U.S. patent application number 14/917314 was filed with the patent office on 2016-08-04 for apparatus and methods for diagnosis and treatment of patterns of nervous system activity affecting disease.
The applicant listed for this patent is TYLERTON INTERNATIONAL INC.. Invention is credited to Shlomo BEN-HAIM.
Application Number | 20160220835 14/917314 |
Document ID | / |
Family ID | 52629057 |
Filed Date | 2016-08-04 |
United States Patent
Application |
20160220835 |
Kind Code |
A1 |
BEN-HAIM; Shlomo |
August 4, 2016 |
APPARATUS AND METHODS FOR DIAGNOSIS AND TREATMENT OF PATTERNS OF
NERVOUS SYSTEM ACTIVITY AFFECTING DISEASE
Abstract
A method for diagnosing and/or treating a medical condition,
comprising modeling an activity of the autonomic nervous system,
and treating the medical condition by guiding a therapeutic agent
according to the model.
Inventors: |
BEN-HAIM; Shlomo; (London,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TYLERTON INTERNATIONAL INC. |
Road Town, Tortola |
|
VG |
|
|
Family ID: |
52629057 |
Appl. No.: |
14/917314 |
Filed: |
September 8, 2014 |
PCT Filed: |
September 8, 2014 |
PCT NO: |
PCT/IB2014/064319 |
371 Date: |
March 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61875070 |
Sep 8, 2013 |
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61875069 |
Sep 8, 2013 |
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61875074 |
Sep 8, 2013 |
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61925670 |
Jan 10, 2014 |
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61925669 |
Jan 10, 2014 |
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62003108 |
May 27, 2014 |
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62030972 |
Jul 30, 2014 |
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62030740 |
Jul 30, 2014 |
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62030917 |
Jul 30, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G06T 2207/30016
20130101; A61B 6/506 20130101; A61N 2/02 20130101; G06T 2207/30048
20130101; G06T 2207/10076 20130101; A61B 6/037 20130101; G06T
2207/30092 20130101; A61B 2018/00577 20130101; A61B 34/10 20160201;
G06T 7/0014 20130101; A61N 2/006 20130101; G06T 2207/10072
20130101; G06T 7/0012 20130101 |
International
Class: |
A61N 2/00 20060101
A61N002/00; A61N 2/02 20060101 A61N002/02; A61B 6/00 20060101
A61B006/00; A61B 6/03 20060101 A61B006/03 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 24, 2014 |
IL |
PCT/IL2014/050086 |
Jan 24, 2014 |
IL |
PCT/IL2014/050088 |
Jan 24, 2014 |
IL |
PCT/IL2014/050089 |
Jan 24, 2014 |
IL |
PCT/IL2014/050090 |
Mar 11, 2014 |
IL |
PCT/IL2014/050246 |
Claims
1. A method of treating a medical condition comprising: determining
a pattern of autonomic innervation activity associated with a
physiological parameter affecting said medical condition; matching
said determined pattern to a modeled pattern; selecting an
adjustment of said modeled pattern; and guiding a therapeutic agent
to adjust said determined pattern in correspondence with said
adjustment of said modeled pattern, thereby treating said medical
condition.
2. The method of claim 1, wherein said adjustment of said
determined pattern adjusts autonomic control of said physiological
parameter from a first mode of modulation to a second mode of
modulation.
3. The method of claim 2, wherein a difference between said first
and second modes comprises a different homeostatic set point of
said physiological parameter.
4. The method of claim 2, wherein a difference between said first
and second modes comprises a different range of available values
for said physiological parameter.
5. The method of claim 2, wherein said adjustment of said modeled
pattern is associated with a mode of autonomic modulation of said
physiological parameter.
6. The method of claim 5, wherein said second mode of modulation
corresponds to said associated mode.
7. The method of claim 1, wherein said determined pattern comprises
activity measured for a plurality of ANS locations.
8. The method of claim 1, wherein said determined pattern comprises
activity measured in at least one ANS location for a plurality of
physiological states.
9. The method of claim 1, wherein said guiding comprises
administering said therapeutic agent to an ANS location within said
determined pattern, said location being chosen for its
correspondence to said selected adjustment.
10. The method of claim 1, wherein said guiding comprises
administering said therapeutic agent at a time selected for its
correspondence to said selected adjustment.
11. The method of claim 1, wherein said guiding comprises
administering said therapeutic agent at a dosage chosen for its
correspondence to said selected adjustment.
12. The method of claim 2, wherein said second mode of modulation
comprises modulation of said physiological parameter away from a
physiological norm, relative to said first mode of modulation.
13. The method of claim 2, wherein adjusting said determined
pattern adjusts modulation of said physiological parameter to
reduce a vulnerability to control feedback leading to a progression
of said medical condition.
14. The method of claim 2, wherein adjusting said determined
pattern adjusts the sensitivity of a first non-neural system organ
to signaling from a second non-neural system organ.
15. The method of claim 2, wherein adjusting said determined
pattern affects resizing of the cellular bulk of an organ.
16. The method of claim 2, wherein adjusting said determined
pattern comprises reducing ANS activity.
17. The method of claim 2, wherein adjusting said determined
pattern comprises increasing ANS activity.
18. The method of claim 1, wherein said matching comprises matching
ANS neural function activity levels within anatomically defined
boundaries.
19. The method of claim 1, wherein said adjusting comprises
balancing ANS neural function activity levels among a plurality of
organ or nervous system regions.
20. The method of claim 19, wherein at least two of said plurality
of organ or nervous system regions are part of a single organ.
21. The method of claim 19, wherein at least two of said plurality
of organ or nervous system regions are part of separate organs.
22. The method of claim 1, wherein said determining itself
comprises: stimulating to elicit activity in ANS locations; and
defining positions involved in said pattern of autonomic
innervation activity, based on the positions of said ANS
locations.
23. The method of claim 22, wherein said stimulating comprises
administering an electrical or electromagnetic pulse.
24. The method of claim 22, wherein said stimulating comprises
manipulating a physiological state.
25. The method of claim 1, wherein said matching comprises applying
an analysis template configured to transform said pattern according
to characteristics relevant to the disease.
26. The method of claim 25, wherein the configuration of said
analysis template defines a normalization.
27. The method of claim 25, wherein the configuration of said
analysis template defines a mask.
28. A method comprising: measuring autonomic innervation activity
associated with a medical condition; and applying the results of
said measurement to said medical condition, wherein said measuring
comprises determining the distribution of a tracer.
29. (canceled)
30. The method of claim 28, wherein said tracer is radioactive, and
said determining comprises nuclear imaging.
31. The method of claim 28, wherein said medical condition is
selected from among the group comprising: diabetes, benign prostate
hyperplasia, erectile dysfunction, rheumatoid arthritis, irritable
bowel syndrome, syncope, hypothyroidism, idiopathic heart failure,
asthma, deposition disease, IBS, weight gain, hyperhidrosis
hypertrophic cardiomyopathy obesity, chronic obstructive pulmonary
disease, thyrotoxicosis, hypertension, torticollis, idiopathic
dilated cardiomyopathy, right ventricular outflow tachycardia,
Brugada syndrome, tetralogy of Fallot, deposition disease of the
lungs, sleep apnea asthma metabolic liver disease compromised
salivation control, and compromised lacrimation control.
32. The method of claim 28, wherein said applying comprises at
least one of the group consisting of: analyzing said measurement
for a pattern of activity relating to said medical condition,
associating a pattern of activity to a treatment for said medical
condition, mapping said pattern of activity to one or more organs
or nervous system locations affecting said medical condition,
interpreting said measurement as indicating a particular aspect of
said medical condition, reading said measurement as a description
of said medical condition, and examining said measurement for a
finding about said medical condition.
33. The method of claim 28, wherein said autonomic innervation
activity is measured from a plurality of ANS locations.
34. (canceled)
35. The method of claim 58, wherein said plurality of ANS locations
comprises regions of different organs.
36. (canceled)
37. The method of claim 58, wherein at least one of said ANS
locations comprises sympathetic innervation, and at least one of
said ANS locations comprises parasympathetic innervation.
38. A system comprising: a pattern extraction unit, configured to
receive measurements of ANS activity, and determine therefrom a
pattern reflecting ANS activity relevant to an organ system
affected by a medical condition; a pattern manipulation unit,
configured to apply said pattern to highlight a feature of said
medical condition.
39. The system of claim 38, wherein said medical condition is
selected from among the group comprising: diabetes, benign prostate
hyperplasia, erectile dysfunction, rheumatoid arthritis, irritable
bowel syndrome, hyperhidrosis hypertrophic cardiomyopathy obesity,
chronic obstructive pulmonary disease, thyrotoxicosis,
hypertension, syncope, hypothyroidism, idiopathic heart failure,
asthma, deposition disease, IBS, weight gain, torticollis,
idiopathic dilated cardiomyopathy, right ventricular outflow
tachycardia, Brugada syndrome, tetralogy of Fallot, deposition
disease of the lungs, sleep apnea asthma metabolic liver disease
compromised salivation control, and compromised lacrimation
control.
40. The system of claim 38, wherein said applying comprises at
least one of the group consisting of: analyzing said measurement
for a pattern of activity relating to said medical condition, said
feature being said pattern of activity; associating a pattern of
activity to a treatment for said medical condition, said feature
being said association; mapping said pattern of activity to one or
more organs or nervous system parts affecting said medical
condition, said feature being the map of activity to anatomy
generated thereby; interpreting said measurement as indicating a
particular aspect of said medical condition, said feature being
said particular aspect; reading said measurement as a description
of said medical condition, said feature being said description; and
examining said measurement for a finding about said medical
condition, said feature being said finding.
41-57. (canceled)
58. A method comprising: measuring autonomic innervation activity
associated with a medical condition; and applying the results of
said measurement to said medical condition, wherein said autonomic
innervation activity is measured from a plurality of ANS locations,
and at least one of said plurality of ANS locations comprises a
ganglion providing autonomic innervation to another of said
plurality of ANS locations.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35 USC
.sctn.119(e) of:
U.S. Provisional Patent Application No. 61/875,069 filed Sep. 8,
2013, U.S. Provisional Patent Application No. 61/875,070 filed Sep.
8, 2013, U.S. Provisional Patent Application No. 61/875,074 filed
Sep. 8, 2013, U.S. Provisional Patent Application No. 61/925,670
filed Jan. 10, 2014, U.S. Provisional Patent Application No.
61/925,669 filed Jan. 10, 2014, U.S. Provisional Patent Application
No. 62/003,108 filed May 27, 2014, U.S. Provisional Patent
Application No. 62/030,740 filed Jul. 30, 2014, U.S. Provisional
Patent Application No. 62/030,972 filed Jul. 30, 2014, and U.S.
Provisional Patent Application No. 62/030,917 filed Jul. 30,
2014.
[0002] This application claims the benefit of priority under 35 USC
.sctn.120 of:
PCT Patent Application No. PCT/IL2014/050086 filed Jan. 24, 2014,
PCT Patent Application No. PCT/IL2014/050088 filed Jan. 24, 2014,
PCT Patent Application No. PCT/IL2014/050089 filed Jan. 24, 2014,
PCT Patent Application No. PCT/IL2014/050090 filed Jan. 24, 2014,
and PCT Patent Application No. PCT/IL2014/050246 filed Mar. 11,
2014.
[0003] The contents of the above applications are incorporated by
reference as if fully set forth herein in their entirety.
FIELD AND BACKGROUND OF THE INVENTION
[0004] The present invention, in some embodiments thereof, relates
to means and/or methods for diagnosing and/or treating disease
using patterns of nervous system activity, and, more particularly,
but not exclusively, to such means and methods in relation to
diseases affecting and/or involving the autonomic nervous
system.
SUMMARY OF THE INVENTION
[0005] According to an aspect of some embodiments of the present
invention, there is provided a method of treating a medical
condition comprising: determining a pattern of autonomic
innervation activity associated with a physiological parameter
affecting the medical condition; matching the determined pattern to
a modeled pattern; selecting an adjustment of the modeled pattern;
and guiding a therapeutic agent to adjust the determined pattern in
correspondence with the adjustment of the modeled pattern, thereby
treating the medical condition.
[0006] According to some embodiments of the invention, the
adjustment of the determined pattern adjusts autonomic control of
the physiological parameter from a first mode of modulation to a
second mode of modulation.
[0007] According to some embodiments of the invention, a difference
between the first and second modes comprises a different
homeostatic set point of the physiological parameter.
[0008] According to some embodiments of the invention, a difference
between the first and second modes comprises a different range of
available values for the physiological parameter.
[0009] According to some embodiments of the invention, the
adjustment of the modeled pattern is associated with a mode of
autonomic modulation of the physiological parameter.
[0010] According to some embodiments of the invention, the second
mode of modulation corresponds to the associated mode.
[0011] According to some embodiments of the invention, the
determined pattern comprises activity measured for a plurality of
ANS locations.
[0012] According to some embodiments of the invention, the
determined pattern comprises activity measured in at least one ANS
location for a plurality of physiological states.
[0013] According to some embodiments of the invention, the guiding
comprises administering the therapeutic agent to an ANS location
within the determined pattern, the location being chosen for its
correspondence to the selected adjustment.
[0014] According to some embodiments of the invention, the guiding
comprises administering the therapeutic agent at a time selected
for its correspondence to the selected adjustment.
[0015] According to some embodiments of the invention, the guiding
comprises administering the therapeutic agent at a dosage chosen
for its correspondence to the selected adjustment.
[0016] According to some embodiments of the invention, the second
mode of modulation comprises modulation of the physiological
parameter away from a physiological norm, relative to the first
mode of modulation.
[0017] According to some embodiments of the invention, adjusting
the determined pattern adjusts modulation of the physiological
parameter to reduce a vulnerability to control feedback leading to
a progression of the medical condition.
[0018] According to some embodiments of the invention, adjusting
the determined pattern adjusts the sensitivity of a first
non-neural system organ to signaling from a second non-neural
system organ.
[0019] According to some embodiments of the invention, adjusting
the determined pattern affects resizing of the cellular bulk of an
organ.
[0020] According to some embodiments of the invention, adjusting
the determined pattern comprises reducing ANS activity.
[0021] According to some embodiments of the invention, adjusting
the determined pattern comprises increasing ANS activity.
[0022] According to some embodiments of the invention, the matching
comprises matching ANS neural function activity levels within
anatomically defined boundaries.
[0023] According to some embodiments of the invention, the
adjusting comprises balancing ANS neural function activity levels
among a plurality of organ regions.
[0024] According to some embodiments of the invention, at least two
of the plurality of organ regions are part of a single organ.
[0025] According to some embodiments of the invention, at least two
of the plurality of organ regions are part of separate organs.
[0026] According to some embodiments of the invention, the
determining itself comprises: stimulating to elicit activity in ANS
locations; and defining positions involved in the pattern of
autonomic innervation activity, based on the positions of the ANS
locations.
[0027] According to some embodiments of the invention, the
stimulating comprises administering an electrical or
electromagnetic pulse.
[0028] According to some embodiments of the invention, the
stimulating comprises manipulating a physiological state.
[0029] According to some embodiments of the invention, the matching
comprises applying an analysis template configured to transform the
pattern according to characteristics relevant to the disease.
[0030] According to some embodiments of the invention, the
configuration of the analysis template defines a normalization.
[0031] According to some embodiments of the invention, the
configuration of the analysis template defines a mask.
[0032] According to an aspect of some embodiments of the present
invention, there is provided a method comprising: measuring
autonomic innervation activity associated with a medical condition;
and applying the results of the measurement to the medical
condition.
[0033] According to some embodiments of the invention, the
measuring comprises determining the distribution of a tracer.
[0034] According to some embodiments of the invention, the tracer
is radioactive, and the determining comprises nuclear imaging.
[0035] According to some embodiments of the invention, the medical
condition is selected from among the group comprising: diabetes,
benign prostate hyperplasia, erectile dysfunction, rheumatoid
arthritis, and irritable bowel syndrome.
[0036] According to some embodiments of the invention, the medical
condition is selected from among the group comprising: syncope,
hypothyroidism, idiopathic heart failure, asthma, deposition
disease, IBS, and weight gain.
[0037] According to some embodiments of the invention, the medical
condition is selected from among the group comprising:
hyperhidrosis hypertrophic cardiomyopathy obesity, chronic
obstructive pulmonary disease, thyrotoxicosis, and
hypertension.
[0038] According to some embodiments of the invention, the medical
condition is selected from among the group comprising: torticollis,
idiopathic dilated cardiomyopathy, right ventricular outflow
tachycardia, Brugada syndrome, tetralogy of Fallot, deposition
disease of the lungs, sleep apnea asthma metabolic liver disease
compromised salivation control, and compromised lacrimation
control.
[0039] According to some embodiments of the invention, the applying
comprises at least one of the group consisting of: analyzing the
measurement for a pattern of activity relating to the medical
condition, associating a pattern of activity to a treatment for the
medical condition, mapping the pattern of activity to one or more
organs affecting the medical condition, interpreting the
measurement as indicating a particular aspect of the medical
condition, reading the measurement as a description of the medical
condition, and examining the measurement for a finding about the
medical condition.
[0040] According to some embodiments of the invention, the
autonomic innervation activity is measured from a plurality of ANS
locations.
[0041] According to some embodiments of the invention, the
plurality of ANS locations comprise different regions of the same
organ.
[0042] According to some embodiments of the invention, the
plurality of ANS locations comprises regions of different
organs.
[0043] According to some embodiments of the invention, at least one
of the plurality of ANS locations comprises a ganglion providing
autonomic innervation to another of the plurality of ANS
locations.
[0044] According to some embodiments of the invention, at least one
of the ANS locations comprises sympathetic innervation, and at
least one of the ANS locations comprises parasympathetic
innervation.
[0045] According to an aspect of some embodiments of the present
invention, there is provided a system comprising: a modeling unit,
configured to receive measurements of ANS activity, and determine
therefrom a model describing ANS activity relevant to an organ
system affected by a medical condition; a model manipulation unit,
configured to apply the model to highlight a feature of the medical
condition.
[0046] According to some embodiments of the invention, the medical
condition is selected from among the group comprising: diabetes,
benign prostate hyperplasia, erectile dysfunction, rheumatoid
arthritis, and irritable bowel syndrome.
[0047] According to some embodiments of the invention, the medical
condition is selected from among the group comprising:
hyperhidrosis hypertrophic cardiomyopathy obesity, chronic
obstructive pulmonary disease, thyrotoxicosis, and
hypertension.
[0048] According to some embodiments of the invention, the medical
condition is selected from among the group comprising: syncope,
hypothyroidism, idiopathic heart failure, asthma, deposition
disease, IBS, and weight gain.
[0049] According to some embodiments of the invention, the medical
condition is selected from among the group comprising: torticollis,
idiopathic dilated cardiomyopathy, right ventricular outflow
tachycardia, Brugada syndrome, tetralogy of Fallot, deposition
disease of the lungs, sleep apnea asthma metabolic liver disease
compromised salivation control, and compromised lacrimation
control.
[0050] According to some embodiments of the invention, the applying
comprises at least one of the group consisting of: analyzing the
measurement for a pattern of activity relating to the medical
condition, the feature being the pattern of activity; associating a
pattern of activity to a treatment for the medical condition, the
feature being the association; mapping the pattern of activity to
one or more organs affecting the medical condition, the feature
being the map of activity to anatomy generated thereby;
interpreting the measurement as indicating a particular aspect of
the medical condition, the feature being the particular aspect;
reading the measurement as a description of the medical condition,
the feature being the description; and examining the measurement
for a finding about the medical condition, the feature being the
finding.
[0051] According to an aspect of some embodiments of the present
invention, there is provided a method comprising: modeling an
activity of the autonomic nervous system; treating a medical
condition by guiding a therapeutic agent according to the
modeling.
[0052] According to some embodiments of the invention, the method
comprises detecting the medical condition according to the
modeling. According to some embodiments of the invention, the
medical condition is associated with the autonomic nervous system.
According to some embodiments of the invention, the medical
condition is associated with hyperactivity of the ANS. According to
some embodiments of the invention, the medical condition is
associated with hypoactivity of the ANS.
[0053] According to some embodiments of the invention, the guiding
comprises navigating the therapeutic agent according to mapping of
a neurotransmitter marker.
[0054] According to some embodiments of the invention, the modeling
comprises imaging one or more organs by using a
radiopharmaceutical. According to some embodiments of the
invention, the medical condition is one of diabetes, irritable
bowel syndrome, hypertension, cardiomyopathy, rheumatoid arthritis,
prostatic hyperplasia.
[0055] According to some embodiments of the invention, the method
comprises estimating a level of activity of an organ or a portion
of an organ. According to some embodiments of the invention, the
level is an absolute level. According to some embodiments of the
invention, the method comprises comparing the level to an activity
level of another organ. According to some embodiments of the
invention, the method comprises estimating a response to ANS
activity. According to some embodiments of the invention, the
method comprises assessing a stage of the medical condition
according to the modeling. According to some embodiments of the
invention, the method comprises monitoring treatment according to
the modeling. According to some embodiments of the invention, the
treating comprises ablating one or more components of the ANS.
[0056] According to an aspect of some embodiments of the present
invention, there is provided an apparatus for modeling a nervous
system, comprising an imager; and a software configured for
analyzing an activity of the nervous system and for modeling the
activity using an image acquired by the imager.
[0057] According to some embodiments of the invention, the imager
is a SPECT camera.
[0058] According to an aspect of some embodiments of the present
invention, there is provided a method of characterizing
dysfunctional homeostasis, comprising: receiving autonomic nervous
system activity data, and measurements of at least one other
physiological parameter related to a homeostatic system; analyzing
a variation relationship between the activity data and the
measurements; and producing, based on the analyzing, a
characterizing description of autonomic nervous system activity,
associated with an aspect of dysfunction of the homeostatic
system.
[0059] According to some embodiments of the invention, the
characterizing description comprises described locations of
autonomic nervous system loci involved in the dysfunction.
[0060] According to some embodiments of the invention, the method
comprises using the characterizing description to diagnose the role
of autonomic nervous system members and/or organs on generation or
sustainment of disease.
[0061] According to some embodiments of the invention, the method
comprises using the characterizing description to select a tissue
target for intervention, for treating a disease related to the
homeostatic dysfunction.
[0062] According to some embodiments of the invention, the method
comprises guiding an agent to modulate activity of the selected
tissue target related to the homeostatic system.
[0063] According to some embodiments of the invention, the
characterizing description identifies an attractor range in the
analyzed variation relationship between the activity data and the
measurements.
[0064] According to some embodiments of the invention, the
characterizing description identifies a repeller range in the
analyzed variation relationship between the activity data and the
measurements.
[0065] According to some embodiments of the invention, the method
comprises classification of the characterizing description to a
pattern associated with a treatment of a disease involving the
dysfunctional homeostasis.
[0066] According to some embodiments of the invention, the method
comprises classification of the characterizing description to a
pattern associated with a particular disease state.
[0067] According to some embodiments of the invention, the
autonomic nervous system activity data comprise data taken over a
range comprising at least two different activity levels.
[0068] According to some embodiments of the invention, the
measurements of the at least one other physiological parameter are
taken over a range comprising at least two different levels of the
physiological parameter.
[0069] According to some embodiments of the invention, the at least
two different levels of the physiological parameter comprise a
level associated with a healthy state, and a level associated with
a pathological state.
[0070] According to an aspect of some embodiments of the present
invention, there is provided an autonomic nervous system disease
decoding (ADD) system for characterizing a pathological condition,
comprising a mapping module, configured to: receive and autonomic
nervous system activity data and physiological parameter
measurements, and map a variation relationship between the activity
data and the measurements to produce a control graph.
[0071] According to some embodiments of the invention, the ADD
system comprises a feature detection module, configured to:
classify regions of the control graph, and produce a
characterization of autonomic nervous system activity associated
with a dysfunction of the homeostatic system expressed terms of the
classified regions.
[0072] According to some embodiments of the invention, the
characterization comprises described locations of autonomic nervous
system loci involved in the dysfunction.
[0073] According to some embodiments of the invention, the ADD
system comprises a diagnosis module, configured to use the
characterization to diagnose the role of autonomic nervous system
members and/or organs on generation or sustainment of disease.
