Methods and systems for nerve conduction blockade

Abstract

Disclosed herein are systems and methods for nerve conduction blockade, which may include safely delivering relatively high amounts of electrical charge to tissue. Such systems and methods may include a control system for safely monitoring a direct current electrode system, which includes delivering direct current to a target tissue of a patient via an electrode lead; measuring a drive voltage through the electrode; comparing the drive voltage through the electrode to a predetermined threshold range value; measuring body impedance; determining a voltage drop through the lead from the body impedance measurement; and adjusting the drive voltage to maintain the voltage drop through the lead within a predetermined voltage range.

Description

[0001] Incorporation by reference into any priority application

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 632,485, filed February 20, 2018, and U.S. Provisional Application No. 62 / 640,579, filed March 9, 2018, both of which are hereby incorporated by reference in their entireties. Any and all applications for which foreign or domestic priority claims are identified in the Application Data Sheet filed with this application are hereby incorporated by reference pursuant to 37 CFR §1.57.

[0003] This application incorporates by reference U.S. application No. 15 / 943,601, filed on April 2, 2018, which in turn claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 481,092, filed on April 3, 2017, and Non-provisional Application No. 62 / 485,882, filed on April 14, 2017, each of which is incorporated herein by reference in its entirety. Technical Field

[0004] The present application, in some embodiments, relates to promoting the blockade of biological signals through neural tissue. Background Art

[0005] The gate control theory of pain was developed in the 1860s and led to the emergence of stimulation-based pain management therapies, which reduce pain input to the brain by selectively stimulating non-nociceptive fibers (non-pain transmission fibers) in the spinal cord to inhibit the transmission of painful stimuli to the brain (see Mendell, Constructing and Deconstructing the Gate Theory of Pain, Pain, 2014 Feb 155 (2): 210-216). Current stimulation systems for spinal cord stimulation (SCS) that act on this gate control theory to indirectly reduce pain typically rely on stimulation signals in the frequency range of <100 Hz, and more recently in the kHz frequency range. Stimulating the dorsal root ganglion DRG in a similar frequency range has also been used to alleviate segmental pain through the same mechanism.

[0006] However, technologies based on this premise are not perfect, as the inhibition of pain transmission is not complete, and side effects such as paresthesia may cause discomfort to the patient. Therefore, it is desirable to have systems and methods for treating pain that can directly block pain fibers from transmitting pain signals, rather than indirectly reducing pain signals through gate-type activation of non-nociceptive fibers. Furthermore, the blockade of neural tissue or neural activity is relevant not only to affecting pain, but also to the management of movement disorders, psychiatric disorders, cardiovascular health, and disease states such as diabetes. SUMMARY OF THE INVENTION

[0008] The methods and devices or apparatus disclosed herein each have several aspects, no single aspect being solely responsible for its desirable attributes.Without limiting the scope of the disclosure, for example, as expressed by the appended claims, its more prominent features will now be discussed briefly.

[0009] In some embodiments, disclosed herein are methods for more safely monitoring a direct current electrode system. The method may include delivering direct current to a target tissue of a patient via an electrode lead. The method may include measuring a driving voltage across the electrode. The method may include comparing the driving voltage across the electrode to a predetermined threshold range. The method may include measuring body impedance. The method may include determining a voltage drop across the lead from the body impedance measurement. The method may include adjusting the driving voltage to maintain the voltage drop across the lead within a predetermined voltage range.

[0010] In some embodiments, measuring body impedance can include delivering a short-circuit current input through electrode leads.

[0011] In some embodiments, the short circuit current input may be about or less than about 100 microamperes.

[0012] In some embodiments, the short circuit current input is delivered for less than about 200 microseconds.

[0013] In some embodiments, the predetermined voltage range is below the electrolysis potential of water.

[0014] In some embodiments, adjusting the drive voltage can include adjusting the amplitude of the delivered direct current.

[0015] In some embodiments, the direct current can include cathodic direct current and anodic direct current, wherein the cathodic direct current and the anodic direct current are circulated.

[0016] In some embodiments, the direct current can include a frequency of less than about 1 Hz.

[0017] In some embodiments, a system for direct current nerve block can include a direct current generator. The system can include a working electrode and a counter electrode. The system can include a controller that can cyclically apply direct current of a first polarity for a first duration and a second polarity opposite to the first polarity for a second duration. The controller can receive a measurement of a peak voltage of the first polarity for the first duration and a measurement of a peak voltage of the second polarity for the second duration. The controller can adjust the direct current by analyzing the peak voltages for the first duration and the second duration. The controller can increase the current intensity by a predetermined amount up to a current limit when the measured peak voltages for the first duration and the second duration are below an absolute threshold limit. The controller can reduce the current intensity by a certain amount when the measured peak voltages for the first duration or the second duration are above an absolute threshold limit.

[0018] In some embodiments, the direct current can include a frequency of less than about 1 Hz.

[0019] In some embodiments, the absolute threshold limit is less than the electrolysis potential of water.

[0020] In some embodiments, the working electrode can include silver chloride.

[0021] In some embodiments, the current limit may be a predetermined current limit, and the current intensity is reduced by a predetermined amount.

[0022] In some embodiments, the controller is configured to fix the current intensity when the change in the peak voltage of the first polarity is below a configured value.

[0023] In some embodiments, disclosed herein are methods for more safely monitoring direct current regulation of a working electrode. The method may include applying a direct current of a first polarity for a first duration. The method may include applying a direct current of a second polarity opposite to the first polarity for a second duration. The method may include receiving a measurement of a peak voltage of the first polarity for the first duration and a measurement of a peak voltage of the second polarity for the second duration. The method may include regulating the direct current by analyzing the peak voltages for the first duration and the second duration. The method may include increasing the current intensity by a predetermined amount up to a current limit when the measured peak voltages for the first duration and the second duration are below an absolute threshold limit.

[0024] In some embodiments, the method may include increasing the current intensity by a predetermined amount.

[0025] In some embodiments, the first polarity is an anode and the second polarity is a cathode.

[0026] In some embodiments, the current limit is about 5 mA.

[0027] In some embodiments, the peak voltage absolute threshold limit is about 1.5V.

[0028] In some embodiments, the method may include reducing the current intensity by a predetermined amount when the measured absolute peak voltage during the first duration or the second duration is above an absolute threshold limit.

[0029] In some embodiments, the method can include applying a direct current of a first polarity for a first duration, and applying a direct current of a second polarity opposite to the first polarity for a second duration can include cycles of direct current delivery. The method can include at least about 10 cycles of direct current delivery.

[0030] In some embodiments, the working electrode can include silver chloride, titanium nitride, and / or other materials, including those disclosed elsewhere herein.

[0031] In some embodiments, disclosed herein are methods for increasing the effectiveness of alternating current electrode systems. The methods may include delivering alternating current to a target tissue of a patient via electrodes and electrode leads using a DC offset waveform. The electrodes or electrode leads may include one or more of: a high-density charge material, a SINE electrode, and / or a silver-silver chloride material. The methods may include increasing the excitability of target neurons, thereby lowering the threshold and extending the therapeutic window for stimulation of the target tissue.

[0032] In some embodiments, the target tissue may include the spinal cord.

[0033] In some embodiments, the frequency of the alternating current is at least about 10 kHz.

[0034] In some embodiments, the methods are used to treat or prevent pain in a patient.

[0035] The system disclosed herein can be configured to increase the effectiveness of an alternating current electrode system. The system can include a pulse generator. The system can include a controller capable of signaling the pulse generator using a DC offset waveform to deliver alternating current to a patient's target tissue via electrodes and electrode leads. The electrodes or electrode leads can include one or more of: a high-density charge material, a SINE electrode, and / or a silver-silver chloride material. The system can increase the excitability of target neurons, thereby lowering the threshold and extending the therapeutic window for stimulation of the target tissue.

[0036] In some embodiments, the target tissue may include the spinal cord.

[0037] In some embodiments, the frequency of the alternating current is at least about 10 kHz.

[0038] In some embodiments, the system is used to treat or prevent pain in a patient.

[0039] In some embodiments, the system can reduce the excitability of non-target tissue.

[0040] In some embodiments, the system can reduce side effects.

[0041] In some embodiments, a system for modulating action potential transmission along a nerve body includes an electron to ion current conversion cell (EICCC) comprising electrodes at which an electrochemical process occurs to generate an electric current in the form of ions to alter the electrical potential around the nerve and modulate the nerve membrane potential.

[0042] In some embodiments, a system for modulating action potential transmission along a nerve body includes an electron-to-ion current conversion unit comprising electrodes at which a capacitive charging process occurs to generate an ionic current to change the charge density around the nerve and modulate the nerve membrane potential.

[0043] In some embodiments, a system for modulating stimulus delivery along a nerve body includes an electron-to-ion current conversion unit comprising electrodes at which an electrochemical process occurs to generate an ionic current to alter the charge density around the nerve and modulate the nerve membrane potential.

[0044] In some embodiments, a system for modulating stimulus delivery along a nerve body includes an electron-to-ionic current conversion unit comprising electrodes at which electrochemical and capacitive charging processes occur to generate an ionic current to change the charge density around the nerve and modulate the nerve membrane potential.

[0045] In some embodiments, the system modulates electrical potentials near a nerve to place the neural tissue in a blocked state.

[0046] In some embodiments, the system places the target nerve in a state of severe nerve block.

[0047] In some embodiments, the system places the target nerve in a state of long-term nerve blockade.

[0048] In some embodiments, the system modulates the electrical potential to place the neural tissue in an inhibitory state.

[0049] In some embodiments, the system places the target nerve in a state of severe neural inhibition.

[0050] In some embodiments, the system places the target nerve in a state of neural hyperinhibition.

[0051] In some embodiments, the electrode comprises an electrode material of silver, silver chloride (Ag / AgCl).

[0052] In some embodiments, the electrode comprises an electrode material of silver (Ag).

[0053] In some embodiments, the electrode comprises an electrode material of silver chloride (AgCl).

[0054] In some embodiments, the quality of the electrode constituent materials is maintained within a specific range.

[0055] In some embodiments, the electrochemical process occurring at the electrodes is reversible.

[0056] In some embodiments, the electrodes are sacrificial and cannot be restored.

[0057] In some embodiments, the system includes an ionically conductive fluid immersed in an electrolyte and in electrical contact with neural tissue and electrically coupled electrodes.

[0058] In some embodiments, the ion conductor comprises a hydrogel material.

[0059] In some embodiments, the system includes one or more power sources connected to the one or more electrodes via leads.

[0060] In some embodiments, the ion conductor includes a proximal layer, such as a barrier or filter element, to selectively isolate electrochemical process byproducts within the electrolyte volume.

[0061] In some embodiments, the ion conductor includes a distal barrier or filter element to selectively isolate electrochemical process byproducts from neural tissue.

[0062] In some embodiments, the ion conductor includes multiple barriers or filter elements to selectively isolate electrochemical process byproducts from neural tissue.

[0063] In some embodiments, the system includes a biocompatible material that contacts the tissue.

[0064] In some embodiments, two or more systems for modulating stimulus delivery along a nerve body include an electron to ion current conversion unit to change the electrical potential around the nerve and modulate the nerve membrane potential.

[0065] In some embodiments, a method of maintaining constant nerve block using two or more systems by delivering direct current in the form of ions comprises operating one system in a block mode using current of one polarity while simultaneously operating the other system or systems in a mode using current of the opposite polarity.

[0066] In some embodiments, a method of delivering prolonged block to neural tissue comprises initially delivering an ionic current proximate the neural tissue to place the neural tissue in an inhibited state, wherein the block continues after cessation of the current.

[0067] In some embodiments, a method of delivering prolonged block to neural tissue comprises initially delivering an ionic current proximate to the neural tissue to place the neural tissue in an inhibited state, wherein the block continues after cessation of the current, and subsequently delivering current to maintain the nerve in its inhibited state.

[0068] In some embodiments, a method of delivering prolonged block to neural tissue comprises initially delivering an ionic current proximate to the neural tissue to place the neural tissue in an inhibited state, wherein the block continues after the current is ceased, and subsequently delivering current to maintain the nerve in its inhibited state such that current of opposite polarity between current delivery phases does not affect the inhibitory state of the nerve.

[0069] In some embodiments, a system for acquiring and modulating neural signal transmission characteristics of a DRG includes an introducer needle including an optional radiopaque marker and a probe and electrode configured to fit within the needle bore. The electrode includes strain relief and fixation features such as barbs and wires that provide electrical communication with a power source.

[0070] In some embodiments, a system for acquiring and modulating neural signal transmission characteristics of the spinal cord includes an introducer needle including an optional radiopaque marker and a stylet and electrode configured to fit within the needle bore. The electrode includes strain relief and fixation features such as barbs and wires that provide electrical communication with a power source.

[0071] In some embodiments, a method for obtaining and modulating the neural signal transmission characteristics of a DRG comprises inserting an introducer needle into a body cavity up to the nerve site, removing the probe, inserting an electrode, securing the electrode at a desired tissue site, removing the needle, and connecting an EICCC electrode lead to a power source and delivering an electric current to place the nerve in an inhibitory state.

[0072] In some embodiments, a method for acquiring and modulating neural signal transmission characteristics of the spinal cord comprises inserting an introducer needle into a body cavity to a nerve site, removing the probe, inserting an electrode, securing the electrode at a desired tissue site, removing the needle, and connecting an EICCC electrode lead to a power source and delivering an electric current to place the nerve in an inhibitory state.

[0073] In some embodiments, the system includes an external power source.

[0074] In some embodiments, the system includes an implantable power source.

[0075] In some embodiments, the system includes a programmable power supply.

[0076] In some embodiments, the system includes a sensor proximate to the neural tissue to monitor the neural tissue membrane potential and provide a feedback measurement for the power supply.

[0077] In some embodiments, the system includes a sensor that is an electrode used as a reference electrode to the working electrode in EICCC to monitor the electrode potential.

[0078] In some embodiments, methods for maintaining a nerve in a blocked state are disclosed wherein the nerve membrane potential is monitored and used as a signal to provide feedback to a power supply and power supply controller to enable modulation of the power supply output to an electrode.

[0079] In some embodiments, a system for delivering ionic current to neural tissue comprises: a current delivery source, a power source, an electrical connection to an EICCC using a connector element connectable to ionically conductive electrodes, wherein the system is hermetically sealed.

[0080] In some embodiments, a system for capturing and modulating the neural signaling properties of a DRG is used to alleviate pain caused by neuropathic pain.

[0081] In some embodiments, a system for capturing and modulating the neural signaling properties of a DRG or DRGs is used to alleviate pain caused by angina.

[0082] In some embodiments, a system for capturing and modulating the neural signaling properties of a DRG or DRGs is used to alleviate pain caused by ischemic pain.

[0083] In some embodiments, a system for capturing and modulating the neural signaling properties of a DRG or DRGs is used to alleviate pain due to Complex Regional Pain Syndrome (CPRS).

[0084] In some embodiments, systems for capturing and modulating the neural signaling properties of a DRG or DRGs are used to alleviate pain in specific areas of the body.

[0085] In some embodiments, a system for capturing and modulating the neural signaling properties of a DRG or DRGs is used to alleviate pain in a specific limb of the body.

[0086] In some embodiments, a system for capturing and modulating the neural signaling properties of a DRG or DRGs is used to alleviate pain in a specific area of ​​a body limb.

[0087] In some embodiments, a system for acquiring and modulating the neural signal transmission characteristics of a DRG or DRGs can deliver different current signals to different DRGs to improve the coverage of pain relief.

[0088] In some embodiments, a system for acquiring and modulating neural signaling properties of the spinal cord includes more than one electrode lead.

[0089] In some embodiments, a system for acquiring and modulating neural signaling characteristics of the spinal cord includes more than one electrode lead including one or more regions that contact and deliver electrical current to tissue.

[0090] In some embodiments, a system for acquiring and modulating neural signaling properties of the spinal cord includes more than one electrode lead at different levels along the spinal cord including one or more regions that contact and deliver electrical current to tissue.

[0091] In some embodiments, a system for acquiring and modulating neural signal transmission characteristics of the spinal cord includes more than one electrode lead that includes one or more regions for contacting and delivering current to tissue and can be individually adjusted to deliver a desired current and electric field to the tissue.

[0092] In some embodiments, methods for accessing and modulating neural signaling properties of the spinal cord include producing pain relief as part of perioperative pain blockade.

[0093] In some embodiments, methods for accessing and modulating neural signaling properties of the spinal cord include producing pain relief as part of rapidly reversible perioperative pain blockade.

[0094] In some embodiments, a method for harvesting and modulating neural signaling properties of a peripheral nerve to produce pain relief comprises delivering direct current to peripheral nerve tissue using an EICCC to relieve focal pain.

[0095] In some embodiments, a method for harvesting and modulating neural signaling properties of a peripheral nerve to produce pain relief comprises delivering direct current to peripheral nerve tissue using an EICCC to alleviate phantom limb pain.

[0096] In some embodiments, a method for harvesting and modulating the neural signaling properties of a peripheral nerve to produce pain relief comprises utilizing an EICCC to deliver direct current to peripheral nerve tissue to alleviate neuroma pain.

[0097] In some embodiments, a method for accessing and modulating the neural signaling properties of a peripheral nerve to produce pain relief comprises delivering direct current to peripheral nerve tissue using an EICCC to relieve neuropathic pain.

[0098] In some embodiments, methods for accessing and modulating neural signaling properties of renal nerves include reducing activity of the sympathetic nervous system to reduce hypertension.

[0099] In some embodiments, methods for accessing and modulating neural signaling properties of sympathetic ganglia include reducing activity of cervical sympathetic ganglia to reduce progression of heart failure.

[0100] In some implementations, a method for acquiring and modulating neural signaling characteristics of a sympathetic cervical ganglion includes reducing activity of the sympathetic cervical ganglion to reduce or prevent tachycardia.

[0101] In some embodiments, methods for accessing and modulating neural signaling properties of the vagus nerve include decreasing vagus nerve activity to increase heart rate.

[0102] In some implementations, methods for accessing and modulating neural signaling characteristics of the vagus nerve innervating the stomach include reducing vagus nerve activity to increase satiety and fullness.

[0103] In some embodiments, methods for accessing and modulating neural signaling properties of hepatic nerves include reducing activity of the sympathetic nervous system to increase insulin production.

[0104] In some embodiments, methods for accessing and modulating neural signaling properties of hepatic nerves include reducing activity of the sympathetic nervous system to reduce insulin resistance.

[0105] In some embodiments, methods for accessing and modulating neural signaling properties of brain tissue include accessing a desired area of ​​the brain and reducing the activity of neural tissue to treat a movement disorder.

[0106] In some embodiments, methods for accessing and modulating neural signaling properties of brain tissue include accessing a desired area of ​​the brain and reducing the activity of neural tissue to treat a psychiatric disorder.

