Device and method for suppressing pain by selectively and reversibly adjusting nervous system structure

Abstract

To provide a system and a method for selectively and reversibly adjusting a target nerve tissue and a non-nerve tissue of a nervous system for treating pain.SOLUTION: In a stimulator 100, an electric stimulation generated by a control device 130 and a signal generator 140 electrically connected to a power source 180 is transmitted to a part to be treated N via an electrode 120, a target nerve tissue and a non-nerve tissue of a nervous structure are selectively and reversibly adjusted, and pain is suppressed while maintaining other sensibility, motor functions, and proprioception.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 776,908, filed December 7, 2018, which is incorporated by reference in its entirety.

[0002] The present invention relates generally to devices and methods for modulating activity of neural and non-neural tissue to treat pain, and more particularly to devices and methods for selectively and reversibly modulating neural and non-neural tissue activity of neural structures to inhibit pain while preserving other sensory and motor functions, as well as proprioception. [Background technology]

[0003] Pain can be treated by disrupting the arrival of pain signals originating from the body to the brain, both destructively and non-destructively. Destructive methods are routinely used to treat chronic pain symptoms and include thermal ablation, cryoablation, chemical ablation (e.g., with phenol, lidocaine, Botox®, ultrasound diagnostic ablation, and mechanical cutting). However, the destruction of neural structures can cause an immediate loss of nerve function, leading to long-term atrophy, neuropathy, and ultimately more pain. Furthermore, due to the desire to preserve motor and non-painful sensory functions, mixed nerves and ganglia are not usually targeted using destructive interventions for chronic pain. Furthermore, the destruction of neural structures does not contribute to post- and peri-operative pain management, where it is desired to preserve motor and non-painful sensory functions. As a result, destructive methods of disrupting pain signals are generally not used for acute pain applications, such as post-operative pain.

[0004] Non-destructive methods for treating pain include the use of prescription painkillers (e.g., opioids), local anesthetic injections, topical or injectable cocktails consisting of steroids and other anti-inflammatory agents, continuous infusion of local anesthetics, electrical blockade, electrical stimulation, and application of pulsed radiofrequency energy. Each of these methods has its own challenges that impair the efficacy and usability of the treatment. For example, prescription painkillers have undesirable side effects and can lead to addiction. On the other hand, local anesthetics and injectable cocktails have a short period of effectiveness lasting only a few hours, while continuous infusion of anesthetics requires tethering the patient to an external device for long-term treatment (days). Furthermore, the use of local anesthetics presents risks of neurotoxicity, vascular toxicity, and allergic reactions. Finally, these agents are not selective for the type of neural activity they block (e.g., they block both nerve fiber activity associated with pain and nerve fiber activity associated with motor function).

[0005] Electrical neuromodulation techniques offer adjustable localized control of pain with a lower risk of side effects than chemical interventions. However, existing electrical blocking techniques have only been used to treat chronic pain after amputation and require the patient to be implanted with an internal pulse generator and nerve cuff for long-term blockade. The need for surgical implantation therefore places a significant burden on the use of electrical blocking for acute pain applications of both large and small nerves, as well as electrical blocking for acute head and face pain. Furthermore, even though electrical stimulation devices are commonly used to relieve pain, their effectiveness has not been sufficient to manage moderate to severe pain levels, such as those experienced by patients suffering from severe or chronic migraines, perioperative pain and / or experiencing postoperative pain days to weeks after surgery. Electrical neurostimulation devices have also been used in peripheral nerves, dorsal root ganglia, and spinal cord to treat chronic pain, but all of these devices are burdened by the need for surgical implantation and, when applied to mixed nerves or ganglia, may activate motor fibers or non-painful sensory fibers, which may be undesirable. Furthermore, although radiofrequency energy therapy is procedural and does not burden the patient with take-home equipment, it cannot be used to treat large nerves and the results of treating small nerves are inconsistent. Furthermore, the selectivity and time course of reversibility of radiofrequency energy therapy for acute pain is unknown.

[0006] Therefore, there is a need for electrical devices and methods that can temporarily and selectively suppress pain by modulating neural and non-neural activity in both small and large peripheral nerves, cranial nerves, ganglia, autonomic nerves, plexuses, and spinal cord, with effects lasting days to weeks, where the temporary and selective blockade does not pose the risk of neurotoxicity, vascular toxicity, or allergy. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure is directed to systems and methods for selectively and reversibly modulating targeted neural and non-neural tissues of the nervous system for the treatment of pain. Electrical stimulation is delivered to a treatment site to selectively and / or reversibly modulate targeted neural and non-neural tissues of neural structures to inhibit pain while preserving other sensory and motor functions, as well as proprioception. In one aspect, a system for selectively and / or reversibly modulating targeted neural and non-neural tissues of nervous system structures (e.g., to treat a medical condition in a patient) is disclosed. The system includes an electrical stimulator having one or more electrodes (e.g., having a size, shape and contact surface configuration suitable for delivering electrical stimulation to a nervous system structure) (e.g., monopolar or bipolar) (single electrode or electrode array) that deliver electrical stimulation to a treatment site proximate to target neural and non-neural tissue of a nervous system structure, and a controller configured to connect to the one or more electrodes of the electrical stimulator and to a power source that provides electrical energy to the one or more electrodes, the controller being configured to direct operation of the electrical stimulator (e.g., via current control, voltage control, power control, and / or temperature control) and apply electrical stimulation to the treatment site via the electrodes, the application of electrical stimulation to the treatment site selectively modulates the target neural and non-neural tissue, inhibits pain, and preserves other sensory and motor functions and proprioception.

[0008] In some embodiments, the pain comprises at least one of acute pain, post-surgical pain, neuropathic pain, chronic pain, and head and facial pain.

[0009] In some embodiments, a single application of the electrical stimulation to the treatment site selectively modulates the target neural and non-neural tissue resulting in subsequent inhibition of pain (e.g., for a period of about 1 day to about 30 days, for a period of about 30 days to about 60 days, for a period of about 60 days to about 90 days, for a period of about 90 days to about 120 days, for a period of about 120 days to about 150 days, for a period of about 150 days to about 180 days, for a period of about 180 days to about 270 days, for a period of about 270 days to about 365 days) (e.g., if the pain is chronic pain, a single application of the electrical stimulation to the treatment site selectively modulates the target neural and non-neural tissue resulting in subsequent inhibition of pain for a period of about 90 days to about 365 days).

[0010] In some embodiments, a single application of electrical stimulation to a treatment site selectively modulates targeted neural and non-neural tissue, resulting in subsequent pain suppression for about 5 days to about 30 days.

[0011] In some embodiments, application of electrical stimulation to the treatment site modulates (e.g., selectively modulates and / or reversibly modulates) targeted neural and non-neural tissue, inhibits nerve signaling through nerve fibers involved in pain transmission (e.g., also involved in transmitting thermoreception, autonomic activity, and visceral function, nerve signaling through nerve fibers involved in other sensory and motor functions, proprioception is preserved, and other sensory functions are selected from the group consisting of touch, vision, hearing, taste, smell, and balance).

[0012] In some embodiments, the one or more electrodes are configured (e.g., of suitable size and shape) to be placed adjacent to nervous system structures including at least one of peripheral nerves, cranial nerves, ganglia and autonomic nerves, plexuses, and the spinal cord (e.g., ganglia including at least one of dorsal root ganglia, sympathetic ganglia, parasympathetic ganglia, pterygopalatine ganglion, and gasserian ganglion).

[0013] In some embodiments, the nervous system structure includes a nerve or ganglion having a diameter greater than about 2.5 mm (e.g., cranial nerves, autonomic nerves, plexuses, and spinal cord), and at least one of the one or more electrodes has a size and shape and contact surface configuration sufficient to deliver electrical stimulation to the nerve or ganglion (e.g., greater than 1 mm 2 ~ approx. 100mm 2 (e.g., the controller is configured to generate appropriate waveforms that form electrical stimulation to modulate (e.g., selectively modulate or reversibly modulate) targeted neural and non-neural tissue of the nervous system structure).

[0014] In some embodiments, application of electrical stimulation to a treatment site selectively inhibits nerve signaling through at least one of myelinated Aδ fibers and unmyelinated C fibers supplying a peripheral nerve, while preserving nerve signaling through at least one of Aβ and Aα fibers, and / or motor fibers.

[0015] In some embodiments, application of stimulation to the treatment site selectively inhibits nerve signaling through at least one of myelinated Aδ fibers and unmyelinated C fibers supplying the peripheral nerve, while preserving nerve signaling through at least one of Aβ and Aα fibers, and / or motor fibers of an adjacent nerve or adjacent nerve bundle.

[0016] In some embodiments, the controller is adjustable to vary the electrical stimulation (e.g., parameters of the electrical stimulation) based on measured feedback selected from the group consisting of measured inhibition of neural signal transmission, measured temperature (e.g., at the treatment site, at one or more electrodes or portions thereof, at the electrical stimulation device, at the patient's skin), input from the patient (e.g., related to pain sensation), feedback corresponding to at least one adjustable parameter of the electrical stimulation, treatment settings related to a time course of recovery, electrode contact impedance, electric fields generated in the tissue, the patient's physiological response (e.g., blood flow, skin conductance, heart rate, muscle activity (e.g., myoelectric potential, etc.)), and combinations thereof.

[0017] In some embodiments, the controller is configured to modify the electrical stimulation duty cycle and / or stimulation waveform envelope duration in real time to maximize the voltage delivered to the tissue without exceeding a target tissue temperature at the treatment site (e.g., adjust the stimulation duty cycle and / or stimulation envelope to maximize the voltage without exceeding a destructive tissue temperature at the treatment site).

[0018] In some embodiments, the controller is configured to modify the electrical stimulation duty cycle and / or stimulation waveform envelope duration in real time to maximize the current delivered to the tissue without exceeding the target tissue temperature at the treatment site (e.g., adjusting the stimulation duty cycle or stimulation envelope to maximize the current without exceeding destructive tissue temperatures).

[0019] In some embodiments, the controller modulates at least one parameter of the electrical stimulation to modulate (e.g., selectively inhibit and / or reversibly inhibit) neural signaling through (i) at least one of myelinated A-delta fibers and / or unmyelinated C fibers, or (ii) any of the large nerves or large ganglia or structures (e.g., cranial nerves, ganglia, autonomic nerves, plexuses, spinal cord, dorsal root ganglia, sympathetic ganglia, parasympathetic ganglia, pterygopalatine ganglion, Gasserian ganglion), where the at least one parameter is selected from the group consisting of waveform shape, waveform frequency, waveform amplitude, waveform envelope duration, electric field strength generated at the electrode (e.g., measured at the electrode or treatment site), waveform DC offset, waveform duty cycle, tissue temperature, cooling mechanism parameters (e.g., cooling rate, cooling medium flow rate, cooling medium pressure, temperature measured at the treatment site or part of the cooling mechanism), and treatment duration.

[0020] In some embodiments, the nervous system structure includes a peripheral nerve, and the control device is adjustable to apply electrical stimulation to differentially inhibit the function of myelinated A-delta fibers or nerve fibers involved in sharp / stabbing pain sensations (e.g., a greater proportion of myelinated A-delta fibers and / or nerve fibers involved in sharp / stabbing pain sensations are inhibited than unmyelinated C fibers or nerve fibers involved in dull / tingling pain sensations).

[0021] In some embodiments, the nervous system structure includes a peripheral nerve, and the control device is adjustable to apply electrical stimulation to differentially inhibit the function of unmyelinated C fibers or nerve fibers involved in dull / aching pain sensations (e.g., unmyelinated C fibers or nerve fibers involved in dull / aching pain sensations are inhibited in a greater proportion than myelinated Aδ fibers).

[0022] In some embodiments, the controller varies at least one parameter of the electrical stimulation to modulate (e.g., selectively modulate and / or reversibly modulate) neural signal transmission within a portion of the nervous system structure having a cross-section less than or equal to the complete cross-section of the nervous system structure.

[0023] In some embodiments, the controller is adjustable to vary at least one parameter of the electrical stimulation to reduce activation of the nervous system structure at the onset of an initiation response of the nervous system structure and / or inhibition of the nervous system structure.

[0024] In some embodiments, the controller is adjustable to deliver electrical stimulation to the treatment site having a frequency selected from the group consisting of about 100 kHz, about 200 kHz, about 300 kHz, about 400 kHz, about 500 kHz, about 600 kHz, 700 kHz, about 800 kHz, about 900 kHz and about 1 MHz.

[0025] In some embodiments, the electrical stimulation delivered to the treatment site has an amplitude range of between about 5 mA (e.g., peak-to-center corresponding to 10 mA peak-to-peak) and about 1.25 A (peak-to-center corresponding to 2.5 A peak-to-peak).

[0026] In some embodiments, the electrical stimulation delivered to the treatment site has an amplitude range of about 10V to about 500V (peak-to-center corresponding to 20-1000V peak-to-peak).

[0027] In some embodiments, the electrical stimulation delivered to the treatment site has a power range of about 0.1 W to about 1,250 W.

[0028] In some embodiments, the electrical stimulation delivered to the treatment site creates or induces an electric field strength at the target site and / or electrodes of between about 20 kV / m and about 2,000 kV / m.

[0029] In some embodiments, the electrical stimulation delivered to the treatment site has waveform shape components including at least one of a sinusoidal waveform, a square waveform, a triangular waveform, an impulse waveform, a shape modulated waveform, a frequency modulated waveform, an amplitude modulated waveform that provides continuous delivery of the electrical stimulation (e.g., a chirp) at the treatment site, and combinations (e.g., additional combinations) thereof (e.g., a waveform that is output continuously or a waveform that is output intermittently (e.g., pulses of a predetermined duration)) (e.g., as a charge-balanced waveform or as a non-charge-balanced waveform).

[0030] In some embodiments, the electrical stimulation delivered to the treatment site has a duty cycle of between about 0.1% and about 99%.

[0031] In some embodiments, the electrical stimulation delivered to the treatment site has an interpulse width of between about 1 ms (millisecond) and about 999 ms (milliseconds).

[0032] In some embodiments, the electrical stimulation is delivered to the treatment site for a duration of up to 30 minutes.

[0033] In some embodiments, the controller is adjustable to apply electrical stimulation while maintaining tissue temperature between about 5°C and about 60°C.

[0034] In some embodiments, the electrical stimulation device includes a device body configured for implantation within a patient's body adjacent to a treatment site (eg, percutaneously placed or implanted).

[0035] In some embodiments, the controller includes a stimulator (e.g., a function or waveform generator) (e.g., an external function or waveform generator), the stimulator coupled to both the electrodes and an interface of the controller, and operation of the stimulator directed by the controller to deliver electrical stimulation to the electrodes.

[0036] In some embodiments, the electrodes include an electrode assembly in the form of a paddle, a cuff, a cylindrical catheter or needle, a wire form, or a thin probe.

[0037] In some embodiments, one or more electrodes are sized and / or shaped to maximize and direct the electric field to nervous system structures (e.g., the surface area of ​​the electrical contacts of the electrodes is about 1 mm 2 ~ approx. 100mm 2 (That is.)

[0038] In some embodiments, the one or more electrodes include at least two electrical contacts (e.g., the at least two electrical contacts are configured to be placed near a nervous system structure during treatment) (e.g., the controller is configured to operate each of the at least two electrical contacts independently (e.g., in a multipolar manner to induce current in the resulting electric field)).

[0039] In some embodiments, each electrical contact is located on a single lead and forms a stimulation pair (eg, a cathode and an anode).

[0040] In some embodiments, each of the electrical contacts is about 1 to 50 mm in length (e.g., preferably about 1 mm to about 30 mm in length, about 2 mm to about 20 mm in length, about 2 mm to about 15 mm in length, or about 5 mm to 10 mm in length).

[0041] In some embodiments, the length of each electrical contact is the same.

[0042] In some embodiments, the length of each electrical contact is different.

[0043] In some embodiments, the at least two electrical contacts include a distal electrical contact adjacent a distal end of the electrode and a proximal electrical contact disposed along the electrode at a location between the distal electrical contact and the proximal end of the electrode, wherein the length of the distal electrical contact is greater than the length of the proximal electrical contact (e.g., the length of the distal electrical contact may be about 10 mm and the length of the proximal electrical contact may be about 4 mm).

[0044] In some embodiments, the one or more electrodes comprise an electrode assembly in the form of an elongate body, the distal end of the elongate body including a curvature such that a distal tip portion of the elongate body extends at an angle relative to the longitudinal axis of the elongate body, the angle of the distal tip portion relative to the longitudinal axis of the elongate body being between about 0 degrees and about 50 degrees (e.g., preferably between about 5 degrees and about 15 degrees).

[0045] In some embodiments, the distal tip portion of the elongate body is straight.

[0046] In some embodiments, the distal tip portion of the elongate body is curved.

[0047] In some embodiments, the electrode assembly includes at least two electrical contacts, including a distal electrical contact provided at a distal tip portion of the elongate body and a proximal electrical contact provided along the elongate body between the distal tip portion and a proximal end of the electrode assembly.

[0048] In some embodiments, the distal electrical contacts are sized and configured to interface with targeted neural and non-neural tissue of a nervous system structure, and the proximal electrical contacts are sized and configured to be placed in subcutaneous tissue (e.g., fat, fascia, muscle).

[0049] In some embodiments, each of the one or more electrodes includes at least two electrical contacts, each electrical contact disposed on the same side of the elongate body of the electrode.

[0050] In some embodiments, the conductive regions of each electrical contact are on the same side of the elongate body and do not deliver electrical energy circumferentially to a portion of the circumference of the elongate body without the electrical contacts (e.g., the electrical contacts do not deliver electrical energy circumferentially to the minor axis of the lead, thereby providing voltage-field shaping and current guidance).

[0051] In some embodiments, the system further includes a resistor disposed in electrical series with electrical contacts included in one or more of the electrodes.

[0052] In some embodiments, the electrical contacts provided on one or more electrodes are formed from a material that has a higher impedance or a high level of capacitance.

[0053] In some embodiments, the electrical contacts provided on one or more electrodes have a smoothly curved perimeter.

[0054] In some embodiments, the electrical contacts provided on one or more electrodes have an elliptical perimeter.

[0055] In some embodiments, the electrical contacts provided on one or more electrodes have a rectilinear perimeter.

[0056] In some embodiments, the system further includes a temperature measurement device (eg, thermocouple, thermistor) disposed on one or more of the electrodes to provide tissue temperature measurement.

[0057] In some embodiments, at least one of the electrical contacts and the temperature measurement device provided on one or more electrodes are printed from an electrically and thermally conductive material.

[0058] In some embodiments, electrical contacts provided on one or more electrodes extend partially around the corresponding electrode, the arc length of the electrical contacts is less than 180 degrees, and the electrical contacts extend less than halfway around the electrode.

[0059] In some embodiments, the electrodes are electrically coupled to the controller via a circumferentially shaped contact surface on the electrode and a corresponding circumferentially shaped contact surface on a lead that is electrically coupled to the controller.

[0060] In some embodiments, the circumferential contact surface includes two or more circumferential contact surfaces (e.g., four circumferential contact surfaces of varying diameters) concentrically arranged around the longitudinal axis of the electrode, and a lead electrically coupled between the electrode and the generator includes a corresponding two or more circumferential contact surfaces (e.g., four circumferential contact surfaces of varying diameters) concentrically arranged around the longitudinal axis of the lead.

[0061] In some embodiments, the circumferentially shaped contact surfaces of the electrodes are separated by a dielectric layer (e.g., an electrically insulating material and / or air provided between adjacent conductive surfaces) and the circumferentially shaped contact surfaces of the leads are separated by a dielectric layer (e.g., an electrically insulating material and / or air provided between adjacent conductive surfaces).

[0062] In some embodiments, the electrical circuit of the electrode extends within the electrode within the circumferentially shaped contact surface.

[0063] In some embodiments, at least one of the one or more electrodes is a monopolar electrode configured to be placed on the contact surface of the stimulator, and the return electrode is placed on the external surface of the patient's skin.

[0064] In some embodiments, the stimulator is reusable.

[0065] In some embodiments, the stimulator is disposable.

[0066] In some embodiments, the system further comprises a user interface (including a display (e.g., to provide an indication of the controller, the stimulator, and the patient's status)), the user interface configured to receive input from a user directing application of electrical stimulation to the treatment site (e.g., to alter pain inhibition (while preserving other sensory and motor functions, as well as proprioception)).

[0067] In some embodiments, the system further comprises a display coupled to at least one of the controller and the stimulator, the display providing an indication of a status of the stimulator.

[0068] In some embodiments, the system further comprises a temperature sensor (e.g., a thermistor, thermocouple) coupled to the stimulator for measuring a temperature of at least one of (i) the contact surface of the stimulator and (ii) the patient's tissue adjacent the contact surface or the electrode, the temperature sensor coupled to the controller and providing thermal feedback information regarding the measured temperature, and the controller is adjustable (e.g., by the controller or a user) to vary at least one parameter of the electrical stimulation in response to the thermal feedback information received from the temperature sensor (e.g., adjust the temperature of the contact surface to maintain the temperature of the patient's tissue below a destructive tissue temperature and / or maintain the temperature of the contact surface of the stimulator below a destructive tissue temperature).

[0069] In some embodiments, the system further comprises a cooling mechanism configured to provide a cooling effect to the treatment site (e.g., the contact surface of the stimulator), which cooling effect prevents damage to the treatment site (e.g., by pre-cooling or maintaining the temperature when the electrical stimulation is delivered) (e.g., by keeping the temperature of the patient's tissue below a destructive tissue temperature).

