Methods and systems for neural conduction blocks

Abstract

Disclosed herein are systems and methods for nerve conduction block, which may include safely delivering a relatively high amount of charge to tissue. Such systems and methods may include a control system for safely monitoring a direct current electrode system including delivering direct current to a target tissue of a patient via an electrode lead; measuring a driving voltage through the electrode; comparing the driving voltage passing through the electrode with a predetermined threshold range value; measuring body impedance; determining a voltage drop through the wire from the body impedance measurements; and adjusting the driving voltage to maintain a voltage drop through the wire within a predetermined voltage range.

Description

[0001] Incorporation by reference into any priority application

[0002] This application is a divisional application of Chinese patent application No. 201980025098.7, and claims the benefit of U.S. Provisional Application No. 62 / 632,485 filed on February 20, 2018 and U.S. Provisional Application No. 62 / 640,579 filed on March 9, 2018, under 35 U.S.C. §119(e), which are hereby incorporated by reference in their entirety. 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 in accordance with 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 passing 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 that 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. Stimulation of dorsal root ganglia DRG in a similar frequency range has also been used to relieve segmental pain by the same mechanism.

[0006] However, technology based on this premise is not perfect because the pain transmission inhibition effect 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-theoretic activation of non-nociceptive fibers. In addition, the blockade of neural tissue or neural activity is not only relevant to affecting pain, but also to the management of movement disorders, psychiatric disorders, cardiovascular health, and the management of disease states such as diabetes. SUMMARY OF THE INVENTION

[0008] The methods and devices or apparatus disclosed herein each have several aspects, no single one of which is solely responsible for its desirable attributes.Without limiting the scope of the disclosure, such 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 direct current electrode systems. The method may include delivering direct current to a target tissue of a patient via an electrode lead. The method may include measuring a drive voltage through the electrode. The method may include comparing the drive voltage through the electrode to a predetermined threshold range value. The method may include measuring body impedance. The method may include determining a voltage drop through the lead from a body impedance measurement. The method may include adjusting the drive voltage to maintain the voltage drop through 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 may include adjusting the amplitude of the delivered direct current.

[0015] In some embodiments, the direct current may include a cathodic direct current and an 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 may include a direct current generator. The system may include a working electrode and a counter electrode. The system may include a controller that may cyclically apply a direct current of a first polarity for a first duration and a direct current of a second polarity opposite to the first polarity for a second duration. The controller may 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 may adjust the direct current by analyzing the peak voltage for the first duration and the second duration. The controller may increase the current intensity by a predetermined amount up to the current limit when the measured peak voltage for the first duration and the second duration is below an absolute threshold limit. The controller may reduce the current intensity by a certain amount when the measured amount of peak voltage for the first duration or the second duration is 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 is a method 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 voltage for the first duration and the second duration. The method may include increasing the current intensity by a predetermined amount until the current limit when the peak voltage for the measured first duration and the second duration is 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 may 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 may include cycles of direct current delivery. The method may 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 of increasing the effectiveness of an alternating current electrode system. The method may include delivering alternating current to a target tissue of a patient via an electrode and an electrode lead using a DC offset waveform. The electrode or electrode lead may include one or more of: a high density charge material, a SINE electrode, and / or a silver-silver chloride material. The method may include increasing the excitability of a target neuron, thereby lowering the threshold and extending the therapeutic window of target tissue stimulation.

[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 that can send a signal to the pulse generator using a DC offset waveform to deliver alternating current to a target tissue of a patient 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 expanding the therapeutic window of target tissue stimulation.

[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) that includes electrodes at which an electrochemical process occurs to generate an electric current in the form of ions to change 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 including 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 including electrodes at which an electrochemical process occurs to generate an electric current in the form of ions to change 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 an electrical potential 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 block.

[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 neurological 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 includes 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 an electrode electrically coupled.

[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 in 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 operating another 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, methods of delivering prolonged blockade to neural tissue include initially delivering an ionic current proximate to the neural tissue to place the neural tissue in an inhibited state, wherein the blockade 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 electric current in the form of ions proximate to the neural tissue to place the neural tissue in an inhibited state, wherein the block continues after the electric current is stopped, and subsequently delivering current to maintain the nerve in its inhibited state such that currents of opposite polarity between the current delivery phases do not affect the neural inhibitory state.

[0069] In some embodiments, a system for acquiring and modulating the neural signal transmission characteristics of a DRG includes an introduction needle including an optional radiopaque marker and a probe and electrode configured to fit within the needle hole. The electrode includes stress 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 optional radiopaque markers 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 introduction 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 the EICCC electrode lead to a power source and delivering 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 to a desired tissue site, removing the needle, and connecting the 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 the EICCC using a connector element connectable to ionically conductive electrodes, wherein the system is hermetically sealed.

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

[0081] In some embodiments, systems for harvesting and modulating neural signaling properties of a DRG or DRGs are used to relieve pain caused by angina.

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

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

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

[0086] In some embodiments, systems for harvesting and modulating the neural signaling properties of a DRG or DRGs are used to relieve pain in specific areas 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 characteristics of a 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 tissue and deliver electrical current to the 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 signaling properties of the spinal cord includes more than one electrode lead that includes one or more regions for contacting and delivering current to tissue and that can be individually adjusted to deliver desired currents and electric fields 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 relieve 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 relieve neuroma pain.

[0097] In some embodiments, a method for harvesting 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 sympathetic cervical 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 reducing activity of the vagus nerve to increase heart rate.

[0102] In some implementations, methods for accessing and modulating neural signaling properties of the vagus nerve innervating the stomach include reducing activity of the vagus nerve 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 desired areas of the brain and reducing activity of neural tissue to treat chronic pain.

[0108] In some embodiments, disclosed herein is a system for performing a nerve block in a patient using a regenerative electrode. The system may include a direct current generator and / or at least one electrode including 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 with a first polarity through an electrode sufficient to block conduction in a nerve and / or reduce the amount of silver chloride in the electrode to form 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 with a second polarity through an electrode sufficient to increase the amount of silver chloride to regenerate 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 is occurring, such as a primary silver / silver chloride reaction. 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 when electrolyzing water. The selective barrier may also be configured to prevent silver ions from passing through the barrier toward the nerve junction. The electrode may be placed 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 a first direct current so that the amount of silver chloride reduced is greater than the surface area of ​​the electrode before delivering the first direct current. The controller may also be configured to deliver a first direct current so 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 the amount that can evenly cover the surface area, such as the entire functional surface area of ​​the electrode before delivering the first direct current, or a range including any two of the above values.

[0109] In some embodiments, a system for performing a nerve block in a patient using a regenerative electrode is also disclosed herein. The system may include one or more of the following: a direct current generator; at least one electrode including a solid component, an ionic component, and a nerve junction directly adjacent to the ionic component; a controller configured to send a signal to the direct current generator to perform the following operations: a first direct current with a first polarity is delivered through an electrode sufficient to block conduction in the nerve and reduce the amount of the solid component; and / or a second direct current with a second polarity is delivered through an electrode sufficient to increase the amount of the solid component to regenerate the electrode. The system may also include one or more sensors configured to determine whether a major solid component / ionic component 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 when electrolyzing water. The electrode or multiple 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 spaced between the ionic component and the nerve. The layer may be configured to selectively allow negatively charged ions of the ionic component to pass through the layer and toward the nerve, and prevent positively charged ions of the ionic component from passing through the layer and toward the nerve. The system may not have any mechanical moving parts. The nerve junction may be separated from the electrode by one or more of a gel, a hydrogel, and an ion-conducting polymer. The electrode may be partially or completely surrounded by a solution, such as an electrolyte solution, for example, isotonic saline. The solid component may include silver, and / or the ionic component may include silver chloride. The controller may be configured to deliver the first direct current so that the amount of the reduced solid component is greater than the surface area of ​​the solid component. The controller may 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 more after the delivery of the first direct current stops.

[0110] In some embodiments, methods for performing nerve blockade in a patient using a regenerative electrode are also disclosed herein. The method may include one or more of the following: delivering a first direct current of a first polarity through an electrode including 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 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 block using multiple regenerative electrodes. The method may deliver a first direct current having a first polarity through a first electrode adjacent to the nerve sufficient to block conduction in the nerve, the electrode comprising a solid component and an ionic component; deliver 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 when the nerve is in a high inhibition state; and / or reverse the polarity of the first direct current and the second direct current, wherein reversing the polarity maintains the nerve in a high inhibition state.

