Nerve block by electrical pulses at sub-threshold intensity

Abstract

To provide a method of blocking a nerve or neuron by applying electrical stimulation to the nerve or neuron.SOLUTION: A method of blocking a nerve or neuron comprises applying electrical stimulation to the nerve or neuron, where the electrical stimulation has intensity not causing excitation of the nerve or neuron for a length of time sufficient to produce a block of nerve conduction or neuron excitation. The intensity of the electrical stimulation is below an initial excitation threshold of the nerve or neuron, and optionally is below a pain threshold.SELECTED DRAWING: Figure 15

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Provisional Application No. 62 / 658,147, filed April 16, 2018. The benefit of priority is claimed, and this application is incorporated herein by reference in its entirety. It is considered to be part of.

[0002] Statement regarding federally sponsored research The present invention was developed by the National Institutes of Health (NIH). Supported by government funding under grant number DK068566 awarded by the Department of Health, Laboratories, Inc. The Government has certain rights in this invention. [Technical field]

[0003] Provided herein are methods and related devices for nerve blocks, more particularly It involves applying sub-threshold electrical pulses to a nerve or neuron. and a method for blocking nerve conduction or neuronal excitation by It is a device for carrying out the law. [Background technology]

[0004] Blocking nerve conduction or neuronal excitation can help treat chronic pain, obesity, heart failure, It is widely used in clinical trials to treat a number of conditions, including bladder dysfunction or spasticity after spinal cord injury. However, electrical nerve blocks are currently being used clinically with kilohertz electrical power. These kilohertz pulses are the minimum intensity required to induce neural excitation. Since the stimulation intensity must be greater than the threshold, i.e., it must have a suprathreshold intensity, This will cause early nerve excitation. Early nerve excitation is problematic, e.g. Periods of intense pain or pain can be blocked before dangerous muscle contractions can cause physical damage This can also cause a numbing sensation that many patients find intolerable. Symptoms include palpitations, pressure, and numbness.

[0005] Thus, the prior art does not provide the ultra-high speed processing currently required to provide such blocks. Alleviating or otherwise treating a condition while avoiding the drawbacks associated with the use of threshold intensity pulses Therefore, a method for blocking nerve conduction is needed. Summary of the Invention

[0006] In view of the above needs, the method disclosed herein provides a method for treating a tumor by applying electrical pulses with subthreshold intensity. Thus, a novel method for blocking nerves / neurons, e.g., the intensity of , which is less than the minimum intensity required to excite a nerve / neuron. By locking, pain transmitted along such nerves or through neurons Treating pain by blocking nerve signals, such as pain signals, to reduce or eliminate pain can be done.

[0007] Thus, the methods provided herein include administering electrical stimulation to a nerve or neuron. A method for blocking a nerve or neuron by electrical stimulation, the electrical stimulation being or to a nerve or nerve for a period of time sufficient to produce a blockade of neuronal excitation. It has an intensity that does not cause neuronal excitation.

[0008] The device provided herein also includes a controller and a processor in communication with the controller. A device comprising a pulse generator and an electrode in electrical communication with the pulse generator, The device is configured to provide electrical stimulation to the nerve / neuron, the electrical stimulation providing a neurotransmitter. A nerve / neuron for a period of time sufficient to produce a blockade of conduction or neuronal excitation. The stimulation has an intensity configured to increase the initial excitation threshold of the stimulation.

[0009] The device provided herein also includes a controller and a processor in communication with the controller. a pulse generator and one or more skin surface electrodes or magnetic fields in electrical communication with the pulse generator. a skin surface electrode and a skin coil; The poles or magnetic coils are configured to deliver electrical stimulation to nerves or neurons. The electrical stimulation is administered for a period of time sufficient to produce a blockade of nerve conduction or neuronal excitation. The intensity of the signal is below the initial excitation threshold of a nerve or neuron throughout the signal.

[0010] The methods provided herein also include administering electrical stimulation to a peripheral nerve or a central neuronal population. The method of the present invention relates to a method for reducing peripheral pain in a patient by administering electrical stimulation to the patient, the electrical stimulation being performed by nerve conduction or A nerve or neuron for a period of time sufficient to produce a blockade of neuronal excitation. The intensity is such that it does not cause neuroexcitation, thereby reducing peripheral pain.

[0011] Further embodiments or aspects are provided in the following sections.

[0012] Item 1: A method for blocking a nerve or neuron in a patient, comprising: to deliver a subthreshold electrical current to a nerve or neuron for a period of time sufficient to produce a blockade of This includes applying a pulse (i.e., applying said electrical pulse to or near a nerve or neuron). (by giving a russ), method.

[0013] Item 2: The method of item 1, wherein the electrical pulse is biphasic.

[0014] Item 3: The biphasic pulse is symmetric between the positive and negative phases of the biphasic pulse. The method according to item 2.

[0015] Item 4: The biphasic pulse is asymmetric between the positive and negative phases of the biphasic pulse. The method according to item 2.

[0016] Item 5: The method of item 1, wherein the electric pulse is in charge balance.

[0017] Item 6: Electrical pulses block or block nerve conduction after application of the pulse for a period of time. alters intracellular and extracellular ion concentrations to block neuronal excitation. 6. The method according to any one of items 1 to 5, having a sufficiently high frequency.

[0018] Item 7: The frequency of the electric pulse determines the intracellular and extracellular inactivation rate of the electric pulse. To restore the on concentration, the rate of the sodium-potassium pump in the nerve or neuron 7. The method according to any one of items 1 to 6, wherein the method is carried out faster than

[0019] Item 8: The frequency of the electrical pulse is greater than 1Hz to block the nerve, Item 1 The method according to any one of claims 1 to 7.

[0020] Item 9: The frequency of the electrical pulse is within the range of 1 Hz to 50 kHz. The method according to any one of the above.

[0021] Item 10: The frequency of the electrical pulse is greater than 1Hz to block the nerve. 8. The method according to any one of 1 to 7.

[0022] Item 11: The frequency of the electrical pulse is within the range of 1 Hz to 50 kHz, as described in Item 10. How to.

[0023] Item 12: Any of items 1 to 6, in which the subthreshold electric pulse is applied for at least 1 minute. The method described.

[0024] Item 13: The subthreshold electrical pulse is applied for a time period ranging from 5 minutes to 300 minutes; Item 13. The method according to item 12.

[0025] Item 14: The subthreshold electrical pulse is applied for a period ranging from 5 hours to 5 days. The method according to claim 12.

[0026] Item 15: Subthreshold electrical pulses are used to first increase the initial excitation threshold of a nerve or neuron. The initial excitation of a nerve or neuron is initiated over an appropriate period of time sufficient to increase the excitation threshold of the nerve or neuron. The intensity of the subthreshold electrical pulse is then applied to the nerve or neuron. greater than the initial excitation threshold of a neuron and less than the first increased excitation threshold of a nerve or neuron and further increasing the first increased excitation threshold to a second increased excitation threshold. 15. The method according to any of items 1 to 14, wherein the voltage is applied for a length of time.

[0027] Item 16: A first increased excitation threshold of a nerve or neuron is compared to a second increased excitation threshold After increasing the intensity of the subthreshold electrical pulse to the first increased The excitation threshold of the nerve or neuron is increased to a value greater than the excitation threshold and less than a second increased excitation threshold of the nerve or neuron. and a length of time that further raises the second increased excitation threshold to a third increased excitation threshold. 16. The method of claim 15, further comprising applying a subthreshold electrical pulse over the

[0028] Item 17: By increasing the intensity of the electrical pulse in two or more steps, the nerve or involves increasing the excitation threshold of a neuron, and each step involves increasing the excitation threshold of a nerve or neuron. applying a subthreshold electrical pulse for a time period sufficient to cause an increase in the excitation threshold of This allows for increasing the excitation threshold from an initial intensity to an increased intensity and for the subthreshold electrical pulse to an intensity greater than the initial intensity and less than the increased intensity. 15. The method according to any one of 1 to 14.

[0029] Item 18: The time required to induce an increase in the excitation threshold of a nerve or neuron is at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, or at least 30 minutes The method according to any one of Items 15 to 17.

[0030] Item 19: The intensity of the subthreshold electrical pulse is increased until the patient feels a numbing sensation. A subthreshold electrical pulse is applied at that intensity, or The intensity of the electrical pulse is set to 99%, 95%, or 90% of the intensity at which a numbing sensation is felt. 19. The method according to any one of items 1 to 18, wherein the numbness sensation is reduced to a maximum level at which the numbness sensation is felt. .

[0031] Item 20: The intensity of a subthreshold electrical pulse to induce muscle contraction or a physiological response is determined by the Determined by applying pulses of increasing intensity until a contraction or physiological response occurs The subthreshold electrical pulse is 99% to 95% of the intensity at which muscle contraction or a physiological response occurs. or any of items 1-18 applied at a level less than that intensity, such as 90%. (The physiological response may be blood pressure, heart rate, body temperature, or other autonomic response.) can be).

[0032] Item 21: Subthreshold electrical pulses should be administered for at least 1 minute once nerve block has been achieved. The nerve block is then stopped for 5, 10, 15, or 30 minutes. The method according to any one of items 1 to 20, wherein the nerve block is maintained. To continue the lock, the electric pulse is turned on at a level below the intensity at which it was previously stopped without exciting the nerve. By repeatedly stopping and starting, electrical energy can be saved. The nerve block can be maintained for the desired period while reducing the pressure.

[0033] Item 22: A power supply with a fixed or adjustable output and one or more or a plurality of conductive leads, and applying a subthreshold electric pulse according to any one of items 1 to 21. and one or more electrical contacts, such as one or more electrodes, configured to Qi stimulation device.

[0034] Item 23: Fixed output with a frequency or frequency range between 1 Hz and 50 kHz, and and an output strength between 0.01mA and 10mA or between 1mV and 10,000mV. 23. The device according to item 22.

[0035] Item 24: An embedded device that is configured to use a battery or other power source and an external computer Receives control commands from the power supply and adjusts output frequency, output strength, output waveform, power supply Transmit status data from the device, such as status, stimulation patterns, and / or stimulation history 24. The device according to claim 22 or 23, further comprising a wired or wireless receiver for vinegar.

[0036] Item 25: Straps, hook-and-loop fasteners, belts, or wearable clothing The device may be configured as an external device that is placed on or near the patient, such as by a piece of or multiple implantable electrodes, separated interface nerve electrodes (SINEs), which transmit electrical current to the patient's skin. 22 or 23. The method according to claim 21, further comprising: surface electrodes for reaching the brain; or electromagnets for magnetic nerve stimulation. 24. A device according to claim 23.

[0037] Item 26: A controller and computer readable medium for controlling the electrical pulse output of a power supply 26. The device according to any one of items 22 to 25, further comprising a readable instruction.

[0038] Item 27: The device according to any of items 22 to 26, wherein the electrical pulse is biphasic.

[0039] Item 28: The biphasic pulse is symmetric between the positive and negative phases of the biphasic pulse. Item 27. The device according to item 27.

[0040] Item 29: The biphasic pulse is asymmetric between the positive and negative phases of the biphasic pulse. 28. The device according to item 27.

[0041] Item 30: The device according to any one of Items 22 to 26, wherein the electric pulse is in charge balance. .

[0042] Item 31: Electrical pulses can block nerve conduction after application of the pulse for a period of time. or to change intracellular and extracellular ion concentrations to block neuronal excitation. 31. The device according to any one of items 22 to 30, having a frequency sufficiently high to

[0043] Item 32: The frequency of the electric pulse determines the intracellular and extracellular The sodium-potassium pump in nerve cells or neurons to restore ion concentrations 32. The device according to item 31, wherein the speed is faster than

[0044] Item 33: The frequency of the electrical pulse is greater than 1 Hz to block the nerve. 22. A device according to any one of claims 22 to 32.

[0045] Item 34: The frequency of the electrical pulse is within the range of 1 Hz to 50 kHz. Items 22 to 32 2. A device according to claim 1 ,

[0046] Item 35: The frequency of the electrical pulse is greater than 1 Hz to block the nerve. 22. A device according to any one of claims 22 to 32.

[0047] Item 36: The frequency of the electrical pulse is within the range of 1 Hz to 50 kHz, as described in Item 35. device.

[0048] Item 37: Any of Items 22 to 36, wherein the subthreshold electrical pulse is applied for at least 1 minute. or the device described herein.

[0049] Item 38: The subthreshold electrical pulse is applied for a time period ranging from 5 minutes to 300 minutes; Item 37. The device according to item 37.

[0050] Item 39: The subthreshold electric pulse is applied for a period ranging from 5 hours to 5 days; Item 37. The device according to item 37.

