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WO2024187242A1 - Procédé et système de neuromodulation - Google Patents

Procédé et système de neuromodulation Download PDF

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Publication number
WO2024187242A1
WO2024187242A1 PCT/AU2024/050231 AU2024050231W WO2024187242A1 WO 2024187242 A1 WO2024187242 A1 WO 2024187242A1 AU 2024050231 W AU2024050231 W AU 2024050231W WO 2024187242 A1 WO2024187242 A1 WO 2024187242A1
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WIPO (PCT)
Prior art keywords
electrodes
nerve
pair
stimulation signal
blocking
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PCT/AU2024/050231
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English (en)
Inventor
Joel Villalobos
James Bernard Fallon
Sophie Clementine MORGAN
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Bionics Institute
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Bionics Institute of Australia
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Publication date
Priority claimed from AU2023900698A external-priority patent/AU2023900698A0/en
Application filed by Bionics Institute of Australia filed Critical Bionics Institute of Australia
Publication of WO2024187242A1 publication Critical patent/WO2024187242A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/294—Bioelectric electrodes therefor specially adapted for particular uses for nerve conduction study [NCS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/388—Nerve conduction study, e.g. detecting action potential of peripheral nerves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4029—Detecting, measuring or recording for evaluating the nervous system for evaluating the peripheral nervous systems
    • A61B5/4041—Evaluating nerves condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
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    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0551—Spinal or peripheral nerve electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0551—Spinal or peripheral nerve electrodes
    • A61N1/0556—Cuff electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/3615—Intensity
    • A61N1/36157—Current
    • A—HUMAN NECESSITIES
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    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36171—Frequency
    • A—HUMAN NECESSITIES
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    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36175—Pulse width or duty cycle
    • A—HUMAN NECESSITIES
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    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36178—Burst or pulse train parameters
    • A—HUMAN NECESSITIES
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    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36053—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for vagal stimulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36062—Spinal stimulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36071—Pain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36135—Control systems using physiological parameters
    • A61N1/36139—Control systems using physiological parameters with automatic adjustment

Definitions

  • the present disclosure relates to application of electrical signals to the peripheral nervous system, and particularly to electrical stimulation of a nerve for modulation of activity of the nerve.
  • Neuromodulation is the purposeful modulation of activity in a subject’s nervous system and may include stimulating one or more nerves to affect the activity of that nerve. Modulation of nerve activity may be useful for the treatment of disease.
  • Neuromodulation may in some cases involve the application of activating stimulation configmed to upregulate activity and/or evoke a neural response in one or more nerves.
  • Neuromodulation may in some cases involve the application of blocking stimulation configured to downregulate activity in one or more nerves.
  • activating stimulation may be applied to a nerve in combination with blocking stimulation applied to the nerve.
  • the blocking stimulation may be configured to inhibit transmission of an evoked neural response along the nerve past a blocking location, to produce unidirectional stimulation of the nerve.
  • aspects of the present disclosure provide a method for modulating activity in a nerve.
  • the method comprises applying at least one blocking stimulation signal to a nerve at a blocking location.
  • a method for modulating activity in a nerve comprising: applying a blocking stimulation signal at a blocking location at the nerve, wherein the blocking stimulation signal comprises a biphasic pulsatile electrical signal having a frequency of between about 100 Hz to about 40 kHz and a steady state duty cycle of greater than about 75% and less than 100%.
  • the blocking stimulation signal may be configured to inhibit transmission of an evoked neural response along the nerve past the blocking location.
  • An evoked neural response may be understood to be an evoked compound action potential (ECAP) in the nerve.
  • ECAP evoked compound action potential
  • the term evoked compound action potential (ECAP) should be understood to refer to activation of a group of nerve fibres but does not necessarily require activation of the whole nerve.
  • the blocking stimulation signal may be configured to inhibit transmission in one of these directions, such that the evoked neural response transmits (or travels) along the nerve substantially in one direction (i.e. unidirectionally) only.
  • unidirectional stimulation may be provided to the nerve and configured to be substantially afferent nerve stimulation or substantially efferent nerve stimulation.
  • the blocking stimulation signal may comprise a duty cycle of greater than about 80%, greater than about 85%, greater than about 90%, or greater than about 95%.
  • the blocking stimulation signal may comprise at least one pulse phase.
  • the at least one pulse phase may have a pulse width of up to about 25 ps.
  • the at least one pulse phase may comprise a pulse width of greater than about 25 ps, greater than about 50 ps, greater than about 100 ps, greater than about 200 ps, greater than about 300 ps, greater than about 400 ps, greater than about 500 ps, or greater than about 600 ps.
  • the blocking stimulation signal may comprise a frequency of less than 40 kHz, such as less than or equal to about 26 kHz.
  • the blocking stimulation signal may comprise a frequency of less than about 40 kHz, less than about 30 kHz, less than about 26 kHz, less than about 20kHz, less than about 10 kHz, less than about 4 kHz, less than about 3 kHz, or less than about 2 kHz.
  • the blocking stimulation signal may comprise a frequency of between about 500 Hz and about 1 kHz, between about 1 kHz and about 2 kHz, between about 2 kHz and about 3 kHz, or between about 3 kHz and about 4 kHz.
  • the blocking stimulation signal may comprise a frequency of between about 500 Hz and about 2 kHz, between about 500 Hz and about 3 kHz, or between about 500 Hz and about 4 kHz.
  • the blocking stimulation signal may comprise a frequency of between about 1 kHz and about 2 kHz, between about 1 kHz and about 3 kHz, or between about 1 kHz and about 4 kHz.
  • the blocking stimulation signal may comprise a pulse amplitude of between about 1 mA and about 50 mA, between about 1mA and about 40 mA, between about 1mA and about 30mA, between about 2 mA and about 30 mA.
  • the blocking stimulation signal may comprise a pulse amplitude of between about 10 mA and about 50 mA, between about 20 mA and about 40 mA, or between about 20 mA and about 30 mA.
  • the signal may comprise a pulse amplitude of about 1 mA, about 2 mA, about 3 mA, about 4 mA, about 5 mA, about 10 mA, about 20 mA, about 30 mA, about 40 mA or about 50 mA.
  • the method may comprise applying a plurality of blocking stimulation signals at a corresponding plurality of blocking locations at the nerve. Each blocking stimulation signal may be configured to inhibit transmission of an evoked neural response along the nerve past the respective blocking location, to produce unidirectional nerve stimulation.
  • the blocking stimulation may be applied at one or more nerves.
  • the one or more nerves may include one or more different nerve fibre types.
  • the different fibre types may transmit signals at different speeds.
  • the blocking stimulation may be applied at one or more myelinated nerve fibres and/or at one or more unmyelinated nerve fibres.
  • the one or more nerves may include one or more nerves of the somatic nervous system and/or one or more nerves of the autonomic nervous system.
  • the blocking stimulation may be applied at a vagus nerve, a pelvic nerve and/or a sciatic nerve.
  • the blocking stimulation may be applied at one or more spinal (i.e., somatic) nerves, including but not limited to: a femoral nerve, a tibial nerve, a common peroneal nerve, a median nerve, an ulnar nerve and/or a radial nerve.
  • the blocking stimulation may be applied at one or more autonomic nerves, including but not limited to: an abdominal vagus nerve, a gastric vagal nerve branch, a celiac vagus nerve branch, a hepatic vagus nerve, a cervical vagus nerve, a pelvic nerve, a splanchnic nerve, a carotid sinus nerve, a pancreatic nerve, and/or a hypogastric nerve.
  • autonomic nerves including but not limited to: an abdominal vagus nerve, a gastric vagal nerve branch, a celiac vagus nerve branch, a hepatic vagus nerve, a cervical vagus nerve, a pelvic nerve, a splanchnic nerve, a carotid sinus nerve, a pancreatic nerve, and/or a hypogastric nerve.