[0112] In some embodiments, methods for extending nerve blockade using at least one regenerative electrode are also disclosed herein. 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 high inhibition state, at least partially blocking conduction in the nerve after stopping delivering the first direct current. 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 a high inhibition 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 contain 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 converts 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 a 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 in close proximity to the neural tissue, the electrode being sufficient to block the block conduction in the neural tissue. Delivering the first direct current may place the neural tissue in a high inhibition state, at least partially preventing the conduction of the neural tissue after stopping the delivery of the first direct current. The method may also include maintaining the neural tissue in a high inhibition state for at least about 1 minute, 10 minutes, 1 hour, 24 hours, or longer. The method may also include sensing the conduction capacity of the neural tissue, and / or maintaining the neural tissue in a high inhibition state by delivering a third direct current to the neural tissue via an electrode after sensing the conduction capacity of the neural tissue, wherein the third direct current has the same polarity as the first direct current. Sensing the conduction capacity 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: a nerve, such as a spinal, cranial, or peripheral nerve, or a brain tissue, a dorsal root ganglion, a spinothalamic tissue, an autonomic nervous tissue, a sympathetic nervous tissue, or a 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 block using reversible electrodes. The system may include one or more direct current generators; at least one electrode including a solid component, an ionic component, and a nerve interface adjacent to the ionic component; a controller configured to send a signal to the direct current generator to perform the following operations: deliver a first direct current having a first polarity through the electrode sufficient to block conduction in the nerve; maintain the nerve in a high inhibition state, at least partially blocking 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 is a method for providing extended nerve block using a regenerative electrode. The method may 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 including a first component and a second component; highly inhibiting the nerve and at least partially blocking nerve conduction after stopping 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 a highly inhibited state. The first direct current may reduce the amount of the first component and increase the amount of the second component. The second direct current may increase the amount of the first component and reduce the amount of the second component to renew the electrode. In some embodiments, the method may not completely deplete the first component. The method may also include sensing the amount of at least one of the first component and the second component; and stopping the delivery of the first direct current when the amount of the first component reaches a predetermined minimum threshold. After delivering the first direct current and the second direct current, the net charge delivered to the nerve may be zero. The first direct current may be an anodic current or a cathodic current, and the second direct current may be a cathodic current or an anodic current. The method may also include sensing the conduction capacity of the nerve, and / or maintaining the nerve in a high inhibition state by delivering a third direct current to the nerve via the electrode after sensing the conduction capacity of the nerve, wherein the third direct current has the same polarity as the first direct current. Sensing the conduction capacity 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 gap without current between delivering a first direct current of a first polarity and delivering a second direct current of a second polarity.

[0116] The method may also include at least one, two or more additional cycles of direct current. One 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 also include implanting the electrode in a position close to the nerve, placing the electrode percutaneously in a position close to the nerve, and / or placing the electrode percutaneously in a position close to the nerve. The nerve may be separated from the electrode by a gel, a hydrogel, an ion-conducting polymer and / or a 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 detailed description that follows, reference is made to the accompanying drawings that form a part thereof. In the accompanying drawings, similar symbols generally identify similar components unless the context otherwise indicates. 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 restrictive. 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, as generally described herein and shown in the accompanying drawings, various aspects of the present disclosure may be arranged, replaced, combined, and designed in a variety of different configurations, all of which are expressly contemplated and become part of the present disclosure.

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

[0121] Figure 1B The graph shows that by driving 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 correlated with charge delivered to an electrode cell-nerve junction (middle) to provide nerve block (bottom) while achieving zero net charge transfer over a longer charging 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 high inhibition regions 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 source via electrically isolated wires.

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

[0126] Figure 1G Shown with Figure 1EA similar configuration, but with an isolation barrier that separates 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 status versus time.

[0128] Fig. 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 Fig. 1I Similar graphs of 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 reverses again, it resets the electrode to block.

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

[0133] Figure 3C-Figure 3D An embodiment is shown where dual EICCCs are incorporated into the neural N junction but driven 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 for blocking 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 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 having 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 insertable in the form of conventional IPGs (implantable pulse generators) 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-Figure 5B An embodiment of an electrode configuration is shown in which both electrode contacts are housed within the same electrically insulating housing.

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

[0141] Figure 6B An embodiment of a blocking electrode disposed along the DRG to facilitate nerve block is shown, along with 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 Fig.6D and Fig. 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] Fig. 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 electrode lead into the epidural space.

[0147] The wire can be guided along the spine within the epidural space so that it is between the exit areas of the spinal nerves and the tissue interface is close to the lateral spinothalamic tract, such as Figure 8C-Figure 8E shown.

[0148] Fig.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 Fig. 9B , an embodiment of a blocking / inhibiting electrode integrated with a sensing electrode is shown.

[0150] Figure 10A-10C An embodiment of an EICCC electrode is shown in FIG. 1 , wherein multiple tissue interfaces are present on the electrode and are individually addressable.

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

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

[0153] like Fig.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 Fig.12 Shown are the associated sympathetic ganglia, including the cervical and stellate (cervicothoracic) ganglia and their innervated targets in the heart.

[0155] Fig.13 Select sympathetic nervous system-related anatomical structures are shown.

[0156] Fig.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 the 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 encapsulated in a tissue interface in the form of a cuff where ionic current is deposited from the EICCC at the tissue site.

[0158] Fig.17 Non-limiting anatomical structures are schematically shown where sympathetic inhibition or blockade may also be used to regulate liver function and affect glucose and insulin production.

[0159] Fig.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] Fig.19 The drive voltage waveform over time is shown, as well as the positive and negative thresholds.

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

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

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

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

[0165] Fig. 23B Detached junctional nerve electrodes are shown, which may include integrated sensors for detecting the electrochemical state of the reacting / working electrodes.

[0166] Fig.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-battery, or other types of battery chemistries.

[0167] Fig.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] Fig.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. Fig.26B A bandage-type system is shown localized to the treatment site (eg, nerve block). Fig.26C Schematic embodiments of such a wearable device are shown with two different wire exit configurations.

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

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

[0171] Fig.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] Figure 30A-Figure 30C Embodiments of a single-fault-safe DC system and method are shown.

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

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

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

[0176] Fig.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] Fig.35 The processing of the working electrode and the 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] Fig.36 The microstructural changes that may occur after building up the AgCl layer on the bare silver electrode, as well as after performing the formation and stabilization / conditioning steps to condition the AgCl-coated electrode are shown.

[0179] Fig.37 The drive voltage that starts to exceed the lower drive voltage threshold is shown as a function of time.

[0180] Fig.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 Fig.39 The electrodes and body are modeled as shown in . At high drive frequencies, the Fig.40 The system is modeled as shown in , where the capacitor behaves like a short circuit and has no impedance.

[0181] Fig.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 specific 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 without rapid reversibility or recovery after removal or cessation of direct current application. By combining with nerve junctions via ion conduction pathways instead of conventional electrodes that do not have ion conductive 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 metal junctions from neural tissue using ion conductive elements and operating electrodes below the reaction potential of undesirable reactions, such as electrolysis of water or 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, conduction of action potentials in electrically excitable tissues, such as neural tissue, induces 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 a combined absolute and relative refractory period, 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) may 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 are functionally 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 fast sodium channel inactivation gate time constant).

