Dynamic adjustment of electrical variables in nerve stimulation to generate functional muscle movement without muscle fatigue

Abstract

A peripheral neuromodulation system and method for activating peripheral nerves for functional movement control is provided, the system including a multi-channel electrode configured to be placed on or around a peripheral nerve of a patient, a pulse generator configured to deliver stimuli to the nerve via the multi-channel electrode to induce functional limb movement in the patient, the stimuli including a series of current pulses including at least one pulse delay, and a controller operably coupled to the pulse generator.

Description

[Technical Field]

[0001] mutual citation

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 443,046, filed February 3, 2023, the contents of which are incorporated herein by reference.

[0002]

[0002] The subject matter of this application is related to the following pending patent application: International Application No. PCT / US22 / 39202 (Attorney Docket No. 61435-703.601), which claims the benefit of U.S. Provisional Patent Application No. 63 / 228,754, filed August 3, 2021, the entire contents of which are incorporated herein by reference. PRIOR ART

[0003]

[0003] The present disclosure relates to the fields of medicine and biomedical sciences, and more particularly to the fields of treating or alleviating the effects of weakness and paralysis (including reducing muscle atrophy and contracture formation, maintaining muscle mass, and modulating spasticity), and peripheral neuromodulation therapy.

[0004]

[0004] Damage to the brain, spinal cord, and motor control areas of the central nervous system (CNS) can lead to weakness and paralysis. Signals sent from an injured CNS are so deficient that they cannot communicate with the functioning peripheral nervous system (PNS). Without this functioning connection, the PNS cannot initiate movement, or efferent signals are too weak to generate maximum muscle force. This results in numerous clinical consequences, including weakness and / or paralysis, as well as loss of muscle mass, muscle atrophy, contracture formation, and / or spasticity. Additionally, in peripheral nerve injury, assuming nerve transection or other damage, signals cannot reach end organs, resulting in functional disruption within the circuit. Stroke is one of the most common CNS injuries, with approximately 40 million patients worldwide left paralyzed after a stroke. Other etiologies of paralysis and debilitating central and peripheral nervous system pathologies include spinal cord injury (SCI), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), cerebral palsy (CP), and peripheral nerve injury.

[0005]

[0005] Functional improvement of these deficits currently requires prolonged rehabilitation, lasting months to years, and complex surgical procedures involving joint fusions, tendon transfers, and nerve transfers, which are invasive, morbid, and require significant additional recovery time. Prior studies have shown that outcomes at six months for debilitated and paralyzed patients show little progress, and functional rehabilitation outcomes are often absent altogether. Patients are often left with permanent disabilities and are unable to utilize wearable exoskeletons to improve function and quality of life.

[0006]

[0006] The above conditions are not an exhaustive list, but merely examples of debilitating or paralyzing conditions that can be treated by the systems and methods disclosed herein. Summary of the Invention [Means for solving the problem]

[0007]

[0007] A peripheral neuromodulation system is provided that activates peripheral nerves for motor control using specific parameters configured to induce fine muscle contractions without muscle fatigue. Furthermore, the neuromodulation system can be used in an autonomous closed-loop fashion to restore functional limb movement, or in an open-loop fashion to reduce muscle atrophy, maintain muscle mass, regulate spasticity, reduce contracture formation, and promote endogenous limb function. The disclosed peripheral neuromodulation system patent is configured to address all forms of weakness or paralysis and clinical consequences resulting from injury to the CNS or PNS requiring motor control.

[0008] Aspects of the present disclosure provide an exemplary neuromodulation system for producing functional limb movement, the system including: a multi-channel electrode configured to be placed on or around a peripheral nerve of a patient; a pulse generator configured to deliver stimuli to the nerve via the multi-channel electrode to induce functional limb movement in the patient, the stimuli including a series of current pulses including at least one pulse delay; and a controller operably coupled to the pulse generator.

[0009] The system can include a sensing lead configured to detect a patient's voluntary input, a multi-channel electrode configured to be placed around a peripheral nerve, and a pulse generator configured to deliver stimuli to the nerve to elicit functional limb movement, the stimuli including a series of current pulses including pulse delays. The multi-channel electrode can be a cuff configured to be placed around the nerve.

[0010] The controller can be configured to perform one or more of the following actions: apply or adjust stimulation based on the voluntary input. The controller can adjust at least one pulse delay based on the voluntary input. The controller can be implantable.

[0011] The voluntary input can be based on one or more of the patient's nerve or muscle activity. In one example, the one or more of the patient's nerve or muscle activity is obtained from a nerve or muscle different from the nerve to which stimulation is applied or the muscle associated with that nerve.

[0012] The system can also include a manual trigger operably coupled to the controller to receive input from the patient or other user, with the controller configured to take one or more actions to apply or adjust stimulation based on the received input. The trigger can be used to enable the device to operate in a closed-loop manner, where voluntary patient input can activate the device to achieve meaningful efferent motor movement. Additionally, a sensory feedback mechanism can be employed to provide real-time feedback to the controller to enable fine-tuning and coordination of efferent motor movement based on the end user's limb position and intended movement.

[0013]

[0013] The pulse generator can be implanted or external and can adjust stimulation and / or pulse delay based on voluntary input. At least two consecutive pulses in the series of current pulses can be separated by at least one pulse delay. In one example, each pulse in the series of current pulses can be separated by at least one pulse delay. The at least one pulse delay can be between 5 and 75 mS and have an average value of 40 mS. The pulses in the series of current pulses of stimulation can have a pulse width of 50 to 1000 μS. The pulses in the series of current pulses of stimulation can have a pulse current of 50 to 2000 μA. The pulses in the series of current pulses can be charge-balanced, biphasic, or biphasic.

[0014] The sensing lead can be implanted or attached to the outside of the patient with an adhesive. The sensing lead can be an electromyography sensor, an electroencephalography sensor, an electroencephalography sensor, an adhesive electrode, or a manual on / off driver. The sensing lead can be configured to detect a voluntary patient input and can be operably coupled to the controller.

[0015] Voluntary input can be based on the patient's brain or neural activity and / or the patient's muscle activity. Alternatively, or in combination, stimulation can be triggered by input received from a manual trigger, such as a handheld remote control or key fob-like control element. In one example, the voluntary input or sensing lead can communicate with the manual trigger. In another example, the manual trigger can be an external magnet configured to align with an internal coil within the pulse generator to act as the trigger. The device can also function autonomously, independent of the trigger mechanism. Exemplary methods include implanting the system to reduce muscle atrophy following acute CNS injury and deliver programmed therapeutic neurostimulation to promote endogenous motor recovery.

