Adaptive neuromodulation system

Abstract

A neuromodulation system disclosed herein improves urethral function, provides personalized stimulating parameters, and allows the patients to regain control of their bladders according to several implementations. A neuromodulation system disclosed herein provides bilateral stimulation and sensing, and personalized machine learning classifiers for adaptive stimulation. The system may include one or more electrode leads implanted in a first lateral side of the patient and one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side. Mixed urinary incontinence and other conditions are treated using electrical stimulation, according to several implementations.

Description

ADAPTIVE NEUROMODULATION SYSTEMINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 710246, filed October 22, 2024, and U.S. Provisional Application No. 63 / 741,363, filed January 2, 2025, the entire disclosures of which are hereby incorporated by reference herein in their entirety.BACKGROUNDField

[0002] The present disclosure generally relates to systems and methods for providing neuromodulation to treat various types and sub-types of urinary incontinence and other medical conditions. For example, adaptive stimulation is provided, including electrical neurostimulation that is configurable to an individual's needs and capable of responding dynamically to different events. Several embodiments provide technology that permits advantageous patent engagement. For example, the systems and methods disclosed herein provides stimulation using bilateral leads and / or stimulation based on artificial intelligence ("Al”) trained classifiers, which, alone or combined, improves accuracies in the stimulation generated to provide more personalized treatment.Description of the Related Art

[0003] Electrodes may be implanted in a pelvic region of a patient to provide electrical stimulation as clinical treatment and / or condition management. For example, a neuromodulation device, which may include an implantable pulse generator (IPG) coupled with an electrode lead, can electrically stimulate a nerve, which may improve neural communication between the brain and the bladder or the bowel. Once the neuromodulation device is implanted, a physician may program the device to stimulate the nerve.SUMMARY

[0004] Several embodiments described herein advantageously provide neurostimulation configurable to an individual's specific needs that is capable of responding dynamically to different events, including with patent engagement. Adaptive neuromodulation involving patient engagement can improve the clinical outcome when treating a condition, such as incontinence. With respect to urinary incontinence, including mixed urinary incontinence, several embodiments advantageously offer a patient the ability to "be in control of their own bladder”, which can lead to greater efficacy, compliance, and sense of wellbeing.

[0005] Several embodiments described herein advantageously provide bilateral neurostimulation allowing for simultaneous sensing and stimulation to improve therapy and optimize stimulation parameters. Several embodiments described herein advantageously using an Al trained classifier to provide neurostimulation configurable to an individual's specific needs based on a combination of different sensor inputs during different physical activities.

[0006] Incontinence, including a lack of control over micturition or bowel movements, has many causes but may involve injury or weakness of the pelvic floor muscles and / or the nerves that innervate these muscles and involved organs. Several embodiments described herein provide systems and methods for providing adaptive neuromodulation or neurostimulation to treat various conditions, such as urinary incontinence, fecal incontinence, pain, sexual dysfunction, or any combination thereof medical condition and / or diseases within the pelvic region. Although several embodiments are described herein with respect to the pelvic region to treat and / or manage pelvic conditions,they may also be used in other regions of the body or to treat other conditions as described elsewhere herein. With respect to urinary incontinence, several embodiments are particularly beneficial because they address more than one type of incontinence. Systems and methods described herein may be used to treat urge incontinence, stress incontinence, overflow incontinence, mixed incontinence, or any combination thereof. For example, both urge and stress incontinence can be treated with several of the systems described herein. Many patients have mixed urinary incontinence (MUI), which involves features of both stress urinary incontinence (SUI) and urge urinary incontinence (UUI). The combination of an automated background level and a patient-activated higher level benefits a UUI patient, an SUI patient, and / or a MUI patient, according to several embodiments. In some embodiments, severe refractory urge incontinence is treated. For example, the technology described herein may be particularly useful for patients (e.g., patients with urge incontinence) who do not respond to other types of therapy, including for example, botulinum toxin therapy and sacral neuromodulation.

[0007] In several embodiments, the neuromodulation systems described herein, and uses thereof, have at least one or more of the following features or advantages:• provide feedforward and patient-activated adaptive stimulation to allow the patients to be in control of their bladder;• holistically improve urethral or lower urinary tract function, including but not limited to restoring the natural orientation of the urethra;• provide personalized and optimized stimulation parameters based on patient response and the sub-type of incontinence;• combine restoration of nerve activity and / or muscle activity with rehabilitation;• train the patient's body to regain the preemptive reflex against stress incontinence; and• treat both urge and stress incontinence (e.g., in a mixed urinary incontinence patient).• provide bilateral leads with stimulation and sensing capabilities to improve therapy, which is beneficial in several embodiments for reduction of noise, interference, artefacts, reentrant loops, etc.• provide Al-trained classifiers for personalizing and optimizing adaptive stimulation, which is beneficial in several embodiments for more accurate triggering of a different stimulation level.

[0008] The neuromodulation system disclosed herein may include an adaptive nerve stimulation (for example, pudendal nerve stimulation) that toggle between a first operation mode and a second operation mode. The system in the second mode may provide more enhanced stimulation current (e.g., higher intensity) than the first mode. The toggle is controlled by the patient in a feedforward manner. The patient can activate the second mode prior to a stress incontinence event, such as prior to moving from sitting to standing up, coughing, getting out of the car to open the door upon arrival at home, etc. Additionally or alternatively, the patient can activate the second mode prior to an urge incontinence event, such as putting hands in water, arriving at home and putting the key in the door lock, etc. In some instances, the patient may tap on the IPG implanted inside the body to activate the second mode. In some instances, the patient may squeeze or add pressure to the pelvic floor, urethral sphincter, and / or anal sphincter to activate the second mode. The ability of the patient to control the timing of the activation of the second mode may give the control of the body (including but not limited to the bladder, the pelvic floor, etc.) back to the patient.

[0009] Giving a patient control of their bladder according to several embodiments is beneficial because for example, as the patient takes control of a condition that may previously have generated fear and shame, the patient's neurological circuity and / or higher cognitive functions may be altered to be in a higher level of control of continence.

