Closed loop nerve regeneration system and method for customized dosing stimulation therapy

Abstract

A method of delivering a stimulation signal to a target tissue region, including positioning one or more electrodes at or proximal the target tissue region, where the one or more electrodes are operatively connected to a stimulator through a lead. The method also includes generating the stimulation signal at the stimulator, where the stimulation signal travels to and excites the target tissue region from the stimulator via the lead and the one or more electrodes. The method also includes performing a measurement of a patient receiving the stimulation signal at the target tissue region, where the measurement indicates a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the patient. The method also includes controlling a stimulation signal parameter based on the measurement.

Description

PATENT APPLICATION Inventors: Kevin Scanlan Eric R. Walker Derek Lewis Ben Cottrill Docket No.: 37694-00242 TITLE CLOSED LOOP NERVE REGENERATION SYSTEM AND METHOD FORCUSTOMIZED DOSING STIMULATION THERAPY CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The application claims priority to U.S. Patent Application No. 63 / 633,179, filed onApril 12, 2024, entitled “CLOSED LOOP NERVE REGENERATION SYSTEM AND METHOD FOR STIMULATION THERAPY,” which is incorporated herein by reference in its entirety. FIELD OF TECHNOLOGY

[0002] The present disclosure relates generally to nerve regeneration, and more particularly tosystems and methods for delivery of therapeutic electrical stimulation to accelerate or enhance regrowth or recovery of injured or potentially injured nerves before, during, after, or independent of surgical procedures. Specifically, this disclosure focuses on the methodology and delivery mechanisms for the adjustability of stimulation parameters in response to parameters set by the user or conditioned on inputs from sensors. BACKGROUND

[0003] Nerve injuries present clinicians with significant challenges in determining the propercourse of treatment to restore impaired motor and or sensory function. Ultimately, the severity of the nerve injury and time post injury have the greatest influence on the treatment plan and potential for success. In many cases medical treatment and / or surgical intervention may be needed to increase the likelihood that control of muscle function or sensation can be regained. 1 35936527.2Surgical treatment of nerve injuries typically does not provide immediate restoration of function, as nerve fibers must grow from the point of intervention or repair to the target muscle. Nerve fibers under normal conditions grow at a rate of approximately 1 mm / day, and thus recovery takes a significant amount of time. In addition, normal axon regeneration following nerve injury is limited by biological inefficiencies including both the staggered initiation of regrowth and a potential for misdirected growth to a different target muscle or sensory receptor. This inefficient regrowth is further complicated by a limited viability window of denervated muscles, typically around 18 months, during which reinnervation needs to occur to restore neural connectivity.

[0004] Despite advancements in surgical technique and medical device technology, the rate ofgrowth and organization of fiber growth direction remains a significant factor limiting functional outcomes. Electrical stimulation delivered to the injured nerve has been shown to help accelerate nerve regeneration, improve nerve healing, and ultimately improve functional outcomes. Work in the field describes stimulating prior to or following repair, preferably while still in the operating room, to improve functional outcome. It may be desirable to deliver this therapeutic stimulation before, during, or after a surgical intervention. This therapeutic stimulation may be delivered for a period of time as a standalone treatment, or delivered in conjunction with a surgical procedure either outside of the operating room and / or within the operating room. Furthermore, it may be desirable to be able to initiate a period of stimulation prior to a procedure and continue into the operating room, initiating in the operating room and continuing into a post-operative setting, or initiated in the post-operative setting. Moreover, stimulation may be initiated in an office setting as part of a separate care encounter. Additionally, it may be desirable to deliver repeated periods of stimulation during recovery or as part of a therapy of nerve recovery, without the need to replace electrode(s) before each application. It may be desirable to deliver therapy not tied to the initial surgical intervention, either as a preventive measure to delay or avoid surgical intervention, delivered as a response 2 35936527.2to slowed or delayed healing, or if the operative technique or approach prevented therapeutic delivery or efficacy.

[0005] This disclosure is focused on overcoming the shortcomings identified above andproviding nerve stimulation in myriad physical and clinical circumstance as identified above. For example, this disclosure identifies techniques and methodologies for delivering therapeutic electrical stimulation inside and outside the operating room. These techniques address the unique needs for delivery in the operating room, which include patient tolerance, access to the nerve, among others described in detail herein. Further, it may be desirable to have an apparatus that can meet the aforementioned objectives. SUMMARY

[0006] The following presents a summary of this disclosure to provide a basic understandingof some aspects. This summary is intended to neither identify key or critical elements nor define any limitations of embodiments or claims. Furthermore, this summary may provide a simplified overview of some aspects that may be described in greater detail in other portions of this disclosure.

[0007] A nerve regeneration system comprises a stimulation device comprising a housing;control circuitry operatively generating a stimulation signal, wherein the control circuitry may be disposed within the housing. The nerve regeneration system may also comprise a control circuitry that may be the same or different from the prior-mentioned one that may also be positioned in the same housing. The following describes techniques and methodology for delivering therapeutic stimulation where the patient may be awake and / or be aware of stimulation delivery. Patient awareness of stimulation delivery presents a unique set of potential challenges that can impact therapeutic efficacy, such as patient compliance or tolerance of stimulation. It may be desirable for the device to allow user input or interaction to enable patient-specific setting of stimulation parameters, allow for patient control of initiating therapy stimulation, provide feedback on therapy status to the patient, adjustment of therapy 3 35936527.2parameters, and / or pausing therapy delivery. This interaction may enable direct control of a specific stimulation parameter (e.g., stimulation intensity) by the patient or provider, or trigger an automated adjustment made by the device based on patient feedback, user observation, or input from sensor(s). Input on patient perception and / or tolerance of the stimulation dose could enable titration or adjustment of the stimulation intensity to a patient specific therapy which may be based upon a perception threshold, individualized upper tolerance limit, or provide a patient specific range for stimulation intensity. These techniques can be used to individualize therapy settings to account for variation in individual perception, type of nerve (e.g., motor, sensory or mixed) stimulated, location of stimulation, placement of lead or electrode, etc. to improve therapeutic efficacy and / or patient compliance. For example, if the patient experiences discomfort or pain from the stimulation, or potentially evoked muscle contraction, the individual may decide to end treatment before therapeutic efficacy was achieved. Enabling the patient to pause and resume the therapy delivery can also improve patient compliance in the event the individual needs a break to complete another activity (e.g., answer phone or use restroom). Allowing the individual to select when to initiate the therapy, which may be limited or partially controlled by the device, could allow the individual to prepare for the therapeutic stimulation, such as reducing interruptions, finding a comfortable position, etc.

[0008] It may be desirable for the device to deliver therapeutic stimulation in a mannerdependent on input from an individual, a semi-automated manner enabling partial control from the user, or a fully automated manner with limited user control. The device may prompt the user for input or interaction at certain key points, such as defining motor threshold, perception threshold, and / or tolerance limit. The device may automatically adjust or ramp through stimulation parameters during a testing period to help the patient, caregiver, or clinician define these key stimulation settings ranges. Settings and ranges may be selected from a series of pre- set configuration or settings files on the device, to enable adjustment to certain pre-determined conditions. These settings may be set by the individual at the time of therapy delivery, by a 4 35936527.2clinician or health care provider, or fixed on the device. These setting can be used by the device to set the therapy within patient tolerance limits and / or within efficacy ranges, such as sub- perception, sub-motor threshold, or below tolerance level. The device may automatically adjust stimulation settings during therapy delivery and these ranges can ensure the therapy within patient tolerance limits and / or within efficacy ranges.

[0009] It may be desirable for the device to be able to deliver the therapeutic stimulation in afully automated or closed loop fashion. In this methodology, additional sensor(s) maybe used to track a physiological indicator to initially set and / or adjust the stimulation parameters to ensure therapeutic efficacy. In this manner the stimulation setting may be adjusted to the minimum necessary to produce the desired effect, tailoring the settings for each participant or therapy delivery session, or unique delivery needs such as minimizing muscle contraction if delivered during a procedure.

[0010] The closed loop stimulation may use an electrical signal such as electroneurogram(“ENG”) or electromyography (“EMG”) to detect stimulation-induced action potential, muscle contraction, or evoked sensory response to confirm successful delivery and activation of target nerve. Other detection sensors or devices may also be utilized. The system may detect the presence of evoked potential and / or quantify the measure the size or strength of the evoked response to ensure therapeutic benefit and may adjust the stimulation parameters to ensure an evoked response is detected and / or the response is maintained in a specific range. This range may be high enough to produce a nerve activation but be below a sensory or motor-evoked response.

[0011] A closed loop method may measure a motor response using (for example) anaccelerometer or a resistive sensor, to detect stimulation delivery, feeding that signal back to the stimulation control circuitry. The device could use the movement threshold to set the stimulation settings for the therapy and / or use the movement threshold to continuously adjust stimulation throughout delivery. This adjustment may be to maintain a motor response, or to 5 35936527.2minimize movement if delivered during surgery to allow other surgical tasks to take place while therapy is delivered.

[0012] Alternately, a closed loop method may use a physiological indicator such as a chemicalor other biological marker indicating successful activation of therapeutic mechanism of action to ensure successful therapy delivery. Such markers may comprise specific ions (e.g. calcium), either directly or indirectly through local voltage or current changes, indicating sufficient neural activation. It may also involve measurement of other associated biological factors (e.g.regenerative gene expression, macrophage proliferation) that are present when the therapeuticmechanism is activated. Gene expression may be determined by biopsies of tissues and fluids; RNA being isolated from the biopsied tissue and gene expression levels measured by RNA techniques including quantitative real-time reverse transcription polymerase gene reaction (“qPCR”) or RNA sequencing (“RNASeq”) methods. Macrophage infiltration may also be measured by gene expression of macrophage markers, by histochemistry of biopsied tissues and fluids, and by using flow cytometry methods.

[0013] A closed loop stimulation method may use the patient’s own perception of stimulation,allowing patient control of the intensity of stimulation while the overall dose is adjusted based on the patient-controlled titration. An example includes a patient simply turning a knob up and down to the maximum tolerable titration and the duration is adjusted accordingly (e.g., changing total pulses delivered to match a prescribed overall charge, or delivery time is a function of stimulation parameters such as amplitude, pulse duration, and / or frequency).

[0014] The stimulation may be increased and decreased to identify a threshold, such as motorresponse, therapeutic response, or patient perception and then apply the minimum suprathreshold stimulation for therapeutic benefit, which may be sub- or supra-motor or perception threshold. The motor response threshold may include an input from an accelerometer and compound muscle action potentials (CMAP). The therapeutic response may include an input from an ENG and chemical biomarkers. 6 35936527.2

[0015] It may be desirable for the system to include techniques to block or prevent thetherapeutic stimulation from producing a distal muscle contraction. A distal blocking electrode or multi-polar stimulating electrode may be used to reduce or eliminate the distal propagation of action potentials to the muscles while still allowing proximal therapeutic activation. The system may use distal electrode contact(s) and / or separate lead(s) to deliver high frequency stimulation to create a local conduction block, and / or may be used to deliver a paired stimulation patterns with the therapeutic stimulation pattern to prevent the evoked action potentials from stimulation from producing a distal muscle contraction. Preventing distal contractions may be desired to enable surgical techniques to be continued if delivered intraoperatively, and / or to reduce patient discomfort from muscle activation during the therapeutic dose if undesired. These techniques may be used to minimize sensory nerve activation during the therapeutic stimulation.

[0016] A method for stimulating tissue comprises providing a stimulation device; placing alead within range of a target tissue region, wherein the lead is operatively attached to the stimulation device; applying a stimulation signal to the target tissue region with the lead and the stimulation device; and terminating the application of stimulation signal. This stimulation process may be performed before or after performing a subcutaneous surgery.

[0017] In an embodiment, a method of delivering a stimulation signal to a target tissue region,including positioning one or more electrodes at or proximal the target tissue region, where the one or more electrodes are operatively connected to a stimulator through a lead. The method also includes generating the stimulation signal at the stimulator, where the stimulation signal travels to and excites the target tissue region from the stimulator via the lead and the one or more electrodes. The method also includes performing a measurement of a patient receiving the stimulation signal at the target tissue region, where the measurement indicates a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the 7 35936527.2patient. The method also includes controlling a stimulation signal parameter based on the measurement.

[0018] In an embodiment, a stimulation system includes a stimulator that generates astimulation signal. The system also includes one or more electrodes operatively connected to the stimulator, wherein the one or more electrodes are positioned relative to a patient and convey the stimulation signal to a target tissue region of the patient. The system also includes control circuitry in the stimulator that performs a measurement of a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the patient, and automatically adjusts a stimulation signal parameter based on a minimum therapeutic benefit threshold, a motor response threshold, a perception threshold, or a tolerance limit associated with the performed measurement.

[0019] A non-operative Brief Electrical Stimulation Therapy (“BEST”) method comprisesleaving a lead wire connected to or connecting a lead wire to a lead adjacent to the targeted nerve, typically with no tine or anchor due to its transient implant time. The electrode can be placed using ultrasound or electrical stimulation and observed motor response.

[0020] In an embodiment, the lead may comprise a trial lead similar to a configuration of aspinal cord stimulation system and / or a trial lead from an electrical stimulation system for the treatment of an overactive bladder.

[0021] In an embodiment, the lead may comprise a percutaneous lead such as those used inpercutaneous stimulation for the treatment of pain.

[0022] In an embodiment, the lead may comprise an injectable lead.

[0023] In an embodiment, the lead may comprise a percutaneous electrode.

[0024] In an embodiment, the lead may comprise a conductor with biocompatible insulationand a biocompatible conductive contact. The contact may be for example an annular ring, a hemisphere, or an exposed planar surface. In some embodiments, the conductive contact may be formed by selectively removing a portion of the insulation to expose the underlying 8 35936527.2conductor, such that the exposed region functions as an electrode capable of delivering electrical stimulation. The lead may include both a cathode that is a stimulating electrode, and include an anode that is a return electrode. The cathode and the anode may be spaced apart on the same lead to enable bipolar stimulation without requiring a separate reference or return electrode, such as an external needle.

[0025] In an embodiment the lead may comprise a bioresorbable polymer or gel wrapped withconductive addition and dissolvable or easy release connection to lead wire; containing a transcutaneous dissolvable coil (e.g. zinc); and having a pullout.

[0026] In an embodiment, a lead in a nerve regeneration system includes a body forming aproximal end portion of the lead, and an insulation disposed around the body. The insulation blocks transmission of an electrical stimulation signal from the body to an exterior environment. The electrode that is an uninsulated biocompatible conductive contact extended from the body in a longitudinal direction of the lead. The electrode transmits the stimulation signal to the exterior environment at a target tissue region. The lead also includes an anchor forming a distal end portion of the lead, at a side of the electrode opposite the body in the longitudinal direction, where the anchor stabilizes the lead relative to the target tissue region.

[0027] In an embodiment, a method of transmitting an electrical stimulation signal to a targettissue region includes delivering a percutaneous lead to the target tissue region. An anchor forming a distal end portion of the lead is positioned at a first side of the target tissue region, an insulated body forming a proximal end portion of the lead is positioned at a second side of the target tissue region opposite the first side in a longitudinal direction of the lead, and an electrode interposed between the insulated body and the anchor in the longitudinal direction is positioned at the target tissue region. The method also includes transmitting the electrical stimulation signal through the insulated body and the electrode, to the target tissue region. The method also includes detaching the electrode from the insulated body, removing the insulated 9 35936527.2body from the target tissue region, and leaving the electrode at the target tissue region, where the electrode dissolves at the target tissue region.

[0028] In an embodiment, a method of transmitting an electrical stimulation signal to a targettissue region includes delivering a percutaneous lead to the target tissue region. A plurality of electrodes formed from a wire are positioned along the target tissue region in a longitudinal direction of the wire, and at least one insulated portion of the wire is interposed between and separates the plurality of electrodes along the wire in the longitudinal direction. The method also includes transmitting the electrical stimulation signal through the electrode, to the target tissue region. The at least one insulated portion electrically isolates the plurality of electrodes from each other, and each of the plurality of electrodes transmits the electrical stimulation signal to the target tissue region in a bipolar manner.

[0029] The stimulation system may comprise a cathodic block, 2 or 3 contacts, a pre pulse tohyperpolarize distal portion, and capacity for a high frequency stimulation (~10 kHz) to block distal conduction.