  • the method may further comprise: applying an activating stimulation signal at an activating location at the nerve, the activating stimulation signal configured to evoke a neural response in the nerve, wherein the blocking stimulation signal is configmed to inhibit transmission of the evoked neural response along the nerve past the blocking location, to produce substantially unidirectional nerve stimulation.
  • the activating stimulation signal may have a frequency selected for activation of nerve fibres, including different types of nerve fibres.
  • the activating stimulation signal may have a frequency of between about 1 Hz to about 50 Hz, between about 50 Hz to about 100 Hz, between about 50 Hz to about 200 Hz, between about 100 Hz to about 200 Hz, or otherwise.
  • the frequency of the activating stimulation signal may be about at least 50 Hz, about at least 60 Hz, about at least 70Hz, about at least 80Hz, about at least 90 Hz, about at least 100 Hz, about at least 120Hz, about at least 150 Hz, about at least 160 Hz, about at least 170 Hz, about at least 180 Hz, about at least 190 Hz, or about at least 200 Hz.
  • the frequency of the activating stimulation signal may be configured to produce nerve stimulation effective to modulate one or more physiological parameters in the patient.
  • the activating stimulation signal may have an amplitude configured to evoke a neural response in the nerve.
  • the activating stimulation signal amplitude may be above a minimum threshold amplitude at which a compound action potential response is evoked in the nerve (suprathreshold).
  • the activating stimulation signal amplitude may be below a maximum amplitude above which transmission of the evoked neural response is no longer effectively inhibited by the blocking stimulation signal, as discussed in further detail below.
  • the amplitude of the activating stimulation signal may be configured to be within a therapeutic window defined between the minimum amplitude and maximum amplitude.
  • the activating stimulation signal may be configured to have an amplitude in the lower half of the therapeutic window.
  • the amplitude of the activating stimulation signal may be configured to be within a predetermined range above, or at a predetermined level above, the minimum threshold amplitude.
  • the amplitude of the activating stimulation signal may be configured independent of any determination of the maximum threshold amplitude, for example. This may be advantageous if it is difficult to identify a maximum threshold amplitude (e.g. due to any noise effects associated with stimulation or otherwise).
  • the amplitude of the activating stimulation signal may be configured to be within a predetermined range of about 0 to about 6 dB, about 0 to about 5 dB, about 0.5 dB to about 4.5 dB, about 0.5 to about 4 dB, about 0.5 to about 3.5 dB, about 0.5 dB to about 3 dB, about IdB to about 6 dB, about 1 dB to about 5 dB, about 1 dB to about 4.5 dB, about 1 dB to about 4 dB, about 1 dB to about 3.5 dB, or about 1 to about 3 dB, and/or at a predetermined level of about 1.5 dB, about 2 dB, about 2.5 dB, about 3 dB, about 3.5 dB, about 4 dB, about 4.5 dB, about 5 dB, about 5.5 dB, or about 6 dB above the minimum threshold amplitude, for example.
  • the method may comprise estimating an optimal dose of the activating stimulation signal.
  • the optimal dose may include an optimal combination of amplitude and/or rate or duration of the activating stimulation signal.
  • the estimated optimal dose may be confirmed, for example, through receiving experimental data related to one or more physiological parameters of the patient (such as oral glucose tolerance test data carried out on the patient) under no activating stimulation and then under activating stimulation at the estimated optimal dose.
  • the activating stimulation signal with the estimated or confirmed optimal dose may be applied to the nerve, and may have an amplitude within the therapeutic window, within the predetermined range, or at the predetermined level as discussed above.
  • the minimum and/or maximum threshold amplitudes may be determined based on an average of the respective threshold determined from a patient over an initial time period (e.g. 3 days). Alternatively, the minimum and/or maximum threshold amplitudes may be determined based on a moving average of the respective threshold as it changes over time (e.g. over months or years).
  • the blocking stimulation signal may be configured to inhibit transmission of the evoked neural response past the blocking location to produce a partial or full block of the nerve at the blocking location.
  • the unidirectional nerve stimulation may be in an efferent direction.
  • the unidirectional nerve stimulation may be in an afferent direction.
  • the direction of the unidirectional stimulation may be selected based on a desired effect on the patient.
  • the method may further comprise detecting the evoked neural response in the nerve.
  • a method of inhibiting, mitigating, treating and/or preventing one or more disorders, diseases and/or physiological conditions in a patient comprising modulating activity in a nerve according to the presently disclosed method.
  • Modulation of activity in the nerve may be effective to modulate one or more physiological parameters of the patient.
  • Modulation of activity in the nerve may be therapeutically effective to prevent and/or treat the one or more disorders, diseases and/or physiological conditions.
  • modulation of activity in the nerve may be effective to modulate one or more physiological parameters of the patient, which may be therapeutically effective to inhibit, mitigate, prevent and/or treat the one or more disorders, diseases and/or physiological conditions.
  • the method may comprise applying an activating stimulation signal at an activating location at the nerve, the activating stimulation signal configured to evoke a neural response in the nerve, wherein the blocking stimulation signal is configured to inhibit transmission of the evoked neural response along the nerve past the blocking location, to produce unidirectional nerve stimulation.
  • the unidirectional nerve stimulation may be effective to modulate one or more physiological parameters of a patient.
  • the unidirectional stimulation may be configured to be therapeutically effective to inhibit, mitigate, prevent and/or treat the one or more disorders, diseases and/or physiological conditions.
  • the patient may have a condition or disease associated with impaired glucose regulation.
  • a method for inhibiting, mitigating, treating and/or preventing a condition associated with impaired glucose regulation in the patient comprising modulating activity in a nerve according to the method of the present disclosure, where the modulation of the nerve activity is effective to inhibit, mitigate, prevent and/or treat the condition associated with impaired glucose regulation in the patient.
  • the patient may have a condition or disease that causes pain.
  • a method for inhibiting, mitigating, treating and/or preventing a condition associated with pain in a patient comprising modulating activity in a nerve according to the method of the present disclosure.
  • the modifying of activity in the nerve may be therapeutically effective to inhibit, mitigate, prevent and/or treat the condition or disease causing the pain.
  • the modifying of activity in the nerve may be therapeutically effective to reduce pain experienced by the patient.
  • the method of modulating activity in a nerve according to the present disclosure may be used during, or in association with, injection of numbing agents into the spine.
  • the patient may have sciatica or frozen shoulder.
  • the condition may include one or more of: pain from blood vessel spasms; complex regional pain syndrome (previously called reflex sympathetic dystrophy and causalgia); Raynaud’s syndrome; stomach pain; and/or visceral pain.
  • the method may include applying the blocking stimulation at a nerve attached to a sympathetic ganglion.
  • the patient may have an inflammatory condition that causes inflammation and pain
  • the inflammatory condition may include rheumatoid arthritis and/or scleroderma.
  • a method of inhibiting, mitigating, treating and/or preventing an inflammatory condition associated with causing, or contributing to, excessive inflammation comprising modulating activity in a nerve according to the method of the present disclosure.
  • the modifying of activity in the nerve may be therapeutically effective to inhibit, mitigate, prevent and/or treat the inflammatory condition or disease causing the excessive inflammation.
  • the method may include applying the blocking stimulation at a nerve attached to a sympathetic ganglion.
  • the patient may have a condition or disease that causes excessive sweating.
  • a method for inhibiting, mitigating, treating and/or preventing a condition associated with excessive sweating in a patient comprising modulating activity in a nerve according to the method of the present disclosure.
  • the modifying of activity in the nerve may be therapeutically effective to inhibit, mitigate, prevent and/or treat the condition or disease causing the excessive sweating.
  • the method may include applying the blocking stimulation at a nerve attached to a sympathetic ganglion.
  • a method for inhibiting, mitigating, treating and/or preventing a disease or disorder related to excessive and/or abnormal proliferation of cells comprising modulating activity in a nerve according to the method of the present disclosure.
