Multibeam Neuromodulation Technology

Abstract

The subject matter of the present disclosure generally relates to techniques for neuromodulation of tissue, which involve applying energy (e.g., ultrasound energy) to tissue simultaneously or sequentially in multiple target regions. Neuromodulation can result in tissue displacement, which can be observed by changes in one or more molecules of the target.

Description

[Technical field]

[0001] The subject matter disclosed herein relates to neuromodulation, and more specifically, to techniques for modulating physiological responses using energy applied from an energy source. [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. Such treatment can be performed by an implantable device that periodically generates electrical energy that is applied to tissue to activate specific nerve fibers, which in turn can result in a reduced sensation of pain. For spinal cord stimulation, the stimulating electrode is generally placed in the epidural space, but the pulse generator can be placed some distance from the electrode, for example in the abdominal or buttock area, but is connected to the electrode via a wire. In other implementations, deep brain stimulation can be used to stimulate specific areas 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 function, deliver electrical pulses, and are placed at or near the target nerve. However, placing the electrodes at or near the target nerve is difficult. For example, such techniques can include 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 implanted electrode implementations 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 targeted modulation effects may be more clinically useful. Summary of the Invention

[0003] Certain embodiments commensurate in scope with the originally 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, this disclosure may encompass a variety of forms that may be similar to or different from the embodiments set forth below.

[0004] In one embodiment, an ultrasound system is provided. The ultrasound system includes at least one ultrasound transducer having multiple elements. The ultrasound system also includes a controller configured to control a dose of ultrasound energy applied to a target. The controller is configured to receive image data of tissue of the target from the ultrasound transducer, divide the image data of the tissue into multiple segments representing the tissue, focus the ultrasound transducer on multiple target regions, each target region being located within a different one of the multiple segments, and control the ultrasound transducer to apply ultrasound energy distributed among the multiple target regions to cause tissue displacement in each target region.

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

[0006] In one embodiment, a method is provided that includes the steps of receiving image data of a target tissue, dividing the image data of the tissue into a plurality of segments, selecting a plurality of target regions of the tissue associated with respective segments of the plurality of segments, and controlling an ultrasound transducer to apply an ultrasound energy dose distributed among the plurality of target regions, wherein at least one target region of the plurality of target regions includes at least one axon terminal of a neuron, the axon terminal forming 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 be better understood when the following detailed description is read in reference to the accompanying drawings, in which like characters represent like parts throughout the drawings.

[0008] [Figure 1] FIG. 1 is a schematic diagram of an ultrasound configuration including a single ultrasound beam.

[0009] [Diagram 2] FIG. 1 is a schematic diagram of an ultrasound configuration including concurrent ultrasound beams.

[0010] [Diagram 3] 1 is an annotated ultrasound image of a subject being treated with ultrasound stimulation, showing the area of ​​the subject to which ultrasound energy was directed.

[0011] [Figure 4] 1 is an annotated ultrasound image of a subject being treated with ultrasound stimulation of a region of the subject where ultrasound energy is directed.

[0012] [Diagram 5] 1 is an annotated ultrasound image of a subject being treated with ultrasound stimulation of a region of the subject where ultrasound energy is directed.

[0013] [Figure 6]1 is an annotated ultrasound image of a subject being treated with ultrasound stimulation of a region of the subject where ultrasound energy is directed.

[0014] [Figure 7] FIG. 7 shows plots of fasting blood glucose levels at various time points for the subjects of FIGS. 3-6.

[0015] [Figure 8] 1 shows plots of the fraction of ultrasound dose in the spleen, hilus, and pancreas of a subject at half-output stimulation dose.

[0016] [Figure 9] 1 shows plots of the fraction of ultrasound dose in the spleen, hilus, and pancreas of a subject at full output stimulation dose.

[0017] [Figure 10] 7 shows plots of blood TNF-α levels at various time points for the subjects of FIGS.

[0018] [Figure 11] FIG. 7 shows plots illustrating the change in blood TNF-α levels at various time points and relative to baseline for the subjects in FIGS. 3-6.

[0019] [Figure 12] 1 shows plots of fasting blood glucose and TNF-α levels of subjects in the study.

[0020] [Figure 13] FIG. 1 is a schematic diagram of a segmented tissue according to an embodiment of the present disclosure.

[0021] [Figure 14] 1 is a flow diagram of a method for applying a distributed ultrasound dose according to an embodiment of the present disclosure.

[0022] [Figure 15] FIG. 1 is a schematic diagram of an ultrasound neuromodulation system, according to an embodiment of the present disclosure.

[0023] [Figure 16] FIG. 1 is a block diagram of an ultrasound neuromodulation system according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] One or more specific embodiments are described below. In order to provide a concise description of these embodiments, not all features of an actual implementation are described herein. As with any engineering or design project, it is understood that the development of any such actual implementation 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 that may vary from implementation to implementation. Moreover, it is understood that such development efforts may be complex and time-consuming, but will nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill in the art having the benefit of this disclosure.