[0010] The stimulation disclosed herein may holistically improve urethral or lower urinary tract function, for example but not limited to activating the striated muscle complexes surrounding the urethra at different levels. For example, the stimulation may restore the natural orientation of the urethra. In some instances, the stimulation may restore a kink (also known as a "knee”) in the mid-urethra through contraction of a distal part of the urethra. In some implementations, the stimulation that can restore the "knee” may be below a threshold for causing a forceful closure of the sphincter, which is commonly linked to prevention of a leak in a stress event.

[0011] The predetermined stimulation parameter disclosed herein may be personalized and / or optimized based on the patient's response and on whether a MUI patient is urge predominant or stress predominant. In some implementations, the stimulation parameter may be titrated based on the EMG response and / or the specific sub-type of incontinence of the MUI patient. The optimization of the stimulation parameter may allow a more personalized therapy.

[0012] In some embodiments, the neuromodulation system disclosed herein may interact with other forms of therapy for incontinence. The other forms of therapy may include physiotherapy and medication. The combination of restoration of nerve activity and / or muscle activity (e.g., pelvic floor muscle, sphincter muscle, etc.) by the neuromodulation system disclosed herein and rehabilitation therapy may improve the clinical outcome or therapeutic effect. In some embodiments, pudendal stimulation (e.g., early pudendal stimulation, such as immediately after a medical procedure or postpartum) may lead to regeneration of muscle / nerve function through different growth factors release, and / or prevention of incontinence. In one example, the medical procedure may include radical prostatectomy surgery for prostate cancer. In some examples, postpartum may include after a difficult, obstructed, and / or instrumental labor.

[0013] Additionally, once the IPG is implanted, the patient activation of the second mode disclosed herein may provide a training program for the patients to relearn or regain control of the pelvic floor muscles. The training program may allow the patients to regain control of the appropriate section of the pelvic floor by learning how it feels when the pelvic floor muscles contract under stimulation. The training program may work as a biofeedback treatment and / or interoception treatment. Many stress incontinence or MUI patients have lost the preemptive reflex against a leak. Those patients can learn the preemptive reflex again by practicing the muscle control repeatedly, aided by the system disclosed herein. Current methods of biofeedback treatment, e.g., restoration of coordination in the pelvic floor, typically use external devices such as vaginal probes. The systems described herein may advantageously be fully internally implanted. The internally implanted systems may advantageously amplify the biofeedback response, which may strengthen neural connections. For example, the patient's act of trying to contract their muscle may be amplified to trigger the system to boost the contraction.

[0014] In several embodiments, the use of electrical stimulation as described herein addresses unmet needs in the women's health field. For example, whether incontinence results from childbirth, hormonal issues, or post-menopausal laxity, several embodiments treat such incontinence, which in turn leads to an improved quality of life. In several embodiments, the use of electrical stimulation as described herein addresses unmet needs in men's health fields. For example, post prostate surgery and / or urgency and urge incontinence in relation with prostate enlargement.

[0015] In several embodiments, the use of electrical stimulation as described herein, such as neurostimulation, is advantageous alone or when used in combination with other therapies, where synergistic effects may be achieved. In such combined approaches, the undesired side effects of other therapies may be reduced or eliminated. For example, when electrical stimulation is used in lieu of, or combined with, a pharmaceutical therapy, a reduced drug dosage may be needed, thus reducing the side effects associated with a higher dose. With respect to pain, several embodiments of the invention may be used to reduce reliance on pain medication, which in turn can reduce reliance on opioids and other addictive substances.

[0016] In some embodiments, a neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency nerve stimulation through active patient engagement is provided. The system may include an implantable pulse generator comprising an actuator and a processor. The processor may be configured to control the actuator to generate at least a dual frequency nerve stimulation. The dual frequency nerve stimulation may include a first stimulation and a second stimulation. The system may further include one or more electrode leads (e.g., two four, six, eight, or other numbers) in electrical communication with the processor and configured to deliver at least the first stimulation or the second stimulation to a target nerve or tissue adjacent to the target nerve of a patient (e.g., pudendal nerve). The second stimulation can include a higher frequency and / or other parameters (e.g., amplitude, pulse width, etc.) than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation. The second stimulation can be activated in response to the implantable pulse generator detecting the patient's active engagement of the implantable pulse generator. The second stimulation can be configured to enhance stimulation at the target nerve or tissue adjacent to the target nerve. In several embodiments, activating the second stimulation in response to the patient's active engagement of the implantable pulse generator can reduce or prevent habituation. Habituation may result in a decreased response due to the tissue (such as a nerve or other tissue) becoming used to or acclimated to the repeated (same) stimulation parameter(s), thus resulting in less effective therapy. Habituation may result in requiring higher / more intense stimulation to achieve the same effect (which may be impractical) or may result in a non-responsive patient where the therapy no longer works effectively. The reduction or prevention of habituation can, in several aspects, facilitate a therapeutic effect without having to further increase the frequency of the second stimulation.

[0017] In several embodiments, the system disclosed herein are configured such that activating the second stimulation in response to the patient's active engagement of the implantable pulse generator can reduce or prevent habituation, wherein the second stimulation is greater than the first stimulation in one or more of the following parameters: frequency, amplitude, pulse width, intensity, power, duration, and combinations thereof. In addition to a dual frequency system, parameters other than frequency may be varied. Additionally, a third or fourth frequency (or other stimulation pattern) may be used. In some embodiments, 2-20 or more different stimulation patterns are used to reduce or prevent habituation.

[0018] In several embodiments, the system disclosed herein are configured such that the patient's active engagement of the implantable pulse generator may be a feedforward input.

[0019] In several embodiments, the system disclosed herein are configured such that the at least dual frequency nerves stimulation may work synergistically with a pharmaceutical therapy. In several embodiments, thesystem disclosed herein are configured to such that the at least dual frequency nerves stimulation may reduce one or more side effects of a pharmaceutical therapy.