[0051] Item 40: A subthreshold electrical pulse is a first increase in the initial excitation threshold of a nerve or neuron. The initial excitation of a nerve or neuron is initiated over an appropriate period of time sufficient to increase the excitation threshold of the nerve or neuron. The intensity of the subthreshold electrical pulse is applied at an intensity below the excitation threshold, and the intensity of the subthreshold electrical pulse is then applied to the nerve or greater than the initial excitation threshold of a neuron and less than the first increased excitation threshold of a nerve or neuron and further increasing the first increased excitation threshold to a second increased excitation threshold. 40. The method according to any one of claims 22 to 39, wherein a subthreshold electrical pulse is applied for a period of time of device.

[0052] Item 41: A first increased excitation threshold of a nerve or neuron is compared to a second increased excitation threshold. After increasing the intensity of the subthreshold electrical pulse to the first increased The excitation threshold of the nerve or neuron is increased to a value greater than the excitation threshold and less than a second increased excitation threshold of the nerve or neuron. and further increasing the second increased excitation threshold to a third increased excitation threshold. Item 41. The device of item 40, further comprising applying the voltage for a length of time.

[0053] Item 42: Electric pulse strength can be adjusted to two or more stages. This involves increasing the excitation threshold of a nerve or neuron by increasing the , each step is timed to induce an increase in the excitation threshold of a nerve or neuron. A subthreshold electrical pulse is applied over a period of time, thereby increasing the excitation threshold from the initial intensity to an increased intensity. and providing a subthreshold electrical pulse having an intensity greater than the initial intensity and less than the increased intensity. and increasing the intensity of the device to a level equal to or greater than the intensity of the light emitted from the device.

[0054] Item 43: The time required to cause an increase in the excitation threshold of a nerve or neuron is at least 1 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, or at least 30 minutes The device according to any one of items 40 to 42.

[0055] Item 44: The intensity of the subthreshold electrical pulse is increased until the patient feels a numbing sensation. A subthreshold electrical pulse is applied at that intensity, or The intensity of the electrical pulse is set to 99%, 95%, or 90% of the intensity at which a numbing sensation is felt. The maximum level of numbness can be reached by using any of the following items 22 to 43. device.

[0056] Item 45: The intensity of a subthreshold electrical pulse to induce muscle contraction or a physiological response is determined by the Determined by applying pulses of increasing intensity until a contraction or physiological response occurs The subthreshold electrical pulse is 99% to 95% of the intensity at which muscle contraction or a physiological response occurs. or 90% or less of that intensity, any of items 22-44 (The physiological response may be blood pressure, heart rate, body temperature, or other autonomic nervous system activity.) may be considered as a response).

[0057] Item 46: Subthreshold electrical pulses should be administered for at least 1 minute once nerve block has been achieved. The nerve block is then stopped for 5, 10, 15, or 30 minutes. The device according to any one of items 22 to 45, wherein the device maintains a constant current level at the end of the suspension period. To continue the nerve block, apply current at or below the intensity previously stopped without exciting the nerve. The electrical pulse can be applied again. By stopping and starting the electrical energy This allows the nerve block to be maintained for the desired period while conserving energy.

[0058] Item 47: The electric pulse is generated by the device according to any one of items 22 to 46. The method according to any one of items 1 to 21.

[0059] Item 48: A power supply having a fixed or adjustable output and one or more or a plurality of conductive leads and a subthreshold electric pulse generator according to any one of items 1 to 21 and 47. and one or more electrical contacts, such as one or more electrodes, for applying a voltage to the electrical stimulation device. Intense device use.

[0060] Item 49: A method for blocking a nerve or neuron, comprising: The electrical stimulation involves blocking nerve conduction or neuronal excitation. does not cause excitation of nerves or neurons for a period of time sufficient to produce A method having strength.

[0061] Item 50: The intensity of the electrical stimulation is below the initial excitation threshold of the nerve or neuron, 50. The method of claim 49, wherein the intensity of the electrical stimulation is below the pain threshold.

[0062] Item 51: Electrical stimulation is 0.01mA to 10mA and / or 1mV to 10,000 51. The method of claim 49 or 50, wherein the therapeutic dose is delivered at an intensity of 10 ...

[0063] Item 52: Electrical stimulation is 1Hz to 50kHz, or in some cases 100Hz to 1.2kHz. 52. The method according to any one of items 49 to 51, wherein the therapeutic dose is delivered at a frequency of z.

[0064] Item 53: Electrical stimulation is performed for 100 milliseconds to 14 days, or in some cases for 100 milliseconds to 10 minutes. , sometimes 1 minute to 14 days, sometimes 30 minutes to 2 hours, sometimes 1 minute to 7 days, or in some cases 1 minute to 5 days, method.

[0065] Item 54: Electrical stimulation blocks nerve conduction or neuronal excitation for at least 1 minute. 54. The method according to items 49 to 53, wherein the electrical stimulation is subsequently stopped, resulting in locking.

[0066] Item 55: The patient according to any one of Items 49 to 54, wherein the electrical stimulation is a biphasic electrical pulse. Law.

[0067] Item 56: The biphasic pulse is symmetric between the positive and negative phases of the biphasic pulse. 56. The method according to any one of items 49 to 55.

[0068] Item 57: The biphasic pulse is asymmetric between the positive and negative phases of the biphasic pulse. 57. The method according to any one of Items 49 to 56.

[0069] Item 58: Any of items 49 to 57, in which the electrical stimulation includes an electrical pulse in charge balance. The method described above.

[0070] Item 59: Electrical stimulation is given for at least 5 minutes, as described in any of items 49 to 58. How to.

[0071] Item 60: Electrical stimulation increases the initial excitation threshold of a nerve or neuron to a first increased excitation threshold. the initial excitation threshold of a nerve or neuron for a period of time long enough to cause 60. The method according to any of items 49 to 59, wherein the method is administered at an intensity of less than 50%.

[0072] Item 61: A first increased excitation threshold of a nerve or neuron compared to a second increased excitation threshold above the initial excitation threshold of a nerve or neuron for a period of time long enough to a first increased excitation threshold of the nerve or neuron that is greater than or equal to the first increased excitation threshold of the nerve or neuron; Item 49 to 5 further include increasing the intensity of the electrical stimulation to a strong electrical stimulation. 60. The method according to claim 60.

[0073] Item 62: Increasing the second excitation threshold of a nerve or neuron to a third increased excitation threshold first increased excitation threshold of a nerve or neuron for a length of time sufficient to cause A second increased excitation threshold of the nerve or neuron that is greater than or equal to the second increased excitation threshold of the nerve or neuron. increasing the intensity of the first increased intensity electrical stimulus until the first increased intensity electrical stimulus is reached. and optionally further increasing the excitation threshold of the nerve or neuron. and applying the second increased intensity electrical stimulus once or multiple times for a length of time sufficient to 62. The method according to items 49 to 61, comprising increasing the amount several times.

[0074] Item 63: The first increased intensity electrical stimulation and the second increased intensity electrical stimulation were Item 4, with an intensity of .01mA to 10mA and / or 1mV to 10,000mV A method according to any one of claims 9 to 62.

[0075] Item 64: The first increased intensity electrical stimulation and the second increased intensity electrical stimulation are Hz to 50 kHz, and sometimes 100 Hz to 1.2 kHz. A method according to any one of items 49 to 63.

[0076] Item 65: First increased intensity electrical stimulation, second increased intensity electrical stimulation and additional Stimuli of increased intensity were administered for 100 ms to 14 days, or occasionally for 100 ms to 10 minutes. , sometimes 1 minute to 14 days, sometimes 30 minutes to 2 hours, sometimes 1 minute to Any of items 49 to 64, delivered over a period of 7 days, or in some cases 1 minute to 5 days The method according to any one of the preceding claims.

[0077] Item 66: Initial excitation threshold to first or second or third or additional increased excitation threshold As a result of the increase, the nerve is blocked from conducting action potentials or the neuron 66. The method of any of items 49 to 65, wherein the neuronal cell is blocked from generating action potentials.

[0078] Item 67: Once a blockade of nerve conduction or neuronal excitation has been achieved, at least Electricity for 1 minute, sometimes at least 5 minutes, 10 minutes, 15 minutes, or 30 minutes. and ceasing to deliver stimulation to the subject, thereby preventing blockage of nerve conduction or neuronal excitation. The stimulation is maintained for the duration and, after the duration is over, the nerve is stimulated at the same or lower intensity. Or electrical stimulation of the neuron may be resumed to continue the blockade of nerve conduction or neuronal excitation. 67. The method according to any one of items 49 to 66, further comprising continuing or extending the

[0079] Item 68: Once a block of nerve conduction or neuronal excitation has been achieved, electrical stimulation Possibly reducing the intensity of electrical stimulation by modifying the intensity and / or frequency The blockade can be maintained by increasing the frequency of electrical stimulation or 68. The method according to any one of items 49 to 67, further comprising:

[0080] Item 69: A controller, a pulse generator communicating with the controller, and a nerve or neurotransmitter configured to be placed in contact with or surrounding a nerve or neuron; and an electrode in electrical communication with the pulse generator, the device being adapted to receive a nerve or The device is configured to provide electrical stimulation to the neuron, the electrical stimulation providing an initial stimulation to the nerve or neuron. The intensity of the electrical stimulation is below the threshold for neuronal activation, and in some cases the intensity of the electrical stimulation is below the threshold for neuronal activation. Pain in a nerve or neuron for a period of time sufficient to produce a blockade of neuronal excitation Below the threshold, the device.

[0081] Item 70: Pulse generators can be used with 0.01mA to 10mA and / or 1mV to 10,0 Item 70. The method according to item 69, wherein the device is configured to deliver electrical stimulation through the electrodes at an intensity of 0.00 mV. device.

[0082] Item 71: The pulse generator can be used for 100 milliseconds to 14 days, or in some cases for 100 milliseconds to 1 0 minutes, sometimes 1 minute to 14 days, sometimes 30 minutes to 2 hours, sometimes 1 1 Hz to 50 kHz, in some cases, for a period of 1 minute to 7 days, in some cases, 1 minute to 5 days. It is configured to deliver electrical stimulation through the electrodes at frequencies between 100 Hz and 1.2 kHz. and the electrical stimulation includes biphasic charge-balanced electrical pulses, item 69 or 70. The device described in.

[0083] Item 72: The controller increases the initial excitation threshold of a nerve or neuron by a first increased excitation. The initial excitation of a nerve or neuron for a period of time sufficient to cause it to increase to its excitation threshold. Programmed to instruct the pulse generator to deliver electrical stimulation at a subthreshold intensity 72. The device according to any one of items 69 to 71, comprising or configured to:

[0084] Item 73: The controller controls a first increased excitation threshold of a nerve or neuron to a second increased excitation threshold of a second neuron. A nerve or neuron for a length of time sufficient to cause an increased excitation threshold greater than the initial excitation threshold of the nerve or neuron and less than the first increased excitation threshold of the nerve or neuron. The pulse generator 100 generates increasing intensities of electrical stimulation until a first electrical stimulation of increased intensity is generated. Item 69-4 is further programmed or configured to instruct the device to 72. A device according to any one of claims 72 to 72.

[0085] Item 74: The controller increases a second excitation threshold of a nerve or neuron by a third. The first excitation of a nerve or neuron for a period of time sufficient to increase its excitation threshold. greater than the increased excitation threshold and less than a second increased excitation threshold of the nerve or neuron The intensity of a first increased intensity electrical stimulus up to a second increased intensity electrical stimulus and possibly further increasing the excitation threshold of a nerve or neuron. and applying the second increased intensity electrical stimulus once or twice for a period of time sufficient to cause and further programming the pulse generator to instruct the pulse generator to increment the pulse width by one or more additional increments. 74. The device according to any one of items 69 to 73, wherein the device is configured to

[0086] Item 75: The controller is configured to: If you do, you should wait at least one minute, and sometimes at least five, ten, fifteen, or even more minutes. The pulse generator is then programmed to instruct the patient to stop delivering electrical stimulation for 30 minutes. programmed or constructed to block nerve conduction or neuronal excitation The intensity is maintained throughout the period, and after the period ends, the nerve or The electrical stimulation of the neuron is resumed to continue or The device is programmed or configured to instruct the pulse generator to extend the 75. The device according to any one of items 69 to 74,

[0087] Item 76: The controller is configured to: In some cases, the intensity of the electrical stimulation may be reduced or the frequency of the electrical stimulation may be increased. By controlling the pulse generator, the intensity and / or frequency of the electrical stimulation can be altered. Any of items 69 to 75, which are programmed or configured to or the device described herein.