[0107] In some implementations, methods for accessing and modulating neural signaling properties of brain tissue include accessing a desired area of ​​the brain and reducing the activity of neural tissue to treat chronic pain.

[0108] In some embodiments, disclosed herein is a system for performing nerve blockade on a patient using regenerative electrodes. The system may include a direct current generator and / or at least one electrode comprising silver chloride. The system may also include a controller configured to send a signal to the direct current generator to deliver a first direct current having a first polarity through the electrode sufficient to block conduction in the nerve and / or reduce the amount of silver chloride in the electrode, thereby forming solid silver and chloride ions. The controller may also be configured to send a signal to the direct current generator to deliver a second direct current having a second polarity through the electrode sufficient to increase the amount of silver chloride, thereby regenerating the electrode. The system may also include a nerve junction separated from the electrode by a selective barrier. The selective barrier may also be configured to allow chloride ions to pass through the barrier toward the nerve junction to block the nerve. The system may also include a sensor configured to determine whether a reaction, such as a primary silver / silver chloride reaction, is occurring. The controller may also be configured to receive data from the sensor and interrupt or adjust at least one of the first direct current signal or the second direct current signal during water electrolysis. The selective barrier may also be configured to prevent silver ions from passing through the barrier toward the nerve junction. The electrode may be housed in an insulating housing. The selective barrier may include an ion exchange membrane and / or a hydrogel. In some cases, the system may not have any mechanical moving parts. The controller may be configured to deliver the first direct current such that the amount of silver chloride reduced is greater than the surface area of ​​the electrode before the first direct current is delivered. The controller may also be configured to deliver the first direct current such that the amount of silver chloride reduced is greater than an amount such as about 1.25x, 1.5x, 2x, 3x, 4x, 5x, 10x, 15x, 20x, 50x, 100x, 1,000x, or more of an amount that can evenly cover a surface area, such as the entire functional surface area of ​​the electrode before the first direct current is delivered, or a range comprising any two of the foregoing values.

[0109] In some embodiments, disclosed herein are systems for performing nerve blockade on a patient using regenerative electrodes. The system may include one or more of the following: a direct current generator; at least one electrode comprising a solid component, an ionic component, and a nerve junction directly adjacent to the ionic component; and a controller configured to send a signal to the direct current generator to: deliver a first direct current having a first polarity through the electrode sufficient to block conduction in the nerve and reduce the amount of the solid component; and / or deliver a second direct current having a second polarity through the electrode sufficient to increase the amount of the solid component, thereby regenerating the electrode. The system may also include one or more sensors configured to determine whether a primary solid component / ionic component reaction is occurring. The controller may also be configured to receive data from the sensors and interrupt or adjust at least one of the first direct current signal or the second direct current signal during water electrolysis. The electrode or electrodes may be housed in an insulating housing, such as the same or different housings. The electrode may also include a layer, such as a selective barrier, separating the ionic component from the nerve. The layer may be configured to selectively allow negatively charged ions of the ionic component to pass through the layer toward the nerve and prevent positively charged ions of the ionic component from passing through the layer toward the nerve. The system can have no mechanical moving parts. The nerve junction can be separated from the electrode by one or more of a gel, a hydrogel, and an ionically conductive polymer. The electrode can be partially or completely surrounded by a solution, such as an electrolyte solution, for example, isotonic saline. The solid component can include silver, and / or the ionic component can include silver chloride. The controller can be configured to deliver the first direct current so that the amount of the solid component is reduced is greater than the surface area of ​​the solid component. The controller can also be configured to maintain the nerve in a highly inhibited state, at least partially preventing nerve conduction for at least about 10 minutes or longer after delivery of the first direct current ceases.

[0110] In some embodiments, the present invention also discloses a method for performing a nerve block in a patient using a regenerable electrode. The method may include one or more of the following: delivering a first direct current of a first polarity through an electrode comprising a first component adjacent to a nerve sufficient to block conduction in the nerve; and delivering a second direct current of a second polarity opposite to the first polarity through the electrode. The first direct current may reduce the amount of the first component of the electrode, thereby producing a second component that is different from the second component. The second direct current may increase the amount of the first component of the electrode and / or reduce the amount of the second component to renew the electrode. The method may also dynamically sense the amount of the first component or the second component in the electrode while delivering the first direct current; and stop delivering the first direct current when the amount of the first component is sensed to reach a predetermined threshold and / or when the water is electrolyzed.

[0111] Also disclosed herein is a method for extending nerve blockade using multiple regenerative electrodes. The method can include delivering a first direct current having a first polarity through a first electrode adjacent to a nerve sufficient to block conduction in the nerve, the electrode comprising a solid component and an ionic component; delivering a second direct current having a second polarity opposite to the first polarity through a second electrode axially spaced from the first electrode and adjacent to the nerve while the nerve is in a highly inhibited state; and / or reversing the polarity of the first and second direct currents, wherein reversing the polarity maintains the nerve in the highly inhibited state.

[0112] In some embodiments, the present invention also discloses a method for extending nerve blockade using at least one regenerative electrode. The method may include delivering a first direct current having a first polarity to an electrode adjacent to a nerve sufficient to block conduction in the nerve. Delivering the first direct current may place the nerve in a highly inhibited state, and after cessation of delivery of the first direct current, conduction in the nerve is at least partially blocked. The method may also include delivering a second direct current having a second polarity opposite to the first polarity entirely through the electrode while the nerve remains in the highly inhibited state. The electrode may be, for example, an electrochemical or capacitive electrode. The capacitive electrode may include, for example, tantalum or titanium. In some cases, the electrode may include silver and / or silver chloride. Delivering the first direct current may change the electrode from a first configuration to a second configuration, and delivering the second direct current may convert the electrode from the second configuration back to the first configuration, or at least closer to the first configuration. The second configuration may include a lower amount and / or lower charge than the material of the first configuration.

[0113] Also disclosed herein is a method for blocking neural tissue using at least one regenerative electrode. The method may include delivering a first direct current having a first polarity to an electrode proximate to the neural tissue, the electrode being sufficient to block conduction in the neural tissue. Delivery of the first direct current may place the neural tissue in a highly inhibited state, at least partially preventing conduction in the neural tissue after cessation of delivery of the first direct current. The method may also include maintaining the highly inhibited neural tissue for at least about 1 minute, 10 minutes, 1 hour, 24 hours, or longer. The method may also include sensing the conductivity of the neural tissue and / or maintaining the highly inhibited neural tissue in the highly inhibited state by delivering a third direct current to the neural tissue via the electrode after sensing the conductivity of the neural tissue, wherein the third direct current has the same polarity as the first direct current. Sensing the conductivity of the neural tissue may include delivering a stimulation pulse to the neural tissue and measuring a compound action potential signal via a reference electrode, and / or measuring a potential difference. The neural tissue may include one or more of the following: nerves, such as spinal, cranial, or peripheral nerves, or brain tissue, dorsal root ganglia, spinothalamic tissue, autonomic nervous tissue, sympathetic nervous tissue, or parasympathetic nervous tissue. Direct current can be therapeutically effective in treating pain, such as acute or chronic pain and / or ischemic pain. Direct current can also be therapeutically effective in treating psychiatric conditions, such as depression, anxiety, obsessive-compulsive disorder, PTSD, mania, or schizophrenia; movement disorders, such as Tourette syndrome, Parkinson's disease, spasticity, or essential tremor; and / or cardiopulmonary conditions, such as hypertension, congestive heart failure, ischemic cardiomyopathy, angina, or arrhythmia.

[0114] Also disclosed herein is a system for extending nerve blockade using reversible electrodes. The system may include one or more direct current generators; at least one electrode comprising a solid component, an ionic component, and a nerve junction adjacent to the ionic component; and a controller configured to send a signal to the direct current generator to: deliver a first direct current having a first polarity through the electrode sufficient to block conduction in the nerve; maintain the nerve in a highly inhibited state, at least partially preventing nerve conduction after cessation of delivery of the first direct current; and / or deliver a second direct current having a second polarity entirely through the electrode.

[0115] Also disclosed herein are methods for providing extended nerve blockade using regenerative electrodes. The method can include delivering a first direct current of a first polarity through an electrode adjacent to a nerve sufficient to block conduction in the nerve, the electrode comprising a first component and a second component; highly inhibiting the nerve so that nerve conduction is at least partially blocked upon cessation of the first direct current; and / or delivering a second direct current of a second polarity opposite to the first polarity through the electrode while the nerve is in the highly inhibited state. The first direct current can reduce the amount of the first component and increase the amount of the second component. The second direct current can increase the amount of the first component and reduce the amount of the second component to renew the electrode. In some embodiments, the method does not completely deplete the first component. The method can also include sensing the amount of at least one of the first component and the second component; and cessation of delivery of the first direct current when the amount of the first component reaches a predetermined minimum threshold. After delivery of the first and second direct currents, the net charge delivered to the nerve can be zero. The first direct current can be an anodic current or a cathodic current, and the second direct current can be a cathodic current or an anodic current. The method may further include sensing the conductivity of the nerve and / or maintaining the nerve in a highly inhibited state by delivering a third direct current to the nerve via the electrode after sensing the conductivity of the nerve, wherein the third direct current has the same polarity as the first direct current. Sensing the conductivity of the nerve may include delivering a stimulation pulse to the nerve and measuring a compound action potential signal via a reference electrode, and / or measuring a potential difference. In some embodiments, there may be a current-free gap between delivering the first direct current of the first polarity and delivering the second direct current of the second polarity.

[0116] The method may further include at least one, two, or more additional cycles of direct current. A cycle may include delivering a first direct current of a first polarity through the electrode and delivering a second direct current of a second polarity opposite to the first polarity. The method may further include implanting the electrode in proximity to the nerve, placing the electrode percutaneously in proximity to the nerve, and / or placing the electrode percutaneously in proximity to the nerve. The nerve may be separated from the electrode by a gel, hydrogel, ionically conductive polymer, and / or layer. The electrode may be partially or completely surrounded by an electrolyte solution, such as an isotonic saline solution.

[0117] In some embodiments, a direct current power delivery system can include any number or combination of features disclosed herein.

[0118] BRIEF DESCRIPTION OF THE DRAWINGS

[0119] In the following detailed description, reference is made to the accompanying drawings, which form a part thereof. In the accompanying drawings, similar symbols generally identify similar components unless the context indicates otherwise. Therefore, in some embodiments, part numbers may be used for similar components in multiple figures, or part numbers may vary from figure to figure. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It is readily understood that various aspects of the present disclosure, as generally described herein and shown in the accompanying drawings, may be arranged, substituted, combined, and designed in a variety of different configurations, all of which are expressly contemplated and form a part of this disclosure.

[0120] Figure 1A An embodiment of an EICCC electrode is shown, wherein the electrode is immersed in an electrolyte solution that contacts an ionically conductive material-electrolyte solution interface that is in electrical contact with neural tissue N or a region near neural tissue N.

[0121] Figure 1B The graph shows that by pushing a constant current from a power supply, the mass of the AgCl electrode can decrease during the cathodic current (reduction reaction) and then increase with the anodic current during the oxidation reaction.

[0122] Figure 1C Shown is how, according to some embodiments of the present invention, current delivered to an electrode cell (EICCC) (top) can be coupled to charge delivered to an electrode cell-nerve junction (middle) to provide neural blockade (bottom) while achieving zero net charge transfer over a longer charge period.

[0123] exist Figure 1D , waveform patterns delivered to electrode units to facilitate nerve block are shown according to some embodiments of the present invention, wherein current delivered to the electrode units and corresponding nerve block periods are shown, including regions of high inhibition where nerve block occurs regardless of the current delivered to the neural tissue.

[0124] Figure 1E An embodiment of an electron-ion current conversion cell (EICCC) is shown, connected to a power supply via electrically insulated wires.

[0125] Figure 1F A configuration is shown in which the nerve block appears activated when the electronic current has one polarity as designated by the positive axis, and appears inactivated when the polarity of the current is reversed as designated by the negative axis.

[0126] Figure 1G Shown with Figure 1EA similar configuration, but with isolation barriers that separate the conventional electrodes from the ionic conductors, and the ionic conductors from the nerves themselves, respectively.

[0127] Figure 1H Shown with Figure 1F Similar graphs of current versus time and nerve block state versus time.

[0128] Figure 1I Shown with Figure 1H A similar configuration, but also includes feedback sensors that monitor the condition of the neural tissue and / or areas adjacent to the nerve N.

[0129] Figure 1J Shown with Figure 1I Similar graphs are shown for current versus time and nerve block conditions versus time.

[0130] Figure 2A A two-electrode system is shown, wherein according to some embodiments, there are two EICCC interfaces with the nerve.

[0131] like Figure 2B As shown, the two electrodes are driven with currents of opposite polarity as a function of time, such that when one is in the active blocking phase, the other is in the inactive non-blocking phase, and once the current polarity is reversed again, it resets the electrodes to block.

[0132] Figure 3A-3B An embodiment is shown where dual conventional electrodes are incorporated into the nerve junction, but are driven by a power source via electrically insulated wires with currents of opposite polarity, so that when one is in the blocking phase, the other is in the non-blocking phase, which resets the electrodes to block once the current polarity is reversed again.

[0133] Figure 3C-3D An embodiment is shown where dual EICCCs are incorporated into neural N junctions but driven with currents of opposite polarity such that when one is in the blocking phase, the other is in the non-blocking phase, which resets the electrodes to block once the current polarity is reversed again.

[0134] Figure 4A An embodiment of an EICCC electrode is shown wherein the electrode is immersed in an electrolyte solution in contact with an ionically conductive material such as a hydrogel, gel, or other polymer fluid that is in electrical contact with neural tissue or a region near neural tissue.

[0135] Figure 4B Shown with Figure 4A A similar system as shown in , additionally with a reference electrode close to the electrode (working electrode) to monitor the voltage drop across the working electrode, is used for EICCC monitoring purposes.

[0136] Figure 4C Shown with Figure 4A A similar system as shown in , additionally with a reference electrode adjacent to the neural tissue interface to monitor the voltage drop across the EICCC to the neural tissue, for EICCC monitoring purposes.

[0137] Figure 4D-4F An embodiment of an electrode lead configured to be inserted into a conventional IPG (implantable pulse generator) and extending from a power source (not shown, proximal end) is shown.

[0138] Figure 4G A schematic embodiment of an EICCC is shown integrated within a hermetically sealed housing containing a power source, battery, or power supply, and a controller that drives the EICCC.

[0139] Figure 5A-5B An embodiment of an electrode configuration is shown in which both electrode contacts are housed within the same electrically insulating housing.

[0140] Figure 6A The dorsal roots and / or dorsal root ganglia (DRGs) through which pain signals pass are shown.

[0141] Figure 6B Shown are embodiments of blocking electrodes positioned along the DRG to facilitate nerve blockade, as well as leads and a power source.

[0142] Figure 6C It is shown that the DRG can be accessed with a needle, and that the needle can be used to penetrate the dura mater, as shown.

[0143] like Figure 6D and Figure 6E As shown, the electrode-nerve junction contact can then be placed in contact with or near the DRG, and the introducer needle can be retracted to leave the electrode lead and nerve tissue interface in the desired location.

[0144] Figure 7 It was shown that the associated dorsal root ganglion from each vertebral level corresponds to a specific skin patch in the body, and that blocking pain signals at the level of the DRG can reduce pain sensing at the skin patch innervated by that specific DRG.

[0145] Figure 8A Placement of stimulating electrodes near the lateral spinothalamic tract (LT tract) is shown, which can utilize the EICCC to produce nerve block at the desired level (and / or spinal cord level, at the end of the EICCC (away from the head) because pain signals are conducted in an upward direction) and provide selective pain blockade depending on unilateral (left or right) or bilateral placement of the electrodes.

[0146] Figure 8B A percutaneous placement procedure with or without fluoroscopic guidance, such as by using a Tuohy or similar needle, is shown to introduce the lead into the epidural space.

[0147] The wire can be guided along the spinal column within the epidural space so that it is positioned between the spinal nerve exit areas and the tissue junction is close to the lateral spinothalamic tract, e.g. Figure 8C-8E shown.

[0148] Figure 9A An electron-ion current conversion cell (EICCC) electrode configured to interface with a deep brain block (DBB) target in the thalamus is shown.

[0149] exist Figure 9B , an embodiment of a blocking / inhibiting electrode integrated with a sensing electrode is shown.

[0150] Figures 10A-10C An embodiment of an EICCC electrode is shown in FIG, wherein multiple tissue interfaces are present on the electrode and are individually addressable.

[0151] Figure 10B yes Figure 10A A close-up view of 10B-10B.

[0152] Figure 10C yes Figure 10A A close-up view of 10C-10C.

[0153] like Figure 11 As shown, the blocking electrode lead is in contact with the renal nerve to promote blockade or inhibition. Also shown is the EICCC in open connection to a power source (not shown).

[0154] like Figure 12 Shown are the associated sympathetic ganglia, including the cervical and stellate (cervicothoracic) ganglia, and their innervated targets in the heart.

[0155] Figure 13 Select anatomical structures related to the sympathetic nervous system are shown.

[0156] Figure 14 An embodiment of an EICCC electrode is shown placed around or near the right (and / or left) vagus nerve within the right side of the neck and / or chest, with electrode leads extending downward toward an implantable power source shown in the right chest area.

[0157] Figure 15-16 An embodiment of a dual EICCC system is shown in which each vagus nerve is encased in a tissue interface in the form of a cuff where ionic current is deposited from the EICCC at the tissue site.

[0158] Figure 17 Non-limiting anatomy is schematically shown where sympathetic inhibition or blockade can also be used to regulate liver function and affect glucose and insulin production.

[0159] Figure 18 An EICCC system according to some embodiments of the present invention is shown in which the hepatic artery and the nerves surrounding the artery are surrounded by a tissue interface in the form of a cuff.

[0160] Figure 19 The drive voltage waveform and the positive and negative thresholds are shown over time.

[0161] Figure 20 The drive voltage waveform over time is shown, along with the positive and negative thresholds.

[0162] Figure 21 Schematically illustrated are graphs of voltage and current versus time illustrating an electrode conditioning process where the current amplitude is ramped to a set target based on a drive voltage value relative to a set threshold.

[0163] Figure 22 Systems are shown that can include a nerve-tissue interface operably connected to a catheter configured to retain a fluid.

[0164] Figure 23A A system is shown that includes a reaction chamber containing reactive materials.

[0165] Figure 23B Shown are separate junction nerve electrodes that may include integrated sensors for detecting the electrochemical state of the reacting / working electrode.

[0166] Figure 24 Systems and methods are described for delivering DC current to tissue using battery-type chemistries, such as lead-acid, nickel-cadmium, nickel-metal hydride, lithium-ion, lithium polymer, zinc-carbon, bio-batteries, or other types of battery chemistries.

[0167] Figure 25 A SINE type electrode is schematically shown, modified to allow engagement at the site of the patient to reduce the length and impedance of the catheter.

