Multi-beam neuromodulation technology

Abstract

The disclosed subject matter generally relates to techniques for neuromodulation of tissue, which techniques include applying energy (e.g., ultrasound energy) to the tissue at multiple regions of interest in parallel or sequentially. Neuromodulation can cause tissue displacement, which can be observed as changes in one or more molecules of interest.

Description

Technical Field

[0001] The subject matter disclosed herein relates to neuromodulation, and more particularly, to techniques for modulating physiological responses with energy applied from an energy source. Background Art

[0002] Neuromodulation has been used to treat a variety of clinical conditions. For example, electrical stimulation at different locations along the spinal cord has been used to treat chronic back pain. Such treatment can be performed by an implantable device that periodically generates electrical energy, which is applied to tissue to activate certain nerve fibers, which in turn can cause a reduction in pain sensation. In the case of spinal cord stimulation, the stimulating electrodes are typically located in the epidural space, and although the pulse generator may be located at a slightly distant location from the electrodes, such as in the abdominal or buttock region, it is connected to the electrodes by wires. In other embodiments, 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 typically targets local nerve or brain cell function and is mediated by electrodes that deliver electrical pulses and are located at or near the target nerve. However, it is challenging to position the electrodes at or near the target nerve. For example, such techniques may involve surgical placement of the electrodes that deliver energy. Additionally, it is challenging to target specific tissues through neuromodulation. Electrodes located at or near certain target nerves mediate neuromodulation by triggering action potentials in nerve fibers, which in turn causes the release of neurotransmitters at the nerve synapses and synaptic communication with the next nerve. Such propagation can cause a relatively greater or more diffuse physiological effect than desired because current embodiments of implanted electrodes stimulate many nerves or axons at once. Since nerve pathways are complex and interconnected, a more targeted modulation effect may be more clinically useful. Summary of the Invention

[0003] Certain embodiments are summarized below that are equivalent in scope to the originally claimed subject matter. These embodiments are not intended to limit the scope of the claimed subject matter, but rather these embodiments are only intended to provide a brief summary of possible embodiments. In fact, the present disclosure may include a variety of forms that may be similar to or different from the embodiments described below.

[0004] In one embodiment, an ultrasound system is provided. The ultrasound system includes at least one ultrasound transducer having a plurality of elements. The ultrasound system further includes a controller configured to control the dose of ultrasound energy applied to a subject. The controller is configured to receive image data of the subject's tissue from the ultrasound transducer; divide the image data of the tissue into a plurality of segments representative of the tissue; focus the ultrasound transducer on a plurality of regions of interest, each region of interest being located in a different segment of the plurality of segments; and control the ultrasound transducer to apply ultrasound energy, the ultrasound energy being distributed among the plurality of regions of interest to cause tissue displacement in each region of interest.

[0005] In one embodiment, a method is provided that includes the steps of: distributing an ultrasound energy dose among a plurality of regions of interest, where each individual region of interest among the plurality of regions of interest receives a fraction of the ultrasound energy dose, and where the ultrasound energy cumulatively applied to the plurality of regions of interest is approximately equal to the ultrasound energy dose; evaluating the efficacy of the ultrasound energy dose; and modifying instructions to apply a subsequent ultrasound energy dose for neuromodulation therapy based on the evaluation.

[0006] In one embodiment, a method is provided that includes the steps of: receiving image data of a subject's tissue; dividing the image data of the tissue into a plurality of segments; selecting a plurality of regions of interest in the tissue that are associated with respective ones of the plurality of segments; and controlling an ultrasound transducer to apply an ultrasound energy dose distributed among the plurality of regions of interest, where at least one of the plurality of regions of interest includes at least one axon terminal of a neuron that forms a synapse with a non-neuronal cell. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0008] Figure 1 Schematic diagram of an ultrasound arrangement including a single ultrasound beam;

[0009] Figure 2 Schematic diagram of an ultrasound arrangement including parallel ultrasound beams;

[0010] Figure 3 Annotated ultrasound image of a subject being treated with ultrasound stimulation, showing the regions of interest to which the ultrasound energy is directed;

[0011] Figure 4 Annotated ultrasound image of a treated subject, having ultrasound stimulation regions of interest to which the ultrasound energy is directed;

[0012] Figure 5 Annotated ultrasound image of a treated subject, having ultrasound stimulation regions of interest to which the ultrasound energy is directed;

[0013] Figure 6 Annotated ultrasound image of a treated subject, having ultrasound stimulation regions of interest to which the ultrasound energy is directed;

[0014] Figure 7 Shows Figure 3-6 a plot of the fasting blood glucose levels of the subject at different time points;

[0015] Figure 8Displays a plot of the ultrasound dose fraction in the spleen, hilum, and pancreas of a subject at a half-power stimulation dose;

[0016] Figure 9 Displays a plot of the ultrasound dose fraction in the spleen, hilum, and pancreas of a subject at a full-power stimulation dose;

[0017] Figure 10 Displays Figure 3-6 a plot of the blood TNF-α level of a subject at different time points;

[0018] Figure 11 Displays Figure 3-6 a plot of the change in the blood TNF-α level of a subject at different time points and relative to the baseline;

[0019] Figure 12 Displays a plot of the fasting blood glucose and TNF-α level of a subject in the study;

[0020] Figure 13 Is a schematic diagram of a partitioned tissue according to an embodiment of the present disclosure;

[0021] Figure 14 Is a flowchart of a method for applying an allocated ultrasound dose according to an embodiment of the present disclosure;

[0022] Figure 15 Is a schematic diagram of an ultrasound neuromodulation system according to an embodiment of the present disclosure; and

[0023] Figure 16 Is a block diagram of an ultrasound neuromodulation system according to an embodiment of the present disclosure. Detailed Description

[0024] The following describes one or more specific embodiments. To provide a concise description of these embodiments, not all features of actual implementations are described in the specification. It should be understood that in the development of any such actual implementation, as in any engineering or design project, many implementation-specific decisions must be made to achieve the developer's specific goals, such as compliance with system-related and industry-related constraints, which may vary depending on the implementation. Additionally, it should be understood that such development work may be complex and time-consuming, but for those skilled in the art who benefit from the present disclosure, it will still be a matter of routine in design, assembly, and manufacturing.