[0070] In another aspect, a method is disclosed for selectively and reversibly modulating targeted neural and non-neural tissue of nervous system structures with the application of electrical stimulation (e.g., a single application of electrical stimulation) to treat a medical condition in a patient. The method includes identifying a target nervous system structure, placing an electrical stimulation device at a treatment site proximate to target neural and non-neural tissue of the nervous system structure, the electrical stimulation device including electrodes that provide electrical stimulation to the treatment site, and delivering the electrical stimulation to the treatment site via the electrodes, wherein application of the electrical stimulation to the treatment site selectively modulates the target neural and non-neural tissue of the nervous system structure to inhibit pain and preserve other sensory and motor function, and proprioception, and application of the electrical stimulation to the treatment site selectively modulates the target neural and non-neural tissue and subsequent inhibition of pain (e.g., for a period of about 1 day to about 30 days, for a period of about 30 days to about 60 days, for a period of about 60 days to about 90 days, for a period of about 90 days to about 120 days, for a period of about 120 days to about 150 days, for a period of about 150 days to about 180 days, for a period of about 180 days to about 270 days, for a period of about 270 days to about 365 days).

[0071] In some embodiments, the nervous system structure comprises at least one of a peripheral nerve, a cranial nerve, a ganglion (e.g., the ganglion comprises at least one of a dorsal root ganglion, a sympathetic ganglion, a parasympathetic ganglion, a pterygopalatine ganglion, a gasserian ganglion, a plexus, and a spinal cord), an autonomic nerve, and an autonomic ganglion.

[0072] In some embodiments, application of electrical stimulation to the treatment site selectively modulates targeted neural and non-neural tissue, inhibiting nerve signaling through nerve fibers involved in pain transmission and nerve signaling through nerve fibers involved in other sensory and motor functions, where proprioception is preserved, and where the other sensory functions include at least one of touch, vision, hearing, taste, smell, and balance.

[0073] In some embodiments, the pain comprises at least one of acute pain, surgical pain, post-operative pain, traumatic pain, neuropathic pain, chronic pain, and head and facial pain.

[0074] In some embodiments, the pain is acute pain and the electrical stimulation is applied at least one of immediately prior to a surgical procedure, during surgery, and immediately following the surgical procedure or trauma.

[0075] In some embodiments, the electrical stimulation is delivered to the treatment site more than 24 hours prior to the surgical procedure.

[0076] In some embodiments, the pain is post-operative pain following knee arthroplasty and the electrical stimulation is applied to the femoral nerve, sciatic nerve, obturator nerve, and lateral cutaneous nerve and nerve branches, or combinations thereof.

[0077] In some embodiments where the pain is shoulder pain, electrical stimulation is applied to the brachial plexus, axillary nerve, suprascapular nerve, and lateral pectoral nerve, or combinations thereof.

[0078] In some embodiments where the pain is associated with a medical procedure and / or trauma to the arm and / or hand, electrical stimulation is applied to the medial, ulnar and radial nerves, respectively, or the brachial plexus, or combinations thereof.

[0079] In some embodiments, where the pain is associated with a medical procedure and / or trauma to the ankle and / or foot, electrical stimulation is applied to the tibial, peroneal / sural and saphenous nerves, or a combination thereof.

[0080] In some embodiments where the pain is associated with hip arthroplasty, electrical stimulation is applied to the femoral, sciatic, or obturator (e.g., the common obturator before it branches anteriorly and posteriorly) nerves and / or plexuses, or combinations thereof.

[0081] In some embodiments, where the pain is associated with anterior cruciate ligament (ACL) repair, electrical stimulation is applied to the femoral or sciatic nerve, or a combination thereof.

[0082] In some embodiments, the pain is neuropathic pain or chronic pain and the electrical stimulation is used to provide an on-demand bolus of therapeutic treatment.

[0083] In some embodiments, placing the electrical stimulation device proximate to the treatment site includes placing an electrode adjacent to the nervous system structure percutaneously through an opening in the patient's skin or implanting an electrode in the patient adjacent to the treatment site.

[0084] In some embodiments, positioning the electrical stimulator proximate to the treatment site further includes delivering an initial electrical stimulus to the treatment site via the electrodes, measuring at least one of a voltage and a current at the electrodes, and adjusting the position of the electrodes at the treatment site until the measured voltage and current correspond to a threshold voltage and threshold current, respectively.

[0085] In some embodiments, the method further includes adjusting at least one parameter of the electrical stimulation to selectively inhibit neural signal transmission through the targeted neural and non-neural tissue, the at least one parameter selected from the group consisting of waveform shape, waveform frequency, waveform amplitude, waveform envelope duration, electric field strength generated at the electrode (e.g., measured at the electrode or treatment site), waveform DC offset, waveform duty cycle, tissue temperature, cooling mechanism parameters (e.g., cooling rate, cooling medium flow rate, cooling medium pressure, temperature measured at the treatment site or part of the cooling mechanism), and treatment duration.

[0086] In some embodiments, the method further includes adjusting the duty cycle and / or waveform envelope duration of the electrical stimulation in real time to maximize the voltage delivered to the treatment site without exceeding a target tissue temperature at the treatment site (e.g., adjusting the stimulation duty cycle or stimulation envelope to maximize the voltage without exceeding a destructive tissue temperature at the treatment site).

[0087] In some embodiments, the method further includes adjusting the duty cycle and / or waveform envelope duration of the electrical stimulation in real time to maximize the current delivered to the treatment site without exceeding a target tissue temperature at the treatment site (e.g., adjusting the stimulation duty cycle or stimulation envelope to maximize the current without exceeding irreversibly destructive tissue temperatures).

[0088] In some embodiments, the method further comprises slowly titrating the stimulation amplitude of the electrical stimulation to an amplitude plateau.

[0089] In some embodiments, the method further includes adjusting the controller to vary the electrical stimulation based on measured feedback selected from the group consisting of measured inhibition of neural signal transmission, measured temperature (e.g., at the treatment site, at one or more electrodes or portions thereof, at the electrical stimulation device, at the patient's skin), input from the patient (e.g., input related to pain), feedback corresponding to at least one of the adjustable parameters, treatment settings related to a time course of recovery, electrode contact impedance, electric fields generated in the tissue, the patient's physiological response (e.g., blood flow, skin conductance, heart rate, muscle activity (e.g., myoelectric potential, etc.)), and combinations thereof.

[0090] In some embodiments, the electrodes comprise first and second electrodes operating independently, and the step of delivering the electrical stimulus to the treatment site via the electrodes further includes the steps of delivering the first electrical stimulus via the first electrode and delivering the second electrical stimulus via the second electrode, wherein the first and second electrical stimuli are output intermittently, the first electrical stimulus being interleaved with respect to the second electrical stimulus, an on cycle of the first electrical stimulus occurring during an off cycle of the second electrical stimulus, and an on cycle of the second electrical stimulus occurring during an off cycle of the first electrical stimulus.

[0091] In some embodiments, the method further includes measuring a temperature of at least one of the contact surface of the stimulator and the patient's tissue adjacent to the contact surface with a temperature sensor (e.g., a thermistor, a thermocouple) during delivery of the electrical stimulation, the temperature sensor providing thermal feedback information to the stimulator regarding the measured temperature, and adjusting the electrical stimulation (e.g., adjusting a parameter of the electrical stimulation) in response to the thermal feedback information received from the temperature sensor to create a cooling effect on at least one of the contact surface of the stimulator and the patient's tissue adjacent to the contact surface.

[0092] In some embodiments, the method further includes measuring a temperature of at least one of the contact surface of the stimulator and the patient's tissue adjacent to the contact surface with a temperature sensor (e.g., a thermistor, a thermocouple) during delivery of the electrical stimulation, where the temperature sensor provides thermal feedback information to the stimulator regarding the measured temperature; activating a cooling mechanism to cool the contact surface of the stimulator in response to the thermal feedback information received from the temperature sensor, where cooling the contact surface prevents damage to the patient's tissue when the electrical stimulation is delivered by maintaining a temperature of the patient's tissue below a destructive tissue temperature; and activating the cooling mechanism to maintain a temperature of the contact surface of the stimulator below a destructive tissue temperature in response to the thermal feedback information received from the temperature sensor regarding the measured temperature.

[0093] In another aspect, a non-transitory computer readable medium is disclosed having instructions stored thereon, the execution of the instructions by a processor causing the processor to perform any of the methods set forth above.

[0094] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0095] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0096] [Figure 1] FIG. 1 is a schematic diagram of an example of an electrical stimulation device. [Figure 2A] FIG. 2 is a schematic diagram of the electrical stimulation device of FIG. 1. [Figure 2B] FIG. 2 is a schematic diagram of the electrical stimulation device of FIG. 1. [Figure 3A] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 3B] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 3C] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 3D] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 3E] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 3F] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 3G] 1 is a schematic diagram of an exemplary percutaneous electrode. [Figure 4A] FIG. 1 is a schematic diagram of an exemplary percutaneous electrode positioned adjacent to a target nerve. [Figure 4B] 4B is a schematic cross-sectional view of the exemplary electrode of FIG. 4A. [Diagram 5] 1A-1D are various examples of bipolar electrical contact and electrode configurations. [Figure 6A] 1 is an exemplary electrode connection. [Figure 6B] 1 is an exemplary electrode connection. [Figure 7A] 1 is an example of electrical stimuli and corresponding control parameters that can be applied to nerves and / or nearby tissue to selectively and / or reversibly inhibit nervous system activity. [Figure 7B] The waveform shape of the electrical stimulation is shown. [Figure 7C] The waveform shape of the electrical stimulation is shown. [Figure 7D] The waveform shape of the electrical stimulation is shown. [Figure 7E] The waveform shape of the electrical stimulation is shown. [Figure 7F] The waveform shape of the electrical stimulation is shown. [Figure 7G] The waveform shape of the electrical stimulation is shown. [Figure 7H] The waveform shape of the electrical stimulation is shown. [Figure 7I] The waveform shape of the electrical stimulation is shown. [Figure 7J] The waveform shape of the electrical stimulation is shown. [Figure 7K] The waveform shape of the electrical stimulation is shown. [Figure 7L] The waveform shape of the electrical stimulation is shown. [Figure 7M] The waveform shape of the electrical stimulation is shown. [Figure 7N] The waveform shape of the electrical stimulation is shown. [Figure 7O] The waveform shape of the electrical stimulation is shown. [Figure 7P] The waveform shape of the electrical stimulation is shown. [Figure 8] FIG. 1 is a schematic diagram of percutaneous placement of electrodes to deliver electrical stimulation to a target neural structure. [Figure 9A] FIG. 1 is a schematic diagram of electrode placement and delivery of electrical stimulation to the pterygopalatine ganglion. [Figure 9B] FIG. 1 is a schematic diagram of electrode placement and delivery of electrical stimulation to the pterygopalatine ganglion. [Figure 10] 1 is a table verifying the experimental results. [Figure 11] 1 is a table verifying the experimental results.

[0097] Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0098] definition

[0099] The following description of specific examples of the inventive concept should not be used to limit the scope of the claims. Other examples, features, aspects, embodiments, and advantages will become apparent to those skilled in the art from the following description. As will be appreciated, the apparatus and / or method are capable of other different and obvious aspects, all without departing from the spirit of the inventive concept. Accordingly, the drawings and description should be regarded as illustrative in nature and not restrictive.

[0100] For purposes of this description, certain aspects, advantages, and novel features of the disclosed embodiments are described herein. The described methods, systems, and devices should not be construed as limiting in any way. Instead, the disclosure is directed to all novel and non-obvious features and aspects of the various disclosed embodiments, both alone and in various combinations and subcombinations with one another. The disclosed methods, systems, and devices are not limited to any particular aspects, features, or combinations thereof, and the disclosed methods, systems, and devices are not required for any one or more particular advantages to exist or problems to be solved.

[0101] It should be understood that features, integers, properties, compounds, chemical moieties, or groups described in connection with a particular aspect, embodiment, or example of the invention are applicable to other aspects, embodiments, or examples described herein, unless inconsistent therewith. All features disclosed herein (including the accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel, or any novel combination of features disclosed herein (including the accompanying claims, abstract, and drawings), or any novel, or any novel combination of steps of any method or process so disclosed.

[0102] It is understood that all or part of a patent, publication, or other disclosure material that is said to be incorporated herein by reference is incorporated herein only to the extent that the incorporated material does not conflict with existing definitions, descriptions, or other disclosure material set forth in this disclosure. Thus, to the extent necessary, the disclosure expressly set forth herein supersedes any conflicting material incorporated herein by reference. Any material or portion thereof that is said to be incorporated herein by reference but that conflicts with existing definitions, descriptions, or other disclosure material set forth herein is incorporated only to the extent that no conflict arises between the incorporated material and the existing disclosure material.

[0103] As used in the description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges can be expressed herein as from one particular value using "about," and / or to another particular value using "about." When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint.

[0104] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur, and the description includes instances when the event or circumstance occurs and instances when it does not occur.

[0105] The terms "proximal" and "distal" are used herein as relative terms referring to a region of a nerve, a location of a nerve, or an area of ​​a stimulator. "Proximal" means a location closer to the spinal cord, brain, or central nervous system, and "distal" means a location further from the spinal cord, brain, or central nervous system. When referring to the location of a nerve structure along the peripheral nervous system or appendages, proximal and distal refer to a location closer to or further from the central nervous system along the path followed by that nerve structure or appendage. When referring to the location of a nerve structure in the spinal cord, proximal and distal refer to a location closer to or further from the brain along the path followed by the nerve structure.

[0106] Throughout the description and claims of this specification, variations of the terms "comprise" and "comprising" and "comprises" are intended to be non-limiting and not to exclude, for example, other addenda, components, integers or steps. "Exemplary" and "for example" mean "an example of" and are not intended to convey an indication of a preferred or ideal aspect. "Etc." is used for descriptive purposes, not limiting.

[0107] As used herein, the term "nervous structure" or "neural structure" refers to a structure that includes neural tissue and non-neural tissue. In addition to neural tissue (such as neurons and components of neurons including their axons, cell bodies, dendrites, and synapses), a neural structure may also include non-neural tissue such as glial cells, Schwann cells, myelin, immune cells, connective tissue, epithelial cells, neuroglial cells, astrocytes, microglia, ependymal cells, oligodendrocytes, satellite cells, cardiovascular cells, and blood cells.

[0108] As used herein, the term "stimulating electrode" refers to the electrode, also called the "cathode" in the case of monopolar stimulation, that serves to deliver therapeutic energy to a nerve. In the case of bipolar or multipolar stimulation, all electrical contacts are considered to be stimulating electrodes.

[0109] As used herein, a "return electrode," also referred to as an "anode" in the case of monopolar stimulation, refers to an electrode that serves to provide a return path for electrical current through the body. For example, the return electrode provides a return path for electrical current delivered through a stimulation electrode to a target neural structure.

[0110] As used herein, "electrical signal," "electric signal," "electrical stimulation," "stimulation electric signal," "stimulation electrical signal," and "stimulation waveform" refer to an electrical signal delivered by a controller to tissue by a stimulation electrode, or, in the case of monopolar stimulation, by a stimulation electrode and a return electrode. For example, an electrical signal may be described as a time-varying voltage, current, power, or other electrical measure. The delivery of an electrical signal to a target tissue is referred to as electrical treatment, electrical therapy, or simply treatment or therapy. The electrical signal generates an electric field in the tissue, and control of the electrical signal strongly influences control of the electric field in the tissue.

[0111] As used herein, "treatment site" refers to the site on neural and non-neural structures to which electrical signals are delivered by electrodes.

[0112] As used herein, "modulate" refers to modifying or changing the transmission of information. For example, this includes both excitation, pacing, and inhibition / interruption of the passage of stimuli along the axons of neurons in a nerve. Modulation of nerve fiber activity includes inhibition of nerve signal transmission to the point of producing a blocking effect, including partial and complete blocking effects. Modulation of neural activity also includes modifying the transport of molecules, such as macromolecules, along nerve fibers. Modulation of neural activity also includes changing downstream functions of neurons (e.g., at the cell body or synapse), modifying signaling in a way that modifies the signaling of other neurons (e.g., neurons in the central nervous system, such as the spinal cord or brain), modifying the function of non-neural tissues within a neural structure, or modifying the process, function, or activity of a target neural or non-neural tissue.

[0113] As used herein, the terms "inhibit" and "attenuate" refer to any level of reduction, including a partial or complete reduction in neural signal activity through a neural structure, e.g., a reduction in the passage of impulses along the axons of neurons in a nerve.

[0114] As used herein, "percutaneous" refers to electrical stimulation applied with the aid of one or more electrodes that penetrate the surface of the skin, where the electrodes that deliver the electrical stimulation to the target nerves beneath the skin are also located beneath the skin. For percutaneous electrical stimulation, the return electrode or anode may be placed beneath the skin or on the surface of the skin. The term "percutaneous electrode" refers to an electrode assembly that is inserted through the skin and directed near (mm to cm distance) a nerve in a minimally invasive manner to electrically affect the physiology of the nerve structure.

[0115] As used herein, the term "pain sensation" or "painful sensation" refers to an unpleasant sensation, for example, generated by the activation of sensory nociceptors. Nociception refers to the perception of acute pain, and is generally caused by the activation of sensory nociceptors or the disruption of nociceptor pathways (e.g., cut neurons or destruction of nociceptors). Chronic pain sensations can also be generated by the activation of nerve fibers, resulting in unpleasant sensations similar to those generated by the activation of nociceptors (e.g., neuropathic pain). In some cases, such as after surgery aimed at treating chronic pain, both acute and chronic pain can contribute in a mixed way to the overall pain sensation.

[0116] As used herein, the term "target nerve" is synonymous with "neural structure" or "nervous structure" and refers to, for example, a mixed nerve that includes motor and sensory nerve fibers. It may also refer to a sensory nerve that includes only sensory nerve fibers and / or a motor nerve that includes only motor nerve fibers.

[0117] As used herein, the term "transmucosal" refers to electrical stimulation applied to mucosal tissue overlying a target neural structure using one or more electrodes. The electrical stimulation passes through the mucosal tissue to reach the target neural structure.

[0118] As used herein, the term "preserve" or "preserving" refers to cases where neurological functions are partially but not completely preserved, and cases where functions are completely preserved. In a comparative case, one function may be inhibited while another function is preserved, which implies that in a comparative sense, the magnitude of the decrease in the inhibited function is greater than the magnitude of the decrease in the preserved function. Specifically, in a comparative case, the inhibition of one function and the preservation of another function does not require the complete preservation or complete inhibition of either or both functions.

[0119] Anatomy and Physiology

[0120] As provided above and described in more detail below, the present invention relates to devices and methods for selectively and reversibly modulating targeted neural and non-neural tissues of neural structures by application of electrical signals to inhibit pain while preserving other sensory and motor functions, as well as proprioception. The devices and methods can be used to treat acute pain (such as surgical pain, post-operative pain, traumatic pain), neuropathic pain, chronic pain, and head and face pain (migraine, cluster headache, occipital neuralgia, tension headache, sinus headache, post-traumatic headache, post-herpetic neuralgia, post-traumatic pain, chronic daily headache (transformative migraine)) by applying electrical signals to targeted neural and non-neural tissues of neural structures to modulate or inhibit neural signaling.

[0121] Pain is a noxious perception that arises in consciousness. In healthy individuals, the perception of pain is generated by activation of sensory nociceptors and subsequent nociceptive signaling along one or more neural pathways to the brain. Pain arises from activation of a neural pathway, resulting in the perception of pain at any point along that neural pathway. In healthy individuals, pain-causing neural pathways are generally activated via sensory nociceptors, which are sensory nerve endings tuned to detect and signal noxious events (such as harmful mechanical or thermal damage to tissue). This type of pain generally represents a truly noxious condition, and this type of pain subsides when the noxious condition is resolved. If the noxious event is not a chronic tissue dysfunction, this type of pain is referred to as acute pain. In contrast, chronic pain represents a condition in which chronic tissue or nerve dysfunction causes persistent modulation of the pain-causing neural pathway. This may occur at any point along the pain-causing neural pathway due to true activation of sensory nociceptors at the site of chronic dysfunctional tissue, or due to dysfunction of nerve tissue or tissue supporting the nerve tissue.

[0122] Interventions for treating pain can be designed to directly or indirectly modulate neural signal transmission through pain-causing neural pathways at any level along these pathways. For example, direct blockage of axonal conduction of nerve fibers attached to sensory nociceptors can block the perception of pain. As a further example, indirect modulation of synaptic transmission in the spinal cord or ganglion can be achieved by activating or blocking other inputs to the spinal cord or ganglion, resulting in modulation along pain-causing neural pathways. As another example, inhibition of parasympathetic outflow in the pterygopalatine ganglion indirectly affects head and face pain, such as migraine, by modulating sensory input to the brain (e.g., via the superior salivary nucleus). Thus, it is desirable to target various neural structures when modulating and treating acute and chronic pain.