[0168] Figure 26A A wearable system is shown that includes a DC generator, wires, and a reaction chamber, with a portion of the wire / catheter implanted at the desired anatomical site. Figure 26B A bandage-type system is shown localized to the treatment site (eg, nerve block). Figure 26C Schematic embodiments of such a wearable device are shown with two different wire exit configurations.

[0169] Figures 27A-27D Methods of treating pain or other conditions by circulating DC blockade at multiple locations spaced apart from one another are disclosed.

[0170] Figure 28A A DC current system including an optional reference electrode for voltage monitoring is schematically shown. Figure 28B In the simple example shown, the electrode voltage increases with continued DC current delivery.

[0171] Figure 29 This demonstrates that the voltage can be maintained within a desired range with upper and lower threshold bands that limit the electrochemical reactions occurring at the electrode sites.

[0172] Figures 30A-30C An embodiment of a single-fault-safe DC system and method is shown.

[0173] Figure 31 A silver-silver chloride electrode is shown schematically.

[0174] Figure 32 A counter electrode and a working electrode are shown immersed in an electrolyte bath and connected to a power supply that drives a potential across the two electrodes.

[0175] Figure 33 The driving voltage on the working electrode is shown.

[0176] Figure 34 It is shown that under fixed current amplitude and fixed duration, cycling of the silver / silver chloride reaction is demonstrated to cause the peak drive voltage to decrease with increasing cycle number.

[0177] Figure 35 The processing of the working electrode and counter electrode formation in the formation step is shown, where the current level starts at a relatively low value and increases with each cycle when the driving voltage upper threshold is not exceeded.

[0178] Figure 36 The microstructural changes that can occur after building up the AgCl layer on a bare silver electrode, as well as after performing the formation and stabilization / conditioning steps to condition the AgCl-coated electrode are shown.

[0179] Figure 37 The drive voltage at which the lower drive voltage threshold begins to be exceeded is shown as a function of time.

[0180] Figure 38 shows that the electrodes and the body can be modeled as parallel resistors (R 导线 ) and capacitor (C 导线 ), and the body impedance in series with the electrodes (R 身体). At low drive frequencies, the above equation can be used to reflect Figure 39 The electrodes and body are modeled as shown in . At high drive frequencies, the Figure 40 The system is modeled as shown in , where the capacitor behaves like a short circuit and has no impedance.

[0181] Figure 41 A portion of the waveform is shown where the threshold is reached, and the current is reduced to remain below the threshold. Detailed Description of the Invention

[0183] Although certain embodiments and examples are described below, the present disclosure extends beyond the specifically disclosed embodiments and / or uses and obvious modifications and equivalents thereof. Therefore, it is intended that the scope of the present disclosure should not be limited by any particular embodiments described below.

[0184] In some aspects, the present application describes methods and systems for managing chronic and acute pain conditions by safely applying direct current (DC) to promote nerve blockade, including neural hyperinhibition, or nerve blockade that is not rapidly reversible or resilient after removal or cessation of DC application. By coupling to nerve junctions via ion-conducting pathways instead of conventional electrodes that do not have ion-conducting components, intermittent or continuous short-term and long-term nerve blockade can be produced while reducing the risk of damage to nerve cells. In some embodiments, systems and electrodes are disclosed for safely delivering blocking direct current (DC) to neural tissue by delivering circulating cathodic and anodic currents via high-charge chemical processes. Tissue safety can be maintained by separating the metal junction from the neural tissue using ion-conducting elements and operating the electrodes below the reaction potential of undesirable reactions, such as the electrolysis of water or the oxidation and reduction of water (H2O), which can produce harmful reactive species such as OH-, H+, or oxygen radicals.

[0185] Without being limited by theory, the conduction of action potentials in electrically excitable tissues, such as neural tissue, results in a millisecond refractory period for sodium channels, typically between about 1 ms and about 20 ms, or between about 2 ms and about 5 ms for the combined absolute and relative refractory periods, and thus very low frequency AC current waveforms having a half-cycle significantly greater than this refractory period (e.g., greater than about 1 ms, 1.5 ms, 2 ms, 2.5 ms, 3 ms, or longer) can also be used to produce tissue block and be sensed by the electrically excitable tissue as direct current stimulation. Thus, direct current, as defined herein, includes low frequency AC current waveforms that are sensed as and functionally are direct current from the perspective of the tissue whose action potential is being modulated. The frequency can be, for example, less than about 1 Hz, 0.5 Hz, 0.1 Hz, 0.05 Hz, 0.01 Hz, 0.005 Hz, 0.0001 Hz, or a range including any two of the foregoing values, as long as the direction of the current is constant over at least the entire refractory period of the target tissue, or is at least twice as long as the time constant of the membrane channel that causes the refractory period (e.g., the inactivation gate time constant of a fast sodium channel).

[0186] Chronic pain is a significant burden on individuals and society as a whole. In the United States alone, it is estimated that nearly 50 million adults suffer from severe chronic or severe pain. (See Nahin, Estimates of Pain Prevalence and Severity in Adults: United States, 2012, The Journal of Pain, 2015 August 16 (8): 769-780). Worldwide, chronic pain is estimated to affect more than 1.5 billion people. (Borsook, A Future Without Chronic Pain: Neuroscience and Clinical Research, Cerebrum, June 2012). Although surgical techniques are sometimes applied to eliminate specific pain sources, usually due to the influence of nerves, in many cases, the exact cause of the pain is unclear and cannot be reliably resolved by surgery. Alternatively, pain management can be addressed by suppressing the central nervous system using stimulation signals that block access to pain input (gate control theory of pain). Typically, in the case of spinal cord stimulation (SCS), the stimulation is performed using metal electrodes and alternating current (AC) stimulation to generate these additional stimulation signals to prevent pain perception. However, a major disadvantage is the presence of paresthesia, i.e., a tingling sensation in the innervated area downstream of the stimulated nerve. Methods to eliminate paresthesia, which may cause discomfort to the patient, have led to stimulation modalities different from conventional tonic SCS (~30-120 Hz) stimulation, including high-frequency stimulation (~10 kHz) and burst stimulation (e.g., five pulses of 500 Hz delivered 40 times per second). (Tjepkema-Cloostermans et al, Effect of Burst Evaluated in Patients Familiar With Spinal Cord Stimulation, Neuromodulation, 2016 July 19(5):492-497).

[0187] An alternative approach to managing pain signals sent to the central nervous system is to block the conduction of pain signals from peripheral sources by indirectly blocking pain signals, rather than masking the pain signals by generating alternative neural inputs to crowd out and inhibit pain signal transmission as in traditional SCS and gate theories. One way to achieve this is to apply direct current (DC) to the nerve to block the generation and transmission of action potentials (APs). Because this does not stimulate the nerve as in traditional stimulation, paresthesias can be avoided. The mechanism causing AP block has been attributed to depolarization block, which inactivates the sodium channels required for action potential events under the electrode site. (See Bhadra and Kilgore, Direct Current Electrical Conduction Block of Peripheral Nerve, IEEE Transactions on Neural Systems and Rehabilitation Engineering, 2004 September 12(3):313-324).

[0188] Bhadra et al. showed that action potential conduction can be blocked after DC is applied to neural tissue (see Bhadra and Kilgore, Direct Current Electrical Conduction Block of Peripheral Nerve, IEEE Transactions on Neural Systems and Rehabilitation Engineering, September 12, 2004 (3): 313-324). The authors showed that removing DC delivery from the same neural tissue can lead to immediate restoration of nerve conduction. However, direct current has long been considered dangerous to neural tissue due to the production of toxic substances at the electrode-nerve interface (Merrill, Electrical Stimulation of Excitable Tissue: Design of Efficacious and Safe Protocols, Journal of Neuroscience Methods, 2005, 141: 171-198). Ackermann et al and Fridman et al have developed systems and methods for safely delivering DC to neural tissue by separating toxic substances generated at the electrode interface from the neural tissue (U.S. Patents Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface Nerve Electrode Prevents Direct Current Induced Nerve Damage, J Neurosci Methods, 2011 September 201(1):173-176; Fridman and Santina, Safe Direct Current Stimulation to Expand Capabilities of Neural Prostheses, IEEE Transaction of Neural Systems and Rehabilitation Engineering, 2013 March 21(2):319-328; Fridman and Santina, Safe Direct Current Stimulator 2: Concept and Design, Conf Proc IEEE Eng Med BioSoc, 2013:3126-3129), each of which is incorporated herein by reference in its entirety.They also teach that rapid reversibility of nerve block is desirable and can be achieved by stopping DC delivery. Ackermann et al. teach that undesirable but reversible inhibition of neural activity occurs under long-term direct current delivery (wherein neural tissue is shown to be non-conductive shortly after stopping DC delivery) (U.S. Patent Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface Nerve Electrode Prevents Direct Current Induced Nerve Damage, J Neurosci Methods, 2011 September 201(1):173-176), each of which is incorporated herein by reference in its entirety. Those authors explicitly teach methods for reducing the inhibition of neural activity by limiting the duration of DC delivery to allow rapid nerve recovery (e.g., within seconds) after cessation of DC delivery (U.S. Patents Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface Nerve Electrode Prevents Direct Current Induced Nerve Damage, J Neurosci Methods, 2011 September 201(1):173-176). Invented and described herein in some embodiments are systems and methods that perform the opposite of what Ackermann et al teach: intentionally blocking neural activity by using periodic DC pulses to intentionally place neural tissue in a highly inhibited state without rapid reversibility after cessation of DC delivery (reversibility occurs over minutes to hours, as opposed to seconds or less than 1 minute). Furthermore, invented and described herein in some embodiments are systems and methods for treating pain by the above-described systems and methods, particularly by selectively blocking the anterolateral column tissue in the spinal cord. Furthermore, invented and described herein are systems and methods for treating pain by the above-described systems and methods, particularly by selectively blocking dorsal root tissue and / or dorsal root ganglia. Furthermore, invented and described herein are systems and methods for treating pain by the above-described systems and methods, particularly by blocking one or more peripheral nerves.

[0189] With targeted nerve blocks, pain from specific skin patches and pain in localized body parts can be managed. Many local targets related to reducing pain signaling can be addressed. For example, more centrally located neural tissue such as the spinothalamic tract and dorsal root ganglia can be targeted to manage low back pain, sciatica, and complex regional pain syndrome (CPRS), among other pain considerations.

[0190] The electrode for producing an electric current in the form of ions near at least one target nerve can include an ion conductive material, such as a liquid (e.g., saline or other electrolyte solutions), a gel, a hydrogel, a hydrocolloid, a polymer or a film. In an optional embodiment, the ion conductive material can be isolated from the neural tissue by a barrier or other filter or membrane material. The separation interface can be configured to selectively allow ions to enter the nerve to reduce nerve damage, such as microporous sieves, non-woven sieves, ion exchange membranes (IEMs), supported liquid membranes or ion gels, polymer electrolytes, such as polyethylene oxide (PEO), polypropylene oxide (PPO), polyvinylidene fluoride-hexafluoropropylene copolymer (PVDF-HFP), solid ion conductors and ion selective membranes including cation exchange membranes and anion exchange membranes.

[0191] The nerve interface element of the electrode can also be configured to be selectively exposed along the electrode and can additionally be insulated from the nerve by the ion-impermeable layer.The impermeable layer can also be configured to electrically insulate from electrical current.

[0192] The ion conductive material can also be divided into multiple regions, which can contain different types of ion conductive materials. The interface between different regions can be outlined by semipermeable membranes or barriers that allow selective or general ion flow, but can limit the destruction of products generated by the conversion of electron flow to ionic current. The separation element can be configured to selectively allow ions to enter the nerve to reduce nerve damage, such as microporous screens, non-woven screens, ion exchange membranes (IEMs), supported liquid membranes or ion gels, polymer electrolytes, such as polyethylene oxide (PEO), polypropylene oxide (PPO), polyvinylidene fluoride-hexafluoropropylene copolymer (PVDF-HFP), solid ion conductors and ion selective membranes including cation exchange membranes and anion exchange membranes. Different ion conductive materials can also take different forms. For example, the nerve can be in contact with a hydrogel, which is in contact with a liquid such as an electrolyte solution, which is then in contact with a traditional current electrode material.

[0193] In some embodiments, conventional electrodes can be made of materials such as platinum, platinum-iridium, carbon, titanium nitride, copper, tantalum, silver, silver chloride or other metals and materials or combinations thereof. In some embodiments, conventional electrodes can be made of carbon, graphite, glassy carbon, dendritic carbon or other conductive materials. Blockade can be increased by using direct current (DC) of high charge chemical amplitude and duration. Candidate chemical methods include use in an electrolyte bath (or other suitable ion conductive material), such as a combination of Ag / AgCl electrodes in saline that is in ionic contact with the target neural tissue. In some embodiments, the electrode is reversible and can be restored to its original state. In some embodiments, the electrode is sacrificial and the electrochemical reaction occurring at the electrode cannot be reversed to restore the electrode to its original state.

[0194] The electrodes can be made of a variety of materials. In some embodiments, the electrodes can be made of silver (Ag) and / or silver chloride (AgCl). In some embodiments, the electrodes can be made of titanium nitride (TiN). In some embodiments, the electrodes can be made of carbon (C). In some embodiments, the electrodes have an ion-selective coating or membrane. In some embodiments, the electrodes do not have an ion-selective coating or membrane.

[0195] In some embodiments, the electrode may include a contact comprising a high charge capacity material. In some cases, the electrode contact may have a thickness of approximately 1 mm. 2 to about 10mm 2 , or about 1mm 2 , 2mm 2 , 3mm 2 , 4mm 2 , 5mm 2 , 6mm 2 , 7mm 2 , 8mm 2 , 9mm 2 , 10mm 2 , 20mm 2 , 50mm 2 , 100mm 2, or a geometric surface area including a range of any two of the above values. The electrode contact itself can be made of a material with high charge capacity, such as those described in, for example, U.S. Patent No. 10,071,241 of Bhadra et al., which is incorporated herein by reference in its entirety. Alternatively, the electrode contact can include a substrate coated at least partially or completely with a high charge capacity material. In some embodiments, the high charge capacity material can have a Q value of at least about 25, 50, 100, 200, 300, 400, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 1000,000, 500,000 or more μC, or a range including any two of the above values. The Q value of the electrode contact can refer to the total amount of charge that can be transported by the electrode contact before the electrode contact begins to have an irreversible chemical reaction, such as oxygen or hydrogen release, or the dissolution of the electrode material. Non-limiting examples of high charge capacity materials are platinum black, iridium oxide, titanium nitride, tantalum, silver chloride, poly (ethylenedioxythiophene) and suitable combinations thereof. In some embodiments, the electrode can be a fractal coated electrode. In order to produce a larger surface area for electrochemical reactions, conventional electrodes can be made from structures with a high surface area / volume ratio, such as a rough surface, a fabric surface, a patterned surface, a reticulated foam structure, a porous sintered microbead structure, a nanoscale or micrometer-scale patterned structure to expose additional material surface area. In some embodiments, the electrode can be a SINE (separated junction neural electrode) or an EICCC (electron to ion current conversion cell) electrode, wherein the electrode is immersed in an electrolyte solution that contacts an ionically conductive material - an electrolyte solution that is combined with an ionically conductive material interface in electrical contact with cardiac tissue or an area near cardiac tissue, such as described in U.S. Patent No. 9,008,800 of Ackermann et al. and U.S. Publication No. 2018 / 0280691 of Ackermann et al., which are hereby incorporated herein by reference in their entirety.

[0196] The combination of conventional electron-carrying electrode materials and ion-conducting materials, as well as the conversion mechanism, can be collectively characterized as an electron-ion current conversion cell (EICCC). One such example would be a silver / silver chloride (Ag / AgCl) electrode immersed in saline, for example, an isotonic 0.9% NaCl saline solution with a hydrogel fluid base containing saline. Upon driving a current through a conventional electrode, the reduction of solid AgCl drives the conversion of solid Ag and the formation of Cl- ions, thereby generating an ion flow or ionic current. This ionic current can be used to modulate the neural membrane potential and, for example, produce a block in nerve conduction. The membrane potential can be modulated in such a way that the potential ramps up slowly enough to avoid generating an action potential when the neural tissue is depolarized. Upon current reversal, the previously formed Ag or other Ag in the Ag / AgCl electrode is oxidized, thereby generating an AgCl deposit on the electrode, driving the ionic current in the opposite direction. Due to the extremely low solubility of Ag and AgCl in saline, the electrode remains mechanically intact during both forward and reverse current delivery. In combination, the reduction-oxidation reaction produces a fully reversible EICCC. In order to maintain the preferred reduction-oxidation reaction between Ag and AgCl (or other electrode materials), the amount of AgCl on the electrode, such as mass, volume, density or other parameters can be maintained within 5%-95%, 10%-90%, 20%-80%, 25%-75%, 30%-70% of its initial starting mass on the electrode to ensure that AgCl is not depleted or saturated, thereby preventing other harmful reactions from occurring at the electrode. In some embodiments, the amount of the electrode can be maintained at at least about or no more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or a range between about any two of the above values. In other words, the electrode is reversible and can be restored to its original or substantially original state. In order to create a larger surface area for electrochemical reactions, conventional electrodes can be made from structures with a high surface area to volume ratio, such as a rough surface, a fabric surface, a patterned surface, a reticulated foam structure, a porous sintered microbead structure, a nanoscale or microscale patterned structure to expose additional material surface area. High charge chemical electrodes can be biocompatible, or if not, can be properly isolated from the body. The high surface area electrode materials (e.g., Ag / AgCl) in EICCC can be specifically used to reduce the electrode potential drop or reduce the increase in electrode potential drop that may occur with prolonged current delivery.In some embodiments, the EICCC drive current can be about 0 mA to about 1 mA, about 1 mA to about 2 mA, about 2 mA to about 4 mA, about 4 mA to about 8 mA, greater than about 8 mA, about 0.5 mA, 1 mA, 2 mA, 3 mA, 4 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, 10 mA, or a range comprising any two of the foregoing values. In some embodiments, this drive current is then used to generate a corresponding ion current of similar magnitude depending on the specific electrochemical reaction.

[0197] Another embodiment of the EICCC can include materials such as tantalum or titanium nitride to create a capacitive conventional electrode interface rather than an interface where an electrochemical reaction occurs. Transparent conductive oxides (TCOs) such as fluorine-doped tin oxide (FTO), nickel titanium dioxide (Ni / TiO2) and other titanium dioxide (TiO2) configurations are also candidate materials with high capacitance. In this configuration, the charge generation at the surface of the conventional electrode will attract ionic materials from the ion conductive material until the charge at the conventional electrode interface is passivated. Charging the capacitive material with a current having one polarity can generate an ionic current. Converting the polarity of the current to the capacitive material can effectively reset the system for subsequent charging to generate additional ionic current. In order to create a larger surface area to produce an increase in the ability of the ionic current to flow, the conventional electrode can be made from a structure with a high surface area / volume ratio, such as a rough surface, a reticulated foam structure, a porous sintered microbead structure, a nanoscale or microscale patterned structure to expose additional material surface area. In one embodiment, the capacitive structure is in fluid contact with an electrolyte solution that contacts an electrolyte-saturated hydrogel in contact with target neural tissue to enable ionic current flow to the tissue.