[0025] Any examples or figures described herein should not be considered in any manner of limiting, restricting, or expressing a definition for 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 one or more terms in which these examples or figures are utilized encompass 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 that one or more terms. Phrases referring to 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."

[0026] As provided herein, non-invasive ultrasound stimulation devices can be used to vibrate target tissues in the body at multiple locations (i.e., multiple anatomical stimulation locations with different physiological functions) to cost-effectively modulate multiple pathways and / or modulate specific therapeutic effects. Furthermore, dual-beam and multi-beam ultrasound devices can deliver stimulating doses to multiple tissues simultaneously. Most physiological functions are controlled and regulated by multiple molecules under neural and fluid pathways and network control. Provided herein are techniques that facilitate therapeutic treatments by causing body displacements at multiple stimulation sites. This is accomplished by application of non-invasive ultrasound stimulation devices that target and displace tissues at multiple locations in the body. It can also be achieved using ultrasound devices that can deliver stimulation doses to multiple tissues simultaneously or sequentially. Stimulation of multiple anatomical tissue locations can modulate different physiological functions and / or modulate specific therapeutic effects. Furthermore, these techniques facilitate treatments that can be tailored to provide complementary therapeutic interventions.

[0027] Conventional medicines are designed to bind to or act on specific molecular targets. Thus, using conventional medicines to perform multiple pharmacological targeting or multiple systemic treatments may involve administering multiple drugs, which can be costly, involve complex administration protocols, and expose subjects to multiple side effects. For example, each drug in a multi-drug treatment has its own ADME (absorption, distribution, metabolism, and excretion) profile. These differences in ADME profile and the overall differences in the pharmacokinetics and clearance rate of each drug affect the side effects of each individual drug. The neuromodulation technology disclosed herein can avoid the side effects of pharmaceutical treatments and provide more personalized treatment options.

[0028] Stretching and / or displacement can be induced in tissue in multiple ways (spontaneous physical movement, mechanical actuators, ultrasound, electromagnetic, optical, implantable devices). Ultrasound is unique in its property of controlling focus and shape while simultaneously penetrating deep into tissue, and can be applied quickly and efficiently to multiple stimulation sites. Thus, the non-invasive ultrasound neuromodulation systems and methods disclosed herein can be used to vibrate (displace) target tissue at multiple locations within the body (i.e., multiple anatomical stimulation locations with different physiological functions). Neuromodulation techniques can be used in conjunction with a neuromodulation system configured to be used to deliver neuromodulation energy as part of a treatment protocol to cause tissue displacement.

[0029] FIG. 1 is an example of an ultrasound device that may be used in conjunction with the disclosed technology, where an ultrasound beam may be steered to sequentially focus on different target regions of the target tissue. A single ultrasound beam 12 is shown emitted by an ultrasound transducer 14. It includes multiple elements that may be individually addressed (activated) to focus on an operator-selected target region 20 in the target tissue. The target region 20 is generally along the axis of the beam 12 and can be controlled to be deeper (e.g., toward tissue depth 22) or shallower (closer to the transducer 14) depending on the focus of the beam. The axis of the ultrasound beam 12 depends on an active partial aperture 30a, which includes, by way of example, 71 elements of the 192 elements of the transducer 14, and the relative timing of the signals applied to each element. The beam axis is most efficient when aligned with the partial aperture, but steering the focal region by utilizing timing delays gives more flexibility without a significant loss of efficiency. However, activating adjacent elements 30b, 30c or elements of different subsets results in different beam axes of emitted ultrasound beams 12 and different locations of target regions 20. Thus, as provided herein, the arrangement of Figure 1 may be used to target multiple contiguous target regions 20 within a single organ or tissue structure or distributed among two or more organs or tissue structures. In one embodiment, a single ultrasound dose may be distributed among two, three, four, five, or more target regions 20.

[0030] 2 shows a schematic diagram of an alternative configuration in which the transducer 14 is controlled to simultaneously emit multiple ultrasound beams 12a, 12b through respective partial apertures 30d, 30e to simultaneously target multiple anatomical tissue sites, e.g., target regions 20a, 20b. Thus, as provided herein, the arrangement of FIG. 2 can be used to target multiple, concurrent target regions 20 within a single organ or tissue structure, or distributed among two or more organs or tissue structures. In one embodiment, a single ultrasound dose may be distributed among two, three, four, five, or more target regions 20.

