US20160220835A1 - Apparatus and methods for diagnosis and treatment of patterns of nervous system activity affecting disease - Google Patents

Apparatus and methods for diagnosis and treatment of patterns of nervous system activity affecting disease Download PDF

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US20160220835A1
US20160220835A1 US14/917,314 US201414917314A US2016220835A1 US 20160220835 A1 US20160220835 A1 US 20160220835A1 US 201414917314 A US201414917314 A US 201414917314A US 2016220835 A1 US2016220835 A1 US 2016220835A1
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activity
ans
pattern
organ
optionally
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Shlomo Ben-Haim
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Tylerton International Inc
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Tylerton International Inc
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Priority claimed from PCT/IL2014/050086 external-priority patent/WO2014115148A1/fr
Priority claimed from PCT/IL2014/050090 external-priority patent/WO2014115152A1/fr
Priority claimed from PCT/IL2014/050246 external-priority patent/WO2014141247A1/fr
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Priority to US14/917,314 priority Critical patent/US20160220835A1/en
Assigned to TYLERTON INTERNATIONAL INC. reassignment TYLERTON INTERNATIONAL INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEN-HAIM, SHLOMO
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/004—Magnetotherapy specially adapted for a specific therapy
    • A61N2/006—Magnetotherapy specially adapted for a specific therapy for magnetic stimulation of nerve tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/506—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of nerves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
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    • G06T7/00—Image analysis
    • G06T7/0002—Inspection of images, e.g. flaw detection
    • G06T7/0012—Biomedical image inspection
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    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
    • G06T7/00—Image analysis
    • G06T7/0002—Inspection of images, e.g. flaw detection
    • G06T7/0012—Biomedical image inspection
    • G06T7/0014—Biomedical image inspection using an image reference approach
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B34/00—Computer-aided surgery; Manipulators or robots specially adapted for use in surgery
    • A61B34/10—Computer-aided planning, simulation or modelling of surgical operations
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06T—IMAGE DATA PROCESSING OR GENERATION, IN GENERAL
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    • G06T2207/10072—Tomographic images
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    • G06T2207/30092—Stomach; Gastric

Definitions

  • 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.
  • 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.
  • 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.
  • a difference between the first and second modes comprises a different homeostatic set point of the physiological parameter.
  • a difference between the first and second modes comprises a different range of available values for the physiological parameter.
  • the adjustment of the modeled pattern is associated with a mode of autonomic modulation of the physiological parameter.
  • the second mode of modulation corresponds to the associated mode.
  • the determined pattern comprises activity measured for a plurality of ANS locations.
  • the determined pattern comprises activity measured in at least one ANS location for a plurality of physiological states.
  • 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.
  • the guiding comprises administering the therapeutic agent at a time selected for its correspondence to the selected adjustment.
  • the guiding comprises administering the therapeutic agent at a dosage chosen for its correspondence to the selected adjustment.
  • the second mode of modulation comprises modulation of the physiological parameter away from a physiological norm, relative to the first mode of modulation.
  • 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.
  • adjusting the determined pattern adjusts the sensitivity of a first non-neural system organ to signaling from a second non-neural system organ.
  • adjusting the determined pattern affects resizing of the cellular bulk of an organ.
  • adjusting the determined pattern comprises reducing ANS activity.
  • adjusting the determined pattern comprises increasing ANS activity.
  • the matching comprises matching ANS neural function activity levels within anatomically defined boundaries.
  • the adjusting comprises balancing ANS neural function activity levels among a plurality of organ regions.
  • At least two of the plurality of organ regions are part of a single organ.
  • At least two of the plurality of organ regions are part of separate organs.
  • 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.
  • the stimulating comprises administering an electrical or electromagnetic pulse.
  • the stimulating comprises manipulating a physiological state.
  • the matching comprises applying an analysis template configured to transform the pattern according to characteristics relevant to the disease.
  • the configuration of the analysis template defines a normalization
  • the configuration of the analysis template defines a mask.
  • a method comprising: measuring autonomic innervation activity associated with a medical condition; and applying the results of the measurement to the medical condition.
  • the measuring comprises determining the distribution of a tracer.
  • the tracer is radioactive, and the determining comprises nuclear imaging.
  • the medical condition is selected from among the group comprising: diabetes, benign prostate hyperplasia, erectile dysfunction, rheumatoid arthritis, and irritable bowel syndrome.
  • the medical condition is selected from among the group comprising: syncope, hypothyroidism, idiopathic heart failure, asthma, deposition disease, IBS, and weight gain.
  • the medical condition is selected from among the group comprising: hyperhidrosis hypertrophic cardiomyopathy obesity, chronic obstructive pulmonary disease, thyrotoxicosis, and hypertension.
  • 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.
  • 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.
