Neuromodulation Energy Application Technology

Abstract

Embodiments of the present disclosure relate to techniques for facilitating personalized neuromodulation treatment protocols. In one embodiment, a predetermined treatment location of an energy application device is used to guide future treatment of a patient. In one embodiment, the position of the energy application device relative to the predetermined treatment location is determined. In one embodiment, the total dose of ultrasound energy to be applied to a target region is determined. [Selected Figure] Figure 1

Description

[Technical field]

[0001] The subject matter disclosed herein relates to techniques for identifying, targeting, and / or administering to a subject an area of ​​interest via application of neuromodulation energy to induce a targeted physiological outcome. In particular, the disclosed techniques can be part of a personalized or at-home neuromodulation treatment protocol. [Background technology]

[0002] Neuromodulation has been used to treat a variety of clinical conditions. For example, electrical stimulation at various locations along the spinal cord has been used to treat chronic lower back pain. An implantable device can periodically generate electrical energy that is applied to tissue to activate specific nerve fibers, which may result in a reduced sensation of pain. For spinal cord stimulation, the stimulating electrode is typically placed in the epidural space, while the pulse generator may be placed some distance from the electrode, for example in the abdominal or buttock region, but connected to the electrode via a lead. In other implementations, deep brain stimulation can be used to stimulate specific regions of the brain to treat movement disorders, and the stimulation location can be guided by neuroimaging. Such central nervous system stimulation is generally mediated by electrodes that target local nerve or brain cell functions, deliver electrical pulses, and are placed at or near the target nerve. However, positioning the electrode at or near the target nerve is difficult. For example, such techniques may involve surgical placement of electrodes that deliver energy. Furthermore, specific tissue targeting via neuromodulation is difficult. Electrodes placed at or near specific target nerves mediate neuromodulation by inducing action potentials in nerve fibers, which in turn result in neurotransmitter release at the neural synapse and synaptic transmission with the next nerve. Because current implementations of implanted electrodes stimulate many nerves or axons at once, such propagation may result in relatively larger or more diffuse physiological effects than desired. Because neural pathways are complex and interconnected, more selective and targeted modulation effects may be more clinically useful. Summary of the Invention

[0003] Certain embodiments commensurate in scope with the claimed subject matter are summarized below. These embodiments are not intended to limit the scope of the claimed subject matter, but rather, these embodiments are intended only to provide a brief summary of possible embodiments. Indeed, the disclosure may encompass a variety of forms that may be similar to or different from the embodiments set forth below.

[0004] In one embodiment, a neuromodulation system is provided that includes an ultrasound probe including an ultrasound transducer configured to apply an effective amount of ultrasound energy to a target region of a patient's body to induce neuromodulation of one or more neural pathways. The system also includes a controller configured to control the application of ultrasound energy to the target region via the ultrasound probe, receive position information related to a position of the ultrasound probe, determine a position of the ultrasound probe relative to a predetermined treatment location, and determine a total dose of ultrasound energy to be applied to the target region.

[0005] In another embodiment, a neuromodulation system is provided, the system including an ultrasound probe configured to apply energy to a target region of a patient's body, the ultrasound probe including an ultrasound therapeutic transducer and at least one position feedback device including a position sensor, a position fixture, a camera, an ultrasound imaging transducer, or a combination thereof, the position feedback device configured to generate information related to a position of the ultrasound probe, and a controller configured for controlling the application of energy to the target region via the ultrasound probe, receiving the information related to the position of the ultrasound probe, determining a position of the ultrasound probe relative to a predetermined treatment location based on the information, and determining a total dose of energy applied to the target region.

[0006] In another embodiment, a method is provided that includes positioning an ultrasound transducer to deliver ultrasound energy to a target area of ​​a patient's body, determining that the position of the ultrasound transducer is aligned with a predetermined treatment location, commencing application of energy from the ultrasound transducer and delivering a dose of energy to the target area in an amount effective to induce neuromodulation of one or more neural pathways after determining that the position is aligned with the predetermined treatment location, determining a total dose applied to the target area, and ceasing application of energy from the ultrasound transducer if the total dose is equal to or greater than a predetermined threshold. [Brief description of the drawings]

[0007] These and other features, aspects, and advantages of the present invention will be better understood when the following detailed description is read in conjunction with the accompanying drawings, in which like characters represent like parts throughout the drawings.

[0008] [Figure 1] FIG. 1 is a schematic diagram of a neuromodulation system using a pulse generator according to an embodiment of the present disclosure. [Diagram 2] FIG. 1 is a block diagram of a neuromodulation system according to an embodiment of the present disclosure. [Diagram 3] FIG. 1 is a schematic diagram of neuromodulation. [Figure 4] 1 is a schematic diagram of an ultrasonic energy application device in operation, according to an embodiment of the present disclosure. [Diagram 5] 1 is a schematic diagram of a technique for establishing a predetermined treatment position, according to an embodiment of the present disclosure. [Figure 6] 1 is an embodiment of an image associated with a given treatment location according to an embodiment of the present disclosure. [Figure 7] 1 is a flow diagram of a neuromodulation technique, according to an embodiment of the present disclosure. [Figure 8] 1 is a schematic diagram of an off-target position of an energy application device and associated indications according to an embodiment of the present disclosure. FIG. [Figure 9]1 is a schematic diagram of an on-target position of an energy application device and associated indicia, according to an embodiment of the present disclosure. [Figure 10] 13 illustrates an embodiment of patient-mediated steering commands based on position and / or image information, according to an embodiment of the present disclosure. [Figure 11] FIG. 1 is a block diagram of a neuromodulation system according to an embodiment of the present disclosure. [Figure 12] FIG. 1 is a schematic diagram of an energy application device including one or more position feedback devices and associated position signals, according to an embodiment of the present disclosure. [Figure 13] FIG. 1 is a schematic diagram of an energy application device including one or more position feedback devices, according to an embodiment of the present disclosure. [Figure 14] FIG. 14 is a bottom view of the energy application device of FIG. 13. [Figure 15] 1 is a schematic diagram of a technique for identifying a predetermined treatment location of an energy application device, according to an embodiment of the present disclosure. [Figure 16] 1 is a schematic diagram of a technique for determining that an energy application device is not positioned at a predetermined treatment location, according to an embodiment of the present disclosure. [Figure 17] 1 is a schematic diagram of a technique for determining when an energy application device is placed at a predetermined treatment location, according to an embodiment of the present disclosure. [Figure 18] FIG. 2 is a schematic diagram of an energy application device coupled to a steering device which is coupled to a steering controller according to an embodiment of the present disclosure. [Figure 19] FIG. 1 is a schematic diagram of an energy application device including a steerable head coupled to a steering controller, according to an embodiment of the present disclosure. [Figure 20] FIG. 1 is a schematic diagram of an ultrasonic energy application device for steering a beam coupled to a steering controller according to an embodiment of the present disclosure. [Figure 21] FIG. 1 is a schematic diagram of a sweep energy application technique, according to an embodiment of the present disclosure. [Figure 22] 1 is a panel of images obtained from a swept energy application technique. [Diagram 23] 13 is an example of energy application device position data that can be used in conjunction with a sweeping energy application technique to determine total dose, according to an embodiment of the present disclosure. [Figure 24] 1 is an example of a user interface of a system including position feedback, according to an embodiment of the present disclosure. [Diagram 25] 1 is an example of a user interface of a system including dose feedback, according to an embodiment of the present disclosure. [Figure 26] 1 is an example of a therapeutic pulse visualization and recording technique using an energy application device according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] One or more specific embodiments are described below. In an attempt to provide a concise description of these embodiments, not all features of an actual implementation are described herein. It will be appreciated that the development of such an actual implementation, as any engineering or design project, will require numerous implementation-specific decisions to be made in order to achieve the developer's particular goals, such as compliance with system-related and business-related constraints, and may vary from implementation to implementation. Moreover, it will be appreciated that such a development effort may be complex and time-consuming, but will nevertheless be a routine undertaking of design, manufacturing, and fabrication for those of ordinary skill in the art having the benefit of this disclosure.

[0010] Any examples or figures described herein should not be considered as express limitations, limitations, or definitions on any one or more terms in which they are used. Instead, these examples or figures are described with respect to various specific embodiments and should be considered as illustrative only. Those skilled in the art will understand that any term with which these examples or figures are utilized encompasses other embodiments that may or may not be provided together or elsewhere in this specification, and that all such embodiments are intended to be included within the scope of the term. Phrases designating such non-limiting examples and figures include, but are not limited to, "for example," "for instance," "such as," "eg," "including," "in certain embodiments," "in some embodiments," and "in one (an) embodiment."

[0011] Provided herein is a technique for neuromodulation of a target target area as part of a treatment protocol that allows for reproducible and reliable application of energy to a particular target area or areas over the course of the treatment protocol. The disclosed technique may be used in conjunction with a personalized neuromodulation treatment protocol in certain embodiments. For a particular patient, the treatment protocol may include application of energy, e.g., non-invasive ultrasound or mechanical energy application, to the target area of ​​the patient at intervals according to the patient's particular clinical needs, and at doses associated with the physiological outcomes being targeted. Depending on the length of time between energy applications (e.g., hours, days, or weeks), it may be inconvenient and cumbersome to have the patient receive neuromodulation energy in a clinic at each treatment. Therefore, it would be beneficial to allow the patient to receive neuromodulation energy according to a treatment protocol at home, via self-delivery, or with the help of a family member or caregiver. However, it may be difficult to train a patient to administer their own neuromodulation treatment, as the patient is usually unskilled and untrained in operating medical equipment. Furthermore, each patient's treatment protocol is personalized to produce the targeted physiological outcome and may vary from patient to patient depending on the variability of anatomy, the patient's clinical condition, and the patient's responsiveness to energy. For example, a treatment protocol for treating a particular disorder may target a specific target area (e.g., an area of ​​the liver, pancreas, or other tissue). The effective energy application site associated with neuromodulation energy targeting a target area may be in one location for one patient and in a slightly different location for another patient due to differences in patient anatomy.