[0088] Item 77: A controller, a pulse generator in communication with the controller, and a pulse generator and one or more skin surface electrodes or magnetic coils in electrical communication with the device. The pulse generator and one or more skin surface electrodes or magnetic coils are The device is configured to provide electrical stimulation to a neuron, the electrical stimulation being The intensity of the electrical stimulation is below the initial excitation threshold of the nerve. A neuron or neuron is stimulated for a period of time sufficient to produce a blockade of neuronal excitation. The device is below Ron's pain threshold.

[0089] Item 78: The pulse generator can be used with 0.01mA to 10mA and / or 1mV to 10,0 It delivers electrical stimulation through one or more surface electrodes or a magnetic coil at an intensity of 0.100 mV. Item 78. The device of item 77, configured to reach.

[0090] Item 79: The pulse generator can be used for 100 milliseconds to 14 days, or in some cases for 100 milliseconds to 1 0 minutes, sometimes 1 minute to 14 days, sometimes 30 minutes to 2 hours, sometimes 1 1 Hz to 50 kHz, in some cases, for a period of 1 minute to 7 days, in some cases, 1 minute to 5 days. The device uses one or more skin surface electrodes or magnetic contacts at frequencies between 100 Hz and 1.2 kHz. The electrical stimulation is configured to deliver electrical stimulation through the catheter, the electrical stimulation being biphasic charge balanced. 79. The device according to claim 77 or 78, comprising an electrical pulse.

[0091] Item 80: The controller increases the initial excitation threshold of a nerve or neuron by a first increased excitation. The initial excitation of a nerve or neuron for a period of time sufficient to cause it to increase to its excitation threshold. Programmed to instruct the pulse generator to deliver electrical stimulation at a subthreshold intensity 80. The device according to any one of items 77 to 79, comprising or configured to:

[0092] Item 81: The controller controls a first increased excitation threshold of a nerve or neuron to a second increased excitation threshold of a second neuron. A nerve or neuron for a length of time sufficient to cause an increased excitation threshold greater than the initial excitation threshold of the nerve or neuron and less than the first increased excitation threshold of the nerve or neuron. The pulse generator 100 generates increasing intensities of electrical stimulation until a first electrical stimulation of increased intensity is generated. Item 77- is further programmed or configured to instruct the device to 80. A device according to any one of claims 80 to 80.

[0093] Item 82: The controller increases a second excitation threshold of a nerve or neuron by a third. The first excitation of a nerve or neuron for a period of time sufficient to increase its excitation threshold. greater than the increased excitation threshold and less than a second increased excitation threshold of the nerve or neuron The intensity of a first increased intensity electrical stimulus up to a second increased intensity electrical stimulus and possibly further increasing the excitation threshold of a nerve or neuron. and applying the second increased intensity electrical stimulus once or twice for a period of time sufficient to cause and further programming the pulse generator to instruct the pulse generator to increment the pulse width by one or more additional increments. 82. The device according to any one of items 77 to 81, wherein the device is configured to

[0094] Item 83: The controller is configured to: If you do, you should wait at least one minute, and sometimes at least five, ten, fifteen, or even more minutes. The pulse generator is then programmed to instruct the patient to stop delivering electrical stimulation for 30 minutes. programmed or constructed to block nerve conduction or neuronal excitation The intensity is maintained throughout the period, and after the period ends, the nerve or The electrical stimulation of the neuron is resumed to continue or The device is programmed or configured to instruct the pulse generator to extend the 83. The device according to any one of items 77 to 82,

[0095] Item 84: The controller is configured to: In some cases, the intensity of the electrical stimulation may be reduced or the frequency of the electrical stimulation may be increased. By controlling the pulse generator, the intensity and / or frequency of the electrical stimulation can be altered. Any of items 77 to 83, which are programmed or configured to or the device described herein.

[0096] Item 85: A method for reducing peripheral pain in a patient, comprising administering to a peripheral nerve or a central neuronal group The electrical stimulation involves delivering electrical stimulation to the nerve, which blocks nerve conduction or neuronal excitation. A force that does not cause excitation of a nerve or neuron for a sufficient length of time to produce 5, thereby reducing peripheral pain.

[0097] Item 86: The intensity of the electrical stimulation is below the initial excitation threshold of the nerve or neuron, 87. The method of claim 86, wherein the intensity of the electrical stimulation is below the pain threshold.

[0098] Item 87: Electrical stimulation is 0.01mA to 10mA and / or 1mV to 10,000 87. The method of claim 85 or 86, wherein the therapeutic dose is delivered at an intensity of 1000 mV.

[0099] Item 88: Electrical stimulation is 1Hz to 50kHz, or in some cases 100Hz to 1.2kHz. 88. The method of any of items 85 to 87, wherein the therapeutic dose is delivered at a frequency of z.

[0100] Item 89: Electrical stimulation is given for 100 milliseconds to 14 days, or in some cases for 100 milliseconds to 10 minutes. , sometimes 1 minute to 14 days, sometimes 30 minutes to 2 hours, sometimes 1 minute to Any of items 85 to 88, delivered over a period of 7 days, or in some cases 1 minute to 5 days The method according to any one of the preceding claims.

[0101] Item 90: Electrical stimulation increases the initial excitation threshold of a nerve or neuron to a first increased excitation threshold. the initial excitation threshold of a nerve or neuron for a period of time long enough to cause 90. The method according to any one of items 85 to 89, wherein the applied voltage is less than 100 V.

[0102] Item 91: A first increased excitation threshold of a nerve or neuron compared to a second increased excitation threshold above the initial excitation threshold of a nerve or neuron for a period of time long enough to a first increased excitation threshold of the nerve or neuron that is greater than or equal to the first increased excitation threshold of the nerve or neuron; Item 85 further includes increasing the intensity of the electrical stimulation to a strong electrical stimulation. 90. The method according to claim 90.

[0103] Item 92: Increasing the second excitation threshold of a nerve or neuron to a third increased excitation threshold first increased excitation threshold of a nerve or neuron for a length of time sufficient to cause A second increased excitation threshold of the nerve or neuron that is greater than or equal to the second increased excitation threshold of the nerve or neuron. increasing the intensity of the first increased intensity electrical stimulus until the first increased intensity electrical stimulus is reached. and optionally further increasing the excitation threshold of the nerve or neuron. and applying the second increased intensity electrical stimulus once or multiple times for a length of time sufficient to The method according to items 85 to 91, comprising increasing the amount several times.

[0104] Item 93: Once a blockade of nerve conduction or neuronal excitation has been achieved, at least Electricity for 1 minute, sometimes at least 5 minutes, 10 minutes, 15 minutes, or 30 minutes. and ceasing to deliver stimulation to the subject, thereby preventing blockage of nerve conduction or neuronal excitation. The stimulation is maintained for the duration and, after the duration is over, the nerve is stimulated at the same or lower intensity. Or electrical stimulation of the neuron may be resumed to continue the blockade of nerve conduction or neuronal excitation. 93. The method according to any of items 85 to 92, further comprising continuing or extending the method.

[0105] Item 94: Once a block of nerve conduction or neuronal excitation has been achieved, electrical stimulation Possibly reducing the intensity of electrical stimulation by modifying the intensity and / or frequency The blockade can be maintained by increasing the frequency of electrical stimulation or 94. The method according to any one of items 85 to 93, further comprising: [Brief description of the drawings]

[0106] [Figure 1A] 1A-1C are schematic diagrams of various embodiments of an external system (FIGS. 1A and 1B), as well as an implantable system (FIG. 1C), for use in nerve blocks as described herein. [Figure 1B] 1A-1C are schematic diagrams of various embodiments of an external system (FIGS. 1A and 1B), as well as an implantable system (FIG. 1C), for use in nerve blocks as described herein. [Figure 1C] 1A-1C are schematic diagrams of various embodiments of an external system (FIGS. 1A and 1B), as well as an implantable system (FIG. 1C), for use in nerve blocks as described herein. [Diagram 2] FIG. 2 shows a frog sciatic nerve-muscle preparation. [Diagram 3] FIG. 3 shows intensity-dependent block of muscle twitches by high-frequency biphasic stimulation (HFBS), with stimulation duration indicated by the black bar. [Figure 4] FIG. 4 shows HFBS block localized at the HFBS electrode site. [Diagram 5] FIG. 5 shows recovery of muscle twitch responses after prolonged (2 min) HFBS stimulation, with the duration of stimulation indicated by the black bar. [Figure 6] Figure 6 shows that the duration of post-stimulation block depends on the intensity and duration of high-frequency biphasic stimulation. *Significantly different by one-way ANOVA. #Significantly different by two-way ANOVA. [Figure 7] FIG. 7 shows a frog myelinated axon model (Frankenhaeser-Huxely model) for simulating conduction block induced by high frequency biphasic stimulation. [Figure 8] Figure 8 shows the propagation of action potentials along an axon evoked by high frequency biphasic stimulation at different intensities: A. 2.6 mA, B. 5 mA, Stimulus: 8 kHz, Axon diameter: 5 μm, Temperature: 37°C. [Figure 9] Figure 9 shows that blocking thresholds depend on stimulation frequency and axon diameter. [Figure 10] Figure 10 shows that the minimum stimulation frequency required to block axonal conduction varies with temperature. The stimulation intensity is at the blocking threshold. Axon diameter: 10 μm [Figure 11] Figure 11 shows the propagation of membrane potential, ionic current, and activation / inactivation of ion channels near the block electrode when nerve conduction block occurs. The legend in (e) indicates the distance of each node relative to the block electrode (0.0 mm node is below the block electrode). m activation of Na+ channels, h inactivation of Na+ channels, and n activation of K+ channels. [Figure 12] Figure 12 shows the changes in membrane potential, ionic currents and activation / inactivation of ion channels under the blocking electrode after an initial action potential evoked by high frequency biphasic stimulation. The stimulus waveforms are rescaled to show the timing and plotted in the background. m activation of Na+ channels, h inactivation of Na+ channels, n activation of K+ channels. [Figure 13] Figure 13 shows the effect of temperature on potassium channel activation (n) in axon nodes under blocking electrodes. Stimulation: 4 kHz [Figure 14]Figure 14 shows the experimental device for providing subthreshold block stimulation to the pudendal nerve. Block stimulation is provided to the pudendal nerve using a tripolar cuff electrode (Stim.B) to block the propagation of action potentials evoked by a bipolar hook electrode at a central site (Stim.C). Another bipolar hook electrode is placed at a distal site (Stim.D) to ensure that the external urethral sphincter (EUS) is blocked and not simply fatigued. The urethra is slowly perfused by an infusion pump so that contractions of the EUS can be recorded by increasing urethral pressure. [Figure 15] FIG. 15 shows that by gradually increasing the stimulation intensity from a very low intensity to alter the ion concentration, the threshold for exciting the nerve can be increased, resulting in blocking of nerve conduction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] The use of numerical values ​​in various ranges specified in this application is within the recited range unless otherwise indicated. The range is approximate, as if both the minimum and maximum values ​​were preceded by the word "approximately." In this way, slight variations above and below the stated ranges are accounted for. Values ​​within the range may be used to achieve substantially the same results. Unless otherwise stated, disclosure of these ranges is intended to be a continuous range including every value between the minimum and maximum values. For the definitions provided herein, those definitions are intended to refers to forms, synonyms and grammatical variations of the word or phrase.

[0108] The figures accompanying this application are representative in nature and, unless otherwise indicated, do not represent any particular No scale or orientation should be construed to be implied. For purposes of the following explanation, "Top", "Bottom", "Right", "Left", "Vertical", "Horizontal", "Top", "Bottom", "Horizontal", " "Vertical," and their derivatives, refer to the present invention as oriented in the drawings. However, the present invention does not, unless expressly specified to the contrary, It will be appreciated that alternative variations and step sequences may be envisioned. Specific dimensions and other physical characteristics relating to the embodiments disclosed herein are not intended to be limiting. should not be regarded as such.

[0109] As used herein, terms such as "comprises," "includes," and the like are open ended. The term "consisting of" refers to specified materials or steps as well as the claimed invention. Limiting the scope of the claims to those that do not materially affect the basic and novel characteristics of the invention The term "consisting of" refers to any element, step, or ingredient not specified in a claim. Exclude.

[0110] As used herein, the terms "a" and "an" refer to one or more. Refers to...

[0111] As used herein, the term "patient" refers to any mammal, including a human, and "human The term "patient" refers to any human.

[0112] As used herein, the terms "communication" and "communicating" refer to one or more signals. Refers to the receipt, sending, or transmission of a signal, message, command, or other type of data. A unit or device may communicate with another unit or device. A unit or device receives data from another unit or device and / or or to other units or devices. may use direct or indirect connections and may be wired and / or wireless in nature. Furthermore, the data to be transmitted may be between the first and second units or between the data Even though the two units can be modified, processed, routed, etc. Or the devices may be in communication with each other. For example, the first unit may passively transmit data to the The first unit receives data from the second unit even though it does not actively transmit data to the second unit. As another example, an intermediate unit may be in communication with a first unit. Even if the data from the first unit is processed and the processed data is sent to the second unit, The first unit may be in communication with the second unit. Many other arrangements are possible. For example, TCP / IP (including HTTP and other protocols) ), WLAN (802.11a / b / g / n and other radio frequency based protocols and (including the method and method), analog transmission, Global System for Mobile Communications(GSM), 3G / 4G / LTE, BLUETOOTH , ZigBee, EnOcean, TransferJet, Wireless USB, and Use known electronic communications protocols and / or algorithms such as are known to It is possible.