  • the disease or disorder related to excessive and/or abnormal proliferation of cells may include cancer, for example.
  • the method of modulating activity in a nerve may be applied in treatment of one or more cancers such as: pancreatic, colon, anal, bladder; kidney, renal; prostate; gall bladder; liver; small bowel; stomach; thyroid; vaginal, vulvar, penile and/or testicular cancer.
  • the modulation of nerve activity may be configured to be therapeutically effective for treatment of the disease or disorder related to excessive and/or abnormal proliferation of cells.
  • a method for treating and/or preventing a disease or disorder related muscle spasticity comprising modulating activity in a nerve according to the method of the present disclosure.
  • the modulation of nerve activity may be configured to be therapeutically effective to treat the disease or disorder related muscle spasticity.
  • the modulation of nerve activity may be configured to inhibit nerve-mediated muscle twitching.
  • a system comprising an electrode array, comprising: a first pair of electrodes, selectively operable for applying an activating stimulation signal to the nerve, the activating stimulation signal configured to produce an evoked neural response in the nerve, the first pair of electrodes comprising two first electrodes; a second pair of electrodes, selectively operable for applying a blocking stimulation signal to the nerve, the blocking stimulation signal configured to inhibit transmission of the evoked neural response along the nerve past the second pair of electrodes, the second pair of electrodes comprising two second electrodes; and a third pair of electrodes, selectively operable as a pair of detecting electrodes for detecting the evoked neural response, the third pair of electrodes comprising two third electrodes, wherein the two third electrodes are spaced from each other in a longitudinal direction of the electrode array.
  • the second pair of electrodes may be located intermediate the first pair of electrodes and the third pair of electrodes.
  • the first pair of electrodes and the second pair of electrodes may be spaced from each other by a distance A in the longitudinal direction of the electrode array.
  • the second pair of electrodes and the third pair of electrodes may be spaced from each other by a distance B along the longitudinal direction of the electrode array.
  • a spacing between the two third electrodes may be less than the distance A and/or less than the distance B.
  • the two first electrodes of the first pair of electrodes may be spaced from each other along the longitudinal direction of the electrode array. A spacing between the two first electrodes may be less than the distance A and/or less than the distance B.
  • Each of the first pair of electrodes and the third pair of electrodes may be selectively operable for applying the activating stimulation signal and/or for detecting the evoked neural response.
  • the second pair of electrodes may additionally, or alternatively, be selectively operable for applying the activating stimulation signal and/or for detecting the evoked neural response.
  • the first pair of electrodes and/or the third pair of electrodes may be selectively operable for applying the blocking stimulation signal.
  • the two second electrodes of the second pair of electrodes may be positioned opposite (or substantially opposite) each other about the longitudinal axis of the electrode array.
  • substantially opposite means that the electrodes at least partially overlap.
  • the electrodes of an electrode pair e.g. the second electrode pair
  • a longitudinal offset between centres of the two second electrodes may be configured to be less than a diameter of the nerve.
  • the electrode array may include a fourth pair of electrodes.
  • the fourth pair of electrodes may comprise two fourth electrodes.
  • the fourth pair of electrodes may be selectively operable for applying a blocking stimulation signal to the nerve, the blocking stimulation signal configured to inhibit transmission of the evoked neural response along the nerve past the fourth pair of electrodes.
  • the fourth pair of electrodes may be selectively operable for applying the blocking stimulation signal, applying the activating stimulation signal and/or for detecting the evoked neural response.
  • the two fourth electrodes of the fourth pair of electrodes may be positioned opposite each other about the longitudinal axis of the electrode array.
  • the two fourth electrodes of the fourth pair of electrodes may be spaced from each other in the longitudinal direction of the electrode array.
  • the fourth pair of electrodes may be located intermediate the second pair of electrodes and the third pair of electrodes.
  • the third pair of electrodes may be located intermediate the second pair of electrodes.
  • the first pair of electrodes and the second pair of electrodes may be spaced from each other by a distance A in the longitudinal direction of the electrode array.
  • the second pair of electrodes and the third pair of electrodes may be spaced from each other by a distance B in the longitudinal direction of the electrode array.
  • the third pair of electrodes and the fourth pair of electrodes may be spaced from each other by a distance C in the longitudinal direction of the electrode array.
  • the distances A, B and C may be substantially equal. In other embodiments, the distances A, B and C may be different from one another.
  • the electrode array may include fifth, sixth or more pairs of electrodes.
  • an electrode array for stimulating a nerve comprising: a first pair of electrodes, the first pair of electrodes comprising two first electrodes configured to be positioned on opposite sides of the nerve, wherein the two first electrodes are spaced from each other in a longitudinal direction of the electrode array; a second pair of electrodes, the second pair of electrodes comprising two second electrodes configured to be positioned on opposite sides of the nerve, wherein the two second electrodes of the second pair of electrodes are positioned opposite each other about a longitudinal axis of the electrode array.
  • the first pair of electrodes and the second pair of electrodes may be spaced from each other by a distance A along the longitudinal direction of the electrode array.
  • a spacing between the two first electrodes is less than the distance A.
  • the electrode array may comprise or may be connected to one or more electrical signal generators that generate the electrical stimulation signals to apply, via the respective pair(s) of electrodes, to the nerve.
  • the electrode array may comprise or may be connected to one or more monitoring and/or recording devices that receive, from the respective pair(s) of electrodes, detected neural response signal(s) and process the detected neural response signal(s).
  • the first pair of electrodes may be connected to an electrical signal generator configured to generate an activating stimulation signal, wherein the activating stimulation signal is configured to evoke a neural response in the nerve.
  • the second pair of electrodes is connected to an electrical signal generator (for example, the same or a different electrical signal generator as connected to the first pair of electrodes) configured to generate a blocking stimulation signal, the blocking stimulation signal configured to inhibit transmission of the evoked neural response along the nerve past the second pair of electrodes.
  • the array may comprise a third pair of electrodes.
  • the third pair of electrodes may comprise two third electrodes configured to be positioned on opposite sides of the nerve.
  • the second pair of electrodes may be located intermediate the first pair of electrodes and the third pair of electrodes.
  • the two third electrodes may be spaced from each other along a longitudinal direction of the electrode array.
  • the second pair of electrodes and the third pair of electrodes may be spaced from each other by a distance B along the longitudinal direction of the electrode array, and wherein a spacing between the two third electrodes is less than the distance B.
  • the distance A (and/or B) may be configured to be large enough such that application of the blocking stimulation signal at one pair of electrodes does not inhibit generation of an evoked neural response at another pair of electrodes.
  • the third pair of electrodes may be operable as a pair of detecting electrodes for detecting an evoked neural response in the nerve.
  • the third pair of electrodes may be connected to one or more monitoring and/or recording devices configured to receive the detected evoked neural response from the third pair of electrodes.
  • the first pair of electrodes and the third pair of electrodes may each be selectively operable as a pair of detecting electrodes for detecting the evoked neural response. Additionally, or alternatively, the first pair of electrodes and the third pair of electrodes may be selectively operable as a pair of stimulating electrodes for applying an activating stimulation signal configured to evoke a neural response in the nerve.
  • first, second and third electrode pairs does not preclude the provision of fourth, fifth or yet further electrode pairs, whether for applying activating or blocking stimulation signals and/or detecting evoked neural responses.
  • four electrode pairs may be provided.
  • the second pair of electrodes may be a selectively operable for applying an activating stimulation signal to the nerve
  • the third pair of electrodes may be selectively operable for applying a blocking stimulation signal to the nerve
  • the remaining two (e.g. first and fourth) electrode pairs may be selectively operable for detecting an evoked neural response at the nerve in different directions (i.e. at respective first and second detecting locations).