[0198] In another embodiment of the EICCC, a combination of electrochemical and capacitive mechanisms can be used to convert the electrical current in the form of electrons to the form of ions.

[0199] To deliver ionic current to the nerve to facilitate blockade, conventional electrodes can be connected to one or more power sources via conductive wires. When current is applied to the EICCC at one polarity (block phase), a single nerve-electrode junction can provide nerve blockade. When the current polarity is reversed to return the electrode to its original state (which can be either a non-block phase or a block phase), the nerve may or may not continue to block painful stimuli from passing through the nerve. If the nerve is placed in a high inhibitory state, the nerve will continue to prevent AP conduction and block pain regardless of the phase condition of the electrode. Fridman and Santina have described a method for using a series of valves to direct the direction of current to enable continuous blockade when the polarity of the current is reversed, such as by an alternating current (AC) drive (Fridman and Santina, Safe Direct Current Stimulation to Expand Capabilities of Neural Prostheses, IEEE Transaction of Neural Systems and Rehabilitation Engineering, 2013 March 21(2):319-328; Fridman and Santina, Safe Direct Current Stimulator 2: Concept and Design, Conf Proc IEEE Eng Med Bio Soc, 2013:3126-3129). However, in some cases, it is desirable to have a simpler system that does not require the use of valves, which would introduce additional points of failure and increase the size of the implantable system. By using multiple EICCCs to provide constant stimulation of the neural tissue itself, a simpler, more reliable system without valves and such moving parts can be configured. In one embodiment that provides continuous blockade, there are two nerve-electrode interfaces and are connected to one or more power sources. The first nerve-electrode junction EICCC operates with current at one polarity to drive blockade, while the second nerve-electrode junction EICCC operates with the opposite polarity. After a period of time, the current polarity of the first EICCC and the second EICCC is reversed, and the second nerve-electrode junction provides blockade while the state of the first nerve-electrode junction EICCC is reversed to its previous state. By circulating the dual EICCC electrode current, continuous blockade can be maintained at the target nerve. As can be appreciated, more than two, such as 3, 4, 5, 6, 7, 8, 9, 10 or more EICCCs can also be used to promote the same continuous blockade. The electrodes can also be operated in a monopolar or bipolar configuration. In some embodiments, the EICCC system is configured without any mechanically moving parts, such as valves or hinges.

[0200] Optionally, neural activity can be inhibited, meaning that neural activity remains blocked even after the blocking current is removed or interrupted. The nerve can be further placed in a high inhibitory state, wherein the nerve remains blocked without rapid reversibility after cessation of DC delivery. The nerve can be placed in an inhibitory state using an initial current delivered to the neural tissue, including regulation of the ramp rate, current amplitude, total charge delivery, and waveform. During the inhibitory state, the EICCC can be returned to its initial state by reversing the polarity of the current used to produce the initial block and the inhibitory state. The nerve can remain in a high inhibitory state during the reversal of the current. In another configuration, the EICCC can deliver subsequent blocking current inputs that extend the duration of inhibition, wherein there are time periods of no current delivery or reversal of the current during the blocking current. The neural tissue can remain in a high inhibitory state during the non-blocking current input. In another configuration, the EICCC can be configured to deliver subsequent current inputs as planned. In some embodiments, the DC blocking waveform can have an amplitude of 0-250 microamperes, 250-500 microamperes, 500-1000 microamperes, 1000-1500 microamperes, or 2000 microamperes or more, or about, at least about, or no more than about 50, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1800, 1,900, 2000 microamperes or more, or other range including any two of the foregoing values. In some embodiments, placing a nerve in a high inhibitory state can be facilitated by delivering a charge of 10–50 millicoulombs, 50–100 millicoulombs, 100–500 millicoulombs, 500–1000 millicoulombs, or 1000 millicoulombs or more, or about, at least about, or no more than about 10, 25, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000 millicoulombs or more, or other ranges including any two of the foregoing values, and depending on the size of the nerve and the desired duration of high inhibition.The DC block amplitude and current duration can be adjusted to enable high suppression within the following ranges, such as 0-0.5 times the duration of the initial DC block, 0.5-1 times the duration of the initial DC block, 1-1.5 times the duration of the initial DC block, 1.5-2 times the duration of the initial DC block, and more than 2 times the duration of the initial DC block, or about, at least about, or no more than about 0.1x, 0.2x, 0.3x, 0.4x, 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, 1x, 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, 2x, 2.5x, 3x, 4x, 5x or more relative to the duration of the initial DC block, or a range including any two of the foregoing values.

[0201] Sensing the local condition of the neural tissue and its vicinity can also provide a useful measure for determining when to provide current input to extend neural inhibition and for providing a feedback loop for initial current delivery to produce initial nerve blockade by adjusting the nerve potential so that it cannot transmit an action potential. In one embodiment, the ability of the nerve to conduct action potentials is monitored so that, for example, when direct current is delivered to the neural tissue, direct current delivery can be maintained to ensure that nerve blockade is maintained. Nerve conduction function can be monitored by any suitable means, such as delivering stimulation pulses and measuring compound action potential signals.

[0202] In some embodiments, sensing is in the form of a reference electrode to measure the potential difference between two electrodes through which an active current passes. In some embodiments, the active current is regulated in response to one or more measured electrode potentials relative to the reference electrode. In some embodiments, the active current is regulated when the measured electrode potential indicates that an undesirable electrochemical reaction may occur on one or more active electrodes. For example, after measuring an active electrode potential that indicates that water electrolysis is occurring or is likely, the active current can be reduced or stopped. The EICCC can be operated using a direct current input or by applying a potential difference between the working electrode and the auxiliary or counter electrode. In some embodiments, the reference electrode can be located within the EICCC or at the distal end of the EICCC, close to the neural tissue.

[0203] Figure 1AAn embodiment of an EICCC electrode 100 is shown, wherein an electrode 104 is immersed in an electrolyte solution 102, which is in contact with an ionically conductive material-electrolyte solution interface 107, and an ionically conductive material 106 (e.g., a fluid, hydrogel, gel, or other polymer) is in electrical contact with neural tissue N or a region adjacent to neural tissue N. The EICCC electrode 100 also includes an electrically insulating, biocompatible housing 108, which houses the conventional electrode 104, the electrolyte 102, and the biocompatible, ionically conductive material 106, the latter having a hole (near 110) that enables electrical contact with the nerve N or a region adjacent to neural tissue N. The system also includes a current-carrying conductor 112 between a power source 114 and the electrode 104. Depending on the application, the power source 114 can be located externally or internally to the body. An exemplary, non-limiting embodiment of the EICCC 100 includes a silver, silver chloride (Ag / AgCl) electrode in a 0.9% saline solution in fluid contact with an electrolyte-saturated hydrogel (agar formulation with 0.9% saline).

[0204] Using an Ag / AgCl electrode for generating an electric current via AgCl on the electrode in a salt solution (NaCl), a sustainable and reversible electrochemical reaction can be achieved to convert the electric current in the form of electrons into the form of ions. Figure 1B As shown in Region 1 of , by pushing a constant current from the power supply, the mass of the AgCl electrode will drop from mass m2 to mass m1 during the cathode current (reduction reaction), and then rise back from mass m1 to mass m2 with the anode current during the oxidation reaction, as seen in Region 2. Furthermore, it will be appreciated that by limiting the maximum mass of AgCl to m2, such that the mass of unreacted Ag is greater than zero, it helps prevent the Ag / AgCl reaction from depleting the available Ag for the electrochemical reaction, and provides a reserve safety factor in the event of an excess current delivery similar to maintaining m1 greater than zero. In Region 3, the current polarity is reversed again to match the current polarity in Region 1. By not depleting the mass of AgCl to zero, a preferred reaction occurs between solid AgCl converting to solid Ag and generating chloride ions, and vice versa:

[0205]

[0206] Because the reduction potential that water electrolysis or hydrolysis occurs is higher than AgCl, the dissolution of AgCl will be preferred, to prevent undesirable reaction and generate OH-, H+ or oxygen free radicals in EICCC. It is further worth noting that the absolute value of the area between the current amplitude and the x-axis (time) can be used to define the total charge delivered (or removed) from the electrode, to allow determination or prediction and / or control of the quality of the electrode AgCl. It should be understood that the current waveform in different regions need not be a perfect square wave, but can include a finite slope from zero amplitude ramping to its final maximum amplitude and returning to zero current from its maximum waveform amplitude. The pattern of the waveform can also be nonlinear, and there may be differences between regions. In a preferred embodiment, the total charge delivered in region 1 is equal to the total charge removed in region 2. In other words, the size of the region below the current waveform in region 1 is the same as in region 2. Different regions can also be separated in time by a zero current phase (not shown), wherein the quality of the AgCl electrode is retained, and no current is delivered. Without being limited by theory, compared with other electrochemical reactions, the silver-silver chloride system provides several potential advantages. In some embodiments, the electrolysis of silver-silver chloride reaction is carried out by a plurality of sensors. For example, the standard potential of silver-silver chloride reaction is about 0.22V, which is advantageously much lower than the voltage at which electrolysis occurs. When the amplitude of the potential or voltage for driving the reaction exceeds about 1.23 volts for the standard hydrogen electrode of reference, electrolysis will occur. The electrolysis of water can be detected via one or more sensors, and if electrolysis is detected in some cases, then stop or regulate (increase or decrease) current delivery and / or driving voltage. In some cases, the sensor can also detect whether only silver-silver chloride reaction occurs, substantially only occurs or mainly occurs, rather than for example electrolysis, hydrolysis or redox water reaction. In addition, the amount of the electric charge that can be transported by this system is not limited by surface area reaction, as in the case of platinum electrode, platinum electrode forms hydrogenated platinum monolayer on the electrode surface before available reaction platinum is exhausted, causing other potentially harmful products to be formed if the driven reaction continues. On the contrary, in aqueous environments, when silver chloride is reduced, it can form solid silver and release chloride ions to the solution, and vice versa. The reaction in each direction is limited only by the amount of reactants available, so rather than being limited by surface area, the reaction is actually limited by the total volume of available reactants.Thus, the amount of reactant used in the reaction should be greater than the amount of the initial unreacted surface area of ​​the electrode, such as about or at least about 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 250%, 300%, 500%, 1,000%, 5,000%, 10,000%, 25,000%, 50,000%, 100,000% of the initial total unreacted surface area of ​​the electrode. , 500,000%, 1,000,000%, 2,500,000%, 5,000,000%, 10,000,000%, 25,000,000%, 50,000,000%, 100,000,000%, 250,000,000%, 500,000,000%, 1,000,000,000%, or more, or a range comprising any two of the foregoing values, and depending on the amount of silver used. Thus, substantially more, and in some cases orders of magnitude more, charge can be advantageously delivered to body tissue while remaining below the electrolytic threshold. For example, a platinum or platinum-iridium electrode can deliver 5 microcoulombs per pulse in a 5 mA pulse over a 1 millisecond period. Utilizing the embodiments disclosed herein, using DC delivery in the form of 5 mA pulses, with a duration of 10 seconds, it is possible to achieve a charge of about or at least about 1,000x, 5,000x, 10,000x, 50,000x, 100,000x, or more. This can be achieved, for example, by producing a 1 micron AgCl coating on an electrode having nominal geometry of 3.5 mm length (or about 1 mm to about 10 mm in length, about 1 mm to about 5 mm in length, or about 3 mm to about 4 mm in length) and 1.4 mm diameter (or about 0.5 mm to about 5 mm in diameter, about 0.5 mm to about 3 mm in diameter, or about 1 mm to about 2 mm in diameter), comparable to existing platinum electrodes. Those skilled in the art will appreciate that, depending on the configuration and availability of silver chloride, the amount of charge delivered can be increased by 10,000x, 100,000x, 1,000,000x, 10,000,000x, 100,000,000x, or more than that achievable using conventional platinum electrodes, or a range comprising any two of the foregoing values. Thus, silver-silver chloride complexes are uniquely positioned for use in the body environment because the reaction chemistry involves chloride ions, which are one of the most readily available ions in and around body tissues.

[0207] Figure 1CShown is how the current delivered to the electrode unit (EICCC) (top) can be linked to the charge delivered to the electrode unit-nerve junction (middle) to provide nerve block (bottom) while achieving zero net charge transfer over a longer charge phase. In Phase 1, charge can be delivered to the electrode unit with a given polarity and a constant or variable ramp rate (R1) to subsequently provide a constant or variable current (C1) followed by a return to zero current with a constant or variable slope (R2). Phase 1 can be, for example, of a duration of up to 1 second, 1 minute, 1 hour, 1 day, 1 month, or 1 year or longer. In some embodiments, the average current in Phase 1 is not zero, but the instantaneous current may sometimes be zero. In some embodiments, Phase 1 is either cathodic or anodic, but not both. Following the initial phase - Phase 1, there can be an interval phase (Interval 1) between the cathodic and anodic phases that is greater than or equal to zero seconds. After this interval, a second current delivery phase (Phase 2) may be applied, which may last up to 1 second, 1 minute, 1 hour, 1 day, 1 month, or 1 year or longer. The polarity of this second phase is opposite to that of Phase 1, in which the average current is non-zero, but the instantaneous current may sometimes be zero. In Phase 2, charge may be delivered to the electrode unit with a given polarity and a constant or variable ramp rate (R3) to subsequently provide a constant or variable current (C2), followed by a return to zero current with a constant or variable slope (R4). This Phase 2 may then be followed by another interval phase (Interval 2) of greater than or equal to zero seconds. The waveform may be repeated with the same or different amplitude and duration parameters as the previous waveform. Figure 1C The waveform in the embodiment of the present invention can be programmed or adjusted by the clinician and / or patient and / or caregiver and / or control system. Adjustment can include adjusting the current in phase 1 and phase 2 to ramp up and / or down, respectively, and adjusting the duration of phases t1-t0 and t3-t2, respectively. The interval between phases can also be adjusted to extend or shorten their durations t2-t1 and t4-t3. Any delivery or interval period can be, for example, at least about, about, or no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 30, 60, 120 minutes; 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 18, or 24 hours; 2, 3, 4, 5, 6, 7, 14, 21, 28, 30, 45, 60, 75, 90, or more days; 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, or more months; or a range including any two of the foregoing values.

[0208] In Phase 1, as shown, at the nerve junction, the current delivered to the electrode unit can produce an increasing charge (positive or negative) delivered to the nerve junction, and as shown, can be linear, or generally increase in a linear or nonlinear manner. During the gap phase or interval 1, the net charge delivered remains approximately constant and then returns to zero during Phase 2. Initially, the nerve block ( Figure 1C The period of time (bottom) begins somewhere at the beginning of stage 1, and while charge is delivered to the nerve junction, the nerve block will remain active (solid line). However, after the current delivery to the electrode unit is removed, the nerve inhibition as defined by continuous nerve block can continue after the current delivery to the nerve is stopped, and can last until the interval 1 stage (ii), extend to stage 2 (iii), independent of the opposite polarity of the current delivered, or enter stage 2 (iv), or beyond (not drawn). Adjustment of these parameters can result in the nerve being in a high inhibition state, such as Figure 1C (ii), (iii), and (iv), where neural inhibition can occur for a duration exceeding one minute after removal of DC delivery.

[0209] exist Figure 1D , a waveform pattern delivered to an electrode unit to facilitate nerve block is shown, wherein the current delivered to the electrode unit and the corresponding nerve block phases are shown, including a high inhibition region, wherein nerve block occurs regardless of the current delivered to the neural tissue. The electrode unit system should be designed so that the cathode and / or anode phases are designed to place the neural tissue in a non-conductive (or partially conductive) state after the current is stopped for more than one minute (high inhibition) after the current is delivered. Figure 1D In (i), an electronic current has been delivered to the electrode unit to generate an ionic current at the neural tissue that promotes nerve blockade. After this initial current delivery, the neural tissue then enters a highly inhibited state, whereby the nerve cannot conduct signals or cannot conduct signals completely without the delivery of additional current to the neural tissue. The inhibitory state of the neural tissue can also be extended, e.g. Figure 1D (ii) wherein a second current is delivered to the neural tissue some time after the initial current has been delivered, wherein delivery of an extended current (high inhibition) may occur up to one minute after delivery of the initial current or after a period exceeding one minute. This pattern of inhibition of extension may be repeated for a defined period of time or indefinitely with intervals of constant or variable length between current delivery phases. In order to maintain the electrode unit in a charge neutral state during repeated use, a current of opposite polarity may be applied after the initial nerve blocking current has been applied and the nerve is placed in a high inhibition state ( Figure 1D(iii)). Subsequently, as shown, current of the initial polarity can be applied to induce additional high inhibition extension. In this way, the neural tissue can be repeatedly "dosed" with anodic and / or cathodic safe DC current to maintain the neural tissue in a high inhibition state. The high inhibition duration is longer in duration than the cathodic and / or anodic delivery phase, thereby allowing a complete net charge reversal to be achieved during the high inhibition period. In these examples, the duration and / or amplitude of the cathodic and / or anodic phases can be programmed to affect the duration and integrity of the nerve block after current delivery is stopped.

[0210] Figure 1E An embodiment of an electron-ion current conversion cell (EICCC) 100 is shown, which is connected to a power supply 114 via an electrically insulated wire 112. The EICCC 100 includes a conventional electrode (electrode) 104 material (e.g., metal, carbon, etc.) connected to an ionically conductive material (ion conductor 106), which is then bonded to neural tissue N or a tissue interface near neural tissue. In some embodiments, the interface can be approximately 3 cm, 2.5 cm, 2 cm, 1.5 cm, 1 cm, 5 mm, 2 mm, 1 mm, 0.5 mm, 0.1 mm or less near the neural tissue. Those skilled in the art will understand that the conventional electrode 104 and the ionically conductive material 106 can be joined in a variety of ways, such as by being adjacent or in an interlocking manner, etc. The electrode 104 can be inserted into the ion conductor 106, or vice versa. As shown in FIG. Figure 1F As shown, in one configuration, the nerve block is shown as active when the electron current has one polarity as specified by the positive axis, and as inactive when the polarity of the current is reversed as specified by the negative axis. It should be understood that where an initial blocking current is applied to the nerve N in a manner that induces a high inhibitory state, the nerve can remain N-blocked during the current reversal. During the current reversal, the EICCC 100 is in a reset phase, wherein the reactions used to generate the ionic current are reversed to return the EICCC 100 components to their initial state for subsequent generation of the blocking current.