  • the autonomic innervation activity is measured from a plurality of ANS locations.
  • the plurality of ANS locations comprise different regions of the same organ.
  • the plurality of ANS locations comprises regions of different organs.
  • At least one of the plurality of ANS locations comprises a ganglion providing autonomic innervation to another of the plurality of ANS locations.
  • At least one of the ANS locations comprises sympathetic innervation, and at least one of the ANS locations comprises parasympathetic innervation.
  • 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.
  • the medical condition is selected from among the group comprising: diabetes, benign prostate hyperplasia, erectile dysfunction, rheumatoid arthritis, and irritable bowel syndrome.
  • the medical condition is selected from among the group comprising: hyperhidrosis hypertrophic cardiomyopathy obesity, chronic obstructive pulmonary disease, thyrotoxicosis, and hypertension.
  • the medical condition is selected from among the group comprising: syncope, hypothyroidism, idiopathic heart failure, asthma, deposition disease, IBS, and weight gain.
  • 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.
  • 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.
  • a method comprising: modeling an activity of the autonomic nervous system; treating a medical condition by guiding a therapeutic agent according to the modeling.
  • the method comprises detecting the medical condition according to the modeling.
  • the medical condition is associated with the autonomic nervous system.
  • the medical condition is associated with hyperactivity of the ANS.
  • the medical condition is associated with hypoactivity of the ANS.
  • the guiding comprises navigating the therapeutic agent according to mapping of a neurotransmitter marker.
  • the modeling comprises imaging one or more organs by using a radiopharmaceutical.
  • the medical condition is one of diabetes, irritable bowel syndrome, hypertension, cardiomyopathy, rheumatoid arthritis, prostatic hyperplasia.
  • the method comprises estimating a level of activity of an organ or a portion of an organ.
  • the level is an absolute level.
  • the method comprises comparing the level to an activity level of another organ.
  • the method comprises estimating a response to ANS activity.
  • the method comprises assessing a stage of the medical condition according to the modeling.
  • the method comprises monitoring treatment according to the modeling.
  • the treating comprises ablating one or more components of the ANS.
  • 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.
  • the imager is a SPECT camera.
  • 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.
  • the characterizing description comprises described locations of autonomic nervous system loci involved in the dysfunction.
  • 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.
  • the method comprises using the characterizing description to select a tissue target for intervention, for treating a disease related to the homeostatic dysfunction.
  • the method comprises guiding an agent to modulate activity of the selected tissue target related to the homeostatic system.
  • the characterizing description identifies an attractor range in the analyzed variation relationship between the activity data and the measurements.
  • the characterizing description identifies a repeller range in the analyzed variation relationship between the activity data and the measurements.
  • the method comprises classification of the characterizing description to a pattern associated with a treatment of a disease involving the dysfunctional homeostasis.
  • the method comprises classification of the characterizing description to a pattern associated with a particular disease state.
  • the autonomic nervous system activity data comprise data taken over a range comprising at least two different activity levels.
  • 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.
  • 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.
  • 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.
  • ADD autonomic nervous system disease decoding
  • 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.
  • the characterization comprises described locations of autonomic nervous system loci involved in the dysfunction.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • FIG. 6 comprises an ANSmap image for a patient with sigmoid septum and cardiomyopathy, according to some exemplary embodiments of the invention
  • FIG. 7 illustrates an exemplary deposition pathway, according to some exemplary embodiments of the invention.
  • 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.
  • ANS components such as ganglia
  • 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.
  • 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.
  • FIG. 11 is a schematic diagram of an autonomic nervous system, to help understand some embodiments of the present invention.
  • FIG. 12 is a schematic flowchart showing the operation of an ANS-disease decoder (ADD), according to some exemplary embodiments of the invention.
  • ADD ANS-disease decoder
  • 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.
  • FIG. 14 is a schematic graph of a mapping between organ/system function and/or state, according to some exemplary embodiments of the invention.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ANS control is sets the moment-to-moment functional state of organ functions.
  • the liver for instance, has multiple metabolic functions under ANS control.
  • gluconeogenesis occurs under conditions set by ANS control.
  • the ANS by increased sympathetic or decreased parasympathetic tone, the ANS induces accelerated gluconeogenesis so that the blood sugar rises.
  • 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).
  • glycogenesis which will drive a reduction in blood sugar and the building of glycogen storage in 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.
  • mismatching can be among organs within an organ system, for example between a denervated liver and a still-innervated pancreas.
  • organs within an organ system
  • 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”).
  • homeostatic parameter a physiological 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.
  • 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.
  • organs The parasympathetic, sympathetic, and other nervous subsystems also constitute relatively distributed systems in this sense.
  • 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.
  • 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).
  • 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.
  • 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.
  • conflicting subsystems created by differential denervation and/or stimulation increase prevent a steady state from being reached.