[0020] In several embodiments, the system disclosed herein are configured such that the frequency value of the at least first or second stimulation may be determined using artificial intelligence.

[0021] In several embodiments, the system disclosed herein are configured such that the implantable pulse generator further comprises at least one sensor. The at least one sensor may include a motion sensor. The motion sensor may include an accelerometer, a gyroscope, or an inertial measurement unit (I MU). In some embodiments, the at least one sensor can be configured to transmit sensed data to a remote server (e.g., a cloud). In several embodiments, the first or second stimulation may be administered based on artificial intelligence and / or machine learning determination of the patient's activities.

[0022] In several embodiments, the system disclosed herein are configured such that the patient's active engagement of the implantable pulse generator may not be a physiological response associated with the onset of the incontinence event.

[0023] In several embodiments, the system disclosed herein are configured such that the processor may be configured to allow the patient to control timing of activation of the second stimulation.

[0024] In several embodiments, the system disclosed herein are configured such that the processor may be configured to control the actuator to generate the stimulation of a default parameter value and adjust the parameter value based on whether a mixed continence patient is urge predominant or stress predominant. The processor may increase the parameter value in response to determining the patient is stress predominant. The processor may decrease the parameter value in response to determining the patient is urge predominant.

[0025] In several embodiments, the system disclosed herein are configured such that the one or more electrode leads may further include at least one sensing electrode configured to detect a signal indicative of muscle activity (e.g., pelvic muscles, gluteal muscle, leg muscles, etc.). An output of the at least one sensing electrode can be configured to indicate, e.g., when the patient has squeezed the at least one pelvic floor muscle or a different muscle as disclosed herein. The patient squeezing the least one pelvic floor muscle or a different muscle can be configured to switch the processor from the first mode to the second mode to stop the stress urinary incontinence event. The processor may further include a biopotential classifier configured to determine whether the patient has squeezed the at least one pelvic floor muscle or a different muscle. In some embodiments, the biopotential classifier may be trained by artificial intelligence and / or machine learning.

[0026] In some embodiments, a neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency nerve stimulation through active patient engagement is provided. The system may include an implantable pulse generator comprising a processor. The processor may be configured to control the actuator to generate at least a dual frequency nerve stimulation. The dual frequency nerve stimulation may include a first stimulation and a second stimulation. The system may further include one or more electrode leads (e.g., two four, six, eight, or other numbers) in electrical communication with the processor and configured to deliver at least the first stimulation or the second stimulation to a target nerve or tissue adjacent to the target nerve of a patient (e.g., pudendal nerve). The second stimulation can include a higher frequency and / or other parameters (e.g., amplitude, pulse width, etc.) than the first stimulation, thereby providing enhanced stimulationcompared to the first stimulation. The second stimulation can be activated in response to a sensor in communication with the implantable pulse generator detecting the patient's active engagement of the implantable pulse generator. The second stimulation can be configured to enhance stimulation at the target nerve or tissue adjacent to the target nerve.

[0027] In several embodiments, the system disclosed herein are configured such that activating the second stimulation in response to the patient's active engagement of the implantable pulse generator can reduce or prevent habituation.

[0028] In several embodiments, the system disclosed herein are configured such that the patient's active engagement of the implantable pulse generator may be a feedforward input.

[0029] In several embodiments, the system disclosed herein are configured such that the at least dual frequency nerves stimulation may work synergistically with a pharmaceutical therapy. In several embodiments, the system disclosed herein are configured to such that the at least dual frequency nerves stimulation may reduce one or more side effects of a pharmaceutical therapy.

[0030] In several embodiments, the system disclosed herein are configured such that the sensor may include a motion sensor within the implantable pulse generator. The motion sensor may include an accelerometer, a gyroscope, or an inertial measurement unit (I M U).

[0031] In several embodiments, the system disclosed herein are configured such that the frequency value of the at least first or second stimulation may be determined using artificial intelligence.

[0032] In several embodiments, the system disclosed herein are configured such that the sensor can be configured to transmit sensed data to a remote server (e.g., a cloud). In several embodiments, the first or second stimulation may be administered based on artificial intelligence and / or machine learning determination of the patient's activities.

[0033] In several embodiments, the system disclosed herein are configured such that the sensor may include a motion sensor. The motion sensor may include an accelerometer, a gyroscope, or an inertial measurement unit (IMU).

[0034] In several embodiments, the system disclosed herein are configured such that the patient's active engagement of the implantable pulse generator may not be a physiological response associated with the onset of the incontinence event.

[0035] In several embodiments, the system disclosed herein are configured such that the processor may be configured to allow the patient to control timing of activation of the second stimulation.

[0036] In several embodiments, the system disclosed herein are configured such that the processor may be configured to control the actuator to generate the stimulation of a default parameter value and adjust the parameter value based on whether a mixed continence patient is urge predominant or stress predominant. The processor may increase the parameter value in response to determining the patient is stress predominant. The processor may decrease the parameter value in response to determining the patient is urge predominant.

[0037] In several embodiments, the system disclosed herein are configured such that the one or more electrode leads may further include at least one sensing electrode configured to detect a signal indicative of muscle activity (e.g., pelvic muscles, gluteal muscle, leg muscles, etc.).

[0038] In several embodiments, the system disclosed herein are configured such that the first stimulation can be below a threshold configured to cause a tetanic contraction of muscles and the second stimulation can meet or exceed the threshold configured to cause the tetanic contraction of the muscles. In some embodiments, the second stimulation can be configured to cause closure of the patient's urethra.

