BACKGROUND
[0001] The subject matter disclosed herein relates to techniques to target and/or dose
regions of interest in a subject via application of neuromodulating energy to cause targeted
physiological outcomes. In particular, the disclosed techniques may monitor and/or control
ultrasound-induced tissue displacement as a result of a neuromodulation 5 treatment.
[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, positioning electrodes at or near the target nerves is
challenging. For example, such techniques may involve surgical placement of the
10 electrodes that deliver the energy. In addition, specific tissue targeting via
neuromodulation is challenging. Electrodes that are positioned at or near certain target
nerves mediate neuromodulation by triggering an action potential in the nerve fibers, which
in turn results in neurotransmitter release at a nerve synapse and synaptic communication
with the next nerve. Such propagation may result in a relatively larger or more diffuse
15 physiological effect than desired, as current implementation of implanted electrodes
stimulate many nerves or axons at once. Because the neural pathways are complex and
interconnected, a more selective and targeted modulated effect may be more clinically
useful. However, identification of effective energy application parameters that deliver
energy to a desired region of interest and that cause desired physiological outcomes is
20 complex given individual variability in patient anatomy and clinical responses.
BRIEF DESCRIPTION
[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
25 of possible embodiments. Indeed, the disclosure may encompass a variety of forms that
may be similar to or different from the embodiments set forth below.
[0004] In one embodiment, a neuromodulation delivery system is provide that includes
an energy application device configured to deliver neuromodulating energy to a region of
3
interest of an internal tissue in a subject. The system also includes a controller configured
to control application of the neuromodulating energy via the energy application device to
the region of interest to deliver a dose of the neuromodulating energy thereto; receive image
data of the region of interest during and/or after the application of the neuromodulating
energy; identify a change in a molecule of interest in the subject relative 5 to a baseline
acquired at or before the application of the neuromodulating energy as a result of the
application of the neuromodulating energy; and determine a tissue displacement of the
region of interest associated with the change in the molecule of interest, wherein the tissue
displacement is determined based on the image data.
10 [0005] In one embodiment, a neuromodulation delivery system is provide that includes
an ultrasound probe configured to deliver neuromodulating energy to a region of interest
of an internal tissue in 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 to control application of the neuromodulating energy via the therapy transducer
15 of the ultrasound probe to the region of interest to deliver a dose of the neuromodulating
energy thereto, wherein the therapy transducer is controlled under control parameters;
receive image data of the region of interest acquired by the imaging transducer of the
ultrasound probe during the application of the neuromodulating energy; determine tissue
displacement of the region of interest during the application of the neuromodulating energy
20 based on the image data; and modify one or more control parameters of the therapy
transducer based on the determined tissue displacement or based on a change in a
concentration of a molecule of interest in the subject relative to a baseline concentration
acquired at or before the application of the neuromodulating energy.
[0006] In another embodiment, a method is provided that includes the steps of
25 delivering a reference pulse to a region of interest of a subject via an energy application
device; delivering a therapy pulse to the region of interest via the energy application device
subsequent to delivering the reference pulse; delivering a tracking pulse to the region of
interest via the energy application device subsequent to delivering the therapy pulse;
identifying a phase change between the reference pulse and the tracking pulse; and
4
determining a tissue displacement in 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 therapy pulse to the region of interest via the energy 5 application device
subsequent to delivering the reference pulse; delivering a tracking pulse to the region of
interest via the energy application device subsequent to delivering the therapy pulse;
identifying a change in concentration of a molecule of interest relative to a baseline and as
a result of delivering the therapy pulse; and determining a tissue displacement in or near
10 the region of interest that is 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 when the following detailed description is read with reference to
15 the accompanying drawings in which like characters represent like parts throughout the
drawings, wherein:
[0009] FIG. 1 is a schematic representation of ultrasound parameters and ultrasound
radiation force on tissue according to embodiments of the disclosure;
[0010] FIG. 2 is a schematic representation of a tissue displacement model as a result
20 of ultrasound radiation force on tissue according to embodiments of the disclosure;
[0011] FIG. 3 shows images obtained from tissue that are indicative of ultrasoundinduced
tissue displacement;
[0012] FIG. 4 shows a relationship between displacement distance and a pulse time of
ultrasound radiation force on tissue according to embodiments of the disclosure;
5
[0013] FIG. 5 shows a relationship between displacement distance and a pulse time of
ultrasound radiation force on tissue according to embodiments of the disclosure;
[0014] FIG. 6 shows effects on whole blood tumor necrosis factor (TNF) levels for