[0025] Any example or illustration given in this document should not be construed in any way as a constraint, limitation, or expression of a definition for any one or more terms used with them. Instead, these examples or illustrations should be regarded as descriptions of various specific embodiments and are for illustrative purposes only. Those of ordinary skill in the art will understand that any one or more terms used with these examples or illustrations will cover other embodiments, which may or may not be given together with that term or elsewhere in the specification, and all such embodiments are intended to be included within the scope of such one or more terms. Language indicating such non-limiting examples and illustrations includes, but is not limited to: "for example", "such as", "including", "in certain embodiments", "in some embodiments", and "in one embodiment".

[0026] As provided herein, a non-invasive ultrasound stimulation device can be used to vibrate targeted tissue in vivo at multiple locations (i.e., multiple anatomical stimulation locations with different physiological functions), and cost-effectively modulate multiple pathways and / or modulate a specific therapeutic effect. Additionally, dual-beam and multi-beam ultrasound devices can deliver parallel stimulation doses to multiple tissues. Most physiological functions are controlled and regulated by multiple molecules under the control of neural and humoral pathways and networks. Techniques are provided herein for facilitating therapeutic treatment by causing in vivo displacement at multiple stimulation sites. This is achieved by applying a non-invasive ultrasound stimulation device that targets and moves tissue at multiple locations in the body. It can also be accomplished with an ultrasound device that can deliver stimulation doses to multiple tissues either in parallel or sequentially. Stimulation of multiple anatomical tissue locations can modulate different physiological functions and / or modulate a specific therapeutic effect. Additionally, these techniques facilitate treatments that can be customized to provide complementary therapeutic interventions.

[0027] Traditional drugs are designed to bind to or affect specific molecular targets. Thus, using traditional drugs for multi-pharmacological targeting or multi-system therapy may involve administering multiple drugs, which is expensive, may involve complex dosing regimens, and may expose the subject to multiple side effects. For example, each drug in a multi-drug therapy has its own ADME (absorption, distribution, metabolism, and excretion) profile. These differences in ADME profiles, as well as the overall differences in pharmacokinetics and clearance rates of each drug, will affect the side effects of each individual drug. The neuromodulation techniques disclosed herein can avoid the side effects of drug therapy and provide more personalized treatment options.

[0028] Stretching and / or shifting can be induced into tissue in a variety of ways (naturally occurring physical movements, mechanical actuators, ultrasound, electromagnetic, optical, implantable devices). Ultrasound has its unique properties in controlling the focus and shape, while at the same time can penetrate deeply into tissue and can be quickly and effectively applied to multiple stimulation sites. Therefore, the non-invasive ultrasound neuromodulation systems and methods disclosed herein can be used to vibrate (move) the targeted tissue at multiple locations in vivo (i.e., multiple anatomical stimulation locations with different physiological functions). The neuromodulation technique can be used in combination with a neuromodulation system configured to deliver neuromodulation energy as part of a treatment regimen to cause tissue displacement.

[0029] Figure 1 An example of an ultrasound arrangement that can be used in combination with the disclosed techniques is provided, where the ultrasound beam can be steered to successively focus on different regions of interest in a subject's tissue. A single ultrasound beam 12 is shown as being emitted by an ultrasound transducer 14, which includes a plurality of elements that can be individually addressed (activated) to focus on an operator-selected region of interest 20 in the subject's tissue. The region of interest 20 is typically along the axis of the beam 12 and can be controlled to be deeper (e.g., towards tissue depth 22) or shallower (closer to the transducer 14) depending on the beam focus. The axis of the ultrasound beam 12 depends on the active sub-aperture 30a, which includes, for example, 71 of the 192 elements of the transducer 14, and depends on the relative timing of the signals applied to each element. Although the beam axis is most effective when aligned with the sub-aperture, steering the focus region by using timing delays gives greater flexibility with little loss of efficiency. However, activation of adjacent elements 30b, 30c or different subsets of elements will result in different beam axes of the emitted ultrasound beam 12 and different positions of the region of interest 20. Therefore, as provided herein, an Figure 1 arrangement can be used to target multiple successive regions of interest 20 distributed within a single organ or tissue structure or between two or more organ or tissue structures. In one embodiment, a single ultrasound dose can be distributed among two, three, four, five or more regions of interest 20.

[0030] Figure 2 A schematic diagram of an alternative arrangement is shown, where the transducer 14 is controlled to emit multiple ultrasound beams 12a, 12b in parallel via respective sub-apertures 30d, 30e to target multiple anatomical tissue sites in parallel, e.g., regions of interest 20a, 20b. Therefore, as provided herein, an Figure 2 arrangement can be used to target multiple parallel regions of interest 20 distributed within a single organ or tissue structure or between two or more organ or tissue structures. In one embodiment, a single ultrasound dose can be distributed among two, three, four, five or more regions of interest 20.

[0031] It should be understood that Figure 1-2 the examples depicted in can be combined with each other, and the transducer 14 can also emit successive ultrasonic beams 12c in different directions to target one or more additional regions of interest 20c. In addition, in one embodiment, the operator can provide user input defining a single region of interest (e.g., region of interest 20c), and the disclosed techniques can automatically allocate ultrasonic doses between two, three, or more different regions of interest (e.g., regions of interest 20a, 20b) that are spaced apart from the user-defined region of interest 20c and in accordance with the rule-based logic generally disclosed herein. When the ultrasonic transducer 14 is at the position of the treatment site 32 on the subject's skin, as Figure 1-2 shown in, it is capable of steering without moving the ultrasonic transducer 14 relative to the treatment site 32. The ultrasonic transducer 14 can be controlled to treat a series of potential sites successively or in parallel within the focusing range of the transducer 14, depending on the length, number of elements, and radius of curvature of the selected transducer 14.