[0031] It should be understood that the examples shown in Figures 1-2 can be combined with each other, and the transducer 14 can also emit continuous ultrasound beams 12c in different directions to target one or more additional target regions 20c. Furthermore, in an embodiment, an operator can provide user input defining a single target region (e.g., target region 20c), and the disclosed technology can automatically distribute a dose of ultrasound between two, three, or more different target regions (e.g., target regions 20a, 20b) spaced apart from the user-defined target region 20c and according to the rule-based logic generally disclosed herein. When the ultrasound transducer 14 is in position at a treatment site 32 on the subject's skin, as shown in Figures 1-2, it can be manipulated without moving the ultrasound transducer 14 relative to the treatment site 32. The ultrasound transducer 14 can be controlled to treat a range of possible sites within the focal range of the transducer 14 sequentially or simultaneously, 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 with multiple stimulation sites (target regions) in a single organ or tissue structure target, such as the liver, pancreas, gastrointestinal tissue, or immune structures such as the spleen or lymph nodes. The disclosed multi-beam stimulation techniques can be used with one or more stimulation sites (target regions) distributed between two or more organ or tissue structure targets as disclosed herein. Although specific examples are disclosed in connection with specific organs or target regions, such as the spleen and / or pancreas, it should be understood that other targets are also contemplated within the scope of the present disclosure. Thus, the disclosed multi-beam stimulation techniques can be used to apply ultrasound energy doses to two or more target regions of the liver, pancreas, gastrointestinal tissue, spleen, and / or lymph nodes.

[0033] A human multi-site ultrasound targeting study was conducted to evaluate the modulation of inflammatory states as a result of ultrasound neuromodulation. As disclosed herein, ultrasound was used to induce tissue-displacing vibrations in a target tissue, in some cases, as an example, the adjacent tail of the pancreas. The ultrasound dose of tissue displacement was adjusted in the study, with different dose levels applied to different test groups. Modulation of leukocytes to inhibit the release of the pro-inflammatory marker TNF-α was observed in response to different concentrations of lipopolysaccharide (LPS) exposure. Blood TNF-α response to LPS assays was used to characterize the inflammatory state of the subjects. Targeting the spleen and splenic cholinergic anti-inflammatory pathway (CAP) system may result in the observed attenuation of TNF-α release by immune cells. Targeting the tail of the pancreas and pancreatic beta cells to release insulin may also modulate inflammatory states, i.e., further inhibit TNF-α release by leukocytes). The change in observed blood glucose measurements compared to pre-stimulation baseline was used as a proxy for insulin release from the pancreas. The change in blood glucose 1 hour post-change versus the baseline (pre-stimulation) time point characterized the effective insulin release and insulin sensitivity of the subject.

[0034] A group of human subjects received a sham control ultrasound dose of 200 mW / cm 2 of spatial-peak temporal-average intensity (Ispta), or 400 mW / cm2 Subjects receiving ultrasound energy received a total output dose (Ispta) of 1000 ng / mL. The ultrasound dose of subjects receiving ultrasound energy was distributed across multiple target regions (e.g., stimulation sites). Experimental groups were stimulated at one or more splenic regions of interest. Certain subjects were also stimulated at the tail of the pancreas. The splenic sites were selected to examine the effects of ultrasound stimulation at different locations within the spleen. For example, the splenic hilum is a landmark for locating the spleen using ultrasound imaging and may be used to identify the orientation and location of other sites in the spleen. The tail of the pancreas is located next to the splenic hilum. This study examined the effects of ultrasound stimulation using one or more target regions aligned with the splenic hilum.

[0035] Figures 3-6 show ultrasound images with annotated markings indicating the location of different organs of interest and the target regions in a human ultrasound study. The target regions are in the spleen and in the region of the pancreas in a particular subject. The subjects were stimulated with ultrasound at the treatment sites according to different dose parameters as generally indicated in the annotated images. The subjects were fasted and subjected to blood sampling to assess various blood molecule concentrations at baseline and at different time points (1 hour, 2 hours, 24 hours) after ultrasound stimulation. Figures 3-6 show the results of a total administered dose of 200 mW / cm 2 (time-average intensity) at half output dose, with subjects coming from multiple sites, either two or three sites, and divided into test groups at different locations in the spleen and / or pancreas.

[0036] FIG. 3 shows ultrasound images of a subject receiving a half-power dose distributed among three different locations within the spleen. The subject's blood glucose increased 11.7% compared to the pre-stimulation baseline at 1 hour after treatment. FIG. 4 shows ultrasound images of stimulation using two beams, all in the spleen. The subject's blood glucose decreased 6% compared to the pre-stimulation baseline at 1 hour after treatment. FIG. 5 shows ultrasound images of stimulation using two beams, one in the spleen and one in the tail of the pancreas. The subject's blood glucose decreased 31% compared to the pre-stimulation baseline at 1 hour after treatment. FIG. 6 shows ultrasound images of stimulation using two beams, one in the spleen and one in the tail of the pancreas. The subject's blood glucose decreased 38% compared to the pre-stimulation baseline at 1 hour after treatment. The subjects in FIG. 3-FIG. 6 are generally consistent in their test results. Treatment at two different organ sites resulted in overlapping physiological effects and a more significant decrease in the observed concentration of the molecule of interest compared to the baseline as a result of ultrasound stimulation.