[0074] According to some embodiments of the invention, the ADD
system comprises a treatment planning module, configured to uses
the characterization to select a tissue target for intervention,
for treating a disease related to the homeostatic dysfunction.
[0075] Unless otherwise defined, all technical and/or scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which the invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of
embodiments of the invention, exemplary methods and/or materials
are described below. In case of conflict, the patent specification,
including definitions, will control. In addition, the materials,
methods, and examples are illustrative only and are not intended to
be necessarily limiting.
[0076] As will be appreciated by one skilled in the art, aspects of
the present invention may be embodied as a system, method or
computer program product. Accordingly, aspects of the present
invention may take the form of an entirely hardware embodiment, an
entirely software embodiment (including firmware, resident
software, micro-code, etc.) or an embodiment combining software and
hardware aspects that may all generally be referred to herein as a
"circuit," "module" or "system." Furthermore, aspects of the
present invention may take the form of a computer program product
embodied in one or more computer readable medium(s) having computer
readable program code embodied thereon. Implementation of the
method and/or system of embodiments of the invention can involve
performing or completing selected tasks manually, automatically, or
a combination thereof.
[0077] For example, hardware for performing selected tasks
according to embodiments of the invention could be implemented as a
chip or a circuit. As software, selected tasks according to
embodiments of the invention could be implemented as a plurality of
software instructions being executed by a computer using any
suitable operating system.
[0078] In an exemplary embodiment of the invention, one or more
tasks according to exemplary embodiments of method and/or system as
described herein are performed by a data processor, such as a
computing platform for executing a plurality of instructions.
[0079] Optionally, the data processor includes a volatile memory
for storing instructions and/or data and/or a non-volatile storage,
for example, a magnetic hard-disk and/or removable media, for
storing instructions and/or data. Optionally, a network connection
is provided as well. A display and/or a user input device such as a
keyboard or mouse are optionally provided as well.
[0080] Any combination of one or more computer readable medium(s)
may be utilized. The computer readable medium may be a computer
readable signal medium or a computer readable storage medium. A
computer readable storage medium may be, for example, but not
limited to, an electronic, magnetic, optical, electromagnetic,
infrared, or semiconductor system, apparatus, or device, or any
suitable combination of the foregoing. More specific examples (a
non-exhaustive list) of the computer readable storage medium would
include the following: an electrical connection having one or more
wires, a portable computer diskette, a hard disk, a random access
memory (RAM), a read-only memory (ROM), an erasable programmable
read-only memory (EPROM or Flash memory), an optical fiber, a
portable compact disc read-only memory (CD-ROM), an optical storage
device, a magnetic storage device, or any suitable combination of
the foregoing. In the context of this document, a computer readable
storage medium may be any tangible medium that can contain, or
store a program for use by or in connection with an instruction
execution system, apparatus, or device.
[0081] A computer readable signal medium may include a propagated
data signal with computer readable program code embodied therein,
for example, in baseband or as part of a carrier wave. Such a
propagated signal may take any of a variety of forms, including,
but not limited to, electro-magnetic, optical, or any suitable
combination thereof. A computer readable signal medium may be any
computer readable medium that is not a computer readable storage
medium and that can communicate, propagate, or transport a program
for use by or in connection with an instruction execution system,
apparatus, or device.
[0082] Program code embodied on a computer readable medium may be
transmitted using any appropriate medium, including but not limited
to wireless, wireline, optical fiber cable, RF, etc., or any
suitable combination of the foregoing.
[0083] Computer program code for carrying out operations for
aspects of the present invention may be written in any combination
of one or more programming languages, including an object oriented
programming language such as Java, Smalltalk, C++ or the like and
conventional procedural programming languages, such as the "C"
programming language or similar programming languages. The program
code may execute entirely on the user's computer, partly on the
user's computer, as a stand-alone software package, partly on the
user's computer and partly on a remote computer or entirely on the
remote computer or server. In the latter scenario, the remote
computer may be connected to the user's computer through any type
of network, including a local area network (LAN) or a wide area
network (WAN), or the connection may be made to an external
computer (for example, through the Internet using an Internet
Service Provider).
[0084] Aspects of the present invention are described below with
reference to flowchart illustrations and/or block diagrams of
methods, apparatus (systems) and computer program products
according to embodiments of the invention. It will be understood
that each block of the flowchart illustrations and/or block
diagrams, and combinations of blocks in the flowchart illustrations
and/or block diagrams, can be implemented by computer program
instructions. These computer program instructions may be provided
to a processor of a general purpose computer, special purpose
computer, or other programmable data processing apparatus to
produce a machine, such that the instructions, which execute via
the processor of the computer or other programmable data processing
apparatus, create means for implementing the functions/acts
specified in the flowchart and/or block diagram block or
blocks.
[0085] These computer program instructions may also be stored in a
computer readable medium that can direct a computer, other
programmable data processing apparatus, or other devices to
function in a particular manner, such that the instructions stored
in the computer readable medium produce an article of manufacture
including instructions which implement the function/act specified
in the flowchart and/or block diagram block or blocks.
[0086] The computer program instructions may also be loaded onto a
computer, other programmable data processing apparatus, or other
devices to cause a series of operational steps to be performed on
the computer, other programmable apparatus or other devices to
produce a computer implemented process such that the instructions
which execute on the computer or other programmable apparatus
provide processes for implementing the functions/acts specified in
the flowchart and/or block diagram block or blocks.
BRIEF DESCRIPTION OF THE DRAWINGS
[0087] Some embodiments of the invention are herein described, by
way of example only, with reference to the accompanying drawings.
With specific reference now to the drawings in detail, it is
stressed that the particulars shown are by way of example, and for
purposes of illustrative discussion of embodiments of the
invention. In this regard, the description taken with the drawings
makes apparent to those skilled in the art how embodiments of the
invention may be practiced.
[0088] In the drawings:
[0089] FIG. 1 schematically shows a method of using a map of
autonomic nervous system activity in the evaluation and/or
therapeutic treatment of benign prostatic hyperplasia, according to
some exemplary embodiments of the invention;
[0090] FIG. 2 schematically shows a method of using a map of
autonomic nervous system activity in the evaluation and/or
therapeutic treatment of an erectile function disorder, according
to some exemplary embodiments of the invention;
[0091] FIG. 3 schematically shows a method of using a map of
autonomic nervous system activity in the evaluation and/or
therapeutic treatment of diabetes, according to some exemplary
embodiments of the invention;
[0092] FIG. 4 schematically shows a method of using a map of
autonomic nervous system activity in the evaluation and/or
therapeutic treatment of rheumatoid arthritis, according to some
exemplary embodiments of the invention;
[0093] FIG. 5 schematically shows a method of using a map of
autonomic nervous system activity in the evaluation and/or
therapeutic treatment of irritable bowel syndrome, according to
some exemplary embodiments of the invention;
[0094] FIG. 6 comprises an ANSmap image for a patient with sigmoid
septum and cardiomyopathy, according to some exemplary embodiments
of the invention;
[0095] FIG. 7 illustrates an exemplary deposition pathway,
according to some exemplary embodiments of the invention;
[0096] FIG. 8 is a flow chart of a method for processing functional
images to identify and/or locate one or more ANS components (such
as ganglia), according to some exemplary embodiments of the
invention;
[0097] FIG. 9 is a block diagram of a model ANS modeling and/or
pattern evaluation system/unit, in accordance with some exemplary
embodiments of the invention;
[0098] FIG. 10 is a block diagram of a model and/or pattern
analysis and treatment planning system/unit, in accordance with
some exemplary embodiments of the invention;
[0099] FIG. 11 is a schematic diagram of an autonomic nervous
system, to help understand some embodiments of the present
invention.
[0100] FIG. 12 is a schematic flowchart showing the operation of an
ANS-disease decoder (ADD), according to some exemplary embodiments
of the invention;
[0101] FIG. 13 is a schematic flowchart of an initial phase of
analysis performed by an ADD unit, according to some exemplary
embodiments of the invention;
[0102] FIG. 14 is a schematic graph of a mapping between
organ/system function and/or state, according to some exemplary
embodiments of the invention;
[0103] FIG. 15 schematically illustrates a diagnostic measurement
configuration, allowing measurements of a physiological parameter's
changes in response to manipulation, together with measurements of
ANS activity, for use in diagnosis and/or treatment determination,
according to some exemplary embodiments of the invention;
[0104] FIG. 16 is a partial schematic flowchart of operations
performed by an ADD to convert received function data into
determination of an intervention, according to some exemplary
embodiments of the invention; and
[0105] FIG. 17 is a schematic flowchart describing the
ADD-moderated determination of application of treatment to ANS GP
targeted for treatment, according to some exemplary embodiments of
the invention.
DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
[0106] The present invention, in some embodiments thereof, relates
to means and/or methods for diagnosing and/or treating disease
using patterns of nervous system activity, and, more particularly,
but not exclusively, to such means and methods in relation to
diseases affecting and/or involving the autonomic nervous
system.
Overview
[0107] An aspect of some embodiments of the present invention
relates to a method for diagnosing and/or treating disease
comprising acquiring information relating to activity of the
nervous system. Activity of the nervous system is determined, for
example, by relating uptake of a radiolabeled neurotransmitter or
neurotransmitter analog to a location, condition and/or time of
update.
[0108] In some embodiments, the method comprises co-registering the
detected activity with a treatment agent. In some embodiments, the
method comprises treating a disease using the road map
guidance.
[0109] Almost every organ and tissue of the human body is under at
least partial ANS control. ANS control is sets the moment-to-moment
functional state of organ functions. The liver, for instance, has
multiple metabolic functions under ANS control.
[0110] In an example, gluconeogenesis occurs under conditions set
by ANS control. For example, by increased sympathetic or decreased
parasympathetic tone, the ANS induces accelerated gluconeogenesis
so that the blood sugar rises. By a change in operating mode, the
ANS can alter the sympathetic/parasympathetic balance to stop
gluconeogenesis and induce the opposite metabolic
pathway--glycogenesis (which will drive a reduction in blood sugar
and the building of glycogen storage in the liver). In some cases
of disease--involving for example, the liver or the ANS controlling
the liver--partial liver ANS denervation potentially leads to liver
zones under conflicting control: one trying to increase blood sugar
and the other trying to reduce blood sugar. Additionally or
alternatively, mismatching can be among organs within an organ
system, for example between a denervated liver and a
still-innervated pancreas. Herein, where general reference is made
to an organ or an organ system, it is to be understood that the
reference potentially includes tissues, cells and/or cellular
activity which are associated to a common cooperative function; for
example, the homeostatic maintenance and/or control of a
physiological parameter (a "homeostatic parameter"). Such
functional association allows an "organ" to be said to exist, even
where common association to a (optionally physical) structural unit
is absent and/or unclear. For example, cells of the immune system
are considered as an "organ" in some embodiments of the
invention--even though they are distributed throughout the body--in
virtue of their common function. The parasympathetic, sympathetic,
and other nervous subsystems also constitute relatively distributed
systems in this sense. In some cases, the word "system",
particularly in a phrase such as "organ system", and/or the
expression "organ/system" is used as a reminder that the subject
matter described includes and/or potentially includes one or more
structurally-defined organs and/or tissues, cells, and/or cellular
activities which are functionally associated, even though they are
physically distributed. It should be understood that the term
"organ/system" does not exclude cases where an organ is part of a
system, or a system contained within an organ. The phrase "system
component" is also used to denote tissue, cells, and/or cellular
activity selected as having a common basis of operation with
respect to some function (for example, cells being secretory of a
particular hormone, containing cells with a particular immunity
function, belonging to the sympathetic or parasympathetic nervous
systems, or having another function which represents a
physiological commonality for regulation and control).
[0111] Some embodiments of the invention comprise means and/or
methods of identifying disease states caused by interactions among
innervated and denervated tissue of an organ/system. In some
embodiments, the identified disease state relates to a difference
in sensitivity and/or responsiveness to innervation, or another
change which comprises a different system response by and/or in
reaction to structures and/or activity of the ANS. A potential
result of such interactions is a dynamic steady state with an
operating point (set point) that is neither the one driven by the
ANS effect on the innervated tissue nor the operating point that is
created when the ANS is disconnected from the organ/system.
Alternatively, conflicting subsystems created by differential
denervation and/or stimulation increase prevent a steady state from
being reached.
[0112] Alternatively, two or more stable points are created.
Potentially, switching between stable points occurs as a result of
changing conditions, with at least one of the stable points
comprising a symptomatic or organ-damaging state of disease.
[0113] In some embodiments, identification comprises production of
a description characterizing the relationship of ANS activity
(described, for example, in terms of magnitude, location and/or
latency) to a physiological parameter related to a homeostatic
system (for example, the homeostatic parameter itself, or a proxy
parameter, such as a level of activity of an organ having a known
relationship to a homeostatic parameter). Herein, homeostasis, even
when described in relation to a "point" or other compact region of
a control map, should also be understood in relation to a more
generalized concept of a homeostatic "attractor" region. For
example, when there are multiple physiological parameters (N, for
example) impinging on the feed-back regulation of a particular
parameter's level, the region of stability is potentially extended
through an at least relatively flat "surface" of the N-dimensional
space. Additionally or alternatively, a parameter's set point can
oscillate, or "orbit". For example a diurnally varying parameter
(for example, any parameter that changes in relation to the
sleep-wake cycle) can change set point normally throughout the day.
In such a case, a divergence from the normal pattern of variation
is what potentially comprises an observation of a disturbance
relating to disease. Optionally, a disturbance comprises limiting
of the normal range of variation to a subrange, which, though
normal in itself, comprises an abnormality when over-maintained.
Optionally, a disturbance comprises an otherwise normal range of
activity being entered without an appropriate forcing being
present--for example, a rise in heart rate during resting, which is
above normal resting level, but within normal activity levels.
[0114] The degree and nature of homeostasis disturbance upon
denervation (or other disease process) is potentially a function of
the degree of non-homogeneity introduced to the system, the level
of ANS activation, and/or the level of other homeostatic mechanisms
present in the organ/system to counter the effect of the unbalanced
("broken") innervation or innervation target. Disturbance of
homeostasis maintained by the ANS is potentially the result of a
process other than denervation (such as nerve proliferation,
alternation in the health of an innervated target, loss of a
sensitivity, or another reason). Examples of organ and system
states described herein provide exemplary instances where
homeostasis is changed from a condition of normal functioning into
a functional state which describable as disturbed (not operating
normally), vulnerable to disturbance (possibly operating normally,
but easily disturbed), deranged (not operating within normal
parameters), dysfunctional (disturbed, vulnerable to disturbance,
and/or deranged), and/or pathological (having dysfunction which
presents as disease).
[0115] In some embodiments, tissues (for example, organs, cell
types, and/or cells associated by a functional commonality)
involved in the maintenance of a particular physiological parameter
are treated as a homeostatic system. A homeostatic system
particularly comprises those tissues which operate to control a net
effect of their own and/or each other's activity toward an
equilibrium point, upon the activity being disturbed away from that
equilibrium point. The equilibrated parameter of the activity
comprises, for example, a rate of production, a concentration, a
level of activity, and/or a coordination among any of these. In
general, the equilibrated parameter is one that can be said to
assume values which are "more" or "less" than some intermediate
value, towards which the homeostatic system tends to drive it.
[0116] Other concepts useful in the description of homeostatic
disturbances include the notions of "attractors" and "repellers".
These concepts are applicable, for example, to the analysis of a
control graph characterizing the homeostatic behavior of a system
of the body. A control graph is a kind of map, describing how two
or more variable relate to one another in their direct or indirect
effects on each other's magnitude. In some embodiments, a control
graph is constructed on the basis of observed correlations and/or
co-variations, with the causal relationship itself being known or
specified beforehand. In some embodiments, observation of
co-variation is treated as prima facie evidence for a causal
relationship. A "repeller" exists where there is a region of the
control graph that the system tends to move away from, due to a
feed-forward effect: for example, a change in a first parameter
leads to a change in a second--which in turn leads to additional
change in the first parameter, continuing in the same direction. An
"attractor" exists where there is a region of the control graph
that the system tends to move toward, due to a feedback effect: for
example, a change in a first parameter leads to a change in a
second--which in turn tends to counteract the change in the first
parameter, tending thus to a reversal of the change. In general,
the same change behavior can be equivalently be said to be "toward"
an attractor, or "away" from a repeller. It should be understood
that the terms attractor and repeller are employed for their
convenience in describing a homeostatic situation relative to
position one a control graph, and the tendencies of a system to
change state, at various locations within the graph. It should also
be understood that attractors and repellers can be defined with
respect to a limited subset of the parameters influencing a
parameter, for example, between two of three, four or more
variables known to influence the parameter. Potentially, factors
outside a particular attractor's definition appear as driving
forces, serving to deflect a set point from its equilibrium
position as defined for the subsystem. As defined for a space of
larger dimensions, an attractor may be thought of as having a range
of influence within which a set point orbits, according to the
various driving forces acting on it. Even if the attractor fully
defines the forces at work, the attractor's direction of pull is
potentially different at different nearby points in the control
space. This can lead to a form of a naturally "orbiting" attractor,
for example, if a system's set point evolves as a function of its
own recent history.
[0117] In some embodiments of the invention, a disease state
comprises the appearance and/or strengthening of attractors and
repellers which tend to move a system away from a healthy set
point, toward a set point which is pathological. Additionally or
alternatively, a repeller in particular can block the system from
reaching a healthy set point, by acting as a barrier. In some
cases, a system's normal attractors and/or repellers are weakened
and/or relatively weakened according to changes in innervation,
responsiveness, health, or another parameter. In some embodiments,
vulnerability to a pathological attractor and/or repeller is
limited to a particular range of circumstances, for example, during
a particular part of a diurnal cycle, during a condition of stress,
or another temporary condition. In the case of an "orbiting" set
point, the orbit itself may define periods of particular
vulnerability.
[0118] In another example, ANS control affects the maturation of
some of the body's cell lines; in particular, immune cells in the
spleen. Certain sympathetic and parasympathetic innervation
conditions activate T cells, in some cases to become "killer"
cells.
[0119] Some exemplary embodiments of the invention relate to
identifying compromised innervation of the spleen. Potentially,
compromised innervation induces certain autoimmune disease states
and/or cancer types. For example, a body's immune system and
particularly the T cell population are involved in recognizing
targets as host or an invader. T cell lines are among those under
the control of the ANS.
[0120] ANS-induced T cell population lines are potentially induced
according to common function. In the case of a patient that has
areas of the spleen that are denervated, a potential result is
multiple T cell line functional groups induced, with loss of
specificity being at least partially due to disruption in ANS
stimulation in the innervated areas; for example, due to
differential ANS stimulation in the denervated areas. The effect of
such non-homogenous ANS innervation can potentially be large
dispersion of the range of T cell lines present at a given point in
the patient body. Such disruption can in turn lead to the induction
of autoimmune disease.
[0121] Another example relating to the immune system relates to
patients with rheumatoid arthritis patients. Potentially, selective
denervation (such as partial denervation) regresses the damaging
immune response of rheumatoid arthritis patients. Total splenic
denervation, however, potentially accelerates the progression of
generalized atherosclerosis. The knowledge of spatial distribution
of innervation/denervation has potential importance for
understanding ANS-related disease mechanism of rheumatoid
arthritis, and is potentially useful in designing a treatment to
combat disease. For example, where denervation is indicated, it is
a potential advantage to concentrate denervation where it will
restore a particular pattern of innervation (for example, a more
nearly normal pattern, a better balanced pattern, or another
selected pattern), instead simply reducing innervation to the
organ/system without selection as to the portion which is
adjusted.
[0122] In some embodiments of the invention, ANS activity in a
patient with severe rheumatoid arthritis is imaged, for example
according to a method mentioned and/or described herein.
Optionally, a search for areas in the spleen that have "unbroken"
ANS innervation are identified, allowing selective "breakage" of
ANS innervation by targeting target fibers/ganglia of the ANS that
supply zones that are chosen for elimination from control.
Potentially, the targeted selection allows avoiding side effects of
a general ablation, such as accelerated atherosclerosis.
[0123] In some embodiments of the invention, means to quantify
and/or localize the non-homogenous ANS control of an organ/system
are provided. Potentially, this lets the operator assess the
likelihood of a "broken" ANS as a cause for a disease state.
[0124] Optionally, means to compare an observed pattern of ANS
innervation to one or more normal and/or diseased state pattern
templates are provided. In some embodiments, an operator is
informed of and/or is provided with input tools to refine the
result of an automatic assessment, which is linked to a previously
determined association between a template pattern and a disease
state that it potentially underlies. For example, if a template
comprises assumptions about anatomy which do not match the
particulars of an individual patient, the operator is provided with
an opportunity to adjust the template to allow the automatic
assessment to proceed. Optionally or alternatively, the template is
provided with a description of potentially ambiguous situations,
for which it alerts an operator that the automatically determined
matching should be verified by a human operator.
[0125] In some embodiments of the invention, additional means are
provided to allow and operator of a therapeutic system, such as a
therapeutic system described hereinbelow, to plan and predict the
effect of certain ANS/tissue interventions to counter the effect of
the "broken" ANS state. Optionally, a therapeutic system is
configured to administer therapy, for example by means of drug
administration (for example, general or localized), stimulating
signal delivery, an ablation technique, or another method of
treating the observed ANS dysfunction.
[0126] An aspect of some embodiments of the present invention
relates to means and/or methods for diagnosing and/or determining a
treatment using a model of the nervous system, and or patterns
derived from measurements of the nervous system. In some
embodiments, the model or pattern is based on an activity map of
the autonomic nervous system (ANSmap). In some embodiments, the
ANSmap is determined according to a distribution pattern of
radiolabeled marker, the distribution pattern being determined, at
least in part, according to functional (for example,
neurotransmission) activity in the ANS. Optionally, the determined
treatment is suggested to an operator.
[0127] Optionally, determination of a treatment comprises comparing
the model of or pattern demonstrated by the nervous system of the
patient to a normal model/pattern (such as a model/pattern
corresponding to the system of a healthy person, optionally matched
and/or controlled, for example, for age, size, sex, and/or another
parameter).
[0128] Optionally, determination comprises matching the results of
the comparison to one or more treatment options available to the
system. Optionally, available treatment tools are taken into
consideration when determining the treatment.
[0129] In some embodiments a "model" comprises a description having
parts with assigned mappings to aspects of the system being
modeled. Some models have a predictive aspect; for example, the
model can be changed in order to make a prediction about the
behavior of the system it models if subjected to a similar change.
In some embodiments, a "pattern" is any set of observations or
pseudo-observations that capture a state, with or without
interpreted meaning attached. A typical feature of a pattern is
that it can be compared to other patterns, and classified,
categorized, or otherwise assigned an interpretation, whether or
not relationships among its internal parts are themselves
interpretable. A "model" can be considered a specialized form of
pattern having interpretable relationships among its parts which
correspond to the thing modeled. However, the line between model
and pattern is not necessarily clear-cut, and it should be
understood, herein, that where a model is described in an aspect
which applies also to a pattern, a parallel and/or broader pattern
description is also intended.
[0130] In some embodiments, the method comprises acquiring
information relating to activity of the nervous system, acquiring
information relating to the subject anatomy, co-registering the
acquired information, and transmitting the hybrid information (for
example, in the form of a guiding map) to guide a treatment agent
for treating disease.
[0131] In some embodiments of the invention, information relating
to nervous system activity is acquired in relationship to a
particular physiological and/or signaling state.
[0132] Optionally, the physiological or signaling state is a
naturally occurring state, such as blood glucose level in relation
to a meal, parasympathetic innervation in relation to arousal, or
another state. Optionally, a signaling state is artificially
induced, for example, by exogenously stimulating a nerve, GP, or
portion thereof. In some embodiments, a finer mapping of
connections between a nerve or GP and an innervation target is
obtained by artificial stimulation. Optionally, this mapping is
used in diagnosis, treatment planning and/or carrying out
treatment. It should be noted that this potentially is carried out
in some embodiments, as a form of "non-imaging" mapping (though the
result itself may be an image), in that the connections which are
determined link a stimulus delivery position to innervation target
are not necessarily localized within an image; rather localization
is with respect to a position from which stimulation occurs.