[0039] In some embodiments, a neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency nerve stimulation through active patient engagement is provided. The system may include an implantable pulse generator comprising an actuator, a motion sensor (e.g., an accelerometer, a gyroscope, or an inertial measurement unit (IMU)), and a processor. The processor may be configured to control the actuator to generate at least a dual frequency nerve stimulation. The dual frequency nerve stimulation may include a first stimulation and a second stimulation. The system may further include one or more electrode leads (e.g., two four, six, eight, or other numbers) in electrical communication with the processor and configured to deliver at least the first stimulation or the second stimulation to a target nerve or tissue adjacent to the target nerve of a patient (e.g., pudendal nerve). The second stimulation can include a higher frequency and / or other parameters (e.g., amplitude, pulse width, etc.) than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation. In several embodiments, the system disclosed herein are configured to such that the processor may be configured to control the actuator to generate the stimulation of a default parameter value and adjust the parameter value based on whether a mixed continence patient is urge predominant or stress predominant. The second stimulation can be activated in response to the motion sensor of the implantable pulse generator detecting the patient's active engagement of the implantable pulse generator. The second stimulation can be configured to enhance stimulation at the target nerve or tissue adjacent to the target nerve.

[0040] In several embodiments, the system disclosed herein are configured such that the processor may increase the parameter value in response to determining the patient is stress predominant. In several embodiments, the system disclosed herein are configured to such that the processor may decrease the parameter value in response to determining the patient is urge predominant.

[0041] In some embodiments, a neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency stimulation through active patient engagement is provided. The system can include at least one processor configured to generate at least a dual frequency nerve stimulation, wherein the dual frequency stimulation can include a first stimulation and a second stimulation; and one or more effectors to deliver the stimulation to a target nerve or tissue adjacent to the target nerve of a patient. The second stimulation can include a higher frequency than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation, wherein the second stimulation can be activated in response to a sensor in communication with the processor detecting the patient's active engagement of the system. The effectors can comprise one or more of a transducer, piezoelectric element, electrode, or other stimulation delivery mean, or a combination thereof; and wherein the at least dual frequency stimulation can comprise one or more of vibratory, ultrasound, mechanical, electrical stimulation, or a combination thereof. The second stimulation can be configured to treat a condition, wherein the condition is optionally incontinence, a pelvic disorder, pain, or sexual dysfunction.

[0042] In some embodiments, a generator configured to provide at least dual stimulation to tissue is provided. The dual stimulation can comprise a first stimulation and a second stimulation, wherein the secondstimulation provides a different parameter than the first stimulation, thereby providing enhanced stimulation. The second stimulation can be activated when the generator or a sensor detects the patient's active engagement of the generator or the sensor. The different parameter can comprise one or more of frequency, intensity, pulse width, and / or amplitude. The generator or sensor can be partially or fully implantable or non-implantable.

[0043] In some embodiments, a device for charging any of the systems or generators disclosed herein is provided. The device can comprise an inductive battery charger.

[0044] In some embodiments, a neuromodulation system configured to deliver a patient-specific electrical current to a nerve (such as a pudendal nerve or tissue adjacent to the pudendal nerve) of a patient is provided. The system neuromodulation may include an implantable pulse generator including a processor. The processor may be configured to execute software stored on a non-transitory computer readable storage medium to generate a stimulating electrical current. The system neuromodulation may include one or more electrode leads in electrical communication with the processor. One or more electrode leads may include at least one (or more) sensing electrode and at least one (or more) stimulating electrode. The stimulating electrode(s) may be configured to deliver the stimulating electrical current to the pudendal nerve or tissue adjacent the pudendal nerve (and / or other target nerve) of the patient. The sensing electrode(s) may be configured to detect a signal indicative of muscle activity. The system (e.g., the processor) may be configured to execute software stored on a non-transitory computer readable storage medium to determine a patient-specific parameter value of the stimulating electrical current, such as based at least in part on the signal output by the sensing electrode(s) and / or a sub-type of continence of the patient. The signal may be indicative of the muscle activity in response to the stimulating electrical current. The stimulating electrical current of the predetermined parameter value may be configured to cause contraction of muscles surrounding urethra (e.g., to restore a natural orientation of the urethra). Restoring the natural orientation of the urethra may include, for example, restoring a kink (e.g., in a location between proximal and distal ends of the urethra) through contraction of the urethra (e.g., a distal portion of the urethra). The contraction of the urethra (e.g., the distal portion of the urethra) may bend the distal portion of the urethra away from a longitudinal axis of the urethra that extends along a portion of the urethra proximal to the distal portion of the urethra. The contraction of the muscles may include contraction of smooth muscles surrounding the urethra (e.g., to improve a tone along a length of the urethra).

[0045] In some embodiments, a method of delivering personalized neurostimulation to a patient (e.g., to restore a natural orientation of a urethra of the patient) using a neuromodulation system is provided. The neuromodulation system may include an implantable pulse generator and one or more electrodes in electrical communication with the implantable pulse generator (e.g., a processor of the implantable pulse generator). The method may be performed by the processor of the implantable pulse generator. The method may include the step of determining a patient-specific stimulation parameter value based at least in part on a sub-type of incontinence of the patient. The method may further include the step of generating the stimulating electrical current of the patient-specific stimulation parameter value such that the one or more electrode leads can deliver the stimulating electrical current to a nerve (such as the pudendal nerve or tissue adjacent the pudendal nerve and / or another target nerve) of the patient. The stimulating electrical current of the patient-specific stimulation parameter value may be configured to cause contraction of muscles surrounding urethra (e.g., to restore the natural orientation of the urethra). Restoring the natural orientation of the urethra may include, for example, restoring a kink (e.g., in a location between proximal and distalends of the urethra) through contraction of the urethra (e.g., a distal portion of the urethra). The contraction of the urethra (e.g., the distal portion of the urethra) may bend the distal portion of the urethra away from a longitudinal axis of the urethra that extends along a portion of the urethra proximal to the distal portion of the urethra. The contraction of the muscles may include contraction of smooth muscles surrounding the urethra (e.g., to improve a tone along a length of the urethra).

[0046] In several embodiments, the system (e.g., processor) and method disclosed herein are configured to determine a patient-specific parameter value of the stimulating electrical current. The patient-specific parameter value may be a frequency value including but not limited to from about 1 Hz to about 50 Hz, or about 2 Hz to about 14 Hz. Certain frequency values (e.g., frequency value from about 2 Hz to about 14 Hz) may be for a mixed incontinence patient who is urge predominant. The patient-specific parameter value may be a frequency value including but not limited to from about 14 Hz to about 40 Hz. Certain frequency values (e.g., frequency value from about 14 Hz to about 40 Hz) may be for a mixed incontinence patient who is stress predominant. In some embodiments, the patient-specific parameter value may be a pulse width value.