[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 pain is unclear and cannot be reliably resolved by surgery. Alternatively, pain management can be solved by suppressing the central nervous system using stimulation signals that block the entry of 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 sensing. 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 paresthesias that may cause discomfort to patients have led to stimulation methods 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 way to manage 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 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 prevent the generation and transmission of action potentials (APs). Because this does not stimulate the nerves 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 (3) : 313-324, 2004). 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. Pat. Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface Nerve ElectrodePrevents Direct Current Induced Nerve Damage, J Neurosci Methods, September 2011 (1): 173-176; Fridman and Santina, Safe Direct Current Stimulation to Expand Capabilities of Neural Prostheses, IEEE Transaction of Neural Systems and Rehabilitation Engineering, 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 for a short time after stopping DC delivery) (U.S. Pat. Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface Nerve Electrode Prevents Direct Current Induced Nerve Damage, J Neurosci Methods, September 2011 201(1):173-176), each of which is incorporated herein by reference in its entirety. Those authors explicitly teach methods of reducing the inhibition of neural activity by limiting the duration of DC delivery to allow rapid recovery of the nerve (e.g., within seconds) after cessation of DC delivery (U.S. Pat. Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface Nerve Electrode Prevents Direct Current Induced Nerve Damage, J Neurosci Methods, September 2011 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). In addition, 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. In addition, invented and described herein are systems and methods for treating pain by the above-mentioned systems and methods, in particular by selectively blocking dorsal root tissue and / or dorsal root ganglia. In addition, invented and described herein are systems and methods for treating pain by the above-mentioned systems and methods, in particular 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 producing the electric current in the form of ions near at least one target nerve may 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 nerve 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 a microporous sieve, a nonwoven sieve, an ion exchange membrane (IEM), a supported liquid membrane or an ion gel, a polymer electrolyte, such as polyethylene oxide (PEO), polypropylene oxide (PPO), polyvinylidene fluoride-hexafluoropropylene copolymer (PVDF-HFP), a solid ion conductor and an ion selective membrane including a cation exchange membrane and an anion exchange membrane.

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

[0192] Ion-conducting materials can also be divided into multiple regions, which can contain different types of ion-conducting materials. The interface between different regions can be outlined by semipermeable membranes or barriers, which allow selective or general ion flow, but can limit the destruction of products produced by the conversion of electron flow to ion current. The separation element 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 (IEM), 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-conducting materials can also take different forms. For example, nerves can be in contact with hydrogels, which are in contact with liquids such as electrolyte solutions, and then the latter are in contact with traditional current electrode materials.

[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. Blockage 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 initial 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 initial 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 about 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 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. Pat. 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 with a high charge capacity material at least partially or completely. In some embodiments, the high charge capacity material can have 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 higher μC, or a Q value 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 may be a fractal coated electrode. In order to produce a larger surface area for electrochemical reactions, conventional electrodes may be made from structures with a high surface area / volume ratio, such as a rough surface, a fabric surface, a patterned surface, a reticular foam structure, a porous sintered microbead structure, a nanoscale or micrometer patterned structure, to expose additional material surface area. In some embodiments, the electrode may be a SINE (separated junction neural electrode) or an EICCC (electron to ion current conversion unit) electrode, wherein the electrode is immersed in an electrolyte solution that contacts an ion conductive material - an electrolyte solution that is combined with an ion conductive material interface that is in electrical contact with cardiac tissue or an area near cardiac tissue, such as Ackermann et al., U.S. Pat. No. 9,008,800 and Ackermann et al., U.S. Publication No. 2018 / 0280691, which are hereby incorporated herein by reference in their entirety.

[0196] The combination of conventional electron-carrying electrode materials and ion-conducting materials and the conversion mechanism can be collectively characterized as an electron-ion current conversion unit (EICCC). One such example can 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. After driving current through a conventional electrode, the reduction of solid AgCl will drive 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 regulate the neural membrane potential and, for example, produce a blockade of nerve conduction. The membrane potential can be adjusted in such a way that the potential is slowly ramped up to enough to avoid generating an action potential when the neural tissue is depolarized. After the current is reversed, the oxidation of the previously formed Ag or other Ag in the Ag / AgCl electrode will be oxidized, thereby generating AgCl deposits on the electrode, driving the ionic current in the opposite direction. Since the solubility of Ag and AgCl in saline is extremely low, the electrode remains mechanically intact during forward and reverse current delivery. Combined, the reduction-oxidation reaction will produce 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 will not be exhausted or saturated, thereby enabling to prevent other harmful reactions from occurring at the electrode. In some embodiments, the amount of the electrode can be maintained 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 about any range between two of the above values. In other words, the electrode is reversible and can be restored to its original or substantially restored to its near-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 / 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, and 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 above values. In some embodiments, the 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 may include materials such as tantalum or titanium nitride to produce 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, 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 produce an ionic current. Converting the polarity of the current to a capacitive material can effectively reset the system for subsequent charging to produce additional ionic current. In order to produce a larger surface area to produce an increase in the ability to flow ionic current, conventional electrodes can be made from structures with a high surface area / volume ratio, such as a rough surface, a reticular foam structure, a porous sintered microbead structure, a nanoscale or micrometer pattern 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 to flow to the tissue.

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

[0199] In order 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 in 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 failure points 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 a blockade while the first nerve-electrode junction EICCC state 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 to have no mechanically moving parts, such as valves or hinges.

[0200] Optionally, neural activity can be inhibited, meaning that neural activity remains blocked even if the blocking current is removed or interrupted. The nerve can be further placed in a high inhibition state, wherein the nerve remains blocked without rapid reversibility after stopping DC delivery. The nerve can be placed in an inhibition 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 inhibition state, the EICCC can be returned to its initial state by reversing the polarity of the current used to produce the initial block and inhibition state. During the reversal of the current, the nerve can remain in a high inhibition state. In another configuration, the EICCC can deliver subsequent blocking current inputs that extend the duration of inhibition, wherein there is a time period of no current delivery or reversal of the current during the blocking current. During the non-blocking current input, the neural tissue can remain in a high inhibition state. 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 ranges 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, lx, 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 local conditions in and near the neural tissue can also provide useful measures for determining when to provide current input to extend neural inhibition and provide a feedback loop for initial current delivery to produce initial neural blockade by adjusting the neural potential so that it cannot transmit action potentials. 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 is passed. In some embodiments, the active current is adjusted in response to one or more measured electrode potentials relative to the reference electrode. In some embodiments, the active current is adjusted 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 indicating that water electrolysis is occurring or is possible, 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 a working electrode and an 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, the electrolyte solution 102 is in contact with an ion conductive material-electrolyte solution interface 107, and an ion conductive material 106 (such as a fluid, hydrogel, gel or other polymer) is in electrical contact with a nerve tissue N or a region near the nerve tissue N. The EICCC electrode 100 also includes an electrically insulating biocompatible housing 108, which contains a conventional electrode 104, an electrolyte 102, and a biocompatible ion conductive material 106, the latter having a hole (near 110) that enables electrical contact with a nerve N or a region near the nerve tissue N. The system also includes a current delivery wire 112 between a power source 114 and the electrode 104. The power source 114 can be located outside or inside the body as required by the application. An exemplary non-limiting embodiment of the EICCC 100 includes a silver, silver chloride (Ag / AgCl) electrode in a 0.9% saline solution, which is in fluid contact with an electrolyte saturated hydrogel (agar preparation with 0.9% saline).

[0204] Using Ag / AgCl electrodes for generating current via AgCl on the electrode in a salt solution (NaCl), a sustainable and reversible electrochemical reaction can be achieved to convert current in the form of electrons into current in the form of ions. Figure 1B As shown in Region 1 of , by driving 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. In addition, it can be appreciated that by limiting the maximum mass of AgCl to m2, making the mass of unreacted Ag 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 case of 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 between the conversion of solid AgCl to solid Ag and the generation of chloride ions, and vice versa, is achieved:

[0205]