[0012] The neuromodulation techniques disclosed herein facilitate verification of a predetermined treatment location of an energy application device, whereby the predetermined treatment location is a location on the patient's body where the applied energy, when placed at the predetermined treatment location as provided herein, will affect a targeted target area of ​​the patient's body to achieve a targeted physiological outcome. Once established, the patient can administer neuromodulation energy to the target area when the energy application device is properly placed at the predetermined treatment location. Additionally, the disclosed techniques provide feedback to the patient indicating successful positioning of the energy application device at the predetermined treatment location and / or unsuccessful positioning of the energy application device outside of the predetermined treatment location. Such techniques may also be used in combination with multi-site or more complex neuromodulation protocols to guide the patient in administering their own treatment. Additionally, the disclosed techniques provide quality checks for proper positioning to prevent inadvertent off-site application of energy.

[0013] To that end, the disclosed neuromodulation techniques may be used in conjunction with a neuromodulation system configured to be used to administer neuromodulatory energy as part of a treatment protocol. Figure 1 is a schematic diagram of a system 10 for neuromodulation to achieve a neuromodulatory effect, such as release of neurotransmitters and / or activation of synaptic components (e.g., presynaptic cells, postsynaptic cells) in response to application of energy. The illustrated system includes a pulse generator 14 coupled to an energy application device 12 (e.g., an ultrasound transducer). The energy application device 12 is configured to receive, e.g., via a lead or wireless connection, energy pulses that, in use, are directed to a target area of ​​a subject's internal tissue or organ, resulting in a physiological outcome that is in turn targeted.

[0014] In certain embodiments, the energy application device 12 and / or the pulse generator 14 can communicate wirelessly, e.g., with a controller 16 that can in turn provide instructions to the pulse generator 14. In other embodiments, the pulse generator 14 can be an extracorporeal device, e.g., operable to apply energy percutaneously or non-invasively from a location outside the subject's body, and in certain embodiments, integrated internally within the controller 16. In embodiments in which the pulse generator 14 is external to the body, the energy application device 12 can be operated by a caregiver and positioned at a spot on or above the subject's skin such that energy pulses are delivered percutaneously to a desired internal tissue. Once positioned to apply energy pulses to a desired site, the system 10 can initiate neuromodulation of one or more neural pathways to achieve a targeted physiological outcome or clinical effect. In other embodiments, the pulse generator 14 and / or the energy application device 12 can be implanted in a biocompatible site (e.g., the abdomen), and the energy application device 12 and the pulse generator 14 can be internally coupled, e.g., via one or more leads.

[0015] In certain embodiments, the system 10 may include an evaluation device 20 coupled to the controller 16 for evaluating a characteristic that indicates whether modulation of a targeted physiological outcome has been achieved. In one embodiment, the targeted 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 a particular molecule, tissue displacement, increased fluid movement, etc. The targeted physiological outcome may be the goal of a treatment protocol.

[0016] Modulation of one or more neural pathways to achieve a targeted physiological outcome may result in systemic or non-localized changes, where the targeted physiological outcome may be related to changes in the concentration of circulating molecules or changes in tissue properties that do not include the target region where the energy was directly applied. In one example, displacement may be a surrogate measurement of the desired modulation, and a displacement measurement less than an expected displacement value may result in modification of modulation parameters until the expected displacement value is induced. Thus, the evaluation device 20 may be configured to evaluate changes in concentration in some embodiments. In some embodiments, the evaluation device 20 may be an imaging device configured to evaluate changes in organ size, location, and / or tissue properties. In another embodiment, the evaluation device 20 may 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 may be combined with each other. In another embodiment, the evaluation device may evaluate a localized temperature increase in the tissue, which may be detected using a separate temperature sensor or ultrasound image data from the energy application device 12 when configured for ultrasound energy application. Evaluation of differences in sound speed may be detected by differences in imaging techniques before / during / after treatment.

[0017] Additionally, some or all of the elements may be in wired or wireless communication with one another.

[0018] Based on the evaluation, adjustment parameters of the controller 16 may be altered to apply an effective amount of energy. For example, if the desired adjustment relates to a change in concentration (circulating or tissue concentration of one or more molecules) within a defined time frame (e.g., 5 minutes, 30 minutes after the energy application procedure has begun) or relative to a baseline at the start of the procedure, a change in adjustment parameters, such as pulse frequency or other parameters, may be desired, which can be provided by an operator or via an automated feedback loop to the controller 16, which in turn defines or adjusts the energy application or adjustment parameters of the pulse generator 14 until the adjustment parameters result in an effective amount of energy application.

[0019] The system 10 provided herein can provide energy pulses according to various adjustment parameters as part of a treatment protocol for applying an effective amount of energy. For example, the adjustment parameters can include various patterns of stimulation times ranging from continuous to intermittent. In intermittent stimulation, energy is delivered for a period of time at a particular frequency during signal on times. The signal on times are followed by periods of time during which no energy is delivered, denoted signal off times. The adjustment parameters can also include the frequency and duration of application of the stimulation. The frequency of application can be continuous or delivered for various periods of time, for example, within a day or a week. Additionally, the treatment protocol can specify the time of energy application, or the time associated with a meal or other activity. The treatment period to cause the physiological outcome being targeted can last for various periods of time, including, but not limited to, from minutes to hours. In certain embodiments, the treatment period with a particular stimulation pattern can last for one hour and can be repeated, for example, at 72 hour intervals. In certain embodiments, the energy can be delivered for shorter durations, for example, 30 minutes, and more frequently, for example, every 3 hours. The application of energy can be adjustably controlled according to adjustment parameters such as treatment duration, frequency, and amplitude to achieve the desired results.

[0020] 2 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 adapted to generate a plurality of 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 16. The controller 16 includes a processor 30 for controlling the device. Software code or instructions are stored in a memory 32 of the controller 16 for execution by the processor 30 to control various components of the device. The controller 16 and / or the pulse generator 14 may be connected to the energy application device 12 via one or more leads 33 or wirelessly.

[0021] The controller 16 also includes a user interface with input / output circuitry 34 and display 36 adapted to allow the clinician to provide input of selections or adjustment parameters for the adjustment programs. Each adjustment program may include one or more sets of adjustment parameters including pulse amplitude, pulse width, pulse frequency, etc. The pulse generator 14 modifies its internal parameters in response to control signals from the controller device 16 to vary the stimulation characteristics of the energy pulses transmitted via the lead 33 to the subject to which the energy application device 12 is applied. 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 is a function of the current amplitude and pulse width duration. The controller 16 allows for adjustably controlling the energy by modifying the adjustment parameters and / or initiating the application of energy at a particular time or canceling / inhibiting the application of energy at a particular time. In one embodiment, the adjustable control of the energy application device to apply an effective amount of energy is based on information regarding the concentration of one or more molecules (e.g., circulating molecules) in the subject. If the information is obtained from the evaluation device 20, a feedback loop can drive the adjustable control. For example, a diagnosis may be made based on the concentration of circulating glucose measured by the evaluation device 20 in response to neuromodulation. If the concentration exceeds a predetermined threshold or range, the controller 16 may initiate a therapeutic protocol of energy application to the region of interest (e.g., the liver) with modulation parameters associated with a reduction in circulating glucose. The therapeutic protocol may use different modulation parameters than those used in the diagnostic protocol (e.g., higher energy levels, more frequent application).

[0022] In one embodiment, the memory 32 stores different operating modes selectable by the operator. For example, the stored operating modes may include instructions for executing a set of adjustment parameters associated with a particular treatment site, such as a target area of ​​the liver, pancreas, gastrointestinal tract, spleen, etc. Different sites may have different associated adjustment parameters. The controller 16 may be configured to execute the appropriate instructions based on the selection, rather than having the operator manually enter the mode. In another embodiment, the memory 32 stores operating modes for various types of treatments. For example, activation may be associated with a different stimulation pressure or frequency range than that associated with inhibiting or preventing tissue function.

[0023] In a particular example, if the energy application device is an ultrasonic transducer, the effective amount of energy may include a predetermined time-averaged intensity applied to the target area. For example, the effective amount of energy may include a time-averaged power (time-averaged intensity), 1 mW / cm2 to 30,000 mW / cm2 (time-averaged intensity), and a peak positive pressure in the range of 0.1 MPa to 7 MPa (peak pressure). In one example, the time-averaged intensity is less than 35 W / cm2 at the target area to avoid levels associated with thermal damage and ablation / cavitation. In another particular example, if the energy application device is a mechanical actuator, the amplitude of vibration is in the range of 0.1 to 10 mm. The selected frequency may depend on the mode of energy application, e.g., ultrasonic or mechanical actuator. The controller 16 may operate in a verification mode to obtain a predetermined treatment position, which may be implemented as part of a treatment mode of operation configured to execute a treatment protocol when the energy application device 12 is located at the predetermined treatment position.

[0024] The system may also include an imaging device to facilitate focusing of the energy application device 12. In one embodiment, the imaging device may be integrated with or the same device as the energy application device 12, such that various ultrasound parameters (frequency, aperture, or energy) are applied to select (e.g., spatially select) a region of interest and to focus energy on the selected region of interest for targeting and subsequent neuromodulation. In another embodiment, the memory 32 stores one or more targeting or focusing modes used to spatially select a region of interest within an organ or tissue structure. The spatial selection may include selecting a sub-region of the organ to identify a volume of the organ that corresponds to the region of interest. The spatial selection may depend on the image data provided herein. Based on the spatial selection, the energy application device 12 may focus on the selected volume that corresponds to the region of interest. For example, the energy application device 12 may be configured to acquire the predetermined treatment location by first operating in a verification mode to capture image data that is used to identify the predetermined treatment location associated with capturing the region of interest. The energy in the verification mode is not applied at a level and / or modulation parameters suitable for neuromodulation therapy. However, once the region of interest has been identified, the controller 16 can then operate in a therapeutic mode according to adjustment parameters associated with achieving the targeted physiological outcome.