[0030] The stimulation system may comprise a timer controlling dose delivery and having adelay to automatically deliver stimulation after a window where factors limiting efficacy (e.g. nerve block) have worn off, limiting distal spread of action potential.

[0031] A method of delivering a stimulation signal to a target tissue region, the method maycomprise positioning one or more electrodes at or proximal the target tissue region, wherein the one or more electrodes are operatively connected to a stimulator through a lead and generating the stimulation signal at the stimulator, wherein the stimulation signal travels to and excites the target tissue region from the stimulator via the lead and the one or more electrodes. The method may also comprise performing a measurement of a patient receiving the stimulation signal at the target tissue region, wherein the measurement indicates a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the patient, and controlling a stimulation signal parameter based on the measurement. 10 35936527.2

[0032] The method of delivering the stimulation signal to the target tissue region may compriseany of the foregoing in any combination:^ performing the measurement includes measuring a nerve excitability or conduction, anactional potential, a nerve or muscle integrity, or an intensity of the stimulation signal returning to the stimulator at the one or more electrodes.^ positioning an accelerometer at the target tissue region, wherein performing themeasurement includes measuring an acceleration of the target tissue region, and determining a motor response threshold associated with the patient, the motor response threshold being a minimum amplitude or pulse duration of the stimulation signal that produces acceleration at the target tissue region that is measurable by the accelerometer, wherein controlling the stimulation signal includes maintaining the stimulation signal below the motor response threshold.^ positioning the one or more electrodes comprises: positioning a stimulation electrode at orproximal the target tissue region, where the stimulation electrode conveys the stimulation signal to the target tissue region, and positioning a return electrode at or proximal the target tissue region, offset from the stimulation electrode along the target tissue region, where the return electrode forms a return path that conveys the stimulation signal from the target tissue region to the stimulator, performing the measurement includes measuring an intensity of the stimulation signal conveyed to the stimulator from the return electrode, and controlling the stimulation signal parameter includes controlling the intensity of the stimulation signal generated at the stimulator at or above a minimum therapeutic benefit threshold, and at or below a perception threshold associated with the patient.^ performing the measurement includes detecting pulses in the stimulation signal conveyedfrom the return electrode to the stimulator, and controlling the stimulation signal includes transmitting a predetermined number of pulses to the target tissue region, each pulse of the predetermined number being counted up detection at the return electrode. 11 35936527.2^ repeatedly performing the measurement of the patient while generating the stimulationsignal over a single session, and controlling the stimulation signal includes adjusting the stimulation signal parameter based on the repeated measurement.^ the one or more electrodes are percutaneous, the measurement also indicates a location ortype of tissue in the target tissue region, positioning the one or more electrodes is performed based on the measurement, and controlling the stimulation signal includes adjusting the stimulation signal parameter intraoperatively.^ the stimulation signal is transmitted over a plurality of doses during the single session,wherein each dose has a duration of at least 5 to 15 minutes each, separated by rest periods of at least 5 minutes, and an amplitude or a frequency of the stimulation signal is modified between successive doses based on the repeated measurement.^ controlling the stimulation signal parameter includes maintaining an amplitude of thestimulation signal between 0.1 and 20 milliamps, and a frequency of the stimulation signal between 2 Hertz and 1,000 Hertz during the plurality of doses.^ generating a test signal at the stimulator that is received by the patient at the one or moreelectrodes, including ramping one or more test signal parameters through a plurality of grades, and setting a motor response threshold, a perception threshold, or a tolerance limit associated with the patient, wherein controlling the stimulation signal parameter includes maintaining the stimulation signal below the motor response threshold, the perception threshold, or the tolerance limit.^ manually adjusting the stimulation signal parameter toward the motor response threshold,the perception threshold, or the tolerance limit based on patient input during a single session, and automatically adjusting a duration, a number of pulses, or a delivery time of the stimulation signal as a function of stimulation signal parameter including amplitude, pulse duration, or frequency using control circuitry in the stimulator, in response to 12 35936527.2manually adjusting the stimulation signal parameter, maintaining a predetermined overall charge delivered to the target tissue region during the single session.^ manually adjusting the motor response threshold, the perception threshold, or the tolerancelimit during a single session, wherein controlling the stimulation signal parameter includes automatically adjusting or maintaining the stimulation signal parameter below the motor response threshold, the perception threshold, or the tolerance limit during the single session.^ positioning a resistive sensor at the target tissue region, wherein performing themeasurement includes measuring a motor response with the resistive sensor.^ performing the measurement includes performing electroneurography,electrocardiography, or electromyography using the one or more electrodes, wherein the one or more electrodes detect a stimulation-induced action potential, a muscle contraction, an evoked sensory response, activation of a target nerve or muscle included in the target tissue region, or delivery of the stimulation signal, and controlling the stimulation signal parameter includes adjusting at least one of a frequency, amplitude, pulse duration, or waveform of the stimulation signal based on the performed measurement.^ determining a minimum therapeutic benefit threshold associated with the patient based onthe measurement, and controlling the stimulation signal includes adjusting the stimulation signal parameter to an intensity that corresponds with the minimum therapeutic benefit threshold.

[0033] A stimulation system may comprise a stimulator that generates a stimulation signal, oneor more electrodes operatively connected to the stimulator, wherein the one or more electrodes are positioned relative to a patient and convey the stimulation signal to a target tissue region of the patient, and control circuitry in the stimulator that performs a measurement of a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the patient, and automatically adjusts a stimulation signal parameter based on a minimum 13 35936527.2therapeutic benefit threshold, a motor response threshold, a perception threshold, or a tolerance limit associated with the performed measurement.

[0034] The system may comprise any of the foregoing in any combination:^ a return electrode that forms a return path for the stimulation signal from the target tissueregion toward the stimulator, wherein the control circuitry determines a frequency, amplitude, waveform, or number of pulses in the stimulation signal conveyed to the stimulator from the return electrode as the feedback signal parameter, and the control circuitry adjusts the stimulation signal parameter based on the feedback signal parameter.^ the one or more electrodes detect the feedback signal parameter by performingelectroneurography, electrocardiography, or electromyography at the target tissue region, the control circuitry determines the motor response, an associated motor response threshold, the therapeutic benefit, and a therapeutic benefit threshold during stimulation as the feedback signal parameter, and the control circuitry maintains the feedback signal parameter above the therapeutic benefit threshold, and maintains the feedback signal parameter one of above and below the motor response threshold by adjusting the stimulation signal parameter in a closed loop.^ a resistive sensor or an accelerometer operatively connected to the stimulator, wherein theresistive sensor or the accelerometer generate sensor data at the target tissue region as the feedback signal, the control circuitry determines the motor response based on the feedback signal, and the control circuity maintains the motor response within a predetermined range by adjusting the stimulation signal parameter.^ a user interface operatively connected to the stimulator, wherein the user interface adjuststhe perception threshold or the tolerance limit based on user input associated with the stimulation parameter, and the control circuitry adjusts the stimulation signal parameter below the perception threshold or the tolerance limit. 14 35936527.2

[0035] The following description and the drawings disclose various illustrative aspects. Someimprovements and novel aspects may be expressly identified, while others may be apparent from the description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The accompanying drawings illustrate various systems, apparatuses, devices andmethods, in which like reference characters refer to like parts throughout.

[0037] FIG. 1 illustrates a top perspective view of the stimulation system, in accordance withvarious disclosed aspects.

[0038] FIG. 2 illustrates a top perspective view of a stimulation device, in accordance withvarious disclosed aspects.

[0039] FIG.3 illustrates a top plan view of the stimulation device of FIG.1, in accordance withvarious disclosed aspects.

[0040] FIG. 4 illustrates a bottom plan view of the stimulation device of FIG. 1, in accordancewith various disclosed aspects.

[0041] FIG. 5 illustrates a first side view of the stimulation device of FIG. 1, in accordancewith various disclosed aspects.

[0042] FIG. 6 illustrates a second side view of the stimulation device of FIG. 1, in accordancewith various disclosed aspects.

[0043] FIG. 7 illustrates a front view of the stimulation device of FIG. 1, in accordance withvarious disclosed aspects.

[0044] FIG. 8 illustrates a rear view of the stimulation device of FIG. 1, in accordance withvarious disclosed aspects.

[0045] FIG. 9 illustrates a percutaneous lead, in accordance with various disclosed aspects.

[0046] FIG. 10 illustrates a percutaneous lead, in accordance with various disclosed aspects.

[0047] FIG. 11 illustrates a percutaneous lead, in accordance with various disclosed aspects.15 35936527.2

[0048] FIG. 12 illustrates the stimulation device of FIG. 1 operated by a user, in accordancewith various disclosed aspects.

[0049] FIG. 13 is a process flow for operating the stimulation device of FIG. 1, in accordancewith various disclosed aspects.

[0050] The invention may be embodied in several forms without departing from its spirit oressential characteristics. The scope of the invention is defined in the appended claims, rather than in the specific description preceding them. All embodiments that fall within the meaning and range of equivalency of the claims are therefore intended to be embraced by the claims. DETAILED DESCRIPTION

[0051] Reference will now be made in detail to exemplary embodiments of the presentinvention. It is to be understood that other embodiments may be utilized, and structural and functional changes may be made without departing from the respective scope of the invention. Moreover, features of the various embodiments may be combined or altered without departing from the scope of the invention. As such, the following description is presented by way of illustration only and should not limit in any way the various alternatives and modifications that may be made to the illustrated embodiments and still be within the spirit and scope of the invention.

[0052] As used herein, the words “example” and “exemplary” mean an instance, or illustration.The words “example” or “exemplary” do not indicate a key or preferred aspect or embodiment. The word “or” is intended to be inclusive rather an exclusive, unless context suggests otherwise. As an example, the phrase “A employs B or C,” includes any inclusive permutation (e.g., A employs B; A employs C; or A employs both B and C). As another matter, the articles “a” and “an” are generally intended to mean “one or more” unless context suggests otherwise.

[0053] It is noted that the various embodiments described herein may include othercomponents and / or functionality. It is further noted that while various embodiments refer to a stimulator or stimulation device, various other systems may be utilized in view of embodiments 16 35936527.2described herein. For example, embodiments may be utilized in a variety of surgical procedures, other medical procedures or as a stand-alone procedure. As such, embodiments may refer to a particular surgical procedure for purposes of explanation. It is noted that aspects of embodiments, however, may be utilized for various other procedures or as a stand-alone procedure.

[0054] This disclosure generally relates to systems and methods that may improve nervehealing, including nerve regeneration, Wallerian degeneration, axonal regeneration, or neuroregeneration of tissue via electrical stimulation to increase the speed or amount of nerve growth. The terms “nerve” or “nerve tissue” generally refer to any portion of a nerve including, but not limited to, axons, axon terminals, somas, dendrites, or the like, unless context suggests otherwise. Moreover, aspects disclosed herein may be applicable to nerve tissue throughout a body, whether peripheral nervous tissue or otherwise. Further, while embodiments may reference a surgeon performing a particular action(s), it is noted that other clinicians or users, automated machines, or the like may perform such actions.

[0055] In an embodiment of a nerve regeneration system, housing 110 including top andbottom housing portions, display 116, and indicators 119, excluding buttons 114 and ports 122, may comprise a generally continuous surface. In an embodiment, housing 110 including top and bottom housing portions, display 116, and indicators 119, excluding buttons 114 and ports 122, may be hermetically sealed. In an embodiment, housing 110 including top and bottom housing portion, display 116, and indicators 119, and including buttons 114 and ports 112, may be hermetically sealed. In an embodiment, the entire stimulator 100 may be hermetically sealed or liquid tight. Stimulator 100 may include a first or distal end 120 configured to selectively couple with a mating first end of a plug or a proximal end of an intraoperative lead, for example. With this construction, circuitry disposed in the housing 110 is encased and isolated from an external environment of the stimulator 100, such as a surgical field or an environment including a target tissue region. 17 35936527.2

[0056] In an embodiment, an electrical stimulation system may comprise a stimulation device100 that comprises a housing 110; control circuitry operatively generating a stimulation signal, wherein the control circuitry is disposed within the housing 110, and a device for connecting the stimulator 100 to a lead for delivery of diagnostic or therapeutic stimulation. The housing 110 may be of any configuration and is not limited to that shown. In some embodiments, the housing 110 may comprise a handheld device that may be usable in the surgical field, if necessary. In other embodiments, the housing 110 may comprise a tabletop system that may only have a portion of which that is usable in the surgical field.

[0057] An embodiment of the method may include stimulating a target region before asubcutaneous surgery, during a subcutaneous surgery, or after a subcutaneous surgery with electrical stimulation from an electrical stimulator 100. The electrical stimulation may be utilized to generate nerve growth in a nerve or nerves of the target region. The electrical stimulation may comprise the following parameters from 0.1 – 10.0 mA, from 10-1000 microseconds, at a frequency of 10-30 Hz, desirably about 2.0 mA, 100 microseconds, and 16 Hz. The electrical stimulation may be applied in a single dose for a time period comprising five minutes, ten minutes, fifteen minutes or longer, but in most cases for a period of time that is less than 30 minutes. Alternatively, the electrical stimulation may be applied over multiple doses, e.g., two through fifty or more.

[0058] An embodiment of the method may include stimulating a target region before asubcutaneous surgery, during a subcutaneous surgery, or after a subcutaneous surgery, and further comprising stimulating the target region with a second stimulation, wherein the second stimulation may have different attributes from the first stimulation. In such embodiments, the first stimulation may be applied for a first period of time, e.g., five minutes, ten minutes, fifteen minutes or longer, but in most cases for a period of time that is less than 30 minutes and the second stimulation may be applied immediately thereafter or a defined period thereafter. The second stimulation may period of time, e.g., five minutes, ten minutes, fifteen minutes or 18 35936527.2longer, but in most cases for a period of time that is less than 30 minutes. Further, the first and second stimulations may be dosed in any predetermined pattern, e.g., first then second stimulation in a repeating pattern, two first stimulations and then a second stimulation in a repeating pattern.

[0059] The method may also include the following in any combination and utilizing any of thedevices disclosed herein: ^wherein a lead is operatively coupled to the stimulation device;^ wherein the stimulation device operatively generates a first stimulation signal forapplication to a target tissue region before the subcutaneous surgery; ^wherein the stimulation device operatively generates a second stimulation signal aftersurgery for stimulation of the target tissue region after the subcutaneous surgery; ^wherein the stimulation device operatively generates a third stimulation signal forstimulation of the target tissue region during the subcutaneous surgery; ^wherein the stimulation device terminates generation of the first stimulation signalbefore the subcutaneous surgery begins and does not generate another stimulation signal until after the subcutaneous surgery ends; ^wherein the stimulation device generates the first stimulation signal betweengenerally ten minutes and generally 15 minutes; ^wherein the stimulation device generates the second stimulation signal betweengenerally ten minutes and generally 15 minutes; ^wherein the stimulation device generates the third stimulation signal betweengenerally ten minutes and generally 15 minutes; and / or ^wherein the first stimulation signal comprises different attributes as the secondstimulation signal; ^wherein the stimulation device further comprises a pulse counter operatively countingthe number of pulses generated by the control circuitry; 19 35936527.2^ wherein the stimulation device further comprises sensor circuitry to measure actionpotential, chemical titration, acceleration, and resistance; and / or ^wherein the stimulation device further comprises a radio, knobs, and buttons.

[0060] The method may also include the following steps, any of which may be added to theabove method: ^applying a second stimulation signal before, during or after the subcutaneous surgery;^ applying a second stimulation signal before, during or after the subcutaneous surgery;^ applying a third stimulation signal before, during or after the subcutaneous surgery;^ applying the first stimulation signal comprises applying the first stimulation signalfor at least generally ten minutes; and / or ^applying the second stimulation signal comprises applying the second stimulationsignal for at least generally ten minutes.

[0061] An embodiment of an electrical stimulation system may comprise a stimulation deviceor stimulator 100 that comprises a housing 110; control circuitry operatively generating a stimulation signal; wherein the stimulation device 100 operatively generates a first stimulation signal for application to a target tissue region to promote a healing process of a first mechanism and wherein the stimulation device operatively generates a second stimulation signal for stimulation of the target tissue region to promote a healing process of a second mechanism.