[0133] Diagnosis and/or treatment of disease by modeling of and/or
pattern-recognition in the nervous system, in some embodiments of
the invention, comprises a working assumption that the human body
operates under a closed loop control system.
[0134] Optionally, the controlled loop maintains homeostasis. In
some cases, the control system faces a dysfunction or other
condition, such as a heart attack. In such a case, where the heart
might be damaged, with potentially resulting reduction in the blood
pumping capacity of the heart, the control system may try to
correct the blood supply deficiency by "overstimulating" the viable
part of the heart. In some cases, such a correction potentially
creates non-reversible damage to the heart, which can be associated
with reduced, or even impaired, cardiac performance. In some
embodiments, the method includes identifying the part of the
autonomic nervous system (ANS) that is responsible for such
corrective action.
[0135] In some embodiments, dysfunction comprises overactivity or
underactivity of a single side of a closed loop control system.
Potentially, balance in the system is restored by adjusting either
the abnormal side, or a side of a loop which responds to it.
[0136] In some embodiments, dysfunction in feedback control
comprises the entry into, and/or vulnerability to entering a
"runaway loop". In one type of runaway loop, although one side of a
feedback loop responds with modulation (for example, increase or
decrease) of an output, another side fails to respond as usual to
provide damping on the modulation. Potentially, this leads to
increasingly strong modulation, with undesired side effects. For
example, increased insensitivity to a control signal potentially
follows from its overamplification, as another part of the control
system compensates for what may be (from another perspective)
unnecessary overactivity. Additionally or alternatively, control
disturbances potentially occur (for instance) with respect to
increased sensitivity, over-reduction, and/or undercompensation.
This potentially leads to a system state where parts no longer
operate together within an appropriate range of responses and
sensitivities. Entry to such a condition is potentially chronic or
acute. For example, insulin insensitivity potentially develops over
years, while breakdown in feedback in the heart can potentially
develop within seconds.
[0137] In some embodiments, treatments guided by ANS mapping are
tailored to the particular timing requirements of control system
dysfunction. Optionally, the symptoms of loss of feedback control
are only problematic at particular times. Potentially, the problem
is elicited under circumstances which may be predictable and/or
recurrent (for instance, urination), and/or due to less predictable
particulars of a subject's condition and/or environment (for
example, stimulation of fight-or-flight ANS activity). For example,
a potential effect of prostate enlargement is increased difficulty
with urination--when there is a need to do so. The effect in such a
case is recurrent. Erectile dysfunction is potentially only a
problem in the context of sexual activity. A mismatch of
innervation which increases vulnerability to heart fibrillation, on
the other hand, potentially is triggered by a particular stress in
the environment at an unpredictable time--while it is also
necessary for the heart to function well at all times.
[0138] In some embodiments, treatment guidance by an ANSmap
comprises determining a dose and/or timing of a treatment, such as
drug administration. In some embodiments, parameters of the
operation of a stimulation device, for example, a trans- or
percutaneous device configured to stimulate a part of the ANS, are
determined based on ANS map data acquired under one or more
selected conditions. Optionally, the conditions are chosen to
relate to the particulars of a disease--for example, glucose level,
cardiovascular stress, and/or stimuli relating to tumescence.
Optionally, ANS mapping comprises determining a contrast in
activity levels between or among a plurality of conditions.
[0139] In some embodiments, a disturbed control loop comprises
control of a single organ or system component. Control disturbance
optionally comprises control disturbance relating to a whole organ
or system component, and/or to a portion thereof.
[0140] In some embodiments, a disturbed control loop comprises
control of two or more organs or system components. Control
disturbance optionally comprises control disturbance relating to a
plurality of organs or system components, a whole organ or system
component, and/or one or more portions thereof.
[0141] A dysfunction, in some embodiments of the invention, may
refer to a dysfunction associated with an organ/system, and/or to a
dysfunction associated with the control system of the ANS, and/or
any combination thereof, for example a dysfunction associated with
the ANS which causes damage to an organ/system and/or to a
functioning of the organ/system.
[0142] The following are examples of applications that may be used
with an Autonomic Nervous System Map (ANSmap), for example as
described in the application.
[0143] Optionally the ANSmap is a non-invasive ANSmap (niANSmap).
In some embodiments of the invention, functional mapping comprises
indexing responses (in particular, response intensity) measured by
a radiation-sensitive probe (for example a CZT detector) to each of
a plurality of positions at which the responses measured.
[0144] Acquiring an ANSmap, in some embodiments of the invention,
comprises using one or more autonomic nervous system tracers and
locating regions of their accumulation on an anatomical image. In
some embodiments, local tracer accumulation increases with
increasing nervous tissue activity. In some embodiments, use and/or
creation of an ANSmap comprises masking, to segment and/or select
one or more regions of specific interest. In some embodiments,
use/and creation of an ANSmap comprises normalization, for example
relative to an expected value, another ANSmap, a measured clinical
parameter, or other data. In some embodiments, a system for
analyzing an ANSmap comprises a workstation; for example, a
computerized system including processor, memory, and interface
inputs and outputs. In some embodiments, a tool for treatment, for
example, ablation, anesthesia, and/or stimulation of a GP or a
portion thereof is guided by reference to an ANSmap. In some
embodiments, a treatment workstation comprises display (optionally
also production) of an ANSmap for direct guidance of treatment, for
example, guidance of the positioning of a treatment probe.
[0145] In some embodiments of the invention, a data storage medium
is provided having an ANS model (or pattern such as a
visualization) stored thereon. In some embodiments, the stored
information is not or is not merely an image, and includes ganglion
related data, such as size, position, and/or intensity of activity.
In some exemplary embodiments of the invention, the stored
information comprises a non-image representation (such as text) of
the model/pattern information, including ganglion related data,
such as size, position and/or intensity of activity. In some
embodiments, what is stored is a manipulatable data structure, such
as a scalable map.
[0146] In some exemplary embodiments of the invention, a map is
provided with structure in addition or alternative to an image's
pixel array. For instance, the structure includes segmentation
which identifies certain features (such as ganglia and/or axons).
In some examples, the structure includes additional data associated
with parts of the image and/or segments.
[0147] In some exemplary embodiments of the invention, the
representation includes location indications, for example, an
anatomical location, body coordinates and/or a functional location.
Optionally or alternatively to static data, dynamic data per
ganglion may be stored, for example, a time based activation
profile, correlation with organ/system data and/or other dynamic
data, for example, as described herein. In some cases, dynamic data
may be provided as a table or function or time linked data. In
other cases, dynamic data may be provided as statistics. Optionally
or alternatively to ganglion data, what is stored is links between
ganglia, for example, anatomical links (e.g., relatedness to a same
body structure), physical links (e.g., connecting axons) and/or
functional links (e.g., functional relationship between activation
at one and activation at the other). Optionally, the medium may
include indications of relevant input sources to the ganglion
structure, for example, body function and blood hormone levels.
[0148] Optionally or alternatively, the medium stores data relating
to ANS innervation and/or activity in target organ/systems. In one
example, such data is provided as location indications, size/shape
indications and/or static and/or dynamic data regarding activity in
such locations.
[0149] In some embodiments of the invention, ganglion existence,
links and/or data and/or input sources are stored as parameters for
an ANS model- and/or pattern-template, with the actual template,
for example, being stored separately.
[0150] Some embodiments associated with the ANSmap are configured
for diagnostic and/or therapeutic applications. Diagnosis, made
with reference to an ANSmap, is based, for example, on: [0151]
comparison of activity relative to a normal range; [0152]
comparison of activity relative to prior data from the same
subject; [0153] activity differences among organs, organ parts,
and/or system components; [0154] dynamic activity response to
stimulation; and/or [0155] disease state, wherein the ANS is a
causative agent, or is responding to a non-ANS primary
pathology.
[0156] In some embodiments, diagnosis based on ANS mapping provides
a deeper understanding of the role of various signaling subsystems
in the production of symptoms for which the original pathology is
well understood. For example, an enlarged prostate is well
understood to potentially block the flow of urine. But the
resulting symptoms of storage and/or voiding, are potentially
individualized, as a result of the particular interplay of
signaling and control existing in a patient. ANS mapping provides a
potential means to select the right specific treatment for a more
general condition, based on an understanding of the particular
pathway of progressions which the disease is taking.
[0157] Therapy, in some embodiments, is directed to ANS neural
pathways and/or ganglia with the use of an ANSmap, for affecting
function of at least one organ, organ system (or other functional
system), and/or organ part. For example: [0158] Therapy optionally
treats ANS over-activity by: ablating overactive neural tissue,
stimulating the neural tissue innervating a non-overstimulated
organ/system part, modifying neural tissue to balance organ/system
function, and/or administering temporary local anesthesia (for
example, to ganglionic plexuses, and for example with monitoring of
the response). [0159] Therapy optionally treats ANS under-activity
by: ablating neural tissue innervating the non-depressed part of
the organ/system, stimulating under-active neural tissue, and/or
modifying neural tissue to balance organ/system function. [0160]
Therapy optionally treats organ/system primary pathology by:
ablating neural tissue innervating contralateral to a diseased
region, stimulating neural tissue innervating ipsilateral to a
diseased region, and/or modifying neural tissue to balance the
function of the organ/system.
[0161] In some embodiments, a link between a diagnosis and a
therapy is made through the use of one or more disease-treatment
templates, models, and/or patterns. In some embodiments, the
disease-treatment models comprise one or more criteria for absolute
and/or relative activity levels of one or more portions of the ANS.
In some embodiments, a criterion includes reference to other
relevant data, such as test results of blood content, organ/system
function, or any other test relevant to the disease. In some
embodiments of the invention, available data are matched to a
number of available disease-treatment models and/or patterns, to
increase confidence that a finding is unambiguous (or, if the
finding is ambiguous, to alert medical professionals to this). In
some embodiments, a model/pattern is developed in part based on
individualized findings. For example, individual variations in ANS
anatomy are potentially imaged, and the variations themselves
incorporated into the available disease-treatment models/patterns.
This is a potential advantage, for example, when innervation for
multiple organ/systems passes through a particular region, of which
innervation of a particular organ/system needs to be selected for
adequate treatment.
[0162] In some embodiments of the invention, application of therapy
comprises a sacrifice of an aspect of available function or control
in order to prevent the occurrence of further degradation and/or of
a dangerous acute event. For example, it is potentially better to
reduce the responsiveness of a system which is vulnerable to
uncontrolled swings away from homeostasis, even if this results in
a steady-state or other daily condition which is in some respect
worse than the system is currently able to maintain.
[0163] Optionally or alternatively, an uncontrolled feedback loop
can potentially lead to an ultimate condition (for example, disease
progression) which is worse than the one which the feedback is
attempting to correct. It is a potential advantage to adjust a
modulation signal in such a case such that the conditions leading
to progression are reduced, even at the cost of losing some of the
system's existing responsiveness.
[0164] For purposes of better understanding of some embodiments of
the present invention, as illustrated in FIGS. 1-10 of the
drawings, reference is first made to the anatomy and function of an
autonomic nervous system (ANS) of a mammal (e.g., human) as
illustrated in FIG. 11. FIG. 11 shows the components of an ANS
1100, in schematic form. As can be seen, the ANS includes a network
of ganglia, also termed ganglionic plexi (GP). Nerve fibers meet
and synapse at the ganglia.
[0165] The human body has several control systems, including the
hormonal system, the central nervous system and the autonomic
nervous system (ANS). As traditionally depicted, the autonomic
nervous system is (mostly) not under conscious control and serves
to regulate various body functions, including life-sustaining
functions. For example, basal heart rate, breathing and digestion
are controlled by the autonomic nervous system. In some
classifications, the portion of the autonomic nervous system which
relates to digestion is termed the enteric nervous system
(ENS).
[0166] A spinal column 1102 provides both sympathetic and
parasympathetic innervation. As shown, parasympathetic innervation
1106 may proceed directly to organs 1114 and/or to secondary
ganglia 1110. Sympathetic innervation 1108 may be modulated by the
spinal ganglia and then feed into secondary ganglia 1110 or organs
1114. In many cases, the sympathetic and parasympathetic
innervations interact at the secondary ganglia 1110 (such as the
ciliary, celiac, and other ganglia). Secondary ganglia 1110 may be
connected directly to nerve endings 1112 at an organ 1114. In some
cases, an intermediary network or chain of ganglia exists as well
(not shown).
[0167] The ANS is generally considered to include two main
functional layers, the sympathetic nervous system (SNS), generally
(but not exclusively) in charge of excitatory and increased
responsiveness and control, and the parasympathetic nervous system
(PNS), generally (but not exclusively) in charge of damping
responsiveness and control. For example, heart rate is increased by
increased activity of the SNS and decreased by increased activity
of the PNS. In some organs, such as the heart, the nerve fibers of
the SNS and nerve fibers of the PNS meet at certain ganglia.
Ganglia which include both SNS fibers and PNS fibers utilize a
balance between the excitations of the SNS and PNS to determine
their behavior.
[0168] The ANS includes both afferent (leading towards the
innervated tissue) and efferent fibers (leading away from the
innervated tissue).
[0169] From a perspective of diagnosis, it is recognized that
malactivity of the ANS may cause body dysfunction, for example, in
atrial fibrillation. Furthermore, general ANS tone is considered to
be related to some diseases such as high blood pressure. Damage to
the ANS can sometimes occur, causing organ dysfunction, for
example, in transplanted organs.
[0170] From a perspective of treatment, some examples of treating
an undesired condition by ablating a part of the ANS have been
suggested.
[0171] An aspect of some embodiments of the present invention
relates to the analysis of disease state by comparing measurements
of ANS activity to one or more other physiological state
measurements, at different levels of activity and/or
measurement.
[0172] In some embodiments, the measurements are analyzed for
classification as potentially reflecting a pattern associated with
a pathology of control. In some embodiments, the measurements are
analyzed for extraction of features of a control function
(expressible, for example, as a graph or map) which describes the
governing of feedback and/or feed-forward relationships among ANS
activity and the one or more physiological states measured. In some
embodiments, the features extracted comprise divisions of a control
map according to slope. For example, the divisions correspond to
regions of the control map having a monotonic slope. Optionally,
the features extracted comprise "attractors" and/or "repellers",
which are expressed, for example, as zones of division between
zones of monotonic slope. In some embodiments, the control function
is expressed dynamically. For example, the function relating
activity and a physiological parameter optionally evolves as a
function of its own history.
[0173] In some embodiments of the invention, identified features of
a control map correspond to a feature of an underlying pathology.
For example, a homeostatic system that the control map describes
can contain a preferred, normal and/or healthy zone having an
attractor region representing a preferred state of the system, to
which it returns after perturbations. In some embodiments, however,
another region of the control map represents a deranged state
comprising another attractor. If pushed into the vicinity
controlled by this attractor state, the system can potentially
remain there indefinitely, rather than returning to the preferred
set point as should normally occur. A "repeller", in this case, can
potentially comprise a barrier to leaving the pathological
attractor's zone of influence. It should be understood that other
variations affecting the "landscape" of a control map can occur,
for example, a raised minimum, and/or a lowered barrier allowing
escape from the preferred system state, potentially to a region of
increased pathology.
[0174] In some embodiments, identified features of a control map
form a basis for further determinations. In particular, further
determinations optionally comprise a diagnosis of the pathology.
Optionally, the further determinations comprise suggestion and/or
selection of one or more treatment options. Treatment options
arise, for example, from (optionally machine-learned) experience
that a particular pattern responds well to a particular treatment.
Additionally or alternatively, a treatment option is determined by
the application of reasoning to a control map. For example, a
particular ganglion found to be especially associated with an
inverting relationship to a physiological parameter can be targeted
for activity suppression, based on its activity level in the
control map region of a repeller and/or attractor.
[0175] In some embodiments, a diagnosis comprises an analysis of
ANS activity which highlights particular ANS features (for example,
ganglion, efferent, or afferent) and/or controlled tissue as being
implicated in derangements occurring within the zone of a
pathological attractor and/or repeller.
[0176] In some embodiments, a suggested treatment comprises a
determination that actions to treat a particular ANS feature and/or
controlled tissue are likely to restore a more nearly normal form
to the control map, and/or remove regions of the control map of
particular risk to the patient. In some embodiments, control is
substantially impaired, in order to remove the possibility of a
particularly harmful state of mal-control being entered. In some
embodiments, the determination is based on a prior diagnosis
determination based on features of the control map.
[0177] In some embodiments of the invention, there is provided an
apparatus and/or method for determining a pattern of autonomic
innervation activity associated with a medical condition; and
guiding a therapeutic agent to adjust the determined pattern toward
normal physiologic state and away from the diseased state.
[0178] In some embodiments, determination of the pattern comprises
comparing autonomic neural activity relative to: [0179] an
organ/system function; [0180] organ/system function over a range;
[0181] organ/system function over a range and monitoring the change
with the activity of the autonomic neural activity; and/or [0182]
an organ/system function over a range to identify regions where a
monotonic relationship between the autonomic neural activity and
the organ/system function exists.
[0183] In some embodiments, determination of the pattern comprises
identifying the organ/system function that is: [0184] associated
with the lowest or the highest autonomic neural activity; [0185]
associated with the minimal autonomic neural activity of different
organs/systems; and/or [0186] associated with the minimal autonomic
neural activity of different members of the autonomic nervous
system.
[0187] In some embodiments, determination of the pattern comprises
identifying the relationship between organ/system function and
autonomic neural activity of different organs/systems.
[0188] In some embodiments, determination of the pattern comprises
identifying attractor and repeller domains: [0189] of each of the
members of the autonomic nervous system; [0190] of the members of
the autonomic nervous system of the organ/system function; [0191]
that are within pathological domains of the organ/system function;
and/or [0192] that have minimal or maximal neural activity
associated with pathological domains of the organ/system
function.
[0193] In some embodiments, the apparatus is operable for or more
of the following functions relating to a control map describing a
control relationship between autonomic neural activity and organ
and/or system function: [0194] to measure and derive the monotony
of the relationship between autonomic neural activity and
organ/system function; [0195] to measure and derive the peak and
trough of the feedback control relationship between autonomic
neural activity and the organ/system function; [0196] to identify
attractor and repeller values of a member of the autonomic nervous
system; [0197] to identify changes to make in attractor and
repeller values such that the organ/system will retain function
within the normal physiologic/healthy domain; and/or [0198] to
identify modes of other members of the autonomic system that change
attractor and repeller values such that the organ/system will
retain function within the normal physiologic/healthy domain.
[0199] In some embodiments, the treatment apparatus and its method
for use comprise one or more of the following: [0200] information
generated in determining of a pattern or model; [0201] guidance,
based on such information, of intervention toward
organ/systems/members of the autonomic system for which affecting
their function will drive an organ/system toward the normal/healthy
domain, and/or toward an attractor within that domain.
[0202] A further example relating to the immune system relates to
patients with cancer. It is known that certain lines of cancer
cells (LINE YY, for example) release certain chemical substances
that affect the autonomic nervous system either directly or
indirectly by modulating the response of certain ganglia to inputs
that cause increased sympathetic activity to activate a specific
immune cell maturation. The more line YY cells there are, the more
the set point of the ganglia is changed, resulting in reduced
sympathetic activation to address the increased inflammation being
sensed by the afferent pathways to the ganglia. The inappropriately
reduced sympathetic activity from the ganglia halts the maturation
of certain killer T immune cells that would otherwise be produced
to fight the YY cancer cells. Potentially, restoration of an
appropriate balance of activity helps in the reduction of cancerous
growth.
[0203] Another example relates to patients with minimal atrial
fibrosis, where electrical conduction between cells is minimally
impaired under normal operating conditions. Occasionally, people
experience a premature atrial beat: this premature atrial beat
usually is followed with a compensatory period that allows the
atria to become over-extended. The stretch receptors within the
wall of the atria provide afferent fibers input to certain ganglia
adjacent to the atria. These epicardial ganglia, upon sensing
increased stretch in the atria, respond by increasing sympathetic
transmission and reducing parasympathetic tone to the atria. This
increases the force of contraction of both the atria and the
ventricle and reduces the stretch on the atria wall, tending to
bring a healthy heart back into a proper operating range. However,
the same mechanism in patients with fibrosis of the atria can bring
about induction of atrial fibrillation. Increased sympathetic and
decreased parasympathetic activity is associated with atrial
fibrillation. Moreover--in the case of induction of atrial
fibrillation--the stretch in the atria will paradoxically increase.
Feedback leads to increasing the sympathetic tone still further.
Once in this self-perpetuating state, spontaneous termination of
the arrhythmia is difficult to achieve: the more arrhythmia, the
more stretch is induced, and the more sympathetic stimulation is
generated.
[0204] Such situations--where an interrupt delivered to the system
drives it away from its current attractor (or set point) toward a
pathologic attractor (or set point)--show how a vulnerability can
be aggravated when a potentially brief excursion from a homeostasis
moves the system over a "hump", to a place from which the
pathological attractor becomes stronger due to entry into a vicious
cycle.
[0205] It is noted that throughout the application, the term GP,
GPs, ganglion and/or ganglia may also refer to a synaptic center,
to encompass regions other than ganglia (such as where a nerve
meets an organ), as it may be difficult to differentiate between a
ganglion and a GP. In some cases, the difference between an
individual ganglion and a synaptic center comprising a plurality of
ganglia (e.g., a ganglionated plexus) is merely semantic (that is,
wherein different people in the art use different terminology)
and/or of no significant medical importance.
[0206] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not
necessarily limited in its application to the details of
construction and the arrangement of the components and/or methods
set forth in the following description and/or illustrated in the
drawings. The invention is capable of other embodiments or of being
practiced or carried out in various ways.
[0207] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not
necessarily limited in its application to the details set forth in
the following description. The invention is capable of other
embodiments or of being practiced or carried out in various
ways.
Medical Condition Examples
[0208] Following are examples of medical conditions to which the
invention, in some embodiments thereof, is applicable. Optionally,
application uses an ANSmap in diagnosing a condition, guiding
treatment, and/or evaluating response to treatment.
[0209] In some embodiments of the invention, and in several of the
examples presented, an outline is followed, in which: an ANS map is
generated according to conditions appropriate to a disease, the
disease state is determined based upon processing of the ANS map,
and an outcome is generated on that basis--for example, a diagnosis
or a treatment plan.
[0210] Diabetes
[0211] Reference is now made to FIG. 3, which schematically shows a
method 300 of using a map of autonomic nervous system activity in
the evaluation and/or therapeutic treatment of diabetes, according
to some exemplary embodiments of the invention.
[0212] Diabetic Disease and Glucose Control.
[0213] Glucose, though an important energy source for metabolism
(among other functions), is toxic if over-concentrated in the
blood. Diabetes mellitus type 2 is a metabolic disorder wherein
hyperglycemia occurs together with insulin resistance and/or
insulin lack, producing potentially severe long- and short-term
health effects. Among other organs involved in glucose regulation,
the pancreas is normally a regulated producer of insulin. Glucose
uptake and release are regulated target functions adjusted by
insulin, for example in liver and muscle. Liver glucose uptake is
particularly important for regulation of blood glucose levels.
[0214] ANS Involvement in Glucose Control.
[0215] The ANS is involved in modulating insulin release (and also
thus, or through another pathway, blood glucose) both up and down:
by direct innervation, and by blood-borne hormones. Although the
detailed picture is nuanced, it is generally accepted that the
sympathetic ANS stimulates glucose release, while the
parasympathetic ANS stimulates glucose storage.
[0216] A normal pancreas is connected to the ANS via specific parts
of the celiac ganglia (large sympathetic ganglia innervating the
digestive tract), and the vagus nerve (a major source of
parasympathetic innervation of the internal organs). Signaling
molecules associated with the parasympathetic ANS that stimulate
insulin release include acetylcholine; sympathetic ANS-sourced or
-stimulated inhibitors of insulin release include norepinephrine
and epinephrine. Epinephrine is a blood borne hormone, released,
for example, by the adrenal glands under sympathetic ANS
stimulation. Sympathetic ANS-sourced catecholamines are a mixed
stimulating and inhibiting signal, depending on receptor type.