[0025] The controller 16 may also be configured to receive inputs related to the physiological outcome being targeted as inputs to the selection of the modulation parameters. For example, if an imaging modality is used to assess a tissue characteristic, the controller 16 may be configured to receive a calculated index or parameter of the characteristic. 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 made (e.g., via a display). In one embodiment, the parameter may be a measure of tissue displacement of the diseased tissue, or a measure of the depth of the diseased tissue. Other parameters may include assessing the concentration of one or more molecules of interest (e.g., assessing the change in concentration relative to one or more of a threshold or baseline / control, rate of change, determining whether the concentration is within a desired range). Additionally, the energy application device 12 (e.g., an ultrasound transducer) may operate under the control of the controller 16 to a) acquire tissue image data that can be used to spatially select a region of interest within the target tissue, b) apply energy modulation to the region of interest, and c) acquire an image to determine that the physiological outcome being targeted has occurred (e.g., via a displacement measurement). In such embodiments, the imaging device, the evaluation device 20, and the energy application device 12 may be the same device.

[0026] 3 is a particular example in which the energy application device 12 includes an ultrasound transducer 42 (e.g., a transducer array) capable of applying energy to a target tissue 43, e.g., the liver, spleen, pancreas. The energy application device 12 may include control circuitry for controlling the ultrasound transducer 42. The control circuitry of the processor 30 (FIG. 2) may be integrated into the energy application device 12 (e.g., via an integrated controller 16) or may be a separate component. The ultrasound transducer 42 may also be configured to acquire image data to spatially select a desired or targeted region of interest 44 and assist in focusing the applied energy to the region of interest of the target tissue or structure.

[0027] The desired target tissue 43 may be an internal tissue or organ that contains axon terminals and synapses of non-neuronal cells. Synapses may be stimulated by applying energy directly to axon terminals that are within a focal region or zone 48 of an ultrasound transducer 42 focused on a region of interest 44 of the target tissue 43, causing release of molecules into the synaptic gap. For example, neurotransmitter release and / or changes in ion channel activity in turn cause downstream effects. The region of interest 44 may be selected to contain a particular type of axon terminal, e.g., axon terminals of a particular type of neuron and / or those that form synapses with a particular type of non-neuronal cell. Thus, the region of interest 44 may be selected to correspond to a portion of the target tissue 43 that has the desired axon terminals (and associated non-neuronal cells). Application of energy may be selected to preferentially trigger release of one or more molecules, such as neurotransmitters, from nerves in synapses, directly activate the non-neuronal cells themselves via direct energy transfer (i.e., mechanical transfer or voltage-activated proteins in non-neuronal cells), or cause activation in both neuronal and non-neuronal cells that elicit the desired physiological effect. The target region 44 may be selected as a site of nerve entry into the organ. In one embodiment, stimulation or modulation of the liver may refer to modulation of the target region 44 at or adjacent the porta hepatis. Obtaining the predetermined treatment location 46 may include selecting the target region 44, whereby the location on the patient's body where the target region 44 is within the focal zone 48 of the energy application device 12 during operation is the predetermined treatment location 46.

[0028] The energy can be focused or substantially focused on only a portion of the target region 44 and the internal tissue 43, e.g., less than about 50%, 25%, 10%, or 5% of the total volume of the tissue 43. That is, the target region 44 can be a sub-region of the internal tissue 43. In one embodiment, the energy can be applied to two or more target regions 44 of the target tissue 43, and the total volume of the two or more target regions 44 can be less than about 90%, 50%, 25%, 10%, or 5% of the total volume of the tissue 43. In one embodiment, the energy is applied to only about 1%-50% of the total volume of the tissue 43, only about 1%-25% of the total volume of the tissue 43, only about 1%-10% of the total volume of the tissue 43, or only about 1%-5% of the total volume of the tissue 43. In certain embodiments, only axon terminals in the region of interest 44 of the target tissue 43 directly receive the applied energy and release neurotransmitters, while unstimulated axon terminals outside of the region of interest 44 do not receive substantial energy and therefore are not activated / stimulated in the same way. In some embodiments, axon terminals in the portion of the tissue that directly receives the energy will be induced to release altered neurotransmitters. In this manner, sub-regions of tissue may be targeted for neuromodulation in a granular manner, e.g., one or more sub-regions may be selected. In some embodiments, energy application parameters may be selected to induce preferential activation of either neural or non-neural components within the tissue that directly receives the energy to induce a desired combined physiological effect. In certain embodiments, the energy is applied over a 10-minute period of about 25 mm. 3 In certain embodiments, the energy can be focused or concentrated within a volume of less than about 0.5 mm. 3 ~50mm 3 The focal volume and focal depth for focusing or concentrating energy within the target region 44 may be affected by the size / configuration of the energy application device 12. The focal volume of the energy application may be defined by a focal region or focal zone of the energy application device 12.

[0029] As provided herein, energy can be applied substantially only to one or more target regions 44 to preferentially activate targeted synapses to achieve a targeted physiological outcome. Thus, in certain embodiments, only a subset of multiple different types of axon terminals within tissue 43 are exposed to the direct application of energy.

[0030] The energy application device 12 may be configured as an external non-invasive device or an internal device, e.g., a minimally invasive device. As previously mentioned, the energy application device 12 may be an external non-invasive ultrasound transducer or a mechanical actuator. For example, FIG. 4 shows an embodiment of the energy application device 12 configured as a handheld ultrasound probe including an ultrasound transducer 42. However, it should be understood that other non-invasive implementations are also contemplated, including other methods for configuring, adhering, or positioning the ultrasound transducer probe on an anatomical target. Furthermore, in addition to a handheld configuration, the energy application device 12 may include a steering mechanism responsive to commands from the controller 16. The steering mechanism may aim or direct the energy application device 12 to the target tissue 43 (or structure), and the controller 16 may then focus the application of energy to the target region 44. The ultrasound transducer 42 may include an imaging transducer 42A used for spatial selection of the target region 44 within the target tissue 43. The ultrasound transducer 42 may include a therapy transducer 42B that applies neuromodulation energy. In one embodiment, the energy application device 12 may include a MEMS transducer, such as a capacitive micromachined ultrasound transducer.

[0031] FIG. 5 is a schematic diagram of a predetermined treatment location acquisition technique. A patient 70 may begin a treatment protocol upon meeting with an initial physician or a skilled device operator 72 (e.g., an ultrasound technician). The operator 72 acquires images from the device 12 positioned in one or more calibration positions on the patient 70 (e.g., with the energy application device 12 in direct contact with the patient's skin). Using the image on the display 36 to guide positioning, the operator 72 instructs the patient 70 to move the device 12 until an image is acquired that includes the target region 44. For example, as shown in FIG. 6, such an image may be a liver image that includes a target region of the hilum of the liver. Fine positioning may further resolve the target region 44. Selection of the target region 44 and / or the predetermined treatment location 86 may include automatic selection via an image segmentation algorithm that uses acquired images to identify the organ. The target region 44 may be selected to correspond to a particular % of the target organ, tissue within the target location / image. In another embodiment, the region of interest 44 can be selected using Doppler information (i.e., a particular level of blood flow at a particular location, such as the porta hepatis of the liver) or mechanical information (i.e., ultrasound reflectivity or elastography data).

[0032] It should be understood that the positions provided herein may include the angle, orientation, and / or pose of the energy application device 12. In one embodiment, the positions may include absolute positions in space in three dimensions. Additionally, the energy application device 12 may be considered aligned when placed on the correct area of ​​the patient (e.g., a particular area of ​​the patient's skin, a predetermined treatment location) and when the energy application device 12 is in the correct pose, angle, and / or orientation with respect to the patient in one or more degrees of freedom. Position information may also include an assessment of touch or pressure on the target. The orientation may also be determined using an external mechanical fixation that contacts either the patient, the patient's clothing, or a chair / bed / support / area associated with the patient. In one example, the probe head or other portion of the energy application device fits into a mechanical fixation that is placed at the predetermined treatment site on the patient either via a wearable or an external device (i.e., a treatment chair). In some respects, the mechanical fixation is yet another example of a position sensor / controller location.

[0033] In some embodiments, ultrasound images can be used to guide ultrasound stimulation to spatially select a region of interest for targeted delivery of ultrasound stimulation and, accordingly, identify a predetermined treatment location of the energy application device 12 on the patient that results in application of energy to the region of interest. As provided herein, selection of a region of interest can include acquiring an image of a tissue or organ (or a portion of a tissue or organ) and identifying a region of interest within the organ based on the image (e.g., ultrasound image). In some embodiments, the tissue or organ can have anatomical features that are used to guide selection of a region of interest within the organ. Such features, in some embodiments, can include, as non-limiting examples, sites of vascular or neural entry into the organ, tissue types within the organ, interiors or edges of the organ, or sub-organ structures. In certain embodiments, the anatomical features can include the porta hepatis of the liver, sub-organs of the gastrointestinal tract (stomach, small intestine, large intestine), pancreatic duct, or white pulp of the spleen. By identifying anatomical features in the image, a region of interest can be selected to overlap, include, or be adjacent to the anatomical feature. In other embodiments, the anatomical feature can be excluded from the region of interest. For example, intestinal tissue may be selected as the region of interest rather than stomach tissue. Identification of anatomical features may be via morphological features displayed in the image (e.g., displayed in an ultrasound image) or by structure recognition features of the imaging modality used to acquire the image. As disclosed herein, system 10 may be configured such that energy application device 12 operates in an imaging mode to acquire an image, and thereafter, the image is acquired, and is configured to operate in an energy application mode after the region of interest has been spatially selected based on the image.

[0034] In other embodiments, the region of interest may be identified by the presence or absence of one or more biological markers. Such markers may be assessed by staining an organ or tissue and acquiring images showing the staining to identify regions of the organ or tissue that contain the biological markers. In some embodiments, the biological marker information may be acquired by in vivo labeling techniques to acquire location data of the biological markers in a tissue or organ specific to the subject in real time. In other embodiments, the biological marker information may then be acquired by in vitro staining techniques to acquire location data of one or more representative images that are used to predict the location of the biological markers within the tissue or organ of the subject. In some embodiments, the region of interest is selected to correspond to a portion of a tissue or organ that is rich in a particular biological marker or that lacks a particular biological marker. For example, the one or more biological markers may include a marker for neuronal structure (e.g., a marker for myelin sheaths).