[0037] FIG. 7 shows the fasting blood glucose concentrations of the subjects of FIGS. 3-6 at 1 and 2 hours after stimulation compared to the pre-stimulation baseline. The subjects of the study were classified into low and high pancreatic stimulated glucose response groups. A threshold of 12% for fasting blood glucose change at 1 hour was used to classify the subjects as low or high. This threshold was defined using the median absolute percent blood glucose change at 1 hour after stimulation for a total of 39 subjects in the study. Thus, 50% of the subjects in the study were classified as low and the remaining 50% were classified as high. Plots 50 (see FIG. 3) and 52 (see FIG. 4) are plots of subjects classified as low glucose response group, while plots 54 (FIG. 5) and 56 (FIG. 6) are plots of subjects classified as high glucose response group. Thus, combined pancreatic and splenic stimulation showed classification in the high response group.

[0038] FIG. 8 shows plots of the percentage of ultrasound dose in the spleen (plot 60), hilus (plot 62), and pancreas (plot 64) of 16 subjects in the half-power group. FIG. 9 shows plots of the percentage of ultrasound dose in the spleen (plot 70), hilus (plot 72), and pancreas (plot 74) of 12 subjects in the full-power group. Subjects were classified into two groups, low and high pancreatic stimulated glucose response groups, based on the drop in blood glucose at 1 hour after stimulation relative to baseline pre-stimulation. An absolute change of more than 12% was classified as high, otherwise the subject was considered a low glucose responder. Subjects with a larger percentage of ultrasound dose in the pancreas had a larger decrease in glucose 1 hour after stimulation (plots 64, 74). A percentage of the full-power stimulation dose of approximately 10% to the pancreas may be sufficient to cause a decrease in glucose (indicated by the arrow in plot 74). The change in blood glucose 1 hour after stimulation was used as a surrogate for the measurement of insulin release from the tail of the pancreas. This surrogate measure also indicated the insulin sensitivity of each individual subject. The highest concentration of insulin-producing beta cells and extractable insulin is found in the tail of the pancreas. Stimulation of the tail of the pancreas with ultrasound triggered the release of insulin into the bloodstream and caused a significant drop in blood glucose one hour after stimulation in the high responder group.

[0039] Ultrasound stimulation of the spleen may also inhibit the release of TNF-α from macrophages and leukocytes. Figure 10 shows the results of TNF-α release in blood at various time points for individual subjects in the study and in response to LPS administration at baseline. Plots 80 (see Figure 3) and 82 (see Figure 4) are plots of subjects classified as low glucose response group, and plots 84 (Figure 5) and 86 (Figure 6) are plots of subjects classified as high glucose response group. Figure 11 shows the change in TNF-α relative to baseline at 1 hour and 2 hours after stimulation for the subjects of Figure 10, with the glucose low responders (plots 90 and 92) associated with a lower overall reduction or attenuation of TNF-α release compared to the glucose high responders (plots 94 and 96). The results demonstrate the potential for insulin-mediated regulation and reduction of TNF-α release by immune cells.

[0040] Figure 12 shows the fasting blood glucose change (plots 100, 102, 104) at 1, 2, and 24 hours for low and high glucose responder groups for 39 human subjects, and the change in area under the curve for TNF-α response (plots 106, 108, 100) compared to baseline before stimulation. Subjects who stimulated pancreas together with spleen had higher insulin release, more significant glucose reduction, and a greater reduction in observed TNF-α response to LPS. The results demonstrate that targeting CAP in spleen and insulin release from pancreas modulated the inflammatory state of subjects.

[0041] FIG. 13 is a flow diagram of a method 120 for multi-site neuromodulation by application of ultrasound energy to a target tissue. In the method 120, the target tissue is imaged to generate image data (block 122), which is accessed or received by an ultrasound system. The image data may be generated by an ultrasound transducer 14 operating in an imaging mode. In another embodiment, a dedicated imaging transducer may be used at the treatment site 32 to generate the image data. Once received, the target tissue is divided into a number of segments (block 124). A number of target regions are selected, whereby each target region is associated with a different one of the segments (block 126). The ultrasound transducer 14 is controlled to apply a dose of ultrasound energy distributed among the selected target regions (block 126). The application of ultrasound energy causes a desired effect in the target regions, such as tissue displacement, which may be evaluated via a surrogate measure of the efficacy of neuromodulation, as generally presented herein.