[0032] The disclosed multi-beam stimulation techniques can be used in combination with multiple stimulation sites (regions of interest) in a single organ or tissue structure target (e.g., liver, pancreas, gastrointestinal tissue, or immune structures such as spleen or lymph nodes). The disclosed multi-beam stimulation techniques can be used in combination with one or more stimulation sites (regions of interest) distributed between two or more organ or tissue structure targets as disclosed herein. Although certain examples are disclosed in the context of a particular organ or region of interest (e.g., spleen and / or pancreas), it should be understood that other targets are also covered within the scope of the present disclosure. Thus, ultrasonic energy doses can be applied to two or more regions of interest in the liver, pancreas, gastrointestinal tissue, spleen, and / or lymph nodes using the disclosed multi-beam stimulation techniques.

[0033] Human multi-site ultrasound targeting studies were conducted to evaluate the regulation of inflammatory states induced by ultrasound neuromodulation. As disclosed herein, ultrasound was used to cause displacement vibrations of the target tissue and, in some cases, tissues adjacent to the pancreas, such as the adjacent tail of the pancreas. In the study, the ultrasound dose for tissue displacement was modulated, and different dose levels were applied to different study groups. In response to different concentrations of lipopolysaccharide (LPS) exposure, leukocyte regulation that inhibits the release of the pro-inflammatory marker TNF-α was observed. The inflammatory state of the subjects was characterized by measuring the blood TNF-α response to LPS. Targeting the spleen and the cholinergic anti-inflammatory pathway (CAP) system of the spleen can cause inhibition of TNF-α release from immune cells to be observed. Targeting the tail of the pancreas and the β-cells of the pancreas to release insulin can also modulate the inflammatory state, i.e., further inhibit the release of TNF-α from leukocytes. Changes in blood glucose measurements observed relative to the pre-stimulus baseline were used as a surrogate for insulin release from the pancreas. Changes 1 hour after the change in blood glucose relative to the baseline (pre-stimulus) time point characterized the effective insulin release and insulin sensitivity of the subjects.

[0034] A group of human subjects received a sham control ultrasound dose, 200 mW / cm 2 The half-power dose of the spatial peak temporal average intensity (Ispta) or the full-power dose of 400 mW / cm 2 (Ispta). The ultrasound dose for the subjects receiving ultrasound energy was distributed among multiple regions of interest (e.g., the stimulation site). The experimental group was stimulated in one or more regions of interest of the spleen. Some subjects were also stimulated at the tail of the pancreas. The spleen site was selected to examine the effect of ultrasound stimulation at different locations within the spleen. For example, the splenic hilum is a landmark for localizing the spleen using ultrasound imaging and can be used to identify the orientation and location of other sites in the spleen. The tail of the pancreas is close to the splenic hilum. This study examined the effect of ultrasound stimulation using one or more regions of interest aligned with the splenic hilum.

[0035] Figure 3-6 Ultrasound images with annotated markers are shown, showing the organ positions and regions of interest of different subjects in human ultrasound studies. The regions of interest are in the spleen and, in some subjects, in the pancreatic region. The subjects were stimulated with ultrasound according to different dose parameters and at the treatment sites generally shown in the annotated images. The subjects received fasting blood draws to evaluate the concentrations of various blood molecules at baseline and at different time points (1 hour, 2 hours, 24 hours) after ultrasound stimulation. Figure 3-6 For the subjects from the study group, where the total administered dose was 200 mW / cm 2 (temporal average intensity) half-power dose, separated among multiple sites (two or three sites) and at different locations in the spleen and / or pancreas.

[0036] Figure 3Displays the ultrasound image of the subject who received the half-power dose distributed among three different locations in the spleen. At 1 hour after treatment, the subject's blood glucose increased by 11.7% relative to the pre-stimulus baseline. Figure 4 Displays the ultrasound image of the stimulation using two beams both in the spleen. At 1 hour after treatment, the subject's blood glucose decreased by 6% relative to the pre-stimulus baseline. Figure 5 Displays the ultrasound image of the stimulation using two beams, one in the spleen and one in the tail of the pancreas. At 1 hour after treatment, the subject's blood glucose decreased by 31% relative to the pre-stimulus baseline. Figure 6 Displays the ultrasound image of the stimulation using two beams, one in the spleen and one in the tail of the pancreas. At 1 hour after treatment, the subject's blood glucose decreased by 38% relative to the pre-stimulus baseline. Figure 3-6 The subjects in are generally consistent with the following research results, where the treatment at two different organ sites causes overlapping physiological effects and a greater reduction in the concentration of the molecule of interest observed relative to the baseline, which is the result of ultrasound stimulation.

[0037] Figure 7 Displays Figure 3-6 The fasting blood glucose concentrations of the subjects in at 1 and 2 hours after stimulation relative to the pre-stimulus baseline. The subjects in the study were divided into low and high pancreatic stimulation glucose response groups. The subjects were classified as low or high using a 12% threshold of the fasting blood glucose change at 1 hour. In the study, this threshold was defined by the median of the absolute % blood glucose change of a total of 39 subjects at 1 hour after stimulation. Thus, 50% of the subjects in the study were low and the other 50% were classified as high. Plots 50 (see Figure 3 ) and Plot 52 (see Figure 4 ) are plots for the subjects classified in the low glucose response group, and Plots 54 ( Figure 5 ) and Plot 56 ( Figure 6 ) are plots for the subjects classified in the high glucose response group. Thus, the combined stimulation of the pancreas and spleen indicates classification in the high response group.