[0113] As used herein, the "excitation threshold" of a nerve or neuron is the threshold at which an action potential is initiated. The minimum level that must be depolarized to depolarize the neuron and / or nerve membrane in order to stimulate This results in excitation of the nerve or neuron, e.g., initiation and activation of an action potential. This results in the propagation of motor potentials, which in turn causes the propagation of signals in the nerve or neuron. As used herein, the terms "nerve" and "neuron" are used interchangeably, particularly with respect to excitation thresholds. Although the term is used interchangeably, those skilled in the art will recognize that neuron refers to the cell body from which action potentials are generated. It will be understood that a nerve refers to an axon through which an action potential is conducted. For example, stimulation parameters sufficient to block excitation in a neuron may be sufficient to block transmission in a nerve. It will be appreciated that the present invention may be suitable for blocking nerve or neurotransmitters. Depolarization of the membrane potential of the neutron results in a change in membrane voltage, for example from 70 millivolts (mV) to +4 Increase to 0mV.

[0114] As used herein, the term "subthreshold depolarization" or "subthreshold stimulation" refers to a neurotransmitter or The membrane voltage of a neuron is measured from the resting membrane potential (e.g., -70 mV) to the below the excitation threshold such that the neuron is not excited, e.g., action potentials are not initiated or conducted This means stimulation sufficient to increase the level of , motor nerve fibers and sensory nerve fibers have different excitation thresholds, but in non-limiting embodiments Alternatively, in an embodiment, the excitation threshold is in the range of -55 mV or -45 mV, The same sensory nerve may also have a subrange of the stimuli that induce numbness or pain. Therefore, as used herein, subthreshold refers to the stimulation intensity at which Depending on which response (muscle contraction, paralysis, or pain) is blocked, It means below the level that induces pain. Subthreshold stimulation as described herein reduces the membrane voltage from resting (-70 mV) to -55 mV. The voltage is increased to the following voltage: Phasic pulses are used to slightly depolarize neurons / nerves (bring them below their excitation threshold) It will be appreciated that it may then be hyperpolarized.

[0115] The “intensity” of an electrical pulse is determined by the voltage or current (e.g. The increase in intensity is proportional to and refers to either the electrical current (e.g., milliamperes or mA) and is related to the or proportional to the increase in voltage or increase in current applied to the neuron.

[0116] In an embodiment, the methods provided herein include blocking a nerve or neuron in a patient. 1. A method for treating a neurodegenerative disease comprising administering an electrical stimulus to a nerve or neuron, the electrical stimulus comprising: The nerve / neuron is blocked for a length of time sufficient to produce a nerve or neuron block. The membrane potential of a neuron is changed from the resting potential (e.g., -70 mV) to the excitation threshold of the nerve / neuron. As previously mentioned, the subthreshold stimulation is configured to increase the stimulation level of a given nerve to a value of 0.05. / The excitation threshold of a neuron may vary, and one skilled in the art may administer stimuli of various intensities to determine the activity. By determining the threshold at which no electrical potential is generated or conducted, the excitation threshold can be determined. In a non-limiting embodiment, the excitation threshold of the neuron is −55 mV, and thus In certain embodiments, the stimulation increases the membrane potential of the neuron to a value less than -55 mV. In this regard, block induced by subthreshold electrical stimulation includes poststimulus block.

[0117] As used herein, "post-stimulation block" refers to a neuroprotective effect that extends beyond the cessation of electrical stimulation. This means a block, which can last anywhere from a few seconds to a few hours, days, or weeks, depending on the length and intensity of the electrical stimulation. , months, or even years, with increments therebetween. In some embodiments, the post-stimulation block lasts for at least 1 minute. For at least 1 minute, and possibly for at least 5, 10, or 15 minutes after stimulation has stopped. or for 30 minutes, at which point stimulation can be applied again. The stimulation may be ion depletion or prolonged subthreshold stimulation, particularly as described herein. , achieved by prolonged subthreshold stimulation given in stages to increase the excitation threshold. Due to the increased excitation threshold, the initial intensity used to initiate the block was higher than that used to initiate the block. In some embodiments, after post-stimulation block is achieved, electrical stimulation may be continued. The frequency and / or intensity of stimulation can be altered, i.e. to achieve post-stimulation block. After this, the frequency of stimulation can be increased and / or the intensity of stimulation can be decreased. This can be done.

[0118] The electrical stimulation may be achieved by applying electrical pulses that may have any suitable characteristics, so long as the stimulation is a subthreshold stimulation. Thus, the terms "electrical stimulation" and "electrical pulse" are used herein as used herein. As will be appreciated by those of skill in the art, the characteristics of an electrical pulse is, but is not limited to, amplitude (which refers to the level or magnitude of a signal voltage or current, pulse strength) degree), voltage, amperage, duration, frequency, polarity, phase, relative timing, and Symmetry of the positive and negative pulses in biphasic stimulation, and / or the waveform (e.g., square , sine, triangular, sawtooth or any variation or combination thereof) may be to provide the desired subthreshold stimulation and resulting post-stimulation block in the body. Other characteristics of the electrical signal (such as, but not limited to, amplitude, voltage, amperage, Duration, polarity, phase, relative timing, and positive and negative phases of biphasic stimulation The modulation of the pulse frequency is possible as long as the pulse symmetry and / or waveform are within a useful range. achieves the desired result of subthreshold induced block of a nerve or neuron.

[0119] As mentioned above, one characteristic of the electrical signal used to generate a desired response is that The frequency of the pulse. Note that the effective range (e.g., the frequency that can produce the described effect) ) may vary from subject to subject, and the control factors that achieve the desired outcome, Specific non-limiting exemplary ranges include the range in which a stimulus or pulse is active in a target nerve / neuron. Do not induce motor potentials or use a small number of neurons so that continuous firing of the nerve / neuron is avoided. In one embodiment, the method may be as follows, provided that only one action potential is induced. For blocking nerves, useful frequencies are in the range greater than 1 Hz (Hertz), about 1H z to approximately 50 kHz (kilohertz), or 0.5 kHz to 50 kHz In another embodiment, when blocking a nerve / neuron, the frequency is: Ranges greater than 1Hz, ranges from about 1Hz to about 50kHz, 0.5kHz to about 50k Hz range. In embodiments, the range is more typically 5 Hz to 10 kHz. In some embodiments, the stimuli may be in the range of 1 kHz to 4 kHz and all subranges therebetween. In embodiments, the stimulation is administered in a range including ≦1.5 kHz, or ≦1.2 kHz. z, or between 100Hz and 1kHz, including all subranges therebetween. The following data shows a range from at least 5 kHz, and in some examples 1 A 0 kHz pulse is preferred.

[0120] As mentioned above, the subthreshold electrical pulse is determined by the intensity of the electrical stimulation, which is In a medium with a stable or relatively stable resistance, such as tissue of a given type, Ohm's law Based on this, it is either current (I, typically measured in mA) or voltage (V, typically measured in mV). The intensity of the stimulus can therefore be characterized in terms of V and and I, and thus both are proportional to the increase in the intensity of the stimulus, e.g. It should be understood that the pulse width increases substantially in proportion to the pulse width. The characteristic of this is the current applied to produce a subthreshold stimulus capable of blocking the nerve. Subthreshold stimulation can be achieved with a typical range of 0.01 mA to 10 mA. As shown in the examples below, the range of 0.01 mA to 1 mA is used to provide subthreshold stimulation. Another characteristic of the pulses is the voltage. As shown in the following examples, the voltage is 1 to 10,000 mV, for example, 100 to 10,000 mV. This can be achieved in the typical range of V. By applying electrical stimulation at subthreshold intensities for a period of time, the excitation threshold is steadily increased (see above). In some embodiments, such as those described in more detail below, the intensity of the stimulation is then increased to a higher level. but after a period of time, significant poststimulus block occurs below the increased excitation threshold. A period of rest or post-stimulation block can be achieved by electrical stimulation. It is possible to introduce periods that are not provided or are provided at a frequency less than necessary. After this, stimulation can be reintroduced to maintain the block. The delivered stimulus is of reduced intensity compared to the stimulus required to provide the initial block. and / or increased frequency.

[0121] As described herein, the excitation threshold of a nerve or neuron is determined by the amount of subthreshold stimulation. After a sufficient period of time, it may increase, thus increasing the limit of subthreshold stimulation. That is, at the initial time point, after exposing a nerve or neuron to a subthreshold stimulus, the membrane potential is - An increase from 70mV to -55mV depolarizes the nerve or neuron and causes an action potential may be sufficient to produce a neuronal excitation threshold that varies depending on the duration and intensity of the stimulation. The excitation threshold may increase from -55mV to -45mV or even higher. Such an increase can be repeated with increasing subthreshold stimulation, as shown in the examples below. Therefore, a specific I (current) and V (voltage) are useful for the first stage blocks. Although I and / or V may be involved in the firing of action potentials, there is no concern that It can be increased following subthreshold stimulation of sufficient duration.

[0122] As mentioned above, the waveform of the pulse may be varied as long as the desired subthreshold blocking effect is achieved. Those skilled in the art will appreciate that other types of electrical stimulation may also be used in accordance with the present invention. Monophasic or biphasic stimulation, or a mixture of both, may be used. As is known in the art, nerve damage due to application of electrical current can occur in some cases with prolonged use. In contrast to monophasic pulses or waveforms that may damage nerves in This can be minimized by application of a biphasic pulse or biphasic waveform. " or "biphasic waveform" means a waveform that has equal or substantially equal net charges (hence biphasic and charge-balanced) and may be symmetrical or asymmetrical. It may be symmetrical or substantially symmetrical. This may be the case, for example, when the target electrode One or more electrodes are connected to the electrodes so that the net charge applied to the A number of positive pulses are applied, followed by a single negative pulse, typically of the same amplitude and duration as the positive pulses. This can be achieved by applying multiple negative or positive pulses, or vice versa. In the case of load-balanced biphasic stimulation, the net effect of a biphasic pulse pair (a combination of a positive and a negative pulse) is As long as the applied charge is near zero, the opposite polarity pulses can have different amplitudes, profiles, or or duration.

[0123] Waveforms include, but are not limited to, sine, square, rectangular, triangle, sawtooth, and linear. , pulse, exponential, truncated exponential, or any decaying sine wave shape. The pulses may be of any useful shape. In an embodiment, the waveform is rectangular. The pulses may be continuous or spaced apart as desired. As shown below, a particular voltage or current may be applied for a particular time. Stimulating a nerve or neuron produces a post-stimulation nerve block. Thus, stimulation produces a longer-lasting block / relief in terms of hours, days, weeks, months, or years. To achieve this, short periods (e.g., 1-10 minutes) or longer periods (e.g., 360 The stimulus may be administered for up to 10 minutes or more, days, weeks, months, or years. In one embodiment, the stimulation is administered for 30 minutes to 2 hours. In certain embodiments, the stimulation is for at least 70 minutes, at least In one embodiment, the pulse is administered over a period of at least 80 minutes, or at least 90 minutes. 100ms to 14 days, sometimes 100ms to 10 minutes, sometimes 1 minute ~14 days, sometimes 30 minutes to 2 hours, sometimes 1 minute to 7 days, sometimes Given for a period from 1 minute to 5 days, including all subranges therebetween. Thus, stimulation can be delivered continuously or intermittently (i.e., pulses are delivered at intervals) during an interval stimulation protocol. The stimulation may be applied for any period of time (alternating on and off during the stimulation interval). The arousal may occur over an interval of, for example, 1 to 10 minutes or more (for example, hours, days, weeks, months, years). It may be given as 5 seconds on and 5 seconds off. In addition to the intermittent application of pulses An example would be 1-90 seconds on and 1-90 seconds off over a period up to 360 minutes. The suppression may be temporary, as long as other pulse parameters remain within acceptable limits. does not damage the neurons / nerves involved. For example, intermittent application of pulses, i.e. The pulses are administered for as long as they have the desired effect and for as long as the patient desires (i.e., without causing pain to the patient). In one embodiment, the stimulation may be continuous, e.g., For example, severe symptoms or intermittent, short-term stimulation to the extent desired by the clinician or patient. The drug is provided continuously to treat symptoms not associated with

[0124] As noted above and demonstrated below, in embodiments, the excitation threshold intensity of a nerve or neuron A subthreshold electrical stimulus is applied to the nerve or neuron for an appropriate period of time so that Thus, after applying a subthreshold electrical pulse of sufficient duration, the intensity of the electrical pulse is A stepwise increase above the initial threshold intensity but below the newly increased threshold intensity. The appropriate length of time is greater than one minute (see Miles, JD, et al. Effects of ramped amplitude waveforms on the onset response of high-freq uency mammalian nerve block (2007) J. Neural Eng. 4 (2007) 390-398, where is the voltage applied to the nerve ramped from 0V to 10V over time, with a step The durations range from 100 nanoseconds to 60 seconds, and we found such lamp parameters. found that administering immunization to mice failed to prevent the onset response. greater than 7, 8, 9, 10, or 15 minutes, including increments therebetween, in embodiments , greater than 2 minutes, greater than 5 minutes, and even greater than 10 minutes. In an embodiment or aspect, the step of incrementally increasing the excitation threshold comprises: Within the range, for example but not limited to, 1 hour, 2 hours, 3 hours, or more The duration may be within a range of times.