  • 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.
  • 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).
  • 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.
  • 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.
  • a parameter's set point can oscillate, or “orbit”.
  • a diurnally varying parameter for example, any parameter that changes in relation to the sleep-wake cycle
  • a divergence from the normal pattern of variation is what potentially comprises an observation of a disturbance relating to disease.
  • a disturbance comprises limiting of the normal range of variation to a subrange, which, though normal in itself, comprises an abnormality when over-maintained.
  • 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.
  • the degree and nature of homeostasis disturbance upon denervation 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).
  • 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).
  • tissues for example, organs, cell types, and/or cells associated by a functional commonality
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the same change behavior can be equivalently be said to be “toward” an attractor, or “away” from a repeller.
  • 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.
  • 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.
  • a system's normal attractors and/or repellers are weakened and/or relatively weakened according to changes in innervation, responsiveness, health, or another parameter.
  • 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.
  • the orbit itself may define periods of particular vulnerability.
  • 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.
  • Some exemplary embodiments of the invention relate to identifying compromised innervation of the spleen.
  • compromised innervation induces certain autoimmune disease states and/or cancer types.
  • 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.
  • ANS-induced T cell population lines are potentially induced according to common function.
  • 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.
  • Another example relating to the immune system relates to patients with rheumatoid arthritis patients.
  • selective denervation such as partial denervation
  • Total splenic denervation 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.
  • ANS activity in a patient with severe rheumatoid arthritis is imaged, for example according to a method mentioned and/or described herein.
  • 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.
  • 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.
  • means to compare an observed pattern of ANS innervation to one or more normal and/or diseased state pattern templates are provided.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the model or pattern is based on an activity map of the autonomic nervous system (ANSmap).
  • 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.
  • the determined treatment is suggested to an operator.
  • 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).
  • 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.
  • determination comprises matching the results of the comparison to one or more treatment options available to the system.
  • available treatment tools are taken into consideration when determining the treatment.
  • 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.
  • information relating to nervous system activity is acquired in relationship to a particular physiological and/or signaling state.
  • 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.
  • a signaling state is artificially induced, for example, by exogenously stimulating a nerve, GP, or portion thereof.
  • a finer mapping of connections between a nerve or GP and an innervation target is obtained by artificial stimulation.
  • this mapping is used in diagnosis, treatment planning and/or carrying out treatment.
  • treatments guided by ANS mapping are tailored to the particular timing requirements of control system dysfunction.
  • 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.
  • treatment guidance by an ANSmap comprises determining a dose and/or timing of a treatment, such as drug administration.
  • 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.
  • the conditions are chosen to relate to the particulars of a disease—for example, glucose level, cardiovascular stress, and/or stimuli relating to tumescence.
  • ANS mapping comprises determining a contrast in activity levels between or among a plurality of conditions.
  • 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.
  • 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.
  • 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.
  • the ANSmap is a non-invasive ANSmap (niANSmap).
  • 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.
  • 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.
  • 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.
  • 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.
  • the representation includes location indications, for example, an anatomical location, body coordinates and/or a functional location.
  • location indications for example, an anatomical location, body coordinates and/or a functional location.
  • 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.
  • dynamic data may be provided as a table or function or time linked data. In other cases, dynamic data may be provided as statistics.
  • 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).
  • the medium may include indications of relevant input sources to the ganglion structure, for example, body function and blood hormone levels.
  • the medium stores data relating to ANS innervation and/or activity in target organ/systems.
  • data is provided as location indications, size/shape indications and/or static and/or dynamic data regarding activity in such locations.
  • ANSmap 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:
  • 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.
  • the human body has several control systems, including the hormonal system, the central nervous system and the autonomic nervous system (ANS).
  • 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.
  • the portion of the autonomic nervous system which relates to digestion is termed the enteric nervous system (ENS).
  • identified features of a control map form a basis for further determinations.
  • further determinations optionally comprise a diagnosis of the pathology.
  • 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.
  • 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.
  • 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.
  • control is substantially impaired, in order to remove the possibility of a particularly harmful state of mal-control being entered.
  • the determination is based on a prior diagnosis determination based on features of the control map.
  • a further example relating to the immune system relates to patients with cancer.
  • 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 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.
  • 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.
  • FIG. 3 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.
  • 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.
  • insulin release and also thus, or through another pathway, blood glucose
  • the sympathetic ANS stimulates glucose release
  • the parasympathetic ANS stimulates glucose storage.
  • a normal liver is connected to the ANS via different parts of the celiac ganglia (sympathetic ANS), and of the vagus nerve (parasympathetic ANS).
  • 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.
  • 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.
  • a treatment is aimed at adjusting a control system to prevent extreme swings, potentially at the expense of sacrificing optimal baseline control.
  • 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:
  • 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.
  • 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.