[0047] In some embodiments, the system (e.g., processor) and method disclosed herein are further configured to generate the stimulating electrical current of a default parameter value and titrate against the signal of the sensing electrode(s).

[0048] In some embodiments, the system (e.g., processor) and method disclosed herein are configured to adjust the parameter value based on whether a mixed continence patient who is urge predominant or stress predominant. The system (e.g., processor) and method disclosed herein may be configured to increase from the default parameter value in response to the mixed continent patient being stress predominant. The system (e.g., processor) and method disclosed herein may be configured to decrease from the default parameter value in response to the mixed continent patient being urge predominant. In one embodiment, the default parameter value is 14 Hz.

[0049] In some embodiments, the system (e.g., processor) and method disclosed herein are further configured to be in communication with a device external to the patient's body and receive from the device data associated with the sub-type of incontinence of the patient. The sub-type may include, for example but not limited to whether a mixed incontinence patient is urge predominant or stress predominant.

[0050] In some embodiments, the device is a dedicated patient controller and the neuromodulation system includes the dedicated patient controller. In some embodiments, the device is a computer, a laptop, a smartphone, watch or other wearable, or a server.

[0051] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the patient-specific parameter value is a value at which the output of the sensing electrode(s) indicate(s) a certain level of muscle activity. The signal outputted by the sensing electrode(s) may include but are not limited to an EMG signal.

[0052] In some embodiments, the system (e.g., processor) and method disclosed herein are configured to (optionally iteratively): generate the electrical current at an adjusted parameter value; and further adjust the parameter value based at least in part on the signal and the sub-type of incontinence of the patient, until the response indicates a certain level of nerve activity.

[0053] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the stimulating electrical current of the patient-specific stimulation parameter value may be configured to inhibit bladder contraction (such as via afferent activity of the pudendal nerve, which may be at any one or more of the S2, S3 and / or S4 levels, or via another target nerve). In some embodiments, the stimulating electrical current of the predetermined parameter value may be configured to cause contraction of pelvic floor muscles or a sphincter.

[0054] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the stimulating electrical current of the patient-specific parameter value is below a boost threshold. The boost threshold may be configured to causes a stronger and / or more sustained (e.g., tetanic) contraction of a sphincter (e.g., an external urethral sphincter or an external anal sphincter) or muscle of the patient. An absence of the tetanic contraction may reduce a likelihood of habituation or voidance impairment.

[0055] In some embodiments, such neuromodulation systems and methods may be combined with a pharmaceutical therapy to optionally reduce at least one undesired side effect of such pharmaceutical therapy.

[0056] In some embodiments, a neuromodulation system configured to provide a training program to a patient (such as an incontinent patient) is provided. The patient may be unable to voluntarily squeeze a muscle including but not limited to pelvic floor muscles or a sphincter (e.g., prior to or in response to a stress incontinence event or another incontinence event). The system may include an implantable pulse generator including a processor. The processor may be configured to generate a stimulating electrical current. The system may further include one or more electrode leads in electrical communication with the processor. The system (e.g., processor) may be configured to execute software stored on a non-transitory computer readable storage medium to operate a training mode in response to a user input. When in the training mode, the processor is configured to generate a stimulating electrical current such that the electrode lead(s) is / are configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of the patient. The stimulating electrical current may be configured to cause contraction of the muscles (e.g., pelvic floor muscles or a sphincter) such that the patient can learn how it feels when the muscle (e.g., pelvic floor muscles or a sphincter) contract under stimulation. The processor can optionally be configured to generate the stimulating electrical current at a predetermined interval for a predefined period of time in the training mode.

[0057] In several embodiments, a method for training a user (e.g., an incontinent patient) is provided. The patient may be unable to voluntarily squeeze a muscle including but not limited to pelvic floor muscles or a sphincter (such as prior to a stress incontinence event or another incontinence event). In one embodiment, the method comprises (i) electrically stimulating a target nerve or tissue (e.g., in the pelvic region or another location of the body) sufficient to cause contraction of the muscle including but not limited to pelvic floor muscles or a sphincter, (ii) notifying the user that the electrical stimulation is occurring, optionally through an audible, visual or tactile signal so that the user registers the contraction of the muscle, (iii) reducing or stopping the electrical stimulation; and (iv) optionally repeating steps (i) and (ii) (e.g., at least twice) to train the user to contact the muscle including but not limited to pelvic floor muscles or a sphincter voluntarily without electrical stimulation.

[0058] The systems and methods disclosed herein may be particularly useful for a patient immediately after a medical procedure, for example, a surgery or child delivery. For example, one method for training may include: (i) immediately after a medical procedure (e.g., a surgery or child delivery), electrically stimulating a target nerve ortissue (e.g., to cause nerve and / or muscle regeneration), (ii) reducing or stopping the electrical stimulation; and (ill) optionally repeating steps (I) and (II) (e.g., at least twice) to prevent incontinence without electrical stimulation.

[0059] In some embodiments, a neuromodulation system configured to prevent incontinence of a patient immediately after a medical procedure, for example, a surgery or child delivery is provided. The system may include an implantable pulse generator including a processor. The processor may be configured to generate a stimulating electrical current. The system may include one or more electrode leads in electrical communication with the processor. The system (e.g., the processor) is configured to execute software stored on a non-transitory computer readable storage medium to operate a training mode in response to a user input. When in the training mode, the system (e.g., the processor) may configured to, immediately after a medical procedure (e.g., a surgery or child delivery), generate a stimulating electrical current such that the one or more electrode leads are configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of a patient. The stimulating electrical current may cause nerve and / or muscle regeneration. Optionally, the system (e.g., the processor) may be configured to generate the stimulating electrical current at a predetermined interval for a predefined period of time in the training mode.