[0217] A normal liver is connected to the ANS via different parts
of the celiac ganglia (sympathetic ANS), and of the vagus nerve
(parasympathetic ANS). In particular, insulin signaling activates
the hypothalamus of the brain, and through the vagus nerve, leads
to decreased glucose production by the liver through downregulation
of gluconeogenic enzyme activity. Sympathetic activation increases
glucose output.
[0218] Functional Inhomogeneities and Mismatches.
[0219] A variety of situations potentially produce inhomogeneity
and/or mismatch of function, arising, for example, from changes to
the above sketch of signaling pathways involved in insulin release
and/or response.
[0220] Potentially, the controlled function of one or more organs
or system components involved in a function (pancreas and liver,
for instance) becomes deranged without appropriate compensation in
one or more other organs, resulting in functional mismatch. Effects
of such mismatch are described hereinbelow.
[0221] Potentially, control of a single organ or system component
is not homogeneous, and/or becomes inhomogeneous over the course of
a disease such as diabetes. It can be understood, for example, that
wherever there is direct innervation which affects a function
distributed across a significant extent of an organ (as is the case
for pancreatic insulin release, and/or liver glucose production)
there is a potential for partial denervation or another derangement
of innervation distribution that leaves organ/system parts under
unequal control. Since sympathetic and parasympathetic control are
exercised by different control subsystems, it is possible for one
aspect of control to be damaged while the other is intact, or for
both to be damaged in a different pattern of distribution. Even
blood-borne control by hormones is potentially prone to develop
spatial differentiation as result of developed concentration
gradients and/or circulatory impairment.
[0222] Potentially, functional responsiveness to control of a
single organ and/or system component is not homogeneous, and/or
becomes inhomogeneous over the course of a disease such as
diabetes. Reduction of functional responsiveness (considered, for
example, as a reduction in function at some fixed control input
level) can occur over all of an organ or system component, but
potentially only in a part of it or differentially across the
whole, depending on the cause of the reduction.
[0223] Actual function potentially becomes inhomogeneous, even when
change itself is homogeneous. Interactions between signal level and
functional sensitivity are potentially non-linear. For example, a
region of pancreas potentially receives a "supramaximal" amount of
innervating insulin control normally in one part, and only
nominally effective insulin control in another; thus, an evenly
distributed reduction in absolute organ and/or system component
function could still result in a mismatch in response such that the
"supramaximally" controlled region continues to produce insulin
under full control, while the nominally controlled region begins to
underperform.
[0224] Possible Effects of Inhomogeneities and Mismatches.
[0225] Where one or more whole organs of a plurality of different
organs operating within a homeostatic system escapes control, or a
part of control, for example, by one or more of the changes
described above, it is possible that regulation of homeostasis will
simply fail. However, there are many potential scenarios where a
regulatory system continues to operate, though in a pathological,
part-pathological, or vulnerable state. For example, if the liver
loses insulin sensitivity, it potentially occurs that the pancreas
increases insulin production. This could, for example,
insufficiently affect the liver, leaving glucose regulation in an
impaired state. Alternatively, the liver is sufficiently affected
to maintain glucose regulation, but the strain on one or more
signaling mechanisms and/or functional outputs leaves the system
vulnerable to a future insult. In another type of scenario (whether
or not the liver is sufficiently affected), excess insulin
potentially over-affects or otherwise disturbs one or more
additional organs which are not otherwise impaired (such as the
muscles, which also are under a level of insulin-mediated
regulatory control). Thus, a control system's own efforts to
correct one functional imbalance potentially create another
functional imbalance.
[0226] Even with net preservation of at least an imperfect control,
functional derangements/mismatches potentially produce a pattern of
regulation which is significantly different from a better
achievable arrangement, even considering the loss of inherent
function. This is potentially due, for example, to inadequate
adaptation or over-adaptation of the associated control machinery,
and/or due to instabilities introduced. For example, a normal organ
system potentially has different parts operating on different time
scales, and/or with different sensitivities. Loss of a "fast
reacting" component, for example, potentially leads to overreaction
by a "slow acting" component.
[0227] Effects of functional and/or signaling inhomogeneity and/or
imbalance potentially comprise increased difficulty in achieving
homeostasis at all. For example, pancreatic control, and thus
control of insulin release, potentially becomes divided in a
disease condition across the pancreas (into two, for example,
though the division may be into more parts, a continuous range, or
another configuration). The result is potentially to produce
different feedback loops, each with its own "set point" (target
glucose concentration) and/or rates of control (a different balance
of fast innervation and slow hormonal response, for example). The
interaction of such loops has the potential to become
unpredictable, and possibly chaotic. Potentially, the extremes of
occasional chaotic regulation (for example, producing a sharp, wide
swing in blood glucose level) are more dangerous to health than a
condition of normal homeostasis which is less than the best
achievable (for example, slower-reacting to glucose entering the
bloodstream from a meal). In some embodiments, a treatment is aimed
at adjusting a control system to prevent extreme swings,
potentially at the expense of sacrificing optimal baseline
control.
[0228] In another example of an ANS derangement, ANS control over
an organ/system function is brought about by interactions between a
local control loop and one or more non-local control loops. The
control components of the system regulating blood sugar, for
example, comprise one or more of each of the following: [0229]
sensing member, measuring the level or activity or a physical
property or other inputs; [0230] processor member, integrating the
sensed activity information and comparing it to a reference state;
and [0231] effector member, which affects the controlled organ
and/or system component to alter, for example, a certain rate of
activities within the controlled organ and/or system component.
[0232] Each of these members has a potentially non-linear
relationship between its input and its output. This is a typical
"unit" arrangement of homeostatic control for many organs/systems,
but it should be understood that these units are often deeply
interconnected. The sensing, processing and effector members are
potentially connected one to the other and/or to other sensing,
processing and effector systems.
[0233] A pathology in the control system controller can come about
by affecting one or more of the relationships between input and
output of any of the members. Some members have additional
connections to a higher level of control. For example, a processing
member is potentially a controlled organ for a higher level control
loop. Additionally or alternatively, a processing member output
affects the domain of an adjacent or remote processing member (for
example, controlling a different organ).
[0234] Connectivity between different control loops is potentially
at any or all levels of each loop member. Potentially, this results
in a subsystem being locked into an externally driven state that is
outside the healthy range.
[0235] For example, a patient with early stage diabetes is
presented with hypoglycemia following meals. This potentially
manifests, for example a lowered sensitivity of a sensing member in
the gastrointestinal tract that relates sugar ingestion to rising
incretin hormones. In more advanced early cases of diabetes the
lower slope is potentially so low such that it appears as a delay
in the response of incretins to ingested sugar.
[0236] The delay in the response to ingested sugar potentially
allows more ingested sugar to enter the blood, driving blood sugar
level higher. Liver gluconeogenesis has not yet been shut down, so
this also drives blood sugar higher. The sugar levels, accordingly,
are elevated compared to a healthy person. When ingestion stops
sugar level begins decreasing. Then, however, the delayed incretin
rise will finally have its effect. Insulin level rises, shutting
down liver gluconeogenesis and initiating liver glycogenesis
(building of liver glycogen storage). Blood sugar thus
decreases--potentially to a hypoglycemic level.
[0237] Thus, delay in input signal potentially drives a control
system of blood sugar to induce post-prandial hyperglycemia
followed by post-prandial hypoglycemia. In some embodiments of the
invention, an ANSmap shows the activation of a sensing member,
potentially including its strength, and/or its activation slope
(increasing level of response over time). The ANSmap may comprise
information taken from a plurality of periods before, during,
and/or after a meal, for example, to allow measurement of
activation slope according to changes among the information.
[0238] Optionally, this allows the treating physician to localize
of the pathology within the control system that is causing the
disturbance in blood sugar levels. Optionally, treatment is by
altering the slope of the response of incretins to ingested
sugar.
[0239] Optionally, the slope is maintained, but activation is begun
earlier that the start of the actual meal. Adjustment and/or early
activation is achieved, for example, by a pharmacologic
administration, and/or by direct (for example, electrical or
electromagnetic) stimulation of the ganglia connected to the
sensing member.
[0240] The large number of possible disease scenarios which the
foregoing mechanisms indicate--different in detail, though still
forms of diabetes--serves as an illustration of the potential value
in obtaining data which characterizes ANS function in a disease
state (provides a characterizing description of ANS function and/or
its effects), and using it for disease analysis, tailored
treatment, and/or verification of results.
[0241] In some embodiments, the following method, including one or
more of the blocks in the shown order or in a different order, is
suggested. The flowchart of FIG. 3 begins, and, in some
embodiments, a SPECT (single photon emission computed tomography)
or other ANS activity image and/or other data structure mapping the
abdomen is obtained at block 310, an anatomical imaging of the
abdomen is acquired at block 312, and the functional and anatomical
data are co-registered at block 314, for example as described in
relation to FIG. 8, hereinbelow. It should be understood that
combinations of blocks 310, 312, and/or 314 comprise one or more
means--exemplary and non-limiting--by which sufficient data are
gathered, in some embodiments, in order to enable the performance
of operations described in relation to other blocks of the
flowchart.
[0242] In some embodiments of the invention, the images described
as being of the abdomen are limited to one or more organs or organ
regions of particular relevance. This should also be understood
with respect to other descriptions of imaging regions hereinbelow,
changed as necessary. For example, images of the pelvis and/or
lower abdomen are potentially restricted to a particular organ or
organ of interest such as the prostate, bladder, corpora cavernosa,
or another organ of interest.
[0243] In another example: in some cases, a specific organ contains
the sensory apparatus which reports a parameter via the ANS. For
instance, the lipid content of a meal is sensed by certain
receptors located in the duodenum, which modulates in turn the
pathways connecting these sensors to the ANS system, which can in
turn affect hepatic fat metabolism. In some embodiments, this is a
locus of control to which a diabetes treatment is directed in some
patients. In some embodiments, the region of interest will be
ganglia transmitting the afferent signal of these fat duodenal
receptors.
[0244] In the case of diabetes, for example, information is
collected, in some embodiments, from pancreas, liver, stomach
and/or the celiac plexus. Diabetes is potentially affected by
multiple nodes of the ANS in multiple organs, although exemplary
embodiments described hereinbelow focus on, the pancreas and liver
in particular. Functions which related to the diabetes disease
process potentially include, for example, food ingestion,
absorption, gastric hormone secretion, small intestine hormone
secretion, pancreatic hormone secretion, and/or liver
metabolism.
[0245] In some embodiments, information is collected from beyond
the abdomen. For example, there is some central nervous system
(CNS) involvement glucose level and liver metabolism control.
Potentially, an image includes a structure such as the
hypothalamus.
[0246] In other diseases as well, some embodiments comprise ANS
mapping of up to the entire body, although embodiments are
discussed in terms of particular body regions for the sake of
clarity of exposition. Potentially, this allows viewing measuring
and deducing from more complete information about the disease
process, and concomitantly more exact planning of a subsequent
intervention.
[0247] In general, it should be understood that there is a tradeoff
made between obtaining maximal image information relevant to
planning an optimal treatment from those available, and focusing
selectively just on those targets most likely to be relevant to the
particular disease state.
[0248] In some embodiments of the invention, activity imaging of
block 310 is synchronized with respect to functional and/or control
loads on a homeostatic organ system. For example, imaging is after
a predefined period of fasting, and/or within one or more
predetermined periods after eating. Optionally, images are taken
during a period sufficiently removed from the last meal (and/or a
need for another one) that the digestive system's ANS is
potentially in a relatively quiescent state. Alternatively, the
subject has fasted to the point that activation of glucose release
is required. Optionally or alternatively, images are taken while
the digestive system is managing an incoming glucose load which
requires a significant increase in glucose uptake activity.
Optionally or alternatively, images are taken while the digestive
system is in an undershoot mode, where blood sugar is low.
Optionally, imaging is of the ANS effects of administered insulin,
epinephrine, or another hormone related to blood glucose
regulation.
[0249] At block 316, in some embodiments, ANS activity data is
evaluated for parameters including, for example, location (for
example, absolute and/or relative to one or more other organs),
size (for example, absolute, and/or relative to the size of one or
more anatomical structures of the body), intensity (for example,
absolute, relative to a standard, relative to one or more other
locations), type (for example, sympathetic or parasympathetic),
likely effect on an innervated organ and/or system component,
and/or another parameter of activity, for example as described
hereinbelow. Optionally, one or more masks are applied, appropriate
to the condition being evaluated. In some embodiments of the
invention, one or more masks are determined based on conditions
such as those described in relation to 310, above. For example, one
or more patient-specific masks of glucose-regulatory ANS activity
are generated based on imaging under different activating
conditions. Optionally, the conditions chosen for mask generation
are relatively extreme, to acquire good differentiation of
masking.
[0250] Optionally, treatment is evaluated based on an ANS map of
another state, wherein it is potentially harder to distinguish
which part of the ANS is selectively responsible for a specific
innervation, except in view of the previously acquired mask. It is
a potential advantage of such embodiments to overcome variability
in anatomy, by activating a subject's own anatomy to achieve a
clear, stereotyped pattern which guides (in the form of a mask, for
example) the understanding of another, less clearly stereotyped
pattern--wherein potentially lie clues to the individual's disease
state.
[0251] Optionally, any of the parameters is normalized. In some
embodiments, normalization is performed among images taken at
different regulatory states, for example, as described in relation
to block 310, hereinabove. For example, pre-meal and post-meal ANS
activity states are compared to reveal differential activation as a
result of blood glucose and/or glucose availability changes. In
some embodiments, compared images are among visits separated by
days, months, or years. Potentially, such longitudinal comparisons
increase the sensitivity with which physiological changes can be
assigned to specific neural components. Other examples of
normalization include, for example, intensity of ANS activity being
normalized to the size, viability, secretion output, movement,
and/or another non-ANS output or aspect of an innervated organ,
organ part, and/or system component. Optionally, normalization is
with respect to a change in a non-ANS output or aspect. It is a
potential advantage to normalize data, for example, in order to
form a more reliable impression of whether innervation and function
are in balance, and/or to detect changes and/or differences. In
some embodiments, one or more activity parameters comprises
anatomical and/or other data, for example as part of
normalization.
[0252] At block 318, in some embodiments, a plan for treatment is
formulated, for example in light of the mapped ANS activity
evaluated at block 316. Optionally, further information is used in
formulating a treatment plan, for example, results of other
evaluations including clinical history, clinical tests, genetic
disease markers, and/or other imaging results. In some embodiments,
the plan is formulated according to matching of one or more
disease-treatment templates, for example as described
hereinbelow.
[0253] A plan for treatment of diabetes, and/or a pre-diabetic
condition, is optionally developed based upon specific findings
from the ANS imaging. In some embodiments, one or more criteria are
set as a model or pattern, to which available data are compared.
Matching of the model/pattern criteria to available data comprises
a determination that a particular condition, related to a
particular treatment option, has been isolated. Illustrative
examples include the following:
[0254] In some embodiments of the invention, a finding of
over-activity in the portion of the celiac ganglia involved in
innervating the liver is made for some phase of digestion. For
example, a model/pattern criterion is satisfied in which a high
level of glucose is found in the blood, relative to what should be
expected for a mapped level of activity related to this portion of
the celiac ganglia. In some embodiments, one or more additional
criteria are matched in order to confirm the finding of
over-activity.
[0255] Optionally or alternatively, the finding of over-activity is
in another sympathetic pathway involved in the ANS innervation of
the liver. Sympathetic activation of the liver, associated with
glucose production, potentially aggravates a condition of high
blood glucose. Optionally, criteria of other models/patterns are
examined to rule out alternative explanations of a particular
ANSmap finding.
[0256] In some embodiments of the invention, a plan is made to at
least partially ablate the over-active sympathetic innervation of
the liver, with the goal of reducing glucose release. Optionally,
where ambiguity remains with respect to other models/patterns which
have not been ruled out, further tests are performed, and/or due
caution is maintained in the planning of the ablation. Ablation
comprises, for example, whole or partial thermoablation,
cryoablation, drug injection, anesthesia, or another intervention
which reduces ANS activity.
[0257] In some embodiments of the invention, a finding of
over-activity in the portion of the celiac ganglia involved in
innervating the pancreas is made for some phase of digestion. For
example, a disease-treatment model criterion is satisfied in which
a high level of glucose is found in the blood, relative to what
should be expected for a mapped level of activity related to this
portion of the celiac ganglia. In some embodiments, one or more
additional criteria are matched in order to confirm the finding of
over-activity.
[0258] Optionally, the finding of over-activity is in another
sympathetic pathway involved in the ANS innervation of the
pancreas. Sympathetic activation of the pancreas, associated with
the inhibition of insulin production, potentially aggravates a
condition of high blood glucose. Optionally, criteria of other
models/patterns are examined to rule out alternative explanations
of a particular ANSmap finding. In some embodiments of the
invention, a plan is made to at least partially ablate the
over-active sympathetic innervation of the pancreas, with the goal
of increasing insulin production.
[0259] Optionally, where ambiguity remains with respect to other
models/patterns which have not been ruled out, further tests are
performed, and/or due caution is maintained in the planning of the
ablation. Ablation comprises, for example, whole or partial
thermoablation, cryoablation, drug injection, anesthesia, or
another intervention which reduces ANS activity.
[0260] It should be noted that both of the above scenarios relate
to over-active innervation from a portion of the celiac ganglia. In
some embodiments, a selection of preferred treatment course from
among these two options comprises observing that innervation
activity specifically to the liver vs. the pancreas (or vice versa)
is elevated.
[0261] In some embodiments, a finding is that both types of
innervation activity are elevated relative what is expected.
Optionally, both treatment options are performed.
[0262] Alternatively, only one is. Alternatively, neither is
performed. In some embodiments, additional criteria which are met
to fit a disease-treatment model include criteria relating activity
levels to levels of insulin, relating activity levels to maximum or
minimum levels of observed activity (in different conditions), or
one or more other criteria.
[0263] In some embodiments, another target for ablation is decided
upon. For example, excessive production of adrenaline is
potentially indicated by over-activity in the innervation of the
adrenal glands, and/or of the glands themselves. Optionally, the
production of adrenaline is itself "normal", but because it affects
an impaired glucose regulation system, it is determined to reduce
the capacity to produce epinephrine, to reduce stress on the
damaged control system.
[0264] In some embodiments of the invention, a finding of
over-activity in a portion of the vagus nerve involved in
innervating the liver or pancreas is made for some phase of
digestion. For example, a disease-treatment model criterion is
satisfied in which a blood glucose level remains high while vagus
nerve activation is at a high level (for example, according to one
or more chosen normalization schemes). In some embodiments, one or
more additional criteria are matched in order to confirm the
finding of over-activity.
[0265] Optionally, the finding of over-activity is in another
parasympathetic pathway involved in the ANS innervation of the
liver or pancreas.
[0266] High parasympathetic activation of the liver, associated
with glucose uptake, potentially indicates a liver which has
developed a level of insulin insensitivity (which overstimulation
in turn potentially is partial compensation for). Additionally or
alternatively, there is potentially insufficient insulin production
available for uptake.
[0267] Optionally, a determination of the meaning of a particular
level of activity is referenced to a measured level of blood
insulin concentration.
[0268] High parasympathetic activation of the pancreas, associated
with insulin production, potentially indicates a pancreas which is
stimulated to over-produce insulin.
[0269] Alternatively, the pancreas potentially is unable to produce
sufficient insulin, resulting in overstimulation to compensate.
Optionally, a determination of the meaning of a particular level of
activity is referenced to a measured level of blood insulin
concentration.
[0270] A possible secondary effect of insulin resistance is
hyperinsulinemia, which is separately detectable (for example, by
assaying to check for high blood insulin levels), and tends occur
in early stages of type 2 diabetes. It is also associated with
other diseases such as hypertension, obesity, dyslipidemia, and
glucose intolerance. Potentially, hyperinsulinemia itself leads to
further increases in insulin resistance, and disease progression as
a result.
[0271] In some embodiments of the invention (where hyperinsulinemia
is found, for example, either through ANS activity imaging, or by
another method), a plan is made to attempt to reduce long-term
effects of hyperinsulinemia by reducing insulin production. This is
an instance of sacrificing a level of available function in order
to potentially preserve future function. In some embodiments,
insulin production is reduced by ablating a part of the
parasympathetic innervation of the pancreas. Optionally, where
ambiguity remains with respect to other models/patterns which have
not been ruled out, further tests are performed, and/or due caution
is maintained in the planning of the ablation. For example, the
decision to ablate parasympathetic innervation of the pancreas is
optionally contingent on a finding that parasympathetic innervation
is notably overactive, and/or on a finding that parasympathetic
pancreas innervation is well-correlated with insulin level (for
example, by imaging under different conditions of blood insulin
levels). Otherwise, the risk that the ablation will be ineffective
is potentially raised.
[0272] In some embodiments of the invention, the ANSmap is used to
diagnose and/or verify the temporal, spatial, input adjusting,
balancing, and/or outcome adjusting responses of an ANS subsystem.
In more detail, these functional aspects comprise the following
characteristics: [0273] Temporal: the change in function of members
of the ANS control system in time with stimulation during a
specific pattern of response to a state. [0274] Spatial: activation
and deactivation of effector members, sensing members and/or
processing members of the control system within and/or between
organs and/or system components. [0275] Input adjusting: the slope
connecting input and output levels of each of the members.
Different input/output relationships can be normal in the context
of a system. For example, a certain relationship between input and
output of the sensing member can be abnormal, but the overall
control of the organ/system still be normal if, for example,
processor and/or effector function is changed to compensate. [0276]
Balancing: the use of balanced activation/inhibition and/or
opposing or complimentary effects of the control system. [0277]
Outcome adjusting: activity of the ANS control is judged by the end
result of the controlled function of the controlled
organ/system.
[0278] At block 320, in some embodiments, a planned therapy is
delivered. The therapy is, for example, an ablation, or another
activity-affecting therapy such as delivery of a drug or other
bioactive material, implantation of an inhibiting or stimulating
bioactive material eluting device, implantation of a percutaneous
electrical or magnetic field stimulating device, use of a
transcutaneous electrical or magnetic field stimulating device, or
another therapeutic intervention. In some embodiments, the
administration of therapy is under the guidance of an ANSmap. For
example, a specific region of a GP showing elevated activity in an
ANSmap is targeted, and a treatment probe guided to this region
with specific (optionally, automated) reference to the targeted
region.
[0279] At block 321, in some embodiments, therapy results are
monitored. In some embodiments, monitoring comprises re-imaging to
verify that an intended effect of therapy on ANS activity actually
occurred, and/or that no unintended effect occurred or is
developing. In some embodiments, therapy is planned to be delivered
in two or more stages, with monitoring at each stage to verify that
intended effects are occurring, have reached a desired level,
and/or that potential side-effects are tolerable.
[0280] At block 322, in some embodiments, a decision is made as to
whether or not a treatment intervention has reached a sufficient
level of success to terminate therapy. Additionally or
alternatively, the determination relates to whether or not
additional intervention is unlikely to improve an outcome. If yes,
the flowchart ends. Otherwise, in some embodiments, flow returns to
an earlier operation, for example, block 310.
[0281] Benign Prostatic Hyperplasia (BPH)
[0282] Reference is now made to FIG. 1, which schematically shows a
method of using a map of autonomic nervous system activity in the
evaluation and/or therapeutic treatment of benign prostatic
hyperplasia (BPH), according to some exemplary embodiments of the
invention.
[0283] BPH and Lower Urinary Tract Symptoms.
[0284] In BPH--typically a progressive disease, and prevalent in
older men--prostate stromal and epithelial cell numbers increase,
sometimes to form nodules. Androgens such as testosterone, its
metabolites, and related hormones, appear to have a role in
promoting prostate cell proliferation. In some cases of traditional
diagnosis, lower urinary tract symptoms (LUTS) suggestive of BPH
are detected. Some cases involve urodynamic estimations, for
example of urinary flow rate. In some cases, urethrocystoscopy
investigation is applied. In some cases, transrectal ultrasound
scanning is applied.
[0285] Though benign, nodules or other growth can physically
obstruct urine flow, for example by impinging on the urethra.
