Noninvasive tissue displacement control and monitoring for neuromodulation

Abstract

To provide, generally, techniques for neuromodulation that include applying energy (e.g., ultrasound energy) into an internal tissue to cause tissue displacement and identifying that the tissue displacement has occurred.SOLUTION: The techniques include: controlling application of the neuromodulating energy via an energy application device to a region of interest to deliver a dose of the neuromodulating energy to the region of interest, where the energy application device is controlled under control parameters; receiving image data of the region of interest during and / or after the application of the neuromodulating energy; identifying a change in a molecule of interest in a subject relative to a baseline acquired at or before the application of the neuromodulating energy as a result of the application of the neuromodulating energy; and determining a tissue displacement of the region of interest associated with the change in the molecule of interest, where the tissue displacement is determined based on the image data.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The subject matter disclosed herein relates to techniques for targeting and / or administering to a subject's region of interest via application of neuromodulation energy to induce targeted physiological outcomes. In particular, the disclosed techniques can monitor and / or control ultrasound-induced tissue movement as a result of neuromodulation therapy. [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 back pain. However, placing electrodes at or near the target nerve is difficult. For example, such techniques may involve surgical placement of electrodes that deliver energy. Furthermore, specific tissue targeting via neuromodulation is difficult. Electrodes placed at or near specific target nerves mediate neuromodulation by inducing action potentials in nerve fibers, resulting in the release of neurotransmitters at sequential neural synapses and synaptic transmission with the next nerve. Such propagation may result in a relatively larger or more diffuse physiological effect than desired, as the implementation of current in implanted electrodes stimulates many nerves or axons at once. Because neural pathways are complex and interconnected, a more selective and targeted modulation effect may be more clinically useful. However, identification of effective energy application parameters that deliver energy to the desired region of interest and cause the desired physiological outcome is complex given the individual variability in patient anatomy and clinical response. Summary of the Invention

[0003] The disclosed 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, a neuromodulation delivery system is provided that includes an energy application device configured to deliver neuromodulation energy to a region of interest in an internal tissue of a subject. The system also includes a controller configured for controlling application of neuromodulation energy to the region of interest via the energy application device to deliver a dose of neuromodulation energy to the region of interest, receiving image data of the region of interest during and / or after application of the neuromodulation energy, identifying changes in molecules of interest in the subject as a result of application of the neuromodulation energy relative to a baseline obtained at or before the application of the neuromodulation energy, and determining tissue movement of the region of interest associated with the changes in the molecules of interest, where the tissue movement is determined based on the image data.

[0005] In one embodiment, a neuromodulation delivery system is provided that includes an ultrasound probe configured to deliver neuromodulation energy to a region of interest in an internal tissue of a subject via a therapy transducer and acquire image data of the region of interest via an imaging transducer. The system also includes a controller configured for controlling application of neuromodulation energy to the region of interest via the therapy transducer of the ultrasound probe to deliver a dose of neuromodulation energy thereto, where the therapy transducer is controlled under control parameters; receiving image data of the region of interest acquired by the imaging transducer of the ultrasound probe during application of the neuromodulation energy; determining a movement of tissue in the region of interest during application of the neuromodulation energy based on the image data; and modifying one or more control parameters of the therapy transducer based on the determined tissue movement or based on a change in concentration of a molecule of interest in the subject relative to a baseline concentration acquired at or prior to application of the neuromodulation energy.

[0006] In another embodiment, a method is provided that includes the steps of delivering a reference pulse to a region of interest of a subject via an energy application device, delivering a therapeutic pulse to the region of interest via the energy application device following delivery of the reference pulse, delivering a tracking pulse to the region of interest via the energy application device after delivering the therapeutic pulse, identifying a phase change between the reference pulse and the tracking pulse, and determining movement of tissue at or near the region of interest based on the phase change.

[0007] In another embodiment, a method is provided that includes the steps of delivering a reference pulse to a region of interest of a subject via an energy application device, delivering a therapeutic pulse to the region of interest via the energy application device following delivery of the reference pulse, delivering a tracking pulse to the region of interest via the energy application device after delivering the therapeutic pulse, identifying a change in concentration of a molecule of interest relative to a baseline and as a result of delivering the therapeutic pulse, and determining a movement of tissue at or near the region of interest associated with the change in concentration based on the phase change. [Brief description of the drawings]

[0008] These and other features, aspects, and advantages of the present disclosure will become better understood from the following detailed description taken in conjunction with the accompanying drawings, in which like reference numerals represent like parts throughout. [Figure 1] 1 is a schematic diagram of ultrasound parameters and ultrasound radiation force on tissue according to an embodiment of the present disclosure; [Diagram 2] 1 is a schematic diagram of a model of tissue movement as a result of ultrasonic radiation force on tissue, according to an embodiment of the present disclosure. [Diagram 3] 1 shows images obtained from tissue showing ultrasound-induced tissue movement. [Figure 4] 1 illustrates the relationship between distance traveled and pulse time of ultrasonic radiation force relative to tissue, according to an embodiment of the present disclosure. [Diagram 5]1 illustrates the relationship between distance traveled and pulse time of ultrasonic radiation force relative to tissue, according to an embodiment of the present disclosure. [Figure 6] 1 shows the effect of different applied pressures of ultrasound to the spleen on whole blood tumor necrosis factor (TNF) levels in an LPS-exposed animal model. [Figure 7] FIG. 1 shows the effect of different pulse lengths of ultrasound applied to the spleen on glucose levels in an LPS-exposed animal model. [Figure 8] 1 is a schematic diagram of phase changes of reference and tracking pulses used to determine tissue movement, according to an embodiment of the present disclosure; [Figure 9] 1 is a flow diagram of a technique for determining tissue movement according to an embodiment of the present disclosure. [Figure 10] 17 shows an experimental timeline of application of ultrasound energy to human subjects in FIGS. 13-16. [Figure 11] 17-19 show control parameters for experiments of application of ultrasonic energy to human subjects. [Figure 12] 13-16 show focused and distributed regions of interest for application of ultrasound energy to a human subject. [Figure 13] 1 shows a comparison of TNF response to the degree of tissue movement associated with application of ultrasound energy. [Figure 14] 1 shows a comparison of the TNF response to migration associated with focused and diffuse application of ultrasound energy. [Figure 15] 1 shows a comparison of the TNF response to migration associated with focused and diffuse application of ultrasound energy. [Figure 16] Summary of TNF responses and migration at different time points is shown. [Figure 17] FIG. 1 is a schematic diagram of an ultrasound neuromodulation system according to an embodiment of the present disclosure. [Figure 18] FIG. 1 is a block diagram of an ultrasound neuromodulation system according to an embodiment of the present disclosure. [Figure 19] 1 is a flow diagram of a technique for adjusting tissue movement according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] 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. It will be appreciated that in the development of any such actual implementation, such as in an engineering or design project, numerous implementation-specific decisions must be made to achieve the developer's particular goals, such as addressing system-related and business-related constraints, which may vary from implementation to implementation. Moreover, it will be appreciated that such a development effort may be complex and time-consuming, but would nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary skill in the art having the benefit of this disclosure.