different applied pressures of ultrasound to the spleen in an LPS-exposed animal model;
[0015] FIG. 7 shows effects on glucose levels for different pulse lengths 5 of ultrasound
applied to the spleen in an LPS-exposed animal model;
[0016] FIG. 8 is a schematic representation of a phase change in a reference and tracking
pulse used to determine tissue displacement according to embodiments of the disclosure;
[0017] FIG. 9 is a flow diagram of a technique for determining tissue displacement
10 according to embodiments of the disclosure;
[0018] FIG. 10 shows an experimental timeline for ultrasound energy application to
human subjects of FIGS. 13-16;
[0019] FIG. 11 shows experimental control parameters for ultrasound energy
application to human subjects of FIGS. 13-16;
15 [0020] FIG. 12 shows concentrated and distributed regions of interest for ultrasound
energy application to human subjects of FIGS. 13-16;
[0021] FIG. 13 shows a comparison of TNF response relative to degrees of tissue
displacements associated with application of ultrasound energy;
[0022] FIG. 14 shows a comparison of TNF response for displacements associated with
20 concentrated and distributed application of ultrasound energy;
[0023] FIG. 15 shows a comparison of TNF response for displacements associated with
concentrated and distributed application of ultrasound energy;
6
[0024] FIG. 16 shows a summary of TNF response and displacement at different time
points;
[0025] FIG. 17 is a schematic representation of an ultrasound neuromodulation system
according to embodiments of the disclosure;
[0026] FIG. 18 is a block diagram of an ultrasound neuromodulation 5 system according
to embodiments of the disclosure; and
[0027] FIG. 19 is a flow diagram of a technique for tuning tissue displacement
according to embodiments of the disclosure.
DETAILED DESCRIPTION
10 [0028] One or more specific embodiments will be described below. In an effort to
provide a concise description of these embodiments, not all features of an actual
implementation are described in the specification. It should be appreciated that in the
development of any such actual implementation, as in any engineering or design project,
numerous implementation-specific decisions must be made to achieve the developers’
15 specific goals, such as compliance with system-related and business-related constraints,
which may vary from one implementation to another. Moreover, it should be appreciated
that such a development effort might be complex and time consuming, but would
nevertheless be a routine undertaking of design, fabrication, and manufacture for those of
ordinary skill having the benefit of this disclosure.
20 [0029] Any examples or illustrations given herein are not to be regarded in any way as
restrictions on, limits to, or express definitions of, any term or terms with which they are
utilized. Instead, these examples or illustrations are to be regarded as being described with
respect to various particular embodiments and as illustrative only. Those of ordinary skill
in the art will appreciate that any term or terms with which these examples or illustrations
25 are utilized will encompass other embodiments that may or may not be given therewith or
elsewhere in the specification and all such embodiments are intended to be included within
7
the scope of that term or terms. Language designating such non-limiting examples and
illustrations includes, but is not limited to: “for example,” “for instance,” “such as,” “e.g.,”
“including,” “in certain embodiments,” “in some embodiments,” and “in one (an)
embodiment.”
[0030] Neuromodulation within tissues may be achieved 5 by local mechanical
stress/strain, which stretches or displaces tissues and activates different intra-cellular and
inter-cellular processes in response. Provided herein are techniques to control and/or to
monitor the amount of stretch and/or displacement caused by neuromodulating energy
application, e.g., noninvasive ultrasound. By controlling and monitoring the amount of
10 stretch and/or displacement within specific tissues that are targeted for neuromodulating
energy, the control parameters of a neuromodulation energy dose may be adjusted to
produce different levels of effect and/or different types of effects. In an example,
controlling the dose of the amount of stretch and/or the amount of displacement varies the
level of anti-inflammatory effects in certain neuromodulating protocols in humans. Further,
15 the amount of stretch and/or displacement induced by ultrasound energy may be
noninvasively measured also using ultrasound (e.g., using a combination probe) to provide
feedback for real-time quantification and precision control of the delivered dose.
[0031] Displacement in tissue in response to the radiation force of focused ultrasound
may, in certain embodiments, be assessed using shear-wave (elastography) imaging. The
20 present disclosure demonstrates that a threshold effect is observed in living organisms
whereby small amounts of displacement (sub-threshold displacements) do not produce a
neuromodulated effect and larger amounts of displacement (supra-threshold) produce a
neuromodulated effect. A second threshold effect is observed in living organisms where
large amounts of displacement (over-exposure) produce undesired effects and the intended
25 neuromodulation effect is absent or diminished. That is, the control parameters of a dose
may be adjusted for each patient to achieve a desired tissue displacement. In addition to
identifying plateau or maximal displacement levels associated with particular control
parameters, the tissue area over which the displacement is applied and the time-varying
nature of the displacement are observed in the disclosed embodiments to produce different
8
neuromodulation effects. This spatial-temporal relationship and the total duration of the
applied dose has been shown as provided in the present disclosure to produce different
levels of neuromodulation in living organisms.