[0016] An exemplary method for inducing flexion in a target muscle of a patient can include receiving input from the patient or other user, and upon receiving the input, delivering a charge-balanced symmetric biphasic stimulation waveform to the target muscle, the stimulation waveform including a series of current pulses and at least one pulse delay, thereby inducing functional limb movement. Receiving the input can include detecting a voluntary input from the patient.

[0017]

[0017] The method may further include the step of detecting a second voluntary input from the patient and adjusting the stimulation waveform based on the second voluntary input.

[0018]

[0018] The method may further include adjusting at least one of the amplitude, frequency, pulse width, and pulse delay of the stimulation based on the voluntary input.

[0019] The method may further include adjusting at least one of the amplitude, frequency, pulse width, and pulse delay of the stimulation based on input received from a manual trigger, which input may be received from the patient or other user via the manual trigger.

[0020]

[0020] The method may further include a step of detecting signs of muscle fatigue.

[0021] The method may further include the step of varying a pulse delay between at least two pulses of the series of pulses.

[0022]

[0022] An exemplary method of providing dynamic stimulation for functional limb movement may include initiating flexion stimulation of a nerve with a constant current and a series of pulses including at least one pulse delay, detecting a patient's voluntary input, modifying the pulse delay between at least two of the series of pulses based on the voluntary input while maintaining the flexion stimulation, and delivering a relaxation stimulus configured to evoke controlled relaxation.

[0023]

[0023] An exemplary method can also utilize steering of current and magnetic fields to ensure activation of specific nerve bundles for physiological exercise. The method can further include detecting a second voluntary input from the patient and adjusting a stimulation waveform based on the second voluntary input. The method can further include adjusting at least one of amplitude or intensity, frequency, pulse width, and pulse delay based on the voluntary input. The method can further include detecting an indication of muscle fatigue and varying a pulse delay between at least two pulses in the series.

[0024]

[0024] An exemplary method of providing dynamic stimulation for functional limb movement may include initiating stimulation of a nerve with a constant current and a series of pulses including a pulse delay, maintaining the stimulation by varying the pulse delay between two pulses in the series, and delivering a relaxation stimulus configured to evoke controlled relaxation.

[0025]

[0025] Further aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description. In the following description, only exemplary embodiments of the present disclosure are shown and described. As will be recognized, the present disclosure is capable of other and different embodiments, and its various details can be modified in various obvious respects without departing from the present disclosure in any way. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0026] Inclusion by Citation

[0026] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. To the extent that publications and patents or patent applications whose contents are incorporated herein by reference conflict with the disclosure contained herein, it is intended that the present specification supersede and / or take precedence over any such conflicting material.

[0027] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth exemplary embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "Figure" and "FIG."). [Brief explanation of the drawings]

[0028] [Figure 1] 1 illustrates a peripheral neuromodulation system configured to produce functional limb movement, according to certain embodiments, that includes an implantable pulse generator (IPG), implantable sensing leads configured to detect voluntary input, and a multi-channel electrode (MCE) configured to be placed around a peripheral nerve. [Figure 2] 1 illustrates a peripheral neuromodulation system according to certain embodiments, including an implanted receiver stimulator coil (RSC), an external pulse generator (EPG), and an external coil that powers the implanted RSC. [Figure 3] 3A-3C show an MCE having an eight-channel MCE including two parallel electrode rings, according to certain embodiments. [Figure 4A]1 is an image of an MCE according to a specific embodiment, in which each electrode ring has four rectangular electrodes spaced 90° apart within a silicon sheath. [Figure 4B] 1 is a photograph of an intraoperative image of an MCE implanted according to certain embodiments. [Figure 5] 1 illustrates a neuromodulation system according to certain embodiments, the system including an electrode assembly and a pulse generator including an external component and an implantable component. [Figure 6] 6 is an exploded view of the electrode assembly of FIG. 5 showing the arrangement of individual electrode elements according to certain embodiments. [Figure 7] FIG. 6 is a block diagram illustrating circuitry within the external and implantable components of the pulse generator of FIG. 5 in accordance with certain embodiments. [Figure 8] 1 illustrates a charge-balanced symmetrical biphasic waveform with pulse delay, according to certain embodiments. [Figure 9] 1 illustrates a waveform transition from a first frequency to a secondary frequency once muscle contraction has been initiated and muscle fatigue has been alleviated according to certain embodiments. [Figure 10] 1 is a flow diagram illustrating a method for providing a dynamic stimulation framework for functional limb movement, according to certain embodiments. [Figure 11] 1 is a flow chart illustrating a method for performing neuromodulation for functional limb movement, according to certain embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0029]

[0040] While various embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Various modifications, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should also be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0030]

[0041] Whenever the words "at least," "greater than," or "greater than or equal to" precede the first number in a series of two or more numbers, the term "at least," "greater than," or "greater than or equal to" applies to each and every number in the series. For example, 1, 2, or 3 or more is equivalent to 1 or more, 2 or more, or 3 or more.

[0031]

[0042] Whenever the words "no more than," "less than," or "less than or equal to" precede the first number in a series of two or more numbers, the term "only," "less than," or "less than or equal to" applies to each and every number in the series. For example, 3, 2, or 1 or less is equivalent to 3 or less, 2 or less, or 1 or less.

[0032]

[0043] Certain embodiments herein contemplate numerical ranges. When a range is stated, the range includes the endpoints of the range. Additionally, any subranges and values ​​within the range exist as if expressly written out. The terms "about" or "approximately" may mean within an acceptable error range for a particular value, which depends in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, "about" may mean within or more than one standard deviation, as is customary in the art. Alternatively, "about" may mean within 20%, 10%, 5%, or 1% of a given value. When specific values ​​are described in the application and claims, unless otherwise specified, the term "about" may be taken to mean within an acceptable error range for the particular value.

[0033]

[0044] A peripheral nerve modulation system is provided that activates peripheral nerves for motor control with specific parameters configured to induce fine muscle contractions without causing muscle fatigue. The disclosed peripheral nerve modulation system patent is configured to address any form of weakness or paralysis resulting from damage to the CNS or PNS that requires motor control.

[0034]

[0045] Direct nerve stimulation to regulate muscle movement may require a balance between achieving maximal muscle contraction, which may require higher frequencies, and reducing fatigue, which may require lower frequencies.

[0035]

[0046] According to one embodiment, a neuromodulation system for producing functional limb movement is provided. Turning to FIG. 1 , according to one embodiment, a neuromodulation system for producing functional limb movement is provided. The neuromodulation system can include an implantable pulse generator (IPG) 10, implantable sensing leads 12 configured to detect voluntary input, and a multi-channel electrode (MCE) 14 configured to be placed around a peripheral nerve. The IPG can include electronic circuitry, such as a controller, and a battery or other power source within a sealed or titanium case. A surgeon can implant the IPG subcutaneously below the collarbone in the upper chest or axilla and connect the IPG to the sensing leads or stimulation connected to the MCE.