[0206] Since the reduction potential of water electrolysis or hydrolysis is higher than that of AgCl, the dissolution of AgCl will be preferred to prevent undesirable reactions from occurring in EICCC and generating OH-, H+ or oxygen free radicals. 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 up 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 that 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. 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 used to drive the reaction exceeds about 1.23 volts of reference to the standard hydrogen electrode, electrolysis will occur. The electrolysis of water can be detected via one or more sensors, and if electrolysis is detected in some cases, stop or adjust (increase or decrease) current delivery and / or driving voltage. In some cases, the sensor can also detect whether only, substantially only or mainly silver-silver chloride reaction occurs, rather than, for example, electrolysis, hydrolysis or redox water reaction. In addition, the amount of charge that can be delivered by this system is not limited by surface area reaction, as in the case of platinum electrodes, before the available reaction platinum is exhausted, platinum electrodes form hydrogenated platinum monolayers on the electrode surface, resulting in the formation of other potentially harmful products if the reaction continues to be driven. On the contrary, in an aqueous environment, when silver chloride is reduced, it forms solid silver and releases 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 including 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. Using the embodiments disclosed herein, using 5 mA pulses of DC delivery, with a 10 second duration, it is possible to achieve about or at least about 1,000x, 5,000x, 10,000x, 50,000x, 100,000x or more times the charge. This can be achieved, for example, by producing a 1 micron AgCl coating on an electrode of 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 reserves of silver chloride available, the amount of charge delivered can be increased to 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 can be uniquely positioned for use in a 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 associated with 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, 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 cathode or anode, but not both. After the initial phase - Phase 1, there may be an interval phase (Interval 1) between the cathode and anode 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) 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. The adjustment can include adjusting the current in phase 1 and phase 2 so that the current ramps 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 so that its duration t2-t1 and t4-t3 can be extended or shortened. 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 above 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 the continuous nerve block can continue after the current delivery to the nerve is stopped, and can continue to the interval 1 stage (ii), extend to stage 2 (iii), independently 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 may occur for a duration of more than 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 stages of nerve block 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 stages 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 nerve tissue that promotes nerve blockade. After this initial current delivery, the nerve tissue then enters a highly inhibited state, so that the nerve cannot conduct signals or cannot conduct signals completely without additional current delivered to the nerve tissue. The state of nerve tissue inhibition can also be extended, such as 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 of time exceeding one minute. This pattern of inhibition of extended can 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 "given" anodic and / or cathodic safe DC currents 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 phases, 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 completeness 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 ion conductive material (ion conductor 106), which is then bonded to neural tissue N or a tissue interface near the 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 appreciate that the conventional electrode 104 and the ion conductive material 106 can be joined in a variety of ways, such as abutting 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 the nerve block is shown as inactive when the polarity of the current is reversed as specified by the negative axis. It should be understood that in the case 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, in which 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, but with isolation barriers 118, 120, which 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. It will be appreciated by those of ordinary skill in the art that one, two or more, or no barriers, or any combination thereof, may be used. The barriers 118, 120 are configured to selectively allow certain ions to transfer between the respective materials while restricting the movement of other ions whose movement is not desired, for example, to maintain reactive species such as Cl- near the electrodes. The barriers 118, 120 may include ion selective membranes that only allow anions to pass, such as an anion exchange membrane. Figure 1H Shown with Figure 1F Similar graphs of current vs. time and nerve block status vs. time.

[0212] Fig. 1I Shown with Figure 1G A similar configuration, but also includes a feedback sensor 122 that monitors the condition of the nerve tissue N and / or the 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 the EICCC 210 so that it can adjust the electrode current and the nerve junction electrode potential to maintain high inhibition. In some embodiments, the sensor 122 can measure the nerve 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 the action potential cannot be conducted along the nerve cell. In some embodiments, the sensor 122 includes a reference electrode, whereby the potential difference between one or more working electrodes 104 and the reference electrode can be monitored and used as feedback to the power supply 114 to ensure the normal operating range of the EICCC 210. The implantable package may contain an integrated reference or counter electrode. Figure 1J Shown with Figure 1H Similar graphs of current vs. time and nerve block status vs. time.

[0213] Figure 2A A dual electrode system is shown, where 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, so that when one is in an active blocking phase, the other is in an inactive non-blocking phase, and once the current polarity is reversed again, it resets the electrode 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 to the nerve tissue itself.

[0214] Figure 3A-3B An embodiment is shown where two conventional electrodes 104A, 104B are incorporated into the junction of the nerve N, but driven from a power source via electrically insulated wires 112 with current of opposite polarity, so that when one is in the blocking phase, the other is in the non-blocking phase, once the current polarity is reversed again, it resets the electrode 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 the opposite side of the nerve tissue itself.

[0215] Figure 3C-Figure 3D An embodiment is shown where dual EICCCs 230A, 230B are coupled to the junction of the nerve N, but 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, such as Figure 3D The electrodes 230A, 230B are coupled to the junction of the nerve N 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), for example.

[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 ion conductive material 106 such as a hydrogel, gel or other polymer fluid that is in electrical contact with the nerve tissue N or a region near the nerve tissue. The EICCC 240 electrode also includes an electrically insulating housing 108 that houses a conventional electrode 104, an electrolyte 102, and an ion conductive material 106 having a hole (near 110) to enable electrical contact with the nerve or a region near the nerve 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 unit. 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 outside or inside the body as required by 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 a high surface area / volume ratio configuration that 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. 2 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. 2 adds a reference electrode 111 near the nerve tissue interface to monitor the voltage drop across the EICCC 260 to the nerve tissue 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.

[0219] Figure 4D-4F An embodiment of an electrode lead 212 is shown that is 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 Figure 4A The configuration shown is similar except that Figure 4A The nerve interface hydrogel shown in FIG. 4 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 nerve tissue environment. A connector 213 to a power source is shown, wherein a conductive portion of an electrode lead 213 extends distally from the connector 213 to an EICCC 400 that 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 a distal portion of the lead that can be positioned near the target nerve tissue. Contact with the nerve tissue environment occurs via ionic current that leaves the barrier / porous frit 404 that can manipulate the nerve environment.

[0220] Figure 4G A schematic embodiment of an EICCC integrated within a hermetically sealed housing 410 is shown, which contains 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 wires 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 wire is located relatively further away from the power source 412 and extends to the neural location N. Also shown are ionically conductive conduits (e.g., hydrogel connectors) 430, connector elements 432, insulating housing 420, and ionically conductive electrode wires 428.

[0221] Figure 5A-Figure 5B An embodiment of an electrode configuration 500 is shown, wherein two electrode contacts are contained within the same electrically insulating housing 504. Electrodes 502A, 502B are in ionic contact with an ion conductive material 510 / pad 512 in conjunction with neural tissue N and / or a neural attachment region at the interface. Each electrode 502A, 502B is electrically connected via its own conductive wire 506 driven by a power source 508. Internal electrodes 502A, 502B can be driven cyclically with opposite current polarity to provide constant nerve blockade. Power source 508 can be configured to be implantable in the body so that any wire 506 and electrodes 502A, 502B are also fully contained in the body. Optionally, in this or other embodiments, 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 and / or dorsal root ganglion (DRG) ( Fig. 6A The associated dorsal root ganglion from each vertebral level corresponds to a specific dermal patch in the body ( Figure 7 ), and blocking pain signals at the level of the DRG can reduce pain sensing at that particular DRG at the innervated skin graft. 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 may also be used to confirm that the target DRG body is able to provide adequate pain relief when blocked. Once it is confirmed that the needle is properly 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 curl or slack in the electrode body, to accommodate body movement, which without such features could cause the electrode to become dislodged. As shown Fig.6D and Fig. 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 lead 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 appropriate positioning and blocking are achieved, the optional electrode sheath can be retracted to expose a retaining mechanism such as a barb or a friction element that prevents the electrode from being displaced 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 before the retention mechanism is redeployed, and the electrode can be repositioned. 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 approaching a body part proximal to the power supply implant site. The power supply energy source can optionally be capable of being recharged by an external communication unit, such as by inductive charging. Figure 6B An embodiment of a blocking electrode 100 is shown positioned along the DRG to facilitate nerve block, along with a lead 112 and a power source 114. It should be appreciated that nerve block may include high inhibition of the DRG.

[0223] In an alternative embodiment, the power source may be permanently or temporarily located outside the patient's body to enable a nerve block. The electrodes may also be removed once deemed unnecessary, thereby providing a temporary nerve block as needed. The nerve block may 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 a specific skin graft can be used to locate 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 the relevant pain, and the DRG block on one or two levels of these levels located (with or without additional DRG block at other levels) 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 the generation of local blockade 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 the level L2, L3, L4 can alleviate the knee pain on the same 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 limbs and can similarly be relieved by setting an appropriate level of DRG blockade.

[0225] As mentioned above and as Figure 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 pain coverage based on pain manifestations in the body. EICCC electrodes can be placed at target levels associated with pain manifestations and regulated by adjusting the ionic current signal, such as by adjusting the current amplitude at each target DRG level and contact with the EICCC electrode to adjust the level and coverage of pain blockade. Positioning 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 absent, and can be used to signal adverse situations and environmental conditions to individuals.