[0010] Any examples or illustrations provided herein should not be considered in any way as expressing a restriction, limitation, or definition to any one or more terms in which they are used. Instead, these examples or illustrations should be considered as being described in relation 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 illustrations are utilized encompass other embodiments that may or may not be provided therewith or elsewhere in this specification, and 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 illustrations include, but are not limited to, "for example," "for instance," "such as," "eg," "including," "in certain embodiments," "in some embodiments," and "in one (an) embodiment."

[0011] Neuromodulation in tissues can be achieved by localized mechanical stress / strain that stretches or displaces the tissue and activates different intra- and inter-cellular processes accordingly. Provided herein are techniques for controlling and / or monitoring the amount of stretching and / or displacement caused by application of neuromodulation energy, e.g., non-invasive ultrasound. By controlling and monitoring the amount of stretching and / or displacement in a particular tissue targeted with neuromodulation energy, the control parameters of the neuromodulation energy dose can be adjusted to produce different levels of effect and / or different types of effect. In an example, controlling the dose, the amount of stretching and / or the amount of displacement, changes the level of anti-inflammatory effect in a particular neuromodulation protocol in humans. Furthermore, the amount of stretching and / or displacement induced by ultrasound energy can be measured non-invasively, even using ultrasound (e.g., using a combination of probes), giving feedback for real-time quantification and precise control of the dose delivered.

[0012] In certain embodiments, tissue movement in response to the radiation force of focused ultrasound can be assessed using shear wave (elastography) imaging. The present disclosure demonstrates that a threshold effect is observed in the organism, whereby small amounts of movement (below threshold movement) do not result in a neuromodulatory effect, and large amounts of movement (above threshold) result in a neuromodulatory effect. A second threshold effect is observed in the organism, where large amounts of movement (overexposure) result in undesirable effects, where the intended neuromodulatory effect is absent or reduced. That is, the control parameters of the dose can be adjusted for each patient to achieve the desired tissue movement. In addition to identifying plateau or maximum movement levels associated with specific control parameters, the tissue regions to which movement is applied, and the nature of the movement that varies with time, are observed in the disclosed embodiments to result in different neuromodulatory effects. This spatial-temporal relationship and the total duration of the applied dose, as presented in the present disclosure, have been shown to result in different levels of neuromodulation in the organism.

[0013] Producing the appropriate amount of stretching and / or movement in different individuals is difficult due to individual anatomical differences and individual tissue property differences. That is, the liver may respond differently than the pancreas. Measuring and monitoring the amount of stretching and / or movement during neuromodulation energy administration can be used to minimize deviations from an optimal dose for an individual patient. Measuring and monitoring in real time allows for more precise control of the temporal aspects of the applied stretching and / or movement. Measuring and monitoring across tissue regions of size variability allows for more precise control of the spatial aspects of the applied stretching and / or movement. For example, specific regions of interest for energy application can be selected or monitored for desired tissue movement. In certain embodiments, the present technology facilitates determining the appropriate or targeted amount of spatiotemporal stretching and / or movement for a particular individual (personalized) and more reliably produces that determined amount of spatiotemporal stretching and / or movement across multiple time scales. Thus, evaluating tissue movement during and after application of neuromodulation energy allows for fine tuning of energy parameters to produce targeted physiological outcomes as well as to address inter-patient variability in responsiveness and response. It can account for organizational variation in response (inter- and / or intra-organizational).

[0014] Stretching and / or movement can be induced in tissue in multiple ways. The disclosed embodiments are described in the context of non-invasive ultrasound, which allows for deep penetration into tissue while simultaneously controlling the focus and shape of the energy applied to the region of interest. FIG. 1 is a schematic diagram of an ultrasound beam showing the focus and a detailed view of the applied ultrasound energy, showing the characteristics of amplitude and frequency 12, pulse height time or pulse length 14, and pulse repetition interval 16. The present technique demonstrates that changes to the driving voltage (applied pressure) that produces the ultrasound, as well as the pulse length and pulse repetition interval, produce measurable physiological effects that correlate to tissue movement. In certain disclosed embodiments, the effects of full and half amplitude driving voltages are compared. Additionally, changes in pulse length and pulse repetition interval are evaluated.

[0015] Figure 2 is a simplified model of tissue movement showing the movement assuming the ultrasound focus is a simple line source with movement uniformly distributed in the z direction. The model also assumes that the tissue is a homogeneous elastic medium with damping. The model allows for the calculation of the movement F at any observation point of the 2D tissue F(x,y,t). Each arrow represents an applied pulse. Figure 3 is a time series of ultrasound images taken from time 0 to 4 ms showing the movement over a 20 mm x 20 mm area using the source assumption for a length of 10 mm diameter and a total push pulse over 3 ms. Each image represents the movement over 0.5 ms. Every 0.5 ms, an additional 500 microsecond pulse (shown as a yellow arrow in Figure 2) is applied to the tissue. The movements shown are logarithmically scaled with a 30 dB display range. The ultrasound images show tissue movement of several micrometers over the time that a total pulse of 3 ms was applied.