[0062] As described herein, stimulation devices 100 may operatively apply prolongedstimulation to target tissue. In examples, the prolonged stimulation may be applied before a procedure is performed, during a procedure, after a procedure is performed, or as treatment independent of a surgical procedure. This stimulation may be applied in a surgery room or in a different room. If in the surgery room, tissue and other objects may be sterilized before beginning stimulation. As such, there may be no need to sterilize the stimulation device or a container prior to starting surgery. Moreover, in treatment without surgery, the stimulation may be applied in an office or at any other location. 20 35936527.2

[0063] In another example, the stimulation may occur in a different room so that the surgicalroom is available for other uses. Some examples provide for disposal of the stimulation device 100 after the pre-surgery stimulation. Other examples may provide for use of different stimulation devices before surgery and during surgery. Moreover, stimulation may be applied before surgery and not applied during or after surgery. Accordingly, an electrode 812 / 912 / 1012, which may be part of a lead 800 / 900 / 1000, may be positioned for pre-surgical stimulation. The electrode 812 / 912 / 1012 and the corresponding lead 800 / 900 / 1000 may then be removed during or before surgery.

[0064] The electrical stimulation system may include any of the foregoing in any combination:^ wherein the first stimulation signal is applied for a first dosing period, the first dosingperiod being between generally ten minutes and generally 15 minutes; ^wherein the first stimulation signal is applied for a plurality of dosing periods,wherein each of the dosing periods are for an equivalent amount of time; and / or ^wherein the first stimulation signal is applied for a plurality of dosing periods,wherein each of the dosing periods are for a different amount of time.

[0065] A method disclosed herein for stimulating tissue comprises providing a stimulationdevice; placing a lead within range of a target tissue region, wherein the lead is operatively attached to the stimulation device; applying a stimulation signal to the target tissue region with the lead and the stimulation device; terminating the applying stimulation signal; and performing a subcutaneous surgery after terminating the applying stimulation signal.

[0066] A non-operative Brief Electrical Stimulation Therapy (“BEST”) method comprisesleaving a lead wire connected to a lead adjacent to the targeted nerve, typically with no tine or anchor 808 due to its transient implant time. The lead or more specifically the electrode 812 / 912 / 1012 can be placed using ultrasound or electrical stimulation and motor response. 21 35936527.2

[0067] In an embodiment, the lead 800 / 900 / 1000 may comprise a trial lead such as, forexample, and without limitation, from a spinal cord stimulation system, or from an electrical stimulation system for treatment of an overactive bladder.

[0068] In an embodiment, the lead 800 / 900 / 1000 may comprise a percutaneous lead utilizedin peripheral nerve stimulation for the treatment of pain.

[0069] In an embodiment, the lead 800 / 900 / 1000 may comprise an injectable lead.

[0070] In an embodiment, the lead 800 / 900 / 1000 may comprise a percutaneous electrode812 / 912 / 1012.

[0071] In an embodiment, the lead 800 / 900 / 1000 may comprise a conductor withbiocompatible insulation and a biocompatible conductive contact. The contact may be for example an annular ring, a hemisphere, or an exposed planar surface.

[0072] In an embodiment the lead 800 / 900 / 1000 may comprise a bioresorbable polymer or gelwrapped with conductive addition and dissolvable or easy release connection to lead wire; containing a transcutaneous dissolvable coil (e.g. zinc); and having a pullout. This configuration would allow the dissolvable electrode to be placed in contact with the target tissue during a surgical procedure, deliver the therapy, and then the non-dissolvable portion to be removed when done with therapeutic dose(s). In this manner, the electrode 812 / 912 / 1012 is selectively detachable from the insulated body by mechanical release or by dissolution in the exterior environment, at the target tissue region.

[0073] The stimulation system may comprise a cathodic block, 2 or 3 contacts, a pre pulse tohyperpolarize distal portion, and capacity for a high frequency stimulation (~10 kHz) to block distal conduction. These techniques may be used to limit conduction to distal musculature to prevent or reduce muscle contractions during the therapeutic dose delivery.

[0074] The stimulation system may comprise a timer controlling dose delivery and having adelay to automatically deliver stimulation after a window where factors limiting efficacy (e.g. nerve block) have worn off, limiting proximal spread of action potential. 22 35936527.2

[0075] During surgery, for instance, a surgeon may create an incision in a patient. The surgeonmay utilize a stimulation device to apply a stimulation signal within the incision. In some embodiments, no stimulation signal may be utilized during the surgery. Instead, the stimulation may be applied only after the surgery, such as by way of a non-limiting example, during sensory nerve repair, motor or mixed nerve where a clinician does not need to or otherwise utilize a stimulator 100 for nerve identification. It is noted that stimulation may be applied to motor or mixed nerves wherein the surgery does not utilize stimulation during the surgery.

[0076] Regardless of whether stimulation was applied during surgery or after closing of theincision, the surgeon may place a percutaneous lead in or proximal target tissue. The percutaneous lead may be attached to a stimulation device. The stimulation device may apply a prolonged stimulation. In examples, the stimulation device may be the same stimulation device utilized during a procedure or may be a different stimulation device. In another aspect, the stimulation device may be disposed in a container that generally prevents contamination by or movement of the stimulation device 100.

[0077] As described herein, after completion of the stimulation, a surgeon or a clinician mayremove the percutaneous lead 800 / 900 / 1000. In an aspect, the percutaneous lead 800 / 900 / 1000 may be pulled out of target tissue. An embodiment of the BEST system may be decoupled from the initial surgical intervention; either as a preventative measure to delay or avoid surgical intervention, delivered as a response to slowed or delayed healing, or if operative techniques or approach prevented therapeutic delivery or efficacy. Earlier embodiments describe stimulating prior to or following repair, preferably while still in the operating room, to improve functional outcome. This disclosure is focused on a scenario where it may alternatively or additionally be desirable to initiate stimulation outside the operating room. This may be prior, during, or subsequent to a minimally invasive surgery without the need to fully dissect and expose the nerve prior to stimulation or may be performed post-operatively. 23 35936527.2

[0078] In an aspect, the stimulation device may generate the signal to stimulate the nerve tissueprior to the procedure. In some embodiments, the stimulation device 100 may additionally generate signals to stimulate the nerve tissue during the procedure (e.g., a surgical procedure), prior to surgical completion, or in lieu of a surgical procedure. Placement of a percutaneous lead 800 / 900 / 1000 may allow a surgeon to place the lead and stimulate the nerve with a stimulation device 100 during or after the surgery, without requiring the surgeon or any other person to hold the stimulation device in place; the stimulation device may be held in an operative position without the need of human intervention. In percutaneous delivery of stimulation, the clinician may place a lead 800 / 900 / 1000 having an electrode 812 / 912 / 1012 during the surgery. This can be accomplished in any manner. For example, the clinician or surgeon may position a percutaneous lead 800 / 900 / 1000 with an electrode 812 / 912 / 1012 at is distal end in an operative position relative to a nerve, with or without the assistance of an introducer needle. The clinician or surgeon may apply the electrical stimulation to the applicable nerve in an effort to regenerate and / or heal the nerve.

[0079] In addition to or in the alternative, a clinician may position the percutaneous lead800 / 900 / 1000 with the electrode 812 / 912 / 1012 at a distal end through ultrasound guided placement, such as when using an introducer needle. This may be done during or completely without surgery. The ultrasound-guided placement may be accomplished in any manner; the present teachings are not limited to a specific method. By way of a non-limiting example, a clinician may insert an introducer needle into a patient. The clinician may use an ultrasound machine to determine the position of the introducer needle and the electrode 812 / 912 / 1012. Once in the appropriate position, the clinician may eject the lead with the electrode 812 / 912 / 1012 and pull out the introducer needle. The electrode 812 / 912 / 1012 may then be in its operative position relative to the applicable nerve. The clinician may then apply the electrical stimulation through the electrode 812 / 912 / 1012 via the lead 800 / 900 / 1000 to the applicable nerve for the purpose of nerve regeneration and / or healing. In some embodiments, 24 35936527.2a marker or identification device may be used in association with the introducer needle to help identify the location of the introducer needle through the ultra-sound.

[0080] Embodiments provide for stimulation starting at various times before a procedure, post-procedure, during a procedure or stimulation as treatment independent of procedures and for stimulation for various lengths of time. In an aspect, the stimulation may take place generally prior to a procedure for a predetermined period (e.g., i minutes, where i is a number). In at least one embodiment, the stimulation may take place for about an hour or less prior to a procedure but may occur more than an hour before the procedure, e.g., the stimulation may comprise a short simulation of between about one and five minutes, ten minutes, fifteen minutes, twenty minutes (greater than twenty minutes but less than thirty minutes) or a long stimulation of about an hour. It should be understood, however, that when disclosing the therapy times, deviation from the times disclosed are also contemplated. For example, a deviation of 20-30% may also be included as part of the disclosed times. Stimulation before a procedure (e.g., nerve transfer or nerve release) may increase the speed, quality, or amount of nerve regeneration.

[0081] In some embodiments, stimulation may occur at multiple instances leading up to asurgical procedure, during a procedure, post-procedure, and / or or stimulation as treatment independent of procedures. For example, a physician may determine a schedule for stimulation for hours, months, weeks, or days leading up to the surgical procedure or without a surgical procedure, such as an alternative to surgical procedure. The schedule may define a time period for each stimulation session (e.g., 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, etc.), parameters of the stimulation signal (e.g., strength, frequency, etc.), a date / time of stimulation, or the like. In at least one embodiment, the nerve may be stimulated during multiple sessions on the day, such as the day of a procedure or according to a treatment plan. In at least one instance, prior to an operation the nerve may be stimulated for a first length of time, stimulation may be removed for a second length of time, stimulation may be applied again for a third length of time. This process of applying and resting the nerve may continue 25 35936527.2until the surgical procedure is performed and could continue for a defined period during and / or thereafter. Moreover, parameters of the stimulation signal may be different during the different stimulation sessions. In at least one example, a strength of stimulation is adjusted (e.g., increased or decreased) between stimulation sessions. In some instances, the strength of stimulation may progressively increase between sessions leading up to a procedure or may progressively decrease leading up to the procedure.

[0082] An aspect enables the onset of additional stimulation to begin in the operating room,prior to procedure completion, and additionally or alternatively continuing into a post-operative setting. In some embodiments, the stimulation may begin during the procedure and continue after the procedure without disrupting stimulation. Reduction of the delay from the completion of surgical intervention to start of stimulation may provide further clinical benefit. This additional post procedure stimulation may be utilized in combination with pre-procedure stimulation.

[0083] It is noted that stimulation may be applied in an office, in a pre-operative setting, or atanother location, e.g., outside of a surgical facility or room. Moreover, placement of an electrode 812 / 912 / 1012 may be done in at any appropriate location, e.g., outside or inside of a medical facility. Application of the stimulation may likewise occur at any appropriate location. In some examples, a patient may apply stimulation at home with an appropriate stimulation device. The stimulation device may be pre-programmed with stimulation parameters, may communicate with a server to receive updated parameters, may communicate with a user device (e.g., cellular phone, laptop, desktop computer, tablet computer, etc.), or the like. The stimulation device may report to a doctor or provider regarding usage of the stimulation device.

[0084] The control circuitry may apply the electrical stimulation before subcutaneous surgeryfor preventative nerve regeneration therapy, post-surgery, or for treatment without an operation. Nerve regeneration therapy may comprise stimulation to a nerve to alter recovery (e.g., improve, enhance, accelerate, etc.) of the nerve so stimulated, as an alternative to surgery, 26 35936527.2or to prevent or reduce the need for surgery. In another aspect, the control circuitry may apply the electrical stimulation for a period between 5 minutes and one hour or more particularly 10 minutes, 20 minutes or more, but less than 30 minutes.

[0085] In another aspect, embodiments include a method for stimulating tissue prior to asubcutaneous surgery and may comprise performing the subcutaneous surgery. The method may include using a stimulation device to stimulate the tissue and placing a lead within range of a target tissue region, wherein the lead is operatively attached (either selectively or permanently) to the stimulation device and applying a stimulation signal to the target tissue region with the lead and the stimulation device before the subcutaneous surgery. Placing the lead may comprise placing the lead percutaneously or non-percutaneously. The stimulation device may be a handheld stimulation device, or a non-handheld device. The method may include placing the stimulation device within a container before performing subcutaneous surgery.

[0086] It is noted that described systems and methods may be utilized in combination withvarious systems and methods for safeguarding against nerve, muscle, and tendon injury during surgical procedures, other procedures or as a stand-alone procedure or confirming the identity and / or location of nerves, muscles, and tendons and evaluating their function or the function of muscles enervated by those nerves. The systems and methods are particularly well suited for assisting in nerve regeneration via a device that may also be utilized by a surgeon or clinician in identification of nerves and muscles in order to assure nerve and muscle integrity during medical procedures using medical devices such as stimulation monitors, cutting, drilling, and screwing devices, pilot augers, and fixation devices, including without limitation, the system disclosed in U.S. Patent No.10,470,678 which is incorporated herein by reference. It is noted, however, that described systems and methods may utilize other devices that are not utilized during surgical procedures. Moreover, various disclosed aspects may be utilized independent of such systems and methods. 27 35936527.2

[0087] Embodiments described herein provide stimulation of a target nerve or nerves as analternative to or during a surgical procedure or prior to a surgical or other medical procedure, including without limitation, peri-operatively. This pre-procedure, in-procedure or stand-alone stimulation may result in more efficient recovery in comparison to conducting procedures without pre-procedure stimulation or any stimulation. Efficient recovery may include reduced time for nerve regeneration, reduced need for nerve regeneration, improved nerve functionality post operation, reduced need (or no need) for surgical intervention, or the like. Additionally, or alternatively, embodiments may utilize successive stimulation delivered as treatment without surgery, during surgery, prior to repair or treatment of the nerve injury, and / or following repair or treatment of the nerve injury and / or continued post-surgery.

[0088] In an aspect, a surgeon may selectively apply stimulation before, during or after surgeryin response to assessment of nerve function in which the pre-surgical stimulation is utilized as a baseline for comparison. As an example, preoperative stimulation may be applied to the target tissue. Stimulation may be terminated and a surgical operation may be performed. During and / or after the surgical operation, the surgeon may apply stimulation to evaluate nerve function. If nerve function is below a threshold (or the threshold hold previously established), the surgeon may apply stimulation before ending the surgery, after ending the surgery, or before and after ending the surgery. In such circumstances, electrical stimulation may be applied to determine a baseline level of nerve excitability before or at the start of a surgery, or before or at the start of treatment without surgery. During or near completion of the surgery or a treatment plan, a second threshold test of nerve excitability may be conducted. This second threshold test may be compared against the first. If the second threshold test results in lower nerve excitability, prolonged stimulation may be applied after the surgery or treatment to help with nerve regeneration. The application of the second threshold test may determine if the nerve regeneration stimulation is necessary or desirable for the patient, e.g., to treat any potential nerve injury or trauma as suggested by the reduction in nerve excitability between the first and 28 35936527.2second threshold test, or whether surgery is needed for the patient. Further, the application of the second threshold test may help determine the amount of time, parameters of the electrical stimulation (e.g., amplitude of electrical stimulation, velocity, time period, pattern of stimulation, or the like), etc. applied as part of the nerve regeneration stimulation. As an example, based on severity of injury from threshold test, stimulation may be performed for longer duration or higher amplitude. For instance, if the nerve is less responsive to stimulation then a greater amplitude, such as 10 mA instead of 2 mA, may be applied.

[0089] The threshold test may comprise electrical stimulation to a nerve or nerves within atarget tissue region to determine or measure the excitability and or conduction of the nerve or nerves. In such situations, it may only be necessary to test nerve excitability to determine if the post procedure nerve regeneration therapy is needed prior to applying such nerve regeneration therapy or to determine how the nerve regeneration therapy is to be applied. Threshold testing may be done at any time during the surgery, such as when a retractor is removed, a limb of a patient has a force applied to it, or the like.