[0226] Compared to conventional SCS in which 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) ( Fig. 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 electrodes 800. Electrode leads 802 can be placed via a vertebral body cut ( Fig. 8A The lead 802 may be placed in the epidural space (center, right) to gain access to the epidural space, and then the lead 802 may be introduced and placed in position along one or more sides of the spine at the desired level or levels. 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 guide wire 802 can be oriented along the spine within the epidural space such that the guide wire 802 is between the spinal nerve exit areas and the tissue interface is proximal to the lateral meningothalamic tract, such as Figure 8C-Figure 8E As shown. Figure 8C-Figure 8E As shown, the electrode wire 802 is positioned laterally to be located outside the lateral spinothalamic tract so that the ionic current generated from 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 an 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 approaching a body part near the power source implantation 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 In addition, the electrode can be configured to have multiple tissue contact areas, the output of which can be individually adjusted to optimize neural tissue blockade. Figure 10A-10C 4 is shown in which multiple tissue interfaces 404A, 404B are present on the electrode 402 and are individually addressable. Fig. 10B yes Fig. 10A A close up view of 10B-10B. Fig. 10C yes Fig. 10A10C-10C is a close up view of FIG. 5. In this embodiment, there is a dual system of EICCCs 400 with parallel lumens individually associated with each neural tissue interface region. In FIG. 10, 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 block of undesirable structures. An alternative embodiment is captured in FIG. 5, where the individual electrodes can also be individually addressed and can be adjusted to achieve the desired block generation.

[0228] Using 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, specific targeting of pain blockade can be facilitated. For example, trunk pain relieved through the thoracic level can be modulated by placing leads along the thoracic spine, while neck pain can be relieved by providing blockade and / or inhibition in the cervical spine. Upper extremity pain can be relieved by providing a combination of blockade and / or inhibition at the cervical and thoracic levels, while lower extremity pain can be relieved by a combination of blockade and / or inhibition at the lumbar and sacral levels of the spine.

[0229] The generation of pain block can be used to promote perioperative pain block in the case of needing motor control and non-pain sensing. For example, in the child's labor and delivery, one of the challenges faced by pain management, especially epidural anesthesia, is to reduce the perception of the lower body. Due to the non-specific nature of delivering anesthesia in the epidural space, it can affect the perception, pain and motor neurons. Epidural anesthesia may cause difficulty in producing thrust during delivery, and may cause paralysis a few hours after delivery, thereby impairing motor ability, such as walking ability. In some cases, epidural also involves fetal and neonatal health, including breastfeeding difficulties. Using the blocking electrode described above to target the spinothalamic tract and / or dorsal root ganglion, it is possible to target unwanted pain without the side effects (or reduce side effects) associated with the current epidural anesthesia technology, because only the pain tract is targeted, rather than any other movement or sensing tract. In addition, in the case where the ionic current is delivered to the neural tissue in a reversible blocking mode, if necessary, the cessation of the block can enable the patient to immediately return to normal pain sensing, and the off-target block can be reversed so that the body function can be immediately restored.

[0230] In addition to central nervous system interventions, 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 proximally (i.e., close to the spinal cord) from the site of pain for blocking can inhibit pain from distal sites. Specific to neuralgia, postherpetic neuralgia (after herpes zoster) can be targeted based on the outbreak manifestations that will track 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 usually manifests 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 diabetes-related neuropathy, is also a potential target.

[0231] In addition to relieving pain, nerve blocks and activity inhibition can be used to improve cardiovascular health in a specific targeted manner. It has been found that hypertension associated with the causes of cardiovascular disease can be alleviated by regulating the renal nerves to reduce 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 resistanthypertension: 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 blocks can be used to promote reduced activity of the renal nerves and sympathetic nervous system to promote the reduction of hypertension. As Fig.11 As shown, the blocking electrode leads 1100A, 1100B contact the renal nerves to promote blockade or inhibition. Also shown is the 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 with 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 modulating the activity of the sympathetic ganglia, particularly the cervical sympathetic ganglia, using blocking electrodes, excessive cardiac activity can be reduced to relieve the heart from overwork. Similar to dorsal root ganglion access, the cervical ganglia can be accessed for blocking. Fig.12 Shown is 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 modulated by modulation of the sympathetic nervous system, and possibly by targeting the cervical sympathetic ganglia ( Fig.13 ) to provide blockade of the sympathetic ganglia and be affected to a more normal condition. Methods of access include posterior access and through the pleural cavity.

[0234] Modulation of the parasympathetic nerves of the heart can be used to regulate heart 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 turned off to inhibit 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 sinus node to help regulate heart rate, can be blocked or inhibited to enable an increase in heart rate. Fig.14 , the EICCC electrode 1400 can be placed around or near the right (and / or left) vagus nerve within the right side of the neck and / or chest, with the electrode lead 1402 extending downward toward the 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, with most of the signals sent to the brain reporting satiety and fullness. Using the EICCC electrode 1600, vagus nerve blockade or neural inhibition can be produced, resulting in an individual having a greater sense of satiety and fullness. Gastrointestinal nerves can also be modulated to increase or decrease GI transit time. Figure 15-16 , an exemplary dual EICCC system is shown, wherein each vagus nerve is encased in a tissue interface 1606 in the form of a sleeve where ionic current is deposited at the tissue site from an EICCC 1600 connected via electrode leads 1602 and to a power source 1604. The tissue interface may be mediated by a porous frit or other ionically conductive medium, such as a conductive hydrogel as previously described herein. Fig.16 yes Fig.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. Fig.17 As shown. Inhibition or blocking of hepatic nerves can cause an increase in insulin production and reduce resistance to insulin, thereby enabling 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. As shown Fig.18 , 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, where 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 nerve modulation 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 rigidity), essential tremor, spasticity, and epilepsy. These conditions and diseases are characterized by hyperactivity of neural activity 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 disorders including treatment resistant depression (TRD), anxiety, 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 the patient's symptoms. As is well known, the blocks of these targets can be unilateral or bilateral. Other disorders that can be treated can include, for example, schizophrenia, schizophrenic disorders, bipolar disorder, mania, alcoholism, drug abuse, etc.

[0241]

[0242] Table 2. Psychiatric disorders and brain regions targeted for neurological blockade 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 in the thalamus have been identified as targets for decreased 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 region targets for nerve blocks for pain relief.

[0247] In some embodiments, the system is configured to produce a neural block for the illness and disease that can be solved by reducing the neural activity of a specific area of ​​the brain that causes a specific illness. The reduction of neural activity can be promoted by directly blocking and reducing the activity of specific neurons and by blocking the pathways where too much neural signal conduction occurs. In some embodiments, the system for deep brain block (DBB) includes all or some steps of the following: identifying the anatomical target site for blocking, creating access sites for brain external tissue, creating pathways through brain tissue to the target site, assessing the suitability of the target site for blocking, adjusting or improving the position of the target site, providing neural block at the target site, and adjusting the intensity or position of neural tissue block. In fact, this process can be implemented 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), including functional MRI (fMRI), computed tomography (CT), PET scanning and / or X-rays is used to identify the target anatomical site. Stereotactic techniques can then be used to approach the site to log in to the body anatomical structure on the patient from the area identified by imaging. The frame can be fixed to the patient's head and skull to allow spatial access during surgery. An access site into 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 / retract devices fixed to 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 the suitability of the brain region to be assessed. 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 it can be inserted using the active part 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 part (e.g., the area that transports ionic current) at the target site. Extension leads can be connected to fixed blocking electrodes and connected to an implantable power source, similar to an implantable pulse generator (IPG), whose output signal can be adjusted to promote optimal symptom relief. When the contralateral side of the body is affected by a specific anatomical target site, the blocking electrodes can be implanted unilaterally or bilaterally.

[0248] Fig.9AAn electron-ion current conversion cell (EICCC) electrode 900 is shown, which is configured to be combined with 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 the power source 908. Within the lead 902 itself, the EICCC block electrode includes an internal electrode 916, such as an Ag / AgCl wire, which converts electronic current to ionic current in an ion conductive medium 918, such as saline, and generates ionic current at the neural tissue junction 904, via an ion 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 a seizure or upon sensing the onset of a seizure. In addition, systems including blocking electrodes can be configured to alternatively reduce the field potential of neuronal clusters that are susceptible to causing seizures, so that seizures can be prevented rather than reacting to them 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 blocks in a closed-loop fashion to reduce the activity of the target cells. In Fig. 9B , an embodiment of a blocking / inhibiting 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 an 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 implanted deeper than the cortical surface, or can be configured as epidermal cortical electrodes (e.g., by having a planar or conformal element).