[0016] FIG. 4 shows the observed relationship between movement and pulse length in the image of FIG. 3. Over time, the total pulse increases (sum of dose delivery of multiple pulses) for each 500 microsecond pulse length push, and larger movements are observed until all contributing movements from the source cannot be added coherently. Thus, the amplitude of movement (shown as arbitrary units) plateaus. In the illustrated example, the pulse push is an additive 500 microsecond pulse with no relaxation period. Thus, as presented herein, the pulse length and / or total pulse height time over the course of the administration period can be selected to achieve maximum and / or plateau values ​​of potential tissue movement for a particular driving voltage (and particular region of interest) at the lower range of plateau pulse length values, thus minimizing ultrasound energy exposure in the region of interest over the course of the applied dose, which can result in a more targeted effect. Thus, in an embodiment, the technology can track movement in real time over the delivery of the dose and calculate the rate of change of tissue movement. Upon determining that the rate of change is decreasing (e.g., below a selected threshold), indicating approaching a plateau, the controller of the ultrasound probe can automatically modify the energy delivery. For example, the controller may stop energy delivery or modify control parameters to exit the plateau portion of the curve. Such tracking may be desirable because minimizing exposure to ultrasound energy may prevent or delay compensation mechanisms within the tissue, maintaining the region of interest as a suitable treatment site for a longer period of time. Additionally, by avoiding the plateau portion of the curve in FIG. 4, undesirable additional physiological effects of the treatment may not be activated.

[0017] However, as presented herein, other control parameters of ultrasound dose delivery can be altered to achieve desired physiological results related to characteristic tissue movement and / or relaxation. For example, as shown in FIG. 5, a pulse repetition interval of 500 microseconds (at a PRF of 2KHz), or a pulse repetition interval of 5 milliseconds (at a PRF of 500Hz) can be varied in pulse length "on" or pulse high time, with resulting variations in tissue movement. For example, increasing the amount of pulse high time at the same PRF results in greater overall movement over a 10 millisecond period at both higher (2kHz) and lower (500Hz) frequency settings. That is, a pulse high time of 150 microseconds causes less tissue movement than an on time of 350 microseconds. Thus, ultrasound therapy transducers can be tuned to vary the pulse high time within the pulse repetition interval to change the profile of tissue movement. Additionally, increasing the pulse repetition interval also allows for relaxation between pulses, which in turn changes the effectiveness of the compound movement over the administration. A 5 ms pulse repetition interval for 150, 250, and 350 microsecond pulses sometimes allows for near-complete relaxation, while the shorter 500 microsecond pulse repetition interval allows for less-than-complete relaxation. Thus, the 500 microsecond pulse repetition interval pulses exhibit a compound migration effect over time that disappears when administration is stopped. As presented herein, the technology allows for ultrasound dose therapy protocols with control parameters for energy delivery that adjust the driving voltage, frequency, pulse length, and pulse repetition interval, and / or overall dose delivery time. For example, the overall energy delivered to the region of interest observed in the upper panel condition (500 microsecond PRI with 2KHz PRF) was greater than that in the lower panel condition (5 ms PRI with 500Hz PRF). The estimated migration can be evaluated or estimated as the area under the curve over the dose delivery period, and the control parameters can be programmed to fall within a desired range of the area under the curve of tissue migration for a particular region of interest.

[0018] The present technology targets tissue displacement caused by neuromodulation associated with targeted physiological outcomes. Figure 6 shows the effect of various ultrasound pressures (mPa) applied to the spleen on whole blood TNF in an LPS-exposed animal model. The amount of displacement caused by ultrasound is a function of the elastic properties of the tissue and the properties of the energy applied, e.g., how long you push (pulse length, pulse repetition interval) and / or how hard you push (time-averaged intensity mW / cm2 and / or peak pressure mPa). Displacement reaches a maximum value, at which the force applied by ultrasound is greater than the force pushed by the tissue. The force exerted by the LPS-exposed tissue is equal to the force exerted back against it. Once this maximum is reached, pushing longer will not move it any further. Pushing harder (e.g., more pressure) is the way to get more movement (reach a new maximum). In the example shown in FIG. 6 for an LPS-exposed animal model with resultant inflammation and associated baseline increase in TNF, the time to push remained the same, but the amount of pressure was changed. Two threshold effects were observed, one with little physiological effect (0.03 mPa, too low pressure) and a second threshold where physiological effect was absent (1.72 mPa bar, too high pressure). However, data between the thresholds show that the increase in whole blood TNF associated with LPS exposure was reversed for certain ultrasound pressures, but was unaffected by pressures that were too high or too low. Thus, as presented herein, the technology can identify ultrasound pressures that are between thresholds that are not associated with physiological effects, and / or allow for application of ultrasound energy within these identified pressure ranges. As presented herein, tissue movement caused by ultrasound energy can be used as a marker of a desired physiological effect. In one embodiment, the change in effect between 1.27 mPa bar and 1.72 mPa bar is related to a physical change in the tissue's response to the applied ultrasound energy, ranging from tensile movement to heat / cavitation at higher pressures. The desired effect may be observed at pressures associated with tensile movement. Thus, ultrasound dose control parameters may be selected to induce tensile movement, avoiding peak pressures that are too low to induce movement, or too high for the primary tissue effect in or near the region of interest to be heat / cavitation.

[0019] Figure 7 shows the effect of varying the duration of the push (pulse) pressure, kept the same (200 ms) for the control, on the change in glucose relative to baseline. The results show two threshold effects, one where there is little physiological effect (too short duration) and a second where there is no physiological effect (too long duration). Thus, the control parameters can be selected to align with the tissue movement associated with the desired change in glucose rate.

[0020] To that end, the present technology provides systems and methods for monitoring and / or assessing tissue movement. In an embodiment, tissue movement can be assessed by ultrasound. In one embodiment, an ultrasound probe may be a combination probe including a treatment transducer and an assessment (imaging). The imaging transducer may be used to identify and select the region of interest as well as to track tissue movement caused by application of neuromodulation energy. FIG. 8 shows exemplary control or drive signals for identifying tissue movement that may be used to control an ultrasound probe to deliver treatment and track associated tissue effects. In an embodiment, a short reference imaging pulse and a tracking pulse support the treatment pulse. The change in phase between the reference signal and the tracking signal based on the ultrasound image data is used to calculate tissue movement. As shown, the movement may be in a positive or negative direction along the axis, and the total movement, or the area under the curve, may be used as the movement metric.

