BACKGROUND
[0002] The subject matter disclosed herein relates to neuromodulation and more specifically,
to techniques for modulating a physiological response using energy applied from an energy source.
[0003] Neuromodulation has been used to treat a variety of clinical conditions. For example,
10 electrical stimulation at various locations along the spinal cord has been used to treat chronic back
pain. An implantable device may periodically generate electrical energy that is applied to a tissue
to activate certain nerve fibers, which may result in a decreased sensation of pain. With regard to
spinal cord stimulation, the stimulating electrodes are generally positioned in the epidural space,
although the pulse generator may be positioned somewhat remotely from the electrodes, e.g., in
15 the abdominal or gluteal region, but connected to the electrodes via conducting wires. In other
implementations, deep brain stimulation may be used to stimulate particular areas of the brain to
treat movement disorders, and the stimulation locations may be guided by neuroimaging. Such
central nervous system stimulation is generally targeted to the local nerve or brain cell function
and is mediated by electrodes that deliver electrical pulses and that are positioned at or near the
20 target nerves. However, positioning electrodes at or near the target nerves is challenging. For
example, such techniques may involve surgical placement of the 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
25 and synaptic communication with the next nerve. Such propagation may result in a relatively
larger or more diffuse 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.
3
BRIEF DESCRIPTION
[0004] Certain embodiments are summarized below. These embodiments are not intended to limit
the scope of the claimed subject matter, but rather these embodiments are intended only to provide
5 a brief summary of possible embodiments. Indeed, the disclosure may encompass a variety of
forms that may be similar to or different from the embodiments set forth below.
[0005] In one embodiment, a method is provided that includes applying focused ultrasound
energy to a region of interest in a subject to induce neuromodulation of one or more nerve
pathways, wherein the region of interest comprises at least a portion of a celiac plexus.
10 [0006] In one embodiment, a system is provided that includes an ultrasound probe configured to
apply focused ultrasound energy to a region of interest comprising at least a portion of a celiac
plexus in a subject to neuromodulate a peripheral ganglion of the celiac plexus of the subject. The
system also includes a controller that is configured to acquire image data of the subject from the
ultrasound probe operating in an imaging mode, select the region of interest based on the image
15 data; and control the ultrasound probe to apply the focused ultrasound energy to the region of
interest as part of a treatment protocol to treat inflammatory bowel disease in the subject.
[0007] In one embodiment, a method is provided that includes acquiring image data of a subject
from an ultrasound probe operating in an imaging mode, wherein the subject is diagnosed with
inflammatory bowel disease; selecting a region of interest comprising at least a portion of the
20 celiac plexus based on the image data; and controlling the ultrasound probe to apply focused
ultrasound energy to the region of interest as part of a treatment protocol to treat the inflammatory
bowel disease, wherein the region of interest comprises at least a portion of a peripheral ganglion
of a celiac plexus
25 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 the
4
accompanying drawings in which like characters represent like parts throughout the drawings,
wherein:
[0009] FIG. 1 is a schematic illustration of an experimental setup for ultrasound energy application
according to embodiments of the disclosure;
5 [0010] FIG. 2 shows ultrasound imaging used to spatially select a region of interest for ultrasound
energy application;
[0011] FIG. 3 shows changes in disease activity index (DAI) over the course of repeated focused
ultrasound (FUS) treatments in the dextran sulfate sodium (DSS)-ingested animal model relative
to control;
10 [0012] FIG. 4 shows changes in a DAI subcategory of stool consistency over the course of daily
focused ultrasound treatments in the DSS-ingested animal model relative to control;
[0013] FIG. 5 shows changes in in a DAI subcategory of gross bleeding over the course of daily
focused ultrasound treatments in the DSS-ingested animal model relative to control;