[0036]

[0047] According to some embodiments, the neuromodulation system can be configured in an autonomous mode using one or more sensing leads configured to detect one or more signals from the patient or voluntary input, such as electromyography (EMG), electroencephalography (EEG), and / or electroneurography (ENG). According to some embodiments, the voluntary input can be based on the patient's neural activity and / or the patient's muscle activity. According to some embodiments, the neuromodulation system is configured to detect neural activity signals prior to a joint flexion attempt. This can be accomplished by detecting a weak ENG signal using a specific electrode of the multi-channel contact electrode that can detect the weak ENG signal and serve as an input to the system, relaying it to the same equivalent contact on the distal output multi-channel contact electrode. According to some embodiments, the neuromodulation system is configured to detect a weak EMG signal during an arm flexion attempt and delivers a stimulation current to one or more channels of the MCE 14. The MCE 14 is wrapped around the musculocutaneous nerve MN, which innervates the patient's biceps brachii muscle BM. According to some embodiments, the EMG signal can also be detected using implanted sensing leads 12 or surface electrodes. In some embodiments, the signal is an EEG signal detected from an implanted or external EEG sensor. The sensing lead may be implanted or externally attached to the patient with an adhesive. The sensing lead may be an electromyography sensor, an electroencephalography sensor, an electroencephalography sensor, or a manual on / off driver.

[0037]

[0048] According to some embodiments, the neuromodulation system can be configured in an open loop mode with a manual trigger, such as a remote control or key fob-like control element. In some embodiments, the sensor is an on / off driver that activates the system. In one example, the manual trigger can be an external magnet configured to align with an internal coil within the pulse generator.

[0038]

[0049] In some embodiments, the MCE is configured to surround and selectively stimulate one or more motor nerves. In some embodiments, the MCE's placement allows for controlled, localized delivery of graded electrical pulses generated by a pulse generator, ensuring precise activation of the intended muscle group. In one example, the MCE may include an eight-channel multichannel cuff electrode with two parallel electrode rings. In one example, each electrode ring may have four electrodes arranged 90 degrees apart. In some embodiments, the electrodes may be made of typical nerve interfacing materials such as gold, platinum, or platinum / iridium, or may be coated with a conductive polymer. In one example, the MCE 14 may have a cuff measuring 2 mm to 6 mm in diameter and 1 cm to 2 cm in length. The cuff electrode contacts are arranged in two or more "rings," each housing four individual 2 mm x 1 mm rectangular (tripolar) platinum or 90 / 10 platinum / iridium contacts. These contacts are embedded in silicone at 0, 90, 180, and 270 degrees around the circumference of the ring. A 1 to 5 mm space is maintained between the contacts, with a 1 mm gap from the contacts to the edge of the cuff. This arrangement can accommodate monopolar stimulation of discrete nerve locations and bipolar stimulation between two contacts. These dimensions are meant to be exemplary and in no way limiting.

[0039]

[0050] In one example, the MCE 14 may have sutures embedded in the silicone to facilitate cuff placement. The surgeon can position the MCE around the patient's musculocutaneous nerve and connect the lead's connector tip to the IPG. The cuff electrode can apply a current that stimulates the musculocutaneous nerve, causing the arm to flex at the elbow.

[0040]

[0051] This electrode structure allows current to be distributed to any number of electrode elements or other contacts, allowing any number of electrodes to be activated independently and / or synchronously, and each electrode element or contact can be configured as a cathode or an anode during the active phase of stimulation.

[0041]

[0052] In one aspect, the pulse generator is configured to control the pulse intensity, pulse duration, and pulse delay of the stimulation. In one aspect, the pulse generator is configured to deliver graded electrical pulses. In one aspect, the pulse generator is configured to deliver electrical pulses to the target motor nerve based on characteristics of the voluntary input, such as amplitude.

[0042]

[0053] In one aspect, the pulse generator is configured to deliver electrical pulses in stages over a programmable amount of time by delivering pulses with increasing amplitude over time to accommodate smooth motor activation. By adjusting the intensity and duration of stimulation, the system can accommodate fine control of the speed, strength, and range of eccentric movement. Illustratively, electrical stimulation delivered at decreasing levels over a long duration can produce gentle muscle movements, ideal for fine motor control. Conversely, electrical stimulation delivered at increasing levels over a shorter duration can produce enhanced muscle contractions, appropriate for more powerful movements.

[0043]

[0054] In one embodiment, the pulse generator includes a microprocessor, a power source (e.g., a battery), and control software. The pulse generator can also continuously monitor sensors to detect muscle activity and identify changes in the EMG signal when the patient attempts to move. The detected EMG signal is transmitted to the microprocessor for real-time analysis. The microprocessor processes the EMG signal, noting its amplitude, which correlates with the patient's intended muscle force. Based on this analysis, the microprocessor adjusts parameters of the delivered electrical pulses. These parameters include pulse amplitude (strength), pulse duration, and pulse frequency. The microprocessor generates electrical signals tailored to the patient's intention and can modulate the intensity of the electrical pulses in response to the amplitude of the EMG signal. In one embodiment, the pulse generator can be configured to deliver stepped electrical pulses of increasing amplitude over time to accommodate smooth muscle activation. The stepped electrical pulses can then be sent to multi-channel electrodes for precise delivery to the motor nerve.

[0044]

[0055] Stimulation parameters can be programmed, such as intensity (ranging from 0.1 mA to 2.5 mA), pulse width (ranging from 10 μs to 500 μs), and frequency (ranging from 10 Hz to 50 kHz). Stimulation waveforms are typically biphasic, asymmetric, and charge-balanced, with a 100 μs delay between the active and recovery phases. Current intensity can range from 40 μA to 2000 μA.

[0045]

[0056] According to certain embodiments, the neuromodulation system may also include one or more cuff electrodes, which may be configured to stimulate one or more nerves and / or multiple locations on a nerve. Each cuff electrode may incorporate one or more contacts used to stimulate the nerve. Electrode configurations may be as simple as a single ring electrode or more complex with multiple rings.

[0046]

[0057] According to some embodiments, the neuromodulation system may also include voluntary electrodes or sensors that provide information to the system for dynamically adjusting stimulation parameters in real time to perform the movement. According to some embodiments, the neuromodulation system may also include an EMG sensor configured to detect voluntary input signals generated by the patient's muscles. The voluntary input signals represent the patient's intent to initiate an eccentric movement.