[0032] Producing an appropriate amount of stretch and/or displacement in different
individuals is challenging due to variations in individual anatomy 5 and variations in
individual tissue properties. That is, a liver may respond differently than a pancreas.
Measuring and monitoring the amount of stretch and/or displacement during a
neuromodulating energy dose may be used to minimize deviations from optimal dosage for
an individual patient. Measuring and monitoring in real-time allows for more precise
10 control of the temporal aspects of the applied stretch and/or displacement. Measuring and
monitoring over a size-varying tissue region allows for more precise control of the spatial
aspects of the applied stretch and/or displacement. For example, a particular region of
interest for energy application may be selected or monitored for desired tissue
displacement. In certain embodiments, the present techniques facilitate determining an
15 appropriate or target amount of spatial-temporal stretch and/or displacement for a specific
individual (personalized) and more reliably producing that determined amount of spatialtemporal
stretch and/or displacement over multiple time scales. Accordingly, assessing
tissue displacement during and after application of neuromodulating energy may permit
fine-tuning of energy parameters to not only generate targeted physiological outcomes, but
20 to account for patient to patient variability in responsiveness and tissue variability in
responsiveness (inter and/or intra tissue).
[0033] Stretch and/or displacement may be induced into tissues in multiple ways. The
disclosed embodiments are discussed in the context of noninvasive ultrasound, which
permits controlled focus and shape of energy applied to a region of interest while
25 simultaneously penetrating deeply into tissue. FIG. 1 is a schematic representation of an
ultrasound beam, denoting the focus point, and a detailed view of the applied ultrasound
energy, showing characteristics of amplitude and frequency 12, pulse high-time or pulse
length 14, and pulse repetition interval 16. The present techniques demonstrate that
modifications to the driving voltage (applied pressure) that produces the ultrasound waves
9
as well as to the pulse length and the pulse repetition interval generates measurable
physiological effects that are correlated to tissue displacement. In certain disclosed
embodiments, the effects of a full amplitude and half amplitude driving voltage are
compared. In addition, changes to the pulse length and pulse repetition interval are
5 assessed.
[0034] FIG. 2 is a simplified tissue displacement model showing displacement
assuming that the ultrasound focus is a simple line source with uniformly distributed
displacement in the z direction. The model also assumes that the tissue is an attenuating,
homogenous, elastic medium. The model permits calculation of displacement F at any
10 observation point in 2D tissue F(x,y,t). Each arrow represents an applied pulse. FIG. 3 is
a time series of ultrasound images starting at time point zero and taken over 4 milliseconds
showing displacement over a 20mm x 20mm region, using a line source assumption with
a diameter 10mm long and a total push pulse over 3 milliseconds. Each individual image
represents the displacement over 0.5 milliseconds; at every 0.5 milliseconds, an additional
15 500 microsecond pulse (shown as a yellow arrow in FIG. 2) is applied to the tissue. The
displacement shown is log scaled with a 30 dB display range. The ultrasound images
demonstrate displacement in tissue of several micrometers over the time that the 3
millisecond total pulse was applied.
[0035] FIG. 4 shows the observed relationship between displacement and pulse length
20 for the displacement in the images of FIG. 3. Over time, as the total pulse increases (total
dose delivery of multiple pulses) with each 500 microsecond pulse length push, a larger
displacement is observed until all the displacement contributed from the source cannot add
up coherently. Thus, the displacement amplitude (shown as arbitrary units) plateaus. In
the depicted example, the pulse push is additive 500 microsecond pulses with no relaxation
25 period. Accordingly, as provided herein, a pulse length and/or total pulse high-time over
the course of a dose time period may be selected to achieve a maximum and/or plateau
value potential tissue displacement for a particular driving voltage (and for a particular
region of interest) at a lower range of plateau pulse length values, thus minimizing
ultrasound energy exposure at the region of interest over the course of the applied dose,
10
which may lead to more targeted effects. Accordingly, in an embodiment, the present
techniques may track displacement in real time over dose delivery, calculating a rate of
change of tissue displacement. Upon determining that the rate of change is decreasing
(e.g., falls below a selected threshold), indicating an approaching plateau, a controller of
the ultrasound probe may automatically modify energy delivery. 5 For example, the
controller may cease energy delivery or may modify control parameters to move out of the
plateau portion of the curve. Such tracking may be desirable, because minimizing
ultrasound energy exposure may prevent or delay compensating mechanisms in the tissue,
preserving the region of interest as an appropriate therapy site for a longer period of time.
10 Further, by avoiding the plateau portion of the curve of FIG. 4, undesired additional
physiological effects of the therapy may not be activated.