[0014] FIG. 6 shows changes in in a DAI subcategory of weight over the course of daily focused
15 ultrasound treatments in the DSS-ingested animal model relative to control;
[0015] FIG. 7 is a schematic illustration of post-mortem colons of animals in the study group
showing effect of DSS and focused ultrasound on stool consistency;
[0016] FIG. 8 shows a relationship between different concentrations of DSS on DAI scores in
untreated animals;
20 [0017] FIG. 9 shows changes in DAI over the course of twice-daily focused ultrasound treatments
in DSS-ingested animal model relative to control;
[0018] FIG. 10 shows changes in a DAI subcategory of stool consistency over the course of twicedaily focused ultrasound treatments in the DSS-ingested animal model relative to control;
[0019] FIG. 11A shows changes in in a DAI subcategory of gross bleeding over the course of
25 twice-daily focused ultrasound treatments in the DSS-ingested animal model relative to control;
5
[0020] FIG. 11B shows representative photos showing changes in gross bleeding from rats on days
7 and 8 from the various treatment and control groups;
[0021] FIG. 12 shows weight changes as a percent from baseline over the course of twice-daily
focused ultrasound treatments in DSS-ingested animal model relative to control;
5 [0022] FIG. 13 shows individual animal stool consistency scores over the course of twice-daily
focused ultrasound treatments in the DSS-ingested animal model relative to control;
[0023] FIG. 14 shows individual animal gross bleeding scores over the course of twice-daily
focused ultrasound treatments in the DSS-ingested animal model relative to control;
[0024] FIG. 15A shows colon lengths for various groups in the study;
10 [0025] FIG. 15B shows representative photos of colon length sized relative to one another;
[0026] FIG. 16A shows colon hematoxylin and eosin Y stained sections of twice-daily focused
ultrasound treated (DSS)-ingested animals model relative to control;
[0027] FIG. 16B shows colon hematoxylin and eosin Y stained sections of daily focused
ultrasound treated (DSS)-ingested animals model relative to control;
15 [0028] FIG. 16C shows histopathological scores for various groups in the study;
[0029] FIG. 17 shows array coordinates and array data for rat cytokine activity assessed from the
colon of rats in the “Naïve”, “Water + 2X FUS”, “DSS + 2X mock FUS” and “DSS + 2X FUS”
groups;
[0030] FIG. 18 shows changes in activity of individual cytokines in the animal groups from the
20 data of FIG. 17;
[0031] FIG. 19 shows changes in activity of individual cytokines in the animal groups from the
data of FIG. 17;
[0032] FIG. 20 shows changes in activity of individual cytokines in the animal groups from the
data of FIG. 17;
6
[0033] FIG. 21 is a schematic representation of a neuromodulation system according to
embodiments of the disclosure;
[0034] FIG. 22 is a block diagram of a neuromodulation system according to embodiments of the
disclosure; and
5 [0035] FIG. 23 is a flow diagram of a method of neuromodulation according to embodiments of
the disclosure.
DETAILED DESCRIPTION
[0036] One or more specific embodiments are described below. In an effort to provide a concise
description of these embodiments, not all features of an actual implementation are described in the
10 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’ specific goals, such as compliance with system-related and businessrelated 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
15 nevertheless be a routine undertaking of design, fabrication, and manufacture for those of ordinary
skill having the benefit of this disclosure.
[0037] 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
20 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 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 the scope of that term or terms. Language
designating such non-limiting examples and illustrations includes, but is not limited to, “for
25 example”, “for instance”, “such as”, “e.g.”, “including”, “in certain embodiments”, “in some
embodiments”, and “in one (an) embodiment.”
7
[0038] When introducing elements of various embodiments of the present disclosure, the articles
“a”, “an”, “the”, and “said” are intended to mean that there are one or more of the elements. The
terms “comprising”, “including”, and “having” are intended to be inclusive and mean that there
may be additional elements other than the listed elements. Furthermore, any numerical examples
5 in the following discussion are intended to be non-limiting, and thus additional numerical values,
ranges, and percentages are within the scope of the disclosed embodiments.