[0047]

[0058] In one embodiment, an EMG sensor is configured to continuously monitor the patient's muscle activity to detect their intent to initiate an eccentric movement. This input can be used as a trigger signal for the subsequent neuromodulation process.

[0048]

[0059] According to certain embodiments, the neuromodulation system may also include EMG adhesive or sticky electrodes. These electrodes may be placed on the skin over any functional muscle in the body, providing a non-invasive means for obtaining voluntary input from any muscle in the body. In one aspect, the EMG adhesive electrodes provide an alternative or additional input source to implanted EMG sensing leads. In one example, the EMG sensor may communicate with the EPG via wires or wirelessly. In one example, the voluntary input may be transmitted to the RSC or IPG via short-range RF telemetry.

[0049]

[0060] In one embodiment, the EMG sensor may include surface or implanted electrodes tailored for a specific application. Surface electrodes may be non-invasive and may be adhered to the surface of the skin above the target muscle, while implanted electrodes are surgically positioned closer to or within the muscle to more directly access muscle activity. Surface electrodes may capture electrical signals generated by muscle fibers during contraction, while implanted electrodes access muscle activity even more directly.

[0050]

[0061] In one embodiment, the neuromodulation system includes two cuff electrodes: one acts as an input driver by sensing weak ENG activity and communicates with the IPG, which can then send specific parameters to the second, distal cuff electrode to activate nerve bundles and activate motor control.

[0051]

[0062] In one embodiment, the neuromodulation system includes an on / off control that communicates with the IPG to turn stimulation on or off.

[0052]

[0063] According to certain embodiments, the neuromodulation system may also include a wearable device, including an accelerometer, gyroscope, position sensor, and / or implantable device capable of detecting EMG activity, motor unit recruitment, and other measures of limb position. This sensory feedback corresponds to real-time adjustment of stimulation parameters to facilitate the end user's completion of the intended efferent movement.

[0053]

[0064] IPGs can be configured to interface wirelessly with an external handheld device that, when placed on the skin above the implant, provides the patient with a noninvasive means to activate the IPG, adjust stimulation parameters (within physician-prescribed limits), check battery status, and wirelessly charge if necessary. IPGs are typically MRI compatible and can be wirelessly charged via a transcutaneous magnetic charging coil.

[0054]

[0065] Additionally, the IPG can be configured to wirelessly interface with a physician programmer. The physician programmer can include a tablet computer and a telemetry cable with a telemetry head. The telemetry head can communicate with the IPG through the skin by short-range radio frequency (RF) telemetry. The telemetry communication allows a physician to noninvasively interrogate and configure IPG settings. In one example, the physician programmer has the ability to monitor EMG waveforms, configure stimulation modes, adjust stimulation parameter values, and store waveforms and settings.

[0055]

[0066] Turning to FIG. 2, one embodiment provides a neuromodulation system for functional limb movement. The neuromodulation system includes an implantable receiver stimulator coil (RSC) 20 connected to an MCE 24 by a stimulation lead. The RSC is typically MR compatible. A surgeon can implant the RSC 22 subcutaneously in the upper chest, under the clavicle, in the axilla, or in the arm, and connect it to the stimulation lead. The MCE 24 typically includes a cuff with a diameter of 2 mm to 6 mm and a length of 1 cm to 2 cm. The cuff electrode contacts can be arranged in two or more "rings," each containing four individual 2 mm x 1 mm rectangular (tripolar) platinum or 90 / 10 platinum / iridium contacts. These contacts are positioned at 0, 90, 180, and 270 degrees around the ring and are embedded in silicone. The contacts are spaced 1 mm to 5 mm apart, with a 1 mm gap from the contacts to the edge of the cuff. This arrangement allows for monopolar stimulation of discrete nerve locations and bipolar stimulation between the two contacts. The cuff may optionally have sutures embedded within the silicone to facilitate cuff placement. A surgeon typically positions the MCE around the patient's musculocutaneous nerve and connects the lead's connector tip to the RSC. The cuff electrode can be configured to apply a current that stimulates the musculocutaneous nerve and flex the arm at the elbow.

[0056]

[0067] In contrast to the first embodiment, this alternative system employs an external pulse generator (EPG) and an external coil to power the implanted RSC. The EPG and coil are typically located within a housing 26. The housing 26 is positioned above the RSC 20, as indicated by arrow 28 in FIG. 2, allowing the external and internal coils to be aligned. The EPG houses electronics and a battery within a titanium case, includes or is connected to an external EMG sensor, and further includes a processor or controller. The processor or controller is programmed with an algorithm that detects weak electromyogram signals from the EMG sensor when arm flexion is attempted. The algorithm can also be programmed to deliver stimulation to one or more channels of an MCE wrapped around the musculocutaneous nerve. In one example, voluntary input from adhesive electrodes is sent to the EPG. The EPG is typically attached externally with a magnet and interfaces with the implanted RSC via the skin.

[0057]

[0068] Additionally, the alternative system typically also includes a motion remote, typically a handheld device, that is placed on the skin above the implant and configured to provide the patient with a non-invasive means for activating the RSC, adjusting stimulation parameters (within physician-prescribed limits), and checking battery status.

[0058]

[0069] This alternative system also typically includes a physician programmer similar to that of the first embodiment. For example, the physician programmer includes a tablet computer and a telemetry cable / head. The telemetry cable / head communicates with the IPG via short-range radio frequency (RF) telemetry through the skin, allowing the surgeon to noninvasively interrogate and configure IPG settings. The surgeon programmer may have the ability to monitor EMG waveforms, configure stimulation modes, adjust stimulation parameter values, and store waveforms and settings.

[0059]

[0070] Turning to Figures 3A-3C and 4A-4B, an implanted multichannel electrode is shown. In one example, the multichannel electrode may be a cuff electrode sold by MicroProbes for Life Sciences (Gaithersburg, MD, USA). Each cuff has an inner diameter of 1.5 mm, with two separate rings containing four 100-micrometer rectangular electrode contacts arranged concentrically at 90-degree intervals (0°, 90°, 180°, and 270°) within a silicone sheath. This arrangement of rings and contacts allows for monopolar stimulation of unique spatial locations on the nerve. A second parallel ring allows for magnetic field manipulation, allowing two electrodes on the same cuff to be stimulated simultaneously to elicit an amplified response. The charge injection capacity was 164 μC / cm2 at 1 mA, and the phase duration was 82 μS (0.5–1.5 μC / phase). The electrode impedance was 0.5 kΩ at 1000 Hz.