[0038] Figure 8 Displays the plots of the ultrasound dose fractions in the spleen (Plot 60), portal (Plot 62), and pancreas (Plot 64) of 16 subjects in the half-power group. Figure 9Plots of ultrasound dose fractions in the spleen (plot 70), hilum (plot 72), and pancreas (plot 74) of 12 subjects in the full-power group are shown. The subjects were divided into two groups: low and high pancreatic-stimulated glucose response groups, based on the decrease in blood glucose 1 hour after stimulation relative to the pre-stimulation baseline. An absolute change of more than 12% was classified as high, otherwise the subject was considered a low glucose responder. Subjects with a larger ultrasound dose fraction in the pancreas had a larger glucose decrease 1 hour after stimulation (plots 64, 74). A full-power stimulation dose fraction of approximately 10% of the pancreas may be sufficient to cause a glucose decrease (indicated by the arrow in plot 74). The change in blood glucose 1 hour after stimulation was used as a surrogate measure of insulin release from the pancreatic tail. This surrogate measure also indicated the insulin sensitivity of individual subjects. The insulin-producing β-cells and the highest concentration of extractable insulin are located in the pancreatic tail. Stimulating the pancreatic tail with ultrasound triggers insulin release into the bloodstream, causing a significant decrease in blood glucose 1 hour after stimulation in the high-response group.

[0039] Ultrasound stimulation of the spleen can also inhibit the release of TNF-α from macrophages and white blood cells. Figure 10 Results of TNF-α release in the blood of individual subjects in the study at different time points and at baseline in response to LPS administration are shown. Plot 80 (see Figure 3 ) and plot 82 (see Figure 4 ) are plots for subjects classified as the low glucose response group, and plot 84 ( Figure 5 ) and plot 86 ( Figure 6 ) are plots for subjects classified as the high glucose response group. Figure 11 Shows Figure 10 the change in TNF-α relative to baseline 1 hour and 2 hours after stimulation in subjects, where low glucose responders (plots 90 and 92) were associated with a lower overall decrease or inhibition of TNF-α release compared to high glucose responders (plots 94 and 96). The results suggest a potential insulin-mediated regulation and a decrease in the release of TNF-α from immune cells.

[0040] Figure 12 Shows the change in fasting blood glucose (plots 100, 102, 104) and the change in the area under the curve of TNF-α response (plots 106, 108, 100) at 1, 2, and 24 hours relative to the pre-stimulation baseline for the low and high glucose response groups of 39 human subjects. Those subjects who stimulated the pancreas together with the spleen had higher insulin release, a greater glucose decrease, and a greater decrease in the observed TNF-α response to LPS. The results suggest that targeting CAP in the spleen and insulin release from the pancreas regulate the inflammatory state of the subjects.

[0041] Figure 13A flowchart of a method 120 for multi-site neuromodulation by applying ultrasonic energy to a target tissue. In method 120, the target tissue is imaged to generate image data (block 122) accessed or received by an ultrasonic system. The image data can be generated by an ultrasonic transducer 14 operating in an imaging mode. In another embodiment, a dedicated imaging transducer can be used at the treatment site 32 to generate the image data. Once received, the target tissue is divided into a plurality of segments (block 124). A plurality of regions of interest are selected, whereby each region of interest is associated with a different segment among the segments (block 126). The ultrasonic transducer 14 is controlled to apply an ultrasonic energy dose distributed among the selected regions of interest (block 126). Applying the ultrasonic energy produces a desired effect in the regions of interest, such as tissue displacement, which can be evaluated by alternative measures of neuromodulation efficacy, as generally provided herein.

[0042] Figure 14 A schematic diagram of a first organ 150 and a second organ 152 that can be at least partially imaged and, for example, present in the image data ( Figure 13 ). However, it should be understood that the disclosed techniques can be applied to a single organ or two or more organs or non-organ tissue structures. Additionally, the image data can include only a partial image of the organ of interest. Identification of the first organ 150 or the second organ 152, including the organ boundaries and general shape within the image, can be performed by an organ segmentation algorithm, user input, or by a neural network, as generally disclosed in U.S. Patent Application No. 16 / 567,996, which was filed on September 11, 2019, and is hereby incorporated by reference in its entirety for all purposes.

[0043] The identified first organ 150 and second organ 152 can be divided into a plurality of segments. For example, the first organ can be divided into a plurality of first organ segments 160, and the second organ can be divided into a plurality of second organ segments 162. The rules for controlling the number of segments 160, 162 can be preset by the user or the system. In one embodiment, the user can generally identify regions 168, 170 that roughly correspond to the regions of interest through a user interface, such as by drawing or otherwise selecting a portion of the desired size. Once selected, the system can divide the first organ 150, 152 into a plurality of segments 160, 162 that are approximately equal in size to the selected regions 168, 170. In another embodiment, the system can have predetermined rules for dividing the organ into a plurality of segments 160, 162 based on the identified organ type, the focus limitation of the transducer 14, and the desired ultrasonic energy dose. The segments 160, 162 can or may not be of approximately equal volume.

[0044] The section can be made visible, and the section boundaries are indicated on the image generated from the image data. In one embodiment, the user can select one or more desired sections as the region of interest 20 by clicking or otherwise interacting with the visible section on the display. Alternatively, in cases where the section boundaries are visible or not visible on the image, the user can indicate regions 168, 170 corresponding to one or more regions of interest 20, and the system can associate the selected regions 168, 170 with the corresponding one or more sections 152, 162. For example, the user can typically indicate a first region 168 corresponding to a specific section 160a on the first organ 150 and a second region 170 corresponding to a specific section 162a in the second organ 152. Once selected, the system can use these sections 160a, 162a as the regions of interest, and can turn the ultrasound transducer 14 to apply ultrasound energy to the tissue or the location within the tissue corresponding to the sections 160a, 162a.

[0045] In one embodiment, the disclosed techniques can automatically select the region of interest 20 based on user input. For example, the user can indicate the desired distribution of ultrasound energy to three sites, two in the first organ 150 and one in the second organ 152. The user can select a first region of interest 20 associated with section 160a and a second region of interest 20 associated with section 162a. The system can then use rule-based logic to select a third region of interest 20 in the first organ 150 to, for example, avoid adjacent sections (e.g., 160b, 160c, 160d, 160f) and instead select spaced-apart sections 160e, 160g. In another example, the user can select a first region of interest 20 associated with section 160a, and the system can distribute the dose around the selected region of interest 20 based on the input, such as using two adjacent sections (e.g., 160b, 160c, 160d, 160f). In another example, the system can have a stored protocol where sections are ranked based on empirical efficacy information, and the selection can be based on that ranking. In one example, section 162 can be the highest-ranked section, while the adjacent section 162b has a sub-optimal ranking. Thus, section 162a can be part of a first-line treatment protocol, and if section 162a is ineffective for a particular subject, section 162b can be used. Additionally, as disclosed herein, subsequent doses can be moved around the organ such that subsequent doses are distributed to different sections (162b, 162c, 162d).