  • the first pair of electrodes may monitor the evoked neural response in a first direction (e.g. in an efferent direction)
  • the fourth pair of electrodes may monitor the evoked neural response in a second direction (e.g. in an afferent direction).
  • a plurality of electrode pairs may be configured to apply the blocking stimulation signal (or a plurality of blocking stimulation signals) at a corresponding plurality of blocking locations on the nerve.
  • FIG. 1 shows a flowchart illustrating steps in a method of modulating activity in a nerve, according to one embodiment of the present disclosure
  • Fig. 2 shows an example blocking stimulation signal waveform according to one embodiment of the present disclosure
  • FIG. 3 shows a flowchart illustrating steps in a method of modulating activity in a nerve according to another embodiment of the present disclosure
  • FIG. 4 shows an oblique view of an electrode array according to one embodiment of the present disclosure, along with associated activating stimulation signal trace, blocking stimulation signal trace and detected neural response trace;
  • FIG. 5 shows a top view of an electrode array according to another embodiment of the present disclosure
  • Figs. 8 and 9 show examples of the effect of changing the frequency of the blocking stimulation signal on the detected neural response
  • Fig. 10 and 11 show examples of the effect of changing the duty cycle of the blocking stimulation signal on the detected neural response
  • Figs. 13, 14 and 15 show the effect on a nerve block with respect to various combinations of parameters of the blocking stimulation signal
  • Fig. 16 shows a comparison of the effect of charge per pulse on the nerve block, by varying either current level or pulse width of the blocking stimulation signal
  • Fig. 17 shows an oblique view of an electrode array having three pairs of electrodes according to another embodiment of the present disclosure, along with associated stimulation signal traces, blocking stimulation signal traces and detected neural response traces;
  • Fig. 18 shows a comparison of nerve block (eVNS) vs nerve activation adjacent to blocking stimuli (aVNS) using the electrode array of Fig. 17;
  • Fig. 19 shows an oblique view of an electrode array having four pairs of electrodes according to another embodiment of the present disclosure, along with associated stimulation signal traces, blocking stimulation signal traces and detected neural response traces;
  • Fig. 20 shows a comparison of nerve block (eVNS) vs nerve activation adjacent to blocking stimuli (aVNS) using the electrode array of Fig. 19;
  • FIG. 21 shows a system diagram of apparatus according to an embodiment of the present disclosure
  • Fig. 22 shows an example of the effect of changing the frequency of a blocking stimulation signal applied at a sciatic nerve on EMG threshold (dB).
  • Fig. 23 shows an example of the effect of changing the duty cycle of a blocking stimulation signal applied at a sciatic nerve on EMG threshold (dB).
  • FIG. 1 a a method for modulating activity in a nerve according to one example of the present disclosure is illustrated.
  • the method comprises applying 1200 a blocking stimulation signal at a blocking location at a nerve.
  • the nerve may be a nerve of a somatic nervous system or a nerve of an autonomic nervous system.
  • the blocking stimulation signal may be applied at a vagus nerve, a sciatic nerve or a pelvic nerve.
  • the blocking stimulation may be applied at one or more spinal (i.e., somatic) nerves, including but not limited to: a femoral nerve, a tibial nerve, a common peroneal nerve, a median nerve, an ulnar nerve and/or a radial nerve.
  • the blocking stimulation may be applied at one or more autonomic nerves, including but not limited to: an abdominal vagus nerve, a gastric vagal nerve branch, a celiac vagus nerve branch, a hepatic vagus nerve, a cervical vagus nerve, a pelvic nerve, a splanchnic nerve, a carotid sinus nerve, a pancreatic nerve, and/or a hypogastric nerve.
  • blocking stimulation may be applied at more than one nerve.
  • the blocking stimulation signal comprises a biphasic pulsatile electrical signal, having a rectangular pulse waveform.
  • Fig. 2 shows an example signal trace for the blocking stimulation signal 120, showing current over time (charge). One cycle of the blocking stimulation signal 120 is indicated between the dashed lines.
  • Fig. 2 indicates various parameters of an illustrative blocking stimulation signal 120, including pulse width, off time, duty cycle %, frequency, period (1 /frequency), pulse amplitude, and charge per pulse.
  • a method for modulating activity in a nerve comprises applying 1200’ a blocking stimulation signal at a blocking location at a nerve, wherein the blocking stimulation signal 120 comprises a biphasic pulsatile electrical signal having a frequency of between about 100 Hz and about 40 kHz and a steady state duty cycle of greater than about 75% and less than 100%.
  • the method may further comprise applying 1100” an activating stimulation signal at an activating location at the nerve while applying 1200” a blocking stimulation signal at a blocking location at the nerve.
  • the blocking stimulation signal may be a biphasic pulsatile electrical signal having a frequency of between about 100 Hz to about 40 kHz and a steady state duty cycle of greater than about 75% and less than 100%.
  • the activating stimulation signal may be configmed to evoke a neural response in the nerve, wherein the blocking stimulation signal is configmed to inhibit transmission of the evoked neural response along the nerve past the blocking location, to produce 1300” substantially unidirectional nerve stimulation.
  • Unidirectional stimulation may be effective to modulate one or more physiological parameters of a patient.
  • a method of modulating glycaemia in a patient by application of unidirectional vagal nerve stimulation to the vagus nerve is described in the present applicant’s previous patent application PCT/AU2020/051381, filed 16 December 2020, the contents of which me hereby incorporated by reference in their entirety.
  • the direction of the unidirectional stimulation may be selected based on a desired effect on the physiological parameter of the patient. For example, in the case of vagal nerve stimulation to modulate glycaemia, afferent nerve stimulation (aVNS) may be selected to increase glycaemia, while efferent nerve stimulation (eVNS) may be selected to decrease glycaemia.
  • aVNS afferent nerve stimulation
  • eVNS efferent nerve stimulation
  • Modulating one or more physiological parameters of a patient may be useful in prevention and/or treatment of one or more physiological conditions.
  • the method according to the present disclosure may be used in connection with one or more indications and/or treatments including, but not limited to: obesity; type 2 diabetes mellitus; and chronic pain (for example, sciatica, frozen shoulder and/or injection of numbing agents into the spine).
  • the method may be applied in treatment of one or more of: pain from blood vessel spasms; complex regional pain syndrome (previously called reflex sympathetic dystrophy and causalgia); Raynaud’s syndrome; stomach pain; excessive sweating; and visceral pain conditions.
  • the method may include applying the blocking stimulation signal to produce a nerve block.
  • the blocking stimulation may be applied at a nerve attached to a sympathetic ganglion.
  • the disclosed method may be applied in the treatment of one or more inflammatory conditions, including but not limited to, rheumatoid arthritis and/or scleroderma.
  • the method may include applying the blocking stimulation signal to produce a nerve block that inhibits, reduces, treats, and/or prevents an inflammatory condition associated with causing, or contributing to, excessive inflammation.
  • the disclosed method may be applied to modulate one or more physiological parameters in a subject in treatment of a disease or disorder related to excessive and/or abnormal proliferation of cells.
  • the method may be applied in treatment of conditions including but not limited to cancer.
  • the method may be applied in treatment of cancers such as: pancreatic, colon, anal, bladder, kidney, renal, prostate, gall bladder, liver, small bowel, stomach, thyroid, vaginal, vulvar, penile and/or testicular cancer.
  • the disclosed method may be applied to modulate one or more physiological parameters in a subject in the treatment of muscle spasticity.
  • the method may be applied to inhibit nerve-mediated muscle twitching.
  • Fig. 4 shows an example activating stimulation signal 110 and blocking stimulation signal 120, applied to respective activating and blocking locations at a nerve 200.
  • the blocking stimulation signal 120 has a higher frequency than activating stimulation signal 110.
  • the method may further comprise a step of detecting 1400” the evoked neural response.