[0021] 9 is a flow diagram of a method 100 for assessing tissue movement as a result of applying ultrasound energy to a region of interest of a target internal tissue. In the method 100, a transducer of an ultrasound probe delivers a reference imaging pulse to the region of interest and collects reflected ultrasound waves from the tissue to generate baseline or reference data that is received by a controller (e.g., an ultrasound system) of the ultrasound probe (block 102). The same ultrasound transducer or a different ultrasound transducer (e.g., a dedicated therapy transducer) of the ultrasound probe is controlled to apply ultrasound therapy pulses (block 104). The application of ultrasound therapy causes tissue movement in or near the region of interest, which is identified using a tracking pulse delivered after applying ultrasound energy (block 106). The reflected waves from the tracking pulse generate tracking data. The tracking data and the reference data are used to determine the tissue movement caused by the ultrasound energy pulse (block 108).

[0022] In certain embodiments, the control parameters of the reference and tracking pulses are selected to be short and low enough energy so that they cause minimal or no tissue movement. That is, the movement identified is caused by the treatment pulse and not by the reference / tracking pulse. In certain embodiments, a tracking pulse is emitted during the interval between pulses so that the movement is tracked for every applied pulse. In this way, compounding movements can be tracked until a plateau value is reached. Furthermore, the movement can be determined in real time to allow adjustment or modification of the control parameters of the treatment pulse.

[0023] The relationship between tissue movement and physiological effects as a result of neuromodulatory ultrasound therapy was investigated in 60 human subjects. Subjects were randomly assigned to one of six groups (n=10 per group). Ultrasound was used to produce vibrations due to tissue movement in the region of interest of the target internal tissue as disclosed herein. Groups of human subjects received a sham control ultrasound dose, a half amplitude dose (Isppa spatial peak pulse average intensity) of 115 W / cm2, or a full amplitude dose (Isppa) of 362 W / cm2. The time-averaged power (Ispta) at 50% amplitude (368 mW / cm2) is higher than at 100% amplitude (290 mW / cm2) because it is pushed more frequently. The ultrasound dose of subjects receiving ultrasound energy was applied to a single site (groups 1-3) or distributed over multiple sites (groups 4-6).

[0024] Figure 10 shows the experimental protocol for each subject. For human subjects undergoing ultrasound, a therapeutic dose was delivered after fasting blood draws for baseline levels of various blood molecules such as TNF, cytokines (IL-1, IL-6, IL-8, IL-10), glucose, and norepinephrine. The TNF response of blood cells to LPS was assessed by performing an LPS assay on blood from venous blood draws. Blood was exposed to LPS at concentrations of 0, 0.1, 1, 10, and 100 ng / ml, followed by analysis of each sample with a human TNF ELISA. The area under the curve (AUC) for the TNF response concentration across the five LPS concentrations was calculated and used to characterize the TNF response of blood cells. Ultrasound energy was applied to a region of interest in the splenic tissue of each subject. Fasting blood draws were performed 1 hour, 2 hours, and 24 hours after the therapeutic dose. Figure 11 summarizes the control parameters and the resulting subject tissue migration that the various groups achieved. FIG. 12 is a schematic diagram of single versus multiple site delivery of the spleen.

[0025] FIG. 13 shows the results of ultrasound stimulation of the spleen within a focal (single site) region of interest. Greater migration correlates with a greater decrease in the TNF response of blood cells to LPS at 2 hours post-stimulation. The top section shows the P value (Wilcoxon test) comparing small vs. large migration within a single or focal treatment region of interest. Data shown are from 8 subjects in group 1 (small migration), 10 subjects in group 2 (medium migration), and 8 subjects in group 3 (large migration).

[0026] FIG. 14 shows a comparison of tissue migration between focused (single site) and diffuse (multiple site) ultrasound energy application to the medium migration group. In the case of medium migration within the focused region, splenic ultrasound stimulation tends to cause a greater decrease in the TNF response of blood cells to LPS 2 hours after stimulation. The top section shows the P value (Wilcoxon test) comparing medium migration within the focused and diffuse regions. Data shown are from 10 subjects in group 2 (medium migration) and 9 subjects in group 5 (medium migration).

[0027] FIG. 15 shows a comparison of tissue migration between focused (single site) and diffuse (multiple site) ultrasound energy application to the large migration groups. In the case of large migration within the focused region, splenic ultrasound stimulation tends to cause a greater decrease in the TNF response of blood cells to LPS 2 hours after stimulation. The top section shows the P value (Wilcoxon test) comparing large migration within the focused and diffuse regions. Data shown are from 8 subjects in Group 3 (large migration) and 9 subjects in Group 6 (large migration).

[0028] FIG. 16 is a summary of the TNF response in the six subject groups. The upper panel shows the TNF changes with single site energy application and the lower panel shows the TNF changes with distributed energy application. The results show that changes to applied pressure or power between Group 2 and Group 3 were associated with significant changes in TNF response compared to baseline. The test groups also show a return to baseline TNF levels at 24 hours.

[0029] As shown, changes in ultrasound energy application control parameters and region of interest selection affect physiological outcomes in a manner related to the degree of tissue movement. Although experimental results have shown that TNF changes relative to baseline as a result of ultrasound energy application (e.g., ultrasound treatment), it should be understood that these results are presented as examples. The present technology can induce and evaluate the presence or level of tissue movement in a region of interest related to a desired physiological outcome, such as a change in concentration of a molecule of interest relative to a baseline level before treatment. Instead of or in addition to tracking changes in the concentration of a molecule, the present technology can evaluate tissue movement to determine that neuromodulatory ultrasound therapy is effective.

[0030] 17 illustrates a system 200, e.g., a neuromodulation delivery system, for neuromodulation to achieve a neuromodulatory effect, such as tissue movement in one or more regions of interest 202 of a target tissue 204 associated with the release of neurotransmitters and / or activation of components of a synapse (e.g., presynaptic cells, postsynaptic cells) in response to the application of energy. The illustrated system includes a pulse generator 214 coupled to an energy application device 206. The energy application device 206 is configured to receive energy pulses, e.g., via leads or wireless connection, that are directed during use to multiple regions of interest 20 of one or more internal tissues or organs of a subject, thereby producing a targeted physiological outcome.