[0123] The nerve structures of interest include peripheral nerves (small and large), cranial nerves, ganglia, autonomic nerves, plexuses, and spinal cord. Ganglia generally include at least one of dorsal root ganglia, sympathetic ganglia, parasympathetic ganglia, pterygopalatine ganglia, gasserian ganglia, and autonomic ganglia. Generally, large peripheral nerves are peripheral nerves with a diameter of more than about 2.5 mm. Examples of large peripheral nerves include, for example, femoral nerve, sciatic nerve, vagus nerve, tibial nerve, peroneal nerve, median nerve, radial nerve, and ulnar nerve. Examples of small peripheral nerves include, for example, saphenous nerve, sural nerve, geniculate nerve, cranial nerve (such as trigeminal nerve and occipital nerve), obturator nerve, and distal parts of larger nerves (such as vagus nerve, tibial nerve, peroneal nerve, median nerve, radial nerve, and ulnar nerve). Target ganglia include dorsal root ganglia, sympathetic ganglia, parasympathetic ganglia, pterygopalatine ganglion (SPG), gasserian ganglion, nerve plexus, and spinal cord. Each of these neural structures includes neural tissue and non-neural tissue that supports the neural tissue and influences the transmission of information along the neural pathways that cause pain. Examples of non-neural tissue may include, for example, glial cells, Schwann cells, myelin, immune cells, connective tissue, epithelial cells, glial cells, astrocytes, microglia, ependymal cells, oligodendrocytes, satellite cells, cardiovascular cells, and blood cells. Neural tissue generally refers to neurons, including components such as axons, cell bodies, dendrites, receptor terminals, receptors, and synapses.

[0124] Importantly, in the context of the present invention, modulation of neural tissue (neurons including components such as axons, cell bodies, dendrites, receptor terminals, receptors, synapses, etc.) and / or non-neural tissue (glial cells, Schwann cells, myelin, immune cells, connective tissue, neuroglial cells, astrocytes, microglia, ependymal cells, oligodendrocytes, satellite cells, cardiovascular cells, blood cells, etc.) may be responsible in part or in whole for the therapeutic inhibition of pain perception.

[0125] While peripheral nerves are primarily composed of axons, other neural structures, such as ganglia and spinal cords, contain many components, including axons, cell bodies, dendrites, and synapses. Within neural structures, there is variation in the properties of these components, including, for example, variation in size, shape, and interfaces with supporting non-neural tissues. For example, peripheral nerves often contain both large and small diameter axons. Schwann cells are non-neuronal supporting cells that surround some axons and provide an insulating covering rich in a layer of lipid bilayers called the myelin sheath. Some axons are surrounded by myelin sheaths and some are not. In general, the structure of various neural components is related to their function. For example, large diameter axons typically transmit nerve signals faster than small diameter axons because of a relatively large increase in axon conductance for a small increase in membrane conductance as a function of diameter. Similarly, the presence of myelin sheaths on large diameter axons further increases the conduction velocity of action potentials by increasing the resistance to transmembrane currents between unmyelinated regions of the axon, called nodes of Ranvier. Nodes of Ranvier are short, unmyelinated sections of the fiber, and action potentials are relayed along the axon by bursts of transmembrane current at each successive node of Ranvier. Peripheral nerve axons that generally transmit information from the periphery to the central nervous system (e.g., sensory information, including pain) are often called afferent fibers, while axons that generally transmit information from the central nervous system to the periphery (e.g., motor information) are often called efferent fibers.

[0126] The term "fiber" as used herein refers to a myelinated afferent or efferent peripheral axon of the somatic nervous system. Generally, A-fibers are associated with proprioception, somatic motor function, touch and pressure sensation, as well as pain and temperature sensation. Fibers generally have a diameter of about 1-22 micrometers (μm) and a conduction velocity of about 2 meters per second (m / s) to over 100 m / s. Each A-fiber has dedicated Schwann cells that form a myelin sheath around the fiber. As mentioned above, the myelin sheath is rich in lipids, which increases the electrical resistance to transmembrane currents and contributes to the high conduction velocity of action potentials along the nerve fiber. Fibers include alpha, beta, delta, and gamma A-fibers. Alpha, beta, and gamma A-fibers have a diameter of 5-20 micrometers (μm) and are associated with motor function, low-threshold sensory function, and proprioception, but not pain. Delta A-fibers are associated with pain and have a small diameter in the range of 1-5 microns (μm).

[0127] As used herein, the term "C fibers" refers to unmyelinated peripheral axons of the somatic nervous system that have a conduction velocity of less than about 2 m / s. C fibers are approximately 0.2-1.5 micrometers (μm) in diameter, include dorsal root and sympathetic fibers, and are primarily associated with sensations such as pain and temperature, some limited mechanoreception, reflex responses, autonomic effector activity, and visceral function.

[0128] In peripheral nerves, dull and persistent pain sensations are often called "slow pain" and are transmitted to peripheral nerves by C fibers, which transmit nerve signals relatively slowly. Sharp and rapidly perceived pain sensations are often called "fast pain" and are transmitted to peripheral nerves by A-delta fibers, which have a higher conduction velocity than C fibers. A-delta fibers generally contain small diameter sensory axons that are lightly myelinated compared to unmyelinated C fibers. Acute and chronic pain involve both A-delta and C fibers.

[0129] In addition to the example given for peripheral nerve axons above, similar principles of structure and function of components of neural structures such as axons, cell bodies, dendrites, receptor terminals, receptors, synapses, etc., apply to different neural structures including peripheral nerves, cranial nerves, ganglia and autonomic nerves, nerve plexuses, and spinal cord. Subcellular structures within components of non-neural and neural tissues, such as cell membranes, lipid bilayers, ion channels, mitochondria, microtubules, nuclei, vacuoles, and other components of the cytoplasm, are also relevant to the function of such components of neural structures. Furthermore, downstream structures (e.g., cells and subcellular structures downstream of the treatment site) may also be functionally and structurally affected, either primarily or secondarily, by neural treatment (e.g., downstream modulation of gene transcription, synaptic transmission, epigenetics, or modulation along any of the many molecular signaling cascades within neurons). Downstream molecular and cellular mechanisms, and even connectivity and communication between cells, may be significantly different between pain pathways and motor, non-pain sensory, and proprioceptive pathways.

[0130] As another example, the pterygopalatine ganglion is composed of parasympathetic, sympathetic, and sensory neurons. Within the sympathetic ganglion, parasympathetic neurons have cell bodies and synapses, but sympathetic or sensory neurons do not. Rather, only the axons of sympathetic and sensory neurons pass through the pterygopalatine ganglion. The present devices and methods can be used to selectively and / or reversibly modulate neural signal transmission in one of the neural structure types (e.g., cell bodies, synapses, axons), but not other neural structures present in the ganglion. For example, modulation or inhibition of transmission through the parasympathetic pathway can be achieved while maintaining signaling through the sympathetic pathway and at least some sensory pathways, e.g., by inhibiting transmission of signals through the cell bodies or synapses of the pterygopalatine ganglion. As an additional example, modulation or inhibition of transmission through small sensory neurons can be achieved while maintaining signaling through sympathetic, parasympathetic, and other sensory fiber pathways. As another example, modulation of the parasympathetic pathway and small sensory pathways can be achieved while maintaining signaling through all other pathways in the ganglion. In particular, each type of neural component within a neural structure may have its own supporting non-neural tissue that contributes to the ability for selective target modulation via specific pathways.

[0131] As described in more detail below, the device and method can be used to selectively and reversibly modulate nerve signal transmission to inhibit pain, for example by inhibiting or blocking nerve signal transmission. This selective and reversible inhibition of pain does not pose the risk of neurotoxicity, vascular toxicity, or allergy to injected chemicals. The device does not destroy the target nerve structures, is suitable for treating chronic pain indications without the risk of atrophy, neuropathy, and pain, and the nerves are well matched to acute pain indications before, during, or immediately after treatment, so that the patient can go home without the device and still experience pain relief for a day to several weeks after surgery, such as after joint replacement or other orthopedic procedures. In other words, there is no need for devices that require long-term direct contact with the target area or nerve to be treated (e.g., via implantable generators and nerve cuffs). However, the device can still be implanted or partially implanted and / or taken home with the patient, if necessary, especially for chronic pain indications.

[0132] Sample Equipment

[0133] FIG. 1 provides a schematic diagram of an exemplary stimulator 100 (electrical stimulator). The stimulator 100 can be used to selectively and reversibly modulate target neural and non-neural tissues of a neural structure by application of an electrical signal to treat a medical condition in a patient. The stimulator 100 includes an electrode 120 that delivers electrical stimulation to a treatment site, e.g., to target neural and non-neural tissues of a neural structure. Electrical stimulation can be delivered by a lead (L) and electrode 120 placed percutaneously, by an implanted lead (L) and electrode 120, or by an electrode 120 advanced through a body orifice and placed adjacent (e.g., near or in contact with) mucosal tissues overlying the target neural structure (e.g., pterygopalatine ganglion, Gasserian ganglion). Examples of mucosal tissues include oral mucosa, nasal mucosa, gastrointestinal (GI) tract mucosa, intestinal mucosa, and bladder mucosa. The electrode 120 generates an electric field at the treatment site, resulting in selective and reversible modulation of nerve fiber activity and suppression of pain. As noted above, "modulation" of nerve fiber activity includes both excitation and inhibition / interruption of the passage of impulses along the axons of neurons within the nerve, including inhibition of nerve signal transmission to the point of producing a blocking effect.

[0134] The delivery of the electrical signal stimulation includes interaction with other nearby tissues. For example, in the case of percutaneous application and localization of the electrode, the electrical signal stimulation is delivered via the electrode 120 navigated through the patient's external tissues, including skin, fat, bone and muscle, to provide for placement of the electrode 120 in close proximity to the target neural structure. In this example, the electrical stimulation affects not only the target neural structure, but also surrounding tissues, such as connective tissue, supporting tissue of the neural structure, fat, bone, muscle, and cardiovascular tissue and cells, such as those present in and around blood vessels. In the case of transmucosal application, the electrical signal stimulation is delivered via the electrode 120 positioned adjacent (e.g., near or in contact with) the overlying mucosal tissue. The electrical stimulation may affect the target neural structures, as well as tissues beneath and surrounding the electrode 120, tissues interposed between the electrode 120 and the target neural structures, and other surrounding tissues (such as skin, fat, muscle, bone, cartilage, connective tissue, supporting tissues of the neural structures, cardiovascular tissues and cells such as those present in and around blood vessels, and other tissues present in the epidermis, dermis, and neural receptors, hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels). In both transdermal and transnasal applications, application of electrical stimulation to the treatment site modulates (e.g., selectively and / or reversibly) the targeted neural and non-neural tissues of the nervous system structures to inhibit the perception of pain, while the electrical stimulation and stimulation device 100 is designed to avoid damage to the nervous system structures and / or surrounding tissues (e.g., overlying mucosal tissue).

[0135] As shown diagrammatically in FIG. 1, the stimulator 100 and electrodes 120 / leads L may be reusable or disposable. Desirably, the neural structures may be conditioned via disposable leads L and electrodes 120 and driven by a reusable external stimulator / signal generator 140 and controller 130. It is contemplated that the stimulator 100 may be sized and configured for implantation in its entirety within a patient (under the patient's skin (S)) adjacent a target neural structure (N) as diagrammatically shown in FIG. 2A. A power source 180 that provides electrical energy to the controller 130 / signal generator 140 may be located internal or external to the patient. It is also contemplated that only the leads / electrodes 120 are implanted within the patient, with the remaining components including the signal generator 140 and controller 130 being embodied in a handheld device that can be easily manipulated to provide therapy, as shown diagrammatically in FIG. 2B. It is further contemplated that the stimulation device 100, including the signal generator 140, controller 130 and leads / electrodes 120, can be implemented in a larger, non-handheld device designed to remain on a stationary surface or on a mobile cart that can be moved between rooms in a clinic, with only the electrodes 120 / leads (L) being advanced percutaneously through an opening in the patient's skin or other orifice in the patient's body (e.g., via the nasal cavity).

[0136] The stimulation device 100 can be used to reversibly and / or selectively inhibit pain while preserving other sensory functions. In particular, the electrical stimulation provided by the stimulation device 100 can reversibly and / or selectively modulate nerve signal transmission through nerve fibers involved in pain transmission while preserving nerve signal transmission through nerve fibers involved in other sensory and motor functions, as well as proprioception.

[0137] With regard to the reversibility of the modulated neural function, the stimulator 100 can reversibly inhibit pain by inhibiting or blocking neural signal transmission for, for example, about 1 day to about 30 days. Preferably, pain perception is inhibited for about 5 days to about 30 days. For chronic pain, pain perception is inhibited for about 90 days to about 356 days. Reversibility of neural signal transmission and restoration of function after an appropriate period of time after treatment is important, especially for acute pain after surgery. Parameters of the stimulation waveform can be adjusted to adjust the expected duration of pain inhibition so that pain inhibition does not last longer than necessary. For example, in patients undergoing knee replacement surgery, it is important that pain perception returns 15 to 30 days after surgery, since acute pain sensation is an important protective signal that helps regulate the patient's physical activity during recovery.

[0138] With regard to the selection of modulated neural functions, the stimulation device 100 can inhibit the perception of pain and selectively modulate neural and non-neural tissue to preserve other sensory and motor functions and proprioception. This creates a scenario in which the electrical neuromodulation treatment is selective for a subset of neural structure functions while preserving other functions of the neural structures. The perception of pain is inhibited, but other sensory and motor functions and proprioception are preserved. For example, the electrical signal disrupts the transmission of pain signals originating from the periphery and reaching the brain by inhibiting neural signal transmission through nerve fibers involved in pain transmission. This can include direct inhibition of pain signal transmission in neurons of the targeted neural structures or can be achieved by indirect inhibition of other downstream neurons involved in pain signal transmission to the brain, such as neurons in the central nervous system (e.g., spinal cord and brain).

[0139] Preserved sensory functions include, for example, non-painful touch (low threshold sensory functions), vision, hearing, taste, smell, and balance. It is also believed that the disclosed electrical signals can modulate neural signaling through nerve fibers involved in thermoreception, autonomic activity, and transmission of visceral functions.

[0140] Selective modulation of pain perception is particularly useful when it is desirable to apply modulation to mixed nerve structures, such as peripheral nerves that contain motor and sensory axons. For example, in many surgical interventions, it is desirable to modulate pain transmitted through mixed nerves to treat acute surgical pain while preserving the motor and sensory and proprioceptive functions of the nerve. Preserving motor and sensory function as well as proprioceptive function while treating pain is particularly important when physical therapy or other movements of the appendages must be performed during recovery from surgery. For example, many postoperative care programs include procedures to help patients avoid muscle atrophy and other functional stagnation following a surgical procedure. Preserving motor control and sensory and proprioceptive function while treating pain can make such programs possible and enhanced.

[0141] As described in more detail below, one or more parameters of the electrical stimulation can be adjusted to selectively block neural signal transmission through selected regions of selected types of nerve fibers and / or nerve structures. Adjustable parameters of the electrical stimulation include, for example, waveform shape, waveform frequency, waveform amplitude, electric field strength generated at the electrode 120 (e.g., measured at the electrode or treatment site), waveform DC offset, waveform duty cycle (e.g., continuous and / or intermittent delivery through the electrode), tissue temperature, cooling mechanism parameters (e.g., cooling rate, flow rate of cooling medium, cooling medium pressure, temperature measured at the treatment site or part of the cooling mechanism), and treatment duration. As described in more detail below, these parameters are adjustable and controllable by the controller 130, the user interface 170, and a cooling mechanism that may be incorporated into the stimulation device 100.

[0142] For example, when the target nerve structure is a peripheral nerve, e.g., a large peripheral nerve, such as one having a diameter greater than about 2.5 mm, the electrical stimulation can inhibit nerve signaling through myelinated Aδ fibers and / or unmyelinated C fibers in the peripheral nerve, and the electrical stimulation maintains nerve signaling through at least one of Aβ and Aα fibers, and / or motor fibers. It is contemplated that at least one parameter of the electrical stimulation can be adjusted to selectively inhibit myelinated Aδ fibers and / or unmyelinated C fibers, while maintaining nerve signaling through at least one of Aβ and Aα fibers and / or motor fibers.

[0143] In another example, electrical stimulation can inhibit nerve signal transmission through myelinated Aδ fibers and / or unmyelinated C fibers in the target peripheral nerve, and electrical stimulation maintains nerve signal transmission through at least one of Aβ and Aα fibers, and / or motor fibers in adjacent nerves or nerve bundles. By selectively blocking pain sensation, the acuity of pain sensation can be reduced to prevent effects on other large motor fibers while allowing nerve signal transmission through selected nerve fibers of adjacent nerves and / or nerve bundles.

[0144] In another example, a target nerve structure, e.g., the gasserian ganglion, the pterygopalatine ganglion (SPG), is covered with a layer of mucosal tissue. Electrical stimulation is delivered through the mucosal tissue to modulate the nerve unitary transmission through certain types of nerve fibers of the underlying nerve structure and adjacent non-nerve tissue. For example, types of nerve fibers including parasympathetic fibers, sympathetic fibers, and sensory nerve fibers. For example, if the target nerve structure includes the pterygopalatine ganglion (SPG), electrical stimulation selectively inhibits nerve signal transmission through parasympathetic nerve fibers including the SPG, sympathetic nerve fibers including the SPG, and / or sensory nerve fibers including the SPG. It is believed that this nerve signal transmission can be inhibited while selectively maintaining at least one function of non-selected types of nerve fibers (e.g., parasympathetic, sympathetic, and sensory nerve fibers including the SPG).

[0145] Further, at least one parameter of the electrical stimulation can be adjusted to differentially inhibit the function of myelinated Aδ fibers, which are inhibited to a greater extent than the unmyelinated C fibers. Nerve signaling through myelinated Aδ is generally associated with fast, sharp / stabbing pain sensations, and nerve signaling through unmyelinated C fibers is generally associated with dull / tingling pain sensations. Thus, the electrical stimulation can be adjusted to differentially inhibit the function of nerve fibers involved in sharp pain sensations, which are inhibited to a greater extent than the nerve fibers involved in dull / tingling pain sensations.

[0146] Similarly, at least one parameter of the electrical stimulation can be adjusted to differentially inhibit the function of unmyelinated C fibers, which are inhibited to a greater extent than myelinated Aδ fibers, i.e., the electrical stimulation can thus be adjusted to differentially inhibit the function of nerve fibers involved in dull / tingling pain sensations, which are inhibited to a greater extent than nerve fibers involved in fast, sharp / stabbing pain sensations.

[0147] In another example, in target nerve structures covered with a layer of mucosal tissue, such as the Gasserian or pterygopalatine ganglion (SPG), electrical stimulation can be tailored to differentially inhibit the function of parasympathetic, sympathetic, and / or sensory nerve fibers of the ganglion. For example, electrical stimulation delivered to a target site can differentially inhibit the function of parasympathetic nerve fibers of the SPG, where the parasympathetic fibers are inhibited in a greater proportion of fibers than non-parasympathetic fibers and non-nerve tissue. Similarly, for example, electrical stimulation delivered to a target site can differentially inhibit the function of sympathetic nerve fibers of the SPG, where the sympathetic fibers are inhibited in a greater proportion of fibers than non-sympathetic fibers and non-nerve tissue. Similarly, electrical stimulation delivered to a treatment site can differentially inhibit the function of sensory nerve fibers of the SPG, where the sensory nerve fibers are inhibited in a greater proportion of fibers than parasympathetic, sympathetic, and non-nerve tissue.

[0148] An additional mechanism of suppression of pain perception is when the suppression effect is downstream or secondary to the treatment site. For example, when the target nerve structure is a large peripheral nerve, such as a nerve with a diameter of more than about 2.5 mm, electrical stimulation can modulate the activity or function of nerve tissue or non-nerve tissue, resulting in a biochemical signaling cascade that reduces the activation of spinal cord or cortical neurons that represent pain (e.g., via modulation of synaptic signaling), while maintaining neural signaling through central and peripheral nervous system neurons involved in detection, transmission, processing and generation of non-painful touch, motor control, and proprioception. In this case, at least one parameter of electrical stimulation can be adjusted to selectively suppress downstream or secondary effects of pain originating from Aδ fibers and / or unmyelinated C fibers, while maintaining the function of central and peripheral nervous system neurons involved in detection, transmission, processing and generation of non-painful touch, motor control, and proprioception.

[0149] In this case, it is further believed that at least one parameter of the electrical stimulation can be adjusted to differentially inhibit downstream or secondary effects of pain originating from myelinated A-delta fibers, which are inhibited to a greater extent than downstream or secondary effects of unmyelinated C-fibers. Similarly, it is further believed that in this case, at least one parameter of the electrical stimulation can be adjusted to differentially inhibit downstream or secondary effects of pain originating from unmyelinated C-fibers, which are inhibited to a greater extent than downstream or secondary effects of myelinated A-delta fibers.

[0150] Examples of electrical stimulation

[0151] As described above, the electrode 120 provides electrical signals to the treatment site to selectively modulate neural and non-neural tissue to inhibit the perception of pain and preserve other sensory and motor functions as well as proprioception. The electrical signals disrupt the transmission of pain signals by modulating both neural and non-neural tissue. As outlined below, various parameters of the electrical signal can be adjusted to modulate function through neural structures, including, for example, stimulation pulse waveform shape (also referred to herein simply as "waveform shape"), stimulation pulse waveform frequency (also referred to herein simply as "frequency"), stimulation pulse amplitude (also referred to herein simply as "amplitude"), electric field strength generated at the electrode 120, stimulation pulse waveform DC offset, waveform duty cycle (e.g., continuous delivery via the electrode and / or intermittent delivery), tissue temperature, cooling mechanism parameters, and treatment duration. It is believed that some parameters can be adjusted individually to produce a desired effect, while other parameters can be adjusted in combination with the interdependence of the effect on each parameter adjustment to produce a desired effect. As described above and in more detail below, various parameters and / or combinations of parameters of the electrical signal are modulated to selectively and reversibly regulate neural signal transmission through selected regions of selected types of nerve fibers and / or nerve structures.