[0036] However, as provided herein, other control parameters of ultrasound dose
delivery may be modified to achieve desired physiological outcomes associated with
characteristic tissue displacements and/or relaxation. For example, as shown in FIG. 5, a
15 pulse repetition interval of 500 microseconds (at 2KHz PRF) or 5 millisecond pulse
repetition interval (500 Hz PRF) may vary in a pulse length “on” or pulse high-time, with
accompanying variation in resulting tissue displacement. For example, an increased
amount of pulse high-time at the same PRF results in overall greater displacement over the
course of 10 milliseconds at both higher (2 kHz) and lower (500 Hz) frequency settings.
20 That is, the 150 microsecond pulse high-time results in less displacement of tissue than the
350 microsecond on time. Accordingly, an ultrasound therapy transducer may be tuned to
vary a pulse high-time within a pulse repetition interval to change the profile of tissue
displacement. In addition, increasing the pulse repetition interval may also permit
relaxation between pulses, which in turn changes the effects of compounding displacement
25 over the dose. The 5 millisecond pulse repetition interval for 150, 250, and 350
microsecond pulse on times permits near-total relaxation, while the shorter 500
microsecond pulse repetition interval permits less than complete relaxation. In this manner,
the pulses in the 500 microsecond pulse repetition interval demonstrate compounding
displacement effects over time that disappear once the dose is halted. As provided herein,
11
the present techniques permit ultrasound dose therapy protocols with control parameters
for energy delivery that tune the driving voltage, frequency, pulse length, and pulse
repetition interval, and/or overall dose delivery time. For example, the overall energy
delivered to a region of interest observed for the conditions the top panels (500
microseconds PRI at 2KHz PRF) than the conditions for the lower 5 panels (5 millisecond
PRI at 500 Hz PRF). The estimated displacement may be assessed or estimated as an area
under the curve over the dose delivery period, and the control parameters may be
programmed to fall within desired area under the curve values of tissue displacement for a
particular region of interest.
10 [0037] The present techniques target tissue displacement caused by neuromodulation
that is tied to targeted physiological outcomes. FIG. 6 shows varying effects of ultrasound
pressure (mPa) applied to the spleen on whole blood TNF for an LPS-exposed animal
model. The amount of displacement caused by ultrasound is a function of the elastic
properties of the tissue and the characteristics of the applied energy, such as how long the
15 push (pulse length, pulse repetition interval) and/or how hard (temporal average intensity
mW/cm2 and/or peak pressure mPa) the push. The displacement reaches a maximum where
the force exerted by the ultrasound equals the force pushing back by the tissue. Once at this
maximum, pushing longer does not make any more displacement. Pushing harder (e.g.
more pressure) is a way to get more displacement (reach a new maximum). In the case
20 shown in FIG. 6 for an LPS-exposed animal model with resulting inflammation and
associated baseline increases in TNF, the time duration of the push was kept the same but
the amount of pressure was varied. Two threshold effects were observed, one with little
physiological effect (too low pressure at 0.03 mPa) and a second threshold where the
physiological effect goes away (too high pressure at the 1.72 mPa bar). However, the data
25 between the thresholds shows that the increase in whole blood TNF associated with LPS
exposure was reversed for certain ultrasound pressures while being unaffected at too high
or too low pressures. Accordingly, as provided herein, the present techniques may permit
identifying ultrasound pressures that lie between thresholds associated with no
physiological effects and/or applying ultrasound energy within the range of these identified
12
pressures. As provided herein, tissue displacement caused by ultrasound energy may be
used as a marker for desired physiological effects. In an embodiment, the change in effect
between the 1.27 mPa bar and the 1.72 mPA bar is associated with a physical change in
tissue reaction to applied ultrasound energy from stretch displacement to heat/cavitation at
higher pressures. The desired effects may be observed at the pressures 5 associated with
stretch displacement. Accordingly, control parameters for an ultrasound dose may be
selected to cause stretch displacement and may avoid peak pressures that are too low to
cause displacement or that are so high that the dominant tissue effects in or near the region
of interest are heat/cavitation.
10 [0038] FIG. 7 shows results of changing time duration for a pressure of the push (pulse)
kept the same (200 milliseconds) relative to a control for glucose changes relative to
baseline. The results show two threshold effects, one with little physiological effect (too
short a duration) and a second threshold where the physiological effect goes away (too long
a duration). Accordingly, the control parameters may be selected to align with tissue
15 displacement associated with the desired change in glucose percentage.