[0125] In embodiments, the excitation threshold is a threshold that determines whether a neuron and / or nerve is blocked for a long period of time. In some embodiments, the stimulation can be increased repeatedly to provide Sufficient stimulation to increase the initial excitation threshold to the first increased excitation threshold (e.g., >-55 mV) The intensity is below the initial excitation threshold of the neuron for a period of time that is longer than 50 minutes (e.g., −55 mV). Then, the membrane potential of the neuron is raised above the initial excitation threshold of the neuron. a first increased intensity configured to be less than a first increased excitation threshold of the neuron; The first increased excitation threshold of the neuron can be increased by a second This first increased intensity voltage is applied for a period of time sufficient to increase the excitation threshold to the threshold. A second electrical stimulus of increased intensity can then be applied to the neuron. where a second, increased intensity electrical stimulus increases the neuronal excitation threshold. higher than the first increased excitation threshold of the neuron and higher than the second increased excitation threshold of the neuron The second increased intensity electrical stimulation is configured to increase the intensity of the neurotransmitter to a value lower than the first increased intensity. for a period of time sufficient to increase the second excitation threshold of the This process can be repeated any number of times. Although we do not wish to be bound by the above, we do wish to consider the relationship between ion concentrations (e.g., sodium) between intracellular and extracellular compartments. Such a stepwise increase in excitation threshold is due to the significant reconstitution of the sulphuric acid (calcium and potassium). It is believed that long-term blocking can be achieved through

[0126] As a non-limiting example, if the excitation threshold is 1 mA at 1 kHz, a biphasic pulse, i.e. A subthreshold current of 0.9 mA is applied for an appropriate period of time, such as 30 minutes to 2 hours, at which point the The excitation threshold increases to 2 mA. At that point, the subthreshold current increases to 1.9 mA and remains at that level for 30 min. is applied for an appropriate period of time, such as 2 hours from 0.5 to 2 hours, to further increase the excitation threshold, at which point the excitation threshold is increased. The value is increased to 5 mA. The stepwise increase in excitation threshold may, in some embodiments, exceed the cessation of stimulation. The desired length of nerve block is achieved, including post-stimulation nerve block that can be sustained for up to 10 minutes. This can be repeated until

[0127] The time frame over which the excitation threshold can be increased (e.g., stepwise) can be varied. In some embodiments, the increase is so rapid that the increase in intensity is small (e.g., 10 μm). A) in μA scale, but the increase (e.g., at each step) is , e.g. millisecond scale (1 ms, 10 ms, 100 ms, and everything in between) In this embodiment, the duration of each step can be increased rapidly without any restriction. The duration increases over time, e.g. each step is 1 ms, 10 ms, 100 Milliseconds, 1 second, 10 seconds, 1 minute, 10 minutes, 30 minutes, hours(multiple), days(multiple), weeks(multiple) It could be a number, month(s), year(s), etc.

[0128] In aspects, the methods provided herein also include methods for treating, alleviating, or treating pain in a patient. A method of removing a neuron comprising administering electrical stimulation to a nerve or neuron, the electrical stimulation comprising administering electrical stimulation to the nerve or neuron. The stimulation produces a block of the nerve or neuron, and in some embodiments a post-stimulation block. The membrane potential of the neuron is then varied from the resting potential (e.g., -70 mV) for a period of time that allows a subthreshold stimulus configured to increase the excitation level of the neuron from a threshold value to a value below the neuron excitation threshold, In one embodiment, the pain is from the extremities. The method involves stimulating the neurons (central) or nerves (peripheral) that control the limb. In one embodiment, the threshold is determined in a patient experiencing phantom pain in an amputated limb. Electrical pulses are applied to one or more nerves that otherwise innervate the missing limb. In one embodiment, the threshold is set at a single intensity to achieve nerve block, i.e., elimination of phantom limb pain. In another embodiment, a submaximal electrical pulse is applied until a nerve block is achieved, i.e. Subthreshold electrical pulses are administered in a stepwise fashion as described herein until pain is relieved. In an embodiment, the subthreshold electrical pulses described herein are applied in an increasing manner. The method may or may not cause a numbing sensation in the patient. The subject may apply subthreshold electrical pulses in any manner, for example, in a constant or step-increasing manner. Although some anesthetic effects may be experienced when the drug is administered, patients will not experience a typical onset response. No associated acute muscle spasms or pain are experienced.

[0129] In effect, subthreshold electrical pulses can be applied to the patient's nerves until they experience paralysis. can be increased in and then decreased slightly to remove the paralysis effect or If the patient is still able to tolerate the electrical pulses, they are not tapered and are continued until the paralyzing effect has worn off. If paralysis is present, it may disappear after a sufficient length of stimulation, and the event For example, to provide a signal to the patient and / or clinician that a subthreshold block is effective can be used as a signal and the intensity of the applied current can be increased until paralysis is again experienced. Alternatively, the applied current can be set to 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, Increase gradually after an appropriate period of time, such as 45 minutes, 60 minutes, or any increment in between. Stepwise increases in subthreshold electrical pulses are continued until nerve block is achieved. This corresponds to the disappearance of pain, such as the disappearance of phantom limb pain, at which point blocking can be performed. The current may be increased for several minutes (e.g., 5, 10, 15, 20, 30, 45 minutes, or 60 minutes) to several hours (e.g., 2 hours, 4 hours, 6 hours, 12 hours, or 2 of appropriate length ranging from 4 hours, days, or even weeks, months, or years. Maintained in time.

[0130] In a non-limiting embodiment or aspect, the described subthreshold blocking method includes: Once block is achieved, the blocking electrical pulses are then periodically Timed pause and restart at full block intensity without the need for incremental stimulation This means that after the initial stimulation, the blocking electrical pulse periodically, e.g., every hour, to maintain the block at full block strength. can be applied for 2 to 15 minutes or as 15 minutes on and 15 minutes off. In particular, individual nerves, neurons, stimulation devices, and stimulation parameters can be linked together. Considering that the frequency and duration of each application of the pulses will likely be determined, The optimum block timing parameters can be determined on a case-by-case basis.

[0131] Referring to the drawings, and to the devices provided herein, the nerve / neuron following stimulation A device for delivering subthreshold stimulation in a manner sufficient to induce a block. Non-limiting examples of electrical stimulation devices 10 useful in the method embodiments described herein include: A general schematic diagram of one embodiment or aspect is provided. The device 10 is a power source or pulse The power supply / pulse generator 20 may be a fixed output or may be, for example For example, it may be tunable within a useful range as described herein. The device 10 includes a first conductive lead 30 having a first nerve cuff 31 and a second nerve cuff 36. and a second conductive lead 35 having a first conductive lead 30 and a second conductive lead 35 having a second conductive lead 30 and a second conductive lead 35. The conductive leads 30 and 35 are connected to a nerve cuff 3 1 and 36 can be combined into a single lead for connecting the In one embodiment, the nerve cuffs 31 and 36 can also be combined into a single cuff, or Disposed on the conductive leads 30 and 35 or on both the conductive leads 30 and 35 Completely eliminate and replace with a conductive metal / electrode located on a single lead that couples the The conductive leads 30 and 35 are wired directly to the power supply / pulse generator 20. Alternatively, each may have a continuous current between the power supply / pulse generator 20 and each nerve cuff. A plurality of leads and electrical connectors, fasteners, terminals, or clips for making electrical connections. The nerve 37 is also depicted in the figure. The skin 38 is also depicted in the figure. As shown, device 10 is external and can be hand-held or worn on the body. The device may be attached to the body, for example a hook and loop fastener band. The device is held in place by a belt or strap. Chair 10 may be an implantable device (described in more detail below). In this case, the leads are of opposite polarity and are connected to the same circuit board for applying the electrical waveforms described herein. Different leads, probes, electrodes or electrical contacts or combinations thereof may form a path together. Alternative designs having the same configuration will be apparent to those skilled in the art. includes structures useful for applying electrical current directly to nerves or tissues of a patient, such as the patient's skin. Structures for generating a magnetic field and therefore an electric current through induction are not considered electrical contacts. Nonetheless, in embodiments, an inductive probe, i.e., a probe that generates a current The structure capable of generating a magnetic field capable of generating the electrical pulses described herein. It may also be used to

[0132] FIG. 1B is a schematic diagram of another embodiment of a device 10 for nerve block. As with the device in FIG. 1A, it has an external power source. In FIG. 1B, the reference numbers are Like reference numbers refer to like elements of device 10. However, surface electrode 31a and 36a replace the nerve cuffs 31 and 36 of FIG. 1A, and stimulation is transcutaneous. In an alternative embodiment not shown, surface electrodes 31a and 36a are connected to a nerve 37. The electromagnet is replaced by an electromagnet for magnetic induction stimulation of the impulse.

[0133] FIG. 1C illustrates a further embodiment of an implanted nerve block device 110. The housing 112 is connected to a first nerve cuff 131. A power supply / pulse generator 120 connected to a first lead 130 and a pulse generator 136 for stimulating a nerve 137. and a second lead 135 connected to a second cuff 136 for The skin 138 is depicted in the figure for context. 30 and 135 are combined into a single lead for connecting nerve cuffs 131 and 136 As mentioned above, in an embodiment (not shown), the nerve cuff 131 and The conductive leads 130 and 136 may also be combined into a single cuff, or the conductive leads 130 and 135 or a single conductive lead 130 and 135 that couples both conductive leads 130 and 135. The ferroelectric capacitor may be eliminated or replaced entirely by conductive metal / electrodes disposed on the leads of the ferroelectric capacitor. For monopolar stimulation, one of the cuffs / electrodes may be disposed on the housing 112. The implantable device is made of plastic, metal, carbon fiber, or ceramic materials. Biocompatible materials or biocompatible polymers known in the medical field for use in - or polymer coatings such as hydrogel-coated metal or plastic housings The housing 112 may also include a processor 140, a temporary data A storage module 142 including storage (e.g., RAM) and flash memory. Devices1, including non-transient data storage such as memory or solid-state drives 10 various connected sub-units, possibly rechargeable by magnetic induction and a battery 144. The processor 140 also includes a Connect to your smartphone via Bluetooth, Wi-Fi, or cellular networks. tablets, laptops, personal computers, smartwatches, an external computer or Connects to a wireless communication module 150 for wirelessly communicating with a computer network It is possible.

[0134] The devices of FIGS. 1A-1C are battery powered, and in some cases the battery is rechargeable. Where the device is implanted, the device may be wirelessly, as is known, e.g. The device of FIG. 1A and / or FIG. 1B can be charged by an inductive charging method. It also uses smartphones, tablets, laptops, personal computer, workstation, server, or computer network A separate computing device such as a controller app or software on A communication interface, such as a wireless communication interface or module, for receiving instructions from It can include the following aspects: As will be appreciated by those skilled in the art, electrical stimulation and neurostimulation as described herein may be used in a variety of applications. A large number of potential devices to control the devices and systems that provide the blocks and system configuration and implementation schemes can be used.

[0135] Referring to FIG. 1C, a device such as, for example, device 10 of FIG. 1A and / or FIG. 1B may include a Although the device 110 is equally applicable to the embodiments of the device, the device 110 functions in relation to the electrical pulse output of the power source. In some examples, the controller includes a base line A central processing engine that contains an in-processor, memory, and communication capabilities. The controller includes a computer readable memory and can store data in the memory or other sources. The computer may be any suitable processor configured to execute instructions received from the computer. Data-readable memory may be, for example, a disk drive, a solid-state drive, an optical drive, drives, tape drives, flash memory (e.g., non-volatile computer storage chips), A cartridge drive and a control element for loading new software. do.