[0152] To facilitate selective and / or reversible inhibition of nervous system activity (e.g., to block acute pain), stimulators and systems are configured in some embodiments to apply high frequency stimulation directly to nerves and / or nearby tissues, eliciting a sufficient pain inhibitory response by the nervous system. High frequency stimulation may be applied in pulses in a manner that avoids damage to nearby tissues and nervous tissues during the course of a single treatment / application. It has been observed that high frequency stimulation applied at 500 kHz (and temperatures up to 42° C.) in a series of 20 millisecond pulses for several minutes at up to 100 V can be applied and elicit a sufficient pain inhibitory response that can selectively disrupt acute pain sensations, but does not affect other neural functions such as motor control. It has also been observed that the same high frequency stimulation can be applied to elicit a reversible pain inhibitory response, in that pain is blocked for a clinically relevant period that can last from 1 day to 30 days. Without wishing to be bound by a particular theory, it can be hypothesized that the selective and reversible effect may be due to the particularly high voltage field applied to the tissue without causing thermal damage to the treatment site, particularly the nerves.

[0153] FIG. 7A illustrates exemplary electrical stimulation and corresponding control parameters that can be applied to a nerve and / or nearby tissue to selectively and / or reversibly inhibit nervous system activity, according to an exemplary embodiment. As shown in FIG. 7A, the electrical stimulation can be defined by control parameters such as amplitude, pulse duty cycle (including, for example, pulse envelope duration and inter-envelope interval), stimulation waveform shape, and waveform frequency. In addition to a stimulation frequency of 500 kHz, other stimulation frequency ranges can be applied. In some embodiments, the stimulation device and system are configured to apply electrical stimulation having a stimulation frequency selected from the group consisting of about 100 kHz, about 150 kHz, about 200 kHz, about 250 kHz, about 300 kHz, about 350 kHz, about 400 kHz, about 450 kHz, about 500 kHz, about 550 kHz, about 600 kHz, about 650 kHz, about 700 kHz, about 800 kHz, about 850 kHz, about 900 kHz, about 950 kHz, and about 1 MHz. The application of electrical stimuli having a pulse duty cycle allows for higher voltage or current output amplitudes and / or higher frequencies (allowing for the generation of higher voltage fields at the treatment site) without causing thermal damage in the tissue. The application of electrical stimuli having non-sinusoidal waveforms can be used to tailor the energy density applied in a given electrical stimulus and / or allow for the application of higher electric fields.

[0154] 7B, 7C, 7D, 7E, 7F, 7G, 7H, 7I, 7J, 7K, 7L, 7M, 7N, 7O, and 7P each show an electrical stimulation waveform shape according to an exemplary embodiment. As shown in Figures 7B-7F, in some embodiments, the stimulation waveform is a sinusoidal waveform (Figures 7B, 7G), a triangular waveform (Figure 7C), a square or rectangular waveform (Figure 7D), a triangular sawtooth waveform (Figure 7E), or a complex waveform (Figure 7F).

[0155] In some embodiments, the frequency of a given pulse is varied (e.g., as a chirp as shown in FIGS. 7K, 7L, and 7M). In some embodiments, the amplitude envelope of the electrical stimulation is varied for a given pulse (FIGS. 7K and 7L).

[0156] In some embodiments, the electrical stimulus is a voltage controlled output. In some embodiments, the electrical stimulus is a current controlled output. In some embodiments, the electrical stimulus is a power controlled output.

[0157] In some embodiments, the stimulation waveform shape includes a continuous charge-balanced sine wave (see, e.g., Figures 7B-7F, 7K, 7L, 7M, 7N, and 7P), or additional combinations of sine waves (e.g., as sine functions (see, e.g., Figures 7N, 7O, and 7P)).

[0158] The illustrated waveforms are merely exemplary. It is contemplated that other types of waveform shapes can be generated, such as impulse or other shapes. In some embodiments, the stimulation waveform comprises a single pulse having a duration of 1 μs to 10 μs.

[0159] Other stimulation pulse control parameters can be controlled in the feedback mechanism, such as, for example, electric field strength at the electrodes, DC offset, tissue temperature, cooling mechanism parameters, duration of treatment, etc. In some embodiments, the stimulation device and system are configured to control the electrical stimulation based on observed or measured temporal and / or spatial derivatives of voltage, current, power, and temperature (e.g., rate of change of temperature over time). In some embodiments, a combination of two or more of current-controlled, voltage-controlled, power-controlled, and temperature-controlled stimulation can be performed to deliver to the target neural and non-neural tissue of the neural structure. Parameters of amplitude, waveform shape, frequency, DC offset, duty cycle, and duration can be adjusted for such current-controlled, voltage-controlled, power-controlled, and / or temperature-controlled stimulation, or combinations thereof.

[0160] Indeed, stimulation parameters can be optimized to selectively inhibit the perception of pain while preserving neural activity involved in motor activity, low-threshold sensory function, and proprioception. For example, stimulation parameters can be optimized to attenuate or abolish activity of myelinated A-delta and unmyelinated C fibers while preserving (e.g., not attenuating) neural activity of nerve fibers involved in motor activity, low-threshold sensory function, or proprioception.

[0161] The amplitude and other parameters of the stimulation waveform can be adjusted to suitably or optimally modulate activity in a desired region of the nerve (e.g., affecting a specific region of the nerve or affecting the complete nerve cross-section), as described in more detail below. The stimulation waveform can also include changes in parameters that affect and reduce the onset response (e.g., pulsating sensation in the neural structures, motor response of muscles adjacent to the target nerve, such as muscle twitching or twitching) and activation of neural tissue at the onset of stimulation, either at the onset of a continuous waveform or at the onset of each burst of stimulation during intermittent stimulation. Parameters of the stimulation waveform can also be adjusted to control the duration and time course of pain inhibition achieved following treatment, to ensure that adequate pain inhibition is achieved with a single treatment.

[0162] Adjusting the parameters of the stimulation waveform, for example by increasing the amplitude or adjusting other parameters of the stimulation waveform, can increase the spatial size and shape of the electric field, allowing for treatment of larger nerves (e.g., greater than about 2.5 mm in diameter) and larger neural structures, or neural structures that differ in shape, size, and composition of neural and non-neural tissue. Some neural structures, such as the spinal cord and some ganglia and plexuses, are naturally large, and treatment of these large structures is possible through adjustment of the waveform parameters.

[0163] Parameters of the stimulation waveform may also be adjusted to allow for non-injurious treatment and pain control. Hardware and software may also be included to control the amount of DC current delivered simultaneously with the waveform. The controller 130 may include, for example, a current controller or a voltage controller to adjust the amount of DC current or voltage delivered simultaneously with the electrical signal.

[0164] The device and method can be used to selectively and reversibly modulate nerve signal transmission, for example by inhibiting or blocking nerve signal transmission, to inhibit the perception of pain for about 1 day to about 30 days. Preferably, the perception of pain is inhibited for about 5 days to about 30 days. Reversibility of nerve signal transmission and restoration of function after an appropriate period of time after treatment is important, especially for acute pain after surgery. Parameters of the stimulation waveform can be adjusted to adjust the expected duration of pain inhibition so that pain inhibition does not last longer than necessary. In one example, the duty cycle, pulse amplitude, and treatment duration (see, e.g., Figures 10 and 11) can be adjusted to generate the desired reversibility of nerve signal inhibition (see, e.g., Figures 10 and 11). In another example, control of the temperature of the treatment site can be used to generate the desired selectivity of the modulation of nerve signal transmission (see, e.g., Figures 10 and 11).

[0165] As discussed above, the devices and methods of the present invention, including waveform parameters and adjustments thereto, can selectively suppress acute pain (such as post-operative pain) for periods of days to weeks following a procedure. However, it should also be understood that the devices and methods of the present invention, including waveform parameters and adjustments thereto, can also be used to provide therapeutic treatment of chronic pain conditions. Therapeutic treatment of chronic pain may include prophylactic delivery of a continuous signal, or on-demand delivery to halt progression of chronic pain symptoms once they occur. This may be performed via percutaneous, partially implanted, and implanted approaches.

[0166] In comparison to other methods of using electrical signals to modulate the activity of neural structures, the disclosed systems and methods can provide selective and reversible pain relief over a period of days to weeks with a single treatment / application of electrical signals. Other treatments require repeated treatments over several days to provide meaningful and sustained pain relief, especially for the treatment of larger nerves. For example, pulsed radiofrequency, which is frequently used to treat small nerve pain, utilizes intermittent pulses of a 45V high frequency signal to stimulate the target nerve. In this case, pulses are used to avoid temperatures at the treatment site that would damage or destroy nerve tissue. In contrast, the disclosed stimulation parameters allow for the application of high voltage, high frequency waveforms without the temperature limitations associated with pulsed RF signals. By adjusting the parameters of the stimulation waveform, the application of the electrical signal can be controlled to ensure adequate pain control is achieved with a single application while avoiding damage to tissue.

[0167] For example, the system can be configured to deliver electrical signals (also referred to herein as "electrical stimulation") to the treatment site in frequency ranges between about 100 kHz and about 1 MHz, between about 200 kHz and about 800 kHz, between about 400 kHz and about 600 kHz, and between about 450 kHz and about 550 kHz. In an exemplary system, the electrical stimulation delivered to the treatment site is at least 500 kHz. The amplitude range of the electrical signal delivered to the treatment site is between 5 mA or more (e.g., peak-to-center corresponding to 10 mA peak-to-peak) and 1.25 A or less (peak-to-center corresponding to 2.5 A peak-to-peak). In example systems, the amplitude of the electrical signal is 50 mA to 500 mA, 500 mA to 1 A, 1 A to 1.5 A, 1.5 A to 2 A, or 2 A to 2.5 A. In an example system in which the electrical stimulation is delivered transmucosally, the amplitude of the electrical signal is about 10 mA to about 5,000 mA (peak-to-peak). The amplitude range of the electrical signal delivered to the treatment site is 10V to 500V (peak to center corresponding to 20 to 1000V peak to peak). In exemplary systems, the amplitude of the electrical signal is 10V to 1,000V, 20V to 100V, 100V to 200V, 200V to 300V, 300V to 400V, or 400V to 500V. In exemplary systems in which the electrical stimulus is delivered transmucosally, the amplitude range of the electrical signal delivered to the treatment site is 10V to 1,000V (peak to peak). In exemplary systems, the electrical stimulus delivered to the treatment site has a power in the range of about 0.1W to about 1,250W.

[0168] The electrical signal delivered to the treatment site can have a sinusoidal waveform, a square waveform, a triangular waveform, a frequency modulated waveform, an impulse (such as an amplitude modulated waveform, an impulse-like waveform, etc.), and / or additional combinations thereof. An example of a frequency modulated waveform is a chirp. An example of an amplitude modulated waveform is a wavelet. In another exemplary system, the electrical signal delivered to the treatment site has an arbitrary waveform. In another exemplary system, the electrical signal can have a combination of the aforementioned waveforms. Repeated delivery of a waveform means that the waveform shape is repeatedly delivered at a specified repetition frequency. The waveform of the electrical signal can be delivered continuously or intermittently. Continuous delivery means that the waveform is delivered continuously without interruption at a specified waveform frequency. Intermittent delivery means that the waveform is delivered at a specified waveform frequency during an envelope of time separated by breaks during which no stimulation is delivered. For continuous delivery, the duty cycle is 100% (e.g., by a chirp function). For intermittent delivery, the duty cycle ranges from about 0.1% to about 99%, preferably 0.5% to 25%. The term duty cycle refers to the period during which a pulse oscillates multiple times at a given frequency. For intermittent delivery, the width between envelopes of the electrical signal is about 1 ms to about 999 ms, preferably 70 to 999 ms, and the width between envelopes is defined as the duration from the end of an envelope to the start of the next envelope. In one example, the pulse width of an electrical signal delivered at 10 kHz is 30 ms.

[0169] During an exemplary treatment, the electrical signal is delivered for a treatment duration of 30 minutes or less, preferentially 15 minutes or less. In exemplary systems, the electrical signal is delivered for a treatment duration of 1 minute or less, 1-5 minutes, 5-10 minutes, 10-15 minutes, 15-20 minutes, 20-25 minutes, or 25-30 minutes.

[0170] As described below, the controller 130 is adjustable to apply electrical stimulation while maintaining the tissue temperature between about 5° C. and about 60° C. That is, the electrical signal may have a tissue temperature amplitude of about 5° C. to about 60° C.

[0171] The electrical signal delivered to the treatment site may be current-controlled, voltage-controlled, power-controlled, and / or temperature-controlled. The electrical signal includes a continuous, charge-balanced waveform or impulse, or additional combinations thereof. Alternatively, the electrical signal includes a non-charge-balanced waveform or impulse, or additional combinations thereof.

[0172] The strength of the electric field generated at the target site is greater than 10 kV / m. The electrical stimulation delivered to the treatment site generates or induces an electric field strength at the target site and / or electrode between about 20 kV / m and about 2,000 kV / m. The electric field generated at the target site ranges from 20 kV / m to 2,000 kV / m, 25 kV / m to 500 kV / m, or 50 kV / m to 400 kV / m at its time peak. For transmucosal applications, the electrical stimulation generates or induces an electric field strength at the target site and / or electrode, preferably between about 20 V / m and about 1,000,000 V / m. The strength of the electric field varies as a function of other factors such as the distance from the electrode, the shape of the electrode, and the conductivity of different tissues near the electrode. Adjustment of the waveform parameters of the stimulation waveform allows for control of the spatiotemporal electric field within the tissue and at the electrode-tissue interface. Adjustment of the waveform parameters of the stimulation waveform also allows for control of the spatiotemporal thermal field in the tissue and at the electrode-tissue interface. The spatiotemporal variations and levels of the electric and thermal fields are key factors in generating the desired selective and reversible inhibition of pain at the target neural structures. Furthermore, cooling mechanisms implemented in conjunction with the waveform and other aspects of the stimulation such as the electrodes allow for control and reduction of the spatiotemporal thermal field independent or semi-independent of the electric field, as described in detail below. Decoupling these two critical variables ultimately allows for the provision of selective, reversible and tunable treatments that do not damage neural tissue.

[0173] In addition to selectively treating different fiber types, the parameters of the electrical stimulation and induced electric field and the parameters of the electrical waveform can also be adjusted to preferentially modulate neural signal transmission in desired regions of the neural structure, which are portions of the neural structure that are smaller than the complete cross-section.

[0174] The electrical stimulation may also be adjusted to reduce an onset response (e.g., a pulsating sensation in the neural structure, a motor response in muscles adjacent to the target nerve, such as a muscle twitch or contraction) during delivery of the electrical stimulation to the neural structure.

[0175] Example of a cooling mechanism

[0176] It is also contemplated that the stimulation device 100 may include a cooling mechanism to prevent damage to the patient's tissue during delivery of electrical stimulation. The cooling mechanism may be integrated into the electrode 120 and / or the electrode, or may be a separate component from the electrode 120 and may be coupled to the electrode or may be located at the treatment site separate from the electrode 120. The cooling mechanism may be controlled by the controller 130 or may include a separate controller for directing its operation. The cooling mechanism is used to provide a cooling effect in the contact surface of the stimulation device 100 and / or the contact surface of the electrode 120 and / or the tissue near the treatment site.

[0177] Those skilled in the art will appreciate that delivery of electrical stimulation waveforms to tissue may result in heating of tissue adjacent to the delivery electrode 120. Excessive heating of tissue may result in thermal damage to the tissue. One objective of the present invention is to provide selective and reversible inhibition of pain perception while preserving other sensory and motor functions as well as proprioception. Thermal injury of tissue has been purposefully used to eliminate or inhibit transmission of neural action potentials, but these approaches do not preserve sensory and motor functions as well as proprioception. Additionally, cooling of tissue has been used in conjunction with thermal ablation, such as cooled radiofrequency ablation, to allow for increased power dissipation in the tissue, allowing for increased power of the RF waveform and the creation of larger thermal lesions. However, these cooled RF approaches aim to raise tissue temperature to at least 60-90°C to create thermal lesions in the tissue. In contrast, the present disclosure contemplates the use of cooling mechanisms that maintain tissue below thermal injury levels while preserving sensory, motor and proprioceptive functions of neural structures while allowing delivery of electrical signals that may result in inhibition of pain.

[0178] The cooling mechanism creates a cooling effect that prevents damage to the patient's tissue when electrical stimulation is applied by maintaining the temperature of the patient's tissue below a destructive tissue temperature, e.g., below a temperature that may cause thermal damage to the tissue (e.g., avoiding temperatures rising above 42-45° C. for several seconds). The cooling mechanism maintains the temperature of the stimulator 100 and / or the contact surface of the electrode 120 below the destructive tissue temperature in response to feedback information received from the electrode 120 and / or input from the patient and / or operator. The feedback information includes measured temperature data received from a temperature sensor 210 coupled to the stimulator 100. The temperature sensor 210 may measure the temperature of the contact surface of the electrode 120 and / or the temperature of the patient's tissue adjacent the contact surface of the electrode 120. The temperature sensor 210 is electrically coupled to the controller 130 and provides feedback information regarding the measured temperature. In response to the temperature feedback information, as described below, parameters of the operation of the cooling mechanism and / or the electrical stimulation may be adjusted to control the temperature of the contact surface of the electrode 120, thereby reducing the temperature of the adjacent patient tissue.

[0179] In one example, the cooling mechanism may include a pump that circulates a cooling medium, such as a gas or pressurized fluid (e.g., carbon dioxide, nitrogen, water, propylene glycol, ethylene glycol, saline, or mixtures thereof), through the electrode 120 via a conduit 160 provided in the lead (L) (see FIGS. 3A-3E). The circulating gas / fluid serves to remove heat from the electrode 120, the tissue at the treatment site, and adjacent tissue. This gas / fluid may be supplied at room temperature, or may be cooled below room temperature using an incorporated gas / fluid cooling unit, or by using ice or other cooling mechanisms. Cooling of the gas / fluid may be performed before and during treatment. A thermal insulating coating or sheath may also be incorporated around the lead (L) to prevent heating of the cooling medium due to heat transfer to the surrounding environment.

[0180] In another example, the cooling mechanism includes a heat transfer material provided in contact with the tissue at the treatment site and / or the electrode 120. The heat transfer material can be disposed within the electrode 120 / lead (L), on the outer surface of the electrode 120, and / or on the introducer. The heat transfer material acts as a heat sink to remove heat from the electrode 120, the tissue at the treatment site, and adjacent tissue. The heat transfer material can include a material with high thermal conductivity (e.g., metals such as aluminum, ceramic materials, conductive polymers), a material with a high ability to store heat (e.g., good thermal mass such as high specific heat capacity, high heat capacity per unit mass, high volumetric heat capacity, and / or materials with high heat capacity per unit volume), and / or one or more Peltier circuits, or a combination thereof. The heat transfer material can also include a phase change material capable of changing phase at a temperature between about 40° C. and 100° C. An exemplary phase change material includes paraffin wax provided in a pathway extending from the electrode 120 / treatment site to the ambient air. The heat exchange between the paraffin wax and the surrounding air helps remove heat from the electrode 120 / treatment site and adjacent tissue. Additional exemplary cooling mechanisms are described in U.S. Patent Application No. 62 / 403,876, filed October 4, 2016, entitled "Cooled RF Probes," which is incorporated herein by reference.

[0181] In addition to preventing damage to tissue, the cooling mechanism allows for selective inhibition of pain. For example, non-selective inhibition of pain, in which motor functions or non-painful sensory or proprioceptive functions are also inhibited, can be observed if the temperature is not held below a desired threshold (such as 42-45°C for a period of several seconds). By using a cooling mechanism, pain can be selectively inhibited by holding the target tissue below such a temperature threshold without modulating or inhibiting other functions of neural structures. Thus, the temperature of the electrode and tissue are important parameters that can be adjusted by the cooling mechanism to allow selectivity of the inhibition of pain.

[0182] The use of a cooling mechanism also allows for the treatment of neural structures of various shapes, sizes, and compositions. For example, it may be necessary to increase the size of the spatial electric field generated by the electrical waveform in tissue to encompass larger neural structures, such as large peripheral nerves, cranial nerves, ganglia, autonomic nerves, parts of the spinal cord, and plexuses. One way to increase the size of the spatial electric field is to increase the amplitude of the electrical waveform. The use of a cooling mechanism allows the electrical waveform to be delivered at a higher amplitude while maintaining the tissue at a thermal level that avoids thermal damage. For example, when a peripheral nerve with a diameter of more than 2.5 mm is treated by the stimulator 100, the use of a cooling mechanism allows the electrical waveform parameters, including the amplitude, to be adjusted to a level high enough to treat larger neural targets without thermally damaging the neural structure. In another example, a neural structure, such as the spinal cord or ganglia (e.g., Gasserian ganglion, pterygopalatine ganglion (SPG)), may be composed of and surrounded by various tissues with different thermal and electrical conductivities. In this case, the cooling mechanism allows for the delivery of therapeutic waveforms that provide the desired selective and reversible suppression of pain within the desired area of ​​the neural structures while preventing thermal damage at sites susceptible to heating (including the neural structures and surrounding tissue).