[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 producing 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 conveying 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 an electrochemical reaction. If the voltage exceeds a threshold value, such as a predetermined threshold value, the controller can 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 can 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 can be set to zero. In another optional system, if the voltage required to maintain a specific current level becomes too high, the current level can be reversed.

[0252] In some embodiments, the current may 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. In order to prevent these excursions from entering undesirable areas, the delivered current can be adjusted as described above to reduce the driving voltage. Alternatively, the voltage excursion 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 drive voltage and a control loop that generates additional charge on an electrode whose reactant is already detected to be insufficient by its drive 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 driving 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] Fig.19 The driving voltage waveforms and positive and negative thresholds over a period of time are illustrated. As shown, the negative threshold is crossed / broken due to a negative voltage drop before time point 2600. After 2600, the negative drop no longer exists and can be addressed by adjusting the target current level and / or by adjusting the charge transfer distribution between the working electrode and the counter electrode. For example, additional charge can be transferred during the anodic phase of the cycle of the working electrode to produce more reactant species.

[0254] Fig. 20 The drive voltage waveform and 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 characteristically appear 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] Fig.21 Schematically shows a graph of voltage and current relative to time, which shows electrode annealing or conditioning process, wherein the current amplitude is ramped up to a set target, and the driving voltage is maintained below a set threshold. If for a given current amplitude, the driving voltage is not exceeded, then the current can be gradually increased to the target current upwards. If for a given current amplitude, the driving voltage is exceeded, then the current can be similarly gradually reduced until the voltage threshold is no longer exceeded. Multiple cycles under a given current amplitude can be used to determine whether the system is stable under this current level and duration, as assessed by staying within the voltage threshold before the current is increased upwards to the target current. In some embodiments, 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, or more or less cycles, or the scope of any two of the above values ​​can be utilized. 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 direct current resistance to retard neural tissue. The system can allow for indefinite direct current delivery (e.g., without the need for reverse charging). In some cases, water or other appropriate media such as saline can be used as the primary redox reactant; water or other media can be refilled into the reservoir as needed. In some embodiments, there may be one, two, or more vents to exhaust gases produced by the redox reaction. In some embodiments, the vent may include a gas-permeable but liquid-impermeable membrane to enable gas to be exhausted, but liquid remains in the container. The DC generator may have a voltage sufficient to potentially drive a larger wire / catheter impedance. The system may 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, liquid bath. The system may also include a pH sensor to detect the pH of the liquid bath and allow for modifications, for example, buffering, if necessary. The liquid bath may also include a pH buffer solution to maintain a nominally constant liquid bath pH.

[0257] Fig. 22A system 2200 is shown, which may include a nerve-tissue interface 2224 operably connected to a conduit 2212 configured to hold a liquid. The conduit 2212 may be operably connected to a reaction chamber 2204 via the interface 2214. The interface 2214 may include a membrane, such as an anion exchange membrane, to prevent certain particles from flowing into the conduit 2212. The conduit 2212 may have a valve 2216 that may be actuated between different positions to block, allow, or partially restrict fluid flow through the conduit 2212. A reaction chamber 2204 is also shown, which includes a reaction electrode 2220 that may have a high surface area, which may be partially or completely surrounded by a redox reactant 2226 (e.g., water), as previously described. The reaction electrode 2220 may be operably connected to a DC generator 2202 via a conductor 2228. The chamber 2204 may also include a pH sensor 2218. The 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 be sealed from the chamber 2204, such as by a piping system 2222, and a valve or other reversible passage that can be opened when the pH falls outside a predetermined threshold. 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 organization system may include replaceable electrode materials. Over time, the spent reactive metal (or other material) may be optionally removed and fresh reactants supplied to the reaction chamber. This may advantageously allow unidirectional delivery of DC current without the need for a reversal / charging phase. Fig.23A A system 2300 is shown that includes a reaction chamber 2304 that includes a reactant 2316. A rotatable member 2306 can move fresh reactant 2314 into (and consume reactants from) the reaction chamber 2304 as shown, and onto another spool 2308. A DC generator 2302 operably connected to the reaction chamber 2304 and / or the spool 2306 is also shown.

[0259] In some embodiments, isolated junctional neural electrodes are disclosed herein that may include an integrated sensor for detecting the electrochemical state of the reacting / working electrode, such as Fig. 23BSchematically shown. Sensor 2330 can measure one, two or more variables indicating 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 be able to measure the potential between working electrode 2324 and reference electrode 2330, or a sensor to detect the electrochemical reaction occurring at the working electrode 2324-electrolyte interface. Both working electrode 2324 and sensor 2330 can be arranged in housing 2318. Housing 2318 can be operably connected to wire / electrode 2320. Such wire / electrode 2320 can have a relatively short length to reduce impedance. The length of wire 2320 can be in the range of 0-2cm, 2-4cm, 4-8cm or 8-12cm, or in the range of any two of the above values. The distal end of wire 2320 can have a tissue interface 2322. In addition, 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] Fig.24 The system and method can utilize battery-type chemistry to deliver DC current to tissue, such as lead-acid battery, nickel-cadmium, nickel-metal hydride, lithium ion, lithium polymer, zinc-carbon, bio-battery or other types of battery chemistry. System 2400 may include a DC generator 2410, which is operably connected to one, two or more reaction chambers 2402, 2404 via conductors 2412, 2414, and reaction chambers 2402, 2404 may include battery chemistry reactants 2406, 2408. For example, reactants 2406, 2408 may be lead / lead oxide, and redox reactants may be sulfuric acid and / or water, as shown. A membrane or other unit represented by A2420 may prevent harmful components from entering the conduit / conduit 2416, 2418 and the tissue interface 2422, 2424 (e.g., a cation or anion selective membrane) connected to tissue 2426.

[0261] Fig.25A SINE-type electrode 2500 is schematically shown, which is modified to allow engagement at a site in a patient to reduce the length and impedance of the conduit. For example, a DC generator 2502 can be operably connected to a wire 2506 connected to a reaction chamber 2504 (e.g., an electrode system / charge generator including electrodes and an electrode bath), and in turn connected to a fluid conduit / tube 2508, which is configured to deliver a DC current to a target tissue location 2512 via an opening 2513. Although one or more of the above 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 location 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 about 50%, 60%, 70%, 80%, 90%, or more, can be located inside 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. Fig.26A A wearable system 2600 is shown that includes a DC generator 2604, a lead and a reaction chamber 2604, and a portion of a lead / catheter 2606 is implanted at a desired anatomical site 2608 in / on a patient 2602. Fig.26B A bandage-type system 2601 is shown positioned at a treatment site (e.g., a nerve block). An electrode system / charge generator 2604 may be secured to a patient 2602 using a band, strap, adhesive patch, adhesive, or other engaging element 2610. A guide wire / catheter 2606 may be operably connected to the electrode system / charge generator 2604 and deliver a DC current at a target tissue location 2608. Fig.26C An illustrative embodiment of such a wearable device 2604 is shown having two different wire exit configurations, one in which the wire 2606 exits a narrow portion of the system, and one in which the wire 2606 exits a wider portion of the system and can be inserted directly into the patient's body. The wire can be configured to be detachable from the rest of the system for easy insertion into the patient's body before being connected to the rest of the wearable system. The wearable device 2604 can include a power source 2612, a DC generator / control electronics 2614, a reaction chamber 2616 with a liquid bath and electrodes, and engagement locations 2618, 2620.

[0263] In some embodiments, disclosed herein are methods of treating pain or other conditions by cycling DC blockade at multiple locations spaced apart from one another. For example, the electrodes may be present at Fig.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. Fig.27B The variables v(t) (voltage versus time) or i(t) (current versus time) shown in may have very long biphasic cycles. Fig.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 including any two of the foregoing values. The blocked tissue portion of the time may involve electrodes directly below or near the target tissue, thereby providing a 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 Fig.27D Continuous nerve blocks are shown.