[0136] In some embodiments, the controller may include, but is not limited to, programming instructions, which are referred to herein as "programming instructions." So that devices can interact and operate independently or collectively as programmed. A program, code, sequence of instructions, or other program executable by a processor that dynamically instructs the processor In some embodiments, the controller may include any combination of the above. Command the power supply / pulse generator to initiate a sub-threshold electrical pulse as described throughout. and induces nerve / neuron block, and possibly post-stimulus block in a manner sufficient to stimulate the The power supply may be configured to control an output parameter of the power supply (e.g., by applying a voltage to the power supply). , the processors associated with the devices 10 and 110 disclosed herein are Program the device to deliver appropriate subthreshold stimulation as generally described throughout. In either case, it will be appreciated that the controller may Receives and processes electrical pulse parameters programmed into the device or from an external source and in some cases, to determine if the power supply is producing the desired output. The device is configured to output data obtained from the power supply as feedback for the purpose of determining whether the power supply is being used. Processing removes signal artifacts, noise, and other artifacts from the captured signal to improve readability. Apply filters and other techniques to remove noise, baseline waveforms, or other items. This may include:

[0137] In addition to the above, the devices 10 and 110 further include a processor 140 that executes When a neuron is stimulated with a voltage below its initial excitation threshold (e.g., below -55 mV), Increase the initial excitation threshold of the stimuli to the first increased excitation threshold (e.g., >-55 mV). and instructing the power source / pulse generator 120 to apply the electrical stimulus for a sufficient length of time to These parameters are described above and may include programming the frequency from 1 Hz to 50 with intensities from 0.01mA to 10mA and / or 1mV to 10,000 kHz mV for durations ranging from seconds to days for all parameters. The term includes sub-ranges of, but can include, stimulating.

[0138] As previously described, the processor 140 then controls the power supply / pulse generator 120 to A neuron that is higher than its initial excitation threshold and lower than the first increased excitation threshold of the nerve / neuron. a first increased intensity electrical stimulation configured to increase an excitation threshold of a neuron that is The patient can then be instructed to deliver a first electrical stimulation of increasing intensity to the nerve. / sufficient to increase a neuron's first increased excitation threshold to a second increased excitation threshold The power supply / power supply voltage may be applied for a suitable length of time. Configure the pulse generator 120 to provide a second, increased intensity electrical stimulus to the nerve / neuron. where a second electrical stimulus of increased intensity is administered to stimulate nerve / neuron excitation. The threshold membrane potential is increased above the first increased excitation threshold of the nerve / neuron and The second increased excitation threshold of the second amplified stimulation coil is configured to increase the excitation threshold of the second amplified stimulation coil to a value lower than the second increased excitation threshold of the second amplified stimulation coil. The increased intensity of electrical stimulation produces a second increased excitation threshold of the nerve / neuron, and a third increased excitation threshold of the It is possible to administer the drug for a period of time sufficient to increase the excitation threshold. By having the devices 10 and 110 programmed or configured as described above, As explained, providing suprathreshold stimulation would be at the very least uncomfortable / inconvenient and excessively painful. This improves functionality over past devices that may have been prone to injury. Thus, the controller determines whether or not a blockade of nerve conduction or neuronal excitation has been achieved. In some cases, the intensity of the electrical stimulation may be reduced or the frequency of the electrical stimulation may be increased. Instruct the pulse generator to modify the intensity and / or frequency of electrical stimulation by The block can be programmed or configured to: A variety of sensors and devices can be used to determine whether As described above and illustrated in the examples below, the device may include one or more contacts, leads, or In an embodiment, one of the contacts / leads / cuffs may include a bronchoscope. The block can be placed proximal to the blocked contact / lead / cuff and the block can be placed proximal to the The stimulation pulse applied to the cuff blocks the action potential distal to the location of the blocking contact / lead / cuff. It can be determined whether it results in transmission.

[0139] The following illustrative examples are based on long-duration, high-frequency (kHz) biphasic stimulation (H FBS) slowly changes the ion concentration in the nerve being blocked, causing neuropathic pain. This indicates that conduction can be blocked.

[0140] Example 1 - HFBS-induced post-stimulation nerve block Figure 2 shows the isolated sciatic nerve being connected to a bipolar hook electrode (Stim.A = 0.5 Hz single The stimulation was performed with a tripolar cuff electrode (Stim.B = 1-10 kHz HFBS). The frog sciatic nerve-muscle preparation was immersed in Ringer's solution in a bath. do.

[0141] Low intensity (1-6mA) 10kHz HFBS induces strong muscle contractions. decreases as the HFBS intensity increases to higher levels (8–10 mA), whereas the initial The muscle contraction force measured at the end of HFBS was 5–10 times stronger than that measured at the end of HFBS (see Figure 3, Panel A). Complete with a minimum intensity (i.e., blocking threshold) between 4 and 6 mA for 10 kHz HFBS This shows that nerve block occurs (Figure 3, Panel B). than 5 kHz to block muscle spasms induced by im.A at 0.5 Hz. A slightly higher stimulation intensity is required (Figure 3, Panel B). In Figure 3, at the end of HFBS The measured forces were normalized to the maximum response during each experimental trial. After completely blocking the induced muscle spasm, the Stim.B distal site was C still induced muscle spasms (Figure 4), excluding the possibility of a blockade of the neuromuscular junction. While removing the electrode, it shows that nerve block occurs locally at the Stim.B electrode. 10 seconds After the end of the second HFBS, nerve conduction was rapidly restored and the 0.5 Hz Stim.A The muscle spasms induced by the stimulation recurred within a few seconds (Figure 3, Panel A), i.e. No blocks were observed.

[0142] However, when HFBS was sustained for more than 10 seconds, a post-stimulus block was observed (Figure 5 After terminating HFBS, the recovery of nerve conduction consisted of two distinct periods. During this period, complete block was maintained and muscle spasms were suppressed by 0.5 Hz Stim.A. This period is called the absolute recovery period (Figure 5). In the second period, 0.5 The muscle spasms induced by Stim.A at 30 Hz were partially recovered (Figure 5). Duration is the post-stimulus duration required for the muscle twitch response to recover to approximately 95% of the pre-stimulus level. The sudden recovery was noted in 13 of 16 animals (Figure 5). The duration of the post-stimulus block is proportional to the duration and intensity of the stimulation. (Figure 6).

[0143] Example 2 - Mechanisms underlying acute HFBS block revealed by model analysis Figure 7 shows that a myelinated axon 40 mm long has an internode length of Δx = 100d (where d is the axon diameter). Each node (length L = 2.5 μm) is modeled as a membrane electrostatic It is modeled by a capacitance (Cm) and a variable membrane resistance (Rm). Two monopolar electrodes (with an indifferent electrode at infinity) are placed. One monopolar electrode is connected to the HFB. The block electrode is located 25 mm along the axon, where S is delivered. The single-pole electrode is a test electrode located 5 mm from the electrode, and a single-phase pulse (0.5 mA to A pulse width of 0.1 ms at an intensity range of 2 mA was sent to induce an action potential, and this action potential This is to test whether the signal can propagate through the block electrode. The blocking electrode always delivers a biphasic pulse with the cathode phase first. Put out.

[0144] Assume that the axon is in an infinite homogeneous medium (with resistivity ρe = 300 Ωcm). After ignoring the small effect induced by the presence of the axon, the n-th Extracellular potential at the node V e,n can be calculated as follows:

number

number

[0145] Figure 8 shows a typical nerve model simulated by the myelinated axon model shown in Figure 7. Firing patterns and conduction block induced by HFBS are shown. In A), HFBS induced repetitive firing of action potentials (Fig. 8, panel A), but more At higher intensities (5 mA, Fig. 8, Panel B), only early action potentials were elicited. In panel B, a test pulse was applied by the test electrode at 3 ms after the HFBS started. In Figure 8, panel A, no test pulse was applied. The HFBS (8 kHz) generates a spreading action potential at the block electrode. The blockade was successful (Figure 8, Panel B). The results of these simulations are shown in Figure 3. This is in excellent agreement with the results obtained from a cultured frog sciatic nerve-muscle preparation.

[0146] The model simulations also showed that the blocking threshold depends on the HFBS frequency and axon diameter. This shows that small axons need to be blocked more strongly than large axons (Figure 9). On the other hand, higher frequencies also require higher intensity to block axons of the same diameter. Frequency dependence was observed in a frog sciatic nerve-muscle preparation (Figure 3B). Here, 10 kHz is a higher frequency than 5 kHz to completely block nerve conduction. Diameter dependence also indicates that higher stimulation intensities block smaller diameter axons. This has also been reported in previous animal studies showing that it is necessary for the ,The model analysis revealed a minimum blocking frequency of 4 kHz at 20 ,℃ (Figure 9). , which is in excellent agreement with previous studies in animals that showed a minimum blocking frequency of approximately 4-5 kHz. is doing.

[0147] The axon model further reveals that the minimum blocking frequency changes with temperature. At temperatures between 20 and 27°C, the minimum blocking frequency is about 4 to 5 kHz. At lower temperatures (15°C), the minimum blocking frequency decreases to 3 kHz, while At body temperature (37°C), the frequency increased to 6 kHz. In our studies, we were able to achieve consistent blocking at the lowest frequencies between 3 kHz and 5 kHz at room temperature. Unfortunately, the study did not define a specific room temperature. Assuming that the room temperature can vary between 15°C and 27°C, the sciatic nerve of an isolated frog The minimum block frequency of 3 to 5 kHz obtained by the experiment is shown in Fig. 10. In addition, previous studies using cats showed that the It was shown that the minimum blocking frequency for HFBS to block the pudendal nerve was approximately 6 kHz. This also explains why the cat's pudendal nerve is a myelinated axon in mammals, whereas the frog's sciatic nerve is a myelinated axon in humans. Even though the nerves are composed of amphibian myelinated axons, the simulation results matched very well. Matches.

[0148] To understand the possible mechanism of HFBS block, we investigated the mechanism of nerve conduction block. Changes in membrane potential, ionic currents, and activation / inactivation of ion channels near the blocking electrode Figure 11 shows the results of a simulation using the axon model shown in Figure 7. Six nodes at distances of 0 to 5 mm from the electrode were examined consecutively (node ​​0.0 mm). (Figure 11, Panel ac shows the action potential, sodium current, All of the potassium and potassium currents were blocked, although their amplitudes gradually decayed. This propagation is shown to occur from the nodal point under the block electrode to the nodal point under the block electrode. It completely disappeared at 0.0 mm, where the axon membrane was filled with large sodium and potassium The membrane potential and ionic currents are alternately depolarized and hyperpolarized by the current. As shown in df, by activation / inactivation of sodium and potassium channels It can be further explained that as the action potential propagates towards the blocking electrode, sodium Activation of mu channels (m) also changes in each node and becomes oscillatory in nodes under blocking electrodes. (Figure 11, panel d). On the other hand, when the distance to the block electrode was 1.0 mm and 2.0 mm, In the nodes, sodium channel inactivation (h) is maintained at a high level (low value). (Figure 11, panel e). Under the blocking electrode, sodium channel inactivation (h) The combination of sodium channel activation (m) and inactivation (h) (Figure 1 1, panels d and e) show that the amplitude of the sodium current gradually decreases at the node close to the blocking electrode. This decays and finally becomes a pulsed inward current at the node (0.0 mm) under the block electrode. (Figure 11, panel b). Thus, the axon model is a conduit for conduction block. This indicates that sodium channels are not completely blocked when However, this model assumes that the change in potassium activation (n) induced by the action potential is a blockade event. Nodes close to the locking electrode gradually disappear because potassium channels are constantly activated. The level of potassium channel activation was significantly increased in the 10-fold increase ... The maximum occurs at the node under the electrode (0.0 mm), resulting in a large pulse of outward potassium. This large outward potassium current is then converted into a large inward current (Fig. 11, panel c). In response to the sodium current, the node below the block electrode (0.0 mm) becomes non-excitable. This leads to a blockade of action potential propagation.