[0090] In one example, electrical stimulation may be used to assess whether the patient is asuitable candidate for electrical stimulation therapy. In this scenario, electrical stimulation is applied to determine a baseline level of nerve excitability, e.g. minimum stimulation amplitude and / or pulse duration to produce an observable or measurable response, before or at the start of a surgery, or before or at the start of treatment without surgery, i.e., a threshold test. During or near completion of the surgery or a treatment plan, a second test of nerve excitability may be conducted. This second test may be compared against the first and the information may be used to determine if the therapeutic stimulation is necessary, or to determine the parameters of the therapeutic stimulation dose(s). For example, if the second test results in reduced nerve excitability (higher stimulation delivered to produce a response) from the initial evaluation, therapeutic stimulation, e.g., stimulation that lasts from about 10 minutes to about 15 minutes or a time greater than 15 minutes but less than 30 minutes (about being within one minute of 29 35936527.2the defined time) may be applied after the surgery to help with nerve regeneration. This series of tests may be done with a single electrode 812 / 912 / 1012 and stimulation device or may be accomplished with two or more electrodes 812 / 912 / 1012 or stimulation devices 100. Further still, the initial threshold test may be done with a different stimulation and the same lead or a different stimulation device and lead (such as a stimulation device with a permanently fixed lead) or with the same stimulation device and the same lead. The application of the second test may determine if the nerve regeneration stimulation is necessary or desirable for the patient, e.g., to treat any potential nerve injury or trauma as suggested by the reduction in nerve excitability between the first and second test, or whether surgery is needed for the patient. The threshold test may comprise electrical stimulation to a nerve or nerves within a target tissue region to determine or measure the excitability of the nerve or nerves. In such situations, it may only be necessary to test nerve excitability to determine if the post procedure nerve regeneration therapy is needed prior to applying such nerve regeneration therapy. Threshold testing may be done at any time during the surgery, such as when a retractor is removed, a limb of a patient has a force applied to it, or the like. The threshold test may also be used to determine the stimulation parameters to be applied, what kind or level of stimulation dosing should be approved, or any other stimulation factors.

[0091] In another example, stimulation of a nerve may be applied before a procedure andduring surgery prior to treatment or repair of nerve damage, suspected nerve damage, a risk of future nerve damage, or the like. A percutaneous lead may be placed at or near a nerve (e.g., within a range of the signal) to allow a stimulation device to generate and apply a signal to the nerve tissue. The stimulation may take place for a predetermined period of time and may be conducted at any time during surgery. For example, stimulation may occur immediately at the start of surgery and may be conducted for an hour or less. It is noted that the stimulation may be applied at different strengths, frequencies, patterns, or the like. Stimulation at time of a surgical operation may increase the speed, quality, or amount of nerve regeneration or nerve 30 35936527.2function recovery. The percutaneous lead may be anchored, held, or otherwise left in place after stimulation, before, during, and / or after a surgical operation such as without human intervention.

[0092] As described herein, the parameters of the stimulation signal for pre-procedurestimulation, during the procedure, post-procedure stimulation, or stimulation as treatment independent of procedures may be preprogrammed or may be set by a surgeon, clinician, caregiver, or individual. Preprogramed parameters may be fixed or may vary during therapy dose. This change in parameters may be done in a pre-determined manner, e.g. increasing or decreasing ramp, a pseudo-randomized manner, or fully randomized parameter. In at least one embodiment, the pulse width may be held constant (e.g., not adjusted) during the stimulation. In an aspect, the stimulation signal may be applied at generally between 2-100 Hz, 15-30 Hz, or about 16-20 Hz. In some embodiments, the stimulation signal applied may be as low as 0.1 Hz or as high as 20 kHz. Still further, the stimulation signal applied by comprise randomized frequencies (within the range of between 0.1 Hz to 20 kHz), within a pre-defined range of frequencies, pseudo-random, non-constant, or a combination of any of the foregoing. The amplitude of the stimulation may be held constant, be adjusted by the input from the user. In general, the stimulation amplitude will generally be between 0.1-20 mA, typically between 1.0- 2.0 mA. Moreover, the stimulation signal may be applied for a prolonged period (e.g., an hour).

[0093] It is noted that the prolonged stimulation signal may be applied in a single dose ormultiple doses, or for durations up to or more than 8 hours. For example, multiple doses may be applied through the same percutaneous lead, which may be kept in place between doses or may be removed between the doses. The multiple doses may utilize similar or different parameters. For instance, doses may progressively become shorter, longer, follow a curve, or be in any appropriate pattern. In some embodiments, the intensity of stimulation may be similar between doses or may be adjusted. Moreover the duration of a dose, whether as a single dose or repeated doses, may comprise relatively short stimulation periods (e.g., 0-5 minutes, about 31 35936527.25 minutes to 10 minutes) up to relatively longer stimulation periods (e.g., up to one hour or more). In such examples, one lead may be utilized and a different stimulation device utilized depending upon the location of the patient during stimulation, i.e., pre-operative location, surgical location or post-operative location. In these embodiments, the lead may be selectively attached and removable from the stimulation device. In the alternative, one lead may be utilized and a single stimulation device utilized regardless of the location of the patient during stimulation. In these embodiments, the lead may be permanently fixed with the stimulation device or may be selectively attached and removable from the stimulation device or the lead may be permanently affixed. In yet another alternative, a different lead and different stimulation device may be utilized depending upon the location of the patient during stimulation. In these embodiments, the lead may be selectively attached and removable from the stimulation device or the lead may be permanently affixed. In such dosing examples, the electrical stimulation may be applied for a period of time, such as k minutes, where k is a number (e.g., 1, 2, 5, 10, 15, 60, etc.). In an example, the period may be between about 10 minutes.

[0094] Stimulation systems described herein may pre-operatively deliver, post-operativelydeliver, or otherwise deliver (e.g., as a treatment independent of operation), for a period of time, an electrical stimulation to peripheral nerves subject to future repair. An attachment (e.g., a percutaneous electrode 812 / 912 / 1012 lead attachment such as those described in U.S. Patent 10,154,792, which is incorporated by reference herein) may be coupled with a stimulation device after a surgical procedure. It is noted that the stimulation device may be a stimulation device that is to be used or was used during the procedure. For instance, a surgeon may utilize a handheld stimulation device to apply stimulation. The handheld stimulation device may be positioned within a hermetically sealed container or within a container that is not hermetically sealed. The surgeon may place one or more implantable leads at a position where the lead may stimulate nerves that may have damage, potential for damage, or may require recovery after 32 35936527.2completion of the surgical operation. The surgeon may remove the stimulation device from the container for use in a surgical operation and may place the stimulation device in the container or a different container after the surgical operation.

[0095] It is important to note that the present disclosure contemplates providing the electricalstimulation to be preventative or as an alternative to surgery, i.e., to mitigate the impact of a nerve injury, risk of nerve injury, or suspect nerve injury in addition to during surgery. The surgeon may, for instance, place the handheld stimulation device into a sterilized container and may electrically attach one or more leads to the handheld stimulation device via ports of the container or the leads may be permanently affixed to the stimulation device. As such, the patient’s nerve may be stimulated before an operation, during an operation, or independent of an operation. In some instances, a surgeon may stimulate the nerve post-operatively or intra- operatively via the same stimulation device utilized for the surgical operation. Once stimulation is completed, the stimulation device may be discarded or otherwise removed.

[0096] It is noted, however, that different stimulation devices may be utilized for stimulationbefore, during, or after a procedure. For instance, a first stimulation device may be utilized before a procedure. This device may be reusable or disposable. During the operation, a second stimulation device may be utilized. After the operation, the surgeon may utilize the first stimulation device, the second stimulation device, or a third stimulation device to provide post operation stimulation. Moreover, stimulation devices may comprise wire connections to leads 800 / 900 / 1000 ultimately to electrodes 812 / 912 / 1012 or may apply power via a surface coil that delivers power through the patient’s skin.

[0097] As described herein, stimulation devices may be disposable or reusable. Describedsystems may allow a stimulation electrode 812 / 912 / 1012 via the lead to be placed intra- operatively, in close proximity to the nerve to be stimulated; allowing the lead to pass out of the tissue and attach, either permanently or selectively, to the stimulation device. 33 35936527.2

[0098] The stimulation device may provide a prolonged stimulation dose before an operationor as treatment without an operation. In some instances, it may additionally provide prolonged stimulation after an incision is closed or after an initial treatment period. In surgical applications, at a desired stopping time, the lead may be removed post operatively or during the operation if no post-operative stimulation is to be applied. In an aspect, this may eliminate the need for extended operating time and may free up a surgeon or staff from holding the stimulator 100 on the nerve for prolonged stimulation. The lead may also be left in for a period of time, to enable repeated doses of stimulation across multiple days or weeks without need for placement of another lead.

[0099] It is noted that the disclosed systems and methods are applicable for use in a widevariety of medical procedures involving peripheral nerves, whether surgical or non-surgical. By way of a non-limiting example, the various aspects of the invention have application in treatment of nerve transection injuries, nerve crush injuries, suspected nerve injuries, risk of nerve injuries or function reduction, or nerve transfer procedures, including, without limitation nerve decompression procedures (such as carpal tunnel or cubital tunnel syndrome), neurolysis, nerve transfer, nerve repair (such as direct repair, autograft, allograft, or conduit), and iatrogenic injury (thermal, stretch, compression, or transection).

[0100] In at least one embodiment, an electrical stimulation system may comprise astimulation device and an adaptor. The stimulation device may comprise a housing 110, a control circuitry operatively generating a stimulation signal, wherein the control circuitry is disposed within the housing 110, and an operative element coupled with the housing 110 and comprising a lead 800 / 900 / 1000 having at least one electrode 812 / 912 / 1012. The housing 110 may be configured as a hand-held housing that is suitable for use by a surgeon / clinician using a single hand. The adaptor may be selectively attached to the operative element and may comprise a percutaneous lead electrically coupled to the stimulation device through the at least one electrode 812 / 912 / 1012, the percutaneous lead insertable into a patient during a 34 35936527.2subcutaneous surgery and after the subcutaneous surgery and wherein the stimulation device is capable of applying electrical stimulation during the subcutaneous surgery and after the subcutaneous surgery. The percutaneous lead may comprise strands of stainless steel wire insulated with a biocompatible material.

[0101] In at least some embodiments, a surgeon or clinician may utilize a handheldstimulation device to generate a stimulation signal at sufficiently high levels for the purposes of locating, stimulating, and evaluating nerve or muscle, or both nerve and muscle integrity in numerous medical procedures. This may also include evaluating proximity to a target tissue region, evaluating proximity to a nerve or to identify nerve tissue, evaluating nerve integrity (i.e., following a traumatic or repetitive motion injury) to determine if a repair may be needed, evaluating muscle contraction to determine whether or not the muscle is innervated and / or whether the muscle is intact and / or whether the muscle is severed, identifying specific nerve branches or fascicles for repair or transfer, and evaluating muscle and tendon length and function following a repair or tendon transfer prior to completing a surgical procedure.

[0102] Before the procedure or for treatment without a separate procedure, a surgeonmay place an electrode 812 / 912 / 1012 or lead having the electrode 812 / 912 / 1012 on or near the nerve to be stimulated and / or proximal to the site of injury, potential injury, or repair. The electrode 800 may be percutaneous or non-percutaneous (e.g., surface electrode or implanted electrode). In some embodiments, the electrode 812 / 912 / 1012 via the lead 800 / 900 / 1000 may be percutaneously positioned while a component transmits energy to the percutaneously positioned electrode 812 / 912 / 1012 through tissue. It is noted that the transmitting component may be positioned on the skin at an appropriate location, i.e., it may be an external electrical stimulator 100 (or pulse generator). In an aspect, a percutaneous lead may be taped or otherwise held in place on a patient’s skin. This may allow for easy removal after prolonged stimulation.

[0103] One exemplary embodiment of such comprises a patch that may be adhered tothe skin of a patient. The patch may generally circumscribe the insertion point of the 35 35936527.2percutaneous lead and may allow a portion of the lead to extend there through. In this embodiment, a connector may be utilized to operatively couple the percutaneous lead with the stimulation device. Alternatively, the lead may be operatively coupled with the patch and the patch may include an adapter that operatively couples with the stimulation device. The patch may include an electrical path between the percutaneous lead and the adapter such that electrical stimulation may pass from the stimulation device through the patch and to the percutaneous lead. The lead may be coupled (either permanently or removably) to a stimulation device that was used during surgery, or another stimulation device, via a wire or other connector. The stimulation device may be placed in a sealed housing 110 to prevent cross- contamination.

[0104] In some embodiments, it may be desirable to provide a method for automatedor patient specific adjustment of stimulation parameters to ensure therapeutic efficacy. Earlier embodiments describe stimulating prior to or following repair, preferably while still in the operating room, to improve functional outcome. This disclosure is focused on a scenario where it may alternatively or additionally be desirable to initiate stimulation outside the operating room. This may be prior, during, or subsequent to a minimally invasive surgery without the need to fully dissect and expose the nerve prior to stimulation or may be performed post- operatively.

[0105] The stimulation pattern used for Brief Electrical Stimulation Therapy (“BEST”)may, depending on electrode 812 / 912 / 1012 placement, device set up, degree of nerve function, etc. vary from individual to individual. Therefore, it is advantageous to adjust stimulation intensity to the appropriate individual specific level to ensure therapeutic efficacy. Furthermore, it may be advantageous to limit stimulation intensity to the minimum necessary to invoke the therapeutic effect to limit potential negative side effects such as discomfort or pain. In another embodiment of the method, the stimulation signal may be an altering waveform 36 35936527.2to encourage or avoid accommodation to stimulation. The altering waveform may prevent habitation from the stimulation, which may improve the efficacy thereof.

[0106] The stimulation pattern used for BEST may, depending on electrode812 / 912 / 1012 placement and stimulation parameters, be painful or noxious when delivered outside of operating room. It may lead to a motor response that causes lead movement, or an uncomfortable tetanic contraction. There may be a need to deliver therapy before or after operative window due to surgical techniques that could limit therapeutic efficacy (e.g. nerve block, local anesthetics, prolonged tourniquet, etc.) or prevent operative delivery (minimal access, etc.), or because the initial surgeon was unaware of a therapeutic option. This disclosure is aimed at solving issues unique to delivery of the therapy outside the operating room. In an example, a surgeon, clinician, or other medical professional may apply one or more leads to a patient. The leads 800 / 900 / 1000 may be percutaneous, transcutaneous, surface electrodes, or leads directly attached to or in proximity to the applicable nerve. The leads may be placed in a region suspected of nerve damage or diminished function, a region of possible nerve damage or diminished function, and / or a region where an operation is to be performed or is being performed. For instance, a procedure may be planned that requires operation at or near a nerve. This may put the nerve at risk for damage, temporary or permanent diminished function, or rehabilitation after the procedure. The described embodiments can be used prophylactically (i.e., in advance as a way of providing the procedure) to stimulate the nerve prior to the surgical procedure. The electrical stimulation may stimulate a nerve that is already injured, that is anticipated or poses the risk of being injured during a procedure. Stimulation prior to the procedure may reduce recovery or rehabilitation time after the procedure, may reduce or prevent diminished function, or the like of the nerve getting the electrical stimulation. Moreover, the surgeon may apply additional stimulation during or after the procedure in combination with or as an alternative to the stimulation prior to the procedure. The additional stimulation may, in combination with the pre-procedure stimulation, provide benefits to nerve 37 35936527.2rehabilitation. In addition, or in the alternative, the clinician may apply the stimulation without performing a procedure in an effort to aid in nerve healing or regeneration.

[0107] In various embodiments described herein, systems and methods provide forstimulation of a target nerve or nerves as a treatment to the target nerve or nerves for the purpose of nerve regeneration and / or healing of such nerve or nerves. Accordingly, while some examples may refer to pre- and post-operative stimulation, various embodiments may include stimulation without surgical operations or in replacement of surgical intervention. Still further, such stimulation may be provided during the applicable surgery. It is noted that similar or different stimulation parameters (e.g., stimulation patterns, intensity, duration, frequency, single does, repeated dosing, etc.) may be applied to stimulation without surgery, or to stimulation pre- and post-operatively. Further, the stimulation parameters may or may not be related to the type of stimulation being applied, i.e., if it is part of surgery, pre-operative, during surgery, post-operative or with no surgery. In other embodiments, the stimulation parameters may all be the same regardless of the type of stimulation being applied.

[0108] Described procedures may result in more efficient recovery or regeneration ofdamaged or potentially damaged nerves. The stimulation may be provided as a treatment itself, independent of any surgical procedures, or may be the entire surgical procedure. It is noted that stimulation may be conducted via percutaneous delivery of stimulation, transcutaneous delivery of stimulation, transdermal delivery (e.g., implanted electrode and surface coil for power delivery and communication), or a combination thereof.