[0035] The region of interest of an organ or tissue may be spatially selected based on operator input. For example, an operator may specify the region of interest in an acquired image by directly manipulating the image (i.e., by drawing or writing the region of interest on the image) or by providing image coordinate information corresponding to the region of interest. In another embodiment, the region of interest may be automatically selected based on image data to achieve spatial selection. In some embodiments, spatial selection includes storing data associated with the region of interest in memory and accessing the data. Once spatially selected, the system 10 is configured to apply energy to the region of interest according to a treatment protocol and as provided herein.

[0036] Alternatively, an entire patient-specific dataset is annotated by an expert as part of a training session with a physician or caregiver. The dataset contains both on-target and off-target images, and a patient-specific deep learning (DL) model is trained to recognize the on-target location. When at home and using the device to apply treatment, the system runs the DL image classification model in real time to find the on-target location. At that point, the treatment beam can be activated (or associated with the on-target dose).

[0037] Once the energy application device 12 is positioned such that its focal zone 48 includes the target region 44, the operator 72 stores the acquired image as an image associated with a predetermined treatment location 46. The predetermined treatment location 46 refers to a location of the energy application device 46 within or on the patient such that its focal zone 48 includes the target region 44. The predetermined treatment location 46 may include an area of ​​a surface area of ​​the patient's skin (or clothing) where the energy application device 12 is positioned.

[0038] In one embodiment, the predetermined treatment location 46 may be identified with a mark, temporary tattoo, implanted or surface position sensor, sticker, or other indicator. Additionally, the indicator may be shaped to include the outline of the portion of the energy application device 12 that is in direct contact with the patient's skin or clothing, allowing the energy application device 12 to be properly oriented during subsequent treatments. In other embodiments, the position information of the energy application device 12 may also be obtained as a representation of the predetermined treatment location 46, as provided herein. The placement of the indicator may occur during a particular data set collection session prior to sending the patient home with the device 12, where the clinician places an indicator / tattoo on the patient's skin at or near the predetermined treatment location. Then, when scanning to find the predetermined treatment location, the user clicks a button to initiate the storage of the target probe location. The relative position and orientation between the on-probe camera and the on-skin markers are then stored in memory as a patient-specific or device-specific calibration. In one embodiment, in subsequent scans when the patient is at home, the device finds the same relative alignment between the on-probe camera and the on-skin markers before activating the treatment beam.

[0039] The indicator may be visible or may be made visible only under certain conditions (e.g., light of a certain frequency). The energy application device 12 may be configured to provide illumination of a certain frequency at which the indicator is visible. Additionally, the indicator may be encoded with patient-specific information (e.g., an alphanumeric code, QR Code®) when scanned by an optical reader (e.g., a camera or optical scanner that may be integrated into the energy application device 12), which facilitates access to identification information and / or adjustment parameters related to the patient. The indicator itself may also be embedded with patient-specific information (unique patient identifier) ​​or even dose control parameters (prescription). Upon reading the encoded information, the system may initiate a verification to ensure that the programmed treatment is being applied to the appropriate patient. In one particular example, the indicator is a QR Code® with a tattoo bearing a unique patient identifier. However, other patterns are possible. The information in the QR Code® is encrypted such that the raw data is inaccessible when scanned with a common QR Code® reader. In this way, the indicator provides an additional verification step. Other patient verification techniques are also contemplated, including ultrasound imaging verification (comparing a stored ultrasound image of the patient to the acquired image as verification), or biometric verification (facial recognition, fingerprint, etc.). Verification may be a precursor to initiating treatment, without which energy application via the energy application device 12 would not be permitted. In one embodiment, the indicator may be formed from acoustically distinct materials in a grid similar to a QR Code®, but the black and white portions of the QR Code® are instead made from materials with very different acoustic properties resolvable by ultrasound imaging, or from materials with intentional air gaps to reduce ultrasound coupling in the pattern. Thus, the indicator may be visible during the ultrasound image in the near field of the ultrasound image, or as a shadow covering a portion of the image.

[0040] When the patient 70 or other caregiver initiates a subsequent neuromodulation treatment as part of a treatment protocol, an energy application device 12 (either the same energy application device 12 used to obtain the predetermined treatment location 46, or a different energy application device 12 configured to operate in a similar manner) is placed on the patient and it is determined whether its location aligns (is the same as or substantially overlaps) with the predetermined treatment location 46. In one embodiment, the determination includes placing the energy application device 12 on an indicator on the patient. Once placed on the indicator, the energy application device 12 is considered to be in the predetermined location.

[0041] In other embodiments, the system 10 may be configured to automatically control energy application based on the position of the energy application device. Figure 7 is a flow diagram of a method 80 for controlling energy application based on correspondence of the energy application device 12 to a predetermined treatment location 46. The patient may place the energy application device (block 82) substantially in the position of the predetermined treatment location 46, for example, using a skin indicator or by memory. The system 10 may then obtain information regarding the position of the energy application device 12 and determine whether the energy application device is aligned with the predetermined treatment location (block 84).

[0042] For example, the system 10 can acquire ultrasound images at various positions of the energy application device 12 (e.g., the patient 70 can move the energy application device in a limited area of ​​the body near the predetermined treatment location 46). When an image is acquired that matches the ultrasound image acquired from the energy application device 12 at the predetermined treatment location 46, the energy application device 12 is considered to be at the target or predetermined location. Image alignment can be performed using image registration techniques. In another embodiment, position information from one or more sensors (see FIG. 10 ) on the energy application device 12, the patient 70, or both can additionally or alternatively be used to determine whether the position of the energy application device 12 is aligned with the predetermined treatment location 46.

[0043] Based on the determination, treatment can be initiated when the energy application device is aligned with the predetermined treatment location 46 (block 86) and inhibited when the energy application device is not aligned with the predetermined treatment location 46. That is, the system 10 can be configured such that the pulse generator 16 is not permitted to drive the energy application device 12 when the energy application device 12 is not aligned with the predetermined treatment location 46. For example, energy application can be permitted to occur only after or during generation of an alignment signal indicative of alignment with the predetermined treatment location 46. If the position of the energy application device 12 is not aligned with the predetermined treatment location 46, an indication of misalignment can be made (block 88). The method 80 can repeat updating the control of energy application based on any shifts or updates in the movement of the energy application device 12 relative to the predetermined treatment location 46 of the patient.

[0044] FIG. 8 is a schematic diagram of an indication made for an off-target energy application device 12, and FIG. 9 is a schematic diagram of an indication made for an on-target energy application device 12. As shown, the off-target energy application device 12 is partially, but not completely, within the area associated with the predetermined treatment location 46, while the on-target energy application device 12 is completely within the area associated with the predetermined treatment location 46. The system 10 may be configured to allow a certain level of tolerance or deviation from the predetermined treatment location 46 and still be considered to be on-target. In one embodiment, the energy application device 12 is considered to be off-target based on the degree of misalignment with the acquired image associated with the predetermined treatment location 46. For example, a match that is less than 90% per image registration may indicate an off-target location, while a match that is 90% or more may be on-target. In another embodiment, the energy application device 12 is considered to be off-target or on-target based on its location relative to an indicator, such as a mark or tattoo on the patient's skin or an item worn, or relative to a mechanical fixture placed on an external instrument (such as a chair) associated with the patient and / or the patient's location. The energy application device 12 may include one or more sensors that sense the indicators and provide feedback to the system 10 related to the position of the energy application device 12 relative to the indicators. The energy application device 12 may be considered to be off-target if it is positioned more than a predetermined distance from the indicator (e.g., more than 1 cm, 3 cm, 5 cm, etc.) or if it is not positioned within the bounds of the indicator (e.g., a circular indicator). The energy application device 12 may be considered to be on-target if it is positioned less than a predetermined distance from the indicator (e.g., more than 1 cm, 3 cm, 5 cm, etc.) or if it is positioned within or nearly within (e.g., at least 75%, at least 90%) the bounds of the indicator (e.g., a circular indicator).In another embodiment, the energy application device 12 is considered to be off-target or on-target based on its position relative to the patient or its absolute position in space compared to the absolute position of the patient.

[0045] The indication to the caregiver or user related to on-target or off-target positioning may be one or more of a text message, a light (e.g., a red or green light), a sound or alarm, etc. The indication may also be a haptic effect, such as a pattern of vibrations of a vibration actuator embedded in the energy application device 12 (e.g., an ultrasound probe).

[0046] In one example, when scanning around the substantial area, the vibration actuator buzzes once the pre-determined treatment location is found (either by automatic image processing or alignment to an indicator on the skin). The user then learns to find the buzz as they sweep around and intuitively return the probe to where the buzz was felt. In another example, different vibration patterns can be used for on-target and off-target. Additionally, the system 10 can also be configured to provide information related to the length to be administered to instruct the patient 70 to align the energy application device 12 to the pre-determined treatment location 46 for the entire dose or until the total dose is higher than a pre-determined threshold.

[0047] If the energy application device 12 is determined to be off-target, the system 10 may be configured to provide guidance to enable patient-driven steering or repositioning to an on-target position. In the embodiment shown in FIG. 10, if the initial position is determined to be off-target, for example, via acquired image 92 (shown as an image of the spleen), the system 10 may present one or more steering arrows 94 or other indicators to direct the patient 70 to steer the energy application device toward alignment with a predetermined treatment location 46 associated with image 96 (shown as an image of a deeper portion of the spleen, acquired upon repositioning of the device 12 on the patient, showing vascular penetration). Such an image may indicate positioning of the energy application device 12 aligned with the predetermined treatment location 46 of the spleen.

[0048] The user interface displayed to the patient 70 may include arrows with associated images. Simple feedback of the device's location allows the patient to find the desired treatment location without having to interpret images that may be difficult for an untrained operator to interpret. The patient may also find the location using automated support hardware, including holding fixtures and actuators that make probe movement and / or ultrasound focal position available without requiring physical / manual manipulation of the probe itself. As discussed herein, tactile, visual, and / or audio feedback may be activated when the user passes the correct location during some initial sweeps. For example, a beep or other tone may be triggered at the on-target location.