[0060] In some embodiments, the system and method disclosed herein further includes a patient controller, which may be external to the patient's body. The implantable pulse generator may be in wireless communication with the patient controller. In response to one or more generations of the stimulating electrical current, the patient controller may be configured to provide feedback to the patient (such as feedback that the muscle has contracted due to the stimulation or said electrical stimulation is occurring). The feedback may be used to direct a patient to perform a certain task corresponding to the specific feedback, e.g., squeeze pelvic muscles, charge the battery, etc. The feedback may include tactile feedback, audio feedback, visual feedback, or a combination thereof. In some embodiments, the patient controller includes a display. In response to generation(s) of the stimulating electrical current, the display may be configured to display instructions that the patient should squeeze the muscle(s), such as the pelvic floor muscles or a sphincter. In some cases, the system may be configured to provide stimulatory feedback, which may not require a patient controller to observe. The system may output a unique stimulation pattern recognizable by the patient to deliver the feedback. For example, the stimulatory feedback may cause a muscle twitch which may be readily recognizable by the patient. In another example, the stimulatory feedback may be have different stimulation parameters than a background level of stimulation to cause a different sensation than the background level, but not extreme enough to cause pain.

[0061] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that in response to one or more generations of the stimulating electrical current, the processor is configured to output an indicator to the patient such that the patient can attempt to squeeze the muscles including but not limited to pelvic floor muscles or a sphincter. The indicator may include tactile feedback, audio feedback, or a combination thereof.

[0062] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the predetermined interval for repeating is about 10 seconds to about one minute. In some embodiments, the predefined period of time for running the training mode may be about 2 minutes to about 20 minutes.

[0063] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the training mode may be configured to be used in physiotherapy. The nerve may include a pudendal and / or sacral nerve.

[0064] In some embodiments, a neuromodulation system configured to deliver patient-controlled adaptive nerve stimulation is provided. The system may include an implantable pulse generator including a processor. The processor may be configured to execute software stored on a non-transitory computer readable storage medium to generate a stimulating electrical current. The system may include one or more electrode leads in electrical communication with the processor and may be configured to deliver the stimulating electrical current to a target nerve or tissue adjacent to the target nerve of a patient. The system (e.g., the processor) may be further configured to operate in (at least) a first mode or a second mode, which may differ in at least one stimulating parameter. The stimulating electrical current in the first mode may be below a threshold to cause a stronger and / or more sustained (e.g., tetanic) contraction of muscles. The stimulating electrical current in the second mode may meet or exceed the threshold to cause the stronger and / or more sustained (e.g., tetanic) contraction of the muscles. The system (e.g., the processor) may be further configured to switch from the first mode to the second mode in response to a user input. The user input may include a tap on the implantable pulse generator, the patient squeezing at least one muscle (e.g., pelvic floor muscle or sphincter), or an input on an external device (such as a patient controller or a mobile device). The user input may be received prior to an onset of an incontinence event (e.g., a stress urinary incontinence event or otherwise).

[0065] In some embodiments, a method for delivering patient-controlled adaptive nerve stimulation is provided. The method includes operating in a first mode by outputting a stimulating electrical current below a threshold. The threshold may be configured to cause a stronger and / or more sustained (e.g., tetanic) contraction of muscles. The stimulating electrical current is delivered to a target nerve or tissue adjacent to the target nerve of a patient. In response to a user input, the method may include switching from the first mode to a second mode, which differ from each other in at least one stimulating parameter. The stimulating electrical current in the second mode may meet or exceed the threshold to cause the stronger and / or more sustained (e.g., tetanic) contraction of the muscles. The user input may include a tap on an implantable pulse generator, the patient squeezing at least one muscle (e.g., pelvic floor muscle or sphincter), or an input on an external device (such as a patient controller or a mobile device). The user input may be received prior to an onset of an incontinence event (e.g., a stress urinary incontinence event or otherwise).

[0066] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the second mode is configured to preemptively stop an incontinence event (e.g., a stress incontinence event or an urge incontinence event).

[0067] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the implantable pulse generator includes a motion / posture sensor configured to detect the tap. The motion / posture sensor may be an accelerometer, a gyroscope, a piezoelectric sensor, or an inertial measurement unit (IMU).

[0068] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the one or more electrode leads include at least one (or more) sensing electrode and at least one (or more) stimulating electrode. The stimulating electrode(s) is / are configured to deliver the stimulating electrical current to thetarget nerve or the tissue adjacent the target nerve. The nerve may be pudendal and / or sacral nerve. The sensing electrode(s) is / are configured to detect a signal indicative of muscle activity.

[0069] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that an output of the sensing electrode(s) is configured to indicate when the patient has squeezed a muscle (e.g., at least one pelvic floor muscle or sphincter). The output may be but is not limited to an EMG signal.

[0070] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the first and second modes differ in frequency. The frequency may be higher in the second mode than in the first mode. The frequency may be about 1 Hz to about 40 Hz, about 50 Hz, about 60 Hz, about 70 Hz, about 80 Hz, about 90 Hz, about 100 Hz, about 110 Hz, about 120 Hz, about 130 Hz, about 140 Hz, or to about 150 Hz, in the first mode. The frequency may be about 50 Hz to about 1,000 Hz, about 2,000 Hz, about 3,000 Hz, about 4,000 Hz, about 5,000 Hz, about 6,000 Hz, about 7,000 Hz, about 8,000 Hz, about 9,000 Hz, or to about 10 kHz, in the second mode.