[0109] By way of a non-limiting example in a transdermal delivery, a lead having anelectrode 812 / 912 / 1012 may be implanted and may be wirelessly and operatively coupled with a surface coil or may be directly and operatively attached with the surface coil for power delivery and communication so that the electrode 812 / 912 / 1012 may apply the appropriate stimulation. The electrode 812 / 912 / 1012 may be positioned in any appropriate manner, such as through a needle, through surgical intervention or any other appropriate method. 38 35936527.2

[0110] In an example, stimulation of target nerve tissue for nerve regeneration may beapplied as treatment in place of or as an alternative to surgery. For instance, targeted electrical stimulation may be applied to the applicable nerve for carpal tunnel treatment (although that is merely exemplary and the electrical stimulation may be applied to any kind of nerve injury, damage or otherwise for preventative measure). The treatment may include immobilization and stimulation therapy to avoid surgery, if possible. In another example, stimulation may be applied after an injury as the primary treatment. A surgeon or other professional may place a lead having an electrode 812 / 912 / 1012 and may stimulate nerve tissue (or nerve fibers), or surrounding tissues that support nerve healing (Schwan cells, macrophage cells) to accelerate regeneration and healing when surgical intervention is not needed, such as to treat muscle weakness, loss of sensation after traumatic or prolonged injury, or other issues relating to the nerve or surrounding tissue. In some situations, this treatment may be successful enough for a patient such that surgical intervention can be avoided. The stimulation therapy may accelerate nerve regeneration, which may accelerate healing enough that surgery is not needed.

[0111] In some embodiments, the stimulation described above may be delivered as part of anoverall multi-stage treatment program where stimulation may be delivered in one bolus or multiple boluses of pulses. A dose of stimulation is the total measure of pulses – regardless of pulse amplitude – delivered in a therapeutic session, wherein the therapeutic session is a defined period of time. Differing therapies or patterns of the same therapies may be applied over a defined period of time as part of the nerve regeneration treatment. The overall multi- stage treatment program may extend over any appropriate amount of time. It may comprise about 5 minutes to as long as months depending upon the overall goals of the therapy, the state of the nerve to which the therapy is being applied, the healing ability of the person to whom the therapy is being applied, or any other relevant factors (e.g., excitability, conduction velocity, axon count, Schwann cell count, axon growth distance from injury site based on point of measured electrical activity, etc.) 39 35936527.2

[0112] Further, the timing of the doses may comprise any appropriate time period, e.g., 1, 5,10, 15, 30, 45 minutes, an hour, two hours or even more. The time periods between the doses may comprise any appropriate time period, e.g., 1, 5, 10, 15, 30, 45 minutes, an hour, two hours or even days, weeks or months. The timing of the doses and time periods between the dosing periods will depend on many different factors, including, without limitation, the nerve injury, amount of damage to the nerve, location of injury, patient’s regenerative capability, stimulation therapy (patterns and settings of the electrical stimulation (e.g., frequency, amplitude, waveform shape, etc.)) applied to the patient, the lead utilized in the stimulation and the stimulation device utilized. It should be understood, however, that this is not an exhaustive list; any appropriate factor may be utilized in determining the appropriate timing. In at least one embodiment, recovery may be tracked and a pattern of stimulation may be adapted or altered based on patient response, such as nerve healing or regrowth identified by a physical evaluation, electrodiagnostic testing, functional testing, or the like.

[0113] An example of a multi-stage therapy may comprise providing the stimulationtherapy to a nerve or nerves as described above for a first therapy time. The therapy applied could comprise any electrical stimulation therapy for nerve regeneration described above. The therapy may directly correlate to promote a healing process of one or more particular mechanisms, e.g., axon growth. This stimulation may be applied in any manner, e.g., the stimulation may be applied for a first period of time and then repeated a defined number of times over a first therapy time. During the first therapy time, the stimulation may be dosed so that the stimulation is turned off for a non-stimulation period of time and then turned back on for a second period of time with the purpose of regenerating the nerve. The dosing may be done in any manner, such as by way of a non-limiting example, as part of a random dosing (each period of stimulation is of a different time or frequency), pseudo-random (the periods of stimulation are pseudo-random and / or frequencies within a period are pseudo-random), constant, patterned (e.g., cascading or mimicking physiologic response), or any combination 40 35936527.2of the foregoing. The stimulation system may be configured to apply all of the different stimulation patterns required as part of the multi-dosing program.

[0114] The multi-stage treatment program may include optimizing stimulation patternsapplied to the patient to promote the healing process for one or more mechanisms of the patient. For example, the stimulation pattern applied can be optimized for angiogenesis, axon growth, cell migration (e.g., Schwann cells or macrophages), muscle and or neuromuscular junction maintenance, or any other appropriate therapy. The stimulation patterns may be optimized based on many different factors, including, without limitation, the therapy provided, the nerve injury, the amount of damage to the nerve, the tolerance of the patient, the make-up of the patient (body mass index, age, etc.), the location of the nerve to which stimulation is being applied, time point in the regenerative process, etc. The stimulation pattern may be optimized through utilization of computer modeling to determine the optimized stimulation pattern for the specific therapy and / or patient. Further, the optimized stimulation pattern may depend upon the stage of the multi-stage stimulation therapy. The optimized stimulation pattern may change depending upon whether the therapy is in an early stage or a later stage. For example, a stronger stimulation may be applied earlier in the treatment continuum than during a later stage where the nerve has begun its healing process already. Of course, the opposite may also be true, i.e., the optimized stimulation pattern may be a weaker stimulation earlier in the continuum of treatment and gets stronger during the stimulation therapy period. This may be particularly true if there is a significant injury to the nerve and only weaker stimulation can be tolerated by the patient early in the therapy. Additionally, the therapy can be optimized based upon the stage of healing or regeneration. For example, early stimulation may be targeted to increase the early regenerative response (including but not limited to cell recruitment and differentiation, angiogenesis, etc.), then alter to aid in axon guidance or growth to the target, and both stages may be combined with stimulation to the innervation target to improve target viability and overall re-innervation. Any combination of the foregoing may apply. 41 35936527.2

[0115] Throughout the healing process, the stimulation pattern may be altered to reachdifferent optimization of mechanisms for nerve healing. A pattern of mechanisms of nerve healing may be selected by the clinician determined based on prior experience, computer modeling, known therapy outcomes, etc. The stimulation system may be configured to apply all of the different stimulation patterns required as part of the different optimization mechanisms contemplated herein. For example, patterns may be applied based on macrophage recruitment or Schwann cell recruitment initially followed by angiogenesis, followed by axonal guidance.

[0116] The process may further comprise delivery of biologics, drugs, other electricalstimulation therapies or other non-electrical stimulation therapies. The delivery of these additional therapies may fill gaps in the electrical stimulation treatment disclosed above to further enhance nerve regeneration and growth. For example, in addition to the electrical stimulation therapy for nerve regeneration described above, a drug treatment program may be utilized. In these embodiments, drug therapy may be applied before, contemporaneously with, or after the electrical stimulation therapy. Further, the drug therapy (or alternative therapy) may be applied as part of a dosing therapy, e.g., a period of electrical stimulation followed by a period of drug therapy, followed again by electrical stimulation, which may be again followed by drug therapy (or any alternative therapy). Any appropriate combination of electrical stimulation therapy for nerve regeneration and alternative therapy may be applied in any suitable combination. One example may include, but not be limited to, application of electrical stimulation by the stimulation system for a period of time, followed by a drug therapy program. A further dose of the electrical stimulation by the stimulation system may further be applied. This may also be followed by an additional dose of the drug therapy. These steps may be repeated in any order, for any number of doses, and for any appropriation duration. Further, the doses of electrical stimulation and drug therapy do not have to be consecutive, i.e., there may be a one or plurality of doses of electrical stimulation followed by a single or plurality of 42 35936527.2doses of the applicable drug therapy. Further, while the drug therapy being described as following the electrical stimulation, the present teachings are not limited to this configuration. The drug therapy dose may be applied before, contemporaneous with or after the electrical stimulation. In some embodiments, the electrical stimulation may enhance the efficacy of the drug therapy or the drug therapy may enhance the efficacy of the electrical stimulation.

[0117] Further, while drug therapy has been described, any other nerve regenerationtherapy may be utilized in conjunction with the described stimulation, including, without limitation, biologics, stem cell therapy, gene therapy, vitamin therapy, laser therapy, laminin- coated bioresorbable polymer or gel conduits, or any combination of the foregoing. The electrical stimulation for nerve regeneration applied may be the primary treatment or may be an ancillary or secondary treatment with any of the other foregoing treatments. Each of these treatments may be utilized a part of a dosing program, such as with immunosuppression drugs (e.g., tacrolimus also known as FK506). The present teachings are not limited to just those iterations described herein, which for the sake of brevity are not all described but are contemplated by this teaching.

[0118] Turning to Fig. 1, there is a stimulation system that may comprise a stimulationdevice 100 configured for locating, monitoring, and stimulating tissue and other structures throughout the body, and a lead 800. The stimulation system may be utilized for locating and identifying tissue and safeguarding against tissue and / or bone injury during surgical procedures. In another aspect, the stimulation device 100 may be utilized for percutaneously stimulating a nerve before surgery and, in some examples, during or after a surgery for a desired amount of time. In other embodiments, stimulation may be applied as a treatment program as an alternative to surgery, to prevent or reduce the need for surgery, or independent of surgery.

[0119] The stimulation device may include a device for coupling to one or moreattachments or operative elements including, for example, a lead (e.g., which may be blunt, needle-like, etc.), or a fixation device. It is noted that attachments may be removable, 43 35936527.2attachable, or permanently affixed to the stimulation device. It is noted that while embodiments may describe use of a particular attachment (e.g., lead 800 / 900 / 1000) for simplicity of explanation, the various embodiments may utilize other types of attachments.

[0120] In an exemplary embodiment, stimulation device comprises control circuitry,disposed in a housing 110, that may apply a stimulation signal to a desired tissue region. The control circuitry may be coupled to a power source, such as a battery, power mains, or the like. The control circuitry may generate the stimulation signal with desired parameters, as described herein. In an aspect, a user may adjust parameters and / or control the control circuitry to generate the stimulation signal via one or more user interfaces 119, which may comprise at least one of a switch, display 116, button 114, slide, touch screen, or the like.

[0121] For instance, a user may grasp the stimulation device via the housing 110. Thehousing 110 may include gripping portion. The gripping portion may comprise indents, protrusions, elastomeric material, roughened material or other features that may aid in the user grasping the stimulation device. The gripping portion of the housing 110 may include an over molded portion that may comprise all or part of the length of the housing 110. In an aspect, the over molded portion may comprise a thermoplastic elastomer material. It is noted that gripping portion may be removable, attached to, or integrally formed with the housing 110.

[0122] In an example, a user may position the lead accessory so that an uninsulated orstimulating portion or electrode 812 / 912 / 1012 is at a desired location. This may include positioning the electrode 812 / 912 / 1012 relative to a nerve or positioning the electrode 812 / 912 / 1012 within a container or attachment. The user may interact with one or more of the user interfaces 119 to control delivery of stimulation signal, generated by the control circuitry, to the desired tissue region. The gripping portion may aid in a user’s efforts to hold the stimulation device. In an aspect, the control circuitry communicates the stimulation signal via a lead 800 / 900 / 1000 that may travel through an insulated portion 820 / 920 of the lead 800 / 900 / 1000 to the electrode 812 / 912 / 1012. As depicted, the insulated portions 820 / 920 of 44 35936527.2the leads 800 / 900 include an insulation disposed around the wire forming the lead 800 / 900, where the insulation blocks transmission of the electrical stimulation signal from the wire to the exterior environment. More specifically, the insulation wrapped around the insulated body 804 / 904 / 1004 is a first insulation, and the lead 800 / 900 further includes a second insulation disposed around the wire forming the lead 800 / 900 at the insulated portion 820 / 920, where the second insulation blocks transmission of the electrical stimulation signal from the wire at the insulated portion 820 / 920 to the exterior environment.

[0123] The leads 800 / 900 may include a plurality of the electrodes 812 / 912 and aplurality of the insulated portions 820 / 920 and a plurality of the insulated portions 820 / 920, where the electrodes 812 / 912 and the insulated portions 820 / 920 are arranged in an alternating pattern along the lead 800 / 900 in the longitudinal direction. More specifically, the leads 800 / 900 include may include a first of the electrodes 812 / 912 and the insulated portion 820 / 920 at a side of the first of the electrodes 812 / 912 opposite the body 804 / 904 in the longitudinal direction of the wire forming the lead 800 / 900. A second of the electrodes 812 / 912 is disposed at a side of the insulated portion 820 / 920 opposite the first of the electrodes 812 / 912 in the longitudinal direction, where the second of the electrodes 812 / 912. Each of the electrodes 812 / 912 is an uninsulated biocompatible conductive contact that transmits the stimulation signal to the exterior environment at the target tissue region, and the insulated portion 820 / 920 electrically isolates the first of the electrodes 812 / 912 from the second of the electrodes 812 / 912 in the exterior environment.

[0124] It is noted that the lead 800 / 900 / 1000 may comprise one or more flexiblematerials (e.g., metal, plastic, etc.) so that a user may bend or otherwise manipulate the lead 800 / 900 / 1000. This may allow a surgeon or other user to position the uninsulated portion also called the electrode 812 / 912 / 1012 at a desired position of a target tissue region. For example, the uninsulated portion of the lead 800 / 900 / 1000 is positioned in electrical conductive contact with the targeted nerve. 45 35936527.2

[0125] As described herein, a stimulation signal may flow from the stimulation device100 through the lead 800 / 900 / 1000 to an electrode 812 / 912 / 1012. The stimulation device 100 may include one or more other electrodes, such as a return electrode, as described herein. For instance, in monopolar operation, a return electrode (or indifferent electrode) provides a return path for electrical signals passing through the tissue and returning to the stimulation device 100. It is noted that stimulation device 100 may operate in a monopolar, bipolar or other configurations, as described here as well as elsewhere in this disclosure.

[0126] In various embodiments, the control circuitry may generate the stimulationsignal to operatively generate a physical motor response of a tissue (e.g., muscle, innervated muscle, nerve, etc.). The physical motor response may indicate whether the stimulation signal was delivered and / or whether a sufficient stimulation signal was delivered. For example, the motor response may include a physical motor response (e.g., twitching or contraction).

[0127] In another aspect, the stimulation device 100 may generate one or more visualor audio signals (e.g., via a speaker (not shown)), which indicate to the surgeon the status or diagnostic information. For instance, stimulation device 100 may comprise an indicator light. The indicator light may comprise one or more light sources, such as a light emitting diode (LED). In an aspect, the indicator light may comprise a translucent (e.g., semi-translucent, fully translucent, etc.) surface that operatively shines or disperses light from an internal light source (not shown). In an aspect, the light source may generate light in one or more colors (e.g., green, yellow, blue, red, etc.), patterns (e.g., blink rate, pattern of colors, etc.), or the like. According to embodiments, the status or diagnostic information may indicate whether the stimulation signal was delivered and / or whether a sufficient stimulation signal was delivered, i.e., the requested amount of or the designated stimulation signal was delivered. For example, the status or diagnostic information may indicate that an electric signal was returned from tissue, which may indicate sufficient proximity, contact, or delivery of the stimulation signal requested via an operative element (e.g., lead). In another aspect, the indicator light may indicate that the 46 35936527.2stimulation device 100 is on / off, producing or not producing a stimulation signal, or the like. Still further, the indicator light may indicate that the stimulation signal requested from the stimulation device 100 by the user completes the electrical flow path going through the operative element (e.g., lead) and the target tissue region and back through the return electrode 812 / 912 / 1012 at a specified stimulation level equivalent to a control setting selected by the user on the stimulation device 100. The indicator light may provide, in response to determining whether the electrical stimulation signal completes the electrical flow path going through the operative element (e.g., lead 800 / 900 / 1000) and the target tissue region and back through the return electrode in accordance with the specified stimulation level, a first indication signal for confirming delivery of the electrical stimulation signal to the target tissue region through the operative element and back through the return electrode completing the electrical flow path at the specified stimulation level. The indicator light may also provide, in response to determining whether the electrical stimulation signal going to the operative element and the target tissue region and back through the return electrode is not at the specified stimulation level, a secondindication signal to the at least one indicator for indicating a failure of delivery of the electricalstimulation signal to the target tissue region at the specified stimulation level through the operative element to the target tissue region and back through the return electrode. The indicator light incorporated with the housing 110 may provide reliable feedback to the surgeon / user as to the request and delivery of stimulus current.

