well as The neuromodulation energy application system of any one of claims 1-12, wherein the neuromodulation positioning patch is configured to be positioned on the skin of the subject such that an opening formed in the neuromodulation positioning patch is positioned on or above the treatment location; The ultrasound treatment probe is configured to: a therapy transducer coupled to the neuromodulation positioning patch to position the ultrasound therapy probe through the opening and at the treatment location; Ultrasound energy is applied from the ultrasound treatment probe to a treatment site area of ​​interest through the treatment site.

14. The system according to claim 13, wherein: The ultrasound treatment probe applies additional ultrasound energy, the additional ultrasound energy being related to the next planned dose.

15. The system of claim 13, wherein: Acquiring image data of the subject includes coupling the ultrasound imaging probe to a removable docking piece of the neuromodulation localization patch to position an imaging transducer of the ultrasound imaging probe within both a docking piece opening and an opening of the neuromodulation localization patch.

16. The system of claim 15, wherein: The removable docking piece is separated from the frame of the neuromodulation positioning patch.

17. The system of claim 13, wherein: The ultrasound therapy probe is coupled to the neuromodulation localization patch by coupling mating features of the ultrasound therapy probe to complementary mating features of a resilient frame of the neuromodulation localization patch, wherein the frame is positioned around a perimeter of the opening.

18. The system of claim 13, wherein: The neuromodulation positioning patch is positioned on the subject's skin by adhering an application layer of the neuromodulation positioning patch to the subject's skin.

19. A neuromodulation positioning patch, comprising: a compliant substrate comprising a first opening extending through the compliant substrate; an adhesive disposed on an application surface of the compliant substrate; a resilient frame coupled to the base around a perimeter of the opening and protruding from a top surface of the compliant base, the resilient frame including one or more mating features; as well as a plurality of docking members for an ultrasound imaging probe, the plurality of docking members being configured to removably mate with the resilient frame via one or more complementary mating features and the one or more mating features, wherein the docking members form a shaped channel terminating in a second opening, wherein the second opening is located within the first opening when the docking members are mated with the resilient frame, The frame includes one or more mating features configured to reversibly mate with one or more complementary features of the docking member or the ultrasonic therapeutic probe, the ultrasonic therapeutic probe configured to detect connection with the one or more complementary features of the frame and provide a signal indicative of the connection.

Images