  • 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.
  • a specific organ contains the sensory apparatus which reports a parameter via the ANS.
  • 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.
  • this is a locus of control to which a diabetes treatment is directed in some patients.
  • the region of interest will be ganglia transmitting the afferent signal of these fat duodenal receptors.
  • diabetes 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.
  • information is collected from beyond the abdomen.
  • CNS central nervous system
  • an image includes a structure such as the hypothalamus.
  • 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.
  • activity imaging of block 310 is synchronized with respect to functional and/or control loads on a homeostatic organ system.
  • imaging is after a predefined period of fasting, and/or within one or more predetermined periods after eating.
  • 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.
  • the subject has fasted to the point that activation of glucose release is required.
  • images are taken while the digestive system is managing an incoming glucose load which requires a significant increase in glucose uptake activity.
  • images are taken while the digestive system is in an undershoot mode, where blood sugar is low.
  • imaging is of the ANS effects of administered insulin, epinephrine, or another hormone related to blood glucose regulation.
  • 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.
  • one or more masks are applied, appropriate to the condition being evaluated.
  • one or more masks are determined based on conditions such as those described in relation to 310 , above.
  • one or more patient-specific masks of glucose-regulatory ANS activity are generated based on imaging under different activating conditions.
  • the conditions chosen for mask generation are relatively extreme, to acquire good differentiation of masking.
  • 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.
  • any of the parameters is normalized.
  • normalization is performed among images taken at different regulatory states, for example, as described in relation to block 310 , hereinabove.
  • 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.
  • 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.
  • 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.
  • one or more activity parameters comprises anatomical and/or other data, for example as part of normalization.
  • a plan for treatment is formulated, for example in light of the mapped ANS activity evaluated at block 316 .
  • 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.
  • the plan is formulated according to matching of one or more disease-treatment templates, for example as described hereinbelow.
  • a plan for treatment of diabetes, and/or a pre-diabetic condition is optionally developed based upon specific findings from the ANS imaging.
  • 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:
  • 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.
  • 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.
  • criteria of other models/patterns are examined to rule out alternative explanations of a particular ANSmap finding.
  • a plan is made to at least partially ablate the over-active sympathetic innervation of the liver, with the goal of reducing glucose release.
  • Ablation comprises, for example, whole or partial thermoablation, cryoablation, drug injection, anesthesia, or another intervention which reduces ANS activity.
  • 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.
  • 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.
  • criteria of other models/patterns are examined to rule out alternative explanations of a particular ANSmap finding.
  • a plan is made to at least partially ablate the over-active sympathetic innervation of the pancreas, with the goal of increasing insulin production.
  • Ablation comprises, for example, whole or partial thermoablation, cryoablation, drug injection, anesthesia, or another intervention which reduces ANS activity.
  • both of the above scenarios relate to over-active innervation from a portion of the celiac ganglia.
  • 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.
  • 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.
  • the finding of over-activity is in another parasympathetic pathway involved in the ANS innervation of the liver or pancreas.
  • a determination of the meaning of a particular level of activity is referenced to a measured level of blood insulin concentration.
  • 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.
  • therapy results are monitored.
  • 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.
  • 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.
  • LUTS lower urinary tract symptoms
  • One role of sympathetic innervation is control of prostatic musculature (for example, via alpha 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.
  • drugs which block alpha 1 receptors are used effectively to improve urine flow in patients with BPH. Such drugs include terazosin, doxazosin, alfuzosin, tamsulosin, and/or prazosin.
  • 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.
  • ANS stimulation by a selectively placed electrode 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.
  • a GP or nerve contains a partial somatotopic map its innervation target.
  • 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.
  • 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.
  • overactive cholinergic innervation of the bladder provides a suggestion that anticholinergic medication is indicated.
  • a dosage is determined based on the degree of over-activity which is imaged.
  • effects of drug treatment 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).
  • 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.
  • 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.
  • 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.
  • sympathetic and/or parasympathetic innervation of the bladder 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.
  • ablation or blockage is performed to achieve a temporary reduction of symptoms.
  • ablation is partial, leaving sufficient pathways for axonal regrowth that regeneration of the system occurs over a period of time (months) following treatment.
  • 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).
  • CNS/somatic PNS nervous control exercised over erectile function, both to increase and decrease tumescence.
  • Some CNS/somatic subsystems receive ANS input.
  • the spinal cord cells of Onuf's nucleus are anatomically linked with the sacral parasympathetic motorneurons.
  • Sensory stimulation leads to signaling from peripheral nerves to the lower spinal cord, potentially resulting in increased parasympathetic activity.
  • activity imaging 210 is synchronized with respect to functional loads on a homeostatic organ system related to erectile function.
  • 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.
  • erectile function testing is accompanied by use of a drug having an effect on erection, for example, sildenafil, tadalafil, vardenafil, or another drug.