[0128] In an example, the indicator light allows the surgeon to confirm delivery ofstimulus current, or more specifically, the pre-selected or desired stimulus current, to tissue. Through the use of different tones, colors, different flash rates, etc., the indicator allows the surgeon to confirm that the uninsulated tip is in place, the stimulation device 100 instrument is turned ON, and that stimulus current is flowing with sufficient (i.e., the desired) delivery to tissue. Thus, the surgeon has a much greater confidence that the desired stimulation amplitude is actually being delivered to the nerve, as in the case of a nerve transfer of nerve graft, a muscle 47 35936527.2contraction will not be observed since the nerve is no longer in continuity. These indicators can be checked periodically to ensure stimulation (e.g., the desired stimulation) is being delivered for the desired duration (e.g. between about 1 minute and one hour). In these embodiments, the indicator is determining more than just whether the operative element is providing stimulation, it indicates whether or not the electrical stimulation signal completes the electrical flow path going through the operative element (e.g., the lead 800 / 900 / 1000) and the target tissue region and back through the return electrode at a specified stimulation level based on a control setting selected by the user on the stimulation device 100.

[0129] As another example, in use the indicator may be configured to illuminatecontinuously or flashing at one rate in one color when the stimulation device 100 is turned on but not in contact with tissue. After contact with tissue is made, the same or an alternate indicator may flash (i.e., blink) at an alternate rate and or in an alternate color to indicate that stimulation is being delivered (as described above). If the stimulation has been requested, i.e., the stimulation lead has been turned on, but there is no stimulation being delivered because of a lack of continuity between the lead and the return electrode, or an inadequate connection of the lead or the return electrode to the patient tissue, or the stimulation device 100 not delivering to the tissue the desired / pre-selected stimulation signal, the same or another indicator may illuminate in a different color, and may illuminate continuously or may flash. In some embodiments, the indicator may alternate between defined colors to indicate a status of connected or a status of disconnected. The indicator may also or in the alternative blink at a defined rate to indicate a status of connected or a status of disconnected. The indicator may also alternate locations of the lights, which may create a different shape. The shaped lights may be defined to indicate a connected status or a disconnected status. The key is that the indicator distinguishes with specificity between the statuses.

[0130] As described herein, the indicator may comprise one or more lenses or lightpipes corresponding to each of one or more stimulation channels. The lens assembly may also 48 35936527.2include a reflective element to improve and focus the illumination effect of the light emitting source, e.g., one or more LEDs. The lens and the reflective element may be a single component, or more than one component to allow visual distinction between indicators corresponding to different status. Audio feedback also makes possible the feature of assisting the surgeon with monitoring nerve integrity during surgery.

[0131] While stimulation device 100 is described as generating an indication, it is notedthat various other components of the stimulation system may generate all or part of the indication. For instance, the stimulation device 100 (or a separate device) may monitor delivery of the stimulation signal. The stimulation device 100 may transmit status and diagnostic information (e.g. delivered current, stimulation duration, contraction presence, or the like) to a separate device (e.g., laptop, wearable electronic device, cellular phone, tablet, computer, speakers, light source, or the like). In an aspect, the stimulation device 100 may include a communication component that may be wired or wireless. For example, the stimulation device 100 may include a wireless transmitter / receiver configured to communicate via one or more communication protocols (e.g., Wi-Fi, BLUETOOTH, NFC, etc.).

[0132] In embodiments, stimulation device 100 may comprise a hand-held stimulationdevice. Housing 110 may be generally prismatic. According to an aspect, the housing 110 may be ergonomic and sterile for use in operative procedures. For instance, the stimulation device may be packaged in a sealed container that may allow a surgeon to open and use the stimulation device without the need for sterilization. It is noted, however, that parts of the stimulation system may be sterilized, such as the lead.

[0133] In another embodiment, the stimulation device may include alternateprogramming or an alternate means of connecting an operative element (lead) for use during surgical procedures to identify nerves and muscles, muscle attachments, contract muscles to assess the quality of surgical interventions or the need for surgical interventions, evaluate the 49 35936527.2function of nerves already identified through visual means, or provide prolonged stimulation of a nerve.

[0134] The stimulation device may be sized small enough to be held and used by onehand during surgical procedures and may be ergonomically designed for use in either the left or right hand. The stimulation device may be designed to ensure its stationary placement in the surgical field, on a mayo stand, an arm stand, clipped to surgical drape, hung, or placed on the patient’s body, In an embodiment, the stimulator 100 may have a length of about 18-22 centimeters and a width of 7-10 cm (not including the operative element), and a thickness of 10-30 mm.

[0135] In one or more embodiments, as described here as well as elsewhere in thisdisclosure, an operative element (the attached lead) may be monopolar or bipolar. For instance, lead 800 / 900 / 1000 may be monopolar. A return electrode may be coupled to control circuit via an insulated wire, and convey a feedback signal parameter to the stimulator 100 from a target tissue region. The return electrode may comprise any of a variety of electrode 812 / 912 / 1012 types (e.g., paddle, needle, wire, or surface electrode). In another aspect, the stimulation device 100 may be bipolar and may comprise a return electrode in a bipolar lead 800 / 900 / 1000 or other operative element.

[0136] User interfaces 119 may allow a user to turn ON / OFF the stimulation device (orset to standby) and may allow a user to control the stimulation signal amplitude selection within a predefined range (e.g., 0.10.5, or 2.0 mA). In configurations, user interface 113 may be a four or five position switch or a button that cycles through dosage settings. It is noted that the user interface 113 may allow for selection and change of frequencies within a range. Before the first use of the stimulation device, the user interface 113 is in the OFF state and keeps the stimulation output off. After the user interface 113 has been turned ON (e.g., by pressing one or more of the buttons 114 to select therapy delivered), the OFF state is no longer available and corresponds to a standby condition, where no stimulation would be delivered. In one 50 35936527.2embodiment, once the stimulation device has been turned on, it cannot be turned off, it can only be returned to the standby condition and will remain operational for a predetermined time, e.g., at least about four hours. This may allow the stimulation device to be only a single use device, so it cannot be turned OFF and then used again at a later date. It is noted, however, that some embodiments may allow the user to turn off the stimulation device after it has been turned on. In one example, the user interface 113 may allow for selection of “prolonged stimulation.” Once prolonged stimulation has been selected, the stimulation device may disable user control of certain stimulation parameters, may allow the stimulation device to be turned off, or may turn off after a certain time in the prolonged stimulation mode (e.g.1 hour).

[0137] In an embodiment, the buttons 114 may adjust an intensity of electricalstimulation output by the stimulator 100. More specifically, the buttons 114 may increase or decrease the intensity of the electrical stimulation when pressed by a user. In a further embodiment, the buttons 114 may include indicators, such as arrows, provided thereon, where the indicators respectively correspond to an increase or a decrease in the electrical stimulation upon pressing the buttons 114. In such an embodiment, the display 116 may additionally or alternatively include the indicators respectively corresponding to the buttons 114, where the indicators respectively signal an increase or decrease in the intensity of the electrical stimulation upon pressing one or more of the buttons 114. In a method of operating the stimulator 100, a user may adjust the intensity of the electrical stimulation output from the stimulator 100 by pressing the buttons 114 to increase or decrease the electrical stimulation signal based on patient perception and / or tolerance of the stimulation dose. In such a method of operating the stimulator 100, the user may adjust the intensity of the electrical stimulation to a highest intensity that may be achieved under a maximum threshold of patient perception and / or tolerance of the stimulation dose.

[0138] Further still, the stimulation device may shut off automatically after a pre-defined period of time, such as by way of a non-limiting example, two hours or more, one hour, 51 35936527.2thirty minutes, fifteen minutes, ten minutes, five minutes, one minute or thirty seconds. Any pre-defined time may be utilized. In these embodiments, the stimulation device may include a timer. The timer may be operatively coupled with or be integral to the control circuit. The time may be triggered upon the stimulation device being turned on by the user as previously described. For example, the user may actuate, touch or otherwise engage the user interface 113 to turn the stimulation device on to an active state. The time may then count down a predetermined amount of time and at the conclusion of the predetermined amount of time, the stimulation device may turn off, such as without human intervention.

[0139] In some embodiments, the time may continue to run for a second predeterminedamount of time, which may be greater than, less than or equal to the predetermined amount of time. At the conclusion of the second predetermined amount of time, the stimulation device may automatically turn back on to apply electrical stimulation or it may utilize the indicator to identify to the user / surgeon that the second predetermined time has expired and the stimulation device may be turned on to provide stimulation; during the second predetermined amount of time, the stimulation device may not be capable of turning on. In this case, the user / surgeon or even the patient may utilize the user interface 113 to manually turn the stimulation device on to apply electrical stimulation. This may allow the stimulation device to provide an automatic dosing regimen. In fact, this process may be repeated for any number of stimulation cycles whereby the stimulation device is automatically (without human intervention) on for the stimulation predetermined amount of time and off for a resting amount of time. Each cycle may have a different stimulation predetermined amount of time, such as a cascading amount of time, or the time may be the same as the other stimulation predetermined amount(s) of time. Similarly, the resting amount of time may be constant or may vary depending upon the dosing schedule, e.g., it may increase each successive period. Still further, the stimulation predetermined amount of time may be the same as or different from the resting amount of time. The stimulation device can apply a dosing regimen utilizing cycles of the stimulation 52 35936527.2predetermined amount of time that have different stimulation patterns (or in some embodiments, the same stimulation pattern). The stimulation predetermined amount of time and the resting predetermined amount of time may comprise any appropriate period, such as for example, one or more hours, thirty minutes, twenty minutes, fifteen minutes, ten minutes, one minute or thirty seconds. The present teachings are not limited to a specific time.

[0140] In some embodiments, once the predetermined amount of time has elapsed, thestimulation device may be unable to be turned back on to apply stimulation. This essentially results in the stimulation device becoming a single use device.

[0141] In some embodiments the device may include battery monitoring circuitry toensure a therapy dose is not initiated if the full length of the dose (i.e. all pulses) cannot be delivered.

[0142] Still further, the stimulation device may include a pulse counter of anyappropriate configuration. The pulse counter may count the number of pulses applied by the stimulation device and turn off after a predetermined number of pulses has been applied. The pulse counter may be operatively coupled with or integral to the control circuit. Upon occurrence of the predetermined number of pulses, the stimulation device may automatically turn off. The stimulation device may then use a time as described above to turn on after a predetermined amount of time to apply electrical stimulation or it may utilize the indicator to identify to the user / surgeon that the predetermined time has expired and the stimulation device may be turned on to provide stimulation. In this case, the user / surgeon or even the patient may utilize the user interface 113 to manually turn the stimulation device on to apply electrical stimulation. This may allow the stimulation device to provide an automatic dosing regimen. In fact, this process may be repeated for any number of stimulation cycles whereby the stimulation device is automatically (without human intervention) on for the predetermined number of pulses and off for a resting amount of time. Each cycle may have a different predetermined number of pulses, such as a cascading amount of pulses, or may have the same predetermined 53 35936527.2number of pulses. The resting amount of time may be constant or may vary depending upon the dosing schedule, e.g., it may increase or decrease each successive period. The stimulation device can apply a dosing regimen utilizing cycles of the predetermined number of pulses that have different stimulation patterns (or in some embodiments, the same stimulation pattern). The predetermined number of pulses and the resting predetermined amount of time may comprise any appropriate period, such as for example, one or more hours, thirty minutes, twenty minutes, fifteen minutes, ten minutes, one minute or thirty seconds. The present teachings are not limited to a specific time and / or number of pulses.

[0143] In some embodiments, once the predetermined number of pulses has occurred,the stimulation device is unable to be turned back on to apply stimulation. This essentially results in the stimulation device being a single use device.

[0144] In some embodiments, the pulse counter may include a sensor or plurality ofsensors that can determine the number of pulses generated from the stimulation device (or more specifically from the lead 800 / 900 / 1000). Still further, the pulse counter may include a stimulation sensor or a plurality of stimulation sensors that sense or determine the number of pulses actually delivered through the lead from the stimulation device 100 to the targeted tissues (or nerve(s)) of the patient. This stimulation sensor is able to determine if an electrical pulse emitted from the stimulation circuitry is actually delivered to the patient. In this embodiment, therefore, the pulse counter will count the total number of pulses actually delivered to the patient. If a pulse, for any reason, is not delivered to the patient, the pulse counter will not count it and such pulse will not count toward the predetermined number of pulses the pulse counter is counting. Further, the system may be able to compare the number of electrical pulses sent from the device against the number of pulses actually delivered to the patient. This may be utilized to determine the function of the device and / or the stimulation parameters being sent. Such sensors may comprise an electrode 812 / 912 / 1012 attached to the 54 35936527.2nerve to determine if there had been a pulse delivered to the nerve. The electrode 812 / 912 / 1012 may be configured to pick up a generally weak signal amid “background noise” in the patient.

[0145] Still further, the pulse counter may include an action potential sensor or pluralityof action potential sensors that can determine the number of action potentials generated from the stimulation device (or more specifically from the lead 800 / 900 / 1000) through the nerve or nerves of the patient. The action potential sensor or sensors may comprise an electrode 812 / 912 / 1012 (of any appropriate configuration) or a proxy for action potential such as an accelerometer detecting motor response, near-infrared spectroscopy to detect changes in blood flow, or the like. In an example, the system may include one or more leads 800 / 900 / 1000 for stimulation and an action potential sensor(s) comprising one or more leads 800 / 900 / 1000 for recording activity, such recording electrical activity. The action potential sensor may determine generation of an action potential from the nerve or nerves being stimulated through the lead 800 / 900 / 1000 by the stimulation device 100. The action potential sensor is able to determine if an electrical pulse emitted from the lead is actually delivered to the patient and that it generates an action potential. For example, the action potential sensor may be placed on, coupled to or otherwise attached to a location on a patient whereby the action potential can be detected upon application of the stimulation. In such a case, an electrode may be located in an area proximal and / or distal to the location of the stimulation in the patient where the nerve being stimulated innervates. In an example, action potentials going to the spinal cord, going to muscle tissues, or going in other directions may be recorded. The electrode may, alone or in combination with other components (e.g., a processor and memory), determine if an action potential is generated and sends a signal to the pulse counter indicating that the action potential was generated such that the pulse counter can count the generation of the action potential.

[0146] Still further, the action potential sensor may comprise an accelerometer thatmay be placed on, coupled to or otherwise attached to the patient to determine if an action potential was generated through the stimulation from the stimulation device 100. The 55 35936527.2accelerometer may be useful if the stimulation being applied is strong enough to invoke a muscle contraction that the accelerometer can sense and send a signal to the pulse counter indicating that an action potential was generated. Regardless of the configuration of the action potential sensor, the pulse counter will count the total number of action potentials generated in the patient. If an action potential is, for any reason, not generated in the patient, the pulse counter will not count it and such pulse will not count toward the predetermined number of action potentials the pulse counter is counting. In this condition an indicator may inform the user that adequate stimulation is not being delivered and therapy paused until stimulation parameters are adjusted, or stimulation adjustment may be automatically done by the software until action potentials are observed. In some embodiments, the indicator may be triggered after a given number of not generated action potentials are not identified within a given time frame or otherwise missed (e.g., missed x consecutive, missed i out of the last j, missed x within the past y milliseconds, etc.).

[0147] It is noted that in some embodiments, one or more of the pulse counter, actionpotential sensor, or timer may be comprised in a single device, in multiple device, within dedicated hardware and software, or as software stored within a memory and executed by a processor.