[0071] In some embodiments, a neuromodulation system configured to deliver patient-controlled adaptive nerve stimulation is provided. The system may include an implantable pulse generator including a processor and a motion / posture sensor (and / or another sensor). The processor may be configured to execute software stored on a non-transitory computer readable storage medium to generate a stimulating electrical current. The system may include one or more electrode leads in electrical communication with the processor. The one or more electrode leads includes at least one (or more) sensing electrode and at least one (or more) stimulating electrode. The stimulating electrode(s) is / are configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of a patient (e.g. a pudendal nerve and / or a sacral nerve). The sensing electrode(s) is / are configured to detect a signal indicative of muscle activity. The system (e.g., the processor) is configured to operate in (at least) a first mode or a second mode, which may differ in at least one stimulating parameter. The stimulating electrical current in the first mode may be below a threshold. The threshold may be configured to cause a stronger and / or more sustained (e.g., tetanic) contraction of muscles. The stimulating electrical current in the second mode may meet or exceed the threshold configured to cause the stronger and / or more sustained (e.g., tetanic) contraction of the muscles. The system (e.g., the processor) may be configured to switch from the first mode to the second mode in response to a user input. The user input may be configured to be detected by the motion / posture sensor or the sensing electrode(s) or another sensor. The second mode may be configured to preemptively stop an incontinence event (e.g., a stress urinary incontinence event or otherwise).

[0072] In some embodiments, a method for delivering patient-controlled adaptive nerve stimulation is provided. The method includes operating in a first mode by outputting a stimulating electrical current below a threshold. The threshold may be configured to cause a stronger and / or more sustained (e.g., tetanic) contraction of muscles. The stimulating electrode(s) is / are configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of a patient (e.g. a pudendal nerve and / or a sacral nerve). In response to a user input, the method may include switching from the first mode to a second mode. The user input may be configured to be detected, for example, by the motion / posture sensor or the sensing electrode(s) or another sensor. The first mode and the second mode may differ in at least one stimulating parameter. The stimulating electrical current in the second mode may meet or exceed the threshold configured to cause the stronger and / or more sustained (e.g., tetanic) contraction of themuscles. The second mode may be configured to preemptively stop an incontinence event (e.g., a stress urinary incontinence event or otherwise).

[0073] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the tetanic contraction of the muscles includes a tetanic contraction of an external urethral sphincter, which may be configured to cause complete (or substantially complete) closure of a urethra of the patient.

[0074] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the user input includes a tap on the implantable pulse generator by the patient. The motion / posture sensor (or a pressure sensor) may be configured to detect the tap. The motion / posture sensor may be an accelerometer, a gyroscope, a piezoelectric sensor, or an inertial measurement unit (I MU).

[0075] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the user input includes the patient squeezing a muscle (e.g., pelvic floor muscle or sphincter). The signal of the sensing electrode(s) is / are configured to indicate when the patient has squeezed the muscle (e.g., pelvic floor muscle or sphincter). The signal may be but is not limited to an EMG signal.

[0076] In some embodiments, the system (e.g., processor) and method disclosed herein are configured such that the first and second modes may differ in frequency. The frequency may be higher in the second mode than in the first mode. The frequency may be about 1 Hz to about 40 Hz in the first mode. The frequency may be about 50 Hz to about 1,000 Hz in the second mode.

[0077] In some embodiments, the system and method disclosed herein can be configured for the treatment of pain, e.g., pelvic pain. In some embodiments, the system and method disclosed herein can be configured for the treatment of sexual dysfunction.

[0078] The neuromodulation system disclosed herein includes bilateral nerve stimulation and / or sensing in several embodiments. The system may comprise two or more electrode leads, with one or more leads implanted on each lateral side of a patient's body. The one or more electrode leads on each side of the body may comprise one or more stimulation electrodes and / or one or more bioelectrical sensing electrodes. Each of the electrodes may be selected for either stimulation or sensing to provide an optimal stimulation configuration. In some embodiments, the processor of the implantable pulse generator may deliver stimulation to one side of the body while concurrently sensing on the other side of the body to reduce the occurrence of reentrant loops. In some embodiments, the IPG processor may provide alternating bilateral stimulation with a phase difference for reducing habituation and / or muscle fatigue. In some embodiments, the system may provide sensing across two bilateral leads to improve detection of a biopotential breakthrough signature and provide a broad field of sensing to give an optimal stimulation configuration. In some embodiments, the stimulation parameters on each lateral side of the patient may be separately modified and optimized based on sensing data from the corresponding side of the lead.

[0079] With respect to the placement of electrodes, in some embodiments, at least one lead with at least one sensing electrode is placed on one side of the midline and at least one lead with at least one stimulating electrode is placed on the other side of the midline, and thus would be considered bilateral with respect to the vertical midline axis of the human body in a standing position. Thus, the sensing electrode is able to sense muscle contractions (that are not caused by the stimulation) without the noise or interference of post-stimulation muscle contractions at or near the stimulation electrode. In other embodiments, the sensing electrode and stimulation electrode are placed onthe same side of the midline but at a distance such that contractions do not affect the sensing capabilities. The sensing electrode and the stimulation electrode may be placed for diagnostics and therapies related to the pudendal nerve, the sacral nerve and / or nerve branches that lead to or from such nerves. The sensing electrode and the stimulation electrode may be placed for diagnostics and therapies related to other nerves where stimulation may disrupt the sensing function and there is a need for physical separation of the two functions (while still being close enough to provide meaningful sensing data). In some embodiments, at least one sensing electrode is spaced at least 2 mm and / or no more than 250 mm away from the at least one stimulation electrode, for example between 2mm-200 mm, 2 mm-150 mm, 2 mm-100 mm, 2 mm-50 mm, 2 mm-25 mm, 2 mm-10 mm or ranges or values therebetween. Keeping separation between the sensing and stimulation electrodes can help with reentrant loops by minimizing cross coupling of both artefacts. Additionally or alternatively, the system or lead may include a sensing dipole to also try to avoid this issue. There may be blanking window where the sensing electrode is switched off during and after a stimulation phase to remove artefacts.

[0080] One sensing electrode and one stimulating electrode may be used, but multiple electrodes are used in some implementations, for example at least about two electrodes and / or less than or equal to about twelve electrodes, such as four electrodes, six electrodes, eight electrodes, ten electrodes, twelve electrodes, or any number of electrodes therebetween. The total number of electrodes may be split between one or more leads. In some embodiments, at least one lead with 1-6 electrodes (e.g., 4 electrodes) is placed an appropriate distance away from another lead having 1-6 electrodes (e.g., 4 electrodes). This distance may be bilateral with respect to the midline. The electrodes on each lead may be capable of sensing or stimulating, or both.