  • a blocking stimulation signal having a frequency of 26 kHz when applying a blocking stimulation signal having a frequency of 26 kHz, it has been found that applying the activating stimulation signal at 4 to 5 dB above the minimum threshold amplitude may overcome the block and result in bidirectional stimulation. It has been found that applying a blocking stimulation signal having a relatively low frequency (for example, in the range of about 1 kHz to about 4 kHz), particularly in combination with a high charge per pulse, may provide enhanced blocking of the nerve and may allow for a wider therapeutic window for stimulation.
  • Fig. 7 shows a quantification of the evoked neural response detected in the nerve, past the blocking location, when delivering activation stimuli at 15 Hz to an efferent nerve bundle that have different amplitudes (current levels).
  • the left-hand panel of Fig. 7 shows the graded evoked neural response signals specifically (ECAPs) evoked by increasing current levels of the activating stimulation signal 110.
  • the magnitude of the detected evoked response signal in the shaded area has then been plotted as dots in the centre panel of Fig. 7 and fitted with a sigmoid growth function.
  • the threshold referring to the horizontal displacement of the growth function, can be calculated at 10% of the maximal observed ECAP amplitude and is represented in the central panel of Fig. 7.
  • the saturation referring to the ceiling of nerve response amplitude, was calculated from the value of the fitted sigmoid curve at 2 mA (maximal current). In general, a better block is indicated by the detected evoked neural activity exhibiting a higher threshold and a reduced saturation.
  • the right-hand panel shows the fitted sigmoid curves corresponding to changes in the parameters of the blocking signal 120.
  • one or more of a pulse amplitude (current), charge per pulse, pulse width, duty cycle or frequency of the blocking stimulation cycle may be configmed to optimise the nerve block.
  • a charge per pulse of the blocking stimulation signal 120 may be configured to optimise the nerve block. Where amplitude of the blocking stimulation signal 120 is held constant, the charge per pulse may be configured by varying the pulse width.
  • a duty cycle of the blocking stimulation signal 120 may be configured to optimise the nerve block. This may alternatively be understood as varying the off-time of the blocking stimulation signal 120 (inverse of duty cycle). Additionally, or alternatively, the frequency of the blocking stimulation signal 120 may be configured to optimise the nerve block.
  • a pulse amplitude (current) of 4 mA for the blocking stimulation signal 120 was used.
  • these examples applied a method of the present disclosure to nerves in experimental animals (rats). It is expected that a higher pulse amplitude may be required for effective blocking stimulation in larger animals or in human subjects, owing to the larger diameter of the nerves. It is expected that effective blocking stimulation in humans will be achieved with a blocking stimulation signal having a pulse amplitude of between about 1 mA to about 50 mA, such as between about 2 mA to about 30 mA.
  • Blocking stimulation signals having a relatively low frequency such as in the order of 1 kHz to 4 kHz, have been found to allow for longer pulse width and thus may enable enhanced blocking. It is expected that blocking stimulation signals having a frequency below 1 kHz will also be effective.
  • the blocking stimulation signal may have a frequency as low as 100 Hz. However, it may be desirable to avoid frequencies correlating with a band of the ECAP spectral power in the nerve to be stimulated.
  • the frequency of the blocking stimulation may also be limited by resultant changes in the charge density of very wide pulses, which may decrease the safety of application of the blocking stimulation signal (e.g. by increasing the likelihood of damage to the nerve).
  • the nerve block may be improved by applying a blocking stimulation signal having high duty -cycle.
  • the duty cycle may be greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, or greater than about 95%.
  • the blocking stimulation signal may nevertheless have an off-time and thus the duty cycle may be less than 100%, less than about 99%, less than about 98%, less than about 97%, or less than about 96%.
  • the blocking stimulation signal 120 may be characterised as a low frequency, high duty -cycle electrical signal.
  • the blocking stimulation signal 120 may alternatively be characterised as a high pulse-width (or high charge per pulse) and low off-time electrical signal.
  • the blocking effect of the blocking stimulation signal is configured to be localised (or focal) to the blocking location on the nerve at which the blocking stimulation signal is applied (that is, local to the electrode pair used for applying the blocking stimulation signal).
  • the blocking stimulation signal parameters may therefore be configured such that the current spread is limited to a relatively small volume of tissue and such that only ion channels in close proximity to the blocking electrodes are affected. As such, the blocking stimulation signal may not inhibit generation of ECAPs at adjacent locations on the nerve.
  • the activating and blocking stimulation signals 110 and 120 may be applied to the nerve 200 by respective first and second pairs of electrodes 310 and 320 comprised in an electrode array 300.
  • the first and second electrode pairs 310, 320 interface with the nerve 200 at respective first and second locations.
  • the electrode array 300 optionally comprises a third pair of electrodes 330 which interfaces the nerve 200 at a third location.
  • the electrode array 300 is not limited to three pairs of electrodes.
  • the electrode array 300 may further include fourth, fifth, sixth or more pairs of electrodes interfacing the nerve 200 at respective fourth, fifth, sixth or further locations.
  • electrode array 500’ includes a fourth pair of electrodes 540 for interfacing the nerve 200 at a fourth location.
  • the blocking stimulation signal 120 is configured to inhibit transmission of a neural response evoked by the activating stimulation 110, past the blocking location. As such, in the example of Fig. 4, when the blocking stimulation signal 120 and activating stimulation signal 110 are simultaneously applied, the evoked neural response 140 will transmit in substantially one direction only along the nerve 200 (in this case, down the nerve 200 in the direction of the arrow 201).
  • Each of the first and second and third electrode pairs 310, 320, 330 may be selectively operable for applying the activating stimulation signal 110, for applying the blocking stimulation signal 120 and/or for detecting the evoked neural response 140.
  • the relative locations at which the activating and blocking stimulation signals are applied to the nerve may be selected depending on the desired direction of stimulation along the nerve 200. For example, if the second electrode pair 320 (that is, the intermediate electrode pair) is selected for applying the blocking stimulation signal 120, the direction of the nerve stimulation may be determined by whether the proximal or distal pair or electrodes is selected for applying the activating stimulation signal 110.
  • the activating stimulation signal 110 may be applied at the first electrode pair 310 to achieve efferent nerve stimulation, or at the third electrode pair 320 to achieve afferent nerve stimulation.
  • the electrode pairs 310, 320 and 330 are comprised in an electrode mounting device in the form of a cuff 350.
  • the cuff is adapted to mount to the nerve 200 (e.g. the vagus nerve) to electrically interface the electrode pairs 310, 320, 330 with the nerve.
  • Electrode arrays may include electrode pairs having electrodes which are aligned (e.g. positioned opposite each other) and/or misaligned (e.g. spaced from each other, or linearly offset) in the longitudinal direction of the array.
  • the electrode array may be configured such that the opposite (aligned) electrode pairs are operable for applying the blocking stimulation signal and the spaced (misaligned) electrode pairs are operable for applying the activating stimulation signal 110 and/or for detecting the evoked neural response 140.
  • Figs. 17 and 19 show respective example electrode arrays 500 and 500’ in which each of the electrodes comprised in electrode pairs 510, 520, 530 and 540, are positioned opposite one another about a longitudinal axis X of the electrode array 500 or 500’ and can therefore be considered aligned in the longitudinal direction of the electrode array 500, 500’.
  • an electrode array may include a combination of aligned and misaligned electrode pairs.
  • One or more misaligned electrode pairs may be positioned at one or more end respective end positions of the electrode array.
  • One or more aligned electrode pairs may be positioned toward a mid-region of the electrode array.
  • Figs. 5 and 6 show one such example electrode array 400, suitable for use in the above-described method.
  • the array 400 comprises first, second and third electrode pairs 410, 420, 430.
  • the first electrode pair 410 comprises two first electrodes
  • the second electrode pair 420 comprises two second electrodes
  • the third electrode pair 430 comprises two third electrodes.
  • Each of the electrode pairs 410, 420, 430 is comprised in an electrode mounting device, which in the illustrated example is in the form of a cuff 450.