[0148] In embodiments, operating the stimulator 100 includes monitoring, adjusting,and controlling the electrical stimulation output in a feedback loop based on patient input. For example, a patient or user may actuate the stimulator 100 from the user interface 113 for patient-specific setting of stimulation parameters. In this manner, operating the stimulator 100 allows for patient control of initiating or resuming therapy stimulation, providing feedback on therapy status to the patient, adjustment of therapy parameters, or pausing therapy delivery based on patient tolerance or perception of the electrical stimulation output from the stimulator 100. In such an embodiment, the patient or user may directly control specific stimulation parameters of the electrical stimulation output from the stimulator 100 in real time, such as the 56 35936527.2intensity, duration, or waveform of the electrical stimulation. In an embodiment, the stimulator 100 may afford patient control of the intensity of stimulation while the overall dose is adjusted based on the patient-controlled adjustments. For example, a patient may turn a knob up and down or press the buttons 114 at the user interface 113, adjusting the electrical stimulation to the maximum tolerable intensity, and the control circuitry adjusts the duration accordingly by, for example, changing total pulses delivered to match a prescribed overall charge, or changing delivery time as a function of stimulation parameters such as, for example, amplitude, pulse duration, or frequency. The stimulator 100 may additionally or alternatively trigger automated adjustments of the electrical stimulation based on patient feedback, optionally expressed through the user interface 113 or set as predetermined threshold by the user or the patient.

[0149] In another embodiment, the stimulator 100 may prompt the patient or user forinput or interaction at certain key points, such as defining a motor threshold, a perception threshold, or a tolerance limit. In further embodiments, the stimulator 100 may prompt the patient or the user for such input or interaction before, during, or after a medical procedure or therapy session. In this regard, the stimulator 100 may automatically adjust or ramp through stimulation parameters during a testing period to help the patient, user, caregiver, or clinician define these key stimulation settings and ranges. More specifically, the stimulator 100 may increase and decrease the electrical stimulation to identify a threshold, such as a motor response, therapeutic response, or patient perception based on an intensity of the electrical stimulation.

[0150] Such settings and ranges may be selected from a series of pre-set configurationor settings files on the device, to enable adjustment to certain pre-determined conditions. These settings and ranges may be set by the patient before or at the time of therapy delivery, or by a clinician or health care provider as the user. In an embodiment, the stimulator 100 may apply a minimum suprathreshold stimulation for therapeutic benefit, which may be a sub- or supra- 57 35936527.2motor or perception threshold. The motor response threshold employed by the stimulator 100 may include an input from an accelerometer and compound muscle action potentials (CMAP).

[0151] In an embodiment, the settings and ranges determined for operating thestimulator 100 may be used by the stimulator 100 to set the therapy within patient tolerance limits and / or within efficacy ranges, such as sub-perception, sub-motor threshold, or below a tolerance level. With this construction, the electrical stimulation output from the stimulator 100 reliably avoids reaching a perception or tolerance threshold of the patient, including circumstances where the perception or sensitivity of the patient to the electrical stimulation changes over time.

[0152] In another embodiment of operating the stimulator 100 in a feedback loop, thereturn electrode 812 / 912 / 1012 or other sensors of the stimulator 100 may receive an electrical signal as a feedback signal parameter, and the stimulator 100 performs electroneurography (“ENG”), electrocardiography (“ECG” or “EKG”), or electromyography (“EMG”) to detect stimulation-induced action potential, muscle contraction, evoked sensory response, or to confirm successful delivery of the stimulation and activation of a target nerve as a feedback signal parameter. As such, the stimulator 100 may detect the presence of evoked potential and / or quantify the measure, size, or strength of the evoked response to ensure therapeutic benefit, and may adjust the stimulation parameters to ensure that an evoked response is detected, or may adjust the stimulation parameters to maintain the evoked response in a specific range based on patient response to the electrical stimulation from the stimulator 100 in a closed loop system.

[0153] In an embodiment, one of the other sensors of the stimulator 100 is anaccelerometer or a resistive sensor that transmits sensor data indicating a detected condition of the patient to the control circuitry in the housing 110. With this construction, the stimulator 100 may continuously analyze a condition or response of the patient as a feedback signal parameter for a duration of electrical stimulation, and automatically modulate the electrical 58 35936527.2stimulation based on the determined condition or response in a closed loop system. In this manner, the stimulator 100 may automatically adjust the electrical stimulation to a minimum intensity necessary to produce a desired effect, tailoring the settings for each participant or therapy delivery session. The stimulator 100 may also tailor unique delivery needs of the electrical stimulation, such as modulating the electrical stimulation to minimize muscle contraction if delivered during a procedure.

[0154] In an embodiment, the stimulator 100 may include a sensor detecting aphysiological indicator, such as a chemical or other biological marker indicating successful activation of therapeutic mechanism of action to ensure successful therapy delivery. Such markers may comprise specific ions (e.g. calcium), either directly or indirectly through local voltage or current changes, indicating sufficient neural activation.

[0155] The user interface 113 may allow for adjustment of a stimulation signal pulsewidth from a predefined range (e.g., about zero to about 200 microseconds). In one embodiment, the user interface 113 may be a potentiometer to allow a slide control to increase or decrease the stimulation signal pulse width within the predefined range. The stimulation pulse may have a non-adjustable frequency in the range of about 10 Hz to about 30 Hz, and desirably about 16 Hz. In some embodiments, the stimulation pulse may comprise an adjustable frequency.

[0156] As a representative example, the stimulation pulse may have a biphasicwaveform with controlled current during the cathodic (leading) phase, and net DC current less than 10 microamps, switch adjustable from about 0.1 milliamps to about 20 milliamps, and pulse durations adjustable from about zero microseconds up to about 1 millisecond.

[0157] The operative element (e.g., lead 800 / 900 / 1000) exits or attaches to the housing110 at the connector to deliver stimulus current to the excitable tissue

[0158] The size of the uninsulated portion, (the active electrode 812 / 912 / 1012) of thelead 800 / 900 / 1000 ensures a high current density that will stimulate nearby excitable tissue. 59 35936527.2The insulation portion may comprise a medical grade heat shrink, a medical grade tubing, or an applied biocompatible insulative coating.

[0159] The insulative portion may comprise a silicone or urethane or other polymericmaterial to in the form of a cuff or a hook.

[0160] The electrode 812 / 912 / 1012 portion of the lead 800 / 900 / 1000 may have anexposed surface area ranging between 1.5 and 8 square millimeters, desirably about 4 millimeters square. The uninsulated surface area defining the electrode 812 / 912 / 1012 extends entirely around a perimeter of the lead 800 / 900 / 1000 in a circumferential direction perpendicular to the longitudinal direction. The length of the lead may be about 50 – 100 cm, although it is to be appreciated that the length may vary depending on the particular application. As shown, the lead may include flexible and malleable portions to facilitate accurate placement of the electrode 812 / 912 / 1012.

[0161] In an embodiment, the conductive material of the lead 800 / 900 / 1000 is made ofa stainless steel, solid wire, although other conductive materials may be used. In such an embodiment, the insulated body 804 / 904 / 1004, the electrodes 812 / 912 / 1012, the insulated portions 820 / 920, and the anchor 808 / 908 / 1008 are integrally formed with each other along the wire in the longitudinal direction of the lead 800 / 900 / 1000. In a further embodiment, the wire has a diameter of less than 2 millimeters. In a further embodiment, the wire has a diameter less than 0.65 millimeters along an entire length from the insulated body 804 / 904 / 1004 to the anchor 808 / 908 / 1008 in the longitudinal direction.

[0162] Further, the lead 800 / 900 / 1000 may include an anchor 808 / 908 / 1008. Theanchor 808 / 908 / 1008 may be of any appropriate configuration. By way of a non-limiting example, the anchor 808 / 908 / 1008 may comprise a bend in the lead 800 / 900 / 1000 such that upon insertion of the lead 800 / 900 / 1000 into tissue of a patient, or more specifically, the anchor 808 / 908 / 1008 being inserted into tissue of the patient, the anchor 808 / 908 / 1008 prevents an undesired withdrawal of the anchor 808 / 908 / 1008 and / or lead 800 / 900 / 1000. 60 35936527.2

[0163] With reference to the embodiment depicted in Fig. 9, the anchor 808 is anuninsulated distal end portion of the wire forming the lead 800. The anchor 808 is formed from a right-angle bend in the wire that extends the anchor 808 in a radial direction of the lead 800, perpendicular to the longitudinal direction. The anchor 808 has a diameter that narrows along a length of the wire, in a direction taken from the proximal end portion toward the distal end portion formed from the insulated body 804. With this construction, the anchor 808 forms a barb that may fix the electrode 812 with respect to the target tissue region, and may transmit the stimulation signal into the target tissue region.

[0164] Referring to FIG. 10, the anchor 908 is formed from a cap that blockstransmission of the electrical stimulation signal to the exterior environment from the distal end portion of the lead 900 formed from the wire. The cap includes a plurality of tines 916 that extend outward from the wire along the radial direction of the lead 900, perpendicular to the longitudinal direction. The tines 916 also extend backward along the longitudinal direction of the lead 900. The cap includes a flange that defines an outermost surface in the radial direction, where the outermost surface is inclined from the wire in the radial direction, along the wire in a direction taken from the proximal end portion formed at the insulated body 904 toward the distal end portion formed at the anchor 908. The flange is offset from the tines 916 by a length along the wire that is equal to or greater than an overall length of the tines extended from the cap. With this construction, the anchor 908 may be introduced to a physiological environment including the target tissue region with the tines 916 folded radially inward, toward the wire, where the tines provide relatively little resistance to insertion through the physiological environment. Further, in such a bent configuration, the tines 916 cover an adjacent radial surface of the flange, preventing the flange from catching the physiological environment during insertion of the lead 900 in the longitudinal direction. When the tines 916 are unfolded from the wire, the tines 916 and the radial surface of the flange catch and fix the physiological 61 35936527.2environment with the lead 900, stabilizing the electrode 912 relative to the target tissue region, at a side of the electrodes 912 opposite the insulated body 904 in the longitudinal direction.

[0165] As previously described, in monopolar operation, a return electrode (orindifferent electrode), for example, provides an electrical path from the body to the stimulation device. The return electrode may be placed on the surface of intact skin (e.g., surface electrodes as used for electrocardiogic or electromyographic monitoring during surgical procedures) or it might be needle-like and be placed in the surgical field or penetrate through intact skin or an incision.

[0166] The configuration of the stimulating medical devices that form a part of thesystem can vary in form and function. Various representative embodiments of illustrative medical devices will be described.

[0167] Referring now to Figs. 9-11, leads 800 / 900 / 1000 are disclosed in accordancewith various disclosed aspects. Leads 800 / 900 / 1000 may generally include an insulated body 804 / 904 / 1004 forming a proximal end portion, an anchor 808 / 908 / 1008 forming a distal end portion, and one or more uninsulated portions that are electrodes 812 / 912 / 1012. As depicted, the leads 800 / 900 / 1000 include an insulation disposed around the body 804 / 904 / 1004, where the insulation blocks transmission of the electrical stimulation signal from the body 804 / 904 / 1004 to the exterior environment. The electrodes 812 / 912 / 1012 are extended from the insulated body 804 / 904 / 1004 in the longitudinal direction of the lead 800 / 900 / 1000, where the electrodes 812 / 912 / 1012 are interposed between and separate the insulated body and the anchor along the lead 800 / 900 / 1000 in the longitudinal direction.

[0168] In an example method of transmitting an electrical stimulation signal to a targettissue region, the lead 800 / 900 / 1000 is delivered to the target tissue region, where the anchor 808 / 908 / 1008 forms a distal end portion of the lead 800 / 900 / 1000 positioned at a first side of the target tissue region. The insulated body 804 / 904 / 1004 forms a proximal end portion of the lead 800 / 900 / 1000 that is positioned at a second side of the target tissue region opposite the 62 35936527.2first side in the longitudinal direction of the lead 800 / 900 / 1000. The electrodes 812 / 912 / 1012 are interposed between the insulated body 804 / 904 / 1004 and the anchor 808 / 908 / 1008 in the longitudinal direction and positioned at the target tissue region. More specifically, the electrodes 812 / 912 / 1012 are arranged along the wire forming the lead 800 / 900 / 1000, in the longitudinal direction between the insulated body 804 / 904 / 1004 and the anchor 808 / 908 / 1008. In a further embodiment of the method, transmitting the electrical stimulation signal to the target tissue region includes transmitting the electrical stimulation signal to the target tissue region through the anchor 808 / 908, where the anchor 808 / 908 is electrically isolated from the electrodes 812 / 912 by at least one of the insulated portions 820 / 920, and transmits the electrical stimulation signal to the target tissue region in a bipolar manner.

[0169] The method may further include detaching the electrode 812 / 912 / 1012 from theinsulated body 804 / 904 / 1004, removing the insulated body 804 / 904 / 1004 from the target tissue region, and leaving the electrode 812 / 912 / 1012 at the target tissue region, where the electrode 812 / 912 / 1012 transmits the stimulation signal and dissolves at the target tissue region.

[0170] It is noted that the percutaneous electrodes depicted between Figs. 9-11 maycomprise similar aspects, unless context suggests otherwise or specific reference is made to a such difference. As such, while examples may refer to one of the percutaneous electrodes and, for simplicity of explanation, the other may be utilized. Moreover, various other percutaneous electrodes may be utilized by embodiments disclosed herein.

[0171] In an example, percutaneous electrode 812 / 912 / 1012 may be placed at or neara target tissue region and may be coupled with a percutaneous lead or wire, as described herein. It is noted that percutaneous electrode 812 / 912 / 1012 may be positioned while an incision is open and may be left in place while the incision is closed. In at least one other embodiment, percutaneous electrode 812 / 912 / 1012 may be positioned when an incision is closed or by deploying the percutaneous electrode 812 / 912 / 1012. 63 35936527.2

[0172] In embodiments, percutaneous lead 800 / 900 / 1000 may comprise strands ofstainless steel wire insulated with a biocompatible polymer. Each wire strand may have a diameter of approximately 34 μm and the insulated multi-strand lead wire may have a diameter of approximately 250 μm. It should be understood, however, that these dimensions and materials are merely exemplary and the present teachings are not limited to such. Any appropriate sized, shaped and configured percutaneous lead may be used. The insulated wire may be formed into a spiral or helix as has been found to accommodate high dynamic stress upon muscle flexion and extension, while simultaneously retaining low susceptibility to fatigue. The outer diameter of the percutaneous lead 800 / 900 / 1000 may be approximately 580 μm and it may be encased or filled with silicone or the like. In at least some embodiments, percutaneous lead 800 / 900 / 1000 may be made out of a different material (e.g., another metal, conducting polymer), may be insulated with another material, or may not be insulated. Further, the lead 800 / 900 / 1000 may be cylindrical or paddle-like.

[0173] Unlike surface electrodes that are applied to the surface of the patient’s skinusing an adhesive, percutaneous electrode may be surgically implanted or otherwise inserted into select tissue. The terminal end may include an anchor 808 comprised of one or more tines 816. The anchor 808 may be insulated or uninsulated. In at least some embodiments, the anchor 808 may be inserted directly into tissue and may deliver stimulation signals to the tissue. In another aspect, the anchor 808 may generally hold the percutaneous electrode in place. For instance, the one or more tines 816 may comprise a bend, curve, barb, etc., that prevents the percutaneous electrode from substantially moving or unintentionally coming loose. As shown in Figs 3 and 4, disclosed embodiments may include different types of anchors 808. For instance, an anchor 808 may include j tines, where j is a number. In an exemplary embodiment, a patch assembly may be utilized in conjunction with the percutaneous electrode. The patch assembly may comprise several layers, including an adhesive layer, an electrode layer, a reinforcement layer and a cover layer. In one embodiment, the patch assembly may include a 64 35936527.2power source for the stimulation device. Further, the patch assembly may act as a surface electrode. In one embodiment, the patch assembly may include an engagement member or members that electrically couple the stimulation device to the percutaneous electrode to provide stimulation for nerve regeneration. The engagement member may comprise a snap, a magnetic male and female member capable of operable engagement, a bayonet engagement device, or any known engagement mechanisms capable of electrically coupling the stimulation device with the percutaneous electrode 812 / 912 / 1012. The present disclosure contemplates any such configuration of the patch assembly.

[0174] In another aspect, an anchor 808 may include threaded members (e.g., screws)or the like. Further still, the percutaneous electrode 812 / 912 / 1012 may include tines 816 or anchors 808. In these embodiments, the percutaneous electrode may be placed near or around, i.e., generally circumscribing all of or a portion of the applicable nerve. Further, the percutaneous electrode may be placed over, i.e., on top of or at the bottom of, the applicable nerve, or near, i.e., in an operative distance from the applicable nerve in any manner. The present teachings are not limited to a specific configuration. Embodiments may include a nerve cuff, a coiled lead 1000, a straight lead, lead with a hook, lead with a tine 816 / 916 or tines, or the like.