[0031] In certain embodiments, the energy application device 206 and / or the pulse generator 214 can communicate, for example, wirelessly with the controller 216, which can then provide instructions to the pulse generator 214. In other embodiments, the energy application device 206 can be an extracorporeal device, e.g., operated to apply energy percutaneously or non-invasively from a location outside the subject's body, and in certain embodiments, can be integrated with the pulse generator 214 and / or the controller 16. In embodiments where the energy application device 206 is extracorporeal, the energy application device 206 can be operated by a caregiver and positioned at a point 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 region of interest 202, 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 14 and / or the energy application device 206 can be implanted in a biocompatible site (e.g., the abdomen) or can be coupled internally, 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.

[0032] In certain embodiments, the system 200 can include an evaluation device 220 coupled to the controller 216 to evaluate a characteristic indicative of whether a targeted physiological outcome of the modulation has been achieved. In one embodiment, the targeted physiological outcome can be local. For example, modulation of one or more neural pathways can result in a local tissue or functional change, such as a change in tissue structure, a local change in the concentration of a particular molecule, tissue movement, increased fluid movement, etc. The targeted physiological outcome can be the goal of a treatment protocol.

[0033] 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 the properties of tissue that do not include the region of interest where the energy was directly applied. In one example, the movement may be a surrogate measure of the desired modulation, and if the measured movement falls below the expected movement value, the modulation parameters may be modified until the expected movement value is induced. Thus, the evaluation device 220 may be configured to evaluate the change in concentration in some embodiments. In some embodiments, the evaluation device 220 may be configured to evaluate the movement of the tissue. For example, the evaluation device may be configured to use elastography techniques. Elastography may be used to examine the material properties of the tissue. In this technique, elastography may be used to evaluate the changes in the tissue induced by the ultrasound therapeutic pulse or administration protocol. Although the illustrated elements of the system 200 are shown separately, it is understood that some or all of the elements may be combined with each other.

[0034] Based on the evaluation, the modulation parameters of the controller 216 can be altered so that an effective amount of energy is delivered. For example, if the desired modulation relates to a change in concentration (circulating or tissue concentration of one or more molecules) within a defined time frame (e.g., 5 minutes, 30 minutes after beginning the energy application procedure) or relative to a baseline at the beginning of treatment, a change in the modulation parameters, such as pulse frequency or other parameters, can be desired, which can then be provided to the controller 216 by an operator or via an automated feedback loop to define or adjust the energy application or modulation parameters of the pulse generator 214 until the modulation parameters result in an effective amount of energy being applied. In one embodiment, based on feedback from the evaluation device regarding the effectiveness of the neuromodulation energy over the course of the treatment protocol, the initially defined region of interest 202 can be refined to obtain an updated region of interest 202. The feedback can be, for example, tissue movement as a result of the application of the neuromodulation energy. These refinements or updates to the region of interest can be used as part of a patient-specific network, and the network is updated to identify the particular region of interest that most impacts the physiological parameters of interest for that particular individual based on the desired clinical outcome.

[0035] The system 200 presented herein can deliver energy pulses according to various modulated control parameters as part of a treatment protocol to apply an effective amount of energy. For example, the modulated control 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 certain frequency during the signal on time. The signal on time is followed by a period of no energy delivery, called the signal off time. The control parameters can also include the frequency and duration of stimulation application. The frequency of application can be continuous or can be delivered for various periods of time, for example, within a day or a week. Additionally, the treatment protocol can specify the time of day for applying the energy or the time of day relative to meals or other activities. The treatment period to cause a targeted physiological result can last for various periods of time, including, but not limited to, minutes to hours. In certain embodiments, the treatment period with the specified stimulation pattern can last for one hour, repeated at intervals of, for example, 72 hours. In certain embodiments, the energy can be delivered for a shorter duration, for example, 30 minutes, or more frequently, for example, every three hours. According to modulation parameters such as treatment duration, frequency, and amplitude, the application of energy can be adjustably controlled to achieve desired results.

[0036] 18 is a block diagram of certain components of the system 200. As presented 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 interest. 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 code 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 206 via one or more leads or wirelessly.

[0037] The controller 216 may include a user interface having input / output circuitry 234 and a display 236 adapted to allow a clinician to communicate selection inputs (e.g., selecting a particular segment on the image of the target tissue associated with the region of interest 20 or the desired region of interest 20) or control parameters to the modulation program. The processor 230 may be configured to control the energy application device and drive the therapy transducer 208 and / or the imaging transducer 210 presented herein. Additionally, the processor 230 may be configured to determine tissue movement based on data received from the imaging transducer 210.

[0038] The system controls the transducers of the energy application device 206 by controlling one or both of the steering and / or focusing of the energy application device 206 to deliver treatment. The system 200 may include a beam controller 237 that can control the focal position of the 14 energy beams. The beam controller 237 can also control one or more articulated portions of the energy application device 206 to reposition the transducer. The beam controller can receive instructions from the processor 230 to change the focusing and / or steering of the energy beams. 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 206. The beam controller 237 may include motors that facilitate steering of one or more articulated portions of the energy application device 206. It is contemplated that the system 200 may include features that allow for adjustment of position, steering, and / or focus to facilitate the techniques disclosed herein.

[0039] Each modulation program stored in memory 232 may include one or more sets of modulation parameters including pulse amplitude, pulse duration, pulse frequency, pulse repetition rate, etc. The pulse generator 214 alters its internal parameters in response to control signals from the controller 216 to vary the stimulation characteristics of the energy pulses delivered via the leads 233 to the subject to which the energy application device 206 is applied. Any suitable type of pulse generating circuit 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 current amplitude and pulse duration. The controller 216 allows for adjustably controlling the energy by altering the modulation parameters and / or initiating energy application at specific times or inhibiting energy application at specific times. In one embodiment, the adjustable control of the energy application device 206 to apply energy is based on information regarding the determined tissue movement.