  • the cuff 450 is adapted to mount to the nerve 200 (e.g. the vagus nerve) to electrically interface the electrode pairs 410, 420, 430 with the nerve 200.
  • the cuff 450 comprises a pair of cuff portions 401, 402 adapted to be brought together to clamp to opposite sides of the nerve 200.
  • the cuff portions 401, 402 when in a closed configuration, may together define an inner surface with a semi-elliptical, semi-oblong or semi-rectangular profile to contact an outer surface of the nerve.
  • at least one of the cuff portions 401, 402 comprises a recess or channel extending along the cuff and adapted to receive a portion of the nerve therein.
  • the cuff portions 401, 402 may be sutured or otherwise fixed together after clamping to limit movement of the array 400 relative to the nerve.
  • the array 400 includes a tab 460 which may be sutured to an adjacent anatomical structure to provide further stability.
  • One electrode of each of the electrode pairs 410, 420, 430 is disposed in each cuff portion 401, 402.
  • the cuff 450 is adapted for placement on the nerve 200 such that, when the cuff 450 is mounted to the nerve 200, the electrodes of each of the electrode pairs 410, 420, 430 are positioned on opposite sides of the nerve 200.
  • the first, second and third pairs of electrodes 410, 420 and 430 may be in a substantially fixed relationship. Additionally, or alternatively, the electrodes comprised within one or more of the pairs of electrodes 410, 420 and 430 may be in a substantially fixed relationship relative to each other, and/or to the electrodes of the other pairs of electrodes.
  • the electrode mounting device e.g. cuff 450, may be configured to substantially maintain the relative orientation and/or location of the pairs of electrodes 410, 420 and 430 and/or the electrodes within the pairs 410, 420 and 430, with respect to each other.
  • the cuff 450 may comprise resiliently flexible material, which may allow for slight relative movement of the pairs of electrodes but may nevertheless substantially maintain the relative locations and orientations.
  • the second pair of electrodes 420 is situated intermediate the first and third pairs of electrodes 410, 430.
  • the first and second pairs of electrodes 410, 420 are separated from each other by a distance A, while the second and third pairs of electrodes are separated from each other by a distance B.
  • the distances A and B are substantially equal. In other embodiments, the distances A and B may be different to each other.
  • the distances A and/or B may be configured such that the electrode pair selected for applying the activating stimulation signal 110 is sufficiently spaced from the electrode pair selected for applying the blocking stimulation 120, such that generation of evoked neural responses at the activating location is not inhibited by the blocking stimulation applied at the blocking location.
  • the centres of the two first electrodes of the first electrode pair 410 are spaced from each other in the longitudinal direction of the array 400.
  • the centres of the two third electrodes of the third electrode pair 430 are spaced from each other in the longitudinal direction of the array 400.
  • the two second electrodes of the second pair of electrodes 420 are not spaced from each other along the longitudinal direction of the electrode array 400 but are located opposite each other about a longitudinal axis X of the electrode array 400. That is, the centres of the electrodes are aligned opposite each other about the longitudinal axis X of the electrode array 400. As such, when the array 400 is mounted to the nerve 200, the electrodes of the second pair of electrodes are positioned substantially opposite each other about the nerve 200.
  • the first pair of electrodes 410 is separated from the second pair of electrodes 420 by a distance A and the second pair of electrodes 420 is separated from the third pair of electrodes 430 by a distance B, in the longitudinal direction of the array 400 (measured between centres of the respective electrode pairs 410, 420, 430).
  • a spacing D between the centres of the two first electrodes of the first electrode pair 410 is less than the distance A and less than the distance B.
  • a spacing E between the centres of the two third electrodes of the third electrode pair 430 is less than the distance A and less than the distance B between the adjacent pairs of electrodes.
  • the spacing D between the two first electrodes of the first electrode pair 410 is substantially equal to the spacing E between the two third electrodes of the third electrode pair 430. In other embodiments, however, the spacings D and E may be different to each other. In one example, the distances A and B between centres of adjacent electrode pairs is approximately 2.95 mm, the spacing D is approximately 0.9 mm and the spacing E is approximately 0.9 mm.
  • the first and third pairs of electrodes 410, 430 may be selectively operable for applying the activating stimulation signal 110 or for detecting the evoked neural response 140.
  • electrode pairs incorporating a linear offset between the electrodes give improved performance when detecting the evoked neural response 140, as the spacing between the electrodes of the electrode pair allows for improved capturing of the travelling wave of the ECAP.
  • electrode pairs having electrodes positioned opposite each other may provide improved performance in applying the blocking stimulation signal 120.
  • the positioning of the electrodes of electrode pair 420 may provide for improved contact between the electrode pair 420 and the nerve 200, production of a more focal block in the nerve 200 when applying the blocking stimulation signal 120 and/or may reduce the noise created at adjacent electrode pairs 410 and/or 430.
  • the spacing between electrodes may be configured relative to characteristics of the nerve 200 and/or the evoked neural response 140.
  • a spacing between electrodes in an electrode pair e.g. 410, 430
  • an ECAP may be recorded with frequency content between 115 Hz and 330 Hz, with an average frequency content of 220 Hz.
  • the latency of the evoked neural response indicates a nerve conduction velocity of ⁇ 1.1 m/s.
  • the expected conduction velocity for this type of nerve fibre should range from 0.1 - 2 m/s.
  • a spacing between electrodes configured for recording the evoked neural response 140 may approximate the distance between the maximum and minimum points in the period of the signal. This may be calculated as Velocity * Period / 2, which is about 2.5 mm. In this case, the spacing may be between about 2.5mm, or between about 0mm and about 5 mm, such as between about 1.5 mm and about 3 mm. While the example given here is specific to the rat vagus nerve, it will be appreciated that this principle may be applied to adapt the spacing between electrodes in the electrode pairs 410, 430 for suitability to other nerves, or other subjects (including humans).
  • Electrode arrays may include further electrode pairs, such as fourth, fifth or sixth electrode pairs.
  • electrode array 600 shown in Fig. 19 comprises first, second, third, fourth and fifth electrode pairs 510, 520, 530, 540.
  • Electrode arrays having four or more pairs of electrodes may enable additional flexibility in the choice of location for applying the activating stimulation signal, blocking stimulation signal and/or location for recording of the neural response.
  • larger arrays are, in general, more fragile and may involve more complicated surgeries.
  • the method of the present disclosure may be applied using alternative electrode arrays, different to those shown in Figs. 4, 5, 6, 17 or 19.
  • one or more of the electrode pairs may be comprised in separate cuffs, separate mounting devices or otherwise. This may allow the spacing between the electrode pairs to be adjusted, for example.
  • the electrode array may comprise a support that substantially maintains the relative orientation and/or location of the separate cuffs, or mounting devices, to maintain the relative orientation and/or location of the pairs of electrodes with respect to each other. The relative orientation and/or location of the pairs of electrodes may therefore be substantially pre-defined, rather than being selected by a surgeon.
  • a system 600 according to an embodiment of the present disclosure, suitable for use in methods described herein, is shown in Fig. 21.
  • the system 600 may comprise an electrode array 300, 400, 500 or 500’ as described above.
  • the system 600 comprises a system controller 610.
  • the system controller 610 may selectively trigger the applying of the activating stimulation signal 110 and blocking stimulation signal 120.
  • the system controller 610 may be configured to trigger the applying of the activating stimulation signal 110 and blocking stimulation signal 120 in response to an input from the patient, a caretaker, or a clinician.
  • the system controller 610 may be selectively actuated by the patient, a caretaker, or a clinician to initiate or cease the applying of the activating and blocking stimulation signals 110, 120 or to modify one or more parameters of the activating and blocking stimulation signals 110, 120.