[0049] The system 10 may be implemented with position assessment and / or steering capabilities. FIG. 11 is a block diagram of a neuromodulation system according to an embodiment of the present disclosure. The depicted embodiment includes certain features discussed with respect to FIG. 2. Additionally, the system 10 may include one or more position feedback devices integrated in or on the energy application device 12 and configured to generate a corresponding position signal indicative of the position of the energy application device 12. The signal may be communicated to the controller 16, which may then process the signal as part of determining whether the energy application device 12 is on-target or off-target. The position feedback device may include a sensor 100, which may be any type of position sensor, including an optical sensor, a camera, an inertial measurement unit (IMU) that tracks relative motion information from an initial reference, a Hall effect sensor, an electromagnetic position sensor, and the like. Additionally or alternatively, the energy application device 12 may also include one or more contact sensors 102 configured to assess contact of the energy application device 12 with the patient's skin or clothing, or associated mechanical fixation. Alternatively, the system 10 can infer through real-time automated image processing of acquired anatomical images when the energy application device 12 is in sufficient contact with the user. The system 10 can be configured to prevent application of energy when there is a lack of contact or pressure. Additionally or alternatively, the system may also include a steering controller 104 configured to provide instructions for steering the energy application device 12. Although the steering controller 104 is shown as part of the controller 16, in other embodiments, it may be integrated with the steering system of the energy application device 12.

[0050] FIG. 12 is a schematic diagram of an energy application device including a position feedback device, such as one or more optical position sensors 100, and associated position signals indicating camera tracking position, according to an embodiment of the present disclosure. Multiple optical position sensors 100 can be used on the probe and placed on the patient to know the exact position, pitch, and twist of the energy application device 12. In another embodiment, the position sensor 100 can be implemented as a sensor 100 that is tracked by an external electromagnetic field generator (FG) that induces a small current. The sensor 100 is tracked and depends on the distance and angle from the FG. In another embodiment, the position sensor 100 can be a commercially available IMU or orientation sensor based on accelerometers and gyros placed directly on the energy application device 12. Such a sensor can sense changes relative to the position, i.e., to the skin indicators associated with a given treatment position or pose 46.

[0051] FIG. 13 is an embodiment of an energy application device 12 that includes one or more position feedback devices (imaging transducers, position sensors, cameras, etc.) that provide position information. The energy application device 12 can be at least partially disposed within a housing 110 that allows a patient or user to manipulate or position the device 12 on a patient for treatment. The illustrated embodiment of the energy application device 12 includes a treatment transducer 42B, e.g., a piezo element (or other ultrasonic actuator), and an imaging transducer 42A that are in close proximity to one another within the housing 110. The housing 110 can include a camera 112 and associated components, e.g., a lens, a light source, that are oriented to acquire images from, e.g., pointed away from, the treatment surface 120 of the energy application device 12 to acquire images of the patient's skin or clothing as it is applied to the patient. The energy application device 12 can include one or more sensors, such as an inertial measurement unit 114, configured to provide position and / or tilt or angle data associated with the energy application device 12. In some embodiments, the energy application device 12 may include an identification tag, e.g., an RFID tag, encoded memory, which provides identification or other calibration information to the controller 16. In one embodiment, the calibration information may include information related to the spacing between the imaging transducer 42A and the therapy transducer 42B to account for differences between the therapy energies based on the acquired images. That is, the controller 16 may be configured to adjust the positioning determination with respect to which the energy application device 12 occupies the spacing. The energy application device 12 may also include control circuitry to enable the transmission of signals to and from the energy application device. FIG. 14 is a bottom view of the energy application device 12 of FIG. 13, showing a treatment surface 120, e.g., an ultrasound treatment surface, of the device 12. The treatment surface 120 of the energy application device 12 may be applied directly to the skin of a patient.

[0052] It should be understood that other implementations of the energy application device 12 are contemplated. For example, the transducer 42 may be an imaging / treatment transducer 42 with one or more sensors 100 designed to image and apply treatment and embedded within the handle. Additionally, the camera 112 may be mounted at various locations, e.g., higher on the handle, closer to the top of the device 12 but not above the treatment surface 120, to facilitate imaging of the skin and temporary tattoos or other indicators. The energy application device 12 may include a processor such that at least a portion of the image processing, targeting, and / or calibration may be performed at the device 12. Additionally, the energy application device may include communication circuitry to enable wired or wireless communication with another device, e.g., the controller 16, a mobile device.

[0053] FIG. 15 is a schematic diagram of a technique for identifying a predetermined treatment location 46 of the energy application device 12 in conjunction with a specialist or physician 72. The depicted technique may be performed at the initiation or establishment of a treatment protocol or as part of the validation of a treatment protocol. At step 122, an image is acquired using the energy application device 12 in an imaging mode to locate a target area 44 (see FIG. 3) within an internal tissue or structure of a patient 70. The predetermined treatment location 46 is based on a relationship between an external or extracorporeal location of the energy application device 12 on the patient's body and the target area 44 that corresponds to a focal zone of the energy application device 12 when the energy application device 12 is placed at the predetermined treatment location 46. In other words, the predetermined treatment location 46 corresponds to a location of the energy application device 12 on the patient's body (e.g., in direct contact with the patient's skin) where the applied energy passes through the patient's skin to reach the target area 44.

[0054] The predetermined treatment location 46 may be marked on the patient's skin 129 or on the patient's clothing, or by otherwise placing a mechanical fixation device on or near the patient, as shown in step 124. In the illustrated embodiment, the predetermined treatment location 46 is marked with a temporary tattoo 128. However, other markers such as permanent tattoos, stickers, pen markings (visible or fluorescent) may also be used. The predetermined treatment location 46 then serves as a guide for positioning the energy application device 12 for future treatments, as provided herein. Establishing the predetermined treatment location 46 may also include storing data related to correct alignment, such as data from a position feedback device. In one embodiment, positioning data from the inertial measurement unit sensor 114 is used to generate a position guide 130 and position data 132 related to alignment. Deviations from the data (e.g., deviations of more than 5%, deviations of more than 10% in any direction) may be associated with misalignment or lack of alignment. In another embodiment, the position data may include an ultrasound image or a camera image of the patient.

[0055] FIG. 16 is a schematic diagram of an example where the energy application device 12 is not aligned with the predetermined treatment location 46. For example, a patient 70 may apply the energy application device 12 for at-home treatment. In this example, the energy application device is not positioned at the predetermined treatment location 46 marked with a tattoo 128. Instead, the energy application device 12 is positioned at a misaligned location 133. Data is collected from the energy application device 12 at the misaligned location to determine that the energy application device 12 is misaligned. For example, such data may include data from an inertial measurement unit sensor 114 to generate position information 134, 136 regarding the defined points. In certain embodiments, the patient 70 may track the position information 134, 136 in real time as the energy application device 12 is repositioned to evaluate whether the misalignment has been corrected. The data may also include image data, such as ultrasound image data 138. Such data may be provided to the patient 70 or may be stored by the system 10 for review by a person skilled in the art or automated analysis software, or for dose calculations as provided herein.

[0056] 17 is a schematic diagram of a technique for determining when the energy application device 12 is aligned in a predetermined treatment position 46. In the illustrated embodiment, the energy application device 12 can be positioned in the predetermined treatment position in one axis, but tilted incorrectly relative to the skin. Based on position information 142, the patient 70 can be provided with instructions to tilt the energy application device 12 in a particular direction to perfect alignment, as indicated by position information 144.

[0057] 18 is a schematic diagram of an energy application device 12 coupled to a steering device 148 which in turn is coupled to a steering controller 104, according to an embodiment of the present disclosure. The steering device 148 can be a mechanical arm that operates under the control of the steering controller 104 to position / reposition the energy application device 12 until it is aligned with the predetermined treatment location 46. In another example, the device is attached to a belt or garment that the patient straps to the virtual target area. A motion stage on the belt aligns the device 12 to the target location. Similar motion control mechanisms can be provided in ultrasound chairs or benches using other types of motion stages.

[0058] In certain embodiments, the system 10 may be configured to complete or optimize the general movement of the energy application device near a predetermined treatment location 46 of the user. FIG. 19 is a schematic diagram of an energy application device 12 including a steerable head coupled to a steering controller 104, according to an embodiment of the present disclosure. That is, in addition to or instead of steering the entire device 12, the steering controller 104 may be configured to manipulate the head, e.g., the ultrasound probe head, to perform fine positioning. FIG. 20 is a schematic diagram of an ultrasonic energy application device 12 with beam steering coupled to a steering controller 104, according to an embodiment of the present disclosure. That is, rather than or in addition to repositioning all or a portion of the device 12, the energy application device 12 may also be configured to redirect the beam closer to the target region 44 using beam steering.

[0059] In addition to an embodiment in which the energy application device 12 is aligned with a predetermined treatment location 46, FIG. 21 is a schematic diagram of a diffuse energy application technique according to an embodiment of the present disclosure. While the system 10 acquires information (step 152) regarding the swept area (e.g., image 156), the patient 70 scans or sweeps or moves the energy application device 12 around the substantial area (step 150). The substantial area may be at or around a predetermined treatment location previously identified by a caregiver or professional, as discussed herein. The system 10 may use, for example, image segmentation during the sweep (area 164) to determine the volume and / or time during the sweep that is associated with targeted administration of the target area 44. When the total dose reaches a predetermined level, the system 10 may present an indication of the full dose to indicate that the patient should stop the sweep. In certain embodiments, achieving the total dose triggers a shutoff of the energy application device 12. Such a method may be appropriate when tissue surrounding the target area may be stimulated with limited side effects. Additionally, system 10 may be configured to provide a feedback mechanism to inform patient 70 if they are not "accumulating the applied energy" fast enough (i.e., instructions to sweep in a new location). Additionally, in certain embodiments, system 10 may trigger a shutoff to energy application device 12 if off-target site administration accumulates to a level above a threshold. In a preferred embodiment of the present disclosure, the controller is configured to calculate off-target doses of energy to be applied to areas outside the target region based on the position of the ultrasound probe relative to the position of the predetermined region to be treated over a time frame. The disclosed sweeps can be performed with unfocused or softly focused ultrasound to produce wider sweeps.