[0040] 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 tissue movement measured by the evaluation device 220 in response to neuromodulation. If the movement exceeds a selected threshold or range, the controller 216 can initiate a treatment protocol of energy application to the region of interest (e.g., the spleen) with modulation parameters associated with a targeted physiological outcome, such as a reduction in circulating glucose. The treatment protocol can use different modulation parameters (e.g., higher energy levels, more frequent application) than those used in the diagnostic protocol.

[0041] 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 region of interest and executing a set of modulation parameters associated with a particular treatment site, such as a liver, pancreas, gastrointestinal, or spleen region of interest. Each organ or site may have different associated modulation parameters based on the depth of the associated organ, the size of the region of interest, the desired physiological outcome, and the like. 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 different types of treatments. For example, activation may be associated with a range of stimulation pressure or frequency that is different from that associated with inhibiting or blocking tissue function.

[0042] In a particular example, where the energy application device is an ultrasound transducer, the effective amount of energy may include a selected time-averaged intensity applied to the region of interest. For example, the effective amount of energy may include a time-averaged power (time-averaged intensity) and peak positive pressure in the range of 1 mW / cm2 to 30,000 mW / cm2 (time-averaged intensity) and 0.1 MPa to 7 MPa (peak pressure). In an example, the time-averaged intensity is less than 35 mW / cm2, less than 500 mW / cm2, or less than 720 mW / cm2 in the region of interest. In an example, the time-averaged intensity is associated with a level lower than that associated with thermal damage and ablation / cavitation. The controller 216 may be capable of operating in a verification mode to obtain a selected treatment location, which may be implemented as part of a treatment mode of operation configured to execute a treatment protocol when the energy application device 206 is placed at the selected treatment location.

[0043] The system may also include an imaging device to facilitate focusing of the energy application device 206. In one embodiment, the imaging device may be integrated with the energy application device 206 or may be the same device, whereby different ultrasound parameters (frequency, aperture, or energy) are applied to select (e.g., spatially select) a region of interest and focus 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 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 corresponding to the region of interest. The spatial selection may depend on the image data obtained herein. Based on the spatial selection, the energy application device 206 may be focused (e.g., using the beam controller 237) to a focal position of the selected volume corresponding to the region of interest. It is understood that the image data used to guide the focal position may be solid or planar. For example, the energy application device 206 may be configured to acquire the selected treatment location by first operating in a validation mode to capture image data used to identify the selected treatment location associated with capturing the region of interest. In validation mode energy is not applied and / or at levels of modulation parameters appropriate for neuromodulation therapy. However, once the region of interest has been identified, the controller 216 can operate in a therapy mode according to modulation parameters associated with achieving a targeted physiological outcome.

[0044] 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 applying ultrasonic energy directly to the axon terminals within the focal region of an ultrasound transducer focused on a region of interest 20 of the target tissue to cause the release of molecules into the synaptic space. The region of interest may be selected to contain a particular type of axon terminal, e.g., axon terminals of a particular neuronal type, and / or those that form synapses with a particular type of non-neuronal cell. Thus, the region of interest 20 may be selected to correspond to a portion of the target tissue that has the desired axon terminals (and associated non-neuronal cells). Energy application may be selected to preferentially induce the release of one or more molecules, such as neurotransmitters, from nerves within the synapses, or to directly activate the non-neuronal cells themselves via direct energy transduction, or to cause activation within both neuronal and non-neuronal cells that induces a desired physiological effect.

[0045] The controller 216 may also be configured to receive inputs related to targeted physiological outcomes as inputs for the selection of modulation parameters. For example, if an imaging modality is used to assess tissue movement, the controller 216 may be configured to receive a calculated index or parameter of a characteristic (e.g., total movement, rate of change of movement). Based on whether the index or parameter is above or below a predetermined threshold, an indication of a diagnosis or an indication related to a therapeutic goal being reached may be provided (e.g., via a display). In one embodiment, the parameter may be a measure of tissue movement of the diseased tissue or a measure of the depth of the diseased tissue. Other parameters may include evaluating the concentration of one or more molecules of interest (e.g., evaluating one or more of the change in concentration, rate of change, and determining whether the concentration is within a desired range) relative to a threshold or baseline / control. Additionally, the energy application device 206 (e.g., an ultrasound transducer) may operate under the control of the controller 216 to a) acquire tissue image data that may be used to spatially select a region of interest within the target tissue, b) apply modulated energy to the region of interest, and c) acquire image data to determine that a targeted physiological outcome has occurred (e.g., via movement measurements). In such an embodiment, the imaging device, evaluation device 220, and energy application device 206 may be the same device.

[0046] In an embodiment, the system 200 may be configured to set the control parameters of the treatment transducer 208 to achieve a particular profile, molecular changes of interest, or characteristic tissue movement. For example, subjects may vary in their response to neuromodulation energy, and different control parameters may be involved to achieve similar movement between subjects. The control parameters may be adjusted until the characteristic tissue movement is achieved. The characteristic tissue movement or target tissue movement may be an overall movement metric, or may be a threshold or range based metric, whereby achieving a value of movement within the target range indicates successful treatment. In an embodiment, the characteristic tissue movement is the presence of two thresholds, a low threshold and a high threshold, and the target range is the movement between the two thresholds. The control parameters associated with the thresholds may vary from subject to subject, and the system 200 may be adjusted to identify the thresholds based on a test or calibration protocol applied to the subject. Once identified for each subject, the associated parameters that achieve movement between the thresholds and within the effective therapeutic range may be used over the course of the treatment protocol. Tissue movement, or failure to achieve the characteristic tissue movement or target movement may also be used to select a new region of interest 202. In one example, the region of interest 202 may become less therapeutically effective over time. This decrease in therapeutic effectiveness may be identified by a change or decrease in tissue movement over the course of the treatment protocol. In another example, a more responsive region of interest 202 may be identified or mapped based on tissue movement. In one embodiment, at the initiation of treatment, the target tissue 200 may be mapped using the desired control parameters to identify a more responsive organ or tissue sub-region based on the degree of tissue movement caused by application of ultrasound energy with the control parameters. Once mapped, the region of interest 202 may be selected from the more responsive regions (i.e., tissue movement) that are also physically located in an area containing one or more axon terminals that, when stimulated, cause a desired physiological response. This may vary from subject to subject over time and within a subject.