[0039] Inflammatory bowel disease (IBD) subsumes a series of chronic and relapsing
gastrointestinal (GI) disorders with Crohn’s disease (CD) and ulcerative colitis (UC) being the two
major notable mentions. IBD causes chronic inflammation to the GI tract with symptoms
10 comprising of persistent diarrhea, abdominal pain, hemorrhaging and/or rectal bleeding. Many
IBD symptoms also manifest outside of the GI tract including arthritis, episcleritis and fatigue. As
of 2015, there were approximately 3 million adults in the United States diagnosed with IBD, which
represents approximately 1% of the country’s population. The increasing number of diagnoses in
recent years has positioned IBD as a global health problem with estimates of a 20% increase in
15 new diagnoses occurring per decade, which also creates a considerable economic burden.
[0040] Despite efforts, treatment options for IBD are notably lacking in availability and/or
efficacy. Many patients become refractory to first-line pharmacotherapeutics or develop further
complications such as strictures, perforations or fistulas, which may then necessitate a
recommendation for surgery. The recent introduction of anti-tumor necrosis factor (TNF) agents
20 for IBD has been a major advance in treating this disease, but rates of non-responders can be as
high as 60%. Additionally, 30% of individuals become refractory to treatments within 12 months
of administration and relapse with re-emergent symptomatology. Given that hospitalization and
surgery rates for IBD have not decreased and data posit moderate increases in rates of
hospitalization and surgery for CD and UC only further underscores the unmet need and clinical
25 utility to develop new therapeutic interventions to treat IBD.
[0041] There are a variety of etiological components which contribute to the development of
IBD involving complex interactions between genetic, immunological and environmental
conditions. In the absence of a single underlying pathophysiological mechanism for IBD, the
consensus among the field is that particular environmental triggers upset the intestinal homeostasis
8
in individuals with inherent susceptibility to chronic disruption of the immune system and/or
disturbed interactions with gut flora resulting in inflammatory-mediated injury.
[0042] A direct connection between the central nervous system (CNS) and immune system may
involve the spleen for feedback-controlled regulation of cytokine release from splenic and
5 circulating macrophages. This is particularly relevant to IBD due to the role of dysregulated
cytokine levels in modulating intestinal inflammation and colonic injury. Sensory nerve feedback
from circulating cytokines/endotoxins may trigger vagal-mediated signaling to splenic
macrophages to dampen inflammatory responses. This could occur indirectly through adrenergic
neurons in the celiac plexus within the cholinergic anti-inflammatory pathway (CAP). In light of
10 this, the peripheral pathway may serve as a target for novel bioelectric therapeutics, but current
electrical stimulators are unable to administer enteric stimulation.
[0043] Provided herein are techniques to use focused ultrasound to neuromodulate the celiac
plexus (or at least a portion of the celiac plexus) with the goal of improving IBD-like
symptomology. Disclosed herein are results of studies in a rat model of colitis, which involves
15 animals drinking dextran sulfate sodium (DSS) daily via their drinking bottle. The studies assessed
endpoint metrics routinely used in rodent models of IBD with or without focused ultrasound
administration. Focused ultrasound as provided herein was shown to improve IBD-like
symptomology such as stool consistency, gross bleeding/ diarrhea and colon tissue integrity in the
DSS rat model of colitis. Efficacy was noted in both the ‘mild’ and ‘severe’ versions of IBD
20 revealed by using different formulations of DSS. These results demonstrate clinical utility for noninvasive focused ultrasound neuromodulation in IBD. Focused ultrasound may be used to target
specific plexus or ganglion in the peripheral nervous system for diseases such as IBD.