[0060] In another embodiment, the process of scanning includes triggering the on / off of the treatment beam based on real-time alignment. During the scan, the energy application device 12 is configured to continuously image at imaging power levels to find image alignment with a predefined target and / or continuously process camera and transducer (e.g., ultrasound image) data to find alignment with the skin indicator. In another implementation, the treatment beam is intermittently activated during the sweep if alignment is correct and disabled if alignment is incorrect while intermittently counting up the dose to the target. In another embodiment, the system is configured for the user to hold the energy application device 12 stationary at the target position for a period of time (i.e., 1 second) before activating the treatment beam, where the user is assumed to remain stationary during treatment application. User movement is detected by ultrasound imaging, inertial measurement unit, or real-time processing of camera data, and the treatment beam is immediately deactivated. The cycle of activation / deactivation of the treatment beam continues until the dose accumulation reaches the target.

[0061] FIG. 22 shows an example of a panel of images associated with the sweep technique showing an area of ​​interest. The determination of the dose applied to the area of ​​interest 44, and areas outside the area of ​​interest 44, may be determined based at least in part on position feedback from a sensor 100 associated with the energy application device 12, as shown in FIG. 23. In the illustrated example, the feedback may be based on signals from one or more inertial measurement units disposed at or within the energy application device 12. The feedback may also be based on an optical sensor, e.g., camera 112, of the energy application device 12 that acquires data from the patient's skin to generate position information. In one embodiment, the data indicates the location of a tattoo 126 or other sensor-identifiable marker relative to the energy application device. The determination of the dose applied to the area of ​​interest 44 may be made based on the location of the energy application device over a time frame. The dose may be considered to be accumulating when the energy application device 12 is determined to be in a predetermined position on the patient as determined via the camera 112 and / or the sensor 100. The dose may be considered not accumulating when the energy application device 12 is determined to not be in a predetermined position on the patient as determined via the camera 112 and / or the sensor 100. When the energy application device 12 is partially in place, the dose may be considered to be a partial dose. By tracking the total dose to the target area 44 over a treatment time frame, the system may provide an indication of the total dose or the target dose achieved. Additionally, the total dose to the target area 44 may be used as feedback by the controller 16 to control the operation of the energy application device 12. Once the target dose to the target area is achieved, the controller 16 may switch off the application of energy from the energy application device 12.

[0062] In another embodiment, the position data can be used to provide feedback to the patient 70 related to the position of the energy application device 12. FIG. 24 shows the display 36 of the controller 16 presenting a user interface including the proposed positioning of the energy application device 12, for example, via color, arrow, image, or other indicator (audio indicator, light indicator). In certain embodiments, the energy application device 12 can include or be implemented in combination with haptics to guide an unskilled or relatively untrained operator to move up / down / left / right via haptic feedback. Haptics or audio feedback can also be used to provide yes / no guidance utilizing tones / tones or absence of haptics / absence of haptics to indicate the positioning of the energy application device 12. In such embodiments, the use of a display for guidance can be optional. The controller 16 can also be configured to trigger treatment only when the energy application device 12 is correctly positioned (block 170).

[0063] 25 illustrates an embodiment in which the controller 16 provides an indicator related to the total dose via the display 36. For example, a shape may fill in as the dose accumulates. Additionally, the display 36 can provide a user interface that indicates that the energy application device 12 is correctly positioned to deliver a dose to the target region 44. It is understood that the user interface may alternatively or additionally provide information such as acquired images, segmentation data, sensor data, etc.

[0064] The application of therapeutic pulses to tissue results in resolvable changes in the image that can be seen during treatment. For example, the target tissue may move, pulsate, or expand in response to the applied energy. FIG. 26 is an example of an energy application device 12 used to simultaneously (or nearly simultaneously) deliver therapeutic energy via the therapeutic transducer 42B and acquire images (e.g., image 180) via the imaging transducer 42A during treatment. In one embodiment, the imaging transducer 42A and the therapeutic response and / or the therapeutic transducer 42B are frequency matched to allow acquisition of images indicative of the therapeutic effect. Additionally, the dynamic range of the imaging probe is adjusted to target the effect of the ultrasound to the tissue. The energy pulses can be timed relatively quickly to allow for the resolution of tissue that bounces around in the image and is not a continuously moving tissue. Calibration with lower order non-therapeutic pulses can be performed before the therapeutic energy is applied.

[0065] Mechanism of physiological outcome being targeted The present technology relates to targeted modulation of synapses at axon terminals in tissues via direct application of energy by an energy source that causes changes that result in a measurable targeted physiological outcome (e.g., concentration of circulating molecules or a series of concentration changes that form a characteristic physiological profile). Targeted synapses may include axonal extracellular synapses formed between presynaptic axon terminals and postsynaptic non-neuronal cells. Additionally, while certain disclosed embodiments are discussed in the context of axonal extracellular synapses, it should be understood that axon terminals may form axonal secretory, axonal synapses, axonal cells or axonal extracellular synapses, and additionally or alternatively, these types of synapses are considered to be selectively modulated as provided herein. Additionally, certain axon terminals may terminate in interstitial or bodily fluids that may also undergo neurotransmitter release and / or axon / terminal activation as a result of modulation. The disclosed synapses may be modulated to change activity at the synapse, e.g., neurotransmitter release from presynaptic axon terminals, as a result of application of energy. Thus, the altered activity can result in local and / or non-local (e.g., systemic) effects, resulting in an overall profile of physiological changes associated with a desired or targeted physiological outcome. The present technology allows for the concentration of energy in a targeted manner at a volume of tissue that contains specific axon terminals to preferentially and directly activate the targeted axon terminals to achieve a desired targeted physiological outcome. In this manner, targeted axon terminals within the target region are activated, while in certain embodiments, axon terminals within the same organ or tissue structure but outside the target region are not activated. Because organs and tissue structures may contain different types of axon terminals that form synapses with different types of postsynaptic non-neuronal cells, a target region may be selected that contains a specific type of axon terminal that, when activated, results in a targeted physiological outcome. Thus, modulation may target a specific type of axon terminal based on presynaptic neuron type, postsynaptic cell type, or both.As provided herein, energy is applied to a target area of ​​a patient's body in an amount effective to induce neuromodulation of one or more neural pathways, for example, targeted physiological outcomes.Effective amounts can be evaluated as generally disclosed herein, such as via an evaluation device.Effective amounts can also be applied according to one or more modulation parameters as provided herein.

[0066] For example, in one embodiment, one or more neural pathways may include axon terminals that form axon-extracellular synapses with cells of resident (i.e., tissue-resident or non-circulating) liver, pancreas, or gastrointestinal tissue. That is, axon-extracellular synapses are formed at the junction between axon terminals and non-neuronal cells or interstitial or bodily fluids. Thus, application of energy leads to modulation of function in the target region. However, it should be understood that different targeted physiological effects may be achieved based on the population of axon terminal types, as well as the characteristics of the presynaptic neuron types and postsynaptic cells (e.g., immune cells, lymphatic cells, mucosal cells, muscle cells, etc.) of the axon-extracellular synapses. Thus, application of energy to a target region in a tissue of interest may activate the axon terminals and their associated axon-extracellular synapses of one or more neural pathways in the target region, while non-target axon terminals (and associated synapses) outside the target region may not be affected. However, since modulation may result in a systemic effect, non-targeted axon terminals outside the target region may undergo certain systemic changes as a result of activation of axon terminals within the target region. As provided herein, preferential activation or direct activation may refer to cells or structures (e.g., synapses) within the target region that undergo direct application of energy (e.g., energy is applied directly to the cells or structures). For example, axon terminals, axon-extracellular synapses, and / or post-synaptic non-neuronal cells, or interstitial or bodily fluids within the target region may directly undergo the applied energy as provided herein. Preferential or direct activation may be considered in contrast to regions outside the target region that do not undergo direct application of energy, even if such regions undergo physiological changes as a result of the application of energy. Furthermore, in some embodiments, preferential activation may include applying a relatively high dose of neuromodulatory energy to a particular target region, while regions outside the target region receive a relatively low dose.

[0067] The human nervous system is a complex network of nerve cells or neurons found in the central parts of the brain and spinal cord, and in the peripheral parts of the body in various nerves. Neurons have a cell body, dendrites, and an axon. A nerve is a group of neurons that functions in a specific part of the body. A nerve may contain hundreds of neurons to hundreds of thousands of neurons. A nerve often contains both afferent and efferent neurons. Afferent neurons carry signals to the central nervous system, and efferent neurons carry signals to the periphery. A group of nerve cell bodies in one location is known as a ganglion. Electrical signals generated in a nerve (for example, via a stimulus that may be intrinsic or applied externally) are conducted through neurons and nerves. Neurons release neurotransmitters at synapses (connections) adjacent to the receiving cell, allowing the electrical signal to continue and be regulated. In the periphery, synaptic transmission often occurs in ganglia.

[0068] The electrical signal of a neuron is known as an action potential. An action potential is initiated when the electrical potential across the cell membrane exceeds a certain threshold. This action potential then propagates down the length of the neuron. A nerve action potential is complex and represents the sum of the action potentials of the individual neurons in the nerve. The junction between the axon terminal of a neuron and the receiving cell is called a synapse. The action potential travels down the axon of the neuron to its axon terminal, the distal end of a branch of the axon nerve that forms the presynaptic or synaptic terminal of the nerve fiber. The electrical impulse of the action potential causes vesicles containing neurotransmitters to travel to the presynaptic membrane of the presynaptic axon terminal and ultimately release of neurotransmitters into the synaptic cleft (e.g., the space formed between the presynaptic and postsynaptic cells) or extracellular space. The synapse that reaches the synaptic terminal to convert the electrical signal of the action potential into a chemical signal for the release of neurotransmitters is a chemical synapse. A chemical synapse can be contrasted with an electrical synapse, in which an ionic current flowing into the presynaptic axon terminal can cross the barrier of two cell membranes and enter the postsynaptic cell.