[0264] Also disclosed herein are systems and methods for controlling the DC output current amplitude based on measuring variables indicative of the electrochemical state of the DC blocking electrode system. This can advantageously facilitate the safe use of DC current to ensure operation only within an electrochemical range (e.g., reaction type) that is safe for the health of the tissue and the electrode. The variables can be, for example, one, two, or more of voltage, pH, temperature, etc. Fig.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. Fig.28B In the simple example shown, the electrode voltage increases with continued DC current delivery. Once the voltage reaches a threshold maximum value, which indicates 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 the desired operating window. For example, a proportional-integral-differential (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. Fig.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 cycles, more (higher) current can be passed while maintaining the voltage threshold.

[0266] Single-fault-safe DC systems and methods are also disclosed herein in some embodiments. 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 including any two of the above values, such as in Fig. 30A Charge accounting can be performed to deliver known values ​​in each direction, such as using any number of the following parameters: programmed amplitude and duration of delivery; delivery using voltage measurement across a sense resistor; monitoring voltage output (with or without e.g. Fig. 30B Schematically shown in the additional (eg, third or fourth) reference electrode; Fig. 30C A monitoring circuit schematically shown in FIG. 1 that controls a switch to stop or slow current delivery; and / or monitoring by an independent microcontroller or logic device to increase tolerance to single (or multiple) fault conditions.

[0267] Also disclosed are electrode systems and methods for making these 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 an attached silver chloride (AgCl) layer 3104) is disclosed. Fig.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 join the chloride ions to produce silver chloride in an electrochemical process as previously described:

[0268]

[0269] In some embodiments, the electrode can have any desired shape, including but not limited to generally flat or round, such as cylindrical. In one non-limiting embodiment, the electrode can include a size of about 1.4 mm outer diameter and a length of about 3.5 mm. In another embodiment, the electrode can include a flat disk with a diameter of about 3.6 mm. The electrode 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., within about 5 mm 2 To about 20mm 2 A layer of silver chloride can be generated on a silver substrate, the thickness of which is, 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 including any two of the above values ​​(such as between about 1 micron and 10 microns) to achieve sufficient direct current and charge transport necessary for treatment. In one configuration, a cylindrical electrode with a diameter of about 1.4 mm and a length of about 3.5 mm is prepared, which has a silver chloride layer of 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 in a specific environment. 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 the body. Some embodiments can 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 direct current through an electrolyte bath. Fig.32 ).like Fig.32 As seen in FIG. 1 , a counter electrode 3202 and a working electrode 3204 are shown, which are immersed in an electrolyte bath 3206 and connected to a power source 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, such as 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, a current is generated, and the silver on the working electrode 3204 can be converted to silver chloride, thereby generating a layer of silver chloride on the silver substrate.

[0271] A simple method can apply direct current and calculate the total charge required to produce enough AgCl on electrode 3204 by means of coulometry measurement so that the longest cathode pulse at the treatment current level will not exhaust electrode 3204. However, this overly simplistic method cannot address the characteristics of AgCl, which not only affect its ability to easily participate in symmetrical electrochemical reactions, but also maintain a safe driving voltage range below the electrolysis potential threshold. It is important in some embodiments 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 main way to select electrochemical reactions because different reactions occur at different potentials. AgCl electrodes that do not have the correct characteristics may require a voltage potential higher than the allowed threshold to maintain a 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 may be to generate a layer of silver chloride on the silver substrate. In order to do this in a controlled manner that does not cause electrolysis of the aqueous solution, a maximum current may be specified, which may be a target current for therapeutic operation of the electrode or a maximum therapeutic current of the electrode. The maximum current may be in a range of, for example, 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 in a range including any two of the above values. A drive voltage may 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 may be partially immersed in the electrolyte solution 3210 so that the top of the solution 3208 does not cover the entire working electrode 3204, resulting in the formation of a layer of silver chloride 3212 on the immersed portion. A target total charge may be specified to generate a target amount of silver chloride on the electrode surface 3204. A build period for the electrode 3204 may be specified, as well as an etch-back period, where the current is driven in reverse to remove some of the formed silver chloride to produce a more robust silver chloride formation on the electrode surface. One configuration may include a 60 second build period with, for example, a 10% etch-back period, where 10% of the build AgCl layer is then removed before the next build period. Other combinations of build and etch-back or removal periods may be used to generate AgCl on a silver substrate.

[0273] like Fig.33As shown in trace A (solid line), the applied drive voltage can be positive, corresponding to the build-up of AgCl on the working electrode. After a specified build period, a removal or etch-back period will occur, followed by the next build period, until the total charge and the target AgCl layer are deposited, at which point the build process is terminated, as shown by the "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 Fig.33 In, for trace B (dashed line), the driving voltage upper threshold is reached, and the algorithm stored in the controller can limit the driving voltage to the threshold level raised by reducing the current used to build AgCl. After the construction period, it can be a removal or etch-back period as described, 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 reference electrode voltage parameter to more accurately measure the electrochemical interface potential, to control the driving voltage, thereby limiting the generation of potential harmful byproducts.

[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 hazardous condition if used near tissue. In order to condition the electrode so that it can operate within a safe range and the drive voltage is maintained 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. Fig.34 In some embodiments, the driving voltage may be lower than the electrolysis threshold value. However, in some cases, as seen by the peak voltage exceeding or crossing the driving voltage threshold upper and lower limits, if the driving voltage exceeds the electrolysis threshold value, the mode of the fixed current amplitude and duration may cause the generation of undesirable and unsafe by-products, which may result in the undesirable reaction of the product. In some embodiments, the electrode can be prepared in the production bath, and then removed from the bath before being used for the target device bath or directly in the body, the driving voltage can be reduced and within the desired range. 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.

[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 obtain 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 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 the 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 AgCl changes, allowing it to maintain 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 stage continues until the current level that can be maintained reaches a specified value. As shown herein, other electrodes including but not limited to high charge density electrodes can utilize systems and methods 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 to be applied in the anode and cathode stages. If the peak voltage magnitude is less than the voltage limit, increase the current intensity by a fixed proportion until the specified current limit. If the peak voltage magnitude exceeds the voltage limit, reduce the current intensity 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 process continues to repeat.

[0283] exist Fig.35In the forming step, the formation of the working electrode and the counter electrode is processed, wherein when the driving voltage upper threshold is not exceeded, the current level starts with a relatively low value and increases with each cycle. As seen by the solid arrow, when a given current level exceeds the driving voltage upper threshold, the current level applied in the next cycle is reduced, as shown by the open arrow. 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 cathode rather than anode.

[0284] The stabilization / conditioning step can also include repeated cycling of the current, which builds a layer of AgCl over a specific period of time, followed by removal of 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 infrastructure 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 preconfigured value. Fig.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. During this period, measure the peak positive voltage 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 (eg, in memory) a list of previous N peak voltages. The number of samples N 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 to circulate 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 including 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 above values.

[0298] In alternative embodiments, the build charge can be up to about 2500, 3000, 3500, 4000, 4500 or 5000 mA-seconds or above 5000 mA-seconds, 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 that allows the target current amplitude to be delivered within the desired duration, wherein the driving voltage is below a threshold value set, such as an 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, which can execute a specific algorithm in an open-loop or closed-loop form, including but not limited to those disclosed herein.

[0300] Fig.36 The microstructural changes that can occur after building up the AgCl layer on a bare silver electrode, and after performing the formation and stabilization / conditioning steps to condition the AgCl-coated electrode are shown. 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 below the set threshold embodiment, the threshold can be a safety threshold, such as electrolysis potential or as required by another threshold value set in conjunction with safety factors, but 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 be slightly biased, so that the charge deposited on the counter electrode in each cycle is more than that deposited on the working electrode. Through many cycles, this may deprive the working electrode of active, regulated AgCl or other substrate, thereby causing the size of the driving voltage to increase. Fig.37 The drive voltage that begins to exceed the lower threshold of the drive voltage 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 through 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 impedance to change (increase or decrease) over time. At low frequencies, because the drive voltage includes the impedance of the wire in close proximity to the tissue (ΔV 导线 ) and body (ΔV 身体 ) is shown in the following equation:

[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, since 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 drive 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 Fig.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 drive frequencies, the above equation can be used to Fig.39 The electrodes and body are modeled as shown. At high drive frequencies, the Fig.40The modeled system shown in Figure 1, where the capacitor behaves like a short circuit and has no impedance. In this case, the reference Fig.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 can allow the system to maintain the voltage below a set threshold.