[0060]

[0071] In one example, the MCE may have an 8-channel MCE with two parallel electrode rings, each with four rectangular electrodes arranged 90 degrees apart within a silicone sheath. Figure 3B shows intraoperative images of two MCEs implanted in the superior and inferior FN branches of a cat. Figure 3C shows an image of the male Omnetics connector from the MCE.

[0061]

[0072] In one example, the neuromodulation system can also include operational stimulation parameters, such as monophasic or biphasic current, typically ranging from 0.1 to 20 mA, repetition rate ranging from 1 to 50 pulses per second, and duration ranging from 10 to 200 μs. The device is designed and constructed to be physician-programmable and patient-adaptable, for example, to mimic normal use of arm flexion using machine learning capabilities.

[0062]

[0073] 4A, according to certain embodiments, the MCE has two electrode rings, each with four rectangular (1.5 x 0.25 x 0.38 mm) platinum electrodes arranged 90° apart within a silicone sheath. In one example, the current source is controlled by an 8-channel digital-to-analog converter (TDT RX8) and can be configured to deliver biphasic electrical 82 μs pulses according to certain embodiments.

[0063]

[0074] Turning to FIG. 5 , a system 30 for moving a target muscle in accordance with the principles of the present invention will be described. System 30 includes an EMG sensor 32, an electrode assembly 34, and a pulse generator 36. Pulse generator 36 may include an implantable component 38 and an external component 40, with the external component connected to electrode assembly 34 by leads 48 and implantable component 40 connected to EMG sensor 32 by leads 60. Implantable component 38 may include circuitry 52 and an induction coil 54 disposed within an implantable housing 39, and external component 40 may include circuitry 62 and an induction coil 64 disposed within an external housing 41. Implantable housing 39 may be adapted or configured to be implanted subcutaneously in any of the locations previously described, such as in the upper chest, below the collarbone, or in the axilla, with external housing 41 adapted or configured to be secured to the patient's skin in a location proximal to the location of implanted housing 39, preferably directly over the implanted housing, to enhance communication between the external and implanted components of pulse generator 36. Optimally, a magnetic coupling element (schematically shown by dashed line 46 in FIG. 7) is provided to help position and secure the outer housing 41 above the embedded housing 39 .

[0064]

[0075] Turning to FIG. 6 , the electrode assembly 34 can include a cuff 42, typically a multi-electrode cuff having multiple electrode elements 44 formed on its inner surface. The electrode elements 44 can be formed on the inner surface of a liner or other support matrix of the cuff 42, which can be folded or wrapped around the target nerve to engage some or all of the electrode elements with the nerve's outer surface. The electrode elements can be configured in different sizes and orientations, such as two, three, four, or more channel electrodes 44a distributed circumferentially across the inner surface of the liner to surround the nerve when the liner is wrapped or folded over the nerve. Additionally or alternatively, a ring electrode 44b can be formed to continuously surround the inner surface of the cuff, and a ground electrode 44c can be provided when bipolar operation is desired. Alternatively, of course, any two or more of the channel electrodes 44, or one or more of the channel electrodes and the ring electrode and / or ground can be connected to operate in a bipolar mode.

[0065]

[0076] Referring now to FIG. 7 , the circuits 52 and 62 within the implantable component 38 and the external component 40, respectively, will be further described. The circuit 52 within the implantable component 38 may typically include a transmitter / receiver XMTR / REC configured for transcutaneous transmission and reception of low-power data (digital and / or analog) between the implantable component 38 and the external component 40. The transmitter / receiver may receive power from a power source PS, which also powers a signal processing unit SP and a stimulator unit STIM. The power source PS may typically include a battery or a capacitor and may be recharged by an induction coil 54. The induction coil 54 receives its charge from an induction coil 64 within the external component 40. The signal processing unit SP may be programmed to receive commands from the external component 40 and control and / or adjust parameters of the stimulator STIM according to these commands. The stimulator STIM may generate and selectively deliver electrical current to individual wires or channels 50 of the lead 48. A lead 48 is connected to the cuff 34 to activate the target muscle.

[0066]

[0077] The circuitry 62 within the external component 40 typically includes a transmitter / receiver XMTR / REC configured for transcutaneous transmission and reception of low-power data (digital and / or analog) with the implantable component 38. The transmitter / receiver receives power from a power source PS, which also powers a signal processing unit SP and an amplifier AMP. Alternatively, the power source PS may be powered by a rechargeable battery, which can be recharged wired or wirelessly, as is common in handheld digital devices. Although not shown, the external component 40 typically also includes a display and I / O capabilities to enable programming and updating of its internal logic. The amplifier AMP may be configured to be externally connected to the EMG sensor 12 by a lead 60, although wireless communication may also be used.

[0067]

[0078] According to one embodiment, a method of neuromodulation for functional limb movement is provided. The method includes a pulse delay or stimulation frequency configured to evoke sustained muscle contraction without significant fatigue. The method can include stimulation of peripheral motor nerves, such as the sciatic nerve and / or femoral nerve. According to one embodiment, a sensing lead can be placed in the biceps brachii muscle and configured to detect weak EMG signals during attempted arm flexion.

[0068]

[0079] According to one embodiment, a method of neuromodulation for functional limb movement is provided and includes an intermittent waveform 800 (see FIG. 8 ). According to one embodiment, the intermittent waveform 800 can include a charge balanced symmetric biphasic stimulation waveform, which includes a first pulse 810, a second pulse 820, and a pulse delay 830.

[0069]

[0080] In one embodiment, a pulse delay is introduced that is tailored to the patient to achieve a critical factor for inducing functional stimulation without muscle fatigue. The peripheral neuromodulation system can be configured to individually determine stimulation parameters, including pulse delays from 10 mS to 70 mS, to achieve this result.

[0070]

[0081] According to certain embodiments, the pulse delay may be any one of 5-10 mS, 10-15 mS, 15-20 mS, 25-30 mS, 35-40 mS, 45-50 mS, 55-60 mS, 65-70 mS, and 70-75 mS. In one example, the pulse delay adjustment may have an average of 40 mS to elicit a sustained isometric concentric contraction without fatigue. In one aspect, the pulse delay adjustment may be a period of no stimulation between at least two adjacent pulses.

[0071]

[0082] According to one embodiment, a method for neuromodulation for functional limb movement is provided, comprising delivering a series of two or more intermittent waveforms 900 (see FIG. 9 ). According to one aspect, the intermittent waveforms 900 can include a waveform transition from a first frequency 910 configured to evoke a first muscle contraction to a second frequency 920 configured to evoke a second muscle contraction once a muscle contraction has been initiated to reduce muscle fatigue. By varying pulse delay, current amplitude, and pulse width, a second set of stimulation parameters can be instantaneously transitioned to continue stimulating the nerve, albeit with different stimulation parameters, to produce a muscle contraction. Experiments by the inventors have shown that longer pulse delays can reduce muscle fatigue, which is useful for maintaining muscle contraction, as opposed to shorter pulse delays, which are effective for inducing an initial muscle contraction.