[0149] Figure 12 shows how the node (0.0 mm) under the block electrode is detected by HFBS. The waveform of the HFBS is also shown to show the timing. As shown in Figure 12, panel b, after the initial action potential, the potassium The β-K channel is activated (n ≈ 0.4), resulting in a pulsatile outward potassium current. On the other hand, activation (m) and inactivation (h) of sodium channels occur (Figure 12, panel a). ) become oscillatory, resulting in a pulsatile inward sodium current (Figure 12 , panel a). However, during the depolarization phase (cathodic / negative pulse, see Fig. 12, panel a), In some cells, the potassium channels are already open, so the potassium current is the same as the sodium current. This increases the potassium current relative to the sodium current without any delay in its development. This causes the node to become de-excited. The delay between the potassium and sodium currents is It is important for the generation of action potentials and can be seen in the first pulse at the onset of stimulation (Figure 12 , panel a). This is also despite the fact that HFBS alternately depolarizes and hyperpolarizes the membrane. However, they were unable to generate action potentials after the initial action potential (Figure 12, panel a). The reason is explained below (see Figure 8, Panel B). Therefore, according to the axon model, HFBS The conduction block induced by ionizing radiation is due to the constant activation of potassium channels beneath the blocking electrode. It becomes clear that this is due to

[0150] The relationship between temperature and minimum blocking frequency (see Figure 10) indicates that HFBS induces nerve block. However, this cannot be explained by the hypothesis that it induces a constant depolarization This can be explained by the dynamics of ion channels. The numbers show how potassium channel activation (n) changes with temperature. When the temperature changes from 37°C to 15°C, the kinetics of potassium channels slows down. Therefore, potassium channel activation (n) is increased from oscillation to a constant level (approximately 0.6). At temperatures of 15°C and 20°C, potassium channel activation (n) remains constant. This is because low frequencies (<4 kHz) are Explains why nerve conduction can only be blocked at warm temperatures (e.g., <20°C) (Figure 10).

[0151] In addition, the ionic current I i,n (See Figure 7) -Chiu-Ritchie-Rogart-Stagg instead of Huxley model According to the Sweeney (CRRSS) model, the minimum blocking frequency at 37°C is This is because the CRRSS model lacks potassium currents in the membrane dynamics. This is because it is derived from myelinated rabbit nerves. If there are no potassium channels in the model, Frequencies above kHz are required because of fast sodium channel dynamics and nerve conduction blockade. High frequencies are needed to inactivate sodium channels to induce a blockade. The results of the CRRSS model are also consistent with the above result. This indicates that it is the kinetics of potassium channels that determines the frequency to be 5 kHz.

[0152] These simulation studies show that HFBS can be used within seconds of stimulation onset. Not only did we clarify the mechanisms underlying acute nerve blocks (Figures 4, 11 and 12) and also emphasize the mechanisms underlying post-stimulation nerve block observed in animal studies. HFBS induces outward movements during each biphasic stimulation pulse. Since it generates potassium currents and inward sodium currents (Figure 12), long-term HF BS certainly produces a cumulative effect that alters intracellular and extracellular ion concentrations. Thus, at some point during prolonged HFBS, there is a cumulative effect on intracellular and extracellular ion concentrations. The cumulative effect can be large enough to cause axonal conduction block. The ion pump slowly recovers the ion concentration changed by HFBS for a long time. It requires time to activate the HFBS, so it is maintained even after the long-term HFBS is terminated, and post-stimulation blocking is More importantly, the subthreshold HFBS induces a pulsed HFBS can also generate sodium and potassium currents (Figure 12). It is not necessary for the axonal conduction block to have a suprathreshold intensity that would cause a post-block. It takes longer than suprathreshold HFBS to accumulate sufficient ion concentration changes to produce locking. The results presented here show that acute and post-stimulation blockade These results reveal that the underlying mechanisms are different.

[0153] Example 3 - Pudendal nerve block with subthreshold high frequency biphasic stimulation (kHz) The purpose of this example is to determine the excitation threshold of high frequency (10kH) biphasic stimulation (HFBS) in the cat's genital area. The aim of this study was to show that it can increase over time in neurons.

[0154] Experimental preparation One cat was anesthetized with isoflurane (2-5% oxygen) during surgery and α-chloroform during data collection. Anesthesia was switched to larose anesthesia (initial 65 mg / kg, supplemented intravenously as needed). A catheter was placed in the cutaneous vein to administer fluids or anesthetics. The airway was opened by tracheotomy. The patient remained in good health. A catheter was inserted into the right carotid artery to monitor blood pressure. A sigma meter (9847V; NONIN Medical, Plymouth, MN) was used. It was placed on the tongue and monitored heart rate and blood oxygen levels.

[0155] Through the abdominal incision, insert the catheter into the distal urethra and slowly infuse it with saline (1 ml / min) to perfuse the urethra and monitor contractions of the external urethral sphincter (EUS) induced by pudendal nerve stimulation. The increase in intraurethral pressure caused by the ureter was recorded (Figure 14). The left pudendal nerve was drained to the inside and the outside to deliver HFBS (Stim. B in Fig. 14). A tripolar cuff electrode (NEC113, MicroProbes Inc, Maryland, USA) was The lateral ischium of the tail for implantation (Gaithersburg) The cerebellum was exposed through a 3-4 cm incision in the notch. Two hook electrodes were inserted into the tripolar cuff electrode. The right pudendal nerve was also exposed, and the same Three sets of electrodes were implanted in the same area. The pudendal nerve was centrally located to prevent EUS reflex activation. The stimulator (Grass S88, Grass Tech Stimulation pulses (20 Hz) were generated by a 30-Hz pulse generator (Nologies, Rhode Island, USA). , 0.2ms) with a stimulus isolator (SIU5, Grass Technology s, Rhode Island, USA) via a hook electrode (Stim.C or Stim.D) The urethral pressure was then increased to >30 cmH2O. on a computer running tional Instruments, Inc., Texas, USA The generated HFBS (6 or 10 kHz square wave with no pulse interval, see Figure 14) ) with a stimulus isolator (A395, World Precision Instrument The device was delivered to a tripolar cuff electrode via a catheter (Head Office, Breast Cancer Center, FL, USA) to block pudendal nerve conduction. and inhibited EUS contractions induced by Stim.C (Figure 14).

[0156] result Figure 15 shows the results of Stim.C and Stim.B before applying 10 kHz HFBS. The results show that mD induced the same EUS contraction. Then, Stim.B was increased to 0.15 A subthreshold intensity of 0.15 mA was applied for over 5 hours. When it was gradually increased to 0.16-0.2 mA during the first few minutes of stimulation, it was irregular. Although the EUS induced mild spasms, HFBS gradually increased the excitation threshold during the 20 min stimulation. The intensity of the HFBS was then slowly increased to 1.7 mA for 150 min. Increasing the concentration of β-stimuli did not induce EUS contractions, but Stim.C did (Stim .D) significantly blocked EUS contractions and locally at the site of Stim.B. The conduction block of the pudendal nerve was demonstrated. When HFBS was maintained at 1.7 mA for 5 hours, the cells Further changes in intracellular / extracellular ion concentrations result in further blockage of the pudendal nerve, which Further reduces EUS contractions induced by Stim.C, but not by Stim.D. The EUS contractions induced by the stimulation were still strong (indicating that the nerve was blocked, This indicates that it was not simply muscle fatigue that contributed to the significant changes in evoked contractions. After completion of HFBS, the pudendal nerve block was maintained for several hours.

[0157] As is clear from the results in Figure 15, subthreshold HFBS lowered the nerve excitation threshold over time. The intensity of the HFBS can be increased gradually, always remaining below the excitation threshold. It is shown that the HFBS intensity can be gradually increased while the The HF pulse can be increased to a level sufficient to block regional nerve conduction. It persists for a long time after the end of BS, i.e., in the block after HFBS.

[0158] Consideration In this study in cats, rather than fatiguing the muscles, the blockade after HFBS It was confirmed that this can occur locally on the pudendal nerve (Figure 15).

[0159] Our previous computer simulation studies have demonstrated that the unmyelinated model (Hojiki Myelinated (Frankenhauser-Huxley model) and myelinated (Frankenhauser-Huxley model) axons Using a model, each pulse of HFBS induces an inward sodium current and an outward potassium current. Induces electrical currents, reliably increasing intracellular sodium ion and extracellular potassium ion concentrations The HFBS used in this study was a square pulse with no interval between the pulses. The waveform is continuous (Figure 14), and the sodium-potassium pump regulates the ion concentration. Therefore, HFBS, if continued for a long period of time, will cause an increase in intracellular sodium concentration. Cumulatively increase the concentration of ATP and extracellular potassium to levels high enough to block axonal conduction. do. This blockade ensures that the sodium-potassium pump maintains normal ion concentrations even after HFBS has ended. Therefore, the recovery period of the blockade after HFBS depends on the following points: Depends on: 1. the rate of the sodium-potassium pump and / or 2. the total increase in ion concentration Addition.

[0160] As shown in Figure 15, the initial neural firing induced by 10 kHz HFBS was However, this can be prevented as the HFBS continues. HFBS gradually changes the ion concentration. The excitation threshold increases over time to increase the intensity of the subthreshold HFBS. , which can increase to a new subthreshold level minutes or hours after stimulation. The new subthreshold is further increased with stimulation time, and the intensity of HFBS increases with increasing stimulation time. can be repeatedly increased while always remaining at a sub-threshold level without any degradation. In general, HFBS produces large changes in ion concentrations that induce nerve conduction blockade. can reach a strength sufficiently high for

[0161] In this study, we used the cat's pudendal nerve to examine whether blockade after HFBS was achieved by prolonged HFBS. There are scientific findings supporting the hypothesis that this is due to changes in intracellular / extracellular ion concentrations resulting from Understanding the mechanism of HFBS block is essential to understanding how HFBS blocks nerve conduction. The current clinical application of HFBS to treat chronic diseases will be explored. This is important for improving applications.

[0162] The present invention has been described above with reference to certain exemplary embodiments, dispersible compositions and uses thereof. Although the present invention has been described above, any of the exemplary embodiments may be modified without departing from the spirit and scope of the present invention. It will be appreciated by those skilled in the art that various substitutions, modifications, or combinations of any of the above may be made. Accordingly, the invention is not limited by the description of exemplary embodiments.

Claims

1. A method for blocking a nerve or neuron comprising: providing electrical stimulation to the nerve or neuron, the electrical stimulation comprising: or to a nerve or nerve for a period of time sufficient to produce a blockade of neuronal excitation. The method has an intensity that does not cause excitation of the neuron.

2. The intensity of the electrical stimulus is below an initial excitation threshold of the nerve or neuron, The method of claim 1 , wherein optionally the intensity of the electrical stimulation is below a pain threshold.

3. The electrical stimulation may be performed at a voltage of 0.01 mA to 10 mA and / or 1 mV to 10,000 mV.

3. The method of claim 1 or 2, wherein the therapeutic agent is delivered at a high intensity.

4. The electrical stimulation may be performed at a frequency of 1 Hz to 50 kHz, or in some cases, 100 Hz to 1.2 kHz.

3. The method of claim 1 or 2, wherein the radiation is delivered at a frequency of 100 Hz.

5. The electrical stimulation may be administered for 1 minute to 14 days, in some cases for 30 minutes to 2 hours, in some cases for 1 minute 10. The method of claim 1 or 2, wherein the drug is delivered over a period of 1 minute to 7 days, and optionally 1 minute to 5 days. Method of posting.

6. The electrical stimulation blocks nerve conduction or neuronal excitation for at least one minute.

3. The method of claim 1 or 2, further comprising: pressing a button on the patient and subsequently terminating the electrical stimulation.

7. The method of claim 1 or 2, wherein the electrical stimulation comprises a biphasic electrical pulse.

8. The biphasic pulse is symmetric between a positive phase and a negative phase of the biphasic pulse. The method according to claim 7.

9. The biphasic pulse has an asymmetrical distribution between the positive and negative phases of the biphasic pulse. The method according to claim 7, wherein

10. The method of claim 1 or 2, wherein the electrical stimulation comprises a charge-balanced electrical pulse.

11. 3. The method of claim 1 or 2, wherein the electrical stimulation is administered for at least 5 minutes.

12. The electrical stimulation increases the initial excitation threshold of the nerve or neuron to a first increased excitation threshold. The initial concentration of the nerve or neuron is increased for a sufficient period of time to a threshold.

3. The method of claim 2, wherein the stimulation is administered at an intensity below the excitation threshold.

13. Increasing said first increased excitation threshold of said nerve or neuron to a second increased excitation threshold. said initial activation of said nerve or neuron for a period of time sufficient to increase said initial activation of said nerve or neuron a first increased excitation threshold of said nerve or neuron and less than said first increased excitation threshold of said nerve or neuron; increasing the intensity of the electrical stimulus until a first increased intensity electrical stimulus is provided. The method of claim 12 further comprising:

14. Increasing the second excitation threshold of the nerve or neuron to a third increased excitation threshold. said first increased activity of said nerve or neuron for a length of time sufficient to cause said first increased activity of said nerve or neuron greater than the excitation threshold and less than the second increased excitation threshold of the nerve or neuron. The first increased intensity electrical stimulus is then applied to the subject until a second increased intensity electrical stimulus is applied to the subject. and optionally further comprising: The second increased intensity for a length of time sufficient to further increase the excitation threshold.

14. The method of claim 13, further comprising increasing the intensity of the electrical stimulation one or more times. Method of posting.