[0042] FIG. 14 is a schematic diagram of a first organ 150 and a second organ 152 that may be at least partially imaged and present in the image data (FIG. 13) by way of example. However, it should be understood that the disclosed techniques may be applied to a single organ or to more than one organ or tissue structure that is not an organ. Also, the image data may include images of only a portion of the organ of interest. Identification of the first organ 150 or the second organ 152, including the organ's boundaries and overall shape in the image, may be via an organ segmentation algorithm, user input, or via a neural network as generally disclosed in U.S. Patent Application Publication No. 2016 / 567,996, filed September 11, 2019, which is hereby incorporated by reference in its entirety for all purposes.

[0043] The identified first organ 150 and second organ 152 may be divided into a number of segments. For example, the first organ may be divided into a number of first organ segments 160 and the second organ may be divided into a number of second organ segments 162. The rules governing the number of segments 160, 162 may be pre-set by the user or the system. In an embodiment, the user may generally identify a region 168, 170 that approximately corresponds to the region of interest, for example by drawing or selecting a portion of a desired size, via a user interface. Once selected, the system may then divide the first organ 150, 152 into a number of segments 160, 162 that approximately correspond to the size of the selected region 168, 170. In another embodiment, the system may have pre-defined rules based on the type of identified organ, the focal limits of the transducer 14, and the desired ultrasound energy dose for dividing the organ into a number of segments 160, 162. The segments 160, 162 may or may not be of approximately equal volume.

[0044] The segments may be visualized, with the boundaries of the segments indicated on the image generated by the image data. In an embodiment, the user may select a desired segment as the region of interest 20 by clicking or otherwise interacting with a visible segment on the display. Alternatively, if the boundaries of the segments are visible or not visible on the image, the user may indicate a region 168, 170 corresponding to one or more regions of interest 20, and the system may correlate the selected region 168, 170 to the corresponding segment 152, 162. For example, the user may generally indicate a first region 168 corresponding to a particular segment 160a on the first organ 150 and a second region 170 corresponding to a particular segment 162a in the second organ 152. Once selected, the system may use these segments 160a, 162a as the region of interest and steer the ultrasound transducer 14 to apply ultrasound energy to or within the tissue to locations corresponding to the segments 160a, 162a.

[0045] In an embodiment, the disclosed technique can automatically select a region of interest 20 based on a user's input. For example, a user may indicate a desired distribution of ultrasound energy to three sites, two in the first organ 150 and one in the second organ 152. The user may select a first region of interest 20 associated with segment 160a and a second region of interest 20 associated with segment 162a. The system can then select a third region of interest 20 in the first organ 150 using rule-based logic, for example, to avoid adjacent segments (e.g., 160b, 160c, 160d, 160f) and select spaced apart segments 160e, 160g. In another example, a user can select a first region of interest 20 associated with segment 160a, and the system can distribute the dose around the selected region of interest 20 based on the input, for example, using two adjacent segments (e.g., 160b, 160c, 160d, 160f). In another example, the system can store stored protocols in which segments are ranked based on empirical effectiveness information, and selection can be based on the ranking. In one example, segment 162 can be the top-ranked segment, while adjacent segment 162b has a runner-up ranking. Thus, segment 162a can be part of a first-line treatment protocol, and segment 162b can be used when segment 162a is not effective for a particular subject. Furthermore, as disclosed herein, subsequent doses can be moved around the organ such that subsequent doses are distributed to different segments (162b, 162c, 162d).

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

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

[0048] As provided herein, the efficacy of neuromodulation can be evaluated, and the system can track the efficacy of ultrasound energy applied to different segments. The evaluation can be performed via proxy markers, such as changes in the concentration of one or more molecules of interest that serve as indicators of tissue displacement as a result of ultrasound energy. In one embodiment, a particular segment may be associated with an effective treatment for a general population of subjects. However, when ultrasound energy is applied to a target region 20 associated with the segment, an individual subject may not achieve the desired efficacy. Subsequent doses can be distributed to different segments to account for patient-to-patient variability in treatment responsiveness.

[0049] The disclosed technique can also avoid physiological compensation effects for subsequent doses by tracking the location of the target regions 20 used for previous treatments and automatically distributing subsequent doses to the target regions 20 associated with the different segments. Additionally, the system can track the overall energy applied to each segment over the course of the treatment protocol, which can occur over days, weeks, or months, and can use rules-based logic to limit the total energy applied to each individual segment over a particular time frame below a predefined threshold. Additionally, the system can also use the same segments for subsequent doses, but modify the dose distribution between the segments for the individual doses. In one example, if segment 160b receives more than 50% of the initial dose and segments 160b and 162a each receive less than 25%, then segment 160b can only receive 25% or less of the subsequent dose.