[0183] Additionally, the use of a cooling mechanism can adjust the spatial field of the tissue treated by the electrical signal to allow for adjustment of neural signal transmission within a desired region of the neural structure, the desired region of the neural structure being a portion of the neural structure that is less than its complete cross-section. Cooling can be applied to tissue near the electrodes 120 or adjacent to the target treatment site to prevent the tissue temperature from exceeding a desired threshold level. For example, stimulation delivered through the electrodes without cooling may generate a thermal field within the tissue that is thermally damaging at some locations within the tissue. The use and placement of a cooling mechanism at locations that are expected to cause thermal damage to the tissue allows for non-damaging treatment and adjustment of the spatial field of the tissue treated by the electrical signal. In another example, thermal impulses within the tissue may be generated for a short (e.g., less than 1 second) period of time. The cooling mechanism reduces these thermal impulses below a threshold level at specific locations within the tissue, allowing for adjustment of the spatial field of the tissue treated by the electrical signal. In another example, cooling and electrical waveform parameters can be adjusted simultaneously to allow treatment of the neural structure (treatment of a portion less than a complete cross-section of the neural structure or treatment of the entire cross-section of the neural structure) without generating thermal damage.

[0184] Electrode Examples

[0185] 3A-3G provide schematic diagrams of various exemplary electrodes 120 for delivering electrical stimulation to a target neural structure. The electrodes 120 of FIGS. 3A-3E and 3G are in the form of percutaneous electrodes configured for placement near, around, and / or in contact with a target nerve (e.g., without contacting the nervous system structure, the electrode is within about 1 cm, within about 5 mm, or less than 2 mm of the nervous system structure). Exemplary electrodes are shown in side perspective views in FIGS. 3A-3E and 3G. Exemplary percutaneous electrodes are also described in U.S. Patent Application Serial No. 15 / 501,450, filed February 3, 2017, entitled "Selective Nerve Fiber Block Method and System," which is incorporated herein by reference.

[0186] Each electrode used, bipolar or multipolar, has at least one anodic region and at least one cathodic region that is positioned near / in contact with the target nerve "N". The monopolar electrode 120 shown in FIG. 3A can include a cathode located near the nerve and a return electrode (e.g., an anode) located some distance away (e.g., in the form of a patch electrode on the surface of the skin). As shown in FIG. 3B, bipolar and multipolar electrode configurations have at least one cathode and one anode near the nerve. The shape and size of the electrodes, as well as the spacing between the electrodes, are specific to the contours of the electric and temperature fields surrounding and penetrating the nerve, allowing for selective and reversible modulation of the target neural structure. FIG. 3C provides another exemplary percutaneous electrode 120 having a hook or J shape. As shown in FIG. 3C, the electrode 120 is sized and configured to fit the target neural structure laterally within the protrusion of the hook shape, and once positioned, the neural structure is held near the electrode 120, ensuring contact between the neural structure and the electrode contact 150. As shown in FIG. 3C, the electrode 120 includes two electrical contacts, a first contact 150 on the curved hook / J-shaped distal tip of the electrode 120 and a second contact 150 on the elongated body portion of the electrode 120. Such an electrode may be designed to be inserted through an introducer, with the hook / J-shaped portion at the end of the electrode curved within the introducer to reduce its profile. Upon exiting the introducer, the curved portion of the electrode 120 expands and curves around the surface of the neural structure. FIG. 3D illustrates an exemplary electrode 120 in which the electrode tip defines a generally hemispherical shape, providing a generally uniform neural contact surface. The electrode may include an expandable conductive surface that is confined / does not expand when inserted through a small diameter introducer and provides a reduced profile. Upon exiting the introducer, the expandable conductive surface expands to fit around the surface (or a portion of the surface) of the target neural structure. FIG. 3E illustrates an exemplary electrode 120 having a V- or U-shape. As shown in FIG. 3E, the electrodes 120 are sized and configured to be positioned such that the target neural structure lies laterally within the convexity of the V / U shape.When placed at the treatment site, the neural structure is positioned within the electrode 120 on the convex portion of the electrode and maintains contact with the contacts 150 on either longitudinal side of the neural structure.

[0187] FIG. 3G provides another exemplary percutaneous electrode 120 having a distal tip that extends at an angle relative to the body portion of the electrode 120. This bipolar configuration includes two electrical contacts 150 disposed along the elongated body of the electrode to form a cathode and an anode near the nerve (N). As with each electrode depicted in FIGS. 3A-3E and 3G, the length of the electrical contacts can be 1-50 mm in length depending on the size of the target nerve / neural structure. For example, the length of the electrical contacts can range from about 1 mm to about 30 mm in length. In another example, the length of the electrical contacts can range from about 2 mm to about 20 mm in length. In another example, the length of the electrical contacts can range from about 2 mm to about 15 mm in length. In a further example, the length of the electrical contacts can range from about 5 mm to 10 mm in length. It is contemplated that each of the electrical contacts 150 included in the elongated body of the electrode 120 / electrode 120 may be the same or different in length. For example, each of the electrical contacts 150 depicted on the electrode 120 in FIG. 3E have the same length to ensure that a consistent and uniform electric field is generated with respect to the nerve. In the exemplary electrode 120 shown in FIG. 3G, the length of the electrical contacts 150 varies along the electrode 120. In particular, the length of the distal electrical contact 150a located at the distal tip portion 122 of the electrode 120 is greater than the length of the proximal electrode 150b (located along the body 124 of the electrode 120 between the distal electrical contact 150a and the end proximal end of the electrode 120). In general, the distal electrical contact 150a may be at least twice the length of the proximal electrical contact 150b. In one example, the distal electrical contact 150a may be approximately 10 mm long and the proximal electrical contact 150b may be approximately 4 mm long. In another example, the surface areas of the distal electrical contact 150a and the proximal electrical contact 150b may be matched and the lengths of the electrodes may be different. For example, if the proximal electrical contact has a larger circumference / circumferential width than the distal electrical contact, the proximal electrical contact can have a shorter length than the distal electrical contact to achieve matching surface areas.

[0188] As shown in FIG. 3G, the electrode 120 has an elongated body with the distal tip portion 122 of the electrode 120 extending at an angle relative to the longitudinal axis of the body portion of the electrode 120. It is contemplated that the angle of the distal tip portion 122 may range from about 0 degrees to about 50 degrees. The angle of the distal tip portion 122 is between about 5 degrees to about 15 degrees relative to the body 124 / long axis of the electrode 120. The distal tip portion 122 of the electrode 120 can extend in a straight line beyond the curve (as shown in FIG. 3G). It is also contemplated that the distal tip portion 122 may be curved or include a curved surface. As shown in FIG. 3G, the distal electrical contact 150a is disposed along the distal tip portion 122 and the proximal electrical contact 150b is disposed along the elongated main body portion (body 124) of the electrode 120. In this orientation, the distal electrical contact 150a is sized and configured to interface with a target nerve, and the proximal electrical contact 150b is sized and configured to be placed adjacent to subcutaneous tissue, e.g., fat, fascia, muscle, etc. In this configuration, the tissue resistance between the electrode 120 / electrical contacts 150 is increased, resulting in a higher voltage being delivered, resulting in a lower current, and the lower current delivery heats the tissue less.

[0189] FIG. 3F illustrates an exemplary electrode 120 for use in treating neural structures and overlying mucosal tissue. Specifically, the electrode of FIG. 3F is suitable for use in delivering electrical stimulation to the Gasserian and / or pterygopalatine ganglion (SPG). The stimulation device includes an elongated body portion 220 sized and configured to be advanced through a patient's nares and along the superior edge of the middle turbinate. One or more electrodes 120 are provided at a distal end of the elongated body portion 220. The electrodes 120 have a contact surface having a size corresponding to the size of the SPGs, such that electrical stimulation provided to the electrodes 120 can simultaneously modulate the entire SPGs and provide uniform pressure to the mucosal layer adjacent / covering the SPGs. Typically, the contact area of ​​the electrodes 120 is between 1.57 and 56 mm. 2The width of the contact surface of the electrode 120 ranges from at least 1 mm to 6 mm. In one example, the contact surface of the electrode 120 has an elongated triangular shape, a ball tip, or a half ball, or a flat circular shape. As described above, the electrode of FIG. 3F is designed to be advanced through the nasal cavity to a location adjacent to the sphenopalatine ganglion (SPG). Thus, the elongated body portion 220 ranges from 5 cm in length to 20 cm in length. The elongated body portion 220 has a contour corresponding to the superior edge of the middle turbinate. It is contemplated that the elongated body portion 220 may be constructed of a flexible material to facilitate delivery and placement. Although not shown, it is contemplated that the stimulator 100 and / or the electrode 120 may be sized and configured to be placed within a patient's mouth. For example, the electrode 120 may be placed on a mouthpiece that fits around the gums and teeth, with the electrode 120 positioned on the gum tissue (e.g., on the gum line). The electrodes 120 can be positioned on the mouthpiece and, when worn, are positioned adjacent to at least one of the ganglia or peripheral nerves, including, for example, the lingual nerve, the alveolar nerve, and the buccal nerve.

[0190] As discussed above, the electrode 120 can include one or more contacts 150 for delivering electrical stimulation to a treatment area / target neural structure. The contacts 150 are defined as portions of the electrode 120 that are intended to form an interface between the electrode 120 and tissue to which the electrical stimulation is delivered (e.g., to generate an electric field in the tissue). The configuration of the electrode 120 and contacts 150 can be designed to maximize and direct the electric field and current flow to the target neural structure, deliver therapeutic doses of electrical stimulation to nerves of various sizes and shapes and compositions without undesirable stimulation of nearby tissue, and ensure robust placement of the electrode 120 relative to the neural structure for optimal therapeutic benefit.

[0191] Relevant design elements of the electrode include the number of contacts, size, shape, orientation, material, electrolyte medium, delivery method (monopolar, bipolar, multipolar, etc.), and return path. By adjusting and regulating these elements, the electric and temperature fields can be directed through the appropriate nerve structures or portions of nerve structures to selectively and reversibly suppress pain. Furthermore, by adjusting and regulating these factors, the electric and temperature fields can be directed through the appropriate nerve structures or portions of nerve structures to effectively deliver a therapeutic treatment in a single application and tune the time course of reversibility of the therapeutic effect. By adjusting and regulating these factors, the electric and temperature fields can also be shaped to treat entire cross sections of large nerve structures such as large peripheral nerves (greater than 2.5 mm in diameter), cranial nerves, ganglia, autonomic nerves, plexuses, spinal cord, etc., as well as portions of both large and small nerve structures. For example, the size and shape of the electrical contacts, or the number of electrical contacts, can be adjusted to optimize surface area contact with large nerves. Similarly, the size and shape of the electrical contacts, or the number of electrical contacts, can be adjusted to optimize surface area contact / electrical stimulation delivery to the neural structures underlying the mucosal tissue.

[0192] The number of electrode contacts, size, shape, orientation, material, electrolyte medium, delivery method (monopolar, bipolar, multipolar, etc.), and return path can also be adjusted to prevent thermal damage to tissue. These factors affect the temperature field generated by the electrical waveform, including the occurrence of thermal damage at some locations in the tissue relative to the electrodes, and adjustment of these factors, including adjustments in the context of cooling mechanisms and waveform adjustments, allows for the avoidance of thermal damage to tissue.

[0193] For example, the electrodes 120 are sized and configured to maximize and direct the electric field generated by the electrical stimulation delivered to the target neural structure. 2 ~ approx. 100mm 2 10 mm to accommodate the size of the electric and temperature fields required to provide therapeutic treatment to portions of large and small neural structures as well as to portions of all cross-sectional areas of large and small neural structures. 2 ~45mm 2The electrical contacts 150 have a surface area in the range of 0.1 mm to 0.2 mm. An electrical contact that is too large may include portions of the surface of the contacts 150 that do not contact the neural structure, thereby acting as a shunt through which current may flow. When designing electrodes for therapeutic treatment of neural structures, shunt currents are often not recommended because they increase the required current provided by the controller to produce a therapeutic effect. As shown in FIG. 3G, the electrical contacts 150 may also define a perimeter of a smooth curved shape, including, for example, a circular or elliptical contact surface. The sharp edges of linear shaped contacts, e.g., square or rectangular contacts, may result in increased current density and heating. However, it is believed that increased current density and thermal heating may be utilized using linear shaped contacts 150 when specifically sized and positioned on the electrode 120. Thus, the size and shape of the electrical contacts are optimized based on the desire for targeted delivery of therapeutic electric and temperature fields to the neural structures while maintaining the required current from the controller to produce a therapeutic effect.

[0194] In another example, the electrode 120 can include at least two contacts 150 that operate in a multipolar manner, allowing current guidance and / or current focusing of the resulting electric field. In another example, the electrode 120 can include at least two contacts 150 that operate independently (e.g., two contacts 150 on the same electrode 120 or multiple electrodes 120 with corresponding contacts 150). In this manner, the electrical stimulation delivered by each electrode 120 can be interleaved such that the total electrical stimulation delivered to the neural structure is delivered in a shorter (half) amount of time. Specifically, each of the separate electrodes 120 can deliver an intermittent electrical stimulation signal in which the electrical stimulation of the first electrode is interleaved with the electrical stimulation of the second electrode, e.g., an "on cycle" of the first electrical stimulation occurs during an "off cycle" of the second electrical stimulation, and an "on cycle" of the second electrical stimulation occurs during an "off cycle" of the first electrical stimulation.

[0195] In another example, the electrode 120 can include multiple electrode contacts 150 that can be selected for induction of electric and temperature fields by selecting one or more electrode contacts 150 to be used as an anode and one or more other electrode contacts to be used as a cathode. By selecting different combinations of electrode contacts, the shape and size of the electric and temperature fields can be adjusted. For example, with respect to the electrode 120 of FIG. 3G, the distal and proximal electrical contacts 150a, 150b can be located on the same side of the elongated body / electrode 120. Thus, the electrical contacts 150a, 150b do not deliver electrical energy circumferentially around a portion of the circumference of the elongated body electrode 120 without electrical contacts (e.g., the electrical contacts 150a, 150b do not deliver electrical energy circumferentially to the short axis of the body of the electrode 120), thereby providing voltage field shaping and current induction of the delivered electrical stimulation. Brief test pulses of electrical stimulation can be delivered through a subset of contacts to determine nerve proximity and coverage, and additional contacts can be added until sufficient contact with the nerve is confirmed (e.g., by monitoring the motor output of the leg with exercise or by electromyography).

[0196] A resistor can be placed in series with the electrical circuit of the electrical contacts 150 of the electrode 120. For example, with respect to the electrode 120 of FIG. 3G, a resistor can be placed in series with one or both of the electrical contacts 150a, 150b. The resistor increases the stimulation impedance and the voltage delivered from the generator 140 below a desired set point temperature (e.g., destructive tissue temperature) and reduces the stimulation current and thermal changes. Similarly, the electrical contacts 150 can be constructed from a material with a high impedance or a high level of capacitance. For example, a material with a higher impedance or capacitance than stainless steel or platinum can be used to reduce the stimulation current and thermal changes while still allowing the delivery of high voltage levels. This further increases the stimulation impedance and the voltage delivered from the generator 140 below a desired set point temperature (e.g., destructive tissue temperature) while reducing the stimulation current and thermal changes.

[0197] In general, an electrode 120, which may be in the form of a percutaneous electrode assembly, may be utilized to deliver electrical stimulation to a target neural structure to temporarily and selectively modulate nerve fiber activity in the target neural structure. For example, the electrode 120 may include an electrode assembly in the form of a paddle, cuff, cylindrical catheter or needle, wire form, or thin probe configured to be percutaneously introduced through an opening in the patient's skin. In another example, for use in treating head and face pain (as described in more detail herein), electrical stimulation may be applied to the target neural structure via an electrode 120 positioned on the patient's mucosal tissue, for example, an electrical probe sized and configured to be advanced transnasally to a target site proximal to the Gasserian ganglion and / or pterygopalatine ganglion (SPG).

[0198] Additionally, electrical stimulation may be delivered to target neural structures via electrodes 120 implanted in a patient, for example, for the treatment of chronic pain. In this case, the electrodes 120 may be surgically implanted and placed in contact with or around the neural structures during a surgical procedure or a minimally invasive implant procedure. The electrodes 120 may be secured to the neural structures and surrounding tissue using sutures or using fixation structures constructed on the electrode that secure the electrode to the neural structures or adjacent tissue.

[0199] The lead (L) includes a means for transferring electrical energy between the stimulator 100 and the electrode 120, such as via a conductive wire or cable. The lead (L) may be permanently attached directly to the electrode 120 or may be attachable and detachable using a conductive connector. In this case, a compatible connector is present on the electrode 120 and on the lead (L). The lead may be permanently attached directly to the stimulator 100 / signal generator 140 or may be attachable and detachable using a conductive connector. In this case, a compatible connector is present on the stimulator 100 / signal generator 140 and on the lead (L). The lead (L) may also include a means for transferring fluids / gases, such as a conduit 160 used to transfer fluids / gases used to cool the electrode 120. The fluid transfer conduit (conduit 160) may be connected to the electrode 120 and the cooling device directly or via a detachable connector. The lead (L) may also be contoured to provide an optimal shape for placement of the electrode 120, for example, allowing the electrode to be navigated to an ideal location near a neural structure and around obstacles or tissue that present a partial barrier between the insertion point and the target neural structure.

[0200] The leads (L) and electrodes 120 can be placed using lead introducer tools such as cannulas, guidewires, introducer needles and trocars. In particular for percutaneous placement, these lead and electrode introducer tools can be used to guide through the skin and underlying tissue to a location close to the target neural structure. The introducer tools can also be used to allow introduction / placement of all necessary contacts 150 and other electrode components near the target neural structure. The leads (L), electrodes and introducer tools allow placement of electrodes near both large and small target neural structures including peripheral nerves, cranial nerves, ganglia, autonomic nerves, plexuses and spinal cord, and further provide appropriate connections between the electrode(s) and these target neural structures, which assist in the creation of selective and reversible inhibition of pain perception. The leads (L), electrodes and introducer tools also allow placement of the electrodes 120 for percutaneous use, e.g., for acute pain, and for implanted use, e.g., for chronic pain.

[0201] FIG. 4A provides a schematic diagram of an exemplary percutaneous electrode 120 (e.g., FIG. 3G) positioned adjacent to a target nerve structure, e.g., a peripheral nerve, through an opening in the patient's skin. The electrode may be comprised of a single needle-like shaft with two electrical contacts 150. In this example, the distal electrical contact 150a serves as an active electrical contact near the target nerve structure (N) and the proximal electrical contact 150b serves as a return electrode. As discussed above, the material of the shaft of the electrode 120 may be selected based on the desire to maximize thermal conductivity and / or thermal mass (e.g., to allow the electrode 120 to act as a heat sink, allowing for the delivery of higher voltage or current treatment waveforms without increasing the temperature of the tissue). The shaft material of the electrode 120 may also be selected based on the desire to have the probe visible under ultrasound images (e.g., echogenic materials) or fluoroscopic imaging.

[0202] The distance (AB) from the skin surface to the proximal electrical contact 150b (return contact) may be optimized to reduce the risk of damage to the skin or subcutaneous tissue. For example, the distance AB may range from about 0 to about 40 mm. In another example, the distance AB may range from about 0 to about 20 mm. In a further example, the distance AB may range from about 5 mm to about 15 mm. In another example, the distance AB may range from about 10 mm to about 15 mm. The distance (CD) between the proximal electrical contact 150b (return contact) and the bend and / or the distance (CE) between the proximal electrical contact 105b and the distal electrical contact 150a (active contact) are selected to optimize the treatment outcome, e.g., by shaping the voltage field to preferentially point towards the target neural structure, or by focusing the thermal energy during the pulse of the treatment waveform, e.g., by directing the thermal energy away from the target neural structure. In an exemplary system, the distances CD and CE are each in the range of about 2 mm to about 50 mm. Preferably, the distances CD and CE are in the range of about 10 mm to about 30 mm.

[0203] The distance (CD) between the proximal electrical contact 150b (return contact) and the bend and / or the distance (CE) between the proximal electrical contact 150b (return contact) and the distal electrical contact 150a (active contact) can be selected to enable treatment of various target neural structures at various depths in patients with different anatomical configurations (e.g., different thicknesses of muscle, skin, fat layers, different depths to the target neural structures, etc.). For example, the distance between the proximal electrical contact 150b (return contact) and the bend or distal electrical contact 150a (active contact) (CD or CE) can be selected to enable the distal electrical contact 150a (active contact) to be placed near various target neural structures in various patients with various different anatomical configurations, but such that the distance (AB) between the skin and the proximal electrical contact 150b (return contact) is sufficient to enable effective delivery of energy without damaging the skin or other subcutaneous tissue. In another example, the electrodes can have an adjustable distance (CD or CE) such that the proximal electrode contact 150b (return contact) can be repeatedly placed at a desired anatomical location (e.g., a fixed distance within the fat layer or below the skin) regardless of the depth of the targeted neural structure.