[0072]

[0083] This method can involve stimulation of peripheral motor nerves both before and after ischemic damage to the central nervous system (hemispheric infarction). By adjusting pulse delays, stimulation can be instantaneous, gradual, and controllable to produce functional limb movement without nerve fatigue.

[0073]

[0084] According to one embodiment, a method for providing a dynamic stimulation framework for functional limb movement is provided. The method includes step 1010 of initiating stimulation of a nerve with a series of current pulses, step 1020 of varying a pulse delay between at least two pulses in the series, and step 1030 of providing graded stimulation to elicit controlled relaxation (see FIG. 10 ). In one example, controlled limb relaxation can be obtained by stimulating the femoral nerve with 200 μA or 100 μA, with pulse widths of 150 and 75 μS, respectively, and a pulse delay of 10 mS. In one aspect, the initiation, maintenance, and relaxation steps can be optimized to achieve desired movement while mitigating off-target effects.

[0074]

[0085] Dynamic adjustment of stimulation parameters in real time to optimize movement can be dynamically controlled by the patient or provider, or through the use of sensors that provide information to the system. In one aspect, movement can also be sensed and adjusted in real time to allow functional limb movement regardless of starting arm position or load.

[0075]

[0086] According to one embodiment, a system is provided that dynamically adjusts stimulation parameters to produce functional limb movement based on voluntary control and patient intent. Through experimentation, the inventors have discovered that when stimulating a nerve with a constant current, varying the delay between pulses produces functionally relevant limb movement. For example, shorter pulse delays result in rapid tetanic muscle activation, but are countered by rapid muscle fatigue. On the other hand, longer pulse delays result in slower muscle activation but less fatigue. There is a moderate pulse delay that allows for strong muscle activation while reducing muscle fatigue. This is clinically relevant to patients and has been experimentally observed in the inventors' animal studies in pigs. This optimal pulse delay allowed muscles to remain in a stimulated, activated form for more than five minutes without fatigue.

[0076]

[0087] For example, stimulation at a higher frequency (i.e., shorter pulse delay) results in sharper concentric muscle contractions, which over time lead to muscle fatigue. In one example, a higher frequency may be 60-100 Hz, while a lower frequency may be 10-40 Hz. Stimulation frequency can be correlated with pulse delay, since the longer the pulse delay, the lower the stimulation frequency. Muscle fatigue can cause limbs to relax against gravity, which can be functionally ineffective when generating isometric concentric muscle movements to lift a hand to the face and then maintain this position (i.e., isometric contraction).

[0077]

[0088] Through experiments, the inventors have demonstrated a range of muscle contractions, both in strength and velocity, for slow, normal, and fast limb movements, as the current is increased while maintaining the same frequency. The stimulation parameters, frequency and amplitude, ranged from 1 to 100 Hz and 0.01 to 0.20 mA, respectively. Based on the established Medical Research Council Manual Muscle Testing Scale, or the Manual Muscle Testing Rating System, which rates from 0 to 5, the inventors were able to reliably and repeatedly derive graded movements on a scale of 1 to 5. In one embodiment, when movements were elicited and graded responses were obtained, no tissue damage was observed on histological examination, and stable, repeatable movements involving constant stimulation for up to 5 minutes were demonstrated, with the limb remaining in its desired graded position for a specified amount of time without fatigue. Through experiments, the inventors were able to maintain strong contractions for at least 5 minutes without fatigue.

[0078]

[0089] In clinical settings, therapeutic devices seeking to resuscitate limbs to restore function require the ability to generate sustained muscle contractions without fatigue. In one aspect, optimal stimulation settings can be varied between nerves and even over time when stimulating the same nerve. As nerves recover over time, or as patients recover, stimulation parameters may need to be adjusted to account for changes in the patient's intrinsic physiology. For example, by varying the pulse delay—in this case, by lengthening the pulse delay—fatigue-free isometric muscle contractions can be achieved for a certain duration. However, if the pulse delay is too long, it can result in spastic limb movements whose frequency varies based on the pulse delay. Each patient requires individual programming to establish their optimal pulse parameters and enable smooth muscle contractions with minimal muscle fatigue. Furthermore, the system can be programmed to deliver electrical stimulation to nerves to maintain muscle mass and prevent muscle atrophy, as well as to reduce contracture formation and regulate spasticity. This configuration would promote endogenous patient recovery and would be more useful as an augmentation to rehabilitation rather than an explicit therapeutic tool for limb resuscitation.

[0079]

[0090] According to an embodiment, a method 1100 provides neuromodulation for functional limb movement according to a specific embodiment, and can include step 1110 of detecting a patient's voluntary input and step 1120 of delivering a charge-balanced symmetrical biphasic stimulation waveform including a series of current pulses and pulse delays upon detection of the voluntary input (see FIG. 11 ).

[0080]

[0091] According to one embodiment, a method for neural modulation for smooth limb movements is provided. The method includes graded stimulation with an afferent isokinetic phase, an isometric phase, and an isokinetic efferent phase. In one example, the smooth limb movement may include a patient lifting their hand to their face, grasping their hand to complete a task, and smoothly lowering their hand. In one example, graded stimulation may include a sequence of stimulation steps performed to accomplish the smooth limb movement. For example, if a sensory component enabling detection of initial limb position is integrated into the device, these sensory signals can adjust the device's stimulation output to account for variability in the patient's initial limb position while simultaneously facilitating the completion of a useful, functional limb movement as intended by the end user.

[0081]

[0092] In concentric contractions, muscle tension increases to match resistance and then remains stable as the muscle shortens. In one example, the concentric isokinetic phase may include a stimulation algorithm configured to gradually increase current delivery over a period of several seconds to smoothly contract the muscle and lift the limb to the desired height. Once the limb reaches the desired height, maintenance stimulation can be applied at that height to prevent fatigue. In one embodiment, by gradually increasing stimulation in stages over a predetermined period, limb movement can be smooth and functional. In some embodiments, the concentric isokinetic phase is configured to prevent abrupt or unstable muscle contractions and subsequent limb movement, as experienced with instantaneous current delivery. In one example, the concentric isokinetic phase may include a first frequency 910 configured to evoke a first muscle contraction, as shown in FIG. 9 .