  • tumescence and/or detumescence is controlled by electrical or magnetic stimulation, for example, transcutaneous and/or percutaneously.
  • 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.
  • 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.
  • a plan for treatment is formulated, for example in light of the ANS activity parameters evaluated at block 216 .
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • the stimulation comprises transcutaneous electrical nerve stimulation (TENS).
  • a percutaneous stimulating device is used.
  • the stimulation apparatus is applied and/or used within a defined period, for example, a period of planned sexual activity.
  • 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.
  • 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).
  • 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.
  • 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.
  • the stimulation comprises partial ablation, for example, by heat, cooling, and/or chemical injection.
  • another form of nerve block is applied.
  • sympathetic nerve block is applied transiently, for example, preceding and/or within a period of planned sexual activity.
  • 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).
  • 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.
  • 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.
  • 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.
  • therapy results are monitored.
  • 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.
  • 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.
  • a decision is made as to whether or not a treatment intervention has reached a sufficient level of success to terminate therapy.
  • 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 .
  • 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.
  • RA is a disease of the immune system which leads to effects such as chronic inflammatory response of the joints.
  • another organ is affected, such as the lungs, pleura, pericardium, sclera, kidney, and/or heart.
  • insufficient inhibition of inflammatory responses by the parasympathetic system potentially allows RA inflammatory responses to go unchecked.
  • redistribution of sympathetic innervation leads to RA inflammation.
  • partial ablation of splenic innervation may stimulate regrowth which does not reform the original innervation pattern.
  • one or more regions become overstimulated, while a denervated region remains understimulated.
  • 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.
  • 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.
  • activity region and/or anatomical images associated with one or more joints affected by RA is obtained.
  • 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.
  • the control system of T cell maturation in the spleen is mediated via ganglia in the celiac plexus.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a plan for treatment is formulated, for example in light of the ANS activity parameters evaluated at block 416 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • therapy results are monitored.
  • 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.
  • 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.
  • a decision is made as to whether or not a treatment intervention has reached a sufficient level of success to terminate therapy.
  • 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 .
  • IBS The cause of IBS is unknown, and diagnosis is potentially a matter of ruling out other illnesses.
  • IBS is related to stress.
  • IBS symptoms are associated with the sympathetic nervous system firing constantly, for example due to injury of the meninges.
  • 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.
  • SPECT single photon emission computed tomography
  • an anatomical imaging of the abdomen is acquired at block 432
  • the images are co-registered at block 434 , for example as described in relation to FIG. 8 , hereinbelow.
  • 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.
  • 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.
  • 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.
  • 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.
  • a plan for treatment is formulated, for example in light of the ANS activity parameters evaluated at block 436 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • therapy results are monitored.
  • 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.
  • 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.
  • a decision is made as to whether or not a treatment intervention has reached a sufficient level of success to terminate therapy.
  • 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 .
  • the invention is applied to a condition associated with hyperactivity of the ANS.
  • 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.
  • T lymphocytes Induced, for example, when stress in any form triggers an exacerbation of an autoimmune attack.
  • activation of T lymphocytes relates to overstimulation of the sympathetic system.
  • the release of interferon, interleukins and/or certain cytokines is affected by ANS.
  • 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.
  • IBD Irritable Bowel Disease
  • IBD IBD
  • ANS input to the GI tract is well known.
  • symptoms of IBD and IBS can be elicited by changes in ANS function.
  • gastrointestinal motility and/or intestinal absorption are functions potentially affected by ANS activity.
  • 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.
  • Control of blood pressure potentially relates to ANS activity.
  • ANS mapping is used to identify cases of hypertension where over-activity of the ANS is a cause of hypertension.
  • ANS mapping is used to depict the ANS reaction to elevated blood pressure caused by another reason, for example, iatrogenic volume overload.
  • 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.
  • hypertrophy is caused by overstimulation of an organ by the ANS.
  • 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.
  • FIG. 6 comprises an ANSmap image 500 for a patient with sigmoid septum and cardiomyopathy, according to some exemplary embodiments of the invention.
  • the ANSmap clearly identifies increased sympathetic activity in the intra-ventricular septum 504 , compared to the adjacent tissue of the heart wall 502 .
  • 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.
  • 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.
  • a compound for example, a mis-folded protein
  • FIG. 7 illustrates an exemplary deposition pathway 600 , according to some exemplary embodiments of the invention.
  • 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.
  • compound C is resistant to degradation and/or elimination, potentially giving rise to accumulation in the body leading to a disease state.
  • 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.
  • the enzymatic reactions leading to production of molecule C is under at least partial regulation by the ANS.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • deposition diseases for example, increased or decreased ANS tone is associated with a defined region of innervated tissue.
  • this causes a local deposition or a local depletion of a substance at said defined region.