[0046] In some cases, the user may wish to capture multiple organs at a single stimulation site. The region of interest 20 can be selected to include sections that overlap between the organs 150, 152. For example, the region of interest 20 can be within section 160h of the first organ and section 162d of the second organ 162.

[0047] In one embodiment, the system may distribute an ultrasound energy dose among a plurality of regions of interest 20. The distribution may be generally equal or may be skewed such that one or more regions of interest 20 receive more ultrasound energy than other regions. For example, if the ultrasound energy dose for a particular treatment is set at 400 m / Wcm 2 to be distributed between two different regions of interest, a first region of interest 20 corresponding to the selected segment 160a and a second region of interest 20 corresponding to the selected segment 162a, the dose energy may be distributed between the two regions of interest 20 at a ratio of 1:1 - 1:2, 1:1 - 1:3, 1:1 - 1:5, or 1:1 - 1:10. For example, 75 - 90% of the dose may be applied to one region of interest 20 while 10 - 25% of the dose is applied to the other region of interest 20. When there are three regions of interest 20, the dose may be distributed among the three regions of interest 20 at a ratio of 1:1:1 - 1:2:1, 1:1:1 - 1:2:2, 1:1:1 - 1:3:1, 1:1:1 - 1:3:3, 1:1:1 - 1:5:1, :1:1 - 1:5:5, 1:1:1 - 1:10:1, or 1:1:1 - 1:10:10. The distribution ratio may be selected based on the organ type and / or organ size. For example, a particular organ may be associated with a greater reactivity at a lower dose distribution. Thus, a multi-site dose may be distributed where a larger percentage of the dose is applied to the region of interest 20 (or organ) with lower reactivity, while the region of interest 20 with greater reactivity may require less energy to achieve the desired effect. In this way, the dose may be applied to the patient more effectively and in a manner that minimizes the overall ultrasound energy exposure. Additionally, since the ultrasound energy can be focused on the region of interest 20 of concern, off-target exposure can be minimized.

[0048] As provided herein, the efficacy of neuromodulation can be evaluated and the system can track the efficacy of the ultrasound energy applied to different segments. The evaluation can be through surrogate markers such as changes in the concentration of one or more molecules of interest, which serve as an indicator of tissue displacement due to the ultrasound energy. In one embodiment, a particular segment may be associated with an effective treatment for a general subject population. However, when the ultrasound energy is applied to the region of interest 20 associated with that segment, an individual subject may not achieve the desired efficacy. Given the differences in treatment reactivity between patients, subsequent doses may be distributed to different segments.

[0049] By tracking the location of the region of interest 20 for a previous treatment and automatically allocating subsequent doses to the region of interest 20 associated with different segments, the disclosed techniques can also avoid the physiological compensation effect of subsequent doses. Additionally, the system can track the total energy applied to each segment during a treatment regimen that occurs over days, weeks, or months, and within a particular time window, a rule-based logic can be used to limit the total energy applied to each individual segment to be below a predetermined threshold. Further, the system can also use the same segments for subsequent doses, but can vary the dose allocation between segments for an individual dose. In one example, if segment 160b received greater than 50% of a first dose, while segments 160b and 162a each received less than 25%, then the same segment 160b can receive only 25% or less of a subsequent dose.

[0050] Figure 15 A system 200 for neuromodulation to achieve neuromodulatory effects is shown, such as tissue displacement at multiple regions of interest 20 associated with neurotransmitter release and / or activation of components (e.g., presynaptic cell, postsynaptic cell) of a synapse in response to energy application. The depicted system includes a pulse generator 214 coupled to an energy application device 212 (e.g., including an ultrasound transducer 14). The energy application device 212 is configured to receive energy pulses, e.g., via a wire or a wireless connection, which are directed in use to multiple regions of interest 20 in one or more internal tissues or organs of a subject, which in turn causes the targeted physiological outcome.

[0051] In certain embodiments, the energy application device 212 and / or the pulse generator 214 can communicate wirelessly, e.g., with a controller 216, which in turn can provide instructions to the pulse generator 214. In other embodiments, the energy application device 212 can be an extracorporeal device, e.g., operable to apply energy transcutaneously or in a non-invasive manner from a location external to the subject's body, and in certain embodiments, can be integrated with the pulse generator 214 and / or the controller 216. In embodiments where the energy application device 212 is an extracorporeal device, the energy application device 212 can be operated by a caregiver and positioned at a point on or above the subject's skin such that energy pulses are delivered transcutaneously to the desired internal tissue. Once positioned to apply energy pulses to the desired region of interest 20, the system 200 can initiate neuromodulation of one or more neural pathways to achieve the targeted physiological outcome or clinical effect. In other embodiments, the pulse generator 214 and / or the energy application device 212 can be implanted at a biocompatible site (e.g., the abdomen) and can be internally coupled, e.g., via one or more wires. In some embodiments, the system 200 can be implemented such that some or all of the components can communicate with each other in a wired or wireless manner.

[0052] In some embodiments, system 200 may include an evaluation device 220, which is coupled to controller 216 and evaluates characteristics indicating whether 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 cause local tissue or functional changes, such as changes in tissue structure, local changes in the concentration of certain molecules, tissue displacement, increased fluid movement, etc. The targeted physiological outcome may be the goal of a treatment regimen.