[0050] 15 is a schematic diagram of a system 200 for neuromodulation to achieve a neuromodulatory effect such as activation of synaptic components (e.g., presynaptic cells, postsynaptic cells) in response to application of energy and / or tissue displacement at multiple target regions 20 associated with neurotransmitter release. The illustrated 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, e.g., via a lead or wireless connection, energy pulses that, in use, are directed to multiple target regions 20 of one or more internal tissues or organs of the subject, resulting in a sequentially 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 that can sequentially 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 percutaneously or non-invasively from a location outside the subject's body, and in certain embodiments, integrated within the pulse generator 214 and / or the controller 216. In embodiments where the energy application device 212 is extracorporeal, the energy application device 212 can be operated by a caregiver and placed on 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 target area 20, the system 200 can initiate neuromodulation of one or more neural pathways to achieve a targeted physiological outcome or clinical effect. In other embodiments, the pulse generator 214 and / or the energy application device 212 can be implanted in a biocompatible site (e.g., the abdomen) and can be internally coupled, e.g., via one or more leads. In some embodiments, system 200 may be implemented such that some or all of the elements are capable of communicating with each other in a wired or wireless manner.

[0052] In certain embodiments, the system 200 may include an evaluation device 220 coupled to the controller 216 to evaluate 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.

[0053] 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 region of interest where energy was directly applied. In one example, displacement may be a surrogate measurement of the desired modulation, and measurements of displacement less than an expected displacement value may result in modification of modulation parameters until an expected displacement value is induced. Thus, the evaluation device 220 may be configured to evaluate changes in concentration in some embodiments. In some embodiments, the evaluation device 220 may be an imaging device configured to evaluate changes in organ size location, and / or tissue properties. In another embodiment, the evaluation device 220 may be a circulating glucose monitor. Although the depicted elements of the system 200 are shown separately, it should be understood that some or all of the elements may be combined with one another. In another embodiment, the evaluation device may evaluate a localized temperature increase in tissue, which may be detected using a separate temperature sensor or ultrasound image data from the energy application device 212 when configured for ultrasound energy application. Assessment of differences in the speed of sound can be detected using different pre-treatment / peri-treatment / post-treatment imaging techniques.

[0054] Based on the evaluation, the adjustment parameters of the controller 216 may be altered so that an effective amount of energy is delivered. For example, if the desired adjustment relates to a change in concentration (circulating concentration or tissue concentration of one or more molecules) within a defined time frame (e.g., 5 minutes, 30 minutes after the energy application treatment has begun) or relative to a baseline at the start of the treatment, a change in the adjustment parameters, such as pulse frequency or other parameters, may be desired, which can be provided to the controller 216, either by an operator or via an automated feedback loop, to define or adjust the energy application or adjustment parameters of the pulse generator 214 until the adjustment parameters result in an effective amount of energy application. In one embodiment, based on feedback from the evaluation device regarding the effectiveness of the neuromodulatory energy over the course of the treatment protocol, the initially defined target region may be refined to obtain an updated target region. The feedback may be, for example, a change in concentration of a molecule of interest that is a result of the application of the neuromodulatory energy. These refinements or updates to the target region may be used as part of a patient-specific network, where the network is updated to identify the particular target region that most impacts the physiological parameters of that particular individual based on the desired clinical outcome.

[0055] The system 200 provided herein can provide energy pulses according to various modulation parameters as part of a treatment protocol for applying an effective amount of energy. For example, the modulation 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 the time the signal is on. The time the signal is on is followed by a period during which no energy is delivered, referred to as the time the signal is off. The modulation 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 application of energy or the time associated with a meal or other activity. The treatment period for causing 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.

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

[0057] The controller 216 may include a user interface with input / output circuitry 234 and display 236 adapted to allow a clinician to input selections (e.g., selecting a particular segment in the region of interest 20 or an image of the target tissue associated with the desired region of interest 20) or modulation parameters to a modulation program. The processor 230 may be configured to operate to identify one or more organs or tissue structures within the image data and to segment the organs or tissue structures. Additionally, the processor 230 may be configured to apply ultrasound energy to the subject at one or more regions of interest associated with the particular segments.

[0058] The system may include a beam controller 237 that may control one or both of the steering and / or focusing of the energy application device 212 to control the focal position of the energy beam of the transducer 14 of the energy application device 212 to apply simultaneous multi-beam treatments or sequential beam treatments to one or more tissues. The beam controller 237 may also control one or more articulated portions of the energy application device 212 to reposition the transducer. The beam controller may receive instructions from the processor 230 to change the focusing and / or steering of the energy beam. The system 200 may be responsive to a position sensor 238 and / or a contact sensor 239 that provide feedback to the energy application device 212. The beam controller 237 may include motors that facilitate steering of one or more articulated portions of the energy application device 212. It is contemplated that the system 200 may include features that allow for adjustment of the position, steering, and / or focus to facilitate the techniques disclosed herein.