[0211] Figure 1G Shown with Figure 1EA similar configuration is provided, but with isolation barriers 118 and 120 that separate the conventional electrode 104 from the ion conductor 106, and separate the ion conductor 106 from the nerve N itself or tissue adjacent to the nerve, respectively. Those skilled in the art will appreciate that one, two, or more, or no barriers, or any combination thereof, may be used. Barriers 118 and 120 are configured to selectively allow certain ions to transfer between the respective materials while restricting the movement of other ions whose movement is undesirable, for example, to maintain reactive species such as Cl- near the electrodes. Barriers 118 and 120 may comprise ion-selective membranes, such as anion exchange membranes, that only allow the passage of anions. Figure 1H Shown with Figure 1F Similar graphs of current vs. time and nerve block state vs. time.

[0212] Figure 1I Shown with Figure 1G A similar configuration is also provided, but also includes a feedback sensor 122 that monitors the condition of the neural tissue N and / or an area adjacent to the nerve N. In some embodiments, the sensor 122 can be located proximal or distal to the electrode-nerve junction to enable measurement of local compound action potentials to provide feedback to the power supply 114 and EICCC 210, enabling them to adjust the electrode current and nerve junction electrode potential to maintain high inhibition. In some embodiments, the sensor 122 can measure the neural tissue voltage signal and use this information as feedback to adjust the current and potential generated at the nerve junction. In some embodiments, the potential is adjusted to maintain the nerve cell in a depolarized state, in which action potentials cannot conduct along the nerve cell. In some embodiments, the sensor 122 includes a reference electrode, thereby monitoring the potential difference between one or more working electrodes 104 and a reference electrode and serving as feedback to the power supply 114 to ensure the normal operating range of the EICCC 210. The implantable package may include an integrated reference or counter electrode. Figure 1J Shown with Figure 1H Similar graphs of current vs. time and nerve block state vs. time.

[0213] Figure 2A A dual-electrode system is shown in which two EICCCs 220A, 220B are coupled to a nerve N or to a junction of nerve-adjacent tissue. The two electrodes 220A, 220B are driven by currents of opposite polarity as a function of time, such that when one is in an active blocking phase, the other is in an inactive, non-blocking phase. Once the current polarity is reversed again, it resets the electrodes to block, as shown in FIG. Figure 2BAs shown. With this configuration, a constant block can be maintained along the nerve N. It should be understood that in the event that a blocking current is applied to the nerve N in a manner that causes a high inhibitory state, the nerve block can remain active during the current reversal of the electrodes 220A, 220B. Those skilled in the art will understand that the drive currents of the two electrodes 220A, 220B can be spaced apart in time, during which time no current drives one or both electrodes 220A, 220B, and if the nerve N is in an inhibitory state, the block can be maintained during this period. Similarly, the drive current can have different durations, depending on the electrodes 220A, 220B themselves and any recovery time of the nerve N during which the signal remains blocked without the application of the blocking current. The electrodes 220A, 220B can be oriented in series along the nerve N axially as shown, or oriented on the opposite side of the nerve tissue itself.

[0214] Figure 3A-3B An embodiment is shown in which two conventional electrodes 104A, 104B are coupled to the junction of a nerve N, but are driven from a power source via electrically insulated wires 112 with currents of opposite polarity, such that when one is in a blocking phase, the other is in a non-blocking phase. Once the current polarity is reversed again, it resets the electrodes to block. With this configuration, a constant block can be maintained along the nerve. The electrodes 104A, 104B can be oriented in series along the nerve N, as shown, or on opposite sides of the nerve tissue itself.

[0215] Figure 3C-3D An embodiment is shown in which dual EICCCs 230A, 230B are coupled to the junction of the nerve N, but are driven by currents of opposite polarity so that when one is in the blocking phase, the other is in the non-blocking phase, and once the current polarity is reversed again, it resets the electrodes to block. With this configuration, a constant block can be maintained along the nerve N, as shown in FIG. Figure 3D The electrodes 230A, 230B are coupled to the nerve N junction via a barrier that isolates harmful byproducts from dangerous electrochemical reactions to protect the nerve N. The barrier may include an ion-selective membrane, such as an anion exchange membrane, which allows only anions to pass (but not cations).

[0216] Figure 4AAn embodiment of an EICCC electrode 240 is shown, wherein the electrode 104 is immersed in an electrolyte solution 102, which is in contact with an ionically conductive material 106, such as a hydrogel, gel, or other polymer fluid, that is in electrical contact with the neural tissue N or an area near the neural tissue. The EICCC 240 electrode also includes an electrically insulating housing 108 that houses the conventional electrode 104, the electrolyte 102, and the ionically conductive material 106 having pores (near 110) to enable electrical contact with the nerve or an area near the neural tissue. The electrolyte-hydrogel 107 interface can alternatively be mediated by an ion-selective barrier or an ion-conductive polymer to isolate the products of any electrochemical reaction from the aqueous region of the cell. The system also optionally includes a current delivery conductor 112 between a power source 114 and the electrode 104. The power source 114 can be located externally or internally to the body, depending on the application. An exemplary embodiment of the EICCC 240 includes a silver, silver chloride (Ag / AgCl) electrode in a 0.9% saline solution in fluid contact with an electrolyte-saturated hydrogel (agar formulation with 0.9% saline). In other examples, the electrode materials may include metals, carbon, conductive polymer materials, and may be configured in high surface area / volume ratio configurations, which may include configurations such as open-cell foam configurations, sintered particle configurations, dendritic configurations, and the like.

[0217] Figure 4B Shows something like Figure 4A The system 250 shown in FIG. 1 adds a reference electrode 111 near the electrode (working electrode) 104 to monitor the voltage drop across the working electrode 104 for EICCC monitoring purposes, for example, to ensure that the electrode 104 is driven under the desired conditions to ensure that the proper electrochemical reaction occurs.

[0218] Figure 4C Shows something like Figure 4A The system 260 shown in FIG. 1 adds a reference electrode 111 near the neural tissue interface to monitor the voltage drop across the EICCC 260 to the neural tissue for EICCC monitoring purposes, for example, to ensure that the electrode 104 is driven under desired conditions to ensure that the proper electrochemical reaction occurs.

[0219] Figure 4D-4F An embodiment is shown of an electrode lead 212 configured to be inserted into and extend from a power source (not shown, near end 213), which may take the form of a conventional IPG (implantable pulse generator). Figure 4F yes Figure 4D A close-up view of 4E-4E. Figure 4F yes Figure 4D Close up view of 4F-4F in the middle. This configuration can be combined with Figure 4A The configuration shown is similar except that Figure 4A The nerve interface hydrogel shown in FIG is removed, and the nerve tissue interface includes a barrier or porous frit 404 that contains an electrolyte solution but allows ions to enter the neural tissue environment. A connector 213 to a power source is shown, with the conductive portion of the electrode lead 213 extending distally from the connector 213 to the EICCC 400, which couples the electronic current to the ionic current via an electrochemical reaction. The coiled electrode 402 converts the electronic current into an ionic current in the EICCC 400, which is then transmitted to the distal portion of the lead, which can be positioned near the target neural tissue. Contact with the neural tissue environment occurs via the ionic current that leaves the barrier / porous frit 404, which can manipulate the neural environment.

[0220] Figure 4G A schematic embodiment of an EICCC is shown integrated within a hermetically sealed housing 410 containing a power source 412, a battery 414 or power source, and a controller 416 for driving the EICCC 280. The EICCC 280 is directly connected to the power source 412 as shown and includes leads 418 from the power source 412 and electrodes 420 immersed in an electrolyte solution 429, which is in contact with an ionically conductive material 422, such as a hydrogel fluid, which in turn is in contact with the neural tissue N to be blocked. In this embodiment, the electrode element 420 of the EICCC 280 is located relatively proximal to the power source 412, while the nerve contact lead is located relatively further away from the power source 412 and extends to the neural location N. Also shown are an ionically conductive conduit (e.g., a hydrogel connector) 430, a connector element 432, the insulating housing 420, and the ionically conductive electrode lead 428.

[0221] Figure 5A-5B An embodiment of an electrode configuration 500 is shown in which two electrode contacts are housed within the same electrically insulating housing 504. Electrodes 502A, 502B are in ionic contact with an ionically conductive material 510 / pad 512 that interfaces with neural tissue N and / or nerve attachment areas. Each electrode 502A, 502B is electrically connected via its own conductive wire 506 driven by a power source 508. The internal electrodes 502A, 502B can be driven cyclically with opposite current polarity to provide constant nerve block. The power source 508 can be configured to be implantable in the body so that any wires 506 and electrodes 502A, 502B are also fully contained within the body. Alternatively, in this or other embodiments, the power source 508 can be configured to remain outside the body and can be connected via a wired connection or a wireless connection.

[0222] In some embodiments, the system is configured for nerve blockade at a specific nerve. One such nerve is the dorsal root ganglion and / or dorsal root ganglion (DRG) ( Figure 6A The associated dorsal root ganglion from each vertebral level corresponds to a specific dermatome in the body ( Figure 7 ), and blocking pain signals at the level of the DRG can reduce pain perception at that particular DRG at the innervated skin flap. Access to the DRG may be facilitated by initially introducing the needle tip into the DRG. A stylet or obturator in the needle can be used to prevent blockage of the opening or accidental tissue damage due to tissue entrapment caused by the needle opening. The needle tip can be radiopaque to facilitate visualization under fluoroscopy or other radiographic modalities. Removal of the stylet from the probe may also occur in order to inject contrast to enable visualization of local structures and confirm the position of the needle tip. Short-acting nerve blocks can also be used to confirm that the target DRG body can provide adequate pain relief when blocked. Once the needle is confirmed to be correctly placed and the DRG body is a suitable target for nerve block, the stylet can be removed (if not already removed) and a blocking electrode with single or multiple electrode-nerve junction contacts terminating in the EICCC can be introduced through the needle. As Figure 6C As shown, the DRG can be accessed with needle 600 and the dura can be penetrated with needle 600 as shown. Alternatively, needle 600 can be positioned just outside of the dura without piercing the tissue. The introduced electrode can have radiopaque markings to enable visualization under fluoroscopy. The introduced electrode can also be enclosed within a secondary sheath that prevents deployment of the anchoring element until the distal end of the sheath is retracted from the distal end of the introduced electrode to expose the tissue anchoring element. The enclosed electrode can also have stress relief features, such as a crimp or slack in the electrode body, to accommodate body movement that, without such features, could cause the electrode to become dislodged. As Figure 6D and Figure 6EAs shown, the electrode-nerve junction contact 604 can then be positioned to contact or approach the DRG, and the introduction needle 600 can be retracted to leave the electrode wire 602 and the nerve tissue junction 604 in the desired position. The proximal end of the electrode can be connected to a power source to start nerve block and ensure that the electrode is correctly positioned. Once proper positioning and blockade are achieved, the optional electrode sheath can be retracted to expose a retaining mechanism such as a barb or friction element that prevents the electrode from shifting from its desired position. Optionally, if the electrode contact moves relative to the DRG body, a conductive gel can be applied between one or more electrode contacts and the nerve junction to further mitigate the loss of conduction block. In some embodiments, if the placement must be adjusted after the retention mechanism is deployed, the sheath can be advanced to retract the fixing mechanism and reposition the electrode before the retention mechanism is redeployed. Once the electrode is correctly placed, it can be disconnected from the power source and the insertion needle can be removed from the electrode toward its proximal end. The sheath can then be removed in a similar manner. The power supply can then be reconnected to the lead connector to confirm proper placement and that it has not become dislodged after the needle is inserted and the sheath is removed. After an optional evaluation period, the power supply can be implanted in the patient's body and the electrodes and / or leads replaced with permanent electrodes for long-term implantation. The power supply can also include a battery or energy storage unit and electronic circuitry that enables the unit to be programmed from a programming unit that is capable of communicating with the implanted power supply when in proximity to a body part proximal to the power supply implant site. The power supply energy source can optionally be rechargeable via an external communication unit, such as by inductive charging. Figure 6B An embodiment of a block electrode 100 is shown positioned along a DRG to facilitate nerve block, along with a lead 112 and a power source 114. It will be appreciated that nerve block can include high inhibition of the DRG.

[0223] In an alternative embodiment, the power source can be permanently or temporarily located outside the patient's body to enable nerve blockade. The electrodes can also be removed once deemed unnecessary, thereby providing temporary nerve blockade as needed. The nerve block can also be periodically turned on and off by adjusting the power source as needed to enable sensing during procedures requiring, for example, patient feedback.

[0224] The block of DRG at specific skin graft can be used for locating the therapeutic pain relief caused by neuralgia, angina pectoris, ischemic pain and complex regional pain syndrome (CRPS). In the case of angina pectoris, the nerve roots C6 and C7 at the cervical spinal cord level are considered to be frequently associated with relevant pain, and the DRG block (with or without other DRG block on other levels) at one or two levels of these levels of positioning can be used to help manage this pain. (Nakajima et al., Cervical angina: a seemingly still neglected symptom of cervical spine disorder?, Spinal Cord, 2006 44: 509-513). For example, complex regional pain syndrome (CRPS) is usually confined to a single limb, and producing a local block can provide a more specific pain block to the source of pain. For example, it has been shown that using traditional DRG stimulation technology, the lumbar dorsal root ganglion on level L2, L3, L4 can alleviate the knee pain on the ipsilateral side of the spine. (Bussel et al., Successful Treatment of Intractable Complex Regional Pain Syndrome Type I of the Knee With Dorsal Root Ganglion Stimulation: A Case Report, Neuromodulation, 2015 January 18(1): 58-61). Ischemic pain is often particularly localized in patients with poor circulation to the extremities and can similarly be relieved by setting an appropriate level of DRG blockade.

[0225] As mentioned above and as Figures 6A-6D and Figure 7 As shown, EICCC electrodes can be introduced near the DRG to block and / or inhibit neural tissue in the DRG to prevent distal pain signals from the enrolled individual. In addition, multiple dorsal root ganglia can be targeted to produce unilateral and bilateral blocks or adjust the pain coverage based on the pain manifestation in the body. The EICCC electrodes can be placed at target levels related to the pain manifestation and the level and coverage of the pain block can be adjusted by adjusting the ionic current signal, such as by adjusting the current amplitude at each target DRG level and contact with the EICCC electrode. Localizing pain blockers to specific areas of the body can also help maintain normal sensing function in other areas of the body so that pain signals are not present and can be used to signal adverse situations and environmental conditions to individuals.

[0226] Compared to conventional SCS where electrodes are placed along the posterior side of the spinal cord in the epidural space, the stimulating electrode 800 is placed in the lateral spinothalamic tract (LT tract) ( Figure 8A ) can be used to produce nerve blockade at the desired level (and / or at the spinal level distal to the EICCC (away from the head) because pain signals travel in an upward direction) and provide selective pain blockade based on unilateral (left or right) or bilateral placement of the electrodes 800. The electrode leads 802 can be placed via a vertebral incision ( Figure 8A The lead 802 may be placed in the epidural space using a needle 808 (center, right) to allow access to the epidural space, and then the lead 802 may be introduced and positioned at the desired level or levels along one or more sides of the spine. The lead 802 may also be placed using a percutaneous placement procedure with or without fluoroscopic guidance, such as by using a Tuohy or similar needle 808 to introduce the lead 802 into the epidural space ( Figure 8B The guidewire 802 can be oriented along the spinal column within the epidural space such that the guidewire 802 is between spinal nerve exit areas and the tissue interface is proximal to the lateral spinothalamic tract, e.g. Figure 8C-8E As shown. Figure 8C-8E As shown, the electrode wire 802 is positioned laterally to be located outside the lateral spinothalamic tract so that the ionic current generated by the electrode can be used to block the nerve bundle. The wire 802 can also be placed on both sides to facilitate bilateral blockade because each lateral spinothalamic tract carries pain information from the opposite side of the body. The wire 802 can then be connected to a power source via a tissue junction 804 to activate the nerve block to ensure proper positioning and signal blocking. The wire 802 can then be disconnected from the power source and an optional extension cable can be placed to connect the wire 802 to the implantable power source. The power source can also include a battery or energy storage unit and an electronic circuit that enables the unit to be programmed from a programming unit that can communicate with the implanted power source when it is close to a body part near the power source implant site. The power source energy source can optionally be wirelessly charged by an external communication unit, such as by inductive charging.

[0227] In some embodiments, for example, Figure 4D Multiple electrode leads as shown can be placed along the spinal cord, targeting Figure 8C Furthermore, the electrodes can be configured to have multiple tissue contact areas, the output of which can be individually adjusted to optimize neural tissue blockade. Figures 10A-10C , where multiple tissue interfaces 404A, 404B are present on the electrode 402 and are individually addressable. Figure 10B yes Figure 10A A close-up view of 10B-10B. Figure 10C yes Figure 10A10C-10C . In this embodiment, there is a dual system of EICCCs 400, with parallel lumens individually associated with each neural tissue interface region. In FIG10 , the neural tissue interface regions and associated EICCCs are designated by matching letter labels, in this case A and B. Adjusting the current input and corresponding output at the distal ends of the electrodes can shape the electric field to promote the desired nerve block while minimizing blockade of undesirable structures. An alternative embodiment is captured in FIG5 , in which the individual electrodes can also be individually addressed and adjusted to achieve the desired blockade.

[0228] These methods of placing blocking electrodes along the spine to block the spinothalamic tract and the ability to modulate the electric field to produce neural blockade and / or inhibition can facilitate specific targeting of pain blockade. For example, trunk pain can be modulated at the thoracic level by placing leads along the thoracic spine, while neck pain can be alleviated by providing blockade and / or inhibition in the cervical spine. Upper extremity pain can be alleviated by providing a combination of blockade and / or inhibition at the cervical and thoracic levels, while lower extremity pain can be alleviated by providing a combination of blockade and / or inhibition at the lumbar and sacral levels of the spine.

[0229] The generation of pain blockade can be used to promote perioperative pain blockade in situations where motor control and non-pain sensing are required. For example, during labor and delivery of a child, one of the challenges of pain management, especially epidural anesthesia, is reduced sensory ability in the lower body. Due to the non-specific nature of delivering anesthesia in the epidural space, sensory, pain, and motor neurons are affected. Epidural anesthesia may make it difficult to push during labor and may cause paralysis for several hours after delivery, thereby impairing motor ability, such as the ability to walk. In some cases, epidurals are also involved in fetal and neonatal health, including breastfeeding difficulties. Using the blocking electrodes described above to target the spinothalamic tract and / or dorsal root ganglia, unwanted pain can be targeted without the side effects (or reduced side effects) associated with current epidural anesthesia techniques because only the pain tract is targeted, not any other motor or sensory tracts. In addition, in situations where ionic current is delivered to neural tissue in a reversible blocking manner, cessation of the blockade can enable the patient to immediately return to normal pain sensing, if necessary, and off-target blockade can be reversed to enable immediate recovery of body function.