[0175] According to embodiments, percutaneous electrode 812 / 912 / 1012 maycomprise flexible materials that allow some or all of the percutaneous electrode 812 / 912 / 1012 to bend or deform. In an example, the insulated portion 820 / 920 may be a lead 800 / 900 / 1000 that is generally flexible to allow removal, positioning, or other manipulation of the percutaneous electrode 812 / 912 / 1012.

[0176] In embodiments, sections of the uninsulated portion may be separated byinsulated portions 820 / 920. It is noted that different sections of the uninsulated portions 812 may be electrically isolated from each other to allow for bipolar stimulation. In another aspect, the insulated portions may allow for increased strength, positioning, or the like of the 65 35936527.2percutaneous electrode 800. The uninsulated portion 812 may operatively deliver a stimulation current. It is noted that the uninsulated portion 812 may be disposed anywhere along the percutaneous electrode 800. For instance, the uninsulated portion 812 may be disposed at one or more tines 816, at anchor 808, or the like.

[0177] In an embodiment, adaptor may primarily include percutaneous electrode812 / 912 / 1012, wire and connector. Wire may connect terminal end of the percutaneous electrode 812 / 912 / 1012 with connector. In an aspect, wire may comprise an insulated wire that is removably or irremovably attached to the percutaneous electrode 812 / 912 / 1012 and / or connector. As described herein, the adaptor may be configured to allow a stimulation lead to deliver a stimulation signal below the skin of a subject patient.

[0178] In an aspect, connector may include an opening that may receive an operativeelement. The opening may be received by the receptacle of a stimulation device 100. The opening may be tapered to maintain the lead connector in a friction fit within the receptacle. The connector may further include other retaining features, such as a fastener (e.g., screw, clasp, threaded portions, hook and loop, magnet, etc.) to retain the connection between the connector and the lead 800 / 900 / 1000. It is noted that connector may comprise an electrical connection disposed within the connector that may operatively couple an uninsulated or stimulating portion of the lead with the wire. A wire may extend from the connector. Wire may be an electrical conductor in electrical connection with stimulator receptacle when lead is operatively inserted into the stimulator receptacle. It is noted that the wire may be any appropriate length, such as 24 inches or a length between 12 inches and 48 inches. The lead wire may further be any appropriate gauge, such as 24 AWG wire.

[0179] Percutaneous electrode 812 / 912 / 1012 may be coupled to the wire at a terminalend. According to an embodiment, the wire may be removably or irremovably coupled to the terminal end. It is noted that the wire may be coupled directly to the terminal end and / or may be coupled indirectly to the terminal end, such as through one or more other connectors (not 66 35936527.2shown). Moreover, wire may be coupled to other portions of the percutaneous electrode 812 / 912 / 1012. In an aspect, the connection between the wire and the percutaneous electrode 812 / 912 / 1012 may be insulated or uninsulated.

[0180] A connector may be attached to the lead. The surgeon may utilize user interfaces113 to select a stimulation process. For instance, the surgeon may operatively set the stimulation device to deliver a prolonged stimulation to target tissue. In an aspect, prolonged stimulation may be applied prior to surgical intervention (e.g. nerve repair, nerve release, or nerve transfer). In an aspect, prolonged stimulation may be delivered to a nerve or muscle, distal to site of surgical intervention, to increase muscle viability while the nerve re-grows.

[0181] It is noted that the stimulation device may comprise a preprogrammedstimulation process that may operatively generate stimulation signals for prolonged stimulation in a closed loop system based on a feedback signal. In another aspect, user interfaces 113 may allow a user to manually program or adjust stimulation parameters, such as intensity, pattern, time, or the like.

[0182] In this regard, Fig. 12 depicts the stimulator 100 operatively connected to thepatient 2900 for delivering the stimulation signal 2902 to the target tissue region based on the feedback signal 2904 returned from a sensor 2910. The sensor 2910 may be an accelerometer, a resistive sensor, the electrode 812 / 912 / 1012, or another sensor operatively connected to the stimulator 100, where the sensor conveys the feedback signal to the control circuitry in the housing 110. In embodiments of operation, the stimulator 100 delivers the stimulation signal to the target tissue region following a process flow depicted in FIG.13.

[0183] Referring to FIG. 13, a method 3000 for operating the stimulator 100 will bedescribed according to an exemplary embodiment. FIG.13 will be described with reference to FIGS.1-13. For simplicity, the method 3000 will be described as a sequence of blocks, but the elements of the method 3000 can be organized into different architectures, elements, stages, and / or processes. 67 35936527.2

[0184] At block 3002, the method 3000 includes determining whether a motor responseor biomarker has been detected by the sensor 2910 operatively connected with the stimulator 100 and / or whether a threshold of a desired motor response or biomarker has been detected. At block 3002 the method 3000 additionally or alternatively includes evaluating patient tolerance to the stimulation signal 2902. Such evaluation may be performed concurrently with sensing a condition of the patient 2900 based on the feedback signal 2904. Information indicating the tolerance of the patient 2900 to the stimulation signal 2902 may be input to the stimulator 100 at the user interface 113 by the user or a clinician supervising the care of the patient.

[0185] At block 3004, the method 3000 includes determining whether more intensityin the stimulation signal 2902 is desired. The determination may be based on an absence or insufficiency of a motor response or biomarker detection from the sensor 2910 in the feedback signal 2904, or based on user input received at the user interface 113. In some embodiments, the determination may be made automatically by the control circuitry in the housing 110 based on predefined thresholds for a detected physiological signal or treatment protocol stored in memory.

[0186] At block 3010, the method 3000 includes increasing the stimulation outputdelivered by the stimulator 100. Increasing the output may include adjusting one or more stimulation signal parameters, such as amplitude, frequency, or pulse width, in response to the determination made at block 3004. The increase in output may be accompanied by a corresponding reduction in the duration of the stimulation period to maintain a desired total dose, or to improve patient tolerance. The control circuitry may execute these adjustments automatically or in response to input received through the user interface 113.

[0187] At block 3012, the method 3000 includes determining whether the stimulationsignal 2902 remains or is effective for intended therapeutic benefit at a reduced intensity. This determination may be based on continued detection of a motor response or biomarker by the sensor 2910 after reducing the output parameters of the stimulation signal 2902. Additionally 68 35936527.2or alternatively, the stimulator 100 may receive input from the user interface 113 indicating improved tolerance of the stimulation signal 2902, or continued perceived efficacy or therapeutic benefit at lower intensity levels.

[0188] At block 3014, the method 3000 includes determining whether a break fromdelivery of the stimulation signal 2902 is needed. This determination may be made based on user input received at the user interface 113 indicating a need to temporarily suspend therapy— such as for comfort, activity interruption, tolerance, or adverse perception—or based on sensor data indicating overstimulation or motion that may interfere with therapy or an ongoing procedure. In some embodiments, the determination at block 3014 may be made by control logic configured to prompt the user at intervals to assess comfort or provide scheduled breaks.

[0189] At block 3020, the method 3000 includes pausing the stimulation signal. In thisregard, the stimulator 100 may terminate the delivery of the stimulation signal 2902 temporarily during a session while retaining the configured stimulation parameters in memory. The user interface 113 may provide a visual or tactile indicator confirming the paused state, and the stimulator 100 may maintain readiness to resume stimulation upon receiving a resume command or after a predetermined timeout period.

[0190] At block 3022, the method 3000 includes decreasing the output intensity of thestimulation signal 2902. This may include reducing the amplitude, frequency, and / or pulse width of the stimulation signal 2902 generated by the stimulator 100. In some embodiments, the decrease in intensity may be accompanied by an increase in the duration of stimulation to maintain a target overall dose of electrical stimulation. The adjustment may be performed automatically by the control circuitry based on the feedback signal 2904 or input at the user interface 113.

[0191] At block 3024, the method 3000 includes continuing the delivery of thestimulation signal 2902. In this regard, the stimulator 100 may monitor feedback signal parameters and adjust corresponding stimulation signal parameters in a closed loop system for 69 35936527.2delivering the stimulation signal 2902 to the patient 2900. The continuation of stimulation at block 3030 may occur after increasing output intensity of the stimulation signal 2902 at block 3004, after pausing the stimulation signal at block 3014, or after decreasing the output intensity of the stimulation signal 2902 at block 3024. As such, the method 3000 may include resuming delivery of the stimulation signal 2902 from block 3020.

[0192] The control circuitry of the stimulator 100 may maintain a current set of outputsettings, including amplitude, frequency, and pulse width, and apply the stimulation signal 2902 through the lead 800 to the target tissue region based on a detected parameters of the feedback signal 2904. As such, the stimulator 100 may continue therapy using the same or modified parameters that were in effect prior to the pause event at block 3014. Generation of the stimulation signal 2902 may be initiated by the patient 2900 or a clinician through the user interface 113, or it may be automatically triggered by the stimulator 100 after a defined delay or upon satisfaction of predefined resumption conditions.

[0193] The foregoing is considered as illustrative only of the principles of theinvention. Furthermore, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described. While a preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims. 70 35936527.2

Claims

CLAIMS What is claimed is:

1. A method of delivering a stimulation signal to a target tissue region, the method comprising: positioning one or more electrodes at or proximal the target tissue region, wherein the one or more electrodes are operatively connected to a stimulator through a lead; generating the stimulation signal at the stimulator, wherein the stimulation signal travels to and excites the target tissue region from the stimulator via the lead and the one or more electrodes; performing a measurement of a patient receiving the stimulation signal at the target tissue region, wherein the measurement indicates a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the patient; and controlling a stimulation signal parameter based on the measurement.

2. The method of claim 1, wherein performing the measurement includes measuring a nerve excitability or conduction, an actional potential, a nerve or muscle integrity, or an intensity of the stimulation signal returning to the stimulator at the one or more electrodes.

3. The method of claim 1, further comprising: positioning an accelerometer at the target tissue region, wherein performing the measurement includes measuring an acceleration of the target tissue region; and determining a motor response threshold associated with the patient, the motor response threshold being a minimum amplitude or pulse duration of the stimulation signal that produces acceleration at the target tissue region that is measurable by the accelerometer, wherein controlling the stimulation signal includes maintaining the stimulation signal below the motor response threshold.

4. The method of claim 1, wherein: positioning the one or more electrodes comprises: 71 35936527.2positioning a stimulation electrode at or proximal the target tissue region, where the stimulation electrode conveys the stimulation signal to the target tissue region, and positioning a return electrode at or proximal the target tissue region, offset from the stimulation electrode along the target tissue region, where the return electrode forms a return path that conveys the stimulation signal from the target tissue region to the stimulator, performing the measurement includes measuring an intensity of the stimulation signal conveyed to the stimulator from the return electrode; and controlling the stimulation signal parameter includes controlling the intensity of the stimulation signal generated at the stimulator at or above a minimum therapeutic benefit threshold, and at or below a perception threshold associated with the patient.

5. The method of claim 4, wherein performing the measurement includes detecting pulses in the stimulation signal conveyed from the return electrode to the stimulator, and controlling the stimulation signal includes transmitting a predetermined number of pulses to the target tissue region, each pulse of the predetermined number being counted up detection at the return electrode.

6. The method of claim 1, further comprising repeatedly performing the measurement of the patient while generating the stimulation signal over a single session, and controlling the stimulation signal includes adjusting the stimulation signal parameter based on the repeated measurement.

7. The method of claim 6, wherein the one or more electrodes are percutaneous, the measurement also indicates a location or type of tissue in the target tissue region, positioning the one or more electrodes is performed based on the measurement, and controlling the stimulation signal includes adjusting the stimulation signal parameter intraoperatively.

8. The method of claim 6, wherein the stimulation signal is transmitted over a plurality of doses during the single session, wherein each dose has a duration of at least 5 to 15 minutes each, separated by rest periods of at least 5 minutes, and an amplitude or a frequency 72 35936527.2of the stimulation signal is modified between successive doses based on the repeated measurement.

9. The method of claim 8, wherein controlling the stimulation signal parameter includes maintaining an amplitude of the stimulation signal between 0.1 and 20 milliamps, and a frequency of the stimulation signal between 2 Hertz and 1,000 Hertz during the plurality of doses.

10. The method of claim 1, further comprising: generating a test signal at the stimulator that is received by the patient at the one or more electrodes, including ramping one or more test signal parameters through a plurality of grades; and setting a motor response threshold, a perception threshold, or a tolerance limit associated with the patient, wherein controlling the stimulation signal parameter includes maintaining the stimulation signal below the motor response threshold, the perception threshold, or the tolerance limit.

11. The method of claim 10, further comprising: manually adjusting the stimulation signal parameter toward the motor response threshold, the perception threshold, or the tolerance limit based on patient input during a single session; and automatically adjusting a duration, a number of pulses, or a delivery time of the stimulation signal as a function of stimulation signal parameter including amplitude, pulse duration, or frequency using control circuitry in the stimulator, in response to manually adjusting the stimulation signal parameter, maintaining a predetermined overall charge delivered to the target tissue region during the single session.

12. The method of claim 10, further comprising manually adjusting the motor response threshold, the perception threshold, or the tolerance limit during a single session, wherein controlling the stimulation signal parameter includes automatically adjusting or 73 35936527.2maintaining the stimulation signal parameter below the motor response threshold, the perception threshold, or the tolerance limit during the single session.

13. The method of claim 1, further comprising positioning a resistive sensor at the target tissue region, wherein performing the measurement includes measuring a motor response with the resistive sensor.

14. The method of claim 1, wherein performing the measurement includes performing electroneurography, electrocardiography, or electromyography using the one or more electrodes, wherein the one or more electrodes detect a stimulation-induced action potential, a muscle contraction, an evoked sensory response, activation of a target nerve or muscle included in the target tissue region, or delivery of the stimulation signal, and controlling the stimulation signal parameter includes adjusting at least one of a frequency, amplitude, pulse duration, or waveform of the stimulation signal based on the performed measurement.

15. The method of claim 1, further comprising determining a minimum therapeutic benefit threshold associated with the patient based on the measurement, and controlling the stimulation signal includes adjusting the stimulation signal parameter to an intensity that corresponds with the minimum therapeutic benefit threshold.

16. A stimulation system comprising: a stimulator that generates a stimulation signal; one or more electrodes operatively connected to the stimulator, wherein the one or more electrodes are positioned relative to a patient and convey the stimulation signal to a target tissue region of the patient; and control circuitry in the stimulator that performs a measurement of a feedback signal parameter, a perception, a motor response, or a therapeutic benefit associated with the patient, and automatically adjusts a stimulation signal parameter based on a minimum therapeutic 74 35936527.2benefit threshold, a motor response threshold, a perception threshold, or a tolerance limit associated with the performed measurement.

17. The system of claim 16, further comprising a return electrode that forms a return path for the stimulation signal from the target tissue region toward the stimulator, wherein the control circuitry determines a frequency, amplitude, waveform, or number of pulses in the stimulation signal conveyed to the stimulator from the return electrode as the feedback signal parameter, and the control circuitry adjusts the stimulation signal parameter based on the feedback signal parameter.

18. The system of claim 16, wherein the one or more electrodes detect the feedback signal parameter by performing electroneurography, electrocardiography, or electromyography at the target tissue region, the control circuitry determines the motor response, an associated motor response threshold, the therapeutic benefit, and a therapeutic benefit threshold during stimulation as the feedback signal parameter, and the control circuitry maintains the feedback signal parameter above the therapeutic benefit threshold, and maintains the feedback signal parameter one of above and below the motor response threshold by adjusting the stimulation signal parameter in a closed loop.

19. The system of claim 16, further comprising a resistive sensor or an accelerometer operatively connected to the stimulator, wherein the resistive sensor or the accelerometer generate sensor data at the target tissue region as the feedback signal, the control circuitry determines the motor response based on the feedback signal, and the control circuity maintains the motor response within a predetermined range by adjusting the stimulation signal parameter.

20. The system of claim 16, further comprising a user interface operatively connected to the stimulator, wherein the user interface adjusts the perception threshold or the 75 35936527.2tolerance limit based on user input associated with the stimulation parameter, and the control circuitry adjusts the stimulation signal parameter below the perception threshold or the tolerance limit. 76 35936527.2

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