[0039] To that end, the present techniques provide systems and methods for monitoring
and/or assessing tissue displacement. In an embodiment, the tissue displacement may be
assessed via ultrasound. In one embodiment, an ultrasound probe may be a combination
probe that includes a therapy transducer and an assessment (imaging) transducer. The
20 imaging transducer may be used to identify and select a region of interest as well as to track
displacement of tissue caused by application of neuromodulating energy. FIG. 8 shows an
example control or drive signal for identifying tissue displacement that may be used to
control an ultrasound probe to deliver therapy and track associated tissue effects. In an
embodiment, a short reference imaging pulse and a tracking pulse bracket a therapy pulse.
25 A phase change between reference and tracking signals based on the ultrasound image data
is used calculate tissue displacement. As shown, the displacement may be in the positive
or negative direction along an axis, and a total displacement, or area under the curve, may
be used as a displacement metric.
13
[0040] FIG. 9 is a flow diagram of a method 100 for assessing tissue displacement as a
result of ultrasound energy application to a region of interest in 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 (block 102), which is received by a controller 5 of the ultrasound
probe (e.g., an ultrasound system). A same ultrasound transducer of the ultrasound probe
or a different ultrasound transducer (e.g., a dedicated therapy transducer) is controlled to
apply an ultrasound therapy pulse (block 104). The ultrasound therapy application causes
tissue displacement in or near the region of interest, which is identified using a tracking
10 pulse delivered subsequent to applying the 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 tissue displacement caused by the ultrasound energy pulse
(block 108).
[0041] In certain embodiments, the control parameters of the reference and tracking
15 pulses are selected such that they are short and sufficiently low energy to cause minimal or
no displacement of the tissue. That is, the identified displacement is caused by the therapy
pulse and not by the reference/tracking pulses. In certain embodiments, tracking pulses are
emitted between pulse intervals, such that displacement is tracked for every pulse applied.
In this manner, compounding displacement may be tracked until plateau values are reached.
20 Further, displacement may be determined in real-time, to permit adjustment or
modification of therapy pulse control parameters.
[0042] The relationship between tissue displacement and physiological effects as a
result of neuromodulating ultrasound therapy was examined for 60 human subjects. The
subjects were randomly assigned to one of six groups (n=10 for each group). As disclosed
25 herein, ultrasound was used to cause tissue displacement vibrations of a region of interest
of a target internal tissue. Groups of human subjects received a sham control ultrasound
dose, a half amplitude dose of 115 W/cm2 (Isppa spatial-peak pulse average intensity), or
a full amplitude dose of 362 W/cm2 (Isppa). The temporal average power (Ispta) for the
50% amplitude (368 mW/cm2) is higher than the 100 % amplitude (290 mW/cm2) because
14
it pushed more frequently. The ultrasound dose for the subjects receiving ultrasound
energy was applied to a single site (Groups 1-3) or distributed between multiple sites
(Groups 4-6).
[0043] FIG. 10 shows the experimental protocol for each subject. For those human
subjects receiving ultrasound, the therapy dose was delivered after 5 fasted blood draws for
baseline levels of various blood molecules, such as TNF, cytokines (IL-1, IL-6, IL-8, IL-
10), glucose, and norepinephrine. TNF response of blood cells to LPS was assessed by
performing a LPS assay on blood from a venous blood draw. The blood was exposed to
LPS at concentrations of 0, 0.1, 1, 10, and 100ng/ml followed by analysis of each sample
10 with human TNF ELISA. The area under the curve (AUC) for the TNF response
concentration across the five LPS concentrations was computed and used to characterize
the TNF response of blood cells. Ultrasound energy was applied to a region of interest in
a spleen tissue of each subject. Fasted blood draws were performed at 1 hr, 2 hrs, and 24
hrs after therapy dose. FIG. 11 summarized the control parameters and resulting tissue
15 displacement for subjects in reach of the different groups. FIG. 12 is a schematic
representation of the single site vs. multi-site delivery for the spleen.
[0044] FIG. 13 shows results of splenic ultrasound stimulation within a concentrated
(single-site) region of interest. Larger displacement is correlated to greater reduction in
TNF response of blood cells to LPS at 2 hours post stimulation. The top bracket shows the
20 P-value (Wilcoxon test) comparing small and large displacement within a single or
concentrated treatment region of interest. The data shown is from 8 subjects of Group 1
(Small Displacement), 10 subjects of Group 2 (Medium Displacement), and 8 Subjects of
Group 3 (Large Displacement).
[0045] FIG. 14 shows a comparison between tissue displacement between concentrated
25 (single site) and distributed (multi-site) ultrasound energy application for medium
displacement groups. For medium displacement within a concentrated region, splenic
ultrasound stimulation tends to cause greater reduction in TNF response of blood cells to
LPS at 2 hours post stimulation. The top bracket shows the P-value (Wilcoxon test)
15
comparing medium displacement within a concentrated vs. distributed region. The data
shown is from 10 subjects of Group 2 (Medium Displacement) and 9 subjects of Group 5
(Medium Displacement).