[0204] The distance (FG) between the distal electrical contact 150a (active contact) and the distal tip of the electrode 120 may be selected to reduce spatiotemporal thermal spikes during delivery of the therapeutic waveform by avoiding delivery of current through geometric structures on the contact 150a that may generate high current density, such as sharp, pointed tips. In addition, the distance (FG) between the distal electrical contact 150a (active contact) and the tip of the electrode 120 may be selected based on design and manufacturing considerations, such as the selection of materials for the electrode shaft and tip. For example, if the electrode shaft and tip are made of a conductive material and are electrically connected or continuous with the distal electrical contact 150a (active contact), the distal electrical contact 150a (active contact) may also include the tip of the electrode 120 (e.g., because insulation on a sharp tip may be removed when penetrating tissue). Conversely, if the electrode shaft and tip are made of a non-conductive material and are not electrically coupled to the distal electrical contact 150a (active contact), the distance (FG) between the active contact and the tip of the electrode may be greater than 0 mm. The selection of this distance (FG) may also be influenced by the desired echogenicity of the various probe components. Additionally, the tip of the electrode 120 may be configured to be smooth, blunt, or blunt, to minimize high current densities or to overcome the risk of insulation dislodgement upon insertion.

[0205] The angle (α) of the distal tip portion 122 of the electrode 120 may be selected to allow for steering of the contact 150 towards the target neural structure (N) during insertion and placement of the electrode 120. The angle (α) may also help direct the delivery of the therapeutic waveform to the target neural structure, for example, by directing current flow through the target neural structure, shaping a voltage field preferentially towards the target neural structure, and / or focusing thermal energy towards the target neural structure during a pulse of the therapeutic waveform.

[0206] The length (EF) of the distal electrical contact 150a (active contact) may be selected to span the entire diameter of the target neural structure or to span only a portion of the target neural structure (e.g., a fiber bundle or group of fiber bundles). In one embodiment, the length (EF) of the distal electrical contact 150a (active contact) and the length (BC) of the proximal electrical contact 150b (return contact) may be the same. In other embodiments, the length (BC) of the proximal electrical contact 150b (return contact) may be greater than the length (EF) of the distal electrical contact 150a (active contact). A longer proximal electrical contact 150b (return contact) can ensure that the current density at the return contact is lower than the active contact (distal electrical contact 150a) (e.g., if the area of ​​the return contact is greater than the area of ​​the active contact). A longer return contact (proximal electrical contact 150b) can also reduce the possibility of heating near the return contact (proximal electrical contact 150b) or the skin and subcutaneous tissue. In other embodiments, the length (BC) of the proximal electrical contact 150b (return contact) may be less than the length (EF) of the distal electrical contact 150a (active contact). A longer active contact (distal electrical contact 150a) may increase the impedance of the therapeutic waveform circuit. A longer active contact (distal electrical contact 150a) may be used to increase the voltage field at the active contact while maintaining or reducing the current delivered to the tissue or the heating of the tissue. In particular, increasing the impedance of the therapeutic waveform circuit may be achieved in whole or in part by adding a resistive element to the active or return path in the circuit of the electrode 120, as described above. By adding a resistive element in series with the electrical cable or electrical wiring element that connects to the electrical contact 150. The cable itself may also act as a resistive element in the circuit.

[0207] FIG. 4B provides a schematic cross-sectional view of the electrode 120 and electrical contacts 150 of FIG. 4B. The active and / or return contacts of the electrode 120 may also be oriented to have a contact arc length (β) that is fully circumferential (360°), or, as shown in FIG. 4B, a contact arc length (β) that is only partially circumferential (less than 360°). In some embodiments, the contact arc length (β) is less than 180°. The shortening of the contact arc length (β) may be used to help further direct the delivery of the therapeutic waveform to the target neural structure, for example, by directing the flow of current through the target neural structure (N), shaping the voltage field to preferentially point toward the target neural structure, and / or focusing thermal energy toward the target neural structure during a pulse of the therapeutic waveform. Additionally, the shortening of the contact arc length (β) may help reduce the amount of current flowing through paths in tissue that do not include the target neural structure (such as shunt currents), or reduce the exposure of non-target neural structures to the voltage field provided by the tissue treatment waveform. These measures may reduce the power consumption of the system and mitigate risks to non-target tissue. In one example, the distal electrical contact 150a (active contact) closest to the nerve has an arc length less than 180° to reduce shunt current and preferentially direct current to the nerve, while the proximal electrical contact 105b (return contact) furthest from the nerve has an arc length greater than 180°. In this example, using a long arc length for the return electrical contact allows for matching surface areas of the two contacts while minimizing the (longitudinal) length of the return contact, allowing for an optimal separation distance between the two contacts.

[0208] Additionally, the thickness (t) of the electrical contacts 150 may also be specified to allow the electrode 120 to be manufactured with a particular needle gauge while providing sufficient electrical contact mass to withstand mechanical and electrochemical stresses of the contact material that may be encountered during use of the electrode 120. For example, the thickness (t) of the electrical contacts 150 may range from 0.01 / 1000 inch to 50 / 1000 inch.

[0209] An electrode holder 126 may be incorporated into the design to help secure the electrode 120 and minimize movement of the electrode 120 after placement is complete. For example, the electrode holder 126 may help stabilize the position of the distal electrical contact 150a (active contact) relative to the target neural structure (N) during delivery of the therapeutic waveform. The electrode holder 126 may also allow the user to deliver the therapeutic waveform without having to hold the electrode 120 in place for the duration of the waveform delivery. The lead (L) may include an electrical cable and connector to the electrode 120 and may be used to provide electrical connections to the distal electrical contact 150a (active contact), the proximal electrical contact 150b (return contact), and the temperature sensing element 210 (e.g., TC- and TC+).

[0210] Echogenic features, such as laser etched or mechanically etched material, can also be incorporated at desired locations on the electrodes to enhance visualization under ultrasound imaging.

[0211] The temperature sensing element 210 (also referred to as a temperature sensor) can be selected to provide a desired accuracy (e.g., + / -2°C, or e.g., + / -1°C, or e.g., + / -0.5°C, or e.g., + / -0.3°C) and a desired range (e.g., 0-100°C, or e.g., 20-80°C, or e.g., 30-70°C). The accuracy of the thermocouple is affected by the ambient temperature of any cold junction and manufacturing factors. In addition, the temperature sensing element 210 and electrodes 120 can be designed to provide a desired response speed in temperature measurement (e.g., 0-500 ms time constant, or 0-100 ms time constant, or 0-10 ms time constant, or 0-1 ms time constant). The shape / size of the thermocouple junction and the specific heat capacity of the materials used in the electrodes 120 and thermocouple / temperature sensing element 210 can be designed to produce a desired temperature measurement response speed.

[0212] 5 illustrates various example configurations of bipolar electrical contact 150 / electrode 120. As described in more detail below, example configurations A-D illustrate a unitary electrode 120, example configurations E-H illustrate a unitary electrode 120 with the concentric contact structure described with respect to FIGS. 9A and 9B where the electrode 120 is used in conjunction with a windowed introducer cannula 230, example configurations I-J illustrate a flexible electrode 120 used with a curved introducer cannula 230, and example configurations K-M illustrate a straight electrode 120 used with a straight introducer cannula 210. It is contemplated that any of these configurations, individually or in combination, may be used with any of the electrodes 120 described herein.

[0213] As described below, exemplary configurations include unitary and multiple electrode 120 designs. For example, configurations A-D and E-H show examples of unitary configurations comprised of a unitary electrode 120 shaft that includes two electrical contacts 150. The tip of the electrode 120 can be round and smooth (e.g., A, E-H) or sharp (e.g., B-D). The proximal electrical contact 150b (return contact) can be fully circumferential (e.g., A and B) or partially circumferential (e.g., C-H). The distal electrical contact 150a (active contact) can be shaped into a variety of different shapes based on the desire to include / exclude the tip of the electrode 120 as an electrical contact and / or to direct the therapeutic waveform to the target neural structure. A lumen can be incorporated into all designs to allow for the infusion of fluids through the electrode 120. For example, a lumen can be used to deliver a drug therapy to the treatment site (e.g., a pain reliever) before, during, and / or after the delivery of electrical stimulation. In example D, avoidance of a sharp tip as part of the active contact is achieved by the use of a second body without electrical contacts. In this case, a sharp introducer needle protruding from a central lumen extending through the electrode 120. Here, the sharp introducer needle can be removed after placement of the electrode 120 or if fluid is desired to be injected through the lumen. In examples E-H, a cannula 230 without electrical contacts is used to provide a path for insertion of a standalone electrode 120. This cannula 230 may be initially placed without a standalone electrode, for example, using a sharp introducer needle. After placement, the introducer needle may be removed and the electrode 120 may be inserted into the cannula 230. The cannula 230 may be used to provide a fenestrated access 232 to the return or active contacts (e.g., fenestrated access to the return contact in examples E-F). The cannula may be curved or straight (curved in E-F, straight in G-H). The electrodes may also be curved or straight (G-H curved, E-F straight).

[0214] Multi-body designs, such as the examples shown in I-M, are constructed with multiple shafts with electrical contacts 150. In these examples, a return electrical contact 150a is provided on the cannula 230, and a second body 234 with an active electrical contact 150b is inserted through a central lumen of the cannula 230. Multiple bodies can be used to provide electrodes with adjustable distances between the active and return electrical contacts. For example, the second body 234 can be moved longitudinally within the cannula 230 until a desired spacing between the active and return electrodes 150b, 150a is reached. Once in the desired position and orientation, the position of the second body 234 within the cannula 230 is fixed.

[0215] The cannula 230 may be curved (e.g., I-J) or straight (K-M). The electrode body (second body 234) including the active electrical contact 150b may be curved (e.g., K-M) or straight (I-J).

[0216] As shown in FIG. 5, the active and return electrical contacts 150b, 150a can be combined with various combinations of electrical contact arc lengths. For example, configurations A, B, I, K, and L include electrical contacts where both the active and return electrical contacts 150b, 150a extend around a majority of the circumference of the electrode 120 (e.g., more than 180°, 270°, 360°). For example, configuration A illustrates an electrode 120 with active and return electrical contacts 150b, 150a that extend around the entire circumference of the electrode 120. Configurations E-H, J, and M provide exemplary electrodes 120 where the return electrical contact 150a extends around less of the circumference of the electrode than the active electrical contact 150b. Similarly, example configurations illustrate the active and return electrical contacts 150b, 150a combined with various combinations of shapes, such as configuration J where the return electrical contact 150a has a straight shape and the active electrical contact 150b has a curved shape. FIG. 5 also shows active and return electrical contacts 150b, 150a combined at various contact lengths and circumferences, for example, configurations B and C provide an electrode in which the return electrode 150a is shorter (along the longitudinal axis of the electrode 120) than the active electrode 150b, configurations J and M provide an electrode in which the return electrode 150a is longer than the active electrode 150b, and configurations I and K show probes in which the return electrode 150a has a larger circumference than the active electrode 150b.

[0217] 6A and 6B show an exemplary connection between the electrode 120 and a lead (L) that electrically couples the electrode 120 to the generator 140. The connection may be facilitated through the design of the proximal end of the electrode 120 and / or the electrode connector 128 coupled to the proximal end of the electrode 120. As provided in FIG. 6A, the electrode 120 and / or the electrode connector 128 may include a concentric design such that multiple circumferentially shaped contacts are arranged as layered concentric surfaces around the long axis of the electrode 120. For example, as shown in FIG. 6A, contact A is the outermost conductive surface, contact B is the inner conductive surface (facing the long axis of the electrode 120), contact C is another inner conductive surface (facing away from the long axis of the electrode 120), and contact D is the innermost conductive surface (facing the long axis of the electrode 120). Each of the concentric surfaces may be electrically connected to a unique component of the electrode 120 (e.g., the active electrical contact (distal electrical contact 150a), the return electrical contact (proximal electrical contact 150b), and / or the temperature sensing element 210). The concentric surfaces may be separated by a dielectric layer, including, for example, an electrically insulating material and / or air provided between adjacent conductive surfaces. For example, a dielectric layer ranging in thickness from 0.01 / 1000 inch to 50 / 1000 inch may be provided between adjacent concentric surfaces. The needle gauge may vary or be constant along the shaft of the electrode 120 to accommodate the concentric design. Additionally, the needle gauge may be selected to provide for the path of the lumen in addition to the routing of the active, return, and temperature sensing electrical traces / circuitry.

[0218] The lead (L) may include a compatible cable and / or connector for electrically coupling the electrode 120 and / or the electrode's connector 128 with the generator 140. The lead (L) cable / connector has a corresponding size and shape and includes concentric surfaces (e.g., A, B, C, D) configured to electrically mate with corresponding concentric surfaces of the electrode 120 / connector 128 to provide a reliable and consistent electrical connection between the generator 140 and the electrode 120.

[0219] The concentric surfaces can be designed to compress or expand when appropriate mechanical pressure is applied, thus allowing for a reliable, snug joint between the lead (L) and the electrode 120. For example, the concentric surfaces provided on the lead (L) and / or electrode 120 / connector 128 can include notches in some of the conductive surfaces or dielectric layers provided between the concentric surfaces. The notches allow for controlled expansion of the concentric surfaces while maintaining consistent contact with the corresponding surfaces of the electrode 120 (or lead (L)).

[0220] The concentric design of the leads (L) and / or electrodes may include lumens that allow for the passage of fluids through and / or between the leads (L) and electrodes 120. For example, the probe connector (connector 128) may include a lumen that extends into the innermost concentric layer (and / or between the other concentric layers), allowing for attachment of a syringe or tube to the connector 128 and injection of fluids through or between the innermost concentric layers.

[0221] Additionally, the concentric design can be employed not only as a component of the connector, but also as a means for connecting electrical contacts and electrical circuitry of the temperature sensing element from their terminal locations to the proximal end of the electrode 120 for connection to the generator 140. A concentric design including a conductive surface and a dielectric layer can also be used along the shaft of the electrode 120. Such a design lends itself to simple manufacturing methods and is potentially suitable for using the electrode 120 shaft to provide connection to the lead (L), i.e., without using a connector 128, as shown in FIG.

[0222] Additionally, the type and thickness of material for the dielectric layers between the concentric surfaces, as well as the type and thickness of material for the conductive layers, can be selected to minimize capacitance and / or maximize impedance between the conductive layers (e.g., to reduce shunt and parasitic capacitance, maximizing delivery of the therapeutic waveform to the tissue while minimizing generator power requirements).

[0223] One or more temperature sensors / thermal sensing elements 210 may be included in the electrode 120 to provide feedback regarding the temperature of the electrode 120 and / or tissue at a particular location. In one example, the temperature sensor(s) 210 are placed near locations expected to be the hottest sites, e.g., locations where the predicted current density is highest, including, for example, sharp pointed tips, edges of contacts, discontinuities or rapid spatial transitions between materials of different electrical conductivity. The selection of locations for these temperature sensors may be determined based on modeling studies or in vitro or in-vivo temperature measurements in tissue or model media such as saline, conductive gel formulations, egg white, etc. The temperature sensor traces may be routed in a manner that reduces the level of electromagnetic interference caused by the transmission of the waveform to the temperature sensing circuitry.

[0224] In addition to a concentric arrangement, various other arrangements for routing the active and return electrical contacts and temperature sensing elements from the terminal locations to the locations where they connect to the lead (L) cable or generator 140 can be evaluated, including, for example, routing insulated wires, using a dielectric layer with uninsulated wires, printing electrical traces using conductive ink, etc. Furthermore, the materials used to route the active and return contacts and temperature sensing elements from the terminal locations to the locations where they connect to the lead (L) cable or generator 140 may be carefully selected to allow for reliable and effective transmission of electrical signals without contamination or shunting. It should also be appreciated that such an approach can be used when multiple electrical contacts 150 or multiple thermal sensing elements 210 are used on a single electrode 120.

[0225] Signal Generator Example

[0226] The stimulator 100 may include a signal generator 140 coupled to the electrodes 120 and the controller 130. The signal generator 140 generates a stimulation waveform including the parameters of the stimulation waveform described above. The signal generator 140 includes the necessary software and hardware components to generate a specified stimulation waveform and to allow the controller 130 to adjust the stimulation waveform. The signal generator 140 also includes functionality to deliver stimulation to neural structures via the electrodes 120 while electrically isolating the electrodes 120 and the patient from ground circuits and other ground connections to prevent the patient from being grounded when the electrodes are introduced into the patient's body. This may be accomplished, for example, via inductors or optical isolators. Additionally, the signal generator 140 may include capacitors, inductors, resistors, and other passive circuit components near the output to the electrodes 120 to ensure charge balance, reduce DC offsets, or provide desired adjustment of the waveform parameters described above. Additionally, feedback monitoring circuitry may be incorporated to collect information regarding the delivered waveform (current, voltage, power, etc.) and temperature (e.g., monitored via a temperature monitoring mechanism (e.g., temperature sensor 210) within the electrode 120 or tissue). Parameters of the cooling mechanism such as temperature of the fluid / gas cooling medium, fluid / gas flow rate and pressure, heat transfer rate from the electrode 120 and / or surrounding tissue may also be collected.

[0227] Examples of control devices and power supplies

[0228] As generally described above, the controller 130 directs operation of the stimulator 100 / signal generator 140 via the electrodes 120 to provide electrical stimulation to the target neural structures. The controller 130 / signal generator 140 is electrically coupled to a power source 180 that provides electrical energy to the stimulator 100 / electrodes 120. The power source 180 may include an isolated power source, such that all equipment in the system is powered by the isolated power source 180, protecting them from ground faults and power spikes carried by the electrical mains. The power source 180 may also include one or more batteries used for either primary or backup power, allowing the equipment to operate without being connected to the electrical mains of the facility.

[0229] Specifically, the controller 130 directs the operation of the signal generator 140 to deliver electrical stimulation signals to the target neural structures. The controller 130 may have on-board memory to facilitate high speed data capture, output control, and processing, as well as independent waveform sample rates and on-line analysis. These components of the controller allow for the collection of feedback data necessary to understand the waveforms delivered via the electrodes, the parameters of the cooling mechanism, and the thermal and electrical state of the tissue. This feedback allows for the adjustment of such treatment parameters to provide selective and reversible suppression of pain.

[0230] As shown diagrammatically in FIG. 1, the stimulator may include one or more electrodes 120 connected by leads (L) to a controller 130 via a signal generator 140. The controller 130 may include control logic and software designed to deliver the desired electrical stimulation to the patient. The controller 130 may also process analog and digital data, record waveform data and digital information from a patient monitoring system 190, and simultaneously generate waveform, analog, and digital outputs for real-time control of the electrical stimulation (real-time automatic control or manual user control). For example, the controller 130 may adjust the electrical stimulation in response to feedback information received from a temperature sensor coupled to the electrodes 120 and / or the stimulator 100. For example, the stimulator 100 / electrodes 120 may include thermocouples to measure the temperature of the stimulator and / or electrode contact contacts and the patient's tissue adjacent to the electrode 120 contact. The temperature sensor is coupled to the controller 130 and provides feedback information regarding the measured temperature at the contact surface of the stimulator 100 and / or the electrode 120 contact surface and / or other locations within the tissue. The controller 130 or the user can then adjust parameters of the electrical stimulation in response to the feedback information, including, for example, waveform shape, waveform frequency range, waveform amplitude range, electric field strength generated at the electrodes, waveform DC offset, waveform duty cycle (continuous or intermittent delivery), tissue temperature, cooling mechanism parameters, and treatment duration. Additional feedback signals that may be relayed or recorded by the controller or used for feedback control of the electrical signal include temperature, contact impedance, current, voltage, power of the electrical signal, other parameters of the electrical signal, information about the electric field in the tissue, blood flow, skin conductance, heart rate, muscle activity (such as an electromyogram), or other physiological signals.

[0231] Feedback control of electrical stimulation is desirable to avoid the occurrence of tissue damage, to adjust the range of adjustment of electrical stimulation within a target neural structure, and to adjust the range of adjustment of electrical stimulation to target both large and small neural structures and a variety of neural structures such as peripheral nerves, cranial nerves, ganglia, autonomic nerves, plexuses, spinal cord, etc. Feedback control of electrical stimulation is also desirable to allow adjustment of the time course of reversibility of inhibition of pain perception, to adjust the selectivity of inhibition of pain perception, and to ensure that adequate inhibition of pain is achieved with, for example, a single treatment.

[0232] Whether the electrical stimulation is adjusted to selectively modulate nerve signal transmission through selected types of nerve fibers and / or through selected regions of nerve structures, the control and / or operation of the controller 130 may vary and adjust parameters of the electrical stimulation based on measurement feedback of inhibition of nerve signal transmission (e.g., confirmation of absence / limited nerve signal transmission from / through the target nerve), and / or measurement feedback of temperature at the treatment site, and / or feedback from the patient regarding perception of pain. Confirmation of absence / limited nerve signal transmission may be achieved by intraoperative monitoring techniques including, for example, recorded EMG, direct nerve recordings showing changes in latency and / or amplitude or burst area of ​​pain fiber response. The controller 130 and user interface may also be used to adjust parameters of the stimulation waveform, as well as characteristics of the electrode configuration and cooling mechanism in response to feedback. For example, the controller 130 may be configured to vary the duty cycle and / or stimulation envelope duration of the electrical stimulation in real time during treatment to maximize the voltage delivered to the treatment site without exceeding the target tissue temperature, i.e., destructive tissue temperature, at the treatment site. Similarly, in some embodiments, the controller is configured to vary the electrical stimulation duty cycle and / or stimulation waveform envelope duration in real time to maximize the current delivered to the treatment site without exceeding the target tissue temperature at the treatment site, i.e., destructive tissue temperature. By providing an immediate temperature responsive feedback loop, the therapeutic voltage (or current) can be delivered to the neural structures for the longest possible time without causing damage. By controlling the current, the user can more easily control the tissue temperature and safety. Similarly, voltage control correlates with the therapeutic effect.