  • 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).
  • impairment of the ANS and/or of the tissue innervated takes a form which potentially ranges from the well-localized, to more global.
  • the site of symptoms is remote from a site of control and/or innervation which is subject to imbalance and/or derangement of function.
  • 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.
  • the ANSmap is used to diagnose a level of the causative mechanism of hyperhidrosis, and/or as a road map for guiding therapy.
  • 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.
  • some ANS disorders relate to the sources of the ANS system (brain nuclei), while some relate to the pathway or to the ganglia.
  • the functioning of end-organ synapses of the ANS is critical for the ANS control function.
  • 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 measures the response function of the ANS.
  • the total function of the ANS for example from the origin to the response of the function unit is assessed.
  • the map is positive.
  • the end-organ response is diagnosed by the mapping.
  • weight gain may follow blockade of the sympathetic nervous system input to the tissue.
  • COPD Chronic Obstructive Pulmonary Disease
  • 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.
  • detecting the ANS status assists in diagnosing and/or treating the patient.
  • 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.
  • 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.
  • 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.
  • ANS mapping may modify this field, for example by enabling the operator to navigate on top of a function (neurotransmitter marker) road map.
  • the operator can achieve safe, accurate, highly reproducible treatment of any target by tracking specific neuro-activity.
  • the operator will be able to monitor the success of his therapy.
  • the safety and/or efficacy of these conditions may improve.
  • the ANSmap may be used for one or more of the following examples:
  • Such therapies can include:
  • 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.
  • the treatment can be modified accordingly, for example by disconnecting, pacing and/or stimulating the modulation.
  • 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.
  • 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.
  • the data and/or images comprise, for example, a D-SPECT image and/or other images.
  • Received images 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.
  • nerve tissue comprises GPs of the heart, intestines and/or another organ.
  • 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.
  • a two tracers are used; for example, first tracer such as mIBG to label activity, and a second tracer to image tissue vitality.
  • functional data is collected from a body part that has regions where nerve activity is expected, and regions where nerve activity is not expected.
  • 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.
  • noise is received from areas corresponding to the inside of the heart chamber, though no true activity is expected.
  • the noise is removed from the functional data based on the corresponding anatomical image; for example, after image registration.
  • intensity denoting noise within blood- or other fluid-filled chambers and/or vessels is removed.
  • 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.
  • fluid-filled chamber noise is used in obtaining a noise estimate applicable to other tissue locations.
  • 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).
  • the quality of surrogate measures of the autonomic nervous system is potentially lower than that of direct measures of autonomic nervous system activity.
  • surrogate measures of the autonomic nervous system preferably have certain qualities to qualify as useful in some embodiments of this invention.
  • a measure preferably conveys site specificity, and has the ability to generate a valid signal through a dynamic range of health and disease.
  • an anatomical region is extracted from the image.
  • tissue image regions are segmented from hollow spaces (non-innervated, but potentially containing fluid).
  • the wall of the left ventricle (LV) and/or the hollow space within the LV is extracted.
  • 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.
  • the walls of the renal artery are extracted and/or the inside of the artery is extracted.
  • dominant portions of the organ are optionally selected.
  • 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.
  • 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.
  • 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.
  • anatomical data is received that is not personalized to the patient, for example, from a general anatomical model.
  • anatomical data from an anatomical imaging modality is received to reconstruct an anatomical image of a region of a body of a patient.
  • the region comprises a portion of at least one internal body part which borders on a target nerve tissue.
  • the anatomical images and the functional images denote corresponding regions of the body containing the GPs for identification and/or localization.
  • 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.
  • images corresponding to different times during a dynamic cycle are optionally extracted and/or acquired.
  • 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).
  • EDV end diastolic volume
  • ESV end systolic volume
  • images are optionally extracted corresponding to a full bladder and an emptying bladder.
  • the average image is computed, for example, as (EDV+ESV)/2.
  • one or more images are segmented. Segmentation, in some embodiments, is fully automatic. In some embodiments, segmentation requires or potentially involves manual user intervention.
  • an anatomical region is extracted.
  • the anatomical region corresponds to the anatomical region extracted at block 354 .
  • the anatomical region is extracted from the segmented image of block 362 .
  • 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.
  • 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.
  • registration takes into account organ dynamics, for example, heart movement.
  • organ dynamics for example, heart movement.
  • anatomical images during the dynamic cycle are registered, and/or functional data are corrected for the dynamic movement.
  • intensity readings within the heart chamber are corrected to association with nearby moving heart wall.
  • image masks are generated based on the anatomical image and/or data.
  • 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.
  • 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.
  • a dimension of an internal body part of the specific patient is calculated and used to define the mask.
  • the image masks are selected and/or defined for tissue surrounding a hollow chamber.