[0053] Modulating one or more neural pathways to achieve the targeted physiological outcome may cause systemic or non-local changes, and the targeted physiological outcome may involve changes in circulating molecular concentrations or changes in the characteristics of tissues in the region of interest that do not include the direct application of energy. In one example, displacement may be an alternative measurement for the desired modulation, and a displacement measurement below the expected displacement value may result in modifying the modulation parameters until the expected displacement value is induced. Thus, in some embodiments, evaluation device 220 may be configured to evaluate concentration changes. In some embodiments, evaluation device 220 may be an imaging device configured to evaluate changes in organ size, position, and / or tissue characteristics. In another embodiment, evaluation device 220 may be a circulating glucose monitor. Although the depicted elements of system 200 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 local heating of the tissue, which can be detected with a separate temperature sensor or with ultrasonic imaging data from energy application device 212 (when configured for ultrasonic energy application). Evaluation of the difference in sound velocity can be detected by differential imaging techniques before / during / after treatment.

[0054] Based on this evaluation, the modulation parameters of controller 216 may be changed to deliver an effective amount of energy. For example, if the desired modulation is related to a change in concentration (circulating concentration or tissue concentration of one or more molecules) within a defined time window (e.g., 5 minutes, 30 minutes after the start of the energy application process) or relative to a baseline at the start of the process, then it may be necessary to change the modulation parameters, such as the pulse frequency or other parameters, which can in turn be provided to controller 216 by the operator or through an automatic feedback loop for defining or adjusting the energy application parameters or modulation parameters of pulse generator 214 until the modulation parameters cause an effective amount of energy to be applied. In one embodiment, the initially defined region of interest may be refined to generate an updated region of interest based on feedback from the evaluation device regarding the efficacy of the neuromodulation energy during the treatment regimen. For example, the feedback may be a change in the concentration of the molecule of interest due to the application of neuromodulation energy. These refinements or updates to the region of interest may be used as part of a patient-specific network, where the network is updated to identify specific regions of interest that have the greatest impact on the physiological parameters of interest for that particular individual based on the desired clinical outcome.

[0055] The system 200 provided herein can deliver energy pulses as part of a treatment regimen according to various adjustment parameters to deliver an effective amount of energy. For example, the adjustment parameters can include various stimulation time patterns from continuous to intermittent. With intermittent stimulation, energy is delivered at a certain frequency for a period of time during the on-time of the signal. After the on-time of the signal is a period of time during which no energy is delivered, referred to as the off-time of the signal. The adjustment parameters can also include the frequency and duration of the stimulation application. The application frequency can be continuous or delivered in various time periods, such as within a day or a week. In addition, the treatment regimen can specify the time of day to deliver the energy, or the time relative to eating or other activities. The treatment duration to cause the targeted physiological outcome can last for various time periods, including but not limited to from a few minutes to several hours. In certain embodiments, the treatment duration using a specified stimulation pattern can last for one hour, for example, repeated at 72-hour intervals. In certain embodiments, the energy can be delivered at a higher frequency (e.g., every 3 hours) for a shorter duration (e.g., 30 minutes). Depending on the adjustment parameters, such as treatment duration, frequency, and amplitude, the application of energy can be adjustably controlled to achieve the desired result.

[0056] Figure 16 FIG. is a block diagram of certain components of the system 200. As provided herein, the system 200 for neuromodulation can include a pulse generator 214 adapted to generate a plurality of energy pulses for application to a subject's tissue. The pulse generator 214 can be separate or can be integrated into an external device such as a controller 216. The controller 216 includes a processor 230 for controlling the device. Software code or instructions are stored in a memory 232 of the controller 216 for execution by the processor 230 to control the various components of the device. The controller 216 and / or the pulse generator 214 can be connected to an energy application device 212 by one or more wires 233 or wirelessly.

[0057] The controller 216 can include a user interface having an input / output circuit 234 and a display 236 adapted to allow a clinician to provide selection inputs (e.g., select a region of interest 20 or a specific segment on a target tissue image related to the desired region of interest 20) or adjustment parameters to an adjustment program. The processor 230 can be configured to operate to identify one or more organs or tissue structures within the image data and divide the organ or tissue structure into segments. In addition, the processor 230 can be configured to apply ultrasonic energy to the subject in one or more regions of interest related to a specific segment.

[0058] The system may include a beam controller 237 that can control the focal position of the energy beam of the transducer 14 of the energy application device 212 by controlling one or both of the steering and / or focusing of the energy application device 212 to apply parallel multi-beam therapy or sequential beam therapy to one or more tissues. The beam controller 237 can also control one or more articulating portions of the energy application device 212 to reposition the transducer. The beam controller can receive instructions from the processor 230 to effect a change in the focusing and / or steering of the energy beam. The system 200 can respond to a position sensor 238 and / or a contact sensor 239 that provide feedback to the energy application device 212. The beam controller 237 can include an electric motor to facilitate the steering of one or more articulating portions of the energy application device 212. It is contemplated that the system 200 can include components that allow for positioning, steering, and / or focus adjustment to facilitate the techniques disclosed herein.

[0059] Each adjustment program stored in the memory 232 can include one or more sets of adjustment parameters, including pulse amplitude, pulse duration, pulse frequency, pulse repetition rate, etc. The pulse generator 214 modifies its internal parameters in response to a control signal from the controller device 216 to change the stimulation characteristics of the energy pulses transmitted through the wire 233 to the subject to which the energy application device 212 is applied. Any suitable type of pulse generation circuit can be employed, 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 duration. The controller 216 allows for adjustable control of the energy by changing the adjustment parameters and / or initiating energy application at certain times or inhibiting energy application at certain times. In one embodiment, the adjustable control of the energy application device that applies energy is based on information regarding the concentration of one or more molecules (e.g., circulating molecules) in the subject.

[0060] If the information is from the evaluation device 220, the feedback loop can drive the adjustable control. For example, a diagnosis can be made based on the circulating glucose concentration measured by the evaluation device 220 in response to neuromodulation. When the concentration is above a predetermined threshold or range, the controller 216 can initiate a treatment regimen of applying energy to a region of interest (e.g., the spleen) and use adjustment parameters associated with a reduction in circulating glucose. The treatment regimen can use adjustment parameters different from those used in the diagnostic regimen (e.g., higher energy levels, more frequent application).