Complications can include urine storage and/or voiding symptoms,
progressing to changes in the bladder (detrusor) muscle and/or its
control, urinary tract infection, bladder stones, and/or renal
failure.
[0286] The relationship between observed signs of prostate growth
and resulting lower urinary tract symptoms (LUTS) is potentially
complicated by other states of associated organs, tissues, and/or
system components. Possible complicating state factors include
stimulation state of prostatic smooth muscle, variable details of
prostate anatomy, and/or the changing state of the bladder, for
example due to aging or obstruction.
[0287] Urinary storage and/or voiding symptoms resulting from BPH
are, in some cases, linked to destabilization of bladder function,
which is itself under significant ANS control. Bladder function can
be damaged or disturbed, for example, by ischemia or hypertrophy,
which can potentially affect one or both of innervation or innate
muscle function.
[0288] Treatment methods for BPH include phytotherapy,
pharmacotherapy, surgical treatment, or other methods or
combinations thereof. Related to its progressive (and initially
non-life threatening) nature, a goal of BPH disease management is
optionally to balance quality of life issues against the risks and
side-effects of treatment interventions such as surgery.
[0289] ANS Involvement in the Prostate and Bladder, Related to
Symptoms of BPH.
[0290] The normal prostate gland is connected to both the
sympathetic and parasympathetic ANS through the prostatic nerve
plexus. Innervation is both cholinergic (parasympathetic) and
noradrenergic (sympathetic).
[0291] One role of sympathetic innervation is control of prostatic
musculature (for example, via alpha.sub.1 adrenoceptor activation).
When acting in this role, innervation constricts the bladder neck
and/or other smooth muscle of the prostate and urethra when
activated. Activation occurs normally, for example, during
ejaculation of seminal fluid into the urethra. Several drugs which
block alpha.sub.1 receptors are used effectively to improve urine
flow in patients with BPH. Such drugs include terazosin, doxazosin,
alfuzosin, tamsulosin, and/or prazosin.
[0292] Effects on the prostate which have been suggested for
noradrenaline (which parasympathetic innervation of the prostate
provides) include stimulation of stromal cell division. Both
sympathetic and parasympathetic innervation have been suggested to
have roles in the maintenance or growth of the prostate and
prostate cell number.
[0293] Sympathetic innervation of the bladder normally includes
fibers from the hypogastric plexuses and nerves. Parasympathetic
innervation is from pelvic splanchic nerves and the inferior
hypogastric plexus. At least some sympathetic (adrenergic fiber)
innervation normally arises from local ganglia subject to
hypogastric innervation.
[0294] In the bladder, sympathetic (adrenergic) activity tends to
interfere with detrusor activation (bladder constriction) and the
sphincter opening needed to expel urine; it acts in opposition to
parasympathetic (cholinergic) activity, which normally occurs, for
example, in response to signaling from bladder stretch receptors.
Thus, ANS activity in the bladder relates to some of the key
symptoms affecting quality of life as a result of BPH.
[0295] In some embodiments, the following method, including one or
more of the blocks in the shown order or in a different order, is
suggested. The flowchart of FIG. 1 begins, and, in some
embodiments, a SPECT (single photon emission computed tomography)
or other ANS activity image of the pelvis and/or lower abdomen is
obtained at block 110, an anatomical imaging of the pelvis and/or
lower abdomen is acquired at block 112, and the images are
co-registered at block 114, for example as described in relation to
FIG. 8, hereinbelow. It should be understood that combinations of
blocks 110, 112, and/or 114 comprise one or more means--exemplary
and non-limiting--by which sufficient data are gathered, in some
embodiments, in order to enable the performance of operations
described in relation to other blocks of the flowchart.
[0296] In some embodiments of the invention, activity imaging 110
is synchronized with respect to functional loads on a homeostatic
organ system related to prostate function and/or micturition. With
respect to the bladder, for example, imaging optionally occurs
within a period of a predefined bladder state (such as filling,
filled, or recently empty), within a period of predefined bladder
sensing (such as a need to void), and/or within a period where a
particular symptom is occurring (such as a symptom of a urine
storage and/or voiding problem). With respect to the prostate,
imaging optionally occurs within a period of sympathetic activation
of the prostate (for example, during erection). Optionally, imaging
is of the ANS effects of administered testosterone,
dihydrotestosterone (DHT), or another hormone related to prostate
function.
[0297] In some embodiments of the invention, ANS stimulation by a
selectively placed electrode (or other stimulus means) is performed
in concert with ANS activity imaging, for example, to allow more
detailed mapping of innervation targets within the fine structure
of a GP or nerve. Potentially, a GP or nerve contains a partial
somatotopic map its innervation target. Optionally, denervation of
a particular region of an organ can be targeted (for example,
distributed evenly, and/or focused on a problematic region), based
on activity observed in response to selective stimulation.
[0298] At block 116, in some embodiments, ANS activity data is
evaluated for parameters including, for example, a parameter of one
of the classes described in relation to block 316 of FIG. 3
hereinabove, changed as necessary to suit the anatomic and
functional specifics of the prostate and/or lower urinary tract,
for example as described hereinabove. Normalization, in some
embodiments, is performed, for example, according to one of the
types of normalization described in relation to block 316, or
another normalization is performed. In some embodiments, a
parameter is generated by comparison of activity images among ANS
activation states, for example, among activation states described
in relation to block 110, hereinabove.
[0299] At block 118, in some embodiments, a plan for treatment is
formulated, for example in light of the ANS activity parameters
evaluated at block 116. Optionally, further information is used in
formulating a treatment plan, for example, results of other
evaluations including clinical history, clinical tests, genetic
disease markers, and/or other imaging results. In some embodiments,
the plan is formulated according to matching of one or more
disease-treatment templates, for example as described
hereinbelow.
[0300] A plan for treatment of BPH, and/or one or more symptoms
relating to BPH, such as a micturition symptom, is optionally
developed based upon specific findings from the ANS imaging.
Illustrative examples include the following:
[0301] In some embodiments, by mapping neural activity associated
with the prostate gland, severity of hyperplasia is estimated. For
example, an extent and/or intensity of activity is measured in an
ANS activity image.
[0302] In some embodiments of the invention, a treatment option is
tailored based on ANS activity images. Several drug treatments
related to BPH and/or its symptoms are known. For blockage of
sympathetic innervation of the prostate, for example, the drugs
terazosin, doxazosin, alfuzosin, tamsulosin, and/or prazosin are
among those available. Reported side-effects for these drugs vary
according to patient, drug, and/or dosage, and potentially include,
for example, dizziness, headache, syncope (fainting), asthenia,
postural hypotension, and/or retrograde ejaculation. Dosage
required for optimal treatment is also potentially patient
dependent. Other drugs target different mechanisms of BPH disease
and/or its symptoms. For example, 5 alpha reductase inhibitors are
aimed at reducing cellular division stimulated by androgens. In
particular, they decrease DHT concentrations (DHT is a testosterone
breakdown product). Known inhibitors of this class include
finasteride and dutasteride. In another example, anticholinergic
medications potentially help reduce symptoms of an overactive
bladder, for example by reducing the effects of parasympathetic
activation on the bladder. Combinations of drugs acting on
different mechanisms have been found to be effective in further
reducing symptoms.
[0303] A potential use of ANS activity imaging as a basis for
planning a drug treatment regime is to allow a more direct
understanding of the underlying ANS picture which a drug is
expected to affect. In some embodiments, overactive cholinergic
innervation of the bladder provides a suggestion that
anticholinergic medication is indicated.
[0304] Optionally, a dosage is determined based on the degree of
over-activity which is imaged.
[0305] In some embodiments, effects of drug treatment, for example,
an alpha.sub.1 blocker, are imaged with respect to dosage and/or
time course after administration. A feature of some cases of PBH is
that symptoms most interfere with quality of life only periodically
through the day (for example, when the bladder becomes full, but
urination remains difficult). Optionally, imaging results are used
to determine a dosage, frequency, and/or timing of dosage, such
that a desired level of drug treatment effect occurs at predictable
times, while, during intervening periods, potential side-effects
are lowered. In some embodiments, a dosage administered is
determined based on imaged response to one or more test
administrations of a drug. Potentially, this is an advantage for
tailoring a treatment regime to the particular physiology of a
patient, for example, by reducing a need for trial-and-error dosage
determination.
[0306] In some embodiments of the invention, stimulation of
sympathetic and/or parasympathetic innervation to the body of the
prostate is carried out during ANS activity imaging, in order to
correlate specific regions of imaged anatomy with one or more
corresponding sources of innervation. In some embodiments,
innervation which is specific to a nodule or other bulk in the
occluding region of the prostate is noted.
[0307] Optionally, innervation specific to the occluding region is
ablated as it is found.
[0308] Optionally, innervation is ablated after mapping, according
to a subsequently planned procedure. A potential advantage of such
selective ablation is to reduce innervation which possible
contributes to maintaining or increasing prostate bulk in the
region of greatest concern for current or future interference with
urinary flow. Another potential advantage is to avoid the potential
complications of direct surgical excision of prostate bulk, by
instead treating neural tissue remote to the prostate.
[0309] In some embodiments of the invention, sympathetic and/or
parasympathetic innervation of the bladder (and/or of somatic
innervation which ANS innervation synapses with) is at least
partially ablated or blocked, according to urinary storage or
voiding symptoms of a patient. Potentially, this reduces bladder
symptoms which trace to a sensing issue, by rebalancing the
response of the ANS to stretch receptors in the bladder. In some
embodiments, ablation or blockage is performed to achieve a
temporary reduction of symptoms. Optionally, ablation is partial,
leaving sufficient pathways for axonal regrowth that regeneration
of the system occurs over a period of time (months) following
treatment. Optionally, fibers which are ablated are, for example,
sympathetic fibers showing particularly strong activation (tending
to prevent detrusor activation), and/or parasympathetic fibers
showing particularly strong activation (tending to induce
micturition).
[0310] In some embodiments of the invention, a bladder innervation
template is created, based, for example, on activity which is seen
to arise in correlation with stimulation of various regions of the
ANS bladder innervation. In some embodiments of the invention,
ablation is performed under the guidance of an ANSmap to maintain
relatively evenly distributed innervation of the bladder, for
example, by ablating equally innervation reaching each of two or
more subdivisions of the bladder wall. Optionally, ablation is
during imaging which creates the map. Optionally or alternatively,
ablation is during a second procedure, based on the ANSmap
innervation template, and/or on additional findings, such as which
regions of ANS activity are most closely associated with observed
symptoms.
[0311] At block 120, in some embodiments, a planned therapy is
delivered to a nervous system structure related to the prostrate or
bladder. The therapy is, for example, an ablation, or another
activity-affecting therapy such as delivery of a drug or other
bioactive material, implantation of an inhibiting or stimulating
bioactive material eluting device, implantation of a percutaneous
electrical or magnetic field stimulating device, use of a
transcutaneous electrical or magnetic field stimulating device, or
another therapeutic intervention. In some embodiments, the
administration of therapy is under the guidance of an ANSmap. For
example, a specific region of a GP showing elevated activity in an
ANSmap is targeted, and a treatment probe guided to this region
with specific (optionally, automated) reference to the targeted
region.
[0312] In some embodiments, a therapy is delivered for the sake of
achieving an effect within the clinical setting, for the sake of
determining its effect by means of one or more additional ANS
activity imaging sessions. For example, an alpha.sub.1 blocker is
administered, and a time course and/or strength of response is
noted in one or more additional ANS activity imaging sessions.
[0313] At block 121, in some embodiments, therapy results are
monitored. In some embodiments, monitoring comprises re-imaging to
verify that an intended effect of therapy on ANS activity actually
occurred, and/or that no unintended effect occurred or is
developing. In some embodiments, therapy is planned to be delivered
in two or more stages, with monitoring at each stage to verify that
intended effects are occurring, have reached a desired level,
and/or that potential side-effects are tolerable.
[0314] At block 122, in some embodiments, a decision is made as to
whether or not a treatment intervention has reached a sufficient
level of success to terminate therapy.
[0315] Additionally or alternatively, the determination relates to
whether or not additional intervention is unlikely to improve an
outcome. If yes, the flowchart ends. Otherwise, in some
embodiments, flow returns to an earlier operation, for example,
block 110.
[0316] Erectile Dysfunction
[0317] Reference is now made to FIG. 2, which schematically shows a
method of using a map of autonomic nervous system activity in the
evaluation and/or therapeutic treatment of an erectile function
disorder, according to some exemplary embodiments of the
invention.
[0318] Erectile Dysfunction.
[0319] Erectile dysfunction (ED) is characterized by the inability
to develop or maintain an erection during sexual activity. Normally
functioning erectile tissue expands when the relaxation of smooth
muscles of (particularly arteries within) the corpora cavernosa
allows increased blood filling. Other musculature is activated to
compress the veins by which the blood leaves these arteries. Among
many other interacting mechanisms with a role in tumescence,
several neural signaling and control pathways are involved in
normal erectile function; damage or insult affecting any of these
potentially manifests as ED.
[0320] ANS Involvement in Erectile Dysfunction.
[0321] In normal tumescence, parasympathetic ANS innervation
triggers smooth muscle relaxation, for example, by causing
cholinergic-triggered (more particularly, muscarinic
M.sub.3-triggered) elevation of the concentration of nitric oxide,
a vasodilator. Parasympathetic innervation arises, for example,
from the sacral plexus, and more particularly, from the pudendal
plexus. These parasympathetic fibers run, for example, in the
sacral nerves, including the perineal nerve branch leading to the
dorsal penis nerve.
[0322] Activity from sympathetic innervation of the penis tends to
cause arterial smooth muscle to constrict, reducing the volume of
erectile tissue. Sympathetic innervation arises, for example, from
the sympathetic chain ganglia, and the inferior mesenteric,
hypogastric, and pelvic ganglia. As parasympathetic activation
decreases after an erection, baseline sympathetic activity causes
detumescence. Another potential mechanism of tumescence is a
sufficient decrease in baseline sympathetic activity, for example,
during REM sleep.
[0323] Normally, there is also voluntary and involuntary CNS and
non-ANS (somatic) PNS nervous control exercised over erectile
function, both to increase and decrease tumescence. Some
CNS/somatic subsystems receive ANS input. For example, the spinal
cord cells of Onuf's nucleus (implicated, for example, in the
control via the pudendal nerve of musculature involved in venous
compression during tumescence) are anatomically linked with the
sacral parasympathetic motorneurons. Sensory stimulation (for
example, of the penile shaft) leads to signaling from peripheral
nerves to the lower spinal cord, potentially resulting in increased
parasympathetic activity.
[0324] In some embodiments, the following method, including one or
more of the blocks in the shown order or in a different order, is
suggested. The flowchart of FIG. 2 begins, and, in some
embodiments, a SPECT (single photon emission computed tomography)
or other ANS activity image of the pelvis and/or lower abdomen is
obtained at block 210, an anatomical imaging of the pelvis and/or
lower abdomen is acquired at block 212, and the images are
co-registered at block 214, for example as described in relation to
FIG. 8, hereinbelow. It should be understood that combinations of
blocks 210, 212, and/or 214 comprise one or more means--exemplary
and non-limiting--by which sufficient data are gathered, in some
embodiments, in order to enable the performance of operations
described in relation to other blocks of the flowchart.
[0325] In some embodiments of the invention, activity imaging 210
is synchronized with respect to functional loads on a homeostatic
organ system related to erectile function. Optionally, imaging
occurs within a period of, for example, erection (and/or lack of
erection) in response to stimulation of the penis, a period of
sleep (such as morning REM sleep) typically corresponding to
nocturnal erection, and/or erection (and/or lack of erection) in
response to erotic stimulation. In some embodiments of the
invention, erectile function testing is accompanied by use of a
drug having an effect on erection, for example, sildenafil,
tadalafil, vardenafil, or another drug. Use of a drug which
encourages and/or helps with the maintenance of an erection
potentially partially allows imaging to be better correlated with
epochs of ANS activity, for example by encouraging the ANS activity
itself, and/or by helping to synchronize imaging with activity
tending to produce tumescence. In some embodiments, tumescence
and/or detumescence is controlled by electrical or magnetic
stimulation, for example, transcutaneous and/or percutaneously.
[0326] At block 216, in some embodiments, ANS activity data is
evaluated for parameters including, for example, a parameter of one
of the classes described in relation to block 316 of FIG. 3
hereinabove, changed as necessary to suit the anatomic and
functional specifics of erectile function and its control, these
being, for example, as described hereinabove. In some embodiments,
a parameter is generated by comparison of activity images among ANS
activation states, for example, among activation states described
in relation to block 210, hereinabove.
[0327] At block 218, in some embodiments, a plan for treatment is
formulated, for example in light of the ANS activity parameters
evaluated at block 216. Optionally, further information is used in
formulating a treatment plan, for example, results of other
evaluations including clinical history, clinical tests, genetic
disease markers, and/or other imaging results.
[0328] A plan for treatment and/or further evaluation of erectile
dysfunction is optionally developed based upon specific findings
from the ANS imaging. Illustrative examples include the
following:
[0329] In some embodiments of the invention, a finding of
under-activity in a portion of the pudendal plexus involved in
innervating the penis is made for a phase or aspect of erectile
function, for example imaged as described hereinabove. For example,
a model criterion is satisfied in which a pudendal plexus should be
well-activated in at least one condition of activity imaging, but
such activation is not observed. The phase or aspect of erectile
function is, for example, erection (or lack thereof) in response to
stimulation of the penis, a period of sleep typically corresponding
to nocturnal erection, a period following administration of an
erection-enhancing drug, and/or erection in response to erotic
stimulation. Optionally, the finding of under-activity is in
another parasympathetic pathway involved in the ANS innervation of
the penis. Parasympathetic under-activation of the penis,
associated with insufficient relaxation of the arterial smooth
muscle that allows blood filling resulting in tumescence
potentially prevents achieving tumescence.
[0330] In some embodiments of the invention, a plan is made to
artificially stimulate an under-active parasympathetic pathway, for
example, a portion of the perineal nerve, with the goal of
regaining useful erectile function. Optionally, the stimulation
comprises transcutaneous electrical nerve stimulation (TENS).
Optionally or alternatively, a percutaneous stimulating device is
used. Optionally, the stimulation apparatus is applied and/or used
within a defined period, for example, a period of planned sexual
activity.
[0331] In some embodiments, innervation (particularly
parasympathetic innervation) to the smooth muscle fibers of the
corpora cavernosa or to another innervation target related to
erection is mapped by a stimulation procedure combined with
recording of regions in which activity rises as a result of
stimulation. In some embodiments of the invention, treatment
comprises providing means for selectively stimulating regions which
result in an increase in activity relating to one or more erectile
mechanisms. It is a potential advantage to use ANS mapping for
determining an appropriate stimulating position, as it is possible
that stimulation under exploratory conditions is too brief and/or
not fully adequate to induce an erection (for example, it may be
useful to assist in erection maintenance, but only if an erection
already is present). Optionally, ANS activity-guided stimulation is
used to provide indications as to when a nerve or GP near to the
intended target is stimulated. This provides a potential advantage
over attempting to locate a nervous system structure "blindly",
and/or without functional feedback.
[0332] In some embodiments of the invention, a finding of
over-activity in a portion of the inferior mesenteric, hypogastric,
and/or pelvic ganglia involved in sympathetic innervation of the
penis is made for a phase or aspect of erectile function, for
example imaged as described hereinabove. The phase or aspect of
imaged erectile function is, for example, erection in response to
stimulation of the penis, a period of sleep (such as morning REM
sleep) typically corresponding to nocturnal erection,
administration of a drug, electrical or magnetic stimulus, and/or
erection in response to erotic stimulation.
[0333] Optionally or alternatively, the finding of over-activity is
in another sympathetic pathway involved in the ANS innervation of
the penis. Sympathetic over-activation in innervation reaching the
penis, associated with increased tone of the arterial smooth muscle
of erectile tissue potentially prevents achieving tumescence.
[0334] In some embodiments of the invention, a plan is made to
reduce activity of an over-active parasympathetic pathway, for
example, a portion of an overactive ganglion, with the goal of
regaining useful erectile function. Optionally, the stimulation
comprises partial ablation, for example, by heat, cooling, and/or
chemical injection. Optionally, another form of nerve block is
applied. Optionally, sympathetic nerve block is applied
transiently, for example, preceding and/or within a period of
planned sexual activity.
[0335] In some embodiments, similar to as described hereinabove
with respect to parasympathetic stimulation, active-probing
activity mapping is performed by stimulation (optionally, by
inhibition) of sympathetic innervation. Stimulation of the
sympathetic innervation of the corpora cavernosa during stimulation
mapping potentially has no obvious effects on the production of an
erection (although a well-maintained erection is potentially
detumesced by such activity). However, sympathetic stimulation of a
nerve or GP which maps to the corpora cavernosa potentially reveals
a target for ablation, or for a more transient neuromodulatory
block such as anesthesia.
[0336] At block 220, in some embodiments, a planned therapy is
delivered to a nervous system structure related to penile erection.
The therapy is, for example, an ablation, or another
activity-affecting therapy such as delivery of a drug or other
bioactive material, implantation of an inhibiting or stimulating
bioactive material eluting device, implantation of a percutaneous
electrical or magnetic field stimulating device, use of a
transcutaneous electrical or magnetic field stimulating device, or
another therapeutic intervention. In some embodiments, the
administration of therapy is under the guidance of an ANSmap. For
example, a specific region of a GP showing elevated activity in an
ANSmap is targeted, and a treatment probe guided to this region
with specific (optionally, automated) reference to the targeted
region.
[0337] At block 221, in some embodiments, therapy results are
monitored. In some embodiments, monitoring comprises re-imaging to
verify that an intended effect of therapy on ANS activity actually
occurred, and/or that no unintended effect occurred or is
developing. In some embodiments, therapy is planned to be delivered
in two or more stages, with monitoring at each stage to verify that
intended effects are occurring, have reached a desired level,
and/or that potential side-effects are tolerable.
[0338] At block 222, in some embodiments, a decision is made as to
whether or not a treatment intervention has reached a sufficient
level of success to terminate therapy.
[0339] Additionally or alternatively, the determination relates to
whether or not additional intervention is unlikely to improve an
outcome. If yes, the flowchart ends. Otherwise, in some
embodiments, flow returns to an earlier operation, for example,
block 210.
[0340] Rheumatoid Arthritis
[0341] Reference is now made to FIG. 4, which schematically shows a
method of using a map of autonomic nervous system activity in the
evaluation and/or therapeutic treatment of rheumatoid arthritis,
according to some exemplary embodiments of the invention.
[0342] Rheumatoid Arthritis (RA) and the Immune System.
[0343] RA is a disease of the immune system which leads to effects
such as chronic inflammatory response of the joints. In some
patients, another organ is affected, such as the lungs, pleura,
pericardium, sclera, kidney, and/or heart.
[0344] ANS Involvement in Immune System Regulation and RA.
[0345] Neuroanatomical studies have demonstrated that all primary
and secondary immune organs (for example, the thymus, spleen, lymph
nodes, and bone marrow) receive innervation from sympathetic
postganglionic neurons. Sympathetic activity is considered an
exciter of at least the acquired/adaptive immune system.
Parasympathetic activity appears to be implicated in inhibition of
the immune system. Immune system activation, though needed to
defend against infectious invasion, is "expensive" for an organism,
for example, in terms of energy expenditure. Potentially,
mismatched regulation of its activation or inhibition leads disease
production by causing the immune system to dwell in one of these
extremes, or by another mechanism, for example as outlined
hereinbelow. Over-activation of the sympathetic system potentially
causes or potentiates the inflammatory response of RA. Additionally
or alternatively, insufficient inhibition of inflammatory responses
by the parasympathetic system potentially allows RA inflammatory
responses to go unchecked. Potentially, redistribution of
sympathetic innervation leads to RA inflammation. For example,
partial ablation of splenic innervation may stimulate regrowth
which does not reform the original innervation pattern. Instead,
one or more regions become overstimulated, while a denervated
region remains understimulated. Potentially, the two regions should
normally work together to form a balanced immune response (for
example, one free of autoimmune effects). When one becomes
overstimulated, the balance is lost. Additionally or alternatively,
the overstimulated region simply becomes unregulated in its
production of immune response cells, leading to autoimmune disorder
such as RA.