[0311] ΔV 导线 <V 阈值

[0312] Reference again Fig.40, as shown in the circle in the figure, the ability to stimulate the short circuit through the wire or electrode-body interface can be realized 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 size 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 size of any two of the above values. The current input can occur at the beginning of the DC cycle, during the DC cycle, or after the DC cycle, so as 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 an electrolysis potential. Current input may be performed on demand at every cycle or every other cycle or periodically or as needed to allow the wire or electrode voltage drop to be determined. This voltage drop knowledge may 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 may 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 Fig.41 The current amplitude shown is used to adjust the delivered current to adjust it, wherein the portion of the waveform that reaches the threshold value reduces the current to remain below the threshold value. In applications with silver-silver chloride electrodes as counter electrodes and working electrodes, a controller that implements the described algorithm can advantageously achieve self-balancing of charge. When the amount of AgCl available on the corresponding counter electrode is partially depleted, causing the less reactive AgCl to cause a higher potential to drive the reaction, the silver-silver chloride system may exhibit a higher voltage within the anodic phase (positive voltage) of the working electrode. By reducing the amount of charge drawn from the counter electrode in the anodic phase (open arrows), but with a full amplitude current in 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 system and algorithm can also be used to maintain voltage within a specific target drive voltage and lead voltage range as required and set by the end user within the algorithm. In some embodiments, the main current pulse is delivered to the cathode rather than the anode, or the anode rather than the cathode.

[0315] In some embodiments, for any therapy 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, about 2.5 mA to about 5 mA and about 5 mA and higher anode and cathode current levels can be utilized for blocking. In animal studies, responses have been seen, for example, with a range of about 0-1.5 mA, and paresthesia episodes in human peripheral nerves, with 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 target any number of anatomical locations, including, but not limited to, dorsal root ganglia, dorsal roots, dorsal columns, dorsal horns, bundles of Lissauer, and / or anterolateral pain bundles. 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 after the DC source is removed, high inhibition of continuous nerve blocks may result for more than one minute, thereby delaying the recovery of nerve conduction. Depending on the desired application, nerve blocks and inhibition can be produced in an intermittent or continuous manner. A method for continuous nerve blocks has been described that provides for the safe delivery of nerve blocks via ionic currents activated by multiple electrodes or electrode contacts arranged in sequence, enabling the method to 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), and all tissue contacting materials are 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 a spinal cord stimulation (SCS) system for treating chronic pain, such as the SENZA system of Nevro Corporation; the PRECISION system of 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 including any two of the above 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 including any two of the above 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: high density charge materials, SINE electrodes, and / or silver-silver chloride materials. In some cases, such systems and methods may advantageously increase the excitability of target neurons, thereby lowering the threshold and expanding the therapeutic window for stimulation of target tissues. In some embodiments, the systems and methods are configured to reduce side effects, including but not limited to paresthesias, typically tingling, buzzing, or shock, which may manifest during daily activities or sudden movements during other time periods.

[0319] The foregoing description and examples have been stated 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 can 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] Although 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 should cover modifications, equivalents and alternative forms 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, may be 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 simultaneously rather than sequentially, such as through multithreading, interrupt handling, or multiple processors or processor cores or on other parallel architectures.

[0322] Unless explicitly stated otherwise or otherwise understood in 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 operations performed.

[0323] Various illustrative logic plates, 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, plates, modules, operations and steps have been generally described above according to their functions. Whether this function is 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 this implementation decision should not be interpreted as causing a departure from the scope of the present disclosure.

[0324] The various illustrative logical 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, the 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 a DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. The storage medium can be connected to the processor so that the processor can read information from the storage medium and can write information to the storage medium. Alternatively, the storage medium can be integrated in the processor. The processor and the storage medium can be retained in an ASIC. The ASIC can be retained in a user terminal. Alternatively, the processor and the storage medium can be retained 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 include, 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 to include such features, elements, and / or conditions or will execute them in any particular implementation, 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 "instruct to place an electrode."

[0328] The scope disclosed herein also encompasses any and all overlaps, sub-ranges, and combinations thereof. Language such as "up to," "at least," "greater than," "less than," "between," etc. includes the numbers listed. Terms such as "about" or "approximately" after a number include the numbers listed and should be interpreted as appropriate (e.g., as accurately as reasonably possible in the case, such as ±5%, ±10%, ±15%, etc.). For example, "about 1 hour" includes "1 hour." Terms such as "substantially" after a phrase include the phrases listed and should be interpreted as appropriate (e.g., as reasonably possible in the case). 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 each item of a type from each item in a subsequent list. For example, "at least one of A, B, and C" can include A, B, C; A and B; A and C; B and C, or A, B and C.

Claims

1. A method for monitoring a direct current electrode system, comprising: The electrodes of the electrode lead deliver direct current to the target tissue of the patient; measuring a driving voltage across the electrode; comparing a drive voltage across the electrode to a predetermined threshold voltage range value; measuring body impedance of the patient; determining a voltage drop across the electrode leads from the body impedance measurement; as well as The driving voltage is adjusted to maintain the voltage drop across the electrode wire within the predetermined threshold voltage range.

2. The method of claim 1, wherein measuring the body impedance comprises delivering a short circuit current input through the electrode lead.

3. The method of claim 2, wherein the short circuit current input is about or less than about 100 microamperes.

4. The method of claim 2, wherein the short circuit current input is delivered for less than about 200 microseconds.

5. The method of claim 1, wherein the predetermined voltage range is below the electrolysis potential of water.

6. The method of claim 1, wherein adjusting the drive voltage comprises adjusting the amplitude of the delivered direct current.

7. The method of claim 1, wherein the direct current comprises a cathode direct current and an anode direct current, wherein the cathode direct current and the anode direct current are circulated.

8. The method of claim 1, wherein the direct current comprises a frequency of less than about 1 Hz.

9. A method for monitoring direct current regulation of a working electrode, comprising: applying a direct current of a first polarity for a first duration, applying a direct current of a second polarity opposite to the first polarity for a second duration, receiving a measurement of a peak voltage of the first polarity during the first duration and a measurement of a peak voltage of the second polarity during the second duration; The direct current is regulated by analyzing the peak voltage during the first duration and the second duration, and increasing the current intensity of the direct current by a certain amount up to a predetermined current limit when the measured peak voltage during the first duration and the second duration is below an absolute threshold limit.

10. The method of claim 9, wherein the current intensity is increased by a predetermined amount.

11. The method of claim 9, wherein the first polarity is an anode and the second polarity is a cathode.

12. The method of claim 9, wherein the current limit is approximately 5 mA.

13. The method of claim 9, wherein the peak voltage absolute threshold limit is approximately 1.5V.

14. The method of claim 9, further comprising 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.

15. The method of claim 9, wherein 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 comprises cyclical direct current delivery, and wherein the method comprises at least about 10 cycles of direct current delivery.

16. The method of claim 9, wherein the working electrode comprises silver chloride.

17. A method for increasing the effectiveness of an alternating current electrode system, comprising: Using a DC offset waveform, the alternating current is delivered to the patient's target tissue via the electrodes of the electrode lead. The electrodes of the electrode wires include one or more of the following: high-density charge materials, SINE electrodes and / or silver-silver chloride materials, The method increases the excitability of target neurons, thereby lowering the threshold and expanding the therapeutic window for stimulation of the target tissue.

18. The method of claim 17, wherein the target tissue comprises the spinal cord.

19. The method of claim 17, wherein the frequency of the alternating current is at least about 10 kHz.

20. The method of claim 17, for treating or preventing pain in a patient.

21. A system for increasing the effectiveness of an alternating current electrode system, comprising: Pulse generator; a controller configured to send a signal to the pulse generator to deliver alternating current to a target tissue of the patient via the electrodes of the electrode lead using a DC offset waveform, The electrodes of the electrode wires include one or more of the following: high-density charge materials, SINE electrodes and / or silver-silver chloride materials, The system is configured to increase the excitability of target neurons, thereby lowering the threshold and expanding the therapeutic window for stimulation of the target tissue.

22. The system of claim 21, wherein the target tissue comprises a spinal cord.

23. The system of claim 21, wherein the frequency of the alternating current is at least about 10 kHz.

24. The system of claim 21 for use in treating or preventing pain in a patient.

25. The system of claim 21, wherein the system is configured to reduce excitability of non-target tissue.

26. The system of claim 21, wherein the system is configured to reduce side effects.

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