[0047] The neuromodulation techniques discussed herein can be used to cause changes in the concentration (e.g., increase, decrease) of a molecule of interest, and / or changes in the properties of the molecule of interest. That is, treatment can cause changes in tissue production or release of one or more molecules of interest (e.g., a first molecule of interest, a second molecule of interest, etc.), and can refer to changes in the concentration (circulation, tissue) or properties (covalent modification) of a molecule as a result of energy application to one or more regions of interest (e.g., a first region of interest, a second region of interest, etc.) of one or more tissues (e.g., a first tissue, a second tissue, etc.). Changes in a molecule of interest can include changes in the properties of the molecule, such as expression, secretion, protein translocation, and direct activity changes. Changes can be driven based on the action of the applied energy on ion channels, driving neural activity and function itself, or driving modulation of adjacent non-neuronal cells as a result of molecules derived from neural activity or direct activation within the non-neuronal cells. The change of the molecule of interest may also refer to maintaining a desired concentration of the molecule so that expected changes or fluctuations in concentration (e.g., as a result of diet) do not occur as a result of neuromodulation. The change of the molecule of interest may refer to causing a change in molecular properties, such as enzyme-mediated covalent modifications (such as changes in phosphorylation, acylation, ribosylation, etc.). That is, it should be understood that the change of the molecule of interest may refer to molecular concentration and / or molecular properties. The molecule of interest may be a biological molecule, such as one or more of carbohydrates (monosaccharides, polysaccharides), lipids, nucleic acids (DNA, RNA), or proteins. In certain embodiments, the molecule of interest may be a signaling molecule, such as a hormone (amine hormone, peptide hormone, or steroid hormone).

[0048] Physiological differences between subjects may result in variations in the level of tissue movement associated with achieving a target increase or decrease in the concentration of a molecule of interest, or other types of changes in the molecule of interest (e.g., changes in the activation state of the molecule). FIG. 19 is a flow diagram of a method 300 for adjusting control parameters of a treatment pulse to achieve one or both of a desired tissue movement and / or a change in a property or threshold of a molecule of interest, relative to a baseline measurement taken at or before the start of treatment. In the method 300, a transducer of an ultrasound probe delivers a reference imaging pulse to a region of interest and collects reflected ultrasound from the tissue to generate baseline or reference data that is received by a controller of the ultrasound probe (e.g., an ultrasound system) (Block 302). The same ultrasound transducer or a different ultrasound transducer (e.g., a dedicated treatment transducer) of the ultrasound probe is controlled to apply an ultrasound treatment pulse (Block 304). A tracking pulse is delivered after applying ultrasound energy (Block 306), and tissue movement is determined based on a phase change between the reference pulse and the tracking pulse (Block 308). In certain embodiments, changes in the molecule of interest are identified (block 310) and used to evaluate the effectiveness of the therapeutic pulse. In certain embodiments, tissue movement is used to evaluate the effectiveness of the therapeutic pulse. Based on the changes in the molecule of interest and / or the movement of the tissue, control parameters of the therapeutic pulse can be adjusted (block 312) to calibrate the therapeutic pulse for the patient and facilitate a more effective neuromodulation therapy.

[0049] For example, one or more of the drive voltage, pulse repetition interval, and pulse length can be adjusted to adjust the control parameters of the treatment pulse. In one embodiment, a subject-specific calibration can be performed in which the control parameters of the treatment pulse are applied and cycled through various settings while the concentration of the molecule of interest at the various settings is tracked at the various settings. An effective range of parameters is identified in which the desired effect (e.g., threshold percentage change from baseline) is observed. For example, as shown in FIG. 7, increasing the number of cycles of a 200 ms pulse identified a range of cycles in which the treatment pulse caused a significant percentage change in glucose concentration compared to baseline (150-250 cycles). Future treatment pulses can be applied using settings of the control parameters in the range associated with the observed desired change in the molecule of interest. In another embodiment, tissue movement can be tracked during adjustment of the control parameters. Future treatment pulses can be applied to cause tissue movement associated with the observed desired change in the molecule of interest during calibration (e.g., a specific movement at a specific percentage change of the molecule of interest relative to baseline). This may result in dynamically adjusting the control parameters to different settings for different doses, since the subject's tissues may respond differently over the course of the treatment protocol based on the subject's metabolic or clinical state. It is understood that the adjustment of the control parameters may be an adjustment of one or more control parameters and may include a combination of control parameters associated with a desired physiological outcome. Additionally, the adjustment may be an adjustment to the Isppa or Ispta of the treatment pulse. In embodiments, the adjustment may include distributing the treatment pulse among multiple regions of interest, or consolidating the dose distributed to a single region of interest based on an evaluation of changes in the molecule of interest. For example, the treatment protocol may begin with the application of a dose to a single region of interest. Over time, compensation or other effects may reduce the effectiveness of the treatment pulse using the initial control parameters. The treatment protocol may include a specific dose distributed among multiple sites to avoid such compensation.

[0050] The change in the molecule of interest can be a deviation from a threshold concentration or a concentration outside a particular range. The change in the molecule of interest can be a percentage change from baseline, which may be above or below the threshold percentage change. For example, a treatment protocol can have a treatment goal threshold of at least 50% change (increase or decrease) in the concentration of the molecule of interest. If the treatment goal threshold is not reached, the control parameters are adjusted until a threshold associated with the treatment goal is reached, and the method 300 can iteratively return to block 304 until the threshold is exceeded. In an embodiment, the threshold can be at least a 100% increase in the concentration of the molecule of interest. In an embodiment, the treatment goal can be to achieve a concentration of the molecule of interest within a particular range.

[0051] The technical effects of the present disclosure include the controlled application of neuromodulation energy (e.g., ultrasound energy) to cause tissue movement associated with a desired physiological outcome. By tracking tissue movement as a marker of therapeutic efficacy, neuromodulation delivery systems can operate more efficiently by achieving desired movement at lower overall energy levels. Furthermore, neuromodulation energy can be delivered within a region of therapeutic efficacy that correlates with target tissue movement, avoiding lower applied energies that are ineffective and higher applied energies that may be associated with thermal and / or cavitation effects in the tissue.