[0082]

[0093] In one example, the isometric phase may include a stimulation algorithm utilizing different pulse delays and lower frequencies, with initial stimulation parameters configured to maintain smooth muscle contractions while preventing fatigue, tremors, or spasms. In one example, fatigue is induced by short pulse delays and associated with high stimulation frequencies, such as 40-150 Hz. In one example, tremors or spasms may be induced by long pulse delays, resulting in high stimulation frequencies, such as 40-150 Hz. According to certain embodiments, the isometric phase may be maintained in a closed-loop or open-loop manner. In one example, an open-loop system may be activated based on manual input that adjusts pulse delays to mitigate undesirable effects. In one example, a closed-loop system may measure fatigue and / or tremors / spasms and dynamically adjust pulse delays to mitigate undesirable effects.

[0083]

[0094] According to certain embodiments, pulse delays can be individualized for a particular patient to optimize isometric movement, reduce fatigue, and attenuate spasms / tremors. The specific timing between pulses must be customized for each patient and will vary based on a variety of factors, including the patient's intrinsic physiological muscle activation, individual neuromuscular sensitivity to stimulation, and other factors including muscle mass, contracture, and / or spasticity. One mechanism by which optimal stimulation settings can be identified is clinically by manually adjusting pulse delays and visualizing or measuring their effect on limb movement.

[0084]

[0095] In an eccentric contraction, a muscle lengthens as resistance becomes greater than the force it is generating. An example is lifting a heavy object, which requires maximal nerve stimulation and subsequent muscle contraction to maximize limb movement.

[0085]

[0096] Experimental results demonstrated controlled limb relaxation in a porcine model before and after ischemic injury of the sciatic and femoral nerves. Prior to ischemic injury, sciatic nerve stimulation using a dual-channel cuff with parameters of 200 μA current, 100 μS pulse width, and 10 mS pulse delay produced transient afferent muscle movements. Transient afferent muscle movements were also produced by stimulation of the femoral nerve with a dual-channel cuff with parameters of 500 μA current, 50 μS pulse width, and 10 ms pulse delay. Controlled limb relaxation was also achieved by stimulating the femoral nerve with 200 μA or 100 μA current, 150 and 75 μS pulse widths, respectively, and a 10 mS pulse delay. This controlled relaxation may be the result of muscle fatigue, but it can also be modulated by decreasing the current over time, resulting in a gradual drop in current and subsequent efferent muscle relaxation.

[0086]

[0097] By varying the stimulation parameters, stimulation with a current of 1500 μA, a pulse width of 500 μS, and a pulse delay of 40 mS elicits sustained isometric concentric contractions of the femoral nerve without fatigue.

[0087]

[0098] Following ischemic injury, the sciatic nerve was stimulated with an 8-channel MCE using parameters of 1500 μA current, 500 μS pulse width, and 40 mS pulse delay, allowing for sustained contractions without fatigue. Following stroke, isolated twitching movements of the sciatic nerve were elicited using an 8-channel cuff electrode with a constant current of 1500 μA and a pulse width of 500 μS, with pulse delays adjusted from 100 to 250 to 300 mS.

[0088]

[0099] Stimulation of the sciatic nerve with an 8-channel cuff electrode using the following parameters: 250 μA current, 250 μS pulse width, and 10 mS pulse delay, resulted in sustained muscle contraction and force generation against resistance following ischemic injury at 20, 60, 120, and 180 minutes after ischemic injury.

[0089]

[0100] Instantaneous afferent limb movements were reliably observed in the femoral and sciatic nerves at 20, 60, 120, and 180 minutes after stroke using both two-channel and eight-channel electrodes, respectively, with stimulation parameters ranging from 200 μA current, 50 μS pulse width, and 20 mS pulse delay to 2000 μA current, 200 μS pulse width, and 20 mS pulse delay. Additional stimulation ranges that may be beneficial to patients are described below.

[0090] [Table 1]

[0091]

[0101] Regarding motor control, the inventors have found that pulse delay is a critical factor in achieving motor control without fatigue and inducing sustained contractions and movement. By varying pulse delay, current amplitude, and pulse width, instantaneous transitions to a secondary set of stimulation parameters can be achieved, resulting in continued nerve stimulation and muscle contraction, albeit with different stimulation parameters. Through experiments, the inventors have found that longer pulse delays reduce muscle fatigue. This is useful for maintaining muscle contraction, as opposed to shorter pulse delays, which are effective for inducing initial muscle contraction.

[0092]

[0102] According to certain embodiments, the neuromodulation system may be configured to deliver waveforms using a variety of stimulation parameters, including waveforms with specific frequencies ranging from 1 to 100 Hz. Typical waveforms may have cathodic phase durations ranging from 0 to 1000 μs, interphase intervals ranging from 0 to 1000 μs, and anodic phase durations ranging from 0 to 1000 μs, and currents ranging from 0.01 to 20 mA.

[0093]

[0103] According to certain embodiments, the neuromodulation system can be configured as a closed-loop system using an input trigger to detect voluntary movement and deliver stimulation or current to nerves based on the voluntary movement to induce enhanced muscle activation. In one example, enhanced muscle activation can be measured and / or monitored to dynamically adjust stimulation parameters and control functional muscle movement in real time. In one example, the input trigger can be detection of voluntary EMG movement, electroencephalography (EEG) signals, electroneurography (ENG) signals, or other types of input indicative of voluntary movement. In one example, an EEG sensor can be used to detect when a patient thinks about moving their limb and provide an input trigger indicative of their brain activity. The input trigger can be formed as a patient signature to induce muscle activation. The input trigger can be processed to induce delivery of current to the cuff electrodes by a pulse generator. In one aspect, the patient's signature can be programmed postoperatively, such as in a clinic, to enable useful limb movement.

[0094]

[0104] In one example, a patient's prescription can be programmed to activate controlled limb movements to prevent sudden movements. In one embodiment, a patient's prescription can be programmed to automatically adjust for patients carrying objects of different weights / loads. In one embodiment, real-time sensory monitoring of limb movement speed can be used to regulate current delivery to the nerve when a patient's prescription was previously programmed for movement too slowly or too quickly.

[0095]

[0105] The input trigger can be provided from an implantable device or a wearable device. In one example, the neuromodulation system can include a wearable device configured to measure voluntary signals, limb velocity, or other muscle parameters. In one example, the neuromodulation system can also include an implantable device to measure voluntary signals, such as EMG activation.