[0046] FIG. 15 shows a comparison between tissue displacement between concentrated
(single site) and distributed (multi-site) ultrasound energy 5 application for large
displacement groups. For large displacement within a concentrated region, splenic
ultrasound stimulation tends to cause greater reduction in TNF response of blood cells to
LPS at 2 hours post stimulation. The top bracket shows the P-value (Wilcoxon test)
comparing large displacement within a concentrated vs. distributed region. The data shown
10 is from 8 subjects of Group 3 (Large Displacement) and 9 subjects of Group 6 (Large
Displacement).
[0047] FIG. 16 is a summary of TNF response in the six subject groups. The top panels
show the TNF change for the single-site energy application, and the bottom panels show
the TNF change for distributed energy application. The results show that changes to the
15 applied pressure or power between groups 2 and 3 were associated with significant changes
in TNF response relative to baseline. The study groups also show a return to baseline TNF
levels at 24 hours.
[0048] As shown, changes in ultrasound energy application control parameters and
region of interest selection affects physiological outcomes in a manner that is linked to
20 degrees of tissue displacement. While the experimental results showed changes in TNF
relative to baseline as a result of ultrasound energy application (e.g., ultrasound therapy),
it should be understood that these results are presented by way of example. The present
techniques may induce and assess a presence or level of tissue displacement in a region of
interest that is associated with a desired physiological outcome, such as a change in
25 concentration of a molecule of interest relative to a baseline level before treatment. Rather
than or in addition to tracking the change in the molecule concentration, the present
techniques may assess tissue displacement to determine that neuromodulation ultrasound
therapy is effective.
16
[0049] FIG. 17 shows a system 200, e.g., a neuromodulation delivery system, for
neuromodulation to achieve neuromodulating effects such as tissue displacement at one or
more regions of interest 202 of a target tissue 204 associated with neurotransmitter release
and/or activation of components (e.g., the presynaptic cell, the postsynaptic cell) of a
synapse in response to an application of energy. The depicted system 5 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 in
use are directed to multiple regions of interest 20 in one or more internal tissues or organ/s
of a subject, which in turn results in a targeted physiological outcome.
10 [0050] In certain embodiments, the energy application device 206 and/or the pulse
generator 214 may communicate wirelessly, for example with a controller 216 that may in
turn provide instructions to the pulse generator 214. In other embodiments, the energy
application device 206 may be an extracorporeal device, e.g., may operate to apply energy
transdermally or in a noninvasive manner from a position outside of a subject’s body, and
15 may, in certain embodiments, be integrated with the pulse generator 214 and/or the
controller 16. In embodiments in which the energy application device 206 is
extracorporeal, the energy application device 206 may be operated by a caregiver and
positioned at a spot on or above a subject’s skin such that the energy pulses are delivered
transdermally to a desired internal tissue. Once positioned to apply energy pulses to the
20 desired region or regions of interest 202, the system 200 may initiate neuromodulation of
one or more nerve pathways to achieve targeted physiological outcome or clinical effects.
In other embodiments, the pulse generator 14 and/or the energy application device 206 may
be implanted at a biocompatible site (e.g., the abdomen) and may be coupled internally,
e.g., via one or more leads. In some embodiments, the system 200 may be implemented
25 such that some or all of the elements may communicate in a wired or wireless manner with
one another.
[0051] In certain embodiments, the system 200 may include an assessment device 220
that is coupled to the controller 216 and that assesses characteristics that are indicative of
whether the targeted physiological outcome of the modulation have been achieved. In one
17
embodiment, the targeted physiological outcome may be local. For example, the
modulation of one or more nerve pathways may result in local tissue or function changes,
such as tissue structure changes, local change of concentration of certain molecules, tissue
displacement, increased fluid movement, etc. The targeted physiological outcome may be
a goal of the 5 treatment protocol.
[0052] The modulation of one or more nerve pathways to achieve a targeted
physiological outcome may result in systemic or non-local changes, and the targeted
physiological outcome may be related to a change in concentration of circulating molecules
or a change in a characteristic of a tissue that does not include the region of interest to
10 which energy was directly applied. In one example, the displacement may be a proxy
measurement for a desired modulation, and displacement measurements below an expected
displacement value may result in modification of modulation parameters until an expected
displacement value is induced. Accordingly, the assessment device 220 may be configured
to assess concentration changes in some embodiments. In some embodiments, the
15 assessment device 220 may be configured to assess tissue displacement. For example, the
assessment device may be configured to use elastography techniques. Elastography may
be used to examine tissue material properties. In the present techniques, elastography may
be used to assess changes to tissue that are induced by an ultrasound therapy pulse or dosing
protocol. While the depicted elements of the system 200 are shown separately, it should
20 be understood that some or all of the elements may be combined with one another.