  • image masks are defined based on:
  • image masks include tissue surrounding the organ of interest.
  • the image masks are defined, for example, based on:
  • 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.
  • image masks are generated for fat pads.
  • 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.
  • 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.
  • 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.
  • image masks are generated based on an estimated location of the GPs.
  • 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.
  • 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.
  • generated image masks correspond to the segments of the anatomical image.
  • the heart is segmented into chamber walls and the generated image masks correspond to the chamber walls of interest.
  • the image masks are applied to the functional image.
  • the image masks are applied to the functional data.
  • the image masks are applied to combined functional and anatomical images and/or data, for example, overlaid images.
  • 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.
  • the generated image mask is correlated with the functional data for guiding the reconstruction of a functional image depicting the target nerve tissue.
  • functional activity is calculated within the applied image mask space.
  • the average functional activity is calculated.
  • the standard deviation of the functional activity is calculated.
  • 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.
  • average activity and/or standard deviation may be calculated for the entire functional image or data.
  • 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.
  • GPs are identified within the applied image mask space.
  • 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.
  • GPs are identified within the organ volume and/or nearby tissues.
  • 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.
  • 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.
  • areas of extreme activity are identified.
  • EGP epicardial GPs
  • MGP myocardial GPs
  • GPs are identified based on one or more predefined thresholds and/or rules.
  • GPs are identified based on size.
  • GPs are identified based on activity level in reference to average activity and/or surrounding activity.
  • GPs are identified based on connectivity between GPs.
  • the GP is identified as an object within a particular size constraint.
  • the constraint is, for example, at least about 4 ⁇ 4 ⁇ 4 mm, such as for an EGP; or about 2 ⁇ 2 ⁇ 2 mm, such as for an MGP.
  • the GP is identified by comparing calculated activity (image intensity) of a certain region to surrounding activity in the same image mask.
  • the GP is identified by comparing calculated activity within the image mask to activity in another image mask.
  • 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.
  • activity is corrected for volume.
  • the user selects and/or modifies the predefined factor.
  • 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.
  • the user selects and/or modifies the predefined factor.
  • identification of GPs is performed per frame, optionally per frame of the dynamic cycle (e.g., cardiac cycle).
  • the identified GP is automatically related to a tissue type.
  • the identified GP is related to the tissue type based on the applied image mask.
  • 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.
  • 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.
  • one or more parameters are calculated for the identified GPs (also referred to herein as GP parameters). Examples of parameters include:
  • EGP size EGP size
  • EGP specific activity EPG power spectra graph
  • EGP normalized power spectra EGP normalized power spectra
  • 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.
  • calculation of GP parameters is performed per frame, optionally per frame of the dynamic cycle (e.g., cardiac cycle).
  • 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.
  • normalization is performed instead of and/or in addition to the normalization of block 382 before a different block in the process.
  • 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.
  • the calculated data (e.g., blocks 374 , 378 , 380 ) and/or measured functional intensity are corrected for sensitivity.
  • 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.
  • the anatomical data is correlated to the sensitivity.
  • 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.
  • the different sensitivities are normalized to a common baseline.
  • measurements of the functional data are normalized.
  • measurements of uptake of the radioagent are normalized to the level of corresponding chemical in the patient.
  • intensity measurements are normalized according to the level of activity of GP being identified.
  • measurements denoting activity of the GPs are taken.
  • measurements are optionally normalized to the level of norepinephrine (NE), adrenaline and/or epinephrine in the patient.
  • 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.
  • measurements of functional data are normalized to a level of one or more electrical properties.
  • 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.
  • 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.
  • data is compared over time.
  • changes in GP parameters over time are identified.
  • dynamic changes of the calculated parameters between different acquisition times are determined.
  • 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.
  • 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.
  • the characteristics of the GPs within the functional image are reconstructed.
  • the reconstruction is instructed by the image mask.
  • results are provided for presentation on a certain frame, for example, the end systolic frame.
  • results are provided for presentation on multiple frames, for example, a video of the cardiac cycle.
  • FIG. 9 is a block diagram of a model ANS modeling system/unit 1006 , in accordance with some exemplary embodiments of the invention.
  • ANS module 1006 receives functional images and/or imaging data 1012 A (for example, as produced by functional imaging modality 1008 A); and anatomical images and/or imaging data 1012 B (for example, as produced by anatomical imaging modality 1008 B).
  • Groups of elements comprising a system/unit 1000 include, for example, blocks within the boundaries delineating system configurations 1000 A, 1000 B, 1000 C, 1000 D, and/or another system configuration comprising blocks of FIG. 10 .
  • unit 1000 carries out functions of various model analyses described herein, for example, in relation to FIG. 9 .
  • unit 1000 includes analysis/modeling subsystem 1006 , as in configuration 1000 C.
  • 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 1000 D).