[0346] In some embodiments, the following method, including one or
more of the blocks in the shown order or in a different order, is
suggested. The flowchart of FIG. 4 begins, and, in some
embodiments, a SPECT (single photon emission computed tomography)
or other ANS activity image of the abdomen, optionally including
the spleen, is obtained at block 410, an anatomical imaging of the
abdomen is acquired at block 412, and the images are co-registered
at block 414, for example as described in relation to FIG. 8,
hereinbelow. In some embodiments, activity region and/or anatomical
images associated with one or more joints affected by RA is
obtained. It should be understood that combinations of blocks 410,
412, and/or 414 comprise one or more means--exemplary and
non-limiting--by which sufficient data are gathered, in some
embodiments, in order to enable the performance of operations
described in relation to other blocks of the flowchart.
[0347] It should be understood another or a different target is
potentially imaged in some embodiments of the invention. For
example, the control system of T cell maturation in the spleen is
mediated via ganglia in the celiac plexus. As was discussed in
relation to diabetes, the area of imaging is potentially wider or
narrower than a system which is potentially to be targeted for
treatment. Potentially, it is even moved entirely, insofar as
neural control networks have ganglia or other control structures
located remotely from innervated targets. As described, for
example, in relation to glucose sensing, the network structure of
ANS control causes an optimal site of imaging and/or treatment to a
site remote from an organ to be ultimately affected.
[0348] In some embodiments of the invention, activity imaging 410
is synchronized with respect to functional loads on a homeostatic
organ system related to immune function. Stress, for example, is an
activator of sympathetic system, and is a potential condition of
imaging for comparison to a resting state of sympathetic
activity.
[0349] At block 416, in some embodiments, ANS activity data is
evaluated for parameters including, for example, a parameter of one
of the classes described in relation to block 316 of FIG. 3
hereinabove, changed as necessary to suit the anatomic and
functional specifics of immune function and its control. In some
embodiments, a parameter is generated by comparison of activity
images among ANS activation states, for example, among activation
states described in relation to block 410, hereinabove.
[0350] At block 418, in some embodiments, a plan for treatment is
formulated, for example in light of the ANS activity parameters
evaluated at block 416. Optionally, further information is used in
formulating a treatment plan, for example, results of other
evaluations including clinical history, clinical tests, genetic
disease markers, and/or other imaging results.
[0351] A plan for treatment and/or further evaluation of immune
regulatory dysfunction is optionally developed based upon specific
findings from the ANS imaging. For example, parasympathetic
innervation at or near a site of RA inflammation is imaged.
Potentially, a lack of strong activity reflects insufficient
parasympathetic innervation, relative to a level of immune
activation. A potential treatment is to induce stimulation in
parasympathetic ganglia innervating the affected area.
[0352] Additionally or alternatively, there is a potential
oversupply of sympathetic innervation, for example, to one or more
of the sites of immune cell production in the body such as the
spleen, or a portion thereof. Optionally, sympathetic innervation
is reduced in an overactive region, potentially reducing the supply
of overactive immune cells as well, and/or rebalancing production
of cells from an overactive region with those of other regions,
which may serve a role in further regulation of the immune cell
response.
[0353] At block 420, in some embodiments, a planned therapy is
delivered to a nervous system structure related to the immune
system and/or RA activity. The therapy is, for example, an
ablation, or another activity-affecting therapy such as delivery of
a drug or other bioactive material, implantation of an inhibiting
or stimulating bioactive material eluting device, implantation of a
percutaneous electrical or magnetic field stimulating device, use
of a transcutaneous electrical or magnetic field stimulating
device, or another therapeutic intervention. In some embodiments,
the administration of therapy is under the guidance of an ANSmap.
For example, a specific region of a GP showing elevated activity in
an ANSmap is targeted, and a treatment probe guided to this region
with specific (optionally, automated) reference to the targeted
region.
[0354] At block 421, in some embodiments, therapy results are
monitored. In some embodiments, monitoring comprises re-imaging to
verify that an intended effect of therapy on ANS activity actually
occurred, and/or that no unintended effect occurred or is
developing. In some embodiments, therapy is planned to be delivered
in two or more stages, with monitoring at each stage to verify that
intended effects are occurring, have reached a desired level,
and/or that potential side-effects are tolerable.
[0355] At block 422, in some embodiments, a decision is made as to
whether or not a treatment intervention has reached a sufficient
level of success to terminate therapy.
[0356] Additionally or alternatively, the determination relates to
whether or not additional intervention is unlikely to improve an
outcome. If yes, the flowchart ends. Otherwise, in some
embodiments, flow returns to an earlier operation, for example,
block 410.
[0357] Irritable Bowel Syndrome
[0358] Reference is now made to FIG. 5, which schematically shows a
method of using a map of autonomic nervous system activity in the
evaluation and/or therapeutic treatment of irritable bowel
syndrome, according to some exemplary embodiments of the
invention.
[0359] The cause of IBS is unknown, and diagnosis is potentially a
matter of ruling out other illnesses. Optionally, IBS is related to
stress. Optionally, as suggested by previous research, IBS symptoms
are associated with the sympathetic nervous system firing
constantly, for example due to injury of the meninges.
[0360] In some embodiments, the following method, including one or
more of the blocks in the shown order or in a different order, is
suggested. The flowchart of FIG. 5 begins, and, in some
embodiments, a SPECT (single photon emission computed tomography)
or other ANS activity image of the abdomen is obtained at block
430, an anatomical imaging of the abdomen is acquired at block 432,
and the images are co-registered at block 434, for example as
described in relation to FIG. 8, hereinbelow. It should be
understood that combinations of blocks 430, 432, and/or 434
comprise one or more means--exemplary and non-limiting--by which
sufficient data are gathered, in some embodiments, to enable the
performance of operations described in relation to other blocks of
the flowchart.
[0361] In some embodiments of the invention, activity imaging 430
is synchronized with respect to functional loads on a homeostatic
organ system related to immune function. Stress, for example, is an
activator of the sympathetic system, and any applied stress
condition is a potential condition of imaging for comparison to a
resting state of sympathetic activity.
[0362] At block 436, in some embodiments, ANS activity data is
evaluated for parameters including, for example, a parameter of one
of the classes described in relation to block 316 of FIG. 3
hereinabove, changed as necessary to suit the anatomic and
functional specifics of bowel function and its control. In some
embodiments, a parameter is generated by comparison of activity
images among ANS activation states, for example, among activation
states described in relation to block 430, hereinabove.
[0363] At block 438, in some embodiments, a plan for treatment is
formulated, for example in light of the ANS activity parameters
evaluated at block 436. Optionally, further information is used in
formulating a treatment plan, for example, results of other
evaluations including clinical history, clinical tests, genetic
disease markers, and/or other imaging results.
[0364] A plan for treatment and/or further evaluation of irritable
bowel syndrome is optionally developed based upon specific findings
from the ANS imaging. For example, there is a potential oversupply
and/or overactivation of sympathetic innervation, for example, to
one or more of the sites along the bowel. Optionally, sympathetic
innervation is reduced in an overactive region. Potentially, this
serves to rebalance sympathetic and parasympathetic innervation in
a region which can be particularly selected from among possible
candidate regions, due to the guidance by imaging results.
[0365] At block 440, in some embodiments, a planned therapy is
delivered to a nervous system structure related to innervation of
the bowel. The therapy is, for example, an ablation, or another
activity-affecting therapy such as delivery of a drug or other
bioactive material, implantation of an inhibiting or stimulating
bioactive material eluting device, implantation of a percutaneous
electrical or magnetic field stimulating device, use of a
transcutaneous electrical or magnetic field stimulating device, or
another therapeutic intervention. In some embodiments, the
administration of therapy is under the guidance of an ANSmap. For
example, a specific region of a GP showing elevated activity in an
ANSmap is targeted, and a treatment probe guided to this region
with specific (optionally, automated) reference to the targeted
region.
[0366] At block 441, in some embodiments, therapy results are
monitored. In some embodiments, monitoring comprises re-imaging to
verify that an intended effect of therapy on ANS activity actually
occurred, and/or that no unintended effect occurred or is
developing. In some embodiments, therapy is planned to be delivered
in two or more stages, with monitoring at each stage to verify that
intended effects are occurring, have reached a desired level,
and/or that potential side-effects are tolerable.
[0367] At block 442, in some embodiments, a decision is made as to
whether or not a treatment intervention has reached a sufficient
level of success to terminate therapy.
[0368] Additionally or alternatively, the determination relates to
whether or not additional intervention is unlikely to improve an
outcome. If yes, the flowchart ends. Otherwise, in some
embodiments, flow returns to an earlier operation, for example,
block 430.
ANS Hyperactivity and Hypoactivity
[0369] Hyperactivity of ANS
[0370] In some embodiments, the invention is applied to a condition
associated with hyperactivity of the ANS. In some embodiments,
sympathetic and/or parasympathetic activity are determined,
adjusted, and/or re-determined to evaluate disease prognosis and/or
treatment outcome. Diseases potentially involving ANS hyperactivity
include, for example, the following.
[0371] Thyrotoxicosis:
[0372] Induced, for example, by an infectious (viral or bacterial)
trigger of an unknown idiopathic mechanism. Potentially, increased
sympathetic tone increases thyroid hormone release, end-organ
sensitivity and/or decreases the rate of conversion of T4 to rT3 (a
non-active metabolite of thyroid hormone). In embodiments where
sympathetic and parasympathetic tone are adjusted, it is a
potential advantage to reduce thyroid-innervating sympathetic tone
and/or increase parasympathetic tone, to reduce these effects.
[0373] Autoimmune Disease:
[0374] Induced, for example, when stress in any form triggers an
exacerbation of an autoimmune attack. Potentially, activation of T
lymphocytes relates to overstimulation of the sympathetic system.
Potentially, the release of interferon, interleukins and/or certain
cytokines is affected by ANS. In some embodiments where ANS
activity is adjusted, innervating activity reaching the spleen
and/or lymph nodes is adjusted. The spleen and lymph nodes comprise
major organs for the maturation of T lymphocytes, are an optional
target and are potentially affected by alterations in ANS tone.
[0375] Optionally, as suggested by Stojanovich (Stojanovich L and
Marisavljevich D; Stress as a trigger of autoimmune disease.
Autoimmun Rev. 2008 January; 7(3):209-213), physical and
psychological stress has been implicated in the development of
autoimmune disease.
[0376] Irritable Bowel Disease (IBD):
[0377] Stress and stress response, associated with the ANS, are
associated with IBD. For example, IBD is potentially exacerbated by
stress. Furthermore, ANS input to the GI tract is well known.
Potentially, symptoms of IBD and IBS can be elicited by changes in
ANS function. For example, gastrointestinal motility and/or
intestinal absorption are functions potentially affected by ANS
activity.
[0378] Diabetes:
[0379] Many organs and body system components affect glucose
metabolism, either directly or indirectly. Examples include the
liver and the pancreas, respectively. Potentially, these organs
change their function in response to an ANS signal. In some
embodiments of the invention, organ function is changed by
sympathetic stimulation such that blood glucose is elevated and/or
insulin production is inhibited. In some embodiments, one or more
duodenal functions are modulated by modulation of the ANS. A
modulated function is, for example, an endocrine, exocrine and/or
absorption function.
[0380] As suggested by Surwit (Surwit R S and Feinglos M N; Stress
and Autonomic Nervous System in Type II Diabetes, A Hypothesis;
Diabetes Care 1988 11), the sympathetic nervous system is involved
in the pathophysiology of type II (noninsulin-dependent) diabetes
mellitus.
[0381] Hypertension:
[0382] Control of blood pressure potentially relates to ANS
activity. In some embodiments, ANS mapping is used to identify
cases of hypertension where over-activity of the ANS is a cause of
hypertension. In some embodiments, ANS mapping is used to depict
the ANS reaction to elevated blood pressure caused by another
reason, for example, iatrogenic volume overload.
[0383] Hypertrophic cardiomyopathy: optionally, in this condition,
part or all the myocardial tissue undergoes hypertrophy. The cause
may be unknown, and in some cases can be the result of a primary
disease, for example of the muscle. Optionally, hypertrophy is
caused by overstimulation of an organ by the ANS. In some cases,
the disease affects only part of the heart such as in the case of
Hypertrophic Obstructive Cardiomyopathy. The reasons for
non-uniform myocardial hypertrophy can be multiple, and include
local disease--for example, viral disease, and/or a compensatory
ANS response that is trying to drive the contractile force back up
by inducing local hypertrophy. Local hypertrophy potentially causes
partial obstruction of the outflow tract of the ventricles of the
heart, increasing the effort the myocardium has to perform to pump
sufficient amounts of blood. In response, the ANS will increase its
tone to further force the myocardium to deliver the needed amount
of output. This cycle can potentially lead to eventual
non-reversible damage to the myocardium.
[0384] Reference is now made to FIG. 6, which comprises an ANSmap
image 500 for a patient with sigmoid septum and cardiomyopathy,
according to some exemplary embodiments of the invention.
[0385] The ANSmap clearly identifies increased sympathetic activity
in the intra-ventricular septum 504, compared to the adjacent
tissue of the heart wall 502. As discussed hereinabove, increased
activity is potentially related to over-activation of the ANS in
response to the primary pathology, and/or over-activation itself
comprises a direct or primary cause of the pathology.
[0386] It is known in the art that an event of non-ischemic
cardiomyopathy potentially relates to significant MIBG heart
activity (measured as the ratio H/M--Heart to Mediastinum).
[0387] Deposition Disease:
[0388] Deposition disease includes, for example, amyloidosis.
Deposition disease occurs, for example, in the context of chemical
reaction through which a compound (for example, a mis-folded
protein) is degraded, one of the degradation products being
resistant to further degradation; optionally particularly resistant
if stabilized in aggregating concentrations.
[0389] Reference is now made to FIG. 7, which illustrates an
exemplary deposition pathway 600, according to some exemplary
embodiments of the invention.
[0390] At block 602, compound A is targeted for degradation, for
example by a proteolytic enzyme. It is broken down into compounds B
and C (blocks 604 and 606, respectively). Compound B, in turn, is
directly and/or indirectly degraded into one or more final
degradation products D, at block 608, the degradation products D
being susceptible of reuse and/or elimination from the body.
However, compound C is resistant to degradation and/or elimination,
potentially giving rise to accumulation in the body leading to a
disease state. In particular, in some embodiments, the resistance
of compound C to degradation increases as its concentration
increases, due for example, to hydrophobicity resulting in
preferential self-aggregation, binding-up of stabilizing compounds,
and/or another mechanism.
[0391] Potentially, the enzymatic reactions leading to production
of molecule C is under at least partial regulation by the ANS.
Thus, for example, over-activation caused by the ANS in which the
rate of compound A degradation increases (this could be an indirect
effect of overproduction of compound A) generates more of compound
C. Potentially, the concentration of compound C is also raised. It
is a potential advantage to reduce of the production and/or
degradation of compound A by adjusting the ANS activation which
causes it.
[0392] Additionally or alternatively, a build-up of compound B
potentially reduces a rate of degradation of compound A, for
example, by mass action and/or molecular regulatory effects within
the machinery of the cell. If, for example, such a catalysis
pathway between B and D is under ANS influence, then slowing a rate
of breakdown of compound B by adjustment of ANS activity
potentially has a secondary effect of reducing the deposition of
compound C.
[0393] In some embodiments of the invention, ablation or
stimulation specific to an ANS structure involved in one or more of
the above diseases is performed, for example according to
principles outlined in the overview, and/or in relation to FIGS.
1-5 hereinabove.
[0394] Hypoactivity of the ANS
[0395] The following are examples of conditions associated with
hypoactivity of the ANS, which some embodiments of the invention
apply to:
[0396] A. Syncope
[0397] B. Hypothyroidism
[0398] C. Idiopathic heart failure
[0399] D. Asthma
[0400] E. Deposition disease--ineffective
metabolism--amyloidosis
[0401] F. IBS
[0402] G. Weight gain
[0403] In some embodiments of the invention, ablation or
stimulation specific to an ANS structure involved in one or more of
the above diseases is performed, for example according to
principles outlined in the overview, and/or in relation to FIGS.
1-5 hereinabove.
Localization of ANS Pathology
[0404] In some cases, disturbances of the ANS are generalized, and
in some cases disturbances are localized--depending, for example,
on the type of disease and/or its stage. Potentially, intermediate
levels of generalization of ANS disturbance occur. Level of
generalization is, for example, with respect to the extent of a
region affected (innervated), with respect to the extent of
derangement of ANS tissue, and/or with respect to the extent of the
centrality of deranged ANS tissue within the functioning of the
system.
[0405] Deposition Disease:
[0406] In some deposition diseases, for example, increased or
decreased ANS tone is associated with a defined region of
innervated tissue. Optionally, this causes a local deposition or a
local depletion of a substance at said defined region.
[0407] Heart Disease:
[0408] In examples of localized effects in relation to heart
disease, over-activity of the ANS potentially appears as local
tissue hypertrophy, local alteration in electrophysiological
properties (such as local refractoriness and/or conduction
velocity) and/or local alteration in tissue properties (such as
levels of Connexin 43 and types of actin and myosin
iso-enzymes).
[0409] In some cases, impairment of the ANS and/or of the tissue
innervated takes a form which potentially ranges from the
well-localized, to more global. Potentially, the site of symptoms
is remote from a site of control and/or innervation which is
subject to imbalance and/or derangement of function.
[0410] Hyperhidrosis:
[0411] Hyperhidrosis is a potential exemplar of this. The level of
disturbance in hyperhidrosis potentially varies according to
patient and/or disease stage. Potentially, hyperhidrosis affects,
for example, a palm of a hand, the entire arm, both arms, and/or
the entire upper trunk. In some embodiments, the ANSmap is used to
diagnose a level of the causative mechanism of hyperhidrosis,
and/or as a road map for guiding therapy.
[0412] In some embodiments of the invention, ablation or
stimulation specific to an ANS structure involved in one or more of
the above diseases is performed, for example according to
principles outlined in the overview, and/or in relation to FIGS.
1-5 hereinabove.
Other Examples of ANS-Related Disease
[0413] Optionally, some ANS disorders relate to the sources of the
ANS system (brain nuclei), while some relate to the pathway or to
the ganglia. Optionally, the functioning of end-organ synapses of
the ANS is critical for the ANS control function. Optionally, the
functioning of the synapses depends on the nervous component of the
junction and/or the receptor function on the target cell.
Dysfunction of the ANS function may emanate from ANS receptor issue
that affects the responsiveness of the organs to the ANS input. The
ANS mapping system, as described in some embodiments of the
invention, measures the response function of the ANS. Optionally,
the total function of the ANS, for example from the origin to the
response of the function unit is assessed. Optionally, the map is
positive. Optionally, there is no end-organ response to the ANS.
Optionally, in such a case, the end-organ response is diagnosed by
the mapping.
[0414] Obesity:
[0415] In some cases of certain medical conditions such as obesity
or morbid obesity, weight gain may follow blockade of the
sympathetic nervous system input to the tissue.
[0416] COPD:
[0417] Another example is the case of Chronic Obstructive Pulmonary
Disease (COPD). The patients in this disease are subject to certain
stimuli (smoke or other pollutant). Only certain patients
(currently called "susceptible patients") may develop the disease,
while the rest of the patients do not develop the disease. The
inventors postulate that different ANS response to the stimuli is
the cause for developing the disease. This postulation is based on
multiple observations that COPD patients have different level of
activation of the ANS (both locally in the lungs and generally).
These finding of altered ANS activity is COPD patients can be part
of the primary mechanism of the disease, and/or a response to the
pathology brought by the disease. Optionally, detecting the ANS
status assists in diagnosing and/or treating the patient.
[0418] Some embodiments relate to diagnosing a disease based on ANS
mapping showing activity of part of an organ and/or system
component relative to another part of the same organ/system
component and/or a different organ/system component. Some examples
include: [0419] Torticollis: contraction of ipsilateral
sternocleidomastoid muscle in the neck--often treated by local
injection of botulinum toxin into to the over-contracted muscle
[0420] Hypertrophic cardiomyopathy [0421] Idiopathic dilated
cardiomyopathy [0422] Right Ventricular Outflow Tachycardia [0423]
Brugada syndrome [0424] Tetralogy of Fallot, after repair [0425]
Cardiomyopathies: generalized/localized due to pacing [0426]
Hypertrophic obstructive cardiomyopathy [0427] Deposition disease
of lungs [0428] Sleep apnea: delay in autonomic activity, chemo-
and baroreceptors change sensitivity [0429] Asthma: hyperactivity
of airways [0430] liver disease: metabolic derangement of the liver
related to the activity of the ANS [0431] Hyperhidrosis [0432]
Salivation [0433] Lacrimation
[0434] Relating to treatment, sympathetectomies as therapy were
practiced over 50 years ago for many disease states. Generally they
were used in severely sick patients, using a surgical procedure.
The common indication was malignant hypertension. The surgical
approach affected many organs and had many side effects. More
specific surgical ANS interventions were developed over the years
to include therapy for peptic ulcer, for hyperhidrosis, for
vascular disease, some type of psychiatric disease and others.
[0435] In some embodiments of the invention, ablation or
stimulation specific to an ANS structure involved in one or more of
the above diseases is performed, for example according to
principles outlined in the overview, and/or in relation to FIGS.
1-5 hereinabove.
Guidance of Therapy and/or Diagnosis
[0436] Currently, ANS modification is well practiced. It is applied
to multiple conditions using multiple approaches. Some of the
approaches relate to surgical interventions while other
interventions call on using pharmacologic interventions. The
benefit of certain surgical procedures is a localized and specific
effect--some effects are achieved over an organ or set of organs,
while some relate more directly to the sympathetic or to the
parasympathetic systems.
[0437] Common to focused interventions is the lack of ability to
guide to the procedure by identifying the target in a noninvasive
way.
[0438] Current procedures either use an open approach (where the
surgeon exposes the organ and identifies a large nerve trunk or
large ganglia and resects them, or in a minimally invasive
approach, where operators are using surrogate information to guide
themselves to the most likely area in proximity of the nerve or
ganglia to be treated. These approaches are by far less accurate,
carry significant risk, less specific and hard to monitor and
improve. The current invention of ANS mapping may modify this
field, for example by enabling the operator to navigate on top of a
function (neurotransmitter marker) road map. Optionally, the
operator can achieve safe, accurate, highly reproducible treatment
of any target by tracking specific neuro-activity. Optionally, in
some embodiments, the operator will be able to monitor the success
of his therapy.
[0439] These are some examples of ANS intervention procedures known
in the art.
[0440] Optionally, by incorporating ANSmap, the safety and/or
efficacy of these conditions may improve. [0441] Stellate
gangliotomy (anatomy guided procedure). The stellate ganglion
receives input from the paravertebral sympathetic chain and
provides sympathetic efferent to the upper extremities, head, neck,
and heart. [0442] GP ablation for the treatment of atrial
fibrillation (HFS guided therapy) [0443] Vagotomy for peptic ulcer
disease. [0444] Sympathectomy for burger and peripheral vascular
disease. [0445] ANS treatment for the treatment of severe anxiety
and social phobia.
[0446] In some embodiments, the ANSmap may be used for one or more
of the following examples: [0447] Measuring absolute level of
activity on an organ part of an organ, and/or system component
[0448] Measuring the response to a stimuli of the ANS activity
[0449] Measuring the relative activity in the same organ and/or a
different organ [0450] detecting locations within the organ [0451]
detecting time through the day or month [0452] Measuring the
response to therapy [0453] Monitoring the patient [0454] assessing
the Stage the disease [0455] Diagnosing a disease [0456]
Identifying the cause of disease [0457] Evaluating potential
therapies
[0458] Such therapies can include: [0459] Ablation of part of
segments of the ANS [0460] Ablation of certain path innervating
contralateral regions (the "normal" region--in case the ANS
response is in response to certain conditions that can be improved
by abolishing the ANS input to the other sites in the body (as an
example--an infarct induced cardiomyopathy. In this case the
disease and the progression of cardiac failure is caused by ANS
over stimulation of the normal tissue adjacent to the damaged
myocardium. Optionally, the ANS over-stimulation is so intense such
that it leads to lethal arrhythmias (therefore, in such a case, the
denervation of the ANS from the "normal" region will be the therapy
of choice).