[0230] In addition to central nervous system intervention, safe DC resistance blocking can also be promoted in the peripheral nervous system, in which the EICCC electrode is placed in contact with or adjacent to the peripheral nerve to promote blocking. Specific pain targets include focal pain, phantom limb pain, neuroma pain, and neuralgia. Targeting peripheral nerves from the pain site to the proximal end (i.e., near the spinal cord) to block can suppress pain from distal sites. Specific to neuralgia, postherpetic neuralgia (after herpes zoster) can be targeted based on the outbreak manifestations of tracking specific skin patches. For trigeminal neuralgia, the trigeminal nerve (and / or the trigeminal ganglion and / or trigeminal nucleus in the brainstem) can be targeted for blocking to relieve pain that is usually manifested as facial pain. Another target is the glossopharyngeal nerve, which produces pain in the neck and throat. Neuralgia in the limbs such as hands, arms, feet, and legs, which is frequently caused by diabetic-related neuropathy, is also a potential target.

[0231] In addition to relieving pain, nerve blockade and activity inhibition can be used to improve cardiovascular health in a specific targeted manner. It has been found that hypertension related to the causes of cardiovascular disease can be alleviated by regulating the renal nerves to reduce the activation of the sympathetic nervous system. There are current technologies that use a variety of energy sources such as ultrasound and radiofrequency energy to remove or ablate these nerves. (Krumet al., Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. The Lancet. 2009 373 (9671): 1275-1281. U.S. Patent Application: 2012 / 0016226). Using the tools described herein, selective nerve blockade can be used to promote reduced activity of the renal nerves and sympathetic nervous system to promote the reduction of hypertension. As Figure 11 As shown, blocking electrode leads 1100A, 1100B contact the renal nerves to promote blockade or inhibition. Also shown is an EICCC 1104 openly connected to a power source (not shown) at 1106. The contacts can also be configured in the form of a cuff to surround the renal artery and provide circumferential direct current to the periphery of the renal artery and block the neural tissue surrounding the artery. The delivered blocking current can also be adjusted to suit individual physiological responses to sympathetic nerve blockade, which cannot currently be accomplished using destructive methods such as ablation.

[0232] Heart failure is another target disease condition known to be associated with upregulation of the sympathetic nervous system. By using blocking electrodes to moderate the activity of the sympathetic ganglia, particularly the cervical sympathetic ganglia, excessive cardiac activity can be reduced to alleviate the heart's overwork. Similar to dorsal root ganglion access, the cervical ganglia can be accessed for blockade. Figure 12 Figure 1 shows the relevant sympathetic ganglia, including the cervical and stellate (cervicothoracic) ganglia and their innervated targets in the heart. Access methods include posterior access and through the pleural cavity.

[0233] Tachycardia or other tachyarrhythmias, such as atrial fibrillation, atrial flutter, multifocal atrial tachycardia, paroxysmal supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation, can also be regulated by modulation of the sympathetic nervous system, possibly by targeting the cervical sympathetic ganglia ( Figure 13 ) to provide blockade of the sympathetic ganglia and thus be affected to a more normal condition. Methods of access include posterior access and through the pleural cavity.

[0234] Modulation of the cardiac parasympathetic nerves can be used to regulate cardiac function. Stimulation of the vagus nerve is known to cause bradycardia or slow heartbeat and inhibit the heart rate. Conversely, by producing vagal blockade, the heart rate can be reduced or shut down by inhibiting the conduction of nerve signals that cause an increase in heart rate by reducing vagal signals. In particular, the right vagus nerve, which innervates the sinoatrial node to help regulate heart rate, can be blocked or inhibited to enable an increase in heart rate. Figure 14 , an EICCC electrode 1400 can be placed around or near the right (and / or left) vagus nerve within the neck and / or right side of the chest, with an electrode lead 1402 extending downward toward an implantable power source 1404 as shown in the right pectoral region. The electrode lead 1402 can be placed in the right subclavian region or other desired location and tunneled under the skin to the power source.

[0235] In addition to cardiovascular function, the nervous system plays an important role in regulating gastric processes, including satiety (not feeling hungry) and fullness (fullness). The vagus nerve innervates the stomach, where most of the signals sent to the brain report satiety and fullness. Using the EICCC electrode 1600, vagus nerve blockade or neuroinhibition can be produced, resulting in an individual having a greater sense of fullness and satiety. Gastrointestinal nerves can also be modulated to increase or decrease GI transit time. Figure 15-16 , an exemplary dual EICCC system is shown in which each vagus nerve is encased in a tissue interface 1606 in the form of a cuff where ionic current is deposited at the tissue site from an EICCC 1600 connected via electrode leads 1602 to a power source 1604. The tissue interface can be mediated by a porous frit or other ionically conductive medium, such as a conductive hydrogel as previously described herein. Figure 16 yes Figure 15 Close up view near the gastroesophageal junction area.

[0236] Sympathetic inhibition or blockade can also be used to regulate liver, gallbladder, and / or pancreatic function and affect glucose and insulin production, e.g. Figure 17 As shown. Inhibition or blocking of hepatic nerves can cause an increase in insulin production and reduce resistance to insulin, thereby enabling the management of adult onset or type 2 diabetes, in which insulin production is reduced or resistance to insulin function is increased. Using the EICCC electrode 1800, hepatic nerve blockade or nerve inhibition can be produced to increase insulin production and reduce insulin resistance. Figure 18 As shown, an EICCC system is shown in which the hepatic artery and the nerves surrounding the artery are surrounded by a tissue interface 1806 in the form of a sleeve, at which ionic current is deposited at the tissue site from the EICCC 1800 connected via electrode wires 1802 and to a power source 1804. The tissue interface 1806 can be mediated by a porous frit or other ionically conductive medium, such as a conductive hydrogel as previously described herein. In other embodiments, splenic neuromodulation can improve immunosuppression or reduce inflammation or hyperimmune function (e.g., in autoimmune conditions such as SLE, rheumatoid arthritis, Crohn's disease, ulcerative colitis) or other conditions.

[0237] Movement disorders can also be affected by modulating the activity of neural tissue, including Tourette syndrome, dystonia, Parkinson's disease (and related stiffness), essential tremor, spasticity, and epilepsy. These conditions and diseases are characterized by hyperactivity of nerves in specific parts of the brain, which may lead to symptomatic manifestations. Targeting specific areas of the brain for blockade, including those captured in Table 1 below, can be used to help manage the patient's symptoms. As is known, the blockade of these targets can be unilateral or bilateral.

[0238]

[0239] Table 1. Movement disorders and brain regions targeted by neural tissue blocks for symptom relief.

[0240] Likewise, psychiatric conditions including treatment-resistant depression (TRD), anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) are targets for neuroblockade to alleviate symptoms from these conditions. Targeting specific areas of the brain for blocking, including those captured in Table 2 below, can be used to help manage a patient's symptoms. As is well known, the blocks of these targets can be unilateral or bilateral. Other conditions that can be treated can include, for example, schizophrenia, schizoaffective disorders, bipolar disorder, mania, alcoholism, drug abuse, and the like.

[0241]

[0242] Table 2. Psychiatric disorders and brain regions targeted by neurological blocks for symptom relief.

[0243] Chronic pain is another target that involves specific areas of the brain that influence chronic pain. One such area is the thalamus, which is the entry point for pain signals to the brain. Specific areas within the thalamus have been identified as targets for reducing neural activity to reduce chronic pain, as follows

[0244] These are shown in Table 3. As is known, the blockade of these targets can be unilateral or bilateral.

[0245]

[0246] Table 3. Brain regions targeted by nerve blocks for pain relief.

[0247] In some embodiments, the system is configured to produce a neural block for disorders and diseases that can be solved by reducing the neural activity of a specific area of ​​the brain that causes a specific disorder. The reduction of neural activity can be promoted by directly blocking and reducing the activity of specific neurons and by blocking the pathways where excessive neural signal conduction occurs. In some embodiments, the system for deep brain block (DBB) includes all or some of the following steps: identifying the anatomical target site for blockade, creating an access site for tissue outside the brain, creating a pathway through brain tissue to the target site, assessing the suitability of the target site for blockade, adjusting or improving the position of the target site, providing neural blockade at the target site, and adjusting the intensity or position of the neural tissue block. In fact, this process can be achieved using techniques known in the field of deep brain stimulation (DBS), in which a combination of imaging techniques such as, but not limited to, magnetic resonance imaging (MRI), computed tomography (CT), PET scans, and / or X-rays, including functional MRI (fMRI), is used to identify the target anatomical site. Stereotactic techniques can then be used to approach the site to implant the area identified from the imaging into the patient's body anatomical structure. The frame can be fixed on the patient's head and skull to allow space access during surgery. An access site for entering the brain tissue can be formed in the form of a burr hole or craniotomy with or without additional access tools such as insertion cannulas and push-in / retraction devices fixed on the skull to approach the target site. Pushing a neural tissue activity measurement probe into the target site through the brain tissue can be used to enable assessment of the suitability of a brain region. The probe can record neural activity to determine that the measured signal is consistent with the signal of the tissue that needs to be blocked. If the signal characteristics indicate that the position is not optimal or is not suitable for blocking, the probe can be adjusted until the correct position is identified. The measurement probe can be exchanged with the blocking electrode and then inserted using the active portion of the electrode located in the target site. The activation of the blocking signal can then be used to assess the effectiveness of the block and the intensity of the adjustment signal. The blocking electrode can then be fixed to the skull to maintain the position of the active portion (e.g., the region that transports ion current) at the target site. Extension leads can be connected to fixed block electrodes and to an implantable power source, similar to an implantable pulse generator (IPG), whose output signal can be adjusted to promote optimal symptom relief. Block electrodes can be implanted unilaterally or bilaterally when the contralateral side of the body is affected by a specific anatomical target site.

[0248] Figure 9AAn electron-ion current conversion cell (EICCC) electrode 900 is shown, configured to be coupled to a deep brain block (DBB) target junction in the thalamus. A neural tissue junction 904 contacts and provides blockade to the target site in the thalamus, while an electrode lead 902 provides a conduit between the thalamus and the exterior of the skull. An extension port in a skull anchor 910 allows communication between a power source 908 and the electrode lead 902 via an electrode extension 906, which can be electrically connected to the port and power source 908. Within the lead 902 itself, the EICCC block electrode includes an internal electrode 916, such as an Ag / AgCl wire, that converts electron current to ionic current in an ionically conductive medium 918, such as saline, and generates ionic current at the neural tissue junction 904 via an ionically conductive material, such as a porous frit 920, designed to allow ions to flow therethrough, to produce blockade at the neural tissue site. The ionically conductive medium 918 and / or tissue interface material may also include a hydrogel or other ionically conductive material, as described elsewhere herein.

[0249] Specific to epilepsy, electrocorticography (ECoG) can be performed to identify one or more epileptic foci or foci to target electrode placement and neural blocks at that location. Implanted blocking electrodes can be used to block or inhibit neural tissue activity, as desired by the user, during an epileptic seizure or upon sensing the onset of a seizure. Additionally, systems including blocking electrodes can be configured to alternatively reduce the field potential of neuronal clusters that are prone to causing seizures, such that seizures can be prevented rather than reacted to when they are about to occur or when they are occurring. In another embodiment, blocking electrodes are combined with measuring or sensing electrodes such that the activity of one or more neuronal clusters including one or more epileptic foci is monitored, and when activity indicative of the onset of a seizure is measured, the system can automatically generate blockade in a closed loop to reduce the activity of the target cells. In Figure 9B , an embodiment of a blocking / inhibition electrode 950 utilizing an integrated sensing electrode 922 is shown, wherein the sensing electrode 922 is proximate to the neural tissue interface 904 so that sensing of target neuronal activity can occur, and a signal from the sensing electrode 922 is fed back to a power supply 908, which can be activated based on the sensing electrode signal to generate an ionic current at the neural tissue 904 interface to disrupt or prevent the onset of an epileptic seizure. The sensing electrode 922 can include an insulated conductive path to the electrode extension 924. In other embodiments, the blocking electrode can also be used as the sensing electrode 922 (e.g., when a blocking current is not applied). Electrodes used to block tissue to treat epilepsy can be configured as straight probes that are implanted deeper than the cortical surface, or can be configured as epidermal cortical electrodes (e.g., by having planar or conformal elements).

[0250] Disclosed herein in some embodiments is a system and method for maintaining a desired electrochemical reaction by monitoring a signal indicating that a reaction has occurred to change the reaction generating conditions. Without being limited by theory, conventional alternating current stimulation of neural tissue typically delivers a relatively small amount of charge through conventional electrodes (e.g., platinum electrodes). However, in some embodiments, high charge density electrodes, including those described elsewhere herein, deliver a relatively large amount of charge that approaches and exceeds, and in some cases far exceeds, the Shannon limit. Control systems and methods such as those disclosed herein can surprisingly and advantageously allow such current to be safely delivered to tissue.

[0251] In some embodiments, the system for delivering an ionic current driven by an electrochemical reaction may include a monitoring and / or control system, for example, including a hardware and / or software controller configured to measure the voltage required to generate an electric current to drive the electrochemical reaction. If the voltage exceeds a threshold value, such as a predetermined threshold value, the controller may adjust (e.g., increase or decrease) the current output so that the voltage level is within an acceptable range relative to the threshold voltage level. For example, if the voltage required to maintain a specific current level becomes too high, the current level may be reduced to a point where the voltage drops below the defined threshold value. In some embodiments, if the voltage required to maintain a specific current level becomes too high, the current level may be set to zero. In another optional system, if the voltage required to maintain a specific current level becomes too high, the current level may be reversed.

[0252] In some embodiments, the current can adopt a waveform such as a square wave or a similar waveform between a first electrode (e.g., a working electrode) and a second electrode (e.g., a counter electrode), wherein the current passes between the two electrodes. The voltage waveform required to drive the current between the two electrodes may fall within the upper and lower voltage threshold limits. Over time, if it is found that the potential electrochemical reaction drifts due to various conditions, the driving voltage waveform required to maintain the target current waveform may also drift. If the offset / deviation from the target threshold is large enough, this may indicate that an undesirable electrochemical reaction has occurred. Alternatively or additionally, the voltage threshold limit and the associated voltage between the working electrode and the reference electrode can be measured to directly evaluate the voltage drop across the working electrode-electrolyte interface to evaluate the electrochemical reaction and potential across the interface. To prevent these offsets from entering undesirable areas, the current delivered can be adjusted as described above to reduce the driving voltage. Alternatively, the voltage offset may be due to electrochemical changes. For example, in a system where a reaction occurs in which the same target amount of charge is transferred from one electrode to a second electrode and back to the first electrode, the net charge may drift from zero (e.g., become unbalanced) over time due to imperfect charge counting and irreversible reactions. This, in turn, can cause a voltage change required to produce the desired current and indicate that an undesirable electrochemical reaction has occurred. In some embodiments, the drift of the net charge transfer from the target level can be offset by monitoring the driving voltage and generating a control loop of additional charge on electrodes whose reactant deficiency has been detected by their driving voltage characteristics. For example, for an Ag-AgCl system, when driven at the cathode, the depletion of available AgCl on the working electrode may appear as a negative dip in voltage because the lower reaction potential The reaction is no longer available, and a higher drive voltage is required for other higher reaction potential reactions to occur. In this case, if a higher voltage is detected during the cathodic phase of the waveform, additional charge can be imparted to the working electrode during the subsequent anodic phase by increasing the duration, amplitude, or both of the current delivered to the working electrode. Such a control system can also be advantageous for high charge density electrodes, including but not limited to titanium nitride electrodes, such as fractal titanium nitride electrodes.

[0253] Figure 19 The driving voltage waveform and the positive and negative thresholds are shown over a period of time. As shown, the negative threshold is crossed / broken before time point 2600 due to a negative voltage dip. After 2600, the negative dip no longer exists and can be addressed by adjusting the target current level and / or by adjusting the charge transfer profile between the working electrode and the counter electrode. For example, additional charge can be transferred during the anodic phase of the working electrode cycle to produce more reactant species.

[0254] Figure 20 The drive voltage waveform and the positive and negative thresholds are shown over a period of time. As shown, the negative threshold is crossed / broken due to a negative voltage drop, which can be characteristically manifested as a drop or spike on top of a more monotonically increasing or generally flat voltage waveform and can indicate that an undesirable reaction has occurred.

[0255] Figure 21 Schematically illustrate the graph of voltage and electric current relative to time, it shows electrode annealing or conditioning process, wherein current amplitude is ramped up to set target, and driving voltage remains below setting threshold value.If for given current amplitude, do not exceed driving voltage, then electric current can be upwards gradually increased to target current.If for given current amplitude, exceed driving voltage, then similarly can reduce electric current gradually, until no longer exceed voltage threshold.Multiple cycles under given current amplitude can be used for determining whether system is stable under this current level and duration, as by staying within voltage threshold assessed before electric current is upwards increased to target current.In some embodiments, can utilize at least about, about or be no more than about 2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,60,70,80,90,100,150,200,250,500,1,000, or more or less cycles, or comprise the scope of any two above-mentioned values. The voltage threshold for a series of cycles at the target current can also be set to fall within the drive voltage tolerance so that it is considered stable to determine whether the annealing or conditioning process was successful.

[0256] Also disclosed herein are systems and methods for utilizing DC resistance to retard neural tissue. The system can allow for indefinite DC power delivery (e.g., without the need for reverse charging). In some cases, water or other suitable media such as saline can be used as the primary redox reactant; the reservoir can be refilled with water or other media as needed. In some embodiments, there can be one, two, or more vents to vent gases produced by the redox reaction. In some embodiments, the vent can include a gas-permeable but liquid-impermeable membrane to allow gas to escape but liquid to remain within the container. The DC generator can have a voltage sufficient to potentially drive a larger wire / catheter impedance. The system can also include one, two, or more pumps to circulate a medium such as water through a pH neutralizer to maintain a desired, for example, neutral pH, bath. The system can also include a pH sensor to detect the pH of the bath and allow modification, for example, buffering, if necessary. The bath can also include a pH buffer solution to maintain a nominally constant bath pH.