[0233] Alternatively, the user can manually adjust parameters of the stimulation waveform, as well as the characteristics of the electrode configuration and cooling mechanism, in response to feedback provided via the user interface 170.

[0234] User Interface Example

[0235] The stimulator 100 may further include a user interface 170 for receiving input from a user (e.g., a patient or a medical professional) and providing input to the user. The user may provide input directing the operation of the stimulator 100, including changes to the electrical signal. The user interface 170 may further include a display for providing information about the stimulator 100 to the user. For example, the display may provide information about the status of the stimulator 100, e.g., on / off, signal delivery mode, parameter date related to the electrical signal, etc. The user interface 170 may be integral with the stimulator 100. It is also contemplated that the user interface 170 may be incorporated into a remote device that is electrically coupled (wired or wirelessly) to the stimulator. For example, the user interface 170 may be provided on an external tablet computer or phone. The user interface 170 may be used to allow the user to actively control (in real time) parameters of the electrical stimulation in response to feedback information from the controller 130.

[0236] The system may also include a patient monitoring system 190. The patient monitoring system 190 may be used in combination with the stimulator and the user interface 170. The patient monitoring system 190 acquires, amplifies, and filters the physiological signals and outputs them to the controller 130 and / or the user interface 170 for feedback. The monitoring system may include a temperature sensor coupled to an external surface of the patient's skin to measure changes in the patient's body surface temperature, a blood flow meter coupled to or inserted through the patient's skin, a skin conductance meter coupled to the patient's skin, a heart rate monitor to acquire electrocardiogram signals corresponding to the patient's heart rate, and a muscle activity monitor to acquire electromyogram signals. The heart rate monitor may include separate electrocardiogram (ECG) electrodes coupled to an alternating current (AC) amplifier. The muscle activity monitor may include separate EMG electrodes coupled to an AC amplifier. Other types of transducers may also be used. As described, all physiological signals acquired by the patient monitoring system pass through a signal amplifier / conditioner. Parameters of the electrical stimulation can be adjusted by either the controller 130 or the user in response to feedback information received at the patient monitoring system 190. For example, at least one parameter of the electrical signal can be adjusted by the controller 130 in response to feedback information received from a temperature sensor, an impedance meter, a blood flow meter, a skin conductance meter, a heart rate monitor, and a muscle activity monitor. Information regarding the stimulation waveform and parameters, as well as electrical and thermal properties of the tissue, the electrodes, and the cooling mechanism, can also be provided via the user interface 170 and used to adjust at least one parameter of the electrical stimulation or cooling mechanism or the electrode configuration. The adjusted parameters of the electrical signal can include, for example, waveform shape, waveform frequency range, waveform amplitude range, waveform envelope duration range (i.e., the period during which the stimulation energy is delivered ("on"), e.g., continuously delivered stimulation energy has a long envelope duration and pulsed stimulation energy has a short envelope), electric field strength at the electrode, waveform DC offset, waveform duty cycle (e.g., continuous or intermittent delivery), tissue temperature, cooling mechanism parameters, and treatment duration.The electrode configuration (eg, bipolar, multipolar, unipolar, interleaved, etc.) can also be adjusted in response to the feedback information.

[0237] Example method

[0238] The present disclosure encompasses a method for selectively and reversibly modulating targeted neural and non-neural tissue of neural structures with a single application of electrical energy to inhibit the perception of pain by a patient. A method for practicing the invention begins with placing the patient in a comfortable position. A heart rate monitor (ECG), muscle activity monitor (EMG), or other monitor can be used to measure the patient's response to the electrical stimulation signal. The patient may be monitored for a period of time to determine a baseline condition prior to application of the electrical stimulation signal.

[0239] The target neural structure can then be identified and located. When the electrical signal is delivered transcutaneously, the electrode 120 can be used to locate the target neural structure using a stimulation device such as a nerve locator (e.g., the Ambu® Ministim® nerve stimulator and locator). The nerve location can also be identified by passing a low level stimulation energy signal through the stimulation device. Stimulation-induced muscle contractions in distal muscle groups using low stimulation amplitudes (single pulses) indicate that the stimulation point is close enough to modulate neural signal transmission.

[0240] The stimulator 100 is then placed at a treatment site proximate to the target neural and non-neural tissue of the neural structure. The electrode(s) 120 can be placed near the neural structure in a percutaneous or pernasal manner, or by open incision and implantation.

[0241] For example, the electrode 120 may be placed adjacent to the neural structure percutaneously through an opening in the patient's skin (S) (see, e.g., FIG. 5). The (internal) electrode 120 / lead (L) may be attached to an external stimulator / signal generator 140 or fixed to a handheld stimulator. Percutaneous placement of the electrode 120 may include penetration of the skin and navigation of the electrode 120 and / or lead (L) under image guidance (e.g., using ultrasound) to a location proximate to the target neural structure. Additional localization tools such as cannulas, guidewires, introducer needles, and trocars may be used to enable tissue navigation and eventual placement of the electrode proximate to the target neural structure.

[0242] Positioning the electrode 120 near the neural structure may include delivering an initial electrical stimulus (i.e., a low level electrical stimulus, less than 0.5V) via the electrode 120 to the treatment site and measuring the voltage and / or current at the electrode 120. Based on the measured voltage and / or current, the position of the electrode 120 at the treatment site (near the target neural structure) is adjusted. Further initial electrical stimulation signals are sent to the treatment site and the position of the electrode 120 is adjusted, and this is repeated until the measured voltage and / or current corresponds to a threshold voltage and / or threshold current that indicates the electrode 120 is positioned around the nerve in a position to deliver effective treatment.

[0243] If the electrical signal is delivered transcutaneously, the method may further include placing one or more return electrodes on the external surface of the patient's skin. Each anode desirably has a skin-contacting surface such that the skin-contacting surface of the anode has at least the same (or greater) surface area as the contacting surface of the stimulation electrode. The one or more return electrodes may be placed on the skin at a distance sufficient from the one or more stimulation electrodes to avoid current shunting.

[0244] Methods of practicing the invention may further include the use of a coupling medium, such as a conductive liquid, gel, or paste, which may be applied to the skin, for example, in the case of a return electrode, or placed in a sheath around the electrode 120, or placed on the tip of the electrode 120 in the case of a percutaneously placed electrode 120, to maximize and guide the electric field, deliver therapeutic doses of stimulation energy to large and small nerves, and ensure reliable electrode / nerve placement for optimal therapeutic effect. Alternatively and / or additionally, one or more skin moisturizers, hydrating agents, exfoliants, and the like may be applied to the skin to increase skin conductivity and / or reduce skin impedance. Examples of conductive pastes include Ten20® Conductive Paste from Weaver and Company, Aurora, Colorado, and ELEFIX Conductive Paste from Nihon Kohden, with offices in Foothill Ranch, California. Examples of conductive gels include Spectra 360 Electrode Gel from Parker Laboratories, Inc. of Fairfield, NJ, or Electro-Gel from Electro-Cap International, Inc. of Eaton, OH. An example scrub that can be used to prepare the skin prior to application of the percutaneous electrodes is Nuprep Skin Prep Gel from Weaver and company of Aurora, CO.

[0245] In a further example, the electrodes can be implanted in the patient adjacent the treatment site and in close proximity to the target neural structure. The electrodes and stimulator can be implanted at or near the target neural structure. In another example, the electrodes can be implanted at the treatment site and leads can extend through the patient's skin to the stimulator. It is also contemplated that the electrodes can be implanted at the treatment site and can be activated wirelessly through the patient's skin. It is also contemplated that a wireless receiver module can be implanted and used to wirelessly receive input from the controller 130 and communicate with the electrodes via the leads.

[0246] An additional example is the placement of an electrode 120 (e.g., FIG. 3F) in the nasal turbinate via a transnasal approach for transmucosal delivery of an electrical signal to the Gasserian and / or Pterygopalatine Ganglion (SPG). For example, the electrode 120 and lead can be inserted into the patient's nose, placed in the nasal turbinate, and held firmly in place during delivery of the electrical signal (see, e.g., FIGS. 9A and 9B). Methods can be used to suppress the patient's sneeze reflex, such as using chemical or electrical nerve blockade, or intentionally eliciting a sneeze reflex and placing a lead and electrode immediately after sneezing and before the patient can generate a second sneeze reflex. The intentional initial sneeze reflex may be triggered by the lead and / or electrode, or by another probe inserted into the nose. It is also contemplated that the electrode 120 can be placed adjacent to the Gasserian and / or Pterygopalatine Ganglion (SPG) via a percutaneous approach. Whether via a transnasal or percutaneous approach, the location of the SPG may be initially identified using, for example, magnetic resonance imaging (MRI), fluoroscopic imaging, and ultrasound imaging.

[0247] After the electrode 120 is placed, conventional electrical stimulation can be delivered through the electrode 120 to ensure adequate tissue / nerve proximity, and impedance measurements can be collected and used as well. The stimulator can then be programmed to optimize the electrode contact selection, return electrode selection, and stimulation parameters, as described above. It is believed that the selection of optimal stimulation parameters can include the delivery of different candidate waveforms with different parameter configurations until a suitable result is achieved. It is further believed that the selection of optimal electrode contact 150 configuration and return electrode configuration can include the delivery of electrical signals through different configurations of electrode configurations (contacts 150) and return electrodes until a suitable result is achieved. These optimizations may be performed manually by the user or delivered by the controller in a closed loop as part of an iterative algorithmic or pre-programmed search. If necessary, a chemical neuroleptic can also be delivered through the electrode lead before sending the electrical signal. Chemical neuroleptics help to mitigate the onset reaction and improve patient comfort.

[0248] The stimulating electrical signal may then be delivered via the electrode(s) to a treatment site proximate the target neural structure using one or more of the stimulation parameters described above. The controller 130, supplied with electrical energy from the power source 180, may direct the operation of the stimulator to selectively modulate the target neural and non-neural tissue to inhibit the patient's perception of pain while providing sufficient electrical signals to preserve other sensory and motor functions, as well as proprioception. The user may also control the parameters of the electrical signal in real time in response to feedback provided to the user interface 170 via the controller 130. A single application of the electrical signal to the treatment site selectively modulates the target neural and non-neural tissue to provide a subsequent inhibition of the perception of pain for a period of about 1 day to about 30 days.

[0249] When the electrodes include at least two electrodes operating independently, it is considered that the first electrical stimulation signal is delivered via the first electrode and the second electrical stimulation signal is delivered via the second electrode. The first and second electrical stimulation signals are output intermittently, with the first electrical stimulation being interleaved with respect to the second electrical stimulation. In this configuration, an on-cycle of the first electrical stimulation occurs during an off-cycle of the second electrical stimulation. Similarly, an on-cycle of the second electrical stimulation occurs during an off-cycle of the first electrical stimulation.

[0250] The application of electrical signals to the treatment site selectively modulates the target neural and non-neural tissues that modulate nerve signal transmission through nerve fibers involved in pain transmission, thereby suppressing the patient's perception of pain, while preserving nerve signal transmission through nerve fibers involved in other sensory and motor functions and proprioception. Preserved "other" sensory functions include, for example, touch, vision, hearing, taste, smell, and balance. The application of electrical signals may also suppress and / or disrupt nerve signal transmission through nerve fibers involved in the transmission of signals involved in thermoreception, autonomic activity, and visceral function.

[0251] In its simplest form, the method relies on patient feedback regarding perception of pain following delivery of a nerve-blocking stimulation signal to assess the efficacy of temporary and selective neuromodulation. In some instances, patient sensations such as a throbbing sensation, tingling, heaviness and / or pressure experienced during stimulation can be used to dictate various stimulation parameters including, for example, voltage, current, stimulation impedance and treatment time course (duty cycle and time course of stimulation, treatment duration and end time, dosing (stimulation "on" time)).

[0252] Alternatively and / or additionally, because stimulation may occur before, during, or immediately after a surgical procedure where the patient is unable to provide feedback, the method may rely on feedback collected by recording electrodes, such as ECG, galvanic skin response, blood flow, skin or body temperature, and / or electromyogram signals to assess the effectiveness of temporary and selective stimulation adjustments.

[0253] The target nerve structures can include peripheral nerves (large or small), cranial nerves, ganglia, autonomic nerves, plexuses, and spinal cord. The target nerve structures can include a mixture of motor, sensory, and / or autonomic neurons, or can include a single type of nerve activity (motor only, sensory only, autonomic only, etc.). The target ganglia include dorsal root ganglia, sympathetic ganglia, parasympathetic ganglia, pterygopalatine ganglion, gasserian ganglion, plexus, and / or spinal cord. In one example, the target nerve structure includes a large peripheral nerve (e.g., larger than about 2.5 mm), and the electrodes deliver electrical signals to the nerve that selectively and reversibly inhibit nerve signal activity associated with pain for a period of days to weeks, while preserving nerve signaling associated with motor function, non-pain sensation, and proprioception. For example, the electrodes 120 can deliver electrical signals that selectively and reversibly inhibit nerve signal activity of small diameter nerve fibers associated with sensory (pain) function over a period of days to weeks, with minimal or no change in function of larger myelinated fibers associated with motor function, non-painful sensation, and proprioception. In one example, application of the electrical signal to the neural and non-neural tissue of the target neural structure inhibits and / or disrupts nerve signal transmission through at least one myelinated Aδ fiber and / or unmyelinated C fiber provided in the nerve, and the electrical signal preserves nerve signal transmission through at least one of Aβ and Aα fibers, and / or motor fibers. In a further example, various parameters of the electrical signal can be adjusted to selectively inhibit at least one of the myelinated Aδ fibers or unmyelinated C fibers, including, for example, inhibiting nerve signal transmission through myelinated Aδ fibers while preserving nerve signal transmission through unmyelinated C fibers, and vice versa. In further examples, various parameters of the electrical signal are adjusted to differentially inhibit neural signaling / function of myelinated A-delta fibers, which are inhibited in a greater proportion of fibers than unmyelinated C-fibers. Similarly, various parameters of the electrical signal are adjusted to differentially inhibit neural signaling / function of unmyelinated C-fibers, which are inhibited in a greater proportion of fibers than myelinated A-delta fibers.

[0254] In another example, application of the electrical signal to the neural and non-neural tissue of the target neural structure modulates the function of the neural or non-neural tissue in a manner that results in downstream or secondary effects that result in the inhibition of pain while preserving movement, non-painful sensation, and proprioceptive activity. For example, various parameters of the electrical signal can be adjusted to selectively modulate function to reduce pain resulting from activity of myelinated A-delta fibers and / or unmyelinated C fibers, while preserving movement, non-painful sensation, and proprioceptive function, such as that transmitted by A-beta and A-alpha fibers, and / or motor fibers. In a further example, various parameters of the electrical signal can be adjusted to selectively modulate function to reduce pain resulting from activity of myelinated A-delta fibers or unmyelinated C fibers, including, for example, inhibiting pain resulting from activity of myelinated A-delta fibers while maintaining pain from activity of unmyelinated C fibers, or vice versa. In a further example, various parameters of the electrical signal can be adjusted to differentially modulate function to reduce pain resulting from activity of myelinated A-delta fibers, where pain resulting from activity of myelinated A-delta fibers is inhibited to a greater extent than pain resulting from activity of unmyelinated C fibers. Similarly, by adjusting various parameters of the electrical signal to differentially modulate function, pain due to activity of unmyelinated C fibers can be reduced to a greater extent than pain due to activity of myelinated A-delta fibers.

[0255] In another example, certain parameters of the electrical signal can be adjusted to preferentially regulate nerve signal transmission / function within a desired region of the nerve structure. Typically, the desired region is a portion of the nerve structure that contains sensory components involved in transmitting the sensation of pain. For example, with respect to the femoral nerve, the topography of the femoral nerve indicates that the portion of the sensory components that innervate the knee are collected in a region of the nerve cross section. It is therefore conceivable that the electrical signal can be adjusted to preferentially regulate nerve signal transmission through the portion of the nerve cross section that corresponds to these target sensory components.

[0256] Various modifiable parameters of the electrical signal include, for example, waveform, frequency, amplitude, waveform envelope duration, intensity, electric field strength, waveform offset (DC offset), continuous delivery, and / or intermittent delivery via electrodes 120. For example, controller 130 adjusts duty cycle and / or waveform envelope duration in real time to maximize the voltage delivered to the treatment site without exceeding a target tissue temperature at the treatment site, e.g., adjusting the stimulation duty cycle and / or stimulation envelope to maximize the voltage delivered to the treatment site in real time while ensuring that the tissue at the treatment site does not exceed a destructive tissue temperature. Similarly, in some embodiments, controller 130 adjusts duty cycle and / or waveform envelope duration in real time to maximize the current delivered to the treatment site without exceeding a target tissue temperature at the treatment site, e.g., adjusting the stimulation duty cycle and / or stimulation envelope to maximize the current without exceeding a destructive tissue temperature.

[0257] In another example, the stimulation amplitude of the electrical stimulation can be slowly titrated to a steady state. Titrating the electrical stimulation to a steady state can eliminate and / or reduce the magnitude of sensations experienced by the patient during delivery of the electrical stimulation (e.g., a tingling sensation experienced at the receptive field of the nerve when the stimulation energy is continuous, and an intermittent tingling sensation experienced when the stimulation energy is delivered in pulses).

[0258] The disclosed methods include inhibiting pain perception associated with acute pain (including surgical pain, post-operative pain, traumatic pain), neuropathic pain, chronic pain, and head and face pain. When the pain is acute pain, the method of selectively and reversibly modulating targeted neural and non-neural tissues to inhibit pain perception includes applying an electrical signal immediately prior to a surgical procedure. The electrical signal can also be applied during surgery and / or immediately after a surgical procedure to inhibit pain perception associated with surgical procedures and recovery. The electrical signal can also be applied hours and / or days prior to the procedure. For example, the electrical signal may be applied at least 24 hours prior to a surgical procedure. Delivering the electrical signal prior to a procedure, such as a surgical procedure, helps reduce pain and patient discomfort as the patient prepares for the procedure. The electrical signal can also be delivered prior to the procedure or configured such that a peak analgesic effect occurs at the time of the procedure. It is also contemplated that multiple neural structures can be targeted to allow for more comprehensive coverage of the target area. For example, if the pain is acute post-operative pain after knee arthroplasty (including total knee replacement), electrical stimulation can be applied to the femoral nerve, sciatic nerve, obturator nerve, and lateral cutaneous nerve and nerve branches, or combinations thereof. In another example where the pain is shoulder pain, electrical stimulation can be applied to the brachial plexus, axillary nerve, suprascapular nerve, and lateral pectoral nerve, or combinations thereof. If the pain is associated with medical procedures and / or trauma to the arm and / or hand, electrical stimulation can be applied to the medial, ulnar, and radial nerves, or brachial plexus, respectively. If the pain is associated with medical procedures and / or trauma to the ankle and / or foot, electrical stimulation can be applied to the tibial, peroneal / sural, and saphenous nerves, or combinations thereof. If the pain is associated with hip arthroplasty, electrical stimulation can be applied to the femoral, sciatic, or obturator (e.g., common obturator before it branches anteriorly and posteriorly) nerves and / or plexuses, or combinations thereof. When pain is related to the healing of the anterior cruciate ligament (ACL), electrical stimulation can be applied to the femoral or sciatic nerve, or a combination thereof.

[0259] Where the pain is neuropathic or chronic pain, the methods of modulating neural and non-neural tissue of target neural structures include a user (e.g., a physician or patient) applying an electrical signal as part of a predetermined schedule of preventative care and / or as needed by the patient to provide an on-demand bolus of therapeutic treatment / pain relief.

[0260] The method of selectively and reversibly modulating target neural and non-neural tissue to inhibit the perception of pain may further include measuring with the temperature sensor 210 the temperature of the contact surface of the stimulator 100 (e.g., the contact surface of the electrode 120) and / or the temperature of the patient's tissue adjacent to the stimulator contact surface during delivery of the electrical signal. Feedback information regarding the measured temperature is provided to the stimulator. If the feedback information indicates that the temperature of the stimulator contact surface exceeds the device's threshold temperature and / or the temperature of the patient's tissue exceeds the tissue's threshold temperature, the stimulator / controller or user can adjust the operation of the stimulator and electrical signal parameters and / or a cooling mechanism to generate a cooling effect and reduce the temperature of the contact surface and tissue. Reducing the temperature of the contact surface and / or the patient's tissue prevents damage to the patient's tissue. In some examples, the system may include a cooling mechanism coupled and / or integrated with the stimulator 100 and / or the electrode 120. If the feedback information indicates that the temperature of the interface of the stimulator 100 exceeds the device threshold temperature and / or the temperature of the patient's tissue exceeds the tissue threshold temperature, the stimulator 100 / controller 130 and / or user may activate and control operation of a cooling mechanism to cool the interface of the stimulator 100 / electrode 120, which cooling the interface may prevent damage to the patient's tissue when electrical signals are delivered by keeping the temperature of the patient's tissue below the tissue threshold temperature. Similarly, the stimulator 100 / controller 130 and / or user may activate and control operation of a cooling mechanism to maintain the temperature of the interface of the stimulator 100 / electrode 120 below the threshold temperature in response to feedback information regarding the measured temperature received from the temperature sensor 210.