[0052] The written specification uses examples, including the best mode, and is intended to enable one of ordinary skill 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 of ordinary skill 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 language of the claims, or if they include equivalent structural elements that do not differ substantially from the language of the claims. [Explanation of symbols]

[0053] 12 Frequency 14 Pulse Length 16 Pulse Repetition Interval 100 ways 200 Systems 202 Areas of Interest 204 Target tissue 206 Energy Application Device 208 Therapeutic Transducer 210 Imaging Transducer 214 Pulse Generator 216 Controller 220 Evaluation device 230 Processor 232 Memory 234 Input / Output Circuit 236 Display 237 Beam Controller 238 Position Sensor 239 Contact Sensor 300 ways

Claims

1. 1. A neuromodulation delivery system comprising: an energy application device configured to deliver neuromodulation energy to a region of interest in an internal tissue of a subject; and A controller, controlling application of the neuromodulation energy to the region of interest via the energy application device to deliver the dose of the neuromodulation energy to the region of interest; controlling, wherein the energy application device is controlled under control parameters; receiving image data of the region of interest during and / or after the application of the neuromodulation energy; identifying a change in a molecule of interest in the subject as a result of the application of the neuromodulation energy relative to a baseline obtained at or prior to the application of the neuromodulation energy; and A neuromodulation delivery system comprising: a controller configured for determining tissue movement in the region of interest associated with the change in the molecule of interest, the tissue movement being determined based on the image data.

2. The system of claim 1 , wherein the energy application device comprises an ultrasound therapy transducer.

3. The system of claim 2 , wherein the energy applicator comprises an imaging transducer configured to acquire the image data.

4. The system of claim 1 , wherein the controller is configured to obtain a baseline image of the region of interest and determine movement of the tissue based on the baseline image and the image data.

5. The system of claim 1 , wherein the controller is configured to provide dose-related instructions based on the determined tissue movement.

6. The system of claim 1 , wherein the control parameters include a drive voltage, a pulse length, and a pulse repetition interval.

7. The system of claim 6 , wherein the controller is configured to increase or decrease a length of the pulse based on a change in concentration of the molecule of interest that deviates from a threshold value.

8. The system of claim 6 , wherein the controller is configured to increase or decrease the drive voltage based on a change in concentration of the molecule of interest that deviates from a threshold value.

9. The system of claim 6 , wherein the controller is configured to increase or decrease the pulse repetition interval based on a change in concentration of the molecule of interest that deviates from a threshold value.

10. The system of claim 1 , wherein the controller is configured to distribute the dose among multiple regions of interest.

11. The system of claim 1 , wherein the molecule of interest is circulating TNF.

12. The system of claim 1 , wherein the molecule of interest is circulating glucose.

13. 1. A neuromodulation delivery system comprising: an ultrasound probe configured to deliver neuromodulation energy to a region of interest in an internal tissue of a subject via a treatment transducer and acquire image data of the region of interest via an imaging transducer; A controller, controlling application of the neuromodulation energy to the region of interest via the therapy transducer of the ultrasound probe to deliver a dose of the neuromodulation energy thereto, the therapy transducer being controlled under control parameters; receiving image data of the region of interest acquired by the imaging transducer of the ultrasound probe during the application of the neuromodulation energy; determining, based on the image data, movement of tissue in the region of interest during the application of the neuromodulation energy; and A neuromodulation delivery system comprising: a controller configured for modifying one or more control parameters of the therapy transducer based on the determined tissue movement or based on a change in concentration of a molecule of interest in the subject relative to a baseline concentration obtained at or prior to application of the neuromodulation energy.

14. The system of claim 13 , wherein the control parameters include a drive voltage, a pulse length, and a pulse repetition interval.

15. 14. The system of claim 13, wherein the controller is configured to control application of neuromodulation energy at a selected drive voltage, pulse length, and pulse repetition interval until a maximum or threshold tissue movement is identified from the determined tissue movement, and to modify a drive voltage of the therapy transducer in response to identifying the maximum or threshold tissue movement.

16. 14. The system of claim 13, wherein the controller is configured to identify a rate of change of the determined tissue movement and modify the control parameter of the therapy transducer in response to a decrease in the rate of change or a selected rate of change threshold.

17. The system of claim 10 , wherein the region of interest comprises a plurality of sites distributed throughout the internal tissue.

18. 1. A method for delivering neuromodulation energy, comprising: delivering a reference pulse to a region of interest of the subject via an energy application device; delivering a therapeutic pulse to the region of interest via the energy application device subsequent to delivery of the reference pulse; delivering a follow-up pulse to the region of interest via the energy application device after delivering the therapeutic pulse; identifying a phase change between the reference pulse and the tracking pulse; and determining movement of tissue at or near the region of interest based on the phase change.

19. 20. The method of claim 18, wherein the reference pulse and the tracking pulse are delivered by an imaging transducer and the therapy pulse is delivered by a therapy transducer.

20. 20. The method of claim 18, wherein the reference pulses and the tracking pulses are delivered according to a first set of control parameters and the therapy pulses are delivered according to a second set of control parameters that are different from the first set of control parameters.

21. The method of claim 18, wherein the tissue movement is determined based on an area under the curve of the identified phase changes.

22. 20. The method of claim 18, comprising adjusting a control parameter of the therapeutic pulse based on the determined tissue movement.

23. 20. The method of claim 18, comprising determining that the tissue movement is above a selected threshold and selecting a new region of interest for the object.

24. The method of claim 18, wherein the tissue migration is determined to be associated with a change in concentration of a molecule of interest.

25. 1. A method for delivering neuromodulation energy, comprising: delivering a reference pulse to a region of interest of the subject via an energy application device; delivering a therapeutic pulse to the region of interest via the energy application device subsequent to delivery of the reference pulse; delivering a follow-up pulse to the region of interest via the energy application device after delivering the therapeutic pulse; identifying a change in concentration of the molecule of interest relative to baseline and as a result of delivering said therapeutic pulse; and determining a movement of tissue at or near the region of interest associated with the change in concentration based on the phase change.

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