[0461] In cases where the ANS over-stimulation is the disease
itself, for example in the case of rheumatoid arthritis: one can
postulate that ANS over-stimulation of the Spleen accelerating the
rate of formation of certain killer T cells and the "aggressive"
behavior these T cell adopt. The therapy in this case will be
applied to denervate the spleen from the ANS.
[0462] Optionally, by mapping the ANS, the treatment can be
modified accordingly, for example by disconnecting, pacing and/or
stimulating the modulation.
ANS Mapping
[0463] Reference is now made to FIG. 8 which is a flow chart of a
method for processing functional images to identify and/or locate
one or more ANS components (such as ganglia), according to some
exemplary embodiments of the invention.
[0464] A branch of the flowchart of FIG. 8 begins, and in some
embodiments of the invention, at block 352, functional imaging
modality data and/or images are received.
[0465] The data and/or images comprise, for example, a D-SPECT
image and/or other images. Received images, in some embodiments,
are of a body part; for example: a torso, abdomen, heart, or
another body part, according to the scanning protocol selected. The
body part, in some embodiments, includes nervous system tissue to
be imaged, and/or the innervated organ itself. For example, nerve
tissue comprises GPs of the heart, intestines and/or another organ.
Optionally, the functional images include regions of activity that
denote nerve tissue such as a GP made detectable, for example, by
uptake of a radiotracer such as mIBG. In some embodiments, a two
tracers are used; for example, first tracer such as mIBG to label
activity, and a second tracer to image tissue vitality.
[0466] Optionally, functional data is collected from a body part
that has regions where nerve activity is expected, and regions
where nerve activity is not expected. For example, during imaging
of the heart, data denoting nerve activity is expected from the
heart wall and/or surrounding tissues, and no nerve activity is
expected from inside the blood-filled hollow chambers. Potentially,
noise is received from areas corresponding to the inside of the
heart chamber, though no true activity is expected. Optionally, the
noise is removed from the functional data based on the
corresponding anatomical image; for example, after image
registration. Optionally, intensity denoting noise within blood- or
other fluid-filled chambers and/or vessels is removed. For example,
intensity readings of the functional data corresponding to heart
chambers and/or surrounding blood vessels are removed by applying
one or more image mask on functional image. In some embodiments,
fluid-filled chamber noise is used in obtaining a noise estimate
applicable to other tissue locations.
[0467] In some embodiments of the invention, information with
regard to the autonomic nervous system is obtained by measuring
surrogate functions that relate to the autonomic nervous system.
Surrogate measurements include for example, blood levels of
neurotransmitter used by the autonomic nervous system, electrical
activity of nerve fibers or ganglia, temperature of the ganglia,
and/or responses tied to similar autonomic nervous system inputs
(for example, heart rate or blood vessel resistance). It should be
appreciated, however, that the quality of surrogate measures of the
autonomic nervous system is potentially lower than that of direct
measures of autonomic nervous system activity. More specifically,
surrogate measures of the autonomic nervous system preferably have
certain qualities to qualify as useful in some embodiments of this
invention. In particular, a measure preferably conveys site
specificity, and has the ability to generate a valid signal through
a dynamic range of health and disease.
[0468] In some embodiments of the invention, at block 354, an
anatomical region is extracted from the image. Optionally, tissue
image regions (potentially containing nerve structures) are
segmented from hollow spaces (non-innervated, but potentially
containing fluid). For example, the wall of the left ventricle (LV)
and/or the hollow space within the LV is extracted. Optionally, the
extracted region is a layer of tissue, such as the tissue layers
forming the LV wall, instead of, for example, the LV including the
hollow chamber inside the LV. In exemplary cases of kidney imaging,
the walls of the renal artery are extracted and/or the inside of
the artery is extracted. When imaging other organs, dominant
portions of the organ are optionally selected.
[0469] In some embodiments of the invention, at block 356, one or
more registration cues are extracted from the image. Potential
sources of registration cues include, for example, the organ of
interest, and/or surrounding anatomical structures. Particular
examples include the LV axis, liver, heart septum, RV, and/or
torso. Optionally, registration cues are used to match anatomical
images with functional images, and/or to match anatomical images
during a physiological cycle, such as the cardiac cycle.
[0470] Another branch of the flowchart of FIG. 8 begins, and in
some embodiments of the invention, at block 358, anatomical image
modality data and/or images are received. Anatomical image modality
data comprises data obtained, for example, from a CT, MRI, 3D
ultrasound, 2D ultrasound, fluoroscope, or by another modality. The
anatomical image denotes the structure of the tissue and/or organ
innervated by nerve tissue, such as a GP. The anatomical image
denotes the tissue and/or organ structure corresponding to the
location of nerve tissue such as a GP. The anatomical images, in
some embodiments, contain both the nerve tissue to be functionally
imaged and the innervated organ. Alternatively, anatomical data is
received that is not personalized to the patient, for example, from
a general anatomical model.
[0471] Optionally, anatomical data from an anatomical imaging
modality is received to reconstruct an anatomical image of a region
of a body of a patient. Optionally, the region comprises a portion
of at least one internal body part which borders on a target nerve
tissue.
[0472] The anatomical images and the functional images denote
corresponding regions of the body containing the GPs for
identification and/or localization. For example, both modalities
are employable to take pictures of the heart, kidney, or other
organs. To image GPs of the heart, for example, anatomical and/or
functional images of the heart are obtained. To image GPs of the
kidney, in another example, anatomical and/or functional images of
the kidney, renal artery and/or aorta are obtained.
[0473] In some embodiments of the invention, at block 360, images
corresponding to different times during a dynamic cycle are
optionally extracted and/or acquired. For example, for the heart,
images are extracted along the cardiac cycle. Periods selectable
along the cardiac cycle for extraction include, for example, the
end diastolic volume (EDV) and/or the end systolic volume (ESV). In
another example: for the bladder, images are optionally extracted
corresponding to a full bladder and an emptying bladder.
[0474] In some embodiments, the average image is computed, for
example, as (EDV+ESV)/2.
[0475] In some embodiments of the invention, at block 362, one or
more images are segmented. Segmentation, in some embodiments, is
fully automatic. In some embodiments, segmentation requires or
potentially involves manual user intervention.
[0476] In some embodiments of the invention, at block 364, an
anatomical region is extracted. Optionally, the anatomical region
corresponds to the anatomical region extracted at block 354.
Optionally, the anatomical region is extracted from the segmented
image of block 362.
[0477] In some embodiments of the invention, at block 366, one or
more registration cues are extracted from the image. Potential
sources of registration cues include, for example, the organ of
interest, and/or surrounding anatomical structures. Particular
examples include the LV axis, liver, heart septum, RV, and/or
torso.
[0478] The branches of the flowchart merge, and in some embodiments
of the invention, at block 368, the functional images or data and
the anatomical images or data are registered. Optionally, the
images are registered based on alignment of the extracted
anatomical regions of blocks 354 and 364. Registration is performed
manually, automatically and/or semi-automatically.
[0479] Optionally, registration takes into account organ dynamics,
for example, heart movement. As examples: anatomical images during
the dynamic cycle are registered, and/or functional data are
corrected for the dynamic movement. As a particular example:
intensity readings within the heart chamber are corrected to
association with nearby moving heart wall.
[0480] In some embodiments of the invention, at block 370, image
masks are generated based on the anatomical image and/or data.
Optionally, the image masks direct processing and/or visual display
of the nerve tissue to specific locations of the image located
within the image masks. For example: GPs are displayed and/or
processed within the volume of an applied image mask, GPs outside
the volume of the image mask are not processed and/or displayed,
and/or GPs outside the volume of the image mask are processed
and/or displayed differently than those GPs inside the image
mask.
[0481] Optionally, the anatomical images are processed to generate
the image mask corresponding to dimensions of at least one internal
body part, for example, the walls of the chambers of the heart. For
example, a dimension of an internal body part of the specific
patient is calculated and used to define the mask.
[0482] Optionally, the image masks are selected and/or defined for
tissue surrounding a hollow chamber. As examples, image masks are
defined based on: [0483] the shape of the heart chamber walls,
excluding the hollow region within the chambers; [0484] the
arterial wall, excluding the hollow region within the artery; or
[0485] the shape of the bladder, excluding the hollow region within
the bladder.
[0486] It is noted that nerve structures are potentially confined
within the tissues defined by the image masks. The hollow spaces
(potentially filled with fluid such as blood, urine or other
fluids) are expected to be nerve structure free. Optionally, image
masks include tissue surrounding the organ of interest.
[0487] The image masks are defined, for example, based on: [0488]
image segmentation--such as according to the ability of the system
to segment the image; [0489] tissue type--such as muscle vs.
connective tissue; [0490] organ size; [0491] sub-structures within
the organ--such as heart chambers, liver lobes, or kidney parts;
[0492] or another method.
[0493] Different image masks are optionally generated for different
tissue types, and/or for GPs at different locations within the
organ. For example, for each of the GPs within the epicardium and
myocardium, a respective set of image masks is generated.
[0494] Optionally, image masks are generated for fat pads.
[0495] The image mask comprises, for example, a 2-D surface and/or
3-D volume with shape and/or size selected based on tissues and/or
organ parts within the anatomical image. The image mask optionally
corresponds to anatomical parts believed to contain the neural
tissue for imaging, such as GPs. For example, the mask corresponds
to the: walls of the four heart chambers, intestinal wall, bladder
wall, renal artery, aortic branch region of the renal artery,
kidney, and/or another structure. In more particular examples, the
image mask is generated to contain GPs within the epicardial and/or
myocardial tissue of the heart, or kidney innervating GPs at the
aorta-renal artery junction.
[0496] Optionally, image masks are generated based on an estimated
location of the GPs. For example, an estimated location is based on
normal patient anatomy, an initial model of the ANS for a patient,
and/or known previous ablation or other medical data, such as
indications of missing or ablated nervous tissue. Optionally, image
masks are generated based on an estimated location of the GPs and
dimensions of an internal body part inferred, for example, from an
anatomical image. Potentially, this provides an advantage when GPs
are not visible on the anatomical image.
[0497] Optionally, generated image masks correspond to the segments
of the anatomical image. For example, the heart is segmented into
chamber walls and the generated image masks correspond to the
chamber walls of interest.
[0498] In some embodiments of the invention, at block 372, the
image masks are applied to the functional image. Alternatively or
additionally, the image masks are applied to the functional data.
Alternatively or additionally, the image masks are applied to
combined functional and anatomical images and/or data, for example,
overlaid images.
[0499] Optionally, the image masks are applied based on the
registration process (block 368). The anatomical information serves
as a guide, using the selected image masks, for selective
reconstruction of GP related data within the functional image. The
image masks may be correlated with the image to contain anatomical
structures having the neural tissues. The application may be based
on the image registration, for example, applied based on a common
coordinate system. The image masks may be applied to a certain type
of tissue containing neural tissue. For example, the image masks
may be applied to the epicardium of the heart. The image mask may
be applied to have its inner surface aligned with the epicardial
surface of the chamber wall, such that the image mask contains the
epicardial space encompassing the chamber.
[0500] Optionally, the generated image mask is correlated with the
functional data for guiding the reconstruction of a functional
image depicting the target nerve tissue.
[0501] In some embodiments of the invention, at block 374,
functional activity is calculated within the applied image mask
space. Optionally, the average functional activity is calculated.
Optionally, the standard deviation of the functional activity is
calculated. For the heart example, the functional activity is
calculated around each chamber separately, and around the entire
heart. Average activity for the chambers may be denoted by A1LV,
A1RV, A1LA, and A1RA. Average activity for the heart may be denoted
by A1H. Standard deviation of the activity may be denoted by SD1LV,
SD1RV, SD1LA, SD1RA, and SD1H. Optionally, average activity and/or
standard deviation may be calculated for the entire functional
image or data. Optionally, average activity and/or standard
deviation is pre-set, e.g., based on previous imaging of the same
patient, based on "normal" patient activity etc.
[0502] In some embodiments of the invention, at block 378, GPs are
identified within the applied image mask space. It should be noted
that the term "GP" is used for ease of discussion, and that the
method is optionally applied in some embodiments for identifying
ANS component(s) or for extracting or identifying other information
relating to neural activities, or other tissues. Alternatively or
additionally, GPs are identified within the organ volume and/or
nearby tissues. Optionally, GPs identified within multiple
different image masks that are combined into a single image of all
the identified GPs, for example, the identified GPs within the
organ. Alternatively or additionally, GPs identified within
corresponding image masks of multiple frames over time are
combined--such as all image masks of the LV myocardium during the
cardiac cycle.
[0503] Optionally, areas of extreme activity are identified. For
example, epicardial GPs (EGP) and/or myocardial GPs (MGP) are
identified based on extreme mIBG activity.
[0504] Optionally, GPs are identified based on one or more
predefined thresholds and/or rules. Optionally, GPs are identified
based on size. Alternatively or additionally, GPs are identified
based on activity level in reference to average activity and/or
surrounding activity. Alternatively or additionally, GPs are
identified based on connectivity between GPs.
[0505] In some embodiments, the GP is identified as an object
within a particular size constraint. The constraint is, for
example, at least about 4.times.4.times.4 mm, such as for an EGP;
or about 2.times.2.times.2 mm, such as for an MGP. Alternatively or
additionally, the GP is identified by comparing calculated activity
(image intensity) of a certain region to surrounding activity in
the same image mask. Alternatively or additionally, the GP is
identified by comparing calculated activity within the image mask
to activity in another image mask. For example, the EGP is
identified as satisfying the rule that the total activity of the
EGP is a predefined factor times the standard deviation (SD1 and/or
SD2), above average activity (A1 and/or A2), and/or the adjacent
activity surrounding it is lower than half of the EGP activity.
Optionally, activity is corrected for volume. Optionally, the user
selects and/or modifies the predefined factor. For example, the MGP
is identified as satisfying the rule that the total activity of the
MGP is another predefined factor times the standard deviation (SD1
and/or SD2), above average activity (A1 and/or A2), and/or the
adjacent activity surrounding it is lower than half of the MGP
activity, optionally corrected for volume. Optionally, the user
selects and/or modifies the predefined factor.
[0506] Optionally, identification of GPs is performed per frame,
optionally per frame of the dynamic cycle (e.g., cardiac
cycle).
[0507] In some embodiments, the identified GP is automatically
related to a tissue type.
[0508] Optionally, the identified GP is related to the tissue type
based on the applied image mask. Alternatively or additionally, the
identified GP is related to the tissue type based on the
characteristics of the intensity readings. For example, large sizes
(denoting large GPs) are potentially only to be found in certain
tissues. Optionally, different types of GPs are related to
different tissues. For example, myocardial GPs are related to the
myocardium and/or epicardial GPs are related to the epicardium.
[0509] In some embodiments of the invention, at block 380, one or
more parameters are calculated for the identified GPs (also
referred to herein as GP parameters). Examples of parameters
include: [0510] average size; [0511] specific activity--expressed,
for example, in counts per voxel and/or GP/average counts in the
corresponding image mask volume; [0512] power spectra--for example,
the power below 1 Hz, power between 1-5 Hz, and/or a ratio of high
to low frequencies; [0513] normalized power spectra; [0514] GP
connectivity map--for example, connectivity and interaction between
different GPs; and/or [0515] number of GPs per predefined
area--expressed, for example, as GP density number/cm.sup.2.
[0516] For identified EGP, one or more of following parameters is
calculated in some embodiments: EGP size, EGP specific activity,
EPG power spectra graph, EGP normalized power spectra, and/or a map
of EGP connectivity. EGP normalized power spectra are calculated,
in some embodiments, as the difference between the EGP power at
different frequencies minus the power of the total counts from the
myocardial image mask space.
[0517] Optionally, calculation of GP parameters is performed per
frame, optionally per frame of the dynamic cycle (e.g., cardiac
cycle).
[0518] In some embodiments of the invention, at block 382, the
calculated and/or other parameters are normalized. Normalization
optionally takes place at one or more blocks of the method, for
example, during and/or after acquiring the functional and/or
anatomical images, upon calculation of functional activity, upon
identification of GPs, upon calculating parameters for the GP, upon
comparison of data over time, or at other blocks.
[0519] Examples of normalization techniques include: [0520] raw
data; [0521] raw data divided by the raw data value in a known
fixed anatomical location acquired at roughly the same time, for
example, the activity of the tracer in the patient's mediastinum;
[0522] normalization to a normal patient data set; [0523]
normalization to a value of the activity at the first or the last
image acquisition from a sequence of acquisitions; [0524]
normalization to value acquired in different physiological states
such as rest/stress; [0525] a combination of some or all of the
above; and/or [0526] other methods.
[0527] Alternatively, normalization is performed instead of and/or
in addition to the normalization of block 382 before a different
block in the process. For example, normalization is optionally
applied before GPs are identified in block 378. Normalization
potentially assists identifying the GPs. For example, activity at a
local region, such as mIBG activity, is compared to an average
value and/or standard deviation across the organ volume, within the
image mask space and/or relative to a predefined threshold.
[0528] Alternatively or additionally, the calculated data (e.g.,
blocks 374, 378, 380) and/or measured functional intensity are
corrected for sensitivity. Optionally, sensitivity correction is
performed within each image mask and/or in related image masks. For
example, different areas potentially have relatively higher or
lower sensitivity to uptake of the radioagent. Optionally, the
anatomical data is correlated to the sensitivity.
[0529] Optionally, the image masks are generated (block 370) based
on different sensitivity levels; for example: one set of image
masks for higher sensitivity nerve structures, and another set of
image masks for lower sensitivity nerve structures.
[0530] Optionally, the different sensitivities are normalized to a
common baseline.
[0531] Alternatively or additionally, measurements of the
functional data are normalized. For example, measurements of uptake
of the radioagent are normalized to the level of corresponding
chemical in the patient. Optionally, intensity measurements are
normalized according to the level of activity of GP being
identified. Optionally, measurements denoting activity of the GPs
are taken. For example, in the case of mIBG, measurements are
optionally normalized to the level of norepinephrine (NE),
adrenaline and/or epinephrine in the patient. Optionally, the level
of NE is measured in the blood, urine, or other body fluids.
Intensity of mIBG uptake is normalized based on the measured
NE.
[0532] Additionally or alternatively, mIBG measurements are
normalized to a decay function, such as decay over time since
injection of mIBG. In another example, the level of activity is
measured by non-chemical methods. For example, normalization of
mIBG is performed based on measurements taken during a cardiac
stress test. Measurements comprise, for example, ECG measurements,
heart rate, cardiac output, and/or other measurements. Optionally,
measurements are correlated with levels of activity of the GPs
being identified, for example by a table, mathematical equation, or
other method.
[0533] Additionally or alternatively, measurements of functional
data are normalized to a level of one or more electrical
properties. For example, functional data are normalized to impulse
conduction velocity, refractory period, a measured electrical
potential (at one or more phases of contractile state), or another
property of the electrical activity of the tissue. Optionally,
additional weight is given to regions where conduction is
particularly poor: slow to transmit and/or slow to recover, for
instance. This is a potential advantage, for example, when
evaluating a heart region for severity of disease, and/or for
comparing regions for their relative severity of disease.
[0534] In some embodiments of the invention, at block 384, data is
compared over time.
[0535] Optionally, changes in GP parameters over time are
identified. Optionally, dynamic changes of the calculated
parameters between different acquisition times are determined. For
example, the changes in GP activity over time are calculated, from
injection till 6 hours post injection, by repeating the image
acquisition several times during this time window. The functional
images are optionally acquired at more than one time after the
tracer injection.
[0536] In some embodiments of the invention, at block 386, a
functional image is reconstructed based on the mask applied to the
functional data and/or image.
[0537] Alternatively or additionally, an image is reconstructed
based on the mask applied to the combined functional and anatomical
data and/or images. The reconstructed image potentially contains
the identified GPs, for example, as regions of increased intensity.
The reconstructed image is optionally overlaid on the anatomical
image, illustrating the physical location of the GPs.
[0538] Alternatively or additionally, the characteristics of the
GPs within the functional image are reconstructed. The
reconstruction is instructed by the image mask.
[0539] In some embodiments of the invention, at block 388, the
calculated results from, for example, block 378, 380, 382 and/or
384, and/or reconstructed images (block 386) are provided for
presentation or otherwise provided to the operator. They are, for
example, presented on a monitor to a physician. Additionally or
alternatively, the calculated results and/or reconstructed images
are stored in a memory for future use, such as diagnosis. The
calculated results potentially assist in diagnosing the patient
and/or in guiding treatment.
[0540] Optionally, the results are provided for presentation on a
certain frame, for example, the end systolic frame. Alternatively,
results are provided for presentation on multiple frames, for
example, a video of the cardiac cycle.
[0541] In some embodiments, the reconstructed functional image or
combined functional and anatomical image is provided for
registration during a treatment procedure. Optionally, the
reconstructed functional image is overlaid on and/or registered
with anatomical images obtained during the treatment procedure.
Overlaid and/or registered images are optionally used by the
operator to physically determine locations of the GPs during the
treatment.
[0542] The method of FIG. 8 has been described with reference to
the heart. The method is not limited to the heart, and is used in
some embodiments for other organs, including hollow fluid filled
organs such as stomach, aorta, or bladder; and/or solid organs such
as kidney or liver. GPs and/or nerve endings are identifiable in
these other organs in some embodiments. For example, the aorta is
segmented based on surrounding structure such as bones, muscles,
and/or branching arteries; and image masks generated accordingly.
The liver, in an exemplary embodiment, is segmented based on
anatomical liver lobe divisions.
ANS Mapping System or Unit
[0543] Reference is now made to FIG. 9, which is a block diagram of
a model ANS modeling system/unit 1006, in accordance with some
exemplary embodiments of the invention.
[0544] In some embodiments, ANS modeling system/unit 1006 is
provided as a part of a system 900 including functionalities with
which ANS modeling system/unit coordinates in series or in
parallel. For example, a system 900 includes a functional imaging
modality 1008A (such as a SPECT imager), and/or an anatomical
modeling modality 1008B. Anatomical image modality data comprises
data obtained, for example, from a CT (X-ray or gamma-ray, for
instance), MRI, 3-D ultrasound, 2-D ultrasound, or by another
modality. Optionally, an ANS modeling system/unit is comprised in
part of another system configuration, such as a system 1000, as
described in relation to FIG. 10 hereinbelow.
[0545] In some embodiments of the invention, ANS module 1006
receives functional images and/or imaging data 1012A (for example,
as produced by functional imaging modality 1008A); and anatomical
images and/or imaging data 1012B (for example, as produced by
anatomical imaging modality 1008B).
[0546] The ANS module itself produces model information 1020
comprising information, about, for example, GP locations,
interconnections and/or activity levels. In some embodiments, image
data within GP locations resolves one or more distinct and/or
identifiable GP regions. Production of an ANS model comprises, for
example, one or more of the blocks described in relation to FIG. 8,
hereinabove.
[0547] In some embodiments of the invention, ANS module 1006
comprises processor controller 906. Processor/controller carries
out computational tasks of ANS model generation, for example,
computational tasks described in relation to FIG. 8, hereinabove.
Optionally, ANS module 1006 is provide with a GUI 908. In some
embodiments, ANS module 1006 comprises memory 904, used, for
example to receive and store images, associated data, model
information, and/or process/controller instructions. Optionally,
GUI 908 is used, for example, in the selection of image sources,
images, and/or regions of data for analysis. Optionally or
alternatively, GUI 908 is used, for example, to show model results;
for example: regions of tissue health or disease, regions of
innervation or lack of innervation, regions of nervous system
activity/inactivity, and/or any of these regions in relation to one
another. In some embodiments, ANS module 1006 comprises a
workstation 910. The workstation itself, in some embodiments,
optionally comprises the processor/controller 906 and/or GUI 908.
In some embodiments, functions of workstation 910 are distributed;
for example, at least a part of ANS modeling carried out by
processor/controller 906 is calculated remotely, for example, as a
provided service.