[0044] FIG. 1 shows an experimental setup used to perform certain neuromodulation experiments
focused on a target (e.g., a celiac plexus) as provided herein. An energy application device
25 operated according to parameters set by a controller to apply focused ultrasound to a region of
interest to target to the celiac plexus. In rats, this area is located just below the diaphragm. The
ultrasound transducer placement on the rat was determined by initial ultrasound imaging, shown
in FIG. 2, which revealed two major arteries, hepatic and splenic, as landmarks used in locating
the celiac plexus. After, the transducer was positioned just lateral to the xiphoid process
9
approximately 25 mm above the celiac plexus to activate the enteric CAP pathway at the level of
the superior mesenteric ganglion.
[0045] All experiments involving animals complied with the National Institutes of Health and
Albany Medical College (AMC) Institutional Animal Care and Use Committee (IACUC)
5 guidelines. Animals were purchased from Taconic Biosciences (Germantown, NY, USA) with
procedures performed during the light phase (7:00AM to 7:00PM) of the light-dark cycle. Animals
had access to food and liquid ad libitum.
[0046] Male Sprague Dawley rats with an initial weight of 200-350g were anesthetized by placing
them in an inhalant chamber filled with 4% isoflurane set to 2-3 L/min (Harvard Apparatus, MA,
10 USA) so they could be easily handled for a photo of the animals’ anus, followed by a collection of
stool specimen to be tested for consistency and blood analysis. Immediately after, the head of the
rat was placed in a sealed nose cone while positioned on its back and anesthesia was maintained
with 1.5% isoflurane at 2-3 L/min via a tabletop vaporizer (Harvard Apparatus, MA, USA). The
abdomen, specifically the area above the xiphoid process, was shaved and marked with a black
15 pen to target the transducer for focused ultrasound administration. This location targets the anterior
vagal trunk, which is proximal to the superior mesenteric and both the left and right celiac ganglion
as noted using an ultrasound imaging applicator (FIG. 2). After focused ultrasound was applied,
rats were taken off the isoflurane anesthesia, weighed and returned to their individual cages.
[0047] A Dextran Sulfate Sodium (DSS) model was used to induce IBD-like pathophysiology in
20 the rats. Dextran Sulfate Sodium (DSS) is a water-soluble, sulfated polysaccharide that induces
intestinal inflammation in rats when ingested daily in solution with water over time. This stems
from DSS being an epithelial cell irritant which concentrates in the large bowel resulting in
ulcerated lesions throughout the colonic lamina propria. This induces IBD-like pathophysiology
and symptomology by damaging the epithelial barrier and enabling entry of luminal
25 bacteria/antigens into the mucosa. Moreover, mucosal lesions also increase in number and size in
the distal colon, eliciting epithelial damage which resembles that seen in human ulcerative colitis.
DSS is a model for acute, chronic and/or relapsing intestinal inflammation.
[0048] On day 1 of the experiment, animals had DSS added to their drinking water containing
normal tap water, which was available ad libitum. Concentrations ranged from 4-9% depending
10
on the experiment. Animals in the control groups only drank tap water. For all groups, the drinking
bottle was changed every 3-5 days to ensure that the DSS in the water bottles was not degraded
and free from bacterial contamination which would affect DSS-induced symptoms.
[0049] An endpoint metric to assess symptomology in rodent models of IBD is the disease activity
5 index (DAI), which may be used as a metric to assess effectiveness and/or success of
neuromodulation as provided herein. DAI scores were assessed using weight loss, stool
consistency and gross bleeding. Each criterion can range from 0-4 to reflect normal to the most
severe symptomology, respectively. Weight loss was scored relative to baseline weights.

I/We CLAIM
1. A method, comprising:
applying focused ultrasound energy to a region of interest in a subject to induce neuromodulation
of one or more nerve pathways, wherein the region of interest comprises at least a portion of a
5 celiac plexus.
2. The method of claim 1, further comprising:
imaging an internal tissue of the subject to identify a junction of a hepatic and/or splenic artery
with an abdominal aorta; and
10 selecting the region of interest to be adjacent to the junction.