[0061] In one embodiment, the memory 232 stores different operation modes that can be selected by an operator. For example, the stored operation modes can include separate algorithms for identifying a specific region of interest and performing a set of adjustment parameters associated with a specific treatment site (e.g., a region of interest in the liver, pancreas, gastrointestinal tract, spleen). Each organ or site can be associated with a different model. Additionally, different sites can have different associated adjustment parameters based on the depth of the associated organ, the size of the region of interest, the desired physiological outcome, etc. The controller 216 can be configured to execute appropriate instructions based on the selection of a specific organ, rather than having the operator manually input the mode. In another embodiment, the memory 232 stores operation modes for different types of procedures. For example, activation can be associated with a different range of stimulation pressure or frequency as compared to the range of stimulation pressure or frequency associated with inhibiting or blocking tissue function.

[0062] In one specific instance, when the energy application device is an ultrasonic transducer, the effective amount of energy can relate to the predetermined time-average intensity applied to the region of interest. For example, the effective amount of energy can include a time-average power (time-average intensity) and a peak positive pressure in the range of 1 mW / cm 2 – 30,000 mW / cm 2 (time-average intensity) and 0.1 MPa to 7 MPa (peak pressure). In one instance, the time-average intensity is less than 35 mW / cm 2 、less than 500 mW / cm 2 or less than 720 mW / cm 2 in the region of interest. In one instance, the time-average intensity is associated with a level lower than those associated with thermal damage and ablation / cavitation. The controller 216 may be capable of operating in a verification mode to acquire a predetermined treatment location, and the predetermined treatment location can be implemented as part of a treatment operation mode configured to execute a treatment protocol when the energy application device 212 is located at the predetermined treatment location.

[0063] The system may also include an imaging device that facilitates focusing of the energy application device 212. In one embodiment, the imaging device may be integrated with the energy application device 212 or be the same device as the energy application device 212 such that different ultrasound parameters (frequency, aperture, or energy) are used to select (e.g., spatially select) the region of interest and to focus the energy to the selected region of interest for targeting and subsequent neuromodulation. In another embodiment, the memory 232 stores one or more targeting or focusing patterns for spatially selecting 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 corresponding to the region of interest. The spatial selection may rely on the image data provided herein. Based on the spatial selection, the energy application device 212 may focus (e.g., using the beam controller 237) to a focal position on the selected volume corresponding to the region of interest. It should be understood that the image data used to guide the focal position may be volumetric or planar. For example, the energy application device 212 may be configured to first operate in a verification mode to acquire a predetermined treatment position by capturing image data that will be used to identify the predetermined treatment position associated with capturing the region of interest. The verification mode energy is not applied at a level suitable for neuromodulation treatment and / or with adjustment parameters suitable for neuromodulation treatment. However, once the region of interest is identified, the controller 216 may operate in a treatment mode according to adjustment parameters associated with achieving the targeted physiological outcome.

[0064] The target tissue may be internal tissue or an organ including synapses with axon terminals and non-neuronal cells. By directly applying ultrasound energy to axon terminals within the focal field of an ultrasound transducer focused on the region of interest 20 in the target tissue, synapses can be stimulated to cause the release of molecules into the synaptic space. The selectable region of interest may include a certain type of axon terminal, such as axon terminals of a particular neuron type and / or axon terminals that form synapses with a certain type of non-neuronal cell. Thus, the selectable region of interest 20 can be chosen to correspond to a portion of the target tissue having the desired axon terminals (and associated non-neuronal cells). The energy application can be selected to preferentially trigger the release of one or more molecules (such as neurotransmitters) from the nerves within the synapse, or directly activate the non-neuronal cells themselves through direct energy transfer, or cause activation within both nerve cells and non-neuronal cells that elicits the desired physiological effect.

[0065] The controller 216 can also be configured to receive inputs related to the targeted physiological outcome as inputs for the selection of the adjustment parameters. For example, when evaluating tissue characteristics in an imaging mode, the controller 216 can be configured to receive an index or parameter calculated for the characteristic. Based on whether the index or parameter is above or below a predetermined threshold, a diagnosis can be made and an indication of the diagnosis can be provided (e.g., via a display). In one embodiment, the parameter can be a measure of the tissue displacement of the affected tissue or a measure of the depth of the affected tissue. Other parameters can include assessing the concentration of one or more molecules of interest (e.g., assessing one or more of a change in concentration relative to a threshold or baseline / control, a rate of change, determining whether the concentration is within a desired range). Additionally, the energy application device 212 (e.g., an ultrasound transducer) can be operated under the control of the controller 216 to a) acquire image data of the tissue, use the available image data to spatially select a region of interest within the target tissue, b) apply the adjustment energy to the region of interest, and c) acquire image data to determine that the targeted physiological outcome has occurred (e.g., via displacement measurements). In such an embodiment, the imaging device, the evaluation device 220, and the energy application device 212 can be the same device.

[0066] The technical effects of the present disclosure include the controlled application of multi-site neuromodulation energy (e.g., ultrasound energy), which avoids physiological compensation effects and adjusts the dose based on the selected region of interest (e.g., the stimulation site), such that the total energy applied to the patient is minimized. In this way, the neuromodulation system can consume less energy and can operate more efficiently. Multiple stimulation sites for a single energy dose can be selected such that the physiological effects of the neuromodulation energy enhance each other. In one example, stimulation of the spleen causes a decrease in glucose, while stimulation of the pancreas and spleen together produces a greater glucose-lowering effect due to the parallel release of insulin from the pancreas. Additionally, the insulin release also causes a parallel change in the patient's immune status, which may be related to the desired physiological outcome. However, the disclosed experimental results are examples, and the technical effects of the present disclosure can be applied to other multi-site stimulation scenarios.