[0257] Figure 22System 2200 is shown, which may include a nerve-tissue interface 2224 operably connected to a conduit 2212 configured to hold a fluid. Conduit 2212 may be operably connected to reaction chamber 2204 via interface 2214. Interface 2214 may include a membrane, such as an anion exchange membrane, to prevent certain particles from flowing into conduit 2212. Conduit 2212 may have a valve 2216 that can be actuated between different positions to block, allow, or partially restrict fluid flow through conduit 2212. Reaction chamber 2204 is also shown, which includes a reaction electrode 2220, which may have a high surface area and may be partially or completely surrounded by a redox reactant 2226 (e.g., water), as previously described. Reaction electrode 2220 may be operably connected to DC generator 2202 via conductor 2228. Chamber 2204 may also include a pH sensor 2218. Chamber 2204 may include a vent 2234. The chamber 2204 can be operably connected to a pump 2206 and a reservoir 2208 of a pH neutralizer that can typically be sealed from the chamber 2204, as well as a valve or other reversible channel that can be opened when the pH falls outside a predetermined threshold, such as by using a piping system 2222. The chamber 2204 can also include an agitator 2210 (e.g., an ultrasonic probe) to promote the release of bubbles from the electrode 2220. The liquid bath can also include a surfactant to reduce the adhesion of bubbles to the electrode 2220 when formed. The reaction electrode 2220 can be operably connected to the DC generator 2202. The DC generator 2202 can also be connected to a potential second unit 2232 via a conductor 2230 to promote return current. The second unit 2232 can be the same or similar to the system 2220 described above.

[0258] In some embodiments, the DC blocking electrode tissue system can include replaceable electrode materials. Over time, the spent reactive metal (or other material) can be optionally removed and fresh reactants can be supplied to the reaction chamber. This can advantageously allow unidirectional delivery of DC current without the need for a reversal / charging phase. Figure 23A System 2300 is shown including a reaction chamber 2304 containing a reactant 2316. Rotatable member 2306 can move fresh reactant 2314 into (and consume) the reactant into reaction chamber 2304 as shown, as well as onto another spool 2308. Also shown is a DC generator 2302 operably connected to reaction chamber 2304 and / or spool 2306.

[0259] In some embodiments, disclosed herein are isolated junctional neural electrodes that may include integrated sensors for detecting the electrochemical state of the reacting / working electrode, such as Figure 23BSchematically shown. Sensor 2330 can measure one, two, or more variables that indicate the state of working electrode 2324, such as, for example, pH, mass, or voltage. In some embodiments, sensor 2330 can be a reference electrode, such as an Ag-AgCl reference electrode or a platinum reference electrode, to measure the potential between working electrode 2324 and reference electrode 2330, or a sensor to detect electrochemical reactions occurring at the working electrode 2324-electrolyte interface. Both working electrode 2324 and sensor 2330 can be disposed within housing 2318. Housing 2318 can be operably connected to a wire / electrode 2320. Such a wire / electrode 2320 can have a relatively short length to reduce impedance. The length of wire 2320 can be in the range of 0-2 cm, 2-4 cm, 4-8 cm, or 8-12 cm, or a range comprising any two of the foregoing values. The distal end of wire 2320 can have a tissue interface 2322. Furthermore, the combination of the geometry of the wire 2320 and the ionically conductive medium within the wire 2320 can be configured to have an impedance value of less than 1 kOhm / cm long, or 1-3 kOhm / cm, or greater than 3 kOhm / cm. The sensor 2330 can be operably connected to the conductor 2328. The working electrode 2324 can be operably connected to the conductor 2326.

[0260] Figure 24 The system and method can be used to deliver DC current to tissue using battery-type chemistries, such as lead-acid batteries, nickel-cadmium, nickel-metal hydride, lithium-ion, lithium polymer, zinc-carbon, bio-batteries, or other types of battery chemistries. System 2400 may include a DC generator 2410 operably connected to one, two, or more reaction chambers 2402, 2404 via conductors 2412, 2414. Reaction chambers 2402, 2404 may include battery-type reactants 2406, 2408. For example, reactants 2406, 2408 may be lead / lead oxide, and the redox reactants may be sulfuric acid and / or water, as shown. A membrane or other element, represented by A2420, may prevent harmful components from entering the conduits / ducts 2416, 2418 and the tissue interface 2422, 2424 (e.g., a cation or anion selective membrane) connected to tissue 2426.

[0261] Figure 25A SINE-type electrode 2500 is schematically shown, modified to allow for attachment at a patient site to reduce conduit length and impedance. For example, a DC generator 2502 can be operably connected to a lead 2506 connected to a reaction chamber 2504 (e.g., an electrode system / charge generator including electrodes and an electrode bath), which in turn is connected to a fluid conduit / tube 2508 configured to deliver DC current to a target tissue site 2512 via an opening 2513. While one or more of the aforementioned components can be external or internal to the patient, in some embodiments, as shown, only a short section of the fluid conduit / tube 2508 is located between the electrode system 2504 and the target tissue site 2512 in the patient 2510 to reduce length and impedance. In some embodiments, a majority of the length of the fluid conduit / tube 2508, or at least approximately 50%, 60%, 70%, 80%, 90%, or more, can be located internal to the patient's body 2510. In some embodiments, a fluid conduit / tube 2508 of less than about 5 cm, 4 cm, 3 cm, 2 cm, 1 cm, or less in length is located within the patient 2510 .

[0262] In some embodiments, the system can be fully wearable to facilitate patient mobility. The system can include straps, adhesives, bands, or other elements for attachment to a desired body surface, such as the scalp, neck, upper or lower extremities, torso, or abdomen. The guidewire / catheter can be attached percutaneously at the desired anatomical site as shown, or transcutaneously in other embodiments. Figure 26A A wearable system 2600 is shown that includes a DC generator 2604 , a lead, and a reaction chamber 2604 , with a portion of the lead / catheter 2606 implanted at a desired anatomical site 2608 in / on a patient 2602 . Figure 26B A bandage-type system 2601 is shown positioned at a treatment site (e.g., a nerve block). An electrode system / charge generator 2604 can be secured to a patient 2602 using a bandage, strap, adhesive patch, adhesive, or other engaging element 2610. A guidewire / catheter 2606 can be operably connected to the electrode system / charge generator 2604 and deliver a DC current at a target tissue location 2608. Figure 26C A schematic embodiment of such a wearable device 2604 is shown having two different lead exit configurations, one in which the lead 2606 exits a narrow portion of the system, and the other in which the lead 2606 exits a wider portion of the system and can be inserted directly into the patient's body. The lead can be configured to be detachable from the rest of the system for ease of insertion into the patient's body before being connected to the rest of the wearable system. The wearable device 2604 can include a power supply 2612, a DC generator / control electronics 2614, a reaction chamber 2616 with a fluid bath and electrodes, and junction locations 2618, 2620.

[0263] In some embodiments, disclosed herein are methods for treating pain or other conditions by cycling DC blockade at multiple locations spaced apart from one another. For example, electrodes may be present at Figure 27A The electrodes are applied to the spinal cord 2710 at locations A 2704, B 2706, and 2708, schematically shown in FIG. 2706 , powered by a DC generator and operably connected via conductor 2702. Figure 27B The variables v(t) (voltage versus time) or i(t) (current versus time) shown in may have very long biphasic cycles. Figure 27C As shown, the time for each phase of the biphasic wave t1 / 2 can be, for example, at least about 0.1 seconds, 1 second, 5 seconds, 10 seconds, 20 seconds, 50 seconds, 100 seconds, 500 seconds, 1000 seconds, 5000 seconds or longer, or a range comprising any two of the foregoing values. The blocked tissue portion of the time may involve electrodes directly beneath or near the target tissue, thereby providing therapeutic benefit to a person in need thereof. In some embodiments, the DC current block can be near electrode A or B, thereby providing continuous or near-continuous block in the tissue. In some embodiments, 3, 4, 5, or more spaced electrodes 2704, 2706, and 2708 with overlapping charge waveforms can be utilized to advantageously facilitate such Figure 27D Continuous nerve block shown.

[0264] Also disclosed herein are systems and methods for controlling the DC output current amplitude based on measuring a variable indicative of the electrochemical state of a DC blocking electrode system. This can advantageously facilitate safe use of DC current, ensuring operation only within an electrochemical range (e.g., reaction type) that is safe for tissue and electrode health. The variable can be, for example, one, two, or more of voltage, pH, temperature, and the like. Figure 28A A DC current system 2800 including an optional reference electrode 2802 for voltage monitoring is schematically shown. A power source 2804 may be connected to electrodes 2810, 2812 via conductors 2806, 2808. Figure 28B In the simple example shown, the electrode voltage increases with continued DC current delivery. Once the voltage reaches a threshold maximum, indicating that a different chemical reaction (e.g., electrolysis of water) may be occurring, the current can be stopped. In some embodiments, the system can be more complex to allow for reduced delivery interruptions by reducing or otherwise adjusting the output current to keep the voltage within a desired operating window. For example, a proportional-integral-derivative (PID) controller can be used to control the output. In some cases, a net unbalanced charge delivery may be desirable to keep the operating voltage within a desired window.

[0265] Some embodiments may also include an annealing or conditioning process of an electrode, such as a silver-silver chloride electrode with or without a coating, operably connected to a DC generator. The output current may be gradually increased in a periodic manner while monitoring the voltage. Figure 29 As shown, the voltage can be maintained within a desired range with upper and lower threshold bands, which limits the electrochemical reactions occurring at the electrode sites (e.g., to silver-silver chloride reactions, as opposed to water electrolysis). With repeated cycling, more (higher) current can be passed while maintaining the voltage threshold.

[0266] Also disclosed herein in some embodiments are single-fault-safe DC systems and methods. The systems and methods may involve very large series capacitors, such as about or at least about 5,000, 7,500, 10,000, 12,500, 15,000, 50,000, 100,000 or more microfarads (μF), or a range comprising any two of the foregoing values, as in Figure 30A Charge calculations can be performed to deliver known values ​​in each direction, such as using any number of the following parameters: programmed amplitude and delivery duration; delivery using voltage measurements across a sense resistor; monitoring voltage output (with or without Figure 30B Schematically shown in the additional (eg, third or fourth) reference electrode; as shown Figure 30C A monitoring circuit schematically shown in FIG. 1 controls a switch to stop or slow current delivery; and / or monitors via an independent microcontroller or logic device to improve tolerance to single (or multiple) fault conditions.

[0267] Additionally disclosed are electrode systems and methods for making such systems capable of safely delivering direct current to tissue, including titanium nitride or other high charge density electrodes. In some embodiments, a silver-silver chloride electrode configuration 3100 comprising a silver (Ag) substrate 3102 with a bonded silver chloride (AgCl) layer 3104 is disclosed. Figure 31 ). The AgCl layer can be deposited on the surface by a chemical deposition process. Alternatively or additionally, the AgCl layer can also be grown on the silver substrate by immersing the silver substrate in an electrolyte solution containing chloride ions (Cl-) and passing an electric current through the substrate to promote a chemical reaction that oxidizes the silver atoms in the substrate, thereby allowing them to bind the chloride ions to produce silver chloride according to the electrochemical process previously described:

[0268]

[0269] In some embodiments, the electrodes can have any desired shape, including but not limited to being generally flat or round, such as cylindrical. In one non-limiting embodiment, the electrodes can comprise dimensions of approximately 1.4 mm outer diameter and a length of approximately 3.5 mm. In another embodiment, the electrodes can comprise flat disks having a diameter of approximately 3.6 mm. The electrodes can also have a rectangular or pill shape. The electrode surface area can be, for example, less than about 5 mm 2 , about 5-10mm 2 , about 10-15mm 2 , about 15-20mm 2 , greater than 20mm 2 range, or a range including any two of the above values ​​(e.g., at about 5 mm 2 to about 20mm 2 A layer of silver chloride can be generated on a silver substrate having a thickness of, for example, less than about 1 micron, about 1-3 microns, about 3-5 microns, about 5-10 microns, or about 10 microns or greater, or a range comprising any two of the foregoing values ​​(e.g., between about 1 micron and 10 microns) to achieve sufficient direct current and charge transport necessary for treatment. In one configuration, a cylindrical electrode having a diameter of about 1.4 mm and a length of about 3.5 mm was prepared, having a silver chloride layer about 10 microns thick, to enable the transport of up to about 5000 mA-seconds of charge, such as a current of about 5 mA for about 10 seconds under specific circumstances. When the reaction is reversed using a suitable counter electrode, the electrode can be regenerated to enable extended circulation and use of direct current in vivo. Some embodiments may include other high charge density materials, such as titanium nitride and other materials, some of which are disclosed elsewhere herein.

[0270] Silver chloride (AgCl2) can be generated on pure Ag by applying a direct current through an electrolyte bath. Figure 32 ).like Figure 32 , a counter electrode 3202 and a working electrode 3204 are shown immersed in an electrolyte bath 3206 and connected to a power supply 3214 that drives a potential across the two electrodes 3202, 3204. In one configuration, the electrolyte bath 3206 includes chloride ions, such as a salt solution 3210, for example, 0.9 wt% (isotonic) saline. Both the counter electrode 3202 and the working electrode 3204 can be silver, or only the working electrode 3204 can be silver. By applying a driving voltage, an electric current is generated, and the silver on the working electrode 3204 can be converted into silver chloride, thereby producing a layer of silver chloride on the silver substrate.

[0271] A simple approach is to apply direct current and calculate the total charge required to generate enough AgCl on electrode 3204 by means of coulometry measurement so that the longest cathodic pulse at the therapeutic current level does not deplete electrode 3204. However, this overly simplistic approach does not address the properties of AgCl, which affect its ability to readily participate in symmetrical electrochemical reactions while maintaining a safe driving voltage range below the electrolysis potential threshold. In some embodiments, it is important that the electrode system 3200 keeps the ion current isolated from the electrochemical reaction of Ag to AgCl, thereby substantially preventing the generation of potentially harmful byproducts. Controlling the voltage potential applied to electrodes 3204, 3202 can be the primary means of selecting an electrochemical reaction because different reactions occur at different potentials. An AgCl electrode that does not have the correct properties may require a voltage potential above the permitted threshold to maintain the specified current and duration. As a result, the electrochemical reaction may become uncontrolled, resulting in the generation of potentially harmful byproducts.

[0272] An initial step can be to generate a layer of silver chloride on the silver substrate. To achieve this in a controlled manner without causing electrolysis of the aqueous solution, a maximum current can be specified, which can be a target current for therapeutic operation of the electrode or a maximum therapeutic current for the electrode. The maximum current can be, for example, in the range of about 0-3 mA, about 3-5 mA, about 5-7.5 mA, about 7.5-10 mA, or about 10 mA and higher, or a range comprising any two of the foregoing values. A drive voltage can then be applied between the counter electrode 3202 and the working electrode 3204 to generate a layer of silver chloride 3212 on the working electrode 3204. The working electrode 3204 can be partially immersed in the electrolyte solution 3210 such that the top of the solution 3208 does not cover the entire working electrode 3204, resulting in the formation of the silver chloride layer 3212 on the submerged portion. A target total charge can be specified to generate a target amount of silver chloride on the electrode surface 3204. A build period for the electrode 3204 can be specified, as well as an etch-back period, in which the current is driven in the reverse direction to remove some of the formed silver chloride to produce a more robust silver chloride formation on the electrode surface. One configuration can include a 60 second build period with, for example, a 10% etch-back period, in which 10% of the build AgCl layer is then removed before the next build period. Other combinations of build and etch-back or removal periods can be used to generate AgCl on a silver substrate.

[0273] like Figure 33As shown by trace A (solid line), the applied drive voltage can be positive, corresponding to the buildup of AgCl on the working electrode. After a defined buildup period, a removal or etch-back period will occur, followed by another buildup period, until the total charge and target AgCl layer are deposited, at which point the buildup process is terminated, as indicated by an "X". Since the absolute value of the drive voltage threshold is not reached in trace A, no adjustment of the drive voltage is required during the AgCl generation process. However, in Figure 33 In , for trace B (dashed line), the driving voltage upper threshold value is reached, and the algorithm stored in the controller can limit the driving voltage to the threshold level raised by reducing the electric current for building AgCl. After the construction period, it can be as described removal or etch-back period, and continue the process until the target charge is deposited on the working electrode in the form of AgCl. In other embodiments, the driving voltage parameter can be replaced by the working ratio reference electrode voltage parameter to more accurately measure the electrochemical interface potential, to control the driving voltage, thereby limiting the generation of potential harmful by-products.

[0274] Once silver chloride is generated on the electrode, the drive voltage used to convert AgCl to silver and vice versa may still exceed the electrolysis potential, leading to a potentially dangerous condition if used near tissue. In order to condition the electrode so that it can operate within a safe range and the drive voltage remains below the electrolysis potential, the electrode can be cycled in a specific manner.

[0275] Cycling of the silver / silver chloride reaction at a fixed current amplitude and a fixed duration has been shown to cause a decrease in the peak drive voltage with increasing cycle number, e.g. Figure 34 In some embodiments, the driving voltage is lower than the electrolysis threshold value. ...

[0276] To reduce the generation of undesirable byproducts, cycling algorithms have been developed that can be executed by a hardware or software processor that cycles the electrodes in build and remove cycles to achieve the desired current amplitude and duration, which can be cycled repeatedly without exceeding a set drive voltage threshold, which can be the electrolysis potential or vice versa. This process occurs, for example, through formation and stabilization / conditioning steps.

[0277] The formation step involves repeated cycles of electric current that build up a layer of AgCl over a specific time period and then remove the added AgCl. The amount of AgCl deposited is limited by the current level, which in turn is limited by a maximum voltage limit or upper threshold of the driving voltage. There may also be a minimum voltage limit or lower threshold of the driving voltage. As AgCl is repeatedly added and removed, the basic structure of the AgCl changes, enabling it to sustain more current at a fixed driving voltage level. In some processes, these changes can be observed as visible microstructural changes on the surface of the electrode. The formation phase continues until the current level that can be sustained reaches a specified value. As shown herein, other electrodes, including but not limited to high charge density electrodes, can utilize systems and methods as disclosed elsewhere herein.

[0278] One embodiment of an algorithm, which may be executed, for example, by a controller in communication with one or more current generators and one, two, or more sensors, is as follows:

[0279] a. Apply an anodic current to the electrode for a specified period of time. During this period, measure the peak positive voltage as a function of duration.

[0280] b. Apply a cathodic current to the electrode until the total charge applied during the anodic phase has been removed. During this period, measure the peak negative voltage as a function of duration.

[0281] c. Analyze the peak voltage and adjust the current applied to the anodic and cathodic stages. If the peak voltage is less than the voltage limit, increase the current by a fixed percentage until the specified current limit is reached. If the peak voltage exceeds the voltage limit, reduce the current by a proportional amount.

[0282] d. If the anode current has reached the specified current value, it moves to the stabilization / adjustment stage. Otherwise, the cycle continues.

[0283] exist Figure 35In the forming step, the formation of the working electrode and the counter electrode is processed, wherein the current level starts with a relatively low value and increases with each cycle when the driving voltage upper threshold is not exceeded. As seen by the solid arrows, when a given current level exceeds the driving voltage upper threshold, the current level applied in the next cycle decreases, as shown by the open arrows. The duration of the positive current of the working electrode is set to the target duration, and the final amplitude is the target amplitude. Both can be configured to change in other embodiments of the algorithm. In other embodiments, the driving voltage parameter can be replaced by a working reference electrode voltage parameter to more accurately measure the electrochemical interface potential. In other embodiments, the initial current delivery cycle can be cathodic rather than anodic.