3. The method of claim 1, wherein the region of interest comprises a peripheral ganglion, a
superior mesenteric ganglion, celiac ganglion, inferior mesenteric ganglion, or dorsal root
ganglion, of the subject.
15
4. The method of claim 1, wherein the region of interest comprises an anterior vagal trunk
proximal to a superior mesenteric ganglion and a left and right celiac ganglion.
5. The method of claim 1, wherein the subject is a subject with inflammatory bowel disease
20 and wherein applying the focused ultrasound energy treats the inflammatory bowel disease.
6. The method of claim 5, wherein the subject has a diagnosis of Crohn’s disease.
7. The method of claim 5, wherein the subject has a diagnosis of ulcerative colitis.
25
8. The method of claim 1, wherein applying the focused ultrasound energy to the region of
interest results in an improvement of a DAI score of the subject relative to a baseline DAI score,
wherein the baseline DAI score is determined prior to the applying.
40
9. The method of claim 1, wherein applying the focused ultrasound energy to the region of
interest results in a reduction in a stool blood level relative to a baseline stool blood level
determined prior to the applying.
5 10. The method of claim 1, wherein applying the focused ultrasound energy to the region of
interest results in a change in concentration of one or more molecules of interest in the subject
relative to a baseline concentration, and further comprising detecting the changing in
concentration.
10 11. The method of claim 10, wherein the one or more molecules of interest comprises
perinuclear anti-neutrophil antibody, anti-Saccharomyces Cerevisiae antibody, calprotectin, Creactive protein, or anti-flagellin antibody.
12. The method of claim 1, wherein applying the focused ultrasound energy to the region of
15 interest causes enteric cholinergic anti-inflammatory pathway (CAP) stimulation.
13. The method of claim 12, wherein applying the focused ultrasound energy to the region
of interest does not cause splenic CAP stimulation or causes relatively less splenic CAP
stimulation relative to enteric CAP stimulation.
20
14. The method of claim 1, comprising assessing a response to the focused ultrasound energy
over a period of time; and changing a treatment protocol to change a dose frequency based on the
assessing.
25 15. A system, comprising:
an ultrasound probe configured to apply focused ultrasound energy to a region of interest
comprising at least a portion of a celiac plexus in a subject to neuromodulate a peripheral ganglion
of the celiac plexus of the subject; and
a controller configured to:
30 acquire image data of the subject from the ultrasound probe operating in an imaging
mode;
41
select the region of interest based on the image data; and
control the ultrasound probe to apply the focused ultrasound energy to the region
of interest as part of a treatment protocol to treat inflammatory bowel disease in the subject.
5 16. The system of claim 15, wherein the ultrasound transducer comprises a therapy
transducer configured to apply the focused ultrasound energy and an imaging probe configured to
acquire the image data.
17. The system of claim 15, wherein the region of interest comprises at least a portion of a
10 peripheral ganglion of the celiac plexus.
18. The system of claim 15, wherein the treatment protocol comprises applying the
ultrasound energy to the region of interest at least daily over a plurality of days.
15 19. The system of claim 15, wherein the controller is configured to:
cause a display of the image data;
receive a user input indicative of the region of interest in the displayed image data; and
select the region of interest based on the user input.
20 20. A method, comprising:
acquiring image data of a subject from an ultrasound probe operating in an imaging
mode, wherein the subject is diagnosed with inflammatory bowel disease;
selecting a region of interest comprising at least a portion of the celiac plexus based
on the image data; and
25 controlling the ultrasound probe to apply focused ultrasound energy to the region
of interest as part of a treatment protocol to treat the inflammatory bowel disease, wherein
the region of interest comprises at least a portion of a peripheral ganglion of a celiac plexus.
21. The method of claim 20, wherein applying the focused ultrasound energy to the region
30 of interest results in a change in concentration of one or more molecules of interest in the subject
42
relative to a baseline concentration, and further comprising detecting the changing in
concentration.