[0067] This written description uses examples, including the best mode, to enable any person skilled in the art to practice the disclosed technology, including making and using any device or system and performing any combined methods. The scope of the patentable subject matter is defined by the claims and may include other examples that occur to persons 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 language of the claims or if they include equivalent structural elements that do not differ in substance from the literal language of the claims.

Claims

1. An ultrasound system, characterized in that, the ultrasound system comprises: an ultrasound transducer including a plurality of individually addressable elements configured to distribute a dose of ultrasound energy among a plurality of regions of interest of a subject; and a controller, wherein the controller is configured to: control the dose applied by the plurality of individually addressable elements among the plurality of regions of interest; when the ultrasound transducer is operating in an imaging mode, receive ultrasound image data of the tissue of the subject from the ultrasound transducer; divide the ultrasound image data of the tissue into a plurality of segments representative of the tissue; receive an input regarding a selection of the plurality of regions of interest, each region of interest of the plurality of regions of interest being located in a different segment of the plurality of segments; focus the ultrasound transducer on the selected plurality of regions of interest; control the ultrasound transducer in a treatment mode to distribute the dose of ultrasound energy among the plurality of regions of interest to neuromodulate more than two neural pathways of the subject, wherein the ultrasound energy is associated with a level lower than that associated with tissue ablation, and wherein the neuromodulation of the more than two neural pathways induces a physiological effect; and receive an input related to the induced physiological effect.

2. The system according to claim 1, characterized in that, wherein the tissue includes a first organ and a second organ different from the first organ, and wherein a first region of interest of the plurality of regions of interest is in the first organ and a second region of interest of the plurality of regions of interest is in the second organ.

3. The system according to claim 2, characterized in that, wherein at least 75% of the dose is applied to the first organ.

4. The system according to claim 2, characterized in that, wherein the first organ is the pancreas, spleen or liver.

5. The system according to claim 1, characterized in that, wherein the tissue includes an organ, and wherein the plurality of regions of interest are in the organ.

6. The system according to claim 1, characterized in that, wherein the controller is configured to control the applied dose such that no individual segment among the plurality of segments receives more than a selected threshold of ultrasound energy over a period of time.

7. The system according to claim 1, characterized in that, wherein the controller is configured to apply the ultrasound energy to the respective regions of interest in parallel.

8. The system according to claim 1, characterized in that, wherein the controller is configured to apply the ultrasound energy to the respective regions of interest sequentially.

9. The system according to claim 1, characterized in that, wherein the controller is configured to control a first subset of the plurality of elements to apply a first ultrasound energy to a first region of interest of the plurality of regions of interest and control a second subset of the plurality of ultrasound elements to apply a second ultrasound energy to a second region of interest of the plurality of regions of interest.

10. The system according to claim 9, characterized in that, wherein the first region of interest is in the first organ and the second region of interest is in a second organ different from the first organ, and wherein the first ultrasound energy is a greater fraction of the dose than the second ultrasound energy.

11. The system according to claim 1, characterized in that, where tissue displacement is evaluated by monitoring the change in concentration of one or more molecules relative to a baseline.

12. The system according to claim 11, wherein, a first molecule among the one or more molecules is TNF-α, and a second molecule among the one or more molecules is glucose.

13. An ultrasound neuromodulation system, wherein, the system includes a controller and an evaluation device; the controller is configured to: allocate an ultrasound energy dose among a plurality of regions of interest, where each individual region of interest among the plurality of regions of interest receives a fraction of the ultrasound energy dose, and where the cumulative ultrasound energy applied to the plurality of regions of interest is approximately equal to the ultrasound energy dose; control the dose applied among the plurality of regions of interest; receive ultrasound image data of the tissue of the subject; divide the ultrasound image data of the tissue into a plurality of segments representative of the tissue; receive an input regarding the selection of the plurality of regions of interest, each region of interest of the plurality of regions of interest being located in a different segment of the plurality of segments; control the dose of the ultrasound energy allocated among the plurality of regions of interest to neuromodulate more than two neural pathways of the subject, where the ultrasound energy is associated with a level lower than that associated with tissue ablation, and where the neuromodulation of the more than two neural pathways induces a physiological effect; and receive an input related to the induced physiological effect; the evaluation device evaluates the efficacy of the ultrasound energy dose; and the controller is further configured to: based on the evaluation, modify the instructions to apply a subsequent ultrasound energy dose for neuromodulation treatment.

14. The system according to claim 13, wherein, modifying the instructions includes selecting a different plurality of regions of interest among which to allocate the fraction of the subsequent ultrasound energy dose.

15. The system according to claim 13, wherein, modifying the instructions includes changing the relative allocation of the ultrasound energy among the plurality of regions of interest of the subsequent ultrasound energy dose.

16. The system according to claim 15, wherein, the controller is further configured to: based on the change in concentration of a molecule of interest relative to a baseline, change the allocation of the subsequent ultrasound energy dose applied to an individual region of interest among the plurality of regions of interest.

17. An ultrasound neuromodulation system, wherein, the system includes a controller configured to: receive image data of the tissue of the subject; divide the image data of the tissue into a plurality of segments representative of the tissue; select a plurality of regions of interest in the tissue related to each of the plurality of segments; focus an ultrasound transducer on the selected plurality of regions of interest; Control the ultrasonic transducer to distribute a dose of ultrasonic energy between the plurality of regions of interest to neuromodulate more than two neural pathways of the subject, wherein the ultrasonic energy is associated with a level lower than that associated with tissue ablation, wherein the neuromodulation of the more than two neural pathways induces a physiological effect, and at least one of the plurality of regions of interest includes at least one axon terminal of a neuron that forms a synapse with a non-neuronal cell; and Receive an input related to the induced physiological effect.

18. The system according to claim 17, wherein, the controller is further configured to: select different plural segments and control the ultrasonic transducer to apply subsequent doses of ultrasonic energy distributed between the different plural regions of interest.

19. The system according to claim 17, wherein, selecting the plurality of regions of interest includes selecting at least one region of interest in a first organ and at least one region of interest in a second organ.

20. The system according to claim 17, wherein, each of the plural segments has an approximately same volume relative to each other.

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