[0069] The physiological effects of action potentials are mediated by the movement of ions across the cell membrane. Neurons transport Na + , K + , Cl - Neurons actively maintain a resting membrane potential via ion pumps that facilitate the passage of ions such as γ and γ-γ across the neuronal membrane. Different types of neurons may have different resting potentials (e.g., -75 mV to -55 mV). Action potentials are generated by the influx of ions, i.e., the movement of charge to generate a large deviation in membrane potential associated with a temporary increase in voltage across the membrane, e.g., an increase in membrane potential in the range of 30 to 60 mV. Action potentials in individual neurons may be initiated in response to the release of neurotransmitters from presynaptic (e.g., upstream) neurons, which in turn triggers receptor binding at the postsynaptic cell and a cascade of events leading to the influx of ions and membrane depolarization, resulting in an action potential propagating through the nerve.

[0070] A synapse can be located at the junction between two neurons, which allows an action potential to propagate down a nerve fiber. However, axon terminals can also form synapses at junctions between neurons and non-neuronal cells, or terminate in interstitial or body fluids. Examples of synapse types are synapses with immune cells at neuroimmune junctions, synapses with resident sensory cells in organs, or synapses with glandular cells. The release of neurotransmitters into the synaptic cleft and binding to receptors on the postsynaptic membrane of the postsynaptic cell results in downstream effects that depend on the nature of the presynaptic neuron and the particular neurotransmitter released, as well as the nature of the postsynaptic cell, e.g., the type of available receptors on the postsynaptic cell. Furthermore, action potentials can be excitatory or inhibitory. An excitatory postsynaptic action potential is a postsynaptic potential that increases the propensity of the postsynaptic neuron to excite or emit a subsequent action potential, whereas an inhibitory postsynaptic action potential is a postsynaptic potential that decreases the propensity of the postsynaptic neuron to excite or emit a subsequent action potential. Furthermore, several neurons may work together to coordinately release neurotransmitters that either elicit downstream action potentials or inhibit downstream action potentials.

[0071] Neuromodulation is a technique in which energy from an external energy source is applied to specific regions of the nervous system to activate or increase a nerve or nerve function and / or block or decrease a nerve or nerve function. In certain neuromodulation techniques, one or more conventional electrodes are applied to or near a target nerve, and the application of energy is transmitted (e.g., as an action potential) through the nerve, causing a physiological response in the region downstream of the site of energy application. However, because the nervous system is complex, it is difficult to predict the extent and ultimate endpoint of the physiological response at a particular site of energy application. In one example, stimulation of an axon terminal releases neurotransmitters / neuropeptides or induces changes in neurotransmitter release in nearby adjacent non-neuronal cells, such as secretory cells or other cells, modulating cellular activity in adjacent or nearby non-neuronal cells, including postsynaptic cells.

[0072] Advantages of the present technology include localized modulation at targeted regions of tissue to achieve targeted physiological outcomes that can be used to assess a patient's condition. Additionally, localized modulation can include direct activation of relatively small regions of tissue (e.g., less than 25% of the total tissue volume) to achieve these effects. In this manner, the total applied energy is relatively small to achieve the desired targeted physiological outcomes. In certain embodiments, the applied energy can be from a non-invasive external energy source (e.g., ultrasonic energy source, mechanical vibrator). For example, a focused energy probe can apply energy through the subject's skin and focus it to a targeted region of internal tissue. Such embodiments achieve the desired targeted physiological outcomes without invasive procedures or without side effects that may be associated with other types of treatments or therapies.

[0073] In certain embodiments, a technique for neuromodulation is provided in which energy from an energy source (e.g., an external or extracorporeal energy source) is applied to the axon terminal and / or surrounding / supporting tissue, and an induced targeted physiological outcome, e.g., neurotransmitter release at the focal site of energy application, such as the axon terminal, is induced in response to the application of energy and not in response to an action potential. That is, the direct application of energy to the axon terminal acts in place of an action potential to promote the release of neurotransmitters to the nerve junction (i.e., synapse) with a non-neuronal cell. The direct application of energy to the axon terminal further induces changes in the release of neurotransmitters from the axon terminal within the synapse (e.g., axon-extracellular synapse) to nearby adjacent non-neuronal cells, and / or the activation of sensory pathways that regulate the activity of other distant (but specific) regions of the body. In one embodiment, the energy source is an extracorporeal energy source, such as an ultrasonic energy source or a mechanical vibrator. In this manner, non-invasive, targeted neuromodulation can be achieved directly at the site of the energy focus rather than via stimulation at an upstream site, which in turn triggers action potentials to propagate to targets at downstream sites and activate the downstream targets.

[0074] In certain embodiments, the target tissue is an internal tissue or organ that is difficult to access using electrical stimulation techniques with electrodes. Contemplated tissue targets include gastrointestinal (GI) tissue (stomach, intestine), muscle tissue (cardiac muscle, smooth muscle and skeletal muscle), epithelial tissue (epidermis, organ / GI lining), connective tissue, glandular tissue (exocrine / endocrine glands), and the like. In one example, focused application of energy at a neuromuscular junction promotes the release of neurotransmitters at the neuromuscular junction without an upstream action potential. In one embodiment, contemplated targets for modulation may include the portion of the pancreas responsible for controlling the release of insulin, or the portion of the liver responsible for sensing glucose / metabolites and / or regulating their circulating concentrations.

[0075] Assessment of targeted physiological outcomes The neuromodulation techniques discussed herein can be used to cause targeted physiological outcomes of changes in the concentration (e.g., increase, decrease) of a molecule of interest and / or changes in the properties of a molecule of interest. That is, the outcome can include selective modulation of one or more molecules of interest (e.g., a first molecule of interest, a second molecule of interest, etc.), and can refer to modulating or affecting the concentration (circulation, tissue) or properties (covalent modification) of a molecule as a result of application of energy to one or more target regions (e.g., a first target region, a second target region, etc.) of one or more tissues (e.g., a first tissue, a second tissue, etc.). Modulation of a molecule of interest can include changes in the properties of a molecule, such as expression, secretion, protein translocation, and direct activity changes based on ion channel effects resulting from the energy application itself or as a result of the molecule directly affecting an ion channel. Modulation of a molecule of interest can also refer to maintaining a desired concentration of a molecule so that expected changes or fluctuations in concentration do not occur as a result of neuromodulation. Modulation of a molecule of interest may refer to causing a change in molecular properties, such as enzyme-mediated covalent modifications (such as changes in phosphorylation, acetylation, ribosylation, etc.). That is, it is understood that selective modulation of a molecule of interest may refer to molecular concentration and / or molecular properties. The molecule of interest may be a biomolecule, such as one or more of carbohydrates (monosaccharides, polysaccharides), lipids, nucleic acids (DNA, RNA), or proteins. In certain embodiments, the molecule of interest may be a signaling molecule, such as a hormone (amine hormone, peptide hormone, or steroid hormone), a cytokine, or a neurotransmitter.

[0076] The disclosed technology may be used to evaluate a patient's condition as a result of the targeted physiological outcome caused by a neuromodulation treatment protocol. The disclosed technology may use a direct assessment of tissue status or function as the targeted physiological outcome. The assessment may be performed before (i.e., baseline assessment), during, and / or after neuromodulation. The assessment technique may include at least one of functional magnetic resonance imaging, diffusion tensor magnetic resonance imaging, positron emission tomography, acoustic monitoring, thermal monitoring, or chemical sensing (e.g., immunochemical sensing). The assessment technique may also include protein and / or molecular concentration assessment. Images from the assessment technique may be received by the system for automated or manual evaluation. Based on the image data, the modulation parameters may also be altered. For example, changes in organ size or displacement may be utilized as markers of local neurotransmitter concentration and may be effectively used as surrogate markers of local cellular exposure to phenotypic modulation neurotransmitters and as a marker of predicted effects on glucose metabolic pathways. The local concentration may refer to the concentration within the focal field of energy application.

[0077] Additionally or alternatively, the system can assess the presence or concentration of one or more molecules circulating in tissue or blood. Concentration in tissue may be referred to as local or resident concentration. Tissue can be obtained by fine needle aspiration, and assessment of the presence or level of molecules of interest (e.g., metabolic molecules, markers of metabolic pathways, peptide mediators, catecholamines) can be performed by any suitable technique known to those skilled in the art.

[0078] In other embodiments, the targeted physiological outcome may include, but is not limited to, tissue displacement, changes in tissue size, changes in concentration of one or more molecules (either local, non-local, or circulating concentrations), changes in expression of genes or markers, afferent activity, cell migration, and the like. For example, tissue displacement (e.g., liver displacement) may occur as a result of the application of energy to the tissue. By assessing the tissue displacement (e.g., via imaging), other effects may be estimated. For example, a particular displacement may be characteristic of a particular change in molecular concentration. In one example, a 5% liver displacement may indicate or be associated with a desired reduction in circulating glucose concentration based on empirical data. In another example, tissue displacement may be assessed by comparing reference image data (images of the tissue before application of energy to the tissue) with post-treatment image data (images of the tissue taken after application of energy to the tissue) to determine a parameter of displacement. The parameter may be a maximum or average displacement value of the tissue. If the parameter of displacement is greater than a threshold displacement, it may be assessed that the application of energy likely caused the desired targeted physiological outcome.

[0079] In certain embodiments, the disclosed neuromodulation techniques may include a step of evaluating the effectiveness of the treatment protocol. For example, one or more direct or indirect assessments of the appearance of tissue function or status may be used. In one embodiment, the evaluation may be performed before and after applying the energy pulse to evaluate changes in molecule concentration as a result of the modulation. Furthermore, the evaluated property or status may be a value or index, e.g., flow rate, concentration, population of cells, or any combination thereof. These may then be analyzed by appropriate techniques. For example, a relative change above a threshold may be used to diagnose the patient. Diagnosis may be assessed via a measured clinical perturbation, such as the presence or absence of an increase in tissue structure size (e.g., lymph node size) or a change in concentration of one or more released molecules (e.g., compared to baseline concentrations prior to neuromodulation). In one embodiment, the results may include an increase in concentration above a threshold, e.g., greater than about a 50%, 100%, 200%, 400%, 1000% increase in concentration compared to baseline. The evaluation can include tracking a decrease in the concentration of the molecule over time, e.g., at least a 10%, 20%, 30%, 50%, or 75% decrease in the molecule of interest. The increase or decrease or other induced measurable effect can be measured within a particular time frame, e.g., within about 5 minutes, within about 30 minutes, from the start of treatment.