  • images and imaging data 1012 are received by the system/unit 1000 .
  • images and imaging data 1012 are generated by the system/unit 1000 .
  • imaging subsystems 1008 include an imaging modality described in relation to FIG. 9 , for example, a functioning imaging modality 1008 A, and/or an anatomical imaging modality 1008 B.
  • unit 1000 (for example, configurations 1000 A and/or 1000 B) is remotely located relative to other subsystems, and/or is distributed.
  • subsystem 1000 A the functions of, for example, subsystem 1000 A are provided as a service.
  • 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.
  • 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.
  • diagnosis subsystem 1002 includes one or more modules which apply processing on the model to extract diagnose.
  • diagnosis database 1024 is updatable and/or parts thereof are available at different and/or additional cost.
  • the output of diagnosis system 1002 is a personalized diagnosis 1030 .
  • 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.
  • 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.
  • 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.
  • model information 1020 and/or patient information 1022 also serve as input for the treatment planning.
  • the information 1020 , 1022 is used to help determine what effect a treatment may have on a patient.
  • the result is a treatment plan 1032 .
  • 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.
  • the plan 1032 includes a time line indicating the order of treatment and/or delay times between treatment locations.
  • 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.
  • 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.
  • FIG. 12 is a schematic flowchart 1200 showing the operation of an ANS-disease decoder (ADD), according to some exemplary embodiments of the invention.
  • ADD ANS-disease decoder
  • ANS measurements are provided, acquired, for example, according to a method described in relation to FIGS. 1-5 and/or FIG. 8 .
  • measurements are provided as a pattern of activations.
  • measurements are entered into a model description of the ANS from which they were obtained.
  • ANS measurements correspond, for example, to model information 1020 .
  • the ADD receives information from earlier in the processing chain of FIG. 10 , for example, original images and/or imaging data.
  • the output is provided.
  • the output comprises a diagnosis of one or more potentially pathological modes of interaction between the organ and/or organ system and the ANS.
  • the output comprises one or more treatment options.
  • ANS measurements and organ (and/or system) measurements are brought into a mapped relationship.
  • 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).
  • 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)”).
  • ANS state can be represented by the level of activity of a single ganglion.
  • ANS state in some embodiments, comprises a multidimensional function of 2, 3, 4 or more different ANS measurements.
  • 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.
  • the graph 1400 represents a hysteresis-free relationship between the organ/system function/state and the ANS state.
  • 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.
  • ANS activity may rise or fall as a trough bottom is approached; similarly, organ/system state/function measurement can rise or fall.
  • organ/system state/function measurement can rise or fall.
  • 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 1405 A, 1405 B), which block movement to a preferred state and/or strengthen the “attractiveness” of a non-preferred state.
  • 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.
  • At least one peak and valley exist between regions of monotony 1415 A and 1415 B, based on the relaxation behavior and/or relative driven responses measured there.
  • FIG. 15 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.
  • 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 .
  • 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 .
  • a pressor agent such as prostacyclin
  • 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.
  • Blood pressure information and information representing activity levels of ANS ganglion loci 1502 A, 1502 B are brought together in the ADD.
  • sympathetic activity levels in the innervation to the arteries 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.
  • 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.
  • FIG. 16 is a partial schematic flowchart 1600 of operations performed by an ADD 1210 to convert received function data 1601 , 1601 A, 1601 B into determination of an intervention, according to some exemplary embodiments of the invention.
  • 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 .
  • data 1601 comprises, for example, ANS measurements 1202 and organ/system measurements 1204 .
  • identification of attractors/repellers is performed, for example, according to operations described in relation to FIG. 13 .
  • interventions are identified.
  • identification of interventions comprises pattern recognition, where a recognized pattern is mapped to one or more previously determined treatment options.
  • 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.
  • 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.
  • 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.
  • sequence map ANS activity in response to two or more different types of manipulations.
  • 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.
  • additional tests are performed based on to expand the range of data available on which to make a treatment decision.
  • 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.
  • FIG. 17 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.
  • 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.
  • a strategy is selected for intervention.
  • 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.
  • the strategy is determined by the ADD, according to a list, match, model or other method of treatment specification.
  • 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 .
  • 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.
  • the drug is supplied in a targeted fashion, for example, by means of an eluting implant.
  • afferent input is supplied by means of an electrical and/or electromagnetic stimulation device.
  • the device is implanted.
  • the device operates transcutaneously.
  • 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.
  • an overactive pathway is directly ablated in order to reduce overactivity.
  • a negative intervention comprises full or partial ablation of a pathway which inhibits underactive innervation.
  • interventions affecting ANS activity levels and/or the effectiveness of ANS activity are described hereinabove.
  • the term “about” refers to within ⁇ 10%.
  • 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.
  • 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.
  • 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.
  • 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.

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