  • the system controller 610 may also be configured to determine which of the pairs of electrodes 410, 420, 430 (or 310, 320, 330, or 510, 520, 530 540) is selected to apply the activating stimulation signal 110, to apply the blocking stimulation signal 120 and to detect the evoked neural response 140.
  • the system controller 610 may control whether the unidirectional stimulation produced is afferent nerve stimulation or efferent nerve stimulation.
  • the system controller 610 may receive signals from the electrode array 400, as indicated by the dotted line in Fig. 21.
  • the system controller 610 may be configmed to receive evoked neural response signals 140 detected by one or more of the electrode pairs 410, 420, 430 (or 310, 320, 330, or 510, 520, 530 540).
  • the system controller 610 may be configured to adjust one or more parameters of the activating stimulation signal 110 and/or the blocking stimulation signal 120 in response to the detected evoked neural response signal 140.
  • system controller 610 may be configured to automatically tune the activating stimulating signal 110 and/or the blocking stimulating signal 120 to each other, to ensure that the activating stimulating signal 110 is applied within a therapeutic window in which the evoked neural response 140 is effectively blocked. Further, the system controller 610 may be configured to tune one or more parameters of the blocking stimulating signal 120 to enhance the effectiveness of the block.
  • the system 600 further comprises a sensor 620 for detecting a physiological parameter of the patient.
  • the sensor 620 may be associated with the system controller 610, as indicated by the dot-dash line in Fig. 21.
  • the system controller 610 may be configured to trigger the applying of the activating stimulation signal 110 and blocking stimulation signal 120, or to automatically adjust one or more parameters of the activating and/or blocking stimulation signals 110, 120, in response to the detected physiological parameter of the patient.
  • the sensor 620 may comprise a glucose sensor, configured to detect a glycaemia of the patient.
  • the system controller 610 may be configured to trigger the production of eVNS stimulation, or reduce or stop eVNS stimulation, in response to a detected glucose level above a maximum threshold, or to trigger the production of aVNS stimulation, or reduce or stop aVNS stimulation, in response to a detected glucose level below a minimum threshold.
  • the maximum and minimum thresholds may be set by, for example, a patient’s healthcare representative.
  • the system may optionally include a patient interface 630 to receive an input from the patent, caretaker of clinician, e.g. to initiate or cease the applying of the activating and blocking stimulation signals 110, 120 or to modify one or more parameters of the of the activating stimulation signal or blocking stimulation signal 110, 120.
  • the system 600 may optionally include, or be associated with, a diagnostics unit 640 unit.
  • the diagnostics unit 640 may be provided as a software application on a desktop computer, laptop, tablet, smartphone or otherwise.
  • the diagnostics unit 640 may be configured to receive, store and/or display data from the system controller 610 relating to the applied stimulation parameters, glycaemia of the patient over time, therapeutic outcomes or otherwise.
  • the electrode array included platinum electrodes embedded into a medical grade silicone elastomer cuff. Each platinum electrode had an exposed surface area of 0.39 mm 2 . The electrodes were arranged in pairs, with the electrodes of each of the electrode pairs (e.g. El and E2) positioned on opposite sides of the cuff.
  • an electrode array 500 as shown in Fig. 17 was used.
  • the array 500 included first, second and third pairs of platinum (99.95%) electrodes 510, 520 and 530. In this example, the distance between centres of adjacent electrode pairs was 3.4 mm.
  • an alternative electrode array 500’ of the type shown in Fig. 19 was used.
  • the array 500’ included first, second, third and fourth pairs of platinum (99.95%) electrodes 51, 520, 530 and 540. In this example, the distance between centres of adjacent electrode pairs was 2.22 mm. Each electrode pair was spaced from the adjacent electrode pair by 1.52 mm between adjacent edges.
  • a channel (0.55 mm wide x 0.2 mm deep) traversed the length of the array, and was positioned around the vagus nerve such that, when the array was implanted, the vagus nerve was positioned in the channel and electrodes of each of the electrode pairs were positioned on opposite sides of the vagus nerve.
  • the silicone cuff was sutured closed to prevent the nerve from migrating out of the channel and away from the electrode interface.
  • a silicone suturing tab on the lead was used to anchor the array to the oesophagus to provide mechanical stabilisation.
  • a helical cable ran from the electrode array to an external connector.
  • ECAPs evoked compound action potentials
  • the recordings were sampled at a rate of 200 kHz and digitally filtered (20-2000 Hz band pass) using a data acquisition device (USB-6210, National Instruments).
  • the threshold of evoked neural responses was visualized using IGOR Pro-8.
  • An electrically-evoked neural response (ECAP) threshold defined as the perceived inflection point where stimulus intensity produced a monotonically increasing response amplitude within a post-stimulus latency window of 3-9 ms. Wide steps in current were used to cover the stimulator output current range, and further smaller steps of stimulus current (0.5 dB or 1 dB) were used near the perceived ECAP threshold to improve accuracy.
  • the observed latency corresponded to expected conduction velocities within the range of C-fibre responses. In all analysed experiments the stimulation current delivered to the distal electrode pair was suprathreshold.
  • An activating stimulation signal was applied to evoke a neural response (ECAP) in the vagus nerve.
  • the activating stimulation signal comprised biphasic current pulses and was applied using a custom-made external stimulator.
  • the activating stimulation signal was delivered at 15 Hz, 200 ps pulses to the distal electrode pair.
  • a blocking stimulation signal was applied (simultaneously with the activating stimulation signal) to produce a reversible, focal block on the vagus nerve with the purpose of achieving unidirectional stimulation of the vagus nerve.
  • the blocking stimulation signal comprised a biphasic pulsatile electrical signal delivered to the central electrode pair 520.
  • the blocking stimulation signal was delivered at a constant amplitude of 2 mA.
  • the effectiveness of the block was tested using blocking stimulation signal frequencies varied in logarithmic steps (i.e. 1, 1.6, 2.5, 4, 6.3, 10, 16, 26 kHz).
  • Fig. 7 illustrates the process for quantifying the evoked neural response and effectiveness of the blocking stimulation signal.
  • the left panel of Fig. 7 shows stimulation at a variety of current levels.
  • the root-mean-square (RMS) of the ECAP within the post-stimulus window of interest (3-9 ms) was measured and compared to the stimulation current level to define the growth curve.
  • the middle panel of Fig. 7 shows a quantification of the growth curve of the vagal ECAP response when using a 10 kHz block.
  • the response was fit with a logistic growth curve.
  • the fitting curve was then used to define the saturated response, as the ECAP growth plateau (or the maximum response at the limit of 2 mA when the response did not reach the plateau).
  • the analytical ECAP threshold was then defined as the current level in the curve producing 10% of the saturation ECAP RMS.
  • the right panel of Fig. 7 shows examples of evoked compound action potentials (ECAPs) in the rat vagus nerve and the changes observed with blocking stimulation signals applied at a variety of blocking frequencies.
  • ECAPs were successfully recorded from 18 of 20 rats implanted acutely with an electrode cuff on the abdominal vagus nerve.
  • Application of a blocking stimulation signal produced increased the threshold for producing an ECAP, thus resulting in a partial block.
  • a clear and gradual change in the recorded ECAP signal was observed in all of the 18 experimental animals where nerve recordings were possible.
  • Pulsatile stimulation is therefore able to reduce nerve excitability in a manner sufficient to produce directional conduction of evoked activity.
  • the application of the blocking stimulation signal created a window of complete evoked activity block between nerve normal activation threshold and the increased threshold with blocking stimuli.
  • the application of the blocking stimulation signal also diminished the maximal or saturated evoked activity amplitude (likely as a result of reducing the number of fibres available to conduct).
  • Fig. 7 shows the effect of varying the blocking stimulation signal frequency on the evoked neural response.
  • Fig. 8 shows the change in ECAP threshold in the upper panel and change in ECAP saturation amplitude in the lower panel.