[0053] Based on the assessment, the modulation parameters of the controller 216 may
be altered such that an effective amount of energy is delivered. For example, if a desired
modulation is associated with a change in concentration (circulating concentration or tissue
concentration of one or more molecules) within a defined time window (e.g., 5 minutes, 30
25 minutes after a procedure of energy application starts) or relative to a baseline at the start
of a procedure, a change of the modulation parameters such as pulse frequency or other
parameters may be desired, which in turn may be provided to the controller 216, either by
an operator or via an automatic feedback loop, for defining or adjusting the energy
application parameters or modulation parameters of the pulse generator 214 until the
18
modulation parameters result in an effective amount of energy being applied. In one
embodiment, an initially defined region of interest 202 may be refined to yield an updated
region of interest 202 based on feedback from the assessment device as to the efficacy of
the neuromodulating energy over the course of the treatment protocol. The feedback may
be, for example, tissue displacement as a result of the application 5 of neuromodulating
energy. These refinements or updates to the region of interest may be used as part of
patient-specific networks, where the network is updated to identify the specific region of
interest that has the most impact on the physiological parameters of interest for that
particular individual based on the desired clinical outcome.
10 [0054] The system 200 as provided herein may provide energy pulses according to
various modulation control parameters as part of a treatment protocol to apply the effective
amount of energy. For example, the modulation control parameters may include various
stimulation time patterns, ranging from continuous to intermittent. With intermittent
stimulation, energy is delivered for a period of time at a certain frequency during a signal15
on time. The signal-on time is followed by a period of time with no energy delivery,
referred to as signal-off time. The control parameters may also include frequency and
duration of a stimulation application. The application frequency may be continuous or
delivered at various time periods, for example, within a day or week. Further, the treatment
protocol may specify a time of day to apply energy or a time relative to eating or other
20 activity. The treatment duration to cause the targeted physiological outcomes may last for
various time periods, including, but not limited to, from a few minutes to several hours. In
certain embodiments, treatment duration with a specified stimulation pattern may last for
one hour, repeated at, e.g., 72 hour intervals. In certain embodiments, energy may be
delivered at a higher frequency, say every three hours, for shorter durations, for example,
25 30 minutes. The application of energy, in accordance with modulation parameters, such as
the treatment duration, frequency, and amplitude, may be adjustably controlled to achieve
a desired result.
19
[0055] FIG. 18 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
that is adapted to generate a plurality of energy pulses for application to a 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 5 the device.
Software code or instructions are stored in memory 232 of the controller 216 for execution
by the processor 230 to control the various components of the device. The controller 216
and/or the pulse generator 214 may be connected to the energy application device 206 via
one or more leads or wirelessly.
10 [0056] The controller 216 may include a user interface with input/output circuitry 234
and a display 236 that are adapted to allow a clinician to provide selection inputs (e.g.,
selecting a region of interest 20 or a particular segment on an image of the target tissue that
is associated with a desired region of interest 20) or control parameters to modulation
programs. The processor 230 may be configured to control the energy application device
15 and drive a therapy transducer 208 and/or an imaging transducer 210 as provided herein.
Further, the processor 230 may be configured to determine tissue displacement based on
data received from the imaging transducer 210.
[0057] The system may include a beam controller 237 that may control a focus location
of the energy beam of the transducer 14 of the energy application device 206 by controlling
20 one or both of steering and/or focusing of the energy application device 206 to apply
treatment. The beam controller 237 may also control or one or more articulating portions
of the energy application device 206 to reposition the transducer. The beam controller may
receive instructions from the processor 230 to cause changes in focusing and/or steering of
the energy beam. The system 200 may be responsive to position sensor/s 238 and/or
25 contact sensor/s 239 that provide feedback on the energy application device 206. The beam
controller 237 may include a motor to facilitate steering of one or more articulating portions
of the energy application device 206. It is contemplated that the system 200 may include
features to permit position, steering, and/or focus adjustments to facilitate the techniques
disclosed herein.
20
[0058] Each modulation program stored in the 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 modifies its internal parameters in
response to the control signals from controller device 216 to vary the stimulation
characteristics of energy pulses transmitted through lead 233 to 5 a subject to whom the
energy application device 206 is applied. Any suitable type of pulse generating circuitry
may be employed, including but not limited to, constant current, constant voltage, multipleindependent
current or voltage sources, etc. The energy applied is a function of the current
amplitude and pulse duration. The controller 216 permits adjustably controlling the energy
10 by changing the modulation parameters and/or initiating energy application at certain times
or suppressing energy application at certain times. In one embodiment, the adjustable
control of the energy application device 206 to apply energy is based on information related
to a determined tissue displacement.