[0059] Each modulation program stored in memory 232 may include one or more sets of modulation parameters including pulse amplitude, pulse width, pulse frequency, pulse repetition rate, etc. The pulse generator 214 modifies its internal parameters in response to control signals from the controller device 216 to vary the stimulation characteristics of the energy pulses transmitted to the subject to which the energy application device 212 is applied via the lead 233. Any suitable type of pulse generating circuitry may 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 amplitude of the current and the duration of the pulse. The controller 216 allows for adjustably controlling the energy by modifying the modulation parameters and / or initiating the application of energy at specific times or inhibiting the application of energy at specific times. In one embodiment, the adjustable control of the energy application device to apply 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, a feedback loop can drive adjustable control. For example, a diagnosis can be made based on the concentration of circulating glucose measured by the evaluation device 220 in response to neuromodulation. If the concentration exceeds a predetermined threshold or range, the controller 216 can initiate a therapeutic protocol of energy application to the region of interest (e.g., the spleen) with modulation parameters associated with reducing 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).

[0061] In one embodiment, the memory 232 stores different operating modes selectable by the operator. For example, the stored operating modes may include separate algorithms for identifying a particular target region and executing a set of adjustment parameters associated with a particular treatment site, such as a target region of the liver, pancreas, gastrointestinal tract, spleen, etc. Each organ or site may be associated with a different model. Additionally, different sites may have different associated adjustment parameters based on the depth of the associated organ, the size of the target region, the desired physiological outcome, etc. Rather than having the operator manually enter the mode, the controller 216 may be configured to execute appropriate instructions based on the selection of a particular organ. In another embodiment, the memory 232 stores operating modes for various types of treatments. For example, activation may be associated with a different stimulation pressure or frequency range compared to that associated with inhibition or blocking of tissue function.

[0062] In certain examples, where the energy application device is an ultrasound 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 / cm 2 ~30,000mW / cm 2 (time-average intensity), and peak positive pressure in the range of 0.1 MPa to 7 MPa (peak pressure). In one example, the time-average intensity is 35 mW / cm2 at the area of ​​interest. 2 Less than 500mW / cm 2 Less than 720mW / cm 2 In an example, the time-averaged intensity is associated with a level below that associated with thermal damage and ablation / cavitation. The controller 216 can operate in a validation mode to obtain the predetermined treatment position, which can be implemented as part of a treatment mode of operation configured to execute a treatment protocol when the energy application device 212 is located at the predetermined treatment position.

[0063] The system may also include an imaging device to facilitate focusing of the energy application device 212. In one embodiment, the imaging device may be integrated with or the same device as the energy application device 212, 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 at the selected region of interest for targeting and subsequent neuromodulation. In another embodiment, the memory 232 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 an 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 212 may focus (e.g., using the beam controller 237) at a focal position of the selected volume that corresponds to the region of interest. It is 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 obtain 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 with modulation parameters appropriate for neuromodulation therapy. However, once the region of interest has been identified, the controller 216 may then operate in a treatment mode according to modulation parameters associated with achieving the targeted physiological outcome.

[0064] The target tissue may be an internal tissue or organ that contains axon terminals and synapses of non-neuronal cells. The synapses may be stimulated by application of ultrasound energy directly to axon terminals within the focal region of an ultrasound transducer focused on a target tissue region 20, causing the release of molecules into the synaptic space. The target region may be selected to contain a particular type of axon terminal, for example, axon terminals of a particular neuron type and / or those that form synapses with a particular type of non-neuronal cell. Thus, the target region 20 may be selected to correspond to a portion of the target tissue that has the desired axon terminals (and associated non-neuronal cells). The application of energy may be selected to preferentially trigger the release of one or more molecules, such as neurotransmitters, from nerves within the synapses, directly activate the non-neuronal cells themselves via direct energy transfer, or cause activation in both neuronal and non-neuronal cells that elicit a desired physiological effect.

[0065] The controller 216 may also be configured to receive inputs related to the targeted physiological outcome as inputs to the selection of the modulation parameters. For example, if an imaging modality is used to assess a tissue characteristic, the controller 216 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 measurement of tissue displacement of the affected tissue or a measurement of the depth of the affected tissue. Other parameters may include assessing the concentration of one or more molecules of interest (e.g., assessing one or more 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) may operate under the control of the controller 216 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 image data to determine that the targeted physiological outcome has occurred (e.g., via a displacement measurement). In such embodiments, the imaging device, the evaluation device 220, and the energy application device 212 may be the same device.

[0066] The technical effect of the present disclosure includes controlled application of multi-site neuromodulation energy (e.g., ultrasound energy) that avoids physiological compensation effects and adjusts the dosage based on the selected target region (e.g., stimulation site) such that the overall energy applied to the patient is minimized. In this manner, the neuromodulation system can consume less energy and operate more efficiently. Multiple stimulation sites can be selected for a dose of a single energy such that the physiological effects of the neuromodulation energy enhance each other. In one example, stimulation of the spleen resulted in a reduction in glucose, but both the pancreatic and splenic stimulations produced a greater glucose reduction effect due to the simultaneous release of insulin from the pancreas. Furthermore, the release of insulin also results in a simultaneous change in the patient's immune status, which may be related to a desired physiological outcome. However, the disclosed experimental results are by way of example, and the technical effect of the present disclosure may be applied to other cases of multi-site stimulation.