[0261] After the electrical signal has been delivered and pain perception has been suppressed while preserving other sensory and motor functions, and proprioception, the percutaneous (injured) and / or percutaneous (non-injured) electrodes 120 can be removed, while the implanted electrodes 120 (if present) can remain in the body for further use and for full-time treatment.

[0262] Example 1

[0263] In this example, healthy subjects were recruited from the community and consented to the study using an IRB-approved consent form. High-dose opioid users were excluded from the study. Two types of sensory assessments were performed at multiple time points for each subject: (1) mechanical vibration testing to assess the subject's sensitivity to non-painful tactile sensations, and (2) pain-inducing electrical stimulation testing to assess the subject's sensitivity to induced pain. At the beginning of the first session, mechanical vibration testing and pain-inducing electrical stimulation assessments were performed on each leg. These were referred to as baseline assessments. Subjects were then treated using electrical stimulation waveforms via electrodes placed percutaneously on the left leg. After treatment, mechanical and vibration testing was assessed again on each leg. Subjects returned for subsequent mechanical vibration testing and pain-inducing electrical stimulation testing.

[0264] Mechanical vibration testing: subjects wore a surgical gown and sat in a comfortable chair. The right leg was fixed upright on a stand with a foam pad to limit movement. A vibration device was positioned so that it was in contact with the skin within the saphenous nerve distribution. A series of two epochs were then provided to the subject, one involving vibration via the vibration device and the other without vibration, during which a vibration trial was performed. For each trial, the choice of the epoch in which vibration was delivered was determined randomly, and the subject was requested to verbally indicate which epoch they believed vibration was delivered in. If the subject selected the correct epoch, overlapping trials were performed until three consecutive trials of successful selection, after which the vibration amplitude was reduced for the next trial. If the subject selected an incorrect epoch, the next trial was performed with a higher amplitude of stimulation. In this way, a threshold amplitude was identified based on the combined performance from three sets of 50 trials on each leg. A threshold amplitude was identified for each leg in each session.

[0265] Electrical stimulation testing to induce pain: Electrical stimulation was delivered via an adhesive surface electrode placed on the saphenous nerve near the medial malleolus. Stimulus duration was 1 ms per single pulse. The amplitude of stimulation was gradually increased until the subject first perceived a sensation. Stimuli were then delivered in a train of 9 pulses at 500 Hz, and the amplitude of stimulation was gradually increased until the subject perceived a transition from a non-painful sensation to a painful sensation. Pain thresholds were identified by both ascending and descending threshold testing, and the average pain threshold for the session was recorded. This threshold was identified for each leg in each session.

[0266] Electrical Stimulation Treatment: Electrical stimulation treatment was administered to each subject in a single treatment on the left leg only. After the baseline mechanical vibration test and the baseline pain-inducing electrical stimulation test, subjects were ready to undergo electrical stimulation treatment.

[0267] Subjects were placed on the operating table in the supine position and the skin was prepared over the medial saphenous nerve several centimeters distal to the tibial tuberosity. A surface return electrode was placed on the contralateral leg in the gastrocnemius muscle. The saphenous nerve was identified using ultrasound and a radiofrequency probe (22 gauge, 4 mm exposed tip) was inserted into the skin. The position of the active tip of the radiofrequency probe was manipulated and stimuli (1 ms duration, 2 Hz) were delivered at progressively smaller amplitudes. Probe position was manipulated until a sensory threshold of less than 0.2 V was reached.

[0268] Electrical stimulation treatment was then administered to the subjects at 2 Hz for 20 ms for 240 seconds. The amplitude of stimulation was adjusted in real time to maintain the probe tip temperature at 42°C. After completion of stimulation, the probe was removed and the subjects again underwent mechanical vibration testing and pain-inducing electrical stimulation testing, referred to as Visit 0.

[0269] Subjects returned for follow-up evaluations at subsequent visits. Vibration thresholds were plotted over time to assess the effect of electrical stimulation treatment on tactile sensation, i.e., sensation transmitted through large-diameter myelinated fibers. Pain thresholds were normalized to baseline levels and plotted over time to assess the effect of electrical stimulation treatment on nociception, i.e., sensation transmitted through small-diameter fibers.

[0270] Figure 10 shows normalized pain thresholds over time for five subjects who underwent 240 seconds of electrical stimulation treatment. The green line shows the average response to topical analgesics such as lidocaine and bupivacaine, which provide analgesia for periods of less than one day. An increase in pain threshold was evident in all subjects, indicating a decrease in sensitivity to pain. A return to baseline was evident 7 days after the procedure.

[0271] Figure 11 shows the mechanical vibration threshold over time for the same five subjects (240 seconds of electrical stimulation treatment). No systematic changes in mechanical vibration threshold were evident, suggesting the selectivity of the treatment for pain perception. Furthermore, clinical examination results also showed no sensory impairment in the treated leg.

[0272] These results suggest that electrical stimulation treatment selectively and reversibly increases the threshold for pain perception through treated nerves, which was fully reversible within 7 days after treatment.

[0273] Example of a computing system

[0274] While the methods and systems have been described in connection with preferred embodiments and specific examples, the scope is not intended to be limited to the particular embodiments described, as the embodiments herein are intended in all respects to be illustrative and not restrictive.

[0275] A "computing device" as used herein may include multiple computers. A computer may include one or more hardware components, such as, for example, a processor, a random access memory (RAM) module, a read-only memory (ROM) module, a storage device, a database, one or more input / output (I / O) devices, and an interface. Alternatively and / or in addition, a control device may include one or more software components, such as, for example, a computer-readable medium that includes computer-executable instructions for performing methods related to the exemplary embodiments. It is contemplated that one or more of the above hardware components may be implemented using software. For example, a storage device may include a software partition associated with one or more other hardware components. It is understood that the components listed above are exemplary only and are not intended to be limiting.

[0276] The processor may include one or more processors, each configured to execute instructions, process data, and perform one or more computer-related functions for indexing images. The processor may be communicatively coupled to RAM, ROM, storage devices, databases, I / O devices, and interfaces. The processor may be configured to execute sequences of computer program instructions to perform various processes. The computer program instructions may be loaded into RAM for execution by the processor. As used herein, a processor refers to a physical hardware device that executes coded instructions to perform functions on inputs and produce outputs.

[0277] The processor may be a microcontroller, a microprocessor, or a logic circuit such as an application specific integrated circuit (ASIC), a complex programmable logic device (CPLD), a field programmable gate array (FPGA), or other programmable logic integrated circuit. In some embodiments, the processor is configured to execute instructions stored in a memory of the device.

[0278] RAM and ROM may each include one or more devices for storing information associated with the operation of a processor. For example, ROM may include a memory device configured to access and store information associated with the controller, including information for identifying, initializing, and monitoring the operation of one or more components and subsystems. RAM may include a memory device for storing data associated with one or more operations of a processor. For example, ROM may load instructions into RAM for execution by a processor.

[0279] The storage devices may include any type of mass storage device configured to store information that a processor may need to execute processes consistent with the disclosed embodiments. For example, the storage devices may include one or more magnetic and / or optical disk devices, such as a hard drive, a CD-ROM, a DVD-ROM, or other types of mass media devices.

[0280] A database may include one or more software and / or hardware components that cooperate to store, organize, sort, filter, and / or organize data for use by a controller and / or processor. For example, a database may store hardware and / or software configuration data associated with input / output hardware devices and controllers, as described herein. It is contemplated that a database may store additional and / or different information than that listed above.

[0281] An I / O device may include one or more components configured to communicate information with a user associated with the control device. For example, an I / O device may include a console with an integrated keyboard and mouse that allows a user to maintain a database of images, update associations, and access digital content. An I / O device may also include a display including a graphical user interface (GUI) for outputting information to a monitor. An I / O device may also include peripheral devices such as, for example, a printer for printing information associated with the control device, a user-accessible disk drive (e.g., a USB port, a floppy, CD-ROM, or DVD-ROM drive, etc.) that allows a user to input stored data into a portable media device, a microphone, a speaker system, or any other suitable type of interface device.

[0282] An interface may include one or more components configured to transmit and receive data over a communications network, such as the Internet, a local area network, a workstation peer-to-peer network, a direct link network, a wireless network, or any other suitable communications network. For example, an interface may include one or more modulators, demodulators, multiplexers, demultiplexers, network communications devices, radio devices, antennas, modems, and any other types of devices configured to facilitate data communication over a communications network.

[0283] Unless expressly stated otherwise, it is not intended that any method described herein be construed as requiring that its steps be performed in a particular order. Thus, no order is intended to be implied in any way in a method claim unless the order in which the steps are performed is actually recited or the claims or specification herein specifically state otherwise that the steps are limited to being performed in a particular order. This applies to all possible implicit principles of interpretation, including logical considerations regarding the arrangement or operational flow of steps, the plain meaning derived from grammatical construction or punctuation, and the number or type of embodiments described herein.

[0284] Throughout this application, various publications may be referenced. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which the methods and systems pertain.

[0285] It will be apparent to those skilled in the art that various modifications and variations can be made without departing from the scope or spirit. Other embodiments will be apparent to those skilled in the art from consideration of the specification and practice disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit being indicated by the appended claims.

Claims

1. 1. A system for selectively and reversibly modulating targeted neural and non-neural tissue of a nervous system structure, the system comprising: an electrical stimulation device comprising one or more electrodes, the electrodes including at least one first electrode having an elongated body with a proximal electrical contact and a distal electrical setting disposed on a surface of the elongated body, the proximal electrical contact sized and configured to be disposed in subcutaneous tissue and the distal electrical contact sized and configured to interface with the target neural and non-neural tissue of the nervous system structure, the electrical stimulation device configured to deliver electrical stimulation to a treatment site proximate the target neural and non-neural tissue of the nervous system structure via the one or more electrodes; a control device configured to connect to (i) the one or more electrodes of the electrical stimulation device and (ii) a power source that provides electrical energy to the one or more electrodes; the controller is configured to direct operation of the electrical stimulation device to apply the electrical stimulation to the treatment site via the one or more electrodes; the application of the electrical stimulation to the treatment site selectively modulates the target neural and non-neural tissue, thereby inhibiting pain and preserving touch and other sensory and motor function, and proprioception; At least one parameter of the electrical stimulation is automatically adjustable based on real-time feedback during treatment to differentially inhibit the function of at least one of (i) unmyelinated C fibers and (ii) thinly myelinated A-delta fibers, which are involved in dull / tingling or sharp pain sensations, without inhibiting the function of A-beta fibers, A-alpha fibers, and motor fibers, which are involved in touch, motor function, and proprioception.

2. The system of claim 1 , wherein the pain comprises at least one of acute pain, post-operative pain, neuropathic pain, chronic pain, and head and facial pain.

3. 3. The system of claim 1 or 2, wherein a single application of the electrical stimulation to the treatment site selectively modulates the targeted neural and non-neural tissue, resulting in subsequent suppression of pain.

4. 3. The system of claim 1 or 2, wherein a single application of the electrical stimulation to the treatment site selectively modulates the targeted neural and non-neural tissue and results in subsequent pain suppression for 5 to 30 days.

5. the application of the electrical stimulation to the treatment site modulates the target neural and non-neural tissue and inhibits nerve signal transmission through nerve fibers involved in pain transmission; Nerve signal transmission through nerve fibers involved in said other sensory and motor functions and proprioception is preserved; The system according to any one of claims 1 to 4, wherein the other sensory functions are selected from the group consisting of touch, vision, hearing, taste, and smell.

6. 6. The system of claim 1, wherein the one or more electrodes are configured to be positioned adjacent to the nervous system structures including at least one of peripheral nerves, cranial nerves, ganglia and autonomic nerves, nerve plexuses, and spinal cord.

7. the nervous system structure comprises a nerve or ganglion having a diameter greater than 2.5 mm; The system of any one of claims 1 to 6, wherein at least one of the one or more electrodes has a size and shape and contact surface configuration sufficient to deliver the electrical stimulation to the nerve or ganglion.

8. 8. The system of claim 1, wherein the controller is adjustable to vary the electrical stimulation based on measured feedback selected from the group consisting of measured inhibition of neural signal transmission, measured temperature, patient input, feedback corresponding to at least one of adjustable parameters, treatment settings related to a time course of recovery, electrode contact impedance, electric fields generated in tissue, a physiological response of the patient, and combinations thereof.

9. 9. The system of claim 1, wherein the controller is configured to vary the electrical stimulation duty cycle or stimulation waveform envelope duration in real time to maximize voltage delivered to the target neural and non-neural tissue without exceeding a target tissue temperature at the treatment site.

10. 10. The system of claim 1, wherein the controller is configured to vary the electrical stimulation duty cycle or stimulation waveform envelope duration in real time to maximize current delivered to the target neural and non-neural tissue without exceeding a target tissue temperature at the treatment site.

11. The controller modulates at least one parameter of the electrical stimulation to modulate neural signal transmission; 11. The system of claim 1, wherein the at least one parameter is selected from the group consisting of waveform shape, waveform frequency, waveform amplitude, waveform envelope duration, electric field strength generated at the one or more electrodes, waveform DC offset, waveform duty cycle, tissue temperature, cooling mechanism parameters, and treatment duration.

12. 12. The system of claim 1, wherein the controller varies at least one parameter of the electrical stimulation to modulate neural signal transmission within a portion of the nervous system structure having a cross-section less than or equal to a complete cross-section of the nervous system structure.

13. 13. The system of any one of claims 1 to 12, wherein the control device is adjustable to vary at least one parameter of the electrical stimulation to reduce activation of the nervous system structure at the onset of an initiation response of the nervous system structure and / or inhibition of the nervous system structure.

14. The system of any one of claims 1 to 13, wherein the controller is adjustable to deliver the electrical stimulation to the treatment site having a frequency in the range of from 100 kHz to 1 MHz.

15. The system of any one of claims 1 to 14, wherein the electrical stimulation delivered to the treatment site has an amplitude range of 5mA or more and 1.25A or less.

16. The system of any one of claims 1 to 15, wherein the electrical stimulation delivered to the treatment site has an amplitude range of 10V or more and 500V or less.

17. The system of any one of claims 1 to 16, wherein the electrical stimulation delivered to the treatment site has a power range of 0.1 W or more and 1,250 W or less.

18. 18. The system of any one of claims 1 to 17, wherein the electrical stimulation delivered to the treatment site creates or induces an electric field strength at a target site and / or the one or more electrodes of 20 kV / m or more and 2,000 kV / m or less.

19. 19. The system of any one of claims 1 to 18, wherein the electrical stimulus delivered to the treatment site has waveform shape components including at least one of a sine waveform, a square waveform, a triangular waveform, an impulse waveform, a shape modulated waveform, a frequency modulated waveform, an amplitude modulated waveform that provides a continuous delivery of the electrical stimulus at the treatment site, and combinations thereof.

20. The system of any one of claims 1 to 19, wherein the electrical stimulation delivered to the treatment site has a duty cycle in the range of 0.1% or more and 99% or less.

21. 21. The system of any one of claims 1 to 20, wherein the electrical stimulation delivered to the treatment site has an inter-pulse width in the range of 1 millisecond or more and 999 milliseconds or less.

22. The system of any one of claims 1 to 21, wherein the electrical stimulation is delivered to the treatment site for a duration of up to 30 minutes.

23. 23. The system of any one of claims 1 to 22, wherein the controller is adjustable to apply the electrical stimulation whilst maintaining tissue temperature in the range of greater than or equal to 5°C and less than or equal to 60°C.

24. The system of any one of claims 1 to 23, wherein the electrical stimulation device comprises a device body configured for implantation within a patient's body adjacent the treatment site.

25. 25. The system of claim 1, wherein the control device comprises a stimulator coupled to both the one or more electrodes and to an interface of the control device, and operation of the stimulator is directed by the control device to deliver the electrical stimulation to the one or more electrodes.

26. The system of any one of claims 1 to 25, wherein the one or more electrodes comprise an electrode assembly in the form of a paddle, a cuff, a cylindrical catheter or needle, a wire form, or a thin probe.

27. The system of any one of claims 1 to 26, wherein the one or more electrodes are sized and / or shaped to maximize and direct an electric field towards the nervous system structure.

28. The system of claim 1 , wherein each of the proximal electrical contacts and the distal electrical contacts are disposed on a single lead and form a stimulation pair.

29. The system of any one of claims 1 to 28, wherein each of the proximal electrical contact and the distal electrical contact has a length of at least 1 and at most 50 mm.

30. The system of any one of claims 1 to 29, wherein the proximal electrical contact and the distal electrical contact have the same length.

31. The system of any one of claims 1 to 29, wherein the proximal electrical contact and the distal electrical contact have different lengths.

32. the distal electrical contact is adjacent a distal end of the electrode and the proximal electrical contact is disposed along the electrode at a location between the distal electrical contact and the proximal end of the electrode; 32. The system of claim 31, wherein the distal electrical contacts have a length greater than a length of the proximal electrical contacts.

33. 33. The system of any one of claims 1 to 32, wherein the one or more electrodes comprise an electrode assembly in the form of the elongate body, the distal end of the elongate body including a curvature such that a distal tip portion of the elongate body extends at an angle relative to a longitudinal axis of the elongate body, the angle of the distal tip portion relative to the longitudinal axis of the elongate body being between 0 degrees and 50 degrees.

34. The system of claim 33 , wherein a distal tip portion of the elongate body is straight.

35. The system of claim 33 , wherein a distal tip portion of the elongate body is curved.

36. 36. The system of any one of claims 33 to 35, wherein the electrode assembly includes at least two electrical contacts comprising the distal electrical contact provided at a distal tip portion of the elongate body and the proximal electrical contact provided along the elongate body between the distal tip portion and a proximal end of the electrode assembly.

37. The system of any one of claims 1 to 36, wherein each of the proximal electrical contact and the distal electrical contact are disposed on the same side of the elongate body of the electrode.

38. 38. The system of claim 37, wherein the conductive regions of the proximal electrical contact and the distal electrical contact are on the same side of the elongate body and do not deliver electrical energy circumferentially to a portion of the circumference of a lead without the proximal electrical contact and the distal electrical contact.

39. The system of any one of claims 1 to 38, further comprising a resistor disposed in electrical series with the proximal electrical contact or the distal electrical contact included in the one or more electrodes.

40. 40. The system of any one of claims 1 to 39, wherein the proximal and distal electrical contacts on the one or more electrodes are formed from a material having a higher impedance or a higher level of capacitance than the impedance or capacitance of stainless steel or platinum.

41. The system of any one of claims 1 to 40, wherein the proximal and distal electrical contacts on the one or more electrodes have smoothly curved peripheries.

42. The system of any one of claims 1 to 41, wherein the proximal and distal electrical contacts on the one or more electrodes have an elliptical perimeter.

43. The system of any one of claims 1 to 40, wherein the proximal and distal electrical contacts on the one or more electrodes have a rectilinear perimeter.

44. A system according to any preceding claim, further comprising a temperature measurement device provided on the one or more electrodes for providing tissue temperature measurement.

45. 45. The system of any one of claims 1 to 44, wherein at least one of the proximal electrical contacts, the distal electrical contacts and the temperature measuring device provided on the one or more electrodes are printed from an electrically and thermally conductive material.

46. the proximal and distal electrical contacts on the one or more electrodes extend partially around the corresponding electrode; 46. ​​The system of any one of claims 1 to 45, wherein the arc length of the electrical contact is less than 180 degrees and the electrical contact extends less than halfway around the electrode.

47. 47. The system of any one of claims 1 to 46, wherein the electrodes are electrically coupled to the controller via circumferentially shaped contact surfaces on the electrodes and corresponding circumferentially shaped contact surfaces on leads electrically coupled to the controller.

48. the circumferential contact surface includes two or more circumferential contact surfaces arranged concentrically about a longitudinal axis of the electrode; 48. The system of claim 47, wherein a lead electrically coupled between the electrode and the generator includes two or more corresponding circumferentially shaped contact surfaces concentrically arranged about a longitudinal axis of the lead.

49. the circumferentially shaped contact surfaces of the electrodes are separated by a dielectric layer; 49. The system of claim 48, wherein the circumferentially shaped contact surfaces of the leads are separated by a dielectric layer.

50. A system according to any one of claims 47 to 49, wherein the electrical circuit of the electrode extends within the electrode within the circumferentially shaped contact surface.

51. 51. The system of any one of claims 1 to 50, wherein at least one of the one or more electrodes is a monopolar electrode configured to be placed on a contact surface of the electrical stimulation device and a return electrode is placed on an external surface of the patient's skin.

52. The system of any one of claims 1 to 51, wherein the electrical stimulation device is reusable.

53. The system of any one of claims 1 to 51, wherein the electrical stimulation device is disposable.

54. A user interface is provided. A system according to any preceding claim, wherein the user interface is configured to receive input from a user directing the application of the electrical stimulation to the treatment site.

55. 55. The system of any one of claims 1 to 54, further comprising a display coupled to at least one of the controller and the electrical stimulation device, the display providing an indication of a status of the electrical stimulation device.

56. (i) a contact surface of the stimulation device; and (ii) a temperature sensor coupled to the stimulation device for measuring a temperature of at least one of the contact surface or tissue of the patient adjacent the electrode, the temperature sensor coupled to the controller providing thermal feedback information related to the measured temperature; A system according to any preceding claim, wherein the controller is adjustable to vary at least one parameter of the electrical stimulus in response to the thermal feedback information received from the temperature sensor.

57. and a cooling mechanism configured to provide a cooling effect to the treatment site. The system of any one of claims 1 to 56, wherein the cooling effect prevents damage to the treatment area.

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