[0096]

[0106] While preferred embodiments of the present invention have been illustrated and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the present invention be limited to the specific examples set forth herein. While the present invention has been described with reference to the specification, the description and illustration of the embodiments herein are not intended to be construed in a limiting sense. Numerous modifications, changes, and substitutions will now occur to those skilled in the art without departing from the present invention. It will be further understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions set forth herein, as these vary depending upon a variety of conditions and variables. It should also be understood that various alternatives to the embodiments of the present invention described herein can be employed in practicing the present invention. It is therefore intended that the present invention encompass any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims, and their equivalents, are encompassed within the scope of the claims.

Claims

1. 1. A neuromodulation system for enabling a patient to perform functional limb movement, comprising: a multi-channel electrode configured to be placed on or around a peripheral nerve of the patient; a pulse generator configured to deliver stimuli to the nerve via the multi-channel electrode to induce functional limb movement in the patient, the stimuli comprising a series of current pulses comprising at least one pulse delay; a controller operably coupled to the pulse generator; A neuromodulation system comprising:

2. 10. The system of claim 1, wherein the controller is configured to perform one or more of the actions of applying or adjusting the stimulus based on voluntary input.

3. 3. The system of claim 2, further comprising a sensing lead configured to detect a patient's voluntary input, the sensing lead operably coupled to the controller.

4. 3. The system of claim 2, wherein the controller adjusts the at least one pulse delay based on the voluntary input.

5. 3. The system of claim 2, wherein the voluntary input is based on one or more of the patient's neural activity or muscle activity.

6. 4. The system of claim 3, wherein one or more of the patient's nerve activity or muscle activity is from a nerve or muscle different from the nerve or muscle associated with the nerve to which the stimulation is applied.

7. 10. The system of claim 1, further comprising a manual trigger operably coupled to the controller to receive input from the patient or other user, the controller configured to take one or more actions to apply or adjust the stimulation based on the received input.

8. 2. The system of claim 1, wherein at least two consecutive pulses in the series of current pulses are separated by the at least one pulse delay.

9. 10. The system of claim 1, wherein the at least one pulse delay is between 5 and 75 mS.

10. 10. The system of claim 1, wherein the at least one pulse delay has an average of 40 mS.

11. 10. The system of claim 1, wherein the pulses in the series of current pulses of the stimulation have a pulse width between 50 and 1000 μS.

12. 10. The system of claim 1, wherein the pulses in the series of current pulses of the stimulation have a pulse current of 50 to 2000 μA.

13. 10. The system of claim 1, wherein the pulses in the series of current pulses are charge-balanced, biphasic, or both.

14. 10. The system of claim 1, wherein the pulse generator is implantable.

15. The system of claim 1 , wherein the sensing lead is implantable.

16. The system of claim 1 , wherein the controller is embedded.

17. The system of claim 1 , wherein the sensing lead is an adhesive electrode.

18. 10. The system of claim 1, wherein the sensing lead is an electromyography sensor.

19. 10. The system of claim 1, wherein the sensing lead is an electroencephalography sensor.

20. 10. The system of claim 1, wherein the multi-channel electrode is a cuff configured to be placed around the nerve.

21. 1. A method of inducing flexion in a target muscle of a patient, comprising: receiving input from the patient or other user; delivering a charge-balanced symmetrical biphasic stimulation waveform to the target muscle upon receiving the input, the stimulation waveform including a series of current pulses and at least one pulse delay, thereby eliciting functional limb movement; A method comprising:

22. 22. The method of claim 21, wherein receiving the input comprises detecting a voluntary input from the patient.

23. 23. The method of claim 22, wherein the voluntary input is based on one or more of the patient's neural activity or the patient's muscle activity.

24. 24. The method of claim 23, wherein one or more of the patient's nerve or muscle activity is from a nerve or muscle different from the nerve or muscle associated with the nerve to which the stimulation is applied.

25. 23. The method of claim 22, further comprising detecting a second voluntary patient input and adjusting the stimulation waveform based on the second voluntary patient input.

26. 23. The method of claim 22, wherein the voluntary input is received from a sensing lead.

27. 23. The method of claim 22, wherein the voluntary input is received from a muscle or nerve different from the target muscle.

28. 23. The method of claim 22, further comprising adjusting at least one of an amplitude, a frequency, a pulse width, and a pulse delay of the stimulation based on the voluntary input.

29. 22. The method of claim 21, wherein the input is received from the patient or other user via a manual trigger.

30. 30. The method of claim 29, further comprising adjusting at least one of an amplitude, a frequency, a pulse width, and a pulse delay of the stimulation based on input received from the manual trigger.

31. 22. The method of claim 21, wherein the at least one pulse delay is between 5 and 75 mS.

32. 22. The method of claim 21, wherein the at least one pulse delay has an average of 40 mS.

33. 22. The method of claim 21, wherein the stimulation train of current pulses has a pulse width between 50 and 1000 μS.

34. 22. The method of claim 21, wherein the stimulation train of current pulses has a pulse current of 50 to 2000 μA.

35. 22. The method of claim 21, wherein the pulses in the series of current pulses are charge-balanced, biphasic, or both.

36. 22. The method of claim 21, further comprising detecting signs of muscle fatigue.

37. 22. The method of claim 21, further comprising the step of varying a pulse delay between at least two pulses of the series of pulses.

38. 1. A method of providing dynamic stimulation for functional limb movement, comprising: initiating flexion stimulation of the nerve with a constant current and a series of pulses including at least one pulse delay; detecting a patient's voluntary input; Varying the pulse delay between two pulses in the series of pulses based on the voluntary input while maintaining the flexion stimulus; delivering a relaxation stimulus configured to elicit controlled relaxation; A method comprising:

39. 39. The method of claim 38, wherein the voluntary input is based on neural activity of the patient.

40. 39. The method of claim 38, wherein the voluntary input is based on muscle activity of the patient.

41. 39. The method of claim 38, wherein the at least one pulse delay is between 5 and 75 mS.

42. 39. The method of claim 38, wherein the at least one pulse delay has an average of 40 mS.

43. 39. The method of claim 38, wherein the pulses in the series of current pulses of the stimulation have a pulse width between 50 and 1000 μS.

44. 39. The method of claim 38, wherein a pulse in the series of current pulses of the stimulation has a pulse current of between 50 and 2000 μA.

45. 39. The method of claim 38, wherein the pulses in the series of current pulses are charge-balanced, biphasic, or both.

46. 39. The method of claim 38, further comprising detecting a second voluntary input from the patient and adjusting the stimulation based on the second voluntary input.

47. 39. The method of claim 38, further comprising adjusting at least one of amplitude, frequency, pulse width, and pulse delay based on the voluntary input.

48. 39. The method of claim 38, further comprising detecting signs of muscle fatigue.

49. 39. The method of claim 38, further comprising varying the pulse delay between at least two pulses of the series of pulses.

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