[0548] In some embodiments, a system 900 includes one or more tools
for a treatment option such as GP ablation, stimulation,
anesthesia, or another neuromodulatory intervention. In some
embodiments, system 900 is operable for guidance of a probe for
treatment based on real-time display of a probe and ANS map in
registration, direct (for example, robotic) guidance of probe
position, or another method of ANSmap-guided treatment and/or
treatment probe placement.
Exemplary Diagnosis and Treatment Subsystem
[0549] Reference is now made to FIG. 10, which is a block diagram
of a model analysis and treatment planning system/unit 1000, in
accordance with some exemplary embodiments of the invention.
[0550] In some embodiments, once a model is available, it is used
for diagnosis and/or planning a treatment for example as described
hereinabove. Groups of elements comprising a system/unit 1000
include, for example, blocks within the boundaries delineating
system configurations 1000A, 1000B, 1000C, 1000D, and/or another
system configuration comprising blocks of FIG. 10.
[0551] In some embodiments, unit 1000 carries out functions of
various model analyses described herein, for example, in relation
to FIG. 9. For example, it includes analysis/modeling subsystem
1006, as in configuration 1000C. In some embodiments, unit 1000 is
integral to and/or co-located with imaging and/or treatment systems
(for example, it includes imaging subsystem(s) 1008, as in
configuration 1000D). In some embodiments (for example, including
analysis/modeling subsystem 1006), images and imaging data 1012 are
received by the system/unit 1000. In some embodiments (for example,
including imaging subsystem(s) 1008), images and imaging data 1012
are generated by the system/unit 1000. In some embodiments, imaging
subsystems 1008 include an imaging modality described in relation
to FIG. 9, for example, a functioning imaging modality 1008A,
and/or an anatomical imaging modality 1008B.
[0552] In some embodiments, unit 1000 (for example, configurations
1000A and/or 1000B) is remotely located relative to other
subsystems, and/or is distributed.
[0553] Optionally, the functions of, for example, subsystem 1000A
are provided as a service. In exemplary embodiments of the
invention, rather than provide a user with a model of the ANS 1020,
what is provided is a combination model and treatment plan (for
example, a combination comprising the information of model
information 1020 and treatment plan 1032) or possibly just a
treatment plan 1032. Some exemplary treatment plans 1032 are
described below. In some embodiments, the ANS and/or its activity
are described as a pattern (which is not necessarily a model as
such), and the pattern becomes the basis for classification with
respect to the identification of diagnosis and/or planning of
treatment.
[0554] In a first stage of operation of some embodiments of the
invention, model information 1020 and patient information 1022
provided to a diagnosis subsystem 1002. Model information 1020
includes, for example, GP locations, interconnection and/or
activity level. Patient information 1022 includes, for example,
patient demographics, history and/or previous response to therapy.
Optionally, diagnosis subsystem 1002 uses a diagnosis database 1024
to assist in providing a diagnosis. Diagnosis database 1024
includes, for example, rules, example diagnoses, and/or machine
learning data.
[0555] Optionally or alternatively, diagnosis subsystem 1002
includes one or more modules which apply processing on the model to
extract diagnose. In some exemplary embodiments of the invention,
the diagnosis database 1024 is updatable and/or parts thereof are
available at different and/or additional cost.
[0556] The output of diagnosis system 1002, in some embodiments, is
a personalized diagnosis 1030. In some exemplary embodiments of the
invention, the diagnosis database 1024 includes a plurality of
templates, each one optionally associated with one or more possible
diagnoses and/or including instruction for missing data to assist
in diagnosis. Optionally or alternatively, at least one dynamic
template is used. Such a template is potentially useful, for
example, if a disease is characterized by a temporal pattern of
behavior. Such a template includes, for example, multiple snapshots
with a time indicator, and/or defines a function of change over
time and/or in response to a trigger.
[0557] In some exemplary embodiments of the invention, personalized
diagnosis 1030 is provided to a planning subsystem 1004. In some
embodiments, planning subsystem 1004 generates a treatment plan
suitable for the patient, based on the diagnosis and/or best
practices. Optionally, a treatment database 1026 is used to aid in
treatment planning. The treatment database 1026 includes, for
example, exemplary treatments, and/or rules for applying them.
[0558] Optionally or alternatively, planning subsystem 1004 uses
modules to plan various parts of the treatment and/or to determine
if parts of the treatment are reasonable and/or safe. Optionally,
model information 1020 and/or patient information 1022 also serve
as input for the treatment planning. For example, the information
1020, 1022 is used to help determine what effect a treatment may
have on a patient. In some embodiments, the result is a treatment
plan 1032.
[0559] In some exemplary embodiments of the invention, treatment
plan 1032 includes one or more of: a plurality of locations to be
treated, an expected measurement for the effect of treatment of a
location, treatment parameters for one or more of the location
treatments and/or alternatives for one or more of the locations.
Optionally, the plan 1032 includes a time line indicating the order
of treatment and/or delay times between treatment locations.
[0560] In some exemplary embodiments of the invention, a treatment
is defined with a time scale of several minutes, hours or days; for
example, defining a wait of between 1 and 1010 minutes or between 1
and 20 hours between treatment locations.
[0561] It should be noted that diagnosis and/or modeling is
potentially improved, in some embodiments, by taking into account
the effect of treatment. In some exemplary embodiments of the
invention, a treatment plan 1032 includes a suggestion to
recalculate model and/or diagnosis and/or treatment plan, for
example, in response to a measurement exceeding a certain threshold
or matching a certain pattern, and/or otherwise to fulfill a
rule.
ANS-Disease Decoder (ADD)
[0562] Reference is now made to FIG. 12, which is a schematic
flowchart 1200 showing the operation of an ANS-disease decoder
(ADD), according to some exemplary embodiments of the
invention.
[0563] At block 1202, in some embodiments, ANS measurements are
provided, acquired, for example, according to a method described in
relation to FIGS. 1-5 and/or FIG. 8. Optionally, measurements are
provided as a pattern of activations.
[0564] Optionally, measurements are entered into a model
description of the ANS from which they were obtained. In some
embodiments, ANS measurements correspond, for example, to model
information 1020. In some embodiments, the ADD receives information
from earlier in the processing chain of FIG. 10, for example,
original images and/or imaging data.
[0565] At block 1204, in some embodiments, organ and/or organ
system measurements related to organ function are provided; for
example: a measure of a metabolite level, hormonal level,
physiological parameter such as heart rate, muscle state (for
example, state of distension of a bladder and/or stomach), or
another parameter, obtained, for example, as described in relation
to FIGS. 1-5 hereinabove. In some embodiments, measurements
comprise, for example, patient information 1022.
[0566] In some embodiments, data provided at blocks 1202 and/or
1204 was obtained with known relative timing (between the two
blocks) during manipulation of organ and/or ANS function and/or
state Manipulation potentially allows determination of a
relationship between variables, such as showing their relative
tendencies to change, either due to causal relationships between
them, or to common dependencies on separate cause. Manipulation is,
for example, by administration of a drug, administration and/or
withholding of food or liquid, control of activity level, control
of voluntary aspects related to disease symptoms, or another
appropriate manipulation, for example as described in relation to
FIGS. 1-5 hereinabove. Additionally or alternatively, manipulation
is of the ANS, for example as described hereinabove.
[0567] At block 1210, in some embodiments, an ANS-disease decoder
(ADD) operates based on the received measurement inputs to generate
output related to disease diagnosis and/or treatment options. In
some embodiments of the invention, ADD corresponds to one or more
functions of system configuration 1000A, for example, the
functionalities of diagnosis subsystem 1002, and/or a planning
subsystem 1004.
[0568] At blocks 1215 and/or 1220, in some embodiments, the output
is provided. In some embodiments, the output comprises a diagnosis
of one or more potentially pathological modes of interaction
between the organ and/or organ system and the ANS.
[0569] Optionally or alternatively, the output comprises one or
more treatment options.
[0570] In some embodiments, treatment options are presented in the
form of a map, for example, a map of ANS regions. Options are
indicated, for example, as a suggested location for one or more
interventions to alter ANS activity levels.
[0571] Details of the operation of exemplary embodiments of an ADD
1210 are now described in further detail.
[0572] Reference is now made to FIG. 13, which is a schematic
flowchart 1300 of an initial phase of analysis performed by an ADD
unit 1210, according to some exemplary embodiments of the
invention. The flowchart 1300 represents a portion of processing
carried out by ADD 1210, corresponding, in some embodiments, to an
initial phase of detecting in the received data salient features on
the basis of which diagnosis and/or treatment options are to be
determined.
[0573] At block 1302, in some embodiments, the signals
(measurements) 1202, 1204 received by the ADD 1210 are
preconditioned. Preconditioning comprises, for example, operations
on data corresponding to those described in relation to FIG. 8
(creation of an ANS map). Preconditioning optionally comprises, for
example, normalization; relating measurements to particular times,
places, and/or conditions of acquisition; and/or other processing
suitable to convert it to a form usable with the processing of
block 1304.
[0574] At block 1304, in some embodiments, ANS measurements and
organ (and/or system) measurements are brought into a mapped
relationship. At block 1306, the map is analyzed. Particular
features detected by the ADD 120 are shown in blocks 1308
(monotony), 1310 (peaks and troughs), and 1312 (repellers and
attractors).
[0575] Reference is now made to FIG. 14, which is a schematic graph
1400 of a mapping between organ/system function and/or state,
according to some exemplary embodiments of the invention.
[0576] Trace 1401 represents an exemplary relationship (taken
through some range of overall conditions) between a quantifiable
function and/or state relevant to disease ("Organ/System
Function/State"), and ANS state ("ANS State (Activity)"). In a
simplified case, ANS state can be represented by the level of
activity of a single ganglion. However, it should be understood
that ANS state, in some embodiments, comprises a multidimensional
function of 2, 3, 4 or more different ANS measurements. In a
multidimensional condition, certain additional possibilities can
occur, such as conversion of point-like attractor/repeller limits
into limits having extension (line-like, plane-like or other), and
potentially allowing a greater combination of states. Consideration
of such more general conditions is also found, for example, in the
Overview section, hereinabove.
[0577] In a simplified case, the organ/system function and/or state
is represented, for example, by the level of a single measurement.
Such a single measurement optionally comprises, for example, pulse
rate, blood pressure, and/or another indication of activity or
function such as imaged uptake of a radiolabeled metabolic marker;
blood glucose level, and/or a level of another blood-borne marker
of function and/or activity such as a hormone or factor; or another
parameter of bodily function and/or activity. It should be
understood, however, that in some embodiments the organ/system
function and/or state measure comprises 2, 3, 4 or more measured
variables.
[0578] In a simplified case, the graph 1400 represents a
hysteresis-free relationship between the organ/system
function/state and the ANS state. However, it is to be understood
that the relationship between the two is subject to lags, and/or to
differences in shape depending on whether movement along the line
is driven by forcing of the organ/system function/state (for
example, administration of a stress to change the heart rate),
forcing of the ANS activity state (for example, by direct or
indirect stimulation and/or pharmacological blocking), or by a more
generalized stimulus which shifts the system state, by a mechanism
of action which is indeterminately on the ANS or the innervated
organ/system of interest.
[0579] Nevertheless, given control and/or monitoring of even just
two variables of the system, an overall shape of the graph can
potentially be determined with sufficient resolution to reveal its
salient features. In some embodiments, knowledge of these features
guides analysis of the disease, leading to diagnosis. In some
embodiments, knowledge of these features allows determination of
manipulations of the ANS which treat disorders reflected in the
state map 1400.
[0580] In particular, the graph of an organ/system and its control
potentially comprises local and/or global peaks (1405A, 1405B) and
troughs (1410A, 1410B, 1420) in the homeostatic function which
describes their relationship. The range of the graph at or near the
bottoms of the troughs 1410A, 1410B, 1420 are "attractors", in
that, in the absence of driving external to the variables being
considered, the homeostatic system tends to move toward the nearest
such trough. It should be understood that this movement toward a
trough, according to the specifics of the case, can comprise either
increase or decrease in a metric. For example, ANS activity may
rise or fall as a trough bottom is approached; similarly,
organ/system state/function measurement can rise or fall. It can be
readily understood that where the homeostasis graph is a simple "U"
shape, there is only one minimum, the global one, and the system
tends to approach this from any point on the homeostasis graph.
[0581] However, in some instances, derangement in a system's
homeostasis can be understood as the appearance and/or strengthened
effect of "repellers" (ranges of the control graph at and/or near
the peaks 1405A, 1405B), which block movement to a preferred state
and/or strengthen the "attractiveness" of a non-preferred state. In
another sense, a "repeller" is a region of a control graph which a
system tends to move away from in the absence of external driving.
In such a system, there can be a plurality of minima, some of which
potentially reside in a combination of activities which is
pathological. For example, increasing insulin insensitivity by the
liver can potentially make it more difficult to cross a repeller
threshold, such that the ANS must work especially hard to "bump"
the system into a preferred state. Considering the potential
effects of physiological variables representing third and higher
dimensions, a system can potentially even "go on a walk" (also
described hereinabove as an "orbit"), spilling into a range where
the 2-D cross section represented by the graph of state map 1400
changes completely due to movement in this physiological "third
dimension". Examples described herein provide exemplary instances
of diseases where homeostasis is changed from a condition of normal
functioning into a functional state which describable as disturbed
(not operating normally), vulnerable to disturbance (possibly
operating normally, but easily disturbed), deranged (not operating
within normal parameters), dysfunctional (disturbed, vulnerable to
disturbance, and/or deranged), and/or pathological (having
dysfunction which presents as disease). A disturbance in attractors
and/or repellers comprises, for example, an excursion of the
control function through a range of about 10% of the observed
functional range of the parameter. Also for example, the excursion
is about 20%, 30%, 40%, or another greater, smaller, and/or
intermediate relative excursion. In some embodiments, the excursion
comprises the addition of a repeller, the addition of an attractor,
the reduction of a repeller, and/or the reduction of an
attractor.
[0582] Practically, however, there is potentially at any given time
a relatively restricted range of accessible states. Furthermore, it
is optionally not necessary to sample every point (or even a large
number of them) along a homeostasis graph to reveal the existence
of peaks and troughs relative to diagnosis and/or treatment. For
example observation of an inverting relationship in the change of
ANS activity and organ/system state between regions of monotonic
increase or decrease (monotony) 1415B and 1415C is potentially
sufficient to identify the existence of an intermediate peak. The
inversion is potentially identified as specifically a peak, by
observing the tendency of the system to naturally move away from it
in the absence of a counteracting driving force. Similarly, a
minimum 1420 is detectable even away from the minimum itself, for
example, by observation of behavior at regions of monotony 1415C
and 1415D.
[0583] Additionally or alternatively, it can be inferred that at
least one peak and valley exist between regions of monotony 1415A
and 1415B, based on the relaxation behavior and/or relative driven
responses measured there.
[0584] Reference is now made to FIG. 15, which schematically
illustrates a diagnostic measurement configuration 1500, allowing
measurements of a physiological parameter's changes in response to
manipulation, together with measurements of ANS activity, for use
in diagnosis and/or treatment determination, according to some
exemplary embodiments of the invention.
[0585] The exemplary situation shown shows how induction (forcing)
of state changes by a manipulation (which in this case happens to
be controlled-rate injection of a drug), can be combined with
simultaneous measurement of ANS activity and some chosen
physiological parameter to yield data for input into the ADD
1210.
[0586] Motorized syringe 1512 is connected via IV line to subject
1505, and is configured to deliver a controlled-rate dose of a
pressor agent such as prostacyclin during imaging of ANS activity,
for example, by a SPECT instrument 1514. During the period of
imaging, blood pressure is measured by a blood pressure monitor
1510, with the target range of pressures being, for example,
between 90 mmHg and 200 mmHg.
[0587] Blood pressure information and information representing
activity levels of ANS ganglion loci 1502A, 1502B (optionally,
together with anatomically information specifying the relative
positions of other internal organs 1508 are brought together in the
ADD. In a patient with a healthy innervation pattern, it is to be
expected that as blood pressure rises, sympathetic activity levels
in the innervation to the arteries (which is itself
vasoconstrictive) should monotonically decrease. If, at some point
along the graph of increasing blood pressure, one or more
sympathetic ganglia are seen to reverse their direction of change
(so that they increase activity with increasing blood pressure), it
indicates a potential finding of a "repeller" state. Even with the
drug forcing turned off, such a ganglion would be working to force
the blood pressure higher, rather than lower as long as it was
working in such a mode. A repeller condition could indicate, for
example, that an organ/system has been brought to a state during
the period of elevated blood pressure which activates the
sympathetic system more strongly than elevated blood pressure
depresses it. Additionally or alternatively, sympathetic
sensitivity to elevated blood pressure is reduced (for example, due
to loss of sensory inputs), so that it is less sensitive to what
would normally be an overriding input. In either case, a potential
treatment would be to ablate or otherwise deliberately impair
sympathetic function.
[0588] Potentially, this trades a generalized degradation of
regulatory function for the eradication of a specifically dangerous
mode of operation. In some instances, it is potentially found that
increased sympathetic innervation can be selectively attributed to
a subset of imaged ANS ganglia: for example, ganglion 1502B, but
not ganglion 1502A. In such cases, it is a potential advantage to
know which ganglia are the strongest sources of "repeller"
innervation, so that they can be target while leaving other ANS
structures intact.
[0589] Reference is now made to FIG. 16, which is a partial
schematic flowchart 1600 of operations performed by an ADD 1210 to
convert received function data 1601, 1601A, 1601B into
determination of an intervention, according to some exemplary
embodiments of the invention.
[0590] The flowchart portion begins, in some embodiments of the
invention, with the receipt of data 1601, which comprises, for
example, ANS measurements 1202 and organ/system measurements 1204.
At block 1602, in some embodiments, identification of
attractors/repellers is performed, for example, according to
operations described in relation to FIG. 13.
[0591] At block 1604, in some embodiments, interventions are
identified. In some embodiments of the invention, identification of
interventions comprises pattern recognition, where a recognized
pattern is mapped to one or more previously determined treatment
options. In a relatively simple example of such mapping, a ganglion
showing a reversing pattern of activity response through a range of
organ function/state level where a monotonic response is expected
is simply recognized as "faulty", and targeted for ablation or
another form of inactivation.
[0592] In some embodiments of the invention, a modeling approach is
taken, at least in part. For example, weights are assigned to the
importance of noted activity centers as targets for intervention.
In some embodiments, weighting depends, for example, on observed
relative intensities, typical strength of effect in proportion to
activity, and/or another parameter. Parameters are determined based
on empirical experience and/or modeled considerations based on
estimates. In some embodiments, machine learning comprises
prospectively exploring a range of available options, leading to a
suggested intervention which "optimally" (at least, insofar as the
model is accurate) balances constraints such as surgical
practicality, minimized side-effects, certainty of effect, and/or
other constraints which are set to constrain the output to have a
targeted effect.
[0593] In some embodiments of the invention, more than one sequence
of ANS/organ state maps are available to the operations of blocks
1602 and/or 1604. The sequences optionally comprise repeated runs
of the same mapping conditions. Optionally, sequence map ANS
activity in response to two or more different types of
manipulations. Potentially, the multidimensional approach allows a
greater range of possible manipulations to be identified. It is
possible, some embodiments, that data will be suggestive of
homeostatic features such as undesired attractors or repellers
outside of the explored range. In some embodiments, additional
tests are performed based on to expand the range of data available
on which to make a treatment decision. In some embodiments of the
invention, the results of past imaging and/or interventions is
available to the decision-making algorithm, as a basis on which to
refine modeled manipulations and/or select relevant patterns of
activity and their appropriate intervention.
[0594] Reference is now made to FIG. 17, which is a schematic
flowchart 1700 describing the ADD-moderated determination of
application of treatment to ANS GP targeted for treatment,
according to some exemplary embodiments of the invention.
[0595] At block 1702, in some embodiments of the invention,
attractor/repeller features of the observed pattern of one or more
homeostasis maps are selected for repair. Determination comprises,
for example, tests and analyses described in relation to FIGS.
12-16 hereinabove.
[0596] At block 1704, in some embodiments, a strategy is selected
for intervention. For example, treatment targeting is determined
for a particular ANS structure, such as a GP or nerve fiber.
Selection comprises, for example, determination of which GP most
contributes to the pattern that creates a targeted attractor or
repeller. Optionally, the strategy is determined by the ADD,
according to a list, match, model or other method of treatment
specification. Optionally, the strategy is selected by a physician,
based on ADD output which highlights one or more ANS targets for
intervention. Three strategy types are described, corresponding to
branches A, B, and C from block 1704.
[0597] At block 1706, in some embodiments of the invention,
strategy A is implemented. In some embodiments, a temporary block
to a targeted GP is delivered. For example, a GP is cooled,
drugged, or otherwise inactivated. At block 1712, in some
embodiments, the success of the block is determined. Optionally, a
test is performed; for example, a paired
ANS-imaging/organ-function-measuring session. If the results of the
test show that a desired modification of the homeostasis map has
been achieved, then, optionally, permanent and/or long-term
ablation is performed at block 1714 by ablating the targeted GP.
Optionally, in case blocking the targeted GP has not had the
desired effect, the flowchart return to block 1702, and another
attempt, optionally one refined by the test data, is made to select
an attractor repeller and/or choose a treatment strategy.
[0598] At block 1708, in some embodiments of the invention,
strategy B is implemented. Strategy B comprises supplying addition
afferent input. Afferent input is increase, for example, by
supplying a drug known to have potentiating effects on the type of
afferent input which is targeted for enhancement. In some
embodiments, the drug is supplied in a targeted fashion, for
example, by means of an eluting implant. In some embodiments,
afferent input is supplied by means of an electrical and/or
electromagnetic stimulation device. Optionally, the device is
implanted. Optionally, the device operates transcutaneously. In
some embodiments of the invention, afferent fiber proliferation is
encouraged, for example, by denervating a complementary pathway,
supplying trophic and/or structure support for fiber growth,
suppression of factors inhibiting innervation, or another method of
shaping innervation.
[0599] At block 1710, in some embodiments of the invention,
strategy C is implemented. In some embodiments, an afferent pathway
is intervened with. Some forms of pathway-directed positive
intervention are described in relation to strategy B. Negative
intervention comprises full or partial ablation of an innervation
pathway.
[0600] Optionally, an overactive pathway is directly ablated in
order to reduce overactivity. In some embodiments, a negative
intervention comprises full or partial ablation of a pathway which
inhibits underactive innervation. Other examples of interventions
affecting ANS activity levels and/or the effectiveness of ANS
activity are described hereinabove.
[0601] As used herein, the term "about" refers to within
.+-.10%.
[0602] The terms "comprises", "comprising", "includes",
"including", "having" and their conjugates mean: "including but not
limited to".
[0603] The term "consisting of" means: "including and limited
to".
[0604] The term "consisting essentially of" means that the
composition, method or structure may include additional
ingredients, steps and/or parts, but only if the additional
ingredients, steps and/or parts do not materially alter the basic
and novel characteristics of the claimed composition, method or
structure.
[0605] As used herein, the singular form "a", "an" and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0606] The words "example" and "exemplary" are used herein to mean
"serving as an example, instance or illustration". Any embodiment
described as an "example or "exemplary" is not necessarily to be
construed as preferred or advantageous over other embodiments
and/or to exclude the incorporation of features from other
embodiments.
[0607] The word "optionally" is used herein to mean "is provided in
some embodiments and not provided in other embodiments". Any
particular embodiment of the invention may include a plurality of
"optional" features except insofar as such features conflict.
[0608] As used herein the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, techniques and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0609] Throughout this application, various embodiments of this
invention may be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0610] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
[0611] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims.
[0612] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention. To the extent that section headings are used,
they should not be construed as necessarily limiting.
[0613] As used herein, the term "treating" includes abrogating,
substantially inhibiting, slowing or reversing the progression of a
condition, substantially ameliorating clinical or aesthetical
symptoms of a condition or substantially preventing the appearance
of clinical or aesthetical symptoms of a condition.
[0614] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination
or as suitable in any other described embodiment of the invention.
Certain features described in the context of various embodiments
are not to be considered essential features of those embodiments,
unless the embodiment is inoperative without those elements.
* * * * *