[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 incorporated methods. The patentable scope 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 language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

Claims

1. an ultrasound transducer including a plurality of individually addressable elements configured to distribute a dosage of ultrasound energy among a plurality of regions of interest within a subject; a controller, the controller comprising: controlling a dosage applied by said plurality of individually addressable elements between said plurality of regions of interest; receiving ultrasound image data of the target tissue from the ultrasound transducer while the ultrasound transducer is operating in an imaging mode; Segmenting the ultrasound image data of the tissue into a plurality of segments representative of the tissue; receiving an input selecting a single region of interest; selecting a plurality of regions of interest based on the selected single region of interest, wherein each region of interest of the plurality of regions of interest is located within a different segment of the plurality of segments, a first segment of the plurality of segments is not adjacent to one or more segments other than the first segment of the plurality of segments, the selected single region of interest of the plurality of regions of interest is located in the first segment, and a region of interest other than the selected single region of interest of the plurality of regions of interest is located in a segment other than the first segment; focusing the ultrasound transducer on the selected regions of interest; controlling the ultrasound transducer in a therapeutic mode to deliver a dosage of ultrasound energy to the multiple regions of interest for neuromodulating two or more neural pathways of the subject, the ultrasound energy being associated with a level lower than a level associated with ablation of the tissue, the neuromodulation of the two or more neural pathways inducing a physiological effect; receiving input related to the induced physiological effect; 13. An ultrasound system configured to:

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

3. The system of claim 2 , wherein 75% to 90% of the dose is applied to the first organ.

4. The system of claim 2 , wherein the first organ is a pancreas, a spleen, or a liver.

5. The system of claim 1 , wherein the tissue comprises an organ, and the multiple regions of interest are in the organ.

6. 2. The system of claim 1, wherein the controller is configured to control application of the dosage such that individual segments of the plurality of segments do not receive ultrasound energy in excess of a selected ultrasound energy threshold for a period of time.

7. The system of claim 1 , wherein the controller is configured to apply the ultrasound energy to each region of interest simultaneously.

8. The system of claim 1 , wherein the controller is configured to apply the ultrasound energy to each region of interest in series.

9. 2. The system of claim 1, wherein the controller is configured to control a first subset of the plurality of elements to apply a first ultrasonic energy to a first region of interest of the plurality of regions of interest and to control a second subset of the plurality of elements to apply a second ultrasonic energy to a second region of interest of the plurality of regions of interest.

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

11. 2. The system of claim 1, wherein the controller is configured to measure tissue displacement using ultrasound image data acquired prior to and previous ultrasound image data during or after the step of distributing the dosage of ultrasound energy to the multiple regions of interest, and to select modulation parameters for the dosage based on the measured tissue displacement.

12. The system of claim 11 , wherein the controller modifies the parameters by changing a relative distribution of ultrasound energy among the multiple regions of interest for subsequent applications of ultrasound energy.

13. an ultrasonic transducer including a plurality of elements; a controller including a memory, the memory storing instructions for controlling a dosage of ultrasonic energy applied to a subject by the ultrasonic transducer, the instructions, when executed by the controller, receiving image data of the tissue of the target from the ultrasound transducer; Segmenting the image data of the tissue into a plurality of segments representative of the tissue; receiving an input selecting a single region of interest; focusing the ultrasound transducer onto a plurality of regions of interest based on the selected region of interest, the plurality of regions of interest being within the object, each region of interest being located within a different one of the plurality of segments; controlling the ultrasound transducer to apply ultrasound energy distributed among the plurality of regions of interest, the plurality of regions of interest being spaced apart from the selected region of interest; monitoring a change in concentration of one or more molecules relative to a baseline; modifying the instructions based on the concentration change; The ultrasound system of claim 1,

14. 14. The system of claim 13, wherein the controller is configured to apply the ultrasound energy to a first segment including a first selected region of interest and to a second segment including a second selected region of interest.

15. The system of claim 14 , wherein the first segment is not adjacent to the second segment.

16. The system of claim 1 , wherein the input related to the induced physiological effect includes a value of a measured parameter.

17. The input related to the induced physiological effect comprises measured tissue displacement, and the controller The system of claim 1 , configured to modify modulation parameters if the tissue displacement does not correspond to an expected tissue displacement value until an expected displacement value is induced.

18. 2. The system of claim 1, wherein the input related to the induced physiological effect includes a measured circulating molecule concentration value, and the controller is configured to determine that the molecule concentration value deviates from an expected value.

19. 20. The system of claim 18, wherein the controller is configured to modify modulation parameters of the therapy mode based on the deviation and to control ultrasound using the modified modulation parameters.

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