[0080] Treatment of clinical conditions As provided herein, neuromodulation treatment protocols may be used as part of the treatment of clinical conditions. Certain embodiments described herein provide neuromodulation techniques for the treatment of glucose metabolism and related disorders. Glucose regulation is complex and involves a variety of local and systemic metabolic pathways. The application of energy to a targeted region of interest causes characteristic changes in these metabolic pathways that affect glucose regulation. In some embodiments, modulation in one or more target regions may be used to treat disorders including, but not limited to, diabetes (i.e., type 1 or type 2 diabetes), hyperglycemia, sepsis, trauma, infection, physiological stress, dementia associated with diabetes, obesity, or other eating or metabolic disorders. In one example, physiological stress may be medically defined to include various acute medical conditions (infection, severe injury / trauma, heart attack, bypass) as well as surgical instances that present with hyperglycemia.

[0081] In one example, the technology can be used to diagnose subjects with metabolic disorders. The technology can also be used to diagnose and / or treat subjects with impaired glucose regulation. Thus, the technology can be used to promote a targeted physiological outcome to change the concentration of a molecule of interest, or promote a desired circulating concentration or concentration range of one or more molecules of interest (e.g., glucose, insulin, glucagon, or a combination thereof). In one embodiment, the technology can be used to evaluate clinical conditions related to circulating (i.e., blood) glucose levels. In one embodiment, a treatment protocol can be used to treat a patient with blood glucose levels that are out of normal. In another embodiment, a treatment protocol can be used to maintain a desired normal glucose level. Blood glucose levels can be classified as follows: Fasting: Less than 50 mg / dL (2.8 mmol / L): Insulin shock 50~70mg / dL (2.8~3.9mmol / L): Hypoglycemia / hypoglycemia 70~110mg / dL (3.9~6.1mmol / L): Normal 110-125mg / dL (6.1-6.9mmol / L): Elevated / Disordered (Prediabetes) 125(7mmol / L): Diabetes Non-fasting (after a meal, approximately 2 hours after a meal): 70~140mg / dL: Normal 140-199 mg / dL (8-11 mmol / L): High or "borderline" / prediabetic 200mg / dL or more: (11mmol / L): Diabetes

[0082] In another example, as provided herein, neuromodulation of lymphatic tissue can result in changes in immune activity or function. In certain embodiments, neuromodulation of lymph nodes results in local enlargement of lymph nodes relative to contralateral lymph nodes. The enlargement or hypertrophy may be associated with changes in muscle cell tone around lymphatic vessels, long-term recruitment and reorganization of lymphatic vessels around lymph nodes, and / or molecular changes at key barrier tissues (such as high endothelial venules (HEV) in lymph nodes), including changes in key transport proteins (such as aquaporins (water / fluid transport), or CCL21 / CXCL13 secretion (cell chemokines)). The result may result in changes in the overall lymph node tissue environment, including cell density, cell number, and expansion. Furthermore, lymph node activation may result in a cascade of activation that expands or amplifies local activation to activate the lymphatic system systemically. That is, local stimulation may result in downstream and upstream activation of the lymphatic system. Thus, local changes can be used to activate a systemic immune response. Additional changes may include alterations in lymphatic flow, trafficking of immune cells to / from lymphoid tissues, changes in immune cell phenotype or local immune responses, and / or trafficking of antigens to / from lymphoid tissues. Local stimulation may enable tissue- or location-specific increases in lymphatic or immune cell recruitment. Thus, neuromodulation may be used to treat immune conditions by altering the activity and / or function of immune pathways.

[0083] It should be understood that although certain embodiments are disclosed in the context of application of ultrasound energy, other types of energy are contemplated, such as magnetic resonance or radio frequency applied above the skin. Also contemplated is high power EIT, in which a grid of electrodes steers a field of electrical current locally to a target area within the body.

[0084] This written description uses examples to disclose the invention, including the best mode, and also enables any person skilled in the art to practice the invention, including making and using any devices or systems, and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal wording of the claims, or if they include equivalent structural elements that differ substantially from the literal wording of the claims.

Claims

1. A neuromodulatory system comprising: an ultrasound probe including an ultrasound transducer configured to apply an amount of ultrasound energy to a target area of ​​a patient's body effective to induce neuromodulation of one or more neural pathways; identifying the target area of ​​the patient's body which is the location of the predetermined area to be treated; controlling application of the ultrasound energy to the target area via the ultrasound probe; receiving position information relating to a position of the ultrasound probe; determining a position of the ultrasound probe relative to the region of interest; and a controller configured to track a dose to the target area and a dose of ultrasound energy applied to areas outside the target area over a treatment time frame based on the determination of the location, and to determine a dose of ultrasound energy applied to areas outside the target area and a total dose of ultrasound energy applied to the target area.

2. determining that the ultrasonic probe is located at the target region, and determining that ultrasonic energy is being deposited; determining that the ultrasonic probe is not at the target region and that no ultrasonic energy is being deposited; when a predetermined target dose to the region of interest is achieved, the controller switches off the application of energy from the ultrasound probe; The system of claim 1 , wherein the ultrasound probe comprises one or more position sensors configured to generate the position information.

3. The system of claim 2 , wherein the one or more position sensors comprise an inertial measurement unit.

4. The system of claim 2 , wherein the one or more position sensors include a mechanical fixation in a fixed position relative to the patient and / or an external device.

5. The system of claim 1 , wherein the ultrasound probe includes an ultrasound imaging transducer configured to generate the position information.

6. The system of claim 1 , wherein the ultrasound probe includes a camera configured to generate the position information, the camera being pointed away from a treatment surface of the ultrasound probe.

7. 7. The system of claim 6, wherein the position information includes one or more images acquired by the camera, and the controller is configured to determine that the position of the ultrasound probe is aligned with a position of the predetermined area to be treated when the image captures all or a portion of an indicator of the position of the predetermined area to be treated, the indicator being associated with the patient.

8. The system of claim 1 , further comprising a steering controller configured to steer all or a portion of the ultrasound probe during operation, the controller configured to actuate the steering controller based on the position information.

9. The system of claim 1 , wherein the controller is configured to provide an indication of the position of the ultrasound probe relative to the location of the predetermined area to be treated.

10. 2. The system of claim 1, wherein the controller is configured to determine that the position of the ultrasound probe is aligned with the position of the predetermined area to be treated based on the position information, and to enable application of the energy via the ultrasound probe when the ultrasound probe is aligned with the position of the predetermined area to be treated.

11. 2. The system of claim 1, wherein the controller is configured to determine that the position of the ultrasound transducer is aligned with the position of the predetermined area to be treated based on the position information, and to stop or switch off the application of energy via the ultrasound probe when the ultrasound probe is not aligned with the position of the predetermined area to be treated.

12. The system of claim 1 , wherein the controller is configured to provide an indication that the position of the ultrasound probe matches the position of the predetermined area to be treated.

13. The system of claim 1 , wherein the controller is configured to provide an indication that the position of the ultrasound probe is not aligned with the position of the predetermined area to be treated.

14. 14. The system of claim 13, wherein the display includes instructions for moving the ultrasound probe in a direction associated with matching the position of the ultrasound probe with the position of the predetermined area to be treated.

15. The system of claim 14 , wherein the instructions include one or more of text instructions, arrows, or images displayed on a display.

16. 2. The system of claim 1, wherein the controller is configured to calculate an off-target dose of energy to be applied to areas outside the target area based on the position of the ultrasound probe relative to a position of the predetermined area to be treated over a time frame.

17. A neuromodulatory system comprising: an ultrasound probe configured to apply energy to a target region of a patient's body, the ultrasound probe including an ultrasound therapy transducer and at least one position feedback device including a position sensor, a position fixture, a camera, an ultrasound imaging transducer, or a combination thereof, the position feedback device configured to generate information related to a position of the ultrasound probe; and identifying the target area of ​​the patient's body which is the location of the predetermined area to be treated; controlling application of the energy to the region of interest via the ultrasound probe; receiving position information relating to the position of the ultrasound probe; determining the position of the ultrasound probe relative to a location of a predetermined area to be treated based on the position information; and tracking a dose to the target region and a dose of ultrasound energy applied to regions outside the target region over a treatment time frame based on the determination of the location, and determining a dose of ultrasound energy applied to regions outside the target region and a total dose of energy applied to the target region. A system including a controller configured for.

18. In the controller, Identifying a target area on the patient's body which is the location of the predetermined area to be treated; controlling an ultrasound transducer to deliver ultrasound energy to the target area of ​​the patient's body in which the ultrasound transducer is positioned; determining that a position of the ultrasound transducer is aligned with a position of a predetermined area to be treated; upon determining that the location is consistent with the location of the predetermined area to be treated, initiating application of energy from the ultrasound transducer to control the ultrasound transducer to deliver a dose of energy to the target area in an amount effective to induce neuromodulation of one or more neural pathways; tracking a dose to the target region and a dose of ultrasound energy applied to areas outside the target region over a treatment time frame based on the determination of the location, and determining a dose of ultrasound energy applied to areas outside the target region and a total dose applied to the target region; and controlling the ultrasound transducer to discontinue the application of energy from the ultrasound transducer if the total dose is equal to or greater than a predetermined threshold; Software code containing instructions to execute a program.

19. The controller, receiving updated position information of the ultrasonic transducer; determining that the ultrasound transducer has moved relative to the patient and that the updated position of the ultrasound transducer does not match the position of the predetermined area to be treated; and 20. The software code of claim 18, further comprising instructions to be executed to control the ultrasonic transducer to cease the application of energy from the ultrasonic transducer.

20. The controller, 20. The software code of claim 18, comprising instructions to provide an indication that the ultrasound transducer is at a predetermined location or on target when the position of the ultrasound transducer is aligned with the position of a predetermined area to be treated.

21. 20. The software code of claim 18, wherein the region of interest is the liver.

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