CLAIMS
I/We Claim
1. A neuromodulation delivery system, comprising:
an energy application device configured to deliver neuromodulating energy to a
region of interest of an internal tissue 5 in a subject; and
a controller configured to:
control application of the neuromodulating energy via the energy
application device to the region of interest to deliver a dose of the neuromodulating
energy thereto, wherein the energy application device is controlled under control
10 parameters;
receive image data of the region of interest during and/or after the
application of the neuromodulating energy;
identify a change in a molecule of interest in the subject relative to a baseline
acquired at or before the application of the neuromodulating energy as a result of
15 the application of the neuromodulating energy; and
determine a tissue displacement of the region of interest associated with the
change in the molecule of interest, wherein the tissue displacement is determined
based on the image data.
20 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 application device comprises an imaging
transducer configured to acquire the image data.
25
4. The system of claim 1, wherein the controller is configured to acquire a baseline
image of the region of interest and determine the tissue displacement based on the baseline
image and the image data.
29
5. The system of claim 1, wherein the controller is configured to provide an indication
related to the dose based on the determined tissue displacement.
6. The system of claim 1, wherein the control parameters comprise driving voltage,
pulse length, and pulse repetition 5 interval.
7. The system of claim 6, wherein the controller is configured to increase or decrease
the pulse length based on a change in concentration of the molecule of interest deviating
from a threshold.
10
8. The system of claim 6, wherein the controller is configured to increase or decrease
the driving voltage based on a change in concentration of the molecule of interest deviating
from a threshold.
15 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
deviating from a threshold.
10. The system of claim 1, wherein the controller is configured to distribute the dose
20 between 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.
25
13. A neuromodulation delivery system, comprising:
an ultrasound probe configured to deliver neuromodulating energy to a region of
interest of an internal tissue in a subject via a therapy transducer and acquire image data of
the region of interest via an imaging transducer; and
30 a controller configured to:
30
control application of the neuromodulating energy via the therapy
transducer of the ultrasound probe to the region of interest to deliver a dose of the
neuromodulating energy thereto, wherein the therapy transducer is controlled under
control parameters;
receive image data of the region of interest acquired 5 by the imaging
transducer of the ultrasound probe during the application of the neuromodulating
energy;
determine tissue displacement of the region of interest during the
application of the neuromodulating energy based on the image data; and
10 modify one or more control parameters of the therapy transducer based on
the determined tissue displacement or based on a change in a concentration of a
molecule of interest in the subject relative to a baseline concentration acquired at
or before the application of the neuromodulating energy.
15 14. The system of claim 13, wherein the control parameters comprise driving voltage,
pulse length, and pulse repetition interval.
15. The system of claim 13, wherein the controller is configured to control application
of neuromodulating energy with a selected driving voltage, pulse length, and pulse
20 repetition interval until a maximum or threshold tissue displacement is identified from the
determined tissue displacement and to modify a driving voltage of the therapy transducer
in response to identification of the maximium or threshold tissue displacement.
16. The system of claim 13, wherein the controller is configured to identify a rate of
25 change of the determined tissue displacement and to modify the control parameters of the
therapy transducer in response to a decrease in the rate of change or a selected rate of
change threshold.
31
17. The system of claim 10, wherein the region of interest comprises a plurality of sites
distributed in the internal tissue.
18. A method of delivery of neuromodulating energy, the method comprising:
delivering a reference pulse to a region of interest of a subject 5 via an energy
application device;
delivering a therapy pulse to the region of interest via the energy application device
subsequent to delivering the reference pulse;
delivering a tracking pulse to the region of interest via the energy application device
10 subsequent to delivering the therapy pulse;
identifying a phase change between the reference pulse and the tracking pulse; and
determining a tissue displacement in or near the region of interest based on the
phase change.
19. The method of claim 18, wherein the reference pulse and the tracking pulse are
15 delivered by an imaging transducer and the therapy pulse is delivered by a therapy
transducer.
20. The method of claim 18, wherein the reference pulse and the tracking pulse are
delivered according to a first set of control parameters and the therapy pulse is delivered
according to a second set of control parameters that are different than the first set of control
20 parameters.
21. The method of claim 18, wherein the tissue displacement is determined based on
an area under the curve of the identified phase change.
22. The method of claim 18, comprising adjusting control parameters of the therapy
pulse based on the determined tissue displacement.
25 23. The method of claim 18, comprising determining that the tissue displacement is
above a selected threshold and selecting a new region of interest in the subject.