[0284] The stabilization / conditioning step can also include a repeated cycling current that builds a layer of AgCl over a specific time period and then removes the added AgCl. The amount of AgCl deposited is fixed and is determined by the current and duration. As AgCl is repeatedly added and removed, the underlying structure of the AgCl transforms, thereby reducing the voltage potential required to pass the specified current for the duration. The stabilization / conditioning phase continues until the cycle-to-cycle voltage variation drops below a pre-configured value. Figure 35 As shown, the stabilization / regulation phase may include a current amplitude that is substantially consistent from cycle to cycle and a drive voltage whose peak level is consistent within a predetermined variation.

[0285] One implementation of the algorithm is as follows:

[0286] a. Apply an anodic current to the electrode for a specified period of time. Measure the peak positive voltage over this period of time as a function of duration.

[0287] b. Apply a cathodic current to the electrode until the total charge applied during the anodic phase has been removed. Measure the peak negative voltage over this period as a function of duration.

[0288] c. Maintain (e.g., in memory) a list of the previous N peak voltages. The number N of samples is the stable period of the configuration.

[0289] d. If the change in peak anode voltage is less than the configured value, the electrode formation process is complete. Otherwise, continue circulating the current. Optionally, the magnitude of the peak anode voltage is less than the configured value until or when the electrode formation process is complete.

[0290] In some embodiments, the electrodes can have a working surface area of, for example, about, less than about, or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100 mm 2 , or more or less, or a range including any two of the above values.

[0291] In some embodiments, the maximum current limit can be, for example, about, less than about, or no more than about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mA, or more or less, or a range including any two of the above values.

[0292] In some embodiments, the voltage limit can be, for example, about, less than about, or no more than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5V, or more or less, or a range including any two of the above values.

[0293] In some embodiments, the voltage variation limit can be, for example, about, less than about, or no more than about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250 mV, or more or less, or a range including any two of the above values.

[0294] In some embodiments, the time period limit can be, for example, about, less than about, or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 seconds, or more or less, or a range including any two of the above values.

[0295] In some embodiments, the stabilization period can be, for example, at least about, about, or no more than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 500, 1,000 cycles, or more or less, or a range comprising any two of the above values.

[0296] In some embodiments, the build period can be, for example, at least about, about, or no more than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 500, 1,000 seconds, or more or less, or a range including any two of the above values.

[0297] In some embodiments, the build and etch-back periods can be, for example, at least about, about, or no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more or less, or a range including any two of the foregoing values.

[0298] In alternative embodiments, the build charge can be up to about 2500, 3000, 3500, 4000, 4500 or 5000 mA-seconds or above, such as 5500, 6000, 7000, 8000, 9000, 10000 mA-seconds or more, or a range comprising any two of the foregoing values.

[0299] In some embodiments, for example, in the disclosed algorithm, the electrode can be adjusted in a manner allowing the target current amplitude to be delivered within the desired duration, wherein the driving voltage is lower than a threshold value of setting, such as the electrolysis potential. The algorithm also limits the amount of time that the electrode is exposed to a voltage exceeding a driving voltage upper threshold value that may cause the production of toxic byproducts that may damage tissue. In other embodiments, the driving voltage parameter can be replaced by a working ratio reference electrode voltage parameter to more accurately measure the electrochemical interface potential. In other embodiments, the initial current delivery cycle can be cathode rather than anode. Systems and methods as shown herein can relate to sensors for measuring current, voltage, and other parameters that provide input to a controller that can perform a specific algorithm in an open or closed loop form, including but not limited to those disclosed herein.

[0300] Figure 36 Figure 1 shows the microstructural changes that can occur after building an AgCl layer on a bare silver electrode, and after performing formation and stabilization / conditioning steps to condition the AgCl-coated electrode. These microstructural changes can include the formation of Ag-AgCl "islands" that readily transition between the Ag and AgCl forms and increase the surface area available for electrochemical reactions.

[0301] Although described for constructing and adjusting the electrode so that the driving voltage is maintained at an embodiment below a set threshold, the threshold can be a safety threshold, such as the electrolysis potential or as needed as by combining another threshold value set for safety factors, the system may still encounter a situation that tends to push the driving voltage out of the desired target range. For example, the charge exchanged between the working electrode and the counter electrode may deviate slightly, making the charge deposited on the counter electrode more than that deposited on the working electrode in each cycle. Through many cycles, this may deprive the working electrode of active, regulated AgCl or other substrate, thereby causing the magnitude of the driving voltage to increase. Figure 37 The drive voltage that begins to exceed the lower threshold over time is shown. Furthermore, in vivo, the impedance of the system is determined not only by the reaction potential across the electrode-body interface, but also by the impedance of the body tissue itself and the voltage drop that occurs across the tissue. Tissue impedance can change due to capsule formation around the electrode (e.g., fibrosis), exercise, weight gain or loss, or other factors that cause the body's impedance to change (increase or decrease) over time. At low frequencies, because the drive voltage includes the potential across the wire in close proximity to the tissue (ΔV 导线 ) and body (ΔV 身体 ) is shown in the following formula:

[0302] V 驱动 =ΔV 导线 +ΔV 身体 =I*(R 导线 +R 身体 )

[0303] In some cases, it may be advantageous to ensure that the voltage drop across the wire does not exceed a safe threshold, as this voltage drop indicates and drives the electrochemical reaction. 身体 ), then the ΔV of the set current value (I) can be determined 身体 , and can be adjusted by adjusting the driving voltage (V 驱动 ) to calculate and adjust the voltage drop across the wire (ΔV 导线 ) to ensure that ΔV 导线 Stay within safe limits.

[0304] exist Figure 38 In the example, the electrodes and the body can be modeled as parallel resistors (R 导线 ) and capacitor (C 导线 ), and the body impedance in series with the electrodes (R 身体 ). At low driving frequency, the above equation can be used to Figure 39 The electrodes and body are modeled as shown. At high drive frequencies, the Figure 40The modeled system shown in Figure 1 is a capacitor that behaves like a short circuit and has no impedance. In this case, the reference Figure 40 , the system can be defined by the following equation, where ΔV 导线 =0, because R 导线 =0:

[0305] V 驱动 =ΔV 导线 +ΔV 身体 =I*(R 导线 +R 身体 )=I*R 身体

[0306] By knowing V 驱动 and current (I), the body impedance (R 身体 ):

[0307] R 身体 =V 驱动 / I

[0308] Thus, the wire or electrode voltage drop can be calculated (e.g., via a processor) and controlled by adjusting the total drive voltage:

[0309] ΔV 导线 =V 驱动 -ΔV 身体

[0310] This allows the system to maintain the voltage below a set threshold.

[0311] ΔV 导线 <V 阈值

[0312] Reference again Figure 40, as seen in the circle in the figure, the ability to stimulate a short circuit through a wire or electrode-body interface can be achieved by generating a short-circuit current input. In some embodiments, the current input includes up to about 10 microamperes, about 10 to about 20 microamperes, about 20 to about 50 microamperes, about 50 to about 100 microamperes, about 100 microamperes to about 200 microamperes, more than about 200 microamperes, or a current amplitude including the range of any two of the above values. In some embodiments, the current input includes up to about 1 microsecond, about 10 to about 20 microseconds, about 20 to about 100 microseconds, about 100 to about 1 microsecond, about 1 microsecond to about 100 microseconds, more than about 100 microseconds, or a current duration including the range of any two of the above values. This current input can occur at the beginning of the DC cycle, during the DC cycle, or after the DC cycle, in order to determine the body impedance that allows the drive voltage to be adjusted to maintain the wire or electrode voltage below the threshold value set. The threshold value set can be a safety threshold, such as the electrolysis potential. Current input can be performed every cycle or every other cycle, or periodically or as needed, to allow the lead or electrode voltage drop to be determined. This voltage drop knowledge can then be used to adjust the drive voltage in an automatic control loop or manually. After the initial high frequency current input, a DC current waveform can be applied based on the adjusted drive voltage as determined in the previous high frequency current input.

[0313] If it is determined that the wire or electrode voltage exceeds the threshold, the Figure 41 The current amplitude shown is used to regulate the delivered current, wherein the portion of the waveform that reaches the threshold is reduced to remain below the threshold. In applications with silver-silver chloride electrodes serving as both counter and working electrodes, a controller implementing the described algorithm can advantageously achieve self-balancing of charge. The silver-silver chloride system may exhibit a higher voltage within the anodic phase (positive voltage) of the working electrode when the amount of AgCl available on the corresponding counter electrode is partially depleted, causing the less reactive AgCl to induce a higher potential to drive the reaction. By reducing the amount of charge drawn from the counter electrode during the anodic phase (open arrows), but with the full amplitude current during the cathodic phase (solid arrows), a net charge can be added to the counter electrode to help rebalance the charge distribution between the electrodes.

[0314] It should be noted that the above described systems and algorithms can also be used to maintain voltages within specific target drive voltage and lead voltage ranges as desired and set by the end user within the algorithm. In some embodiments, the primary current pulse is delivered cathodically rather than anodeically, or vice versa.

[0315] In some embodiments, for any of the therapies disclosed herein, the direct current (DC) delivery amplitude can be, for example, in the range of about 0 to about 0.5 mA, about 0.5 to about 1.5 mA, and about 1.5 to about 2.5 mA, or in the range of any two of the above values. In some embodiments, anode and cathode current levels of about 2.5 mA to about 5 mA and about 5 mA and higher can be utilized to block. In animal studies, responses have been seen, for example, at a range of about 0-1.5 mA, and in paresthesia episodes in human peripheral nerves, at about 1.5 mA (cathode and anode), where complete blockade was achieved at current delivery of about 2.5 mA and up to about 5.5 mA.

[0316] In some embodiments, direct current delivered to a patient can be targeted to any number of anatomical locations, including, but not limited to, the dorsal root ganglion, dorsal root, dorsal column, dorsal horn, bundle of Lissauer, and / or anterolateral pain fasciculus. In some embodiments, direct current delivery can be directed to peripheral nerves or other target locations as described elsewhere herein. Without being limited by theory, in some embodiments, DC delivery can effectively modulate small diameter fibers in the spinal cord and depolarize spinal neurons. DC delivery may not necessarily be sensitive to fiber size and may have a wider therapeutic window. DC delivery can be used for a variety of indications, including, but not limited to, cardiac delineation of arrhythmias, epilepsy, and movement disorders, as well as various other conditions disclosed elsewhere herein.

[0317] The systems and methods described in the above figures can be used to produce DC nerve blocks. Depending on the specific direct current application of the nerve block, nerve inhibition or continued block may occur after the current is removed or stopped, and high inhibition of continuous nerve block may result for more than one minute after the DC source is removed, thereby delaying the recovery of nerve conduction. Depending on the desired application, nerve block and inhibition can be produced in an intermittent or continuous manner. A method for continuous nerve block has been described that provides for the safe delivery of nerve block via ionic current activated by multiple electrodes or electrode contacts arranged in sequence, so that the method can safely modulate nerve conduction without the need for complex mechanical systems. The system can be fully or partially implantable or completely non-implantable (e.g., percutaneous), with all tissue contacting materials being biocompatible to achieve tissue contact and implant compatibility.

[0318] In some embodiments, the systems and methods disclosed herein can be used or modified for use as part of an alternating current stimulation system, including but not limited to spinal cord stimulation (SCS) systems for treating chronic pain, such as the SENZA system from Nevro Corporation; the PRECISION system from Boston Scientific Corporation, including PRECISION PLUS and PRECISION SPECTRA, and the INTELLIS system from Medtronic PLC. As an example, the systems and methods disclosed herein can increase the effectiveness of an alternating current delivery system, including delivering alternating current to a target tissue of a patient via electrodes and electrode leads using a DC offset waveform generated by a pulse generator and facilitated by a controller. In some embodiments, high frequency as used herein with reference to alternating current (e.g., HFAC) can refer to a frequency of about 1 kHz or higher, such as about 1.5 kHz to about 100 kHz, about 3 kHz to about 50 kHz, about 5 kHz to about 20 kHz, about 1 kHz, 2 kHz, 3 kHz, 5 kHz, 10 kHz, 15 kHz, 20 kHz, 25 kHz, 30 kHz, 40 kHz, 50 kHz, 75 kHz, 100 kHz, or higher, or a range comprising any two of the foregoing values. In some embodiments, the amplitude of the signal can range from about 0.1 mA to about 20 mA, about 0.5 mA to about 10 mA, about 0.5 mA to about 4 mA, about 0.5 mA to about 2.5 mA, or other ranges comprising any two of the foregoing values, or other amplitudes as disclosed elsewhere herein. In some cases, the amplitude of the applied signal can be ramped up and / or down, including nonlinear ramp functions. The frequency or amplitude of the alternating current can also be adjusted. The electrodes and / or electrode leads may include one or more of the following: a high-density charge material, a SINE electrode, and / or a silver-silver chloride material. In some instances, such systems and methods may advantageously increase the excitability of target neurons, thereby lowering the threshold and expanding the therapeutic window for target tissue stimulation. In some embodiments, the systems and methods are configured to reduce side effects, including but not limited to paresthesias, typically tingling, buzzing, or shock, that may manifest during daily activities or sudden movements during other periods of time.

[0319] The foregoing description and examples have been set forth to illustrate the disclosure according to various embodiments and are not intended to be overly limited. The titles provided herein are only for organizational purposes and should not be used to limit the embodiments. Each disclosed aspect and example of the present disclosure may be considered individually or in combination with other aspects, examples, and variations of the present disclosure. In addition, unless otherwise stated, any step of the method of the present disclosure is not limited to any specific execution order. The references cited herein are incorporated herein by reference in their entirety.

[0320] While the methods and apparatus described herein may be susceptible to various modifications and alternative forms, specific examples thereof have been shown in the drawings and described in detail herein. However, it should be understood that the disclosed embodiments are intended to cover modifications, equivalents, and alternatives that fall within the spirit and scope of the various embodiments described herein and the appended claims.

[0321] Depending on the implementation, one or more actions, events, or functions of any algorithm, method, or process described herein may be performed in a different order, added, combined, or omitted entirely (e.g., not all described actions or events are necessary for implementation of the algorithm). In some instances, actions or events may be performed concurrently rather than sequentially, for example, through multithreading, interrupt handling, or on multiple processors or processor cores or other parallel architectures.

[0322] Unless explicitly stated otherwise or understood otherwise from the context of use, the use of sequential or chronological language, such as "then," "next," "after," "subsequently," etc., is generally intended to facilitate the flow of the text and is not intended to limit the order of actions performed.

[0323] The various illustrative logic blocks, modules, processes, methods, and algorithms described in conjunction with the embodiments disclosed herein can be implemented as electronic hardware, computer software, or a combination of the two. In order to clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, operations, and steps have been generally described above according to their functions. Whether such functions are implemented as hardware or software depends on the specific application and design constraints imposed on the entire system. The described functions can be implemented in various ways for each specific application, but such implementation decisions should not be interpreted as resulting in departure from the scope of this disclosure.

[0324] The various illustrative logic blocks and modules described in conjunction with the embodiments disclosed herein may be implemented or executed by a machine designed to perform the functions described herein, such as a general-purpose processor, a digital signal processor (DSP), an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof. A general-purpose processor may be a microprocessor, but alternatively, a processor may be a controller, a microcontroller, or a state machine, a combination thereof, etc. A processor may also be implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors combined with a DSP core, or any other such configuration.

[0325] The modules, operations or steps of the methods, processes or algorithms described in conjunction with the embodiments disclosed herein can be implemented directly in hardware, implemented in a software module executed by a processor, or implemented in a combination of the two. The software module can be present in a RAM memory, a flash memory, a ROM memory, an EPROM memory, an EEPROM memory, a temporary register, a hard disk, a removable disk, an optical disk (such as a CD-ROM or DVD) or any other form of volatile or non-volatile computer-readable storage medium known in the art. A storage medium can be coupled to a processor so that the processor can read information from the storage medium and can write information to the storage medium. Alternatively, a storage medium can be integrated into a processor. The processor and the storage medium can reside in an ASIC. The ASIC can reside in a user terminal. Alternatively, the processor and the storage medium can reside in a user terminal as discrete components.

[0326] Unless expressly stated otherwise or otherwise understood in the context of use, conditional language used herein, such as "can," "might," "could," "for example," and the like, is generally intended to indicate that some instances include, while other instances do not, certain features, elements, and / or conditions. Thus, such conditional language is generally not intended to imply that one or more instances in any way require features, elements, modules, and / or conditions, or that one or more instances necessarily include logic that determines whether such features, elements, and / or conditions are included or will be implemented in any particular embodiment, with or without author input or prompting.

[0327] The methods disclosed herein may include certain actions taken by a practitioner; however, the methods may also include explicit or implicit instructions from any third party regarding these actions. For example, an action such as "place an electrode" includes "instruction to place an electrode."

[0328] The ranges disclosed herein also encompass any and all overlaps, subranges, and combinations thereof. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” etc., includes the numbers listed. Terms following a number, such as “about” or “approximately,” include the numbers listed and should be interpreted as appropriate (e.g., as accurately as reasonably possible in the circumstances, e.g., ±5%, ±10%, ±15%, etc.). For example, “about 1 hour” includes “1 hour.” Terms following a phrase, such as “substantially,” include the phrases listed and should be interpreted as appropriate (e.g., as accurately as reasonably possible in the circumstances). For example, “substantially vertical” includes “vertical.” Unless otherwise stated, all measurements are under standard conditions, including temperature and pressure. The phrase “at least one” is intended to require at least one item from a subsequent list, rather than every item of a type from every item in a subsequent list. For example, “at least one of A, B, and C” may include A, B, C; A and B; A and C; B and C, or A, B, and C.

Claims

1. A system for direct current nerve block, comprising: DC generator; working electrode and counter electrode; as well as a controller configured to cyclically apply a direct current of a first polarity for a first duration and cyclically apply a direct current of a second polarity opposite to the first polarity for a second duration, receive a measurement of a peak voltage of the first polarity for the first duration and a measurement of a peak voltage of the second polarity for the second duration; regulate the direct current by analyzing the peak voltages for the first duration and the second duration, and increase the current intensity by a predetermined amount up to a current limit when the measured peak voltages for the first duration and the second duration are below an absolute threshold limit; And reducing the current intensity by a certain amount when the measured peak voltage during the first duration or the second duration is above an absolute threshold limit.

2. The system of claim 1, wherein the direct current comprises a frequency less than 1 Hz.

3. The system of claim 1, wherein the absolute threshold limit is less than the electrolysis potential of water.

4. The system of claim 1, wherein the working electrode comprises silver chloride.

5. The system of claim 1, wherein the current limit is a predetermined current limit and the current intensity is reduced by a predetermined amount.

6. The system of claim 1, wherein the controller is configured to fix the current intensity when a change in the peak voltage of the first polarity is below a configured value.

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