15. the first increased intensity electrical stimulus, the second increased intensity electrical stimulus, and / or Additional stimulation of increasing intensity may be performed, for example, from 0.01 mA to 10 mA and / or from 1 mV to 10, 15. The method according to claim 13 or 14, wherein the intensity of the pulse is 000 mV.

16. the first increased intensity electrical stimulus, the second increased intensity electrical stimulus, and / or Additional increased intensity stimuli range from 1 Hz to 50 kHz, and in some cases from 100 Hz to 1.

15. The method of claim 13 or 14, delivered at a frequency of 2 kHz.

17. the first increased intensity electrical stimulus, the second increased intensity electrical stimulus, and / or Additional electrical stimulation of increased intensity was administered for 100 milliseconds to 14 days, sometimes 100 milliseconds. Seconds to 10 minutes, in some cases 1 minute to 14 days, in some cases 30 minutes to 2 hours, in some cases In some cases, the drug is delivered over a period of 1 minute to 7 days, and in some cases, 1 minute to 5 days.

15. The method according to claim 14.

18. Increasing the initial excitation threshold to the first or second or third or additional increased excitation threshold. As a result of applying the stimulation, the nerve is blocked from conducting action potentials or the nerve The present invention relates to a method for treating a pulmonary artery disease, the method comprising: The method described.

19. Once blockade of nerve conduction or neuronal excitation has been achieved, the area is In some cases, the electrical stimulation is performed for at least 5 minutes, 10 minutes, 15 minutes, or 30 minutes. and ceasing to administer said nerve conduction or neuronal excitation block. is maintained during said period, and after said period has ended, the same or a lower intensity is Resume electrical stimulation of the nerve or neuron to induce nerve conduction or neuronal excitation. The block is continued or extended as claimed in any one of claims 1, 2 and 12 to 14. How to.

20. Once block of nerve conduction or neuronal excitation is achieved, the intensity of the electrical stimulation is increased. In some cases, the intensity and / or frequency of the electrical stimulation may be altered. By decreasing the frequency of the electrical stimulation or increasing the frequency of the electrical stimulation, The method according to any one of claims 1, 2 and 12 to 14, further comprising maintaining method.

21. A controller; a pulse generator in communication with the controller; Surrounding or placed in contact with a nerve or neuron and an electrode in electrical communication with the pulse generator. 、 The device is configured to provide electrical stimulation to the nerve or neuron, The electrical stimulation is at an intensity below the initial excitation threshold of said nerve or neuron, and optionally The intensity of the electrical stimulation is sufficient to produce a block of nerve conduction or neuronal excitation. The device is below the pain threshold of the nerve or neuron for a period of time of at least 15 minutes.

22. The pulse generator has a current of 0.01mA to 10mA and / or 1mV to 10,000mV.

22. The method of claim 21 , configured to deliver electrical stimulation through the electrodes at a magnitude of V device.

23. The pulse generator may be for 100 milliseconds to 14 days, or in some cases for 100 milliseconds to 10 minutes; In some cases, 1 minute to 14 days, in some cases, 30 minutes to 2 hours, in some cases, 1 minute to 7 1 Hz to 50 kHz, sometimes for a period of 1 minute to 5 days, sometimes for a period of 1 minute to 5 days configured to deliver electrical stimulation through said electrodes at a frequency between 100 Hz and 1.2 kHz.

22. The method of claim 21, wherein the electrical stimulation comprises biphasic charge-balanced electrical pulses. device.

24. The controller increases the initial excitation threshold of the nerve or neuron by a first increased The nerve or neuron is then stimulated with and instructing the pulse generator to deliver electrical stimulation at an intensity below the initial activation threshold.

22. The device of claim 21, which is programmed or configured.

25. The controller increases the first increased excitation threshold of the nerve or neuron by a second for a length of time sufficient to increase the excitation threshold of said nerve or neurite out of said The first increased threshold of the nerve or neuron is greater than the initial excitation threshold of the nerve or neuron. The intensity of the electrical stimulus is increased until a first increased intensity electrical stimulus is provided that is below the excitation threshold. and further programmed to instruct the pulse generator to increase the intensity of the pulse. or configured as described in claim 24.

26. The controller increases the second excitation threshold of the nerve or neuron by a third for a length of time sufficient to increase the excitation threshold of the nerve or neuron said second increased excitation threshold of said nerve or neuron being greater than said first increased excitation threshold; The first increased intensity is then applied to the electrical stimulation device until a second increased intensity electrical stimulation is applied that is below the excitation threshold. and optionally increasing the intensity of the electrical stimulation to the nerve or nerves. said second increase for a length of time sufficient to further increase said excitation threshold of Ron; The pulse is then applied to the subject to one or more additional increases in intensity of the electrical stimulation.

2. The method of claim 1, further comprising:

5. The device described in 5.

27. the controller, once block of nerve conduction or neuronal excitation is achieved, At least 1 minute, and in some cases at least 5 minutes, 10 minutes, 15 minutes, or 30 minutes. and instructing the pulse generator to stop delivering the electrical stimulation for a period of time. programmed or configured to, prior to said nerve conduction or neuronal excitation, The blocks are to be maintained for the said period and, after the said period has expired, the same or more Resume electrical stimulation of the nerve or neuron at a lower intensity to stimulate the nerve conduction or neuron. to instruct said pulse generator to continue or extend said blockage of pulmonary activation. Any one of claims 21 and 24 to 26, wherein the method is programmed or configured to 3. The device according to claim 1 .

28. the controller, once block of nerve conduction or neuronal excitation is achieved, Optionally, the intensity of the electrical stimulation is decreased or the frequency of the electrical stimulation is increased. Increasing the number of and a second instructing the pulse generator to: A device according to any one of claims 21 and 24 to 26.

29. A controller; a pulse generator in communication with the controller; One or more skin surface electrodes or magnetic coils in electrical communication with the pulse generator. A device comprising: The pulse generator and the one or more skin surface electrodes or magnetic coils or configured to provide electrical stimulation to neurons, the electrical stimulation being nerve conduction. or for a period of time sufficient to produce a blockade of neuronal excitation. The electrical stimulus has an intensity below the initial excitation threshold of the neuron, and in some cases the intensity of the electrical stimulus is The device is below the pain threshold of a recording nerve or neuron.

30. The pulse generator has a current of 0.01mA to 10mA and / or 1mV to 10,000mV. Deliver electrical stimulation through the one or more skin surface electrodes or magnetic coils at an intensity of V.

30. The device of claim 29, configured to:

31. The pulse generator may be for 100 milliseconds to 14 days, or in some cases for 100 milliseconds to 10 minutes; In some cases, 1 minute to 14 days, in some cases, 30 minutes to 2 hours, in some cases, 1 minute to 7 1 Hz to 50 kHz, sometimes for a period of 1 minute to 5 days, sometimes for a period of 1 minute to 5 days The one or more skin surface electrodes or magnetic coils are connected at a frequency of 100 Hz to 1.2 kHz. and configured to deliver an electrical stimulus via the catheter, the electrical stimulus being a biphasic charge-balanced 30. The device of claim 29, comprising an electrical pulse at

32. The controller increases the initial excitation threshold of the nerve or neuron by a first increased The nerve or neuron is then stimulated with and instructing the pulse generator to deliver electrical stimulation at an intensity below the initial activation threshold.

30. The device of claim 29, which is programmed or configured.

33. The controller increases the first increased excitation threshold of the nerve or neuron by a second for a length of time sufficient to increase the excitation threshold of said nerve or neurite out of said The first increased threshold of the nerve or neuron is greater than the initial excitation threshold of the nerve or neuron. The intensity of the electrical stimulus is increased until a first increased intensity electrical stimulus is provided that is below the excitation threshold. The pulse generator may be further programmed to instruct the pulse generator to increase the intensity of the pulse.

33. The device of claim 32,

34. The controller increases the second excitation threshold of the nerve or neuron by a third for a length of time sufficient to increase the excitation threshold of the nerve or neuron said second increased excitation threshold of said nerve or neuron being greater than said first increased excitation threshold; The first increased intensity is then applied to the electrical stimulation device until a second increased intensity electrical stimulation is applied that is below the excitation threshold. and optionally increasing the intensity of the electrical stimulation to the nerve or nerves. said second increase for a length of time sufficient to further increase said excitation threshold of Ron; The pulse is then applied to the subject to one or more additional increases in intensity of the electrical stimulation.

4. The method of claim 3, further programmed or configured to:

3. The device described in claim 3.

35. the controller, once block of nerve conduction or neuronal excitation is achieved, At least 1 minute, and in some cases at least 5 minutes, 10 minutes, 15 minutes, or 30 minutes. and instructing the pulse generator to stop delivering the electrical stimulation for a period of time. The blocking of nerve conduction or neuronal excitation is programmed or configured. The lock is maintained for the duration of said period and after said period has expired, the same or a lower Resume electrical stimulation of the nerve or neuron at an intensity to induce nerve conduction or neuronal excitation. to instruct the pulse generator to continue or extend the block of According to any one of claims 29 and 32 to 34, device.

36. the controller, once block of nerve conduction or neuronal excitation is achieved, Optionally, the intensity of the electrical stimulation is decreased or the frequency of the electrical stimulation is increased. Increasing the number of and a second instructing the pulse generator to: A device according to any one of claims 29 and 32 to 34.

37. 1. A method of reducing peripheral pain in a patient, comprising: The electrical stimulation includes applying electrical stimulation to a peripheral nerve or a central neuron group, the electrical stimulation being A nerve or nerve block for a period of time sufficient to produce a block of nerve conduction or neuronal excitation. or at an intensity that does not cause neuronal excitation, thereby reducing peripheral pain. Law.

38. the intensity of the electrical stimulus is below an initial excitation threshold of the nerve or neuron; 38. The method of claim 37, wherein the intensity of the electrical stimulation is below a pain threshold.

39. The electrical stimulation may be performed at a voltage of 0.01 mA to 10 mA and / or 1 mV to 10,000 mV.

39. The method of claim 37 or 38, wherein the therapeutic agent is delivered at a high intensity.

40. The electrical stimulation may be performed at a frequency of 1 Hz to 50 kHz, or in some cases, 100 Hz to 1.2 kHz.

39. The method of claim 37 or 38, wherein the radiation is delivered at a frequency of 100 Hz.

41. The electrical stimulation may be for 100 milliseconds to 14 days, in some cases for 100 milliseconds to 10 minutes, in some cases Depending on the situation, it may take 1 minute to 14 days, in some cases it may take 30 minutes to 2 hours, in some cases it may take 1 minute to 7 days, 39. The method of claim 37 or 38, optionally delivered over a period of 1 minute to 5 days. method.

42. The electrical stimulation increases the initial excitation threshold of the nerve / neuron to a first increased excitation threshold. the initial excitation threshold of the nerve or neuron for a length of time sufficient to 39. The method of claim 37 or 38, wherein the intensity is given at an intensity less than the value.

43. Increasing said first increased excitation threshold of said nerve or neuron to a second increased excitation threshold. said initial excitation of said nerve or neuron for a length of time sufficient to increase a first increased excitation threshold of said nerve or neuron and greater than said first increased excitation threshold of said nerve or neuron increasing the intensity of the electrical stimulus until a first increased intensity electrical stimulus is reached.

40. The method of claim 38, further comprising:

44. Increasing the second excitation threshold of the nerve or neuron to a third increased excitation threshold. said first increased activation of said nerve or neuron for a length of time sufficient to cause said a second increased excitation threshold of said nerve or neuron greater than said first increased excitation threshold of said nerve or neuron and less than said second increased excitation threshold of said nerve or neuron; The intensity of the first increased intensity electrical stimulus is increased until a second increased intensity electrical stimulus is provided. and optionally increasing the intensity of said stimulation of said nerve or neuron. of said second increased intensity for a length of time sufficient to further increase the excitation threshold.

44. The method of claim 43, further comprising increasing the intensity of the electrical stimulation one or more additional times. How to.

45. Once blockade of nerve conduction or neuronal excitation has been achieved, the area is In some cases, the electrical stimulation is performed for at least 5 minutes, 10 minutes, 15 minutes, or 30 minutes. and ceasing to administer said nerve conduction or neuronal excitation block. is maintained during said period, and after said period has ended, the same or a lower intensity is Resume electrical stimulation of the nerve or neuron to inhibit nerve conduction or neuronal excitation. According to any one of claims 37, 38 and 42 to 44, the lock is continued or extended. How to.

46. Once block of nerve conduction or neuronal excitation is achieved, the intensity of the electrical stimulation is increased. In some cases, the intensity and / or frequency of the electrical stimulation may be altered. or increasing the frequency of the electrical stimulation. The method according to any one of claims 37, 38 and 42 to 44, further comprising maintaining a check. The method described.

Images