  • Fig. 9 shows the mean ⁇ standard error of each measure vs. blocking stimulation signal frequency, as a relative change from the control ECAP in each experiment.
  • Figs. 10 and 11 show the effect of varying the blocking stimulation signal duty cycle on the evoked neural response. In this experiment, it was found that the blocking effects were more evident with a blocking stimulation signal having a higher duty cycle.
  • Fig. 10 shows the change in ECAP threshold in the upper panel and change in ECAP saturation amplitude in the lower panel for various blocking stimulation signal duty cycles.
  • Fig. 11 shows the mean ⁇ standard error of each measure vs.
  • Threshold and saturation were correlated when expressed as relative change from control.
  • Fig. 12 illustrates a correlation of changes in ECAP threshold vs saturation amplitude, expressed as a ratio to the control (no-block) condition.
  • a principal component analysis was used to compound the measure of nerve blocking and estimate the contributions of each variable to the response. The first component accounted for 94% of the variance and thus was used for subsequent analysis with weights of -0.43 for threshold and 0.91 for saturation.
  • the resulting nerve block estimate from threshold and saturation changes was compared to the timing parameters of the stimulation pulses.
  • Figs. 13, 14 and 15 show an estimation of nerve block (based on change in threshold and saturation amplitude) with respect to various combinations of pulse timing parameters of the blocking stimulation signal.
  • the shade indicates magnitude of the change in the detected neural response, while the size of each circle indicates the number of animals aggregated for that parameter combination.
  • the contour curves show a 3 rd order polynomial fit as visual aid.
  • the best nerve block was observed when combining lower frequency and longer pulse width (which can be also represented as the combination of lower frequency and higher duty cycle). For example, a significant block above -12 dB was obtained with frequencies below 2 kHz and pulse widths beyond 300 ps (or duty cycle above 70%).
  • An alternative way of describing the pulse parameters is to consider the off- time (or the pause between pulses). The abovementioned block of -12 dB thus occurs with pulse widths longer than 300 ps and an off time below 400 ps before the next pulse.
  • the blocking stimulation signal parameters were assessed using a stepwise linear regression model to prioritise the parameters by quantifying the contribution of each parameter to the variance. After controlling for particular experimental animals, the pulse width explained the highest proportion of the variance (34%). The addition of duty cycle, off time and frequency to the regression model did not significantly increase the predictive power, as shown in Table 1.
  • Figs. 17 to 20 illustrate a comparison of nerve block (efferent nerve stimulation) vs nerve activation adjacent to blocking stimuli (afferent nerve stimulation) using either an electrode array having first, second and third electrode pairs (Figs. 17 and 18) or an electrode array having first, second third and fourth electrode pairs (Figs. 19 and 20).
  • Figs. 18 and 19 show the comparison between directional stimulation in the afferent vs efferent direction.
  • This data confirms that the nerve block is focal and enables activation of the nerve bundle 2 mm away from the blocking location.
  • Application of the blocking stimulation signal may produce local membrane effects such as sustained polarization of ion channels, maintaining a refractory period.
  • the blocking stimulation pulse parameter most predictive of effective nerve blocking was the pulse width.
  • the pulse width can be considered a proxy measure for charge per pulse of the blocking stimulation signal.
  • the data indicates that the second key factor is maximizing the blocking stimulation signal duty cycle, or equivalently, minimizing off-time of the blocking stimulation signal. It was found that duty cycles above approximately 80% had a similar effect. As such, a portion of the time within each cycle of the blocking stimulation signal may be allocated for passive charge recovery strategies, such as electrode shorting, without significant detriment.
  • An activating stimulation signal was applied to the sciatic nerve at an activating location proximal or closest to the rat’s spine and a blocking stimulation signal was applied to the sciatic nerve at a blocking location distal or closer to the rat’s foot.
  • Figure 22 illustrates the relationship between the blocking stimulation frequency (Hz) and change in EMG threshold (dB).
  • Hz blocking stimulation frequency
  • dB EMG threshold
  • Duty cycle % represents maximum pulse width/duty cycle.
  • Figure 23 shows the relationship between the blocking stimulation signal duty cycle % and the change in EMG threshold (dB). In this example, it was found that duty cycles of 75% and above were effective in increasing the threshold of muscle twitching, indicating an inhibition/reduction in activity of fast fibres during blocking.
  • Biphasic as used herein refers to a waveform in which the current travels in two phases having opposite polarity.
  • Charge per pulse means an amount of electric charge delivered to the nerve in one pulse, measured in Coulombs. For rectangular pulses, this is the pulse amplitude (amps) multiplied by the pulse width (seconds).
  • Cycle as used herein means a one repetition of a repeating pattern in the signal. In examples herein, a cycle may include one or more pulses (or pulse phases), an inter-phase gap and/or an off-time between pulses.
  • Duty Cycle as used herein means a percentage duration of one cycle in which charge is delivered to the nerve.
  • the duty cycle is calculated by summing the widths of all pulses during a cycle and dividing by the period (total time) of the cycle. Duty cycle can be increased by increasing the pulse width, by decreasing the interphase gap and/or by decreasing off time.
  • Frequency as used herein means the reciprocal of the period, or cycles per second, measured in Hertz (Hz).
  • Hertz (Hz) as used herein means the unit measure of frequency (cycles per second).
  • Off time as used herein means a continuous duration in seconds within a cycle in which no charge is delivered to the nerve.
  • time as used herein means a length of time within one cycle in which charge is delivered to the nerve.
  • Period as used herein means a duration (in seconds) of one cycle.
  • Pulse as used herein refers to a brief unidirectional flow of charged particles, separated by an interval of no current flow.
  • Pulse amplitude as used herein means a maximum current in amperes of a single stimulation pulse.
  • Pulse width as used herein means a duration in seconds of one pulse.
  • Rectangular waveform as used herein refers to a non-sinusoidal periodic waveform in which the amplitude alternates suddenly between minimum and maximum values.

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Abstract

L'invention concerne un procédé de modulation de l'activité dans un nerf, dans lequel un signal de stimulation de blocage est appliqué à un point de blocage du nerf. Le signal de stimulation de blocage comprend un signal électrique biphasique pulsatile ayant une fréquence comprise entre environ 100 Hz et environ 40 kHz et un rapport cyclique à l'état stable supérieur à environ 75 % et inférieur à 100 %. L'invention concerne également un système configuré pour moduler l'activité d'un nerf et un réseau d'électrodes pour stimuler un nerf.
PCT/AU2024/050231 2023-03-15 2024-03-15 Procédé et système de neuromodulation Pending WO2024187242A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130066411A1 (en) * 2011-09-08 2013-03-14 James R. Thacker Selective high frequency spinal cord modulation for inhibiting pain, including cephalic and/or total body pain with reduced side effects, and associated systems and methods
US20170216602A1 (en) * 2016-02-02 2017-08-03 Enteromedics Inc. High-frequency low duty cycle patterns for nerual regulation
US20180361155A1 (en) * 2015-12-15 2018-12-20 Case Western Reserve University Systems for treatment of a neurological disorder using electrical nerve conduction block
US20190001139A1 (en) * 2016-02-19 2019-01-03 Nalu Medical, Inc. Apparatus with enhanced stimulation waveforms

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130066411A1 (en) * 2011-09-08 2013-03-14 James R. Thacker Selective high frequency spinal cord modulation for inhibiting pain, including cephalic and/or total body pain with reduced side effects, and associated systems and methods
US20180361155A1 (en) * 2015-12-15 2018-12-20 Case Western Reserve University Systems for treatment of a neurological disorder using electrical nerve conduction block
US20170216602A1 (en) * 2016-02-02 2017-08-03 Enteromedics Inc. High-frequency low duty cycle patterns for nerual regulation
US20190001139A1 (en) * 2016-02-19 2019-01-03 Nalu Medical, Inc. Apparatus with enhanced stimulation waveforms

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