[0081] In several embodiments, artificial intelligence and / or machine learning are used. For example, one or more classifiers for detecting a breakthrough signature (which causes the stimulation program to be changed from a first program to a second program, and / or as disclosed elsewhere herein) may include machine learning and / or artificial intelligence models. These classifiers may be trained with sensor data collected from the patient when the patient is performing various triggering activities to improve accuracy in detecting the breakthrough signature. The sensor data may also be collected throughout the patient's daily activity and labelled based on patient and / or clinician input. The sensor data may be labelled based on whether it represents a stress event, e.g., leakage was observed, or the likelihood of representing a stress event. In some embodiments, the classifier may be trained using machine learning optimization routines based on one or more relevant metrics, e.g., F-1 score, F-2 score, area under the curve (AUG), sensitivity, specificity, or any combination thereof, etc. In some embodiments, the training may be partially based on a cost such as power utilization. In some embodiments, the classifier may be biased to favor either false positives or false negatives based on patient preference. In some embodiments, the biasing of the classifier may be adjustable based on the time of day. In some embodiments, the trained classifier may be evaluated based on a minimally acceptable classifier score. In some implementations, the system may disable a first input mode if the classifier is unable to meet the minimally acceptable classifier score and move to a second, less complex input mode.

[0082] In some implementations, the system may provide a patient control feature allowing the patient to control a sensitivity threshold of the classifier algorithm to fine tune the therapy based on preference. The patient control feature may be available in clinic, via telehealth, or otherwise remotely, e.g., at home.

[0083] Disclosed herein are embodiments of devices, systems and methods for neurostimulation. For example, through patient engagement, feedback, neural retraining, or tissue strengthening, or combinations thereof, an incontinence episode or other clinical conditions can be treated or otherwise ameliorated through prevention of one or more actual episode. In several embodiments, any one or more of the feedforward patient engagement, feedback, neural retraining, or tissue strengthening, or combinations thereof as disclosed herein can be used with any one or more of bilateral stimulation and sensing, trained classifiers, or combinations thereof disclosed herein. In several embodiments, any one or more of using time-dependent programming, adaptive stimulation with flexible sensor input(s) selections for determining breakthrough signatures, personalized thresholds, additional patient safety and / or comfort features, or combinations thereof disclosed herein, as well as PCT Application No. XXXX / XXX.XXX [Attorney Docket No. AMBTX.041 WO] titled "TIME-DEPENDENT ADAPTIVE NEUROMODULATION SYSTEM,” filed on the same day as the present application, which is hereby incorporated by reference in its entirety, can be used with any one or more of bilateral stimulation and sensing, trained classifiers, or combinations thereof disclosed herein.

[0084] In some embodiments, a neuromodulation system configured to deliver neuromodulation using bilaterally implanted electrode leads (such as to treat a pelvic condition of a patient including but not limited to incontinence, pain, sexual dysfunction, etc.) is provided. The system may include an implantable pulse generator including a processor. The processor may be configured to execute instructions stored on a non-transitory computer readable storage medium to generate an electrical stimulation of at least first and second levels. The first level may be a first background level. The second level may be triggered by a breakthrough signature. The second level may be different from the first level. The system may further include one or more first electrode leads implanted in a first lateral side of the patient and one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side. The first and second electrode leads may be in electrical communication with the processor. The one or more first electrode leads may include at least one stimulation electrode configured to deliver the electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve on the first lateral side of the patient). The one or more second electrode leads may include at least one sensing electrode configured to measure bioelectrical signals (e.g., from the second lateral side of the patient). The system (e.g., processor) may be further configured to determine a breakthrough signature of a patient using the at least one sensing electrode on the second lateral side. The breakthrough signature may comprise a muscle contraction of the patient. The system (e.g., processor) may be further configured to cause at least one stimulation electrode to output stimulation at the second level (e.g., to the target nerve or tissue adjacent to the target nerve on the first lateral side) when the second level is triggered.

[0085] In some embodiments, a method for delivering neuromodulation using bilaterally implanted electrode leads (such as to treat a pelvic condition of a patient including but not limited to incontinence, pain, sexual dysfunction, etc.) is provided. The method may include providing one or more first electrode leads implanted in a first lateral side of a patient. The one or more first electrode leads may comprise at least one stimulation electrode configured to deliver electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve on the first lateral side of the patient). The method may further include providing one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side, wherein the one or more second electrode leads comprise at least one sensing electrode configured to measure bioelectrical signals (e.g., from the second lateral side of the patient). The method may further include determining a breakthrough signature of a patient using the at leastone sensing electrode on the second lateral side. The breakthrough signature may comprise a muscle contraction of the patient. The method may further include providing at least first and second levels of electrical stimulation to the at least one stimulation electrode on the first lateral side. The first level may be a first background level. The second level may be triggered by the breakthrough signature. The second level may be different than the first level. The method may further include causing the at least one stimulation electrode to output electrical stimulation at the second level (e.g., to the target nerve or tissue adjacent to the target nerve on the first lateral side) when the second level is triggered.

[0086] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the one or more first electrode leads may further comprise at least one sensing electrode configured to measure bioelectrical signals. In some embodiments, a first sensing electrode of the first electrode leads and a second sensing electrode of the second electrode leads may form a sensing dipole configured to measure bioelectrical signals across the bilaterally implanted electrode leads.

[0087] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the one or more second electrode leads may further comprise at least one stimulation electrode configured to deliver the electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve) on the second lateral side of the patient. In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the first electrode leads and the second electrode leads alternate between determining the breakthrough signature and outputting stimulation. In some embodiments, the electrical stimulation may be delivered to the one or more first electrode leads and the one or more second electrode leads with a phase difference. In some embodiments, the electrical stimulation may be delivered to the one or more first electrode leads at different parameters than the electrical stimulation delivered to the one or more second electrode leads. The different parameters may be based at least in part on data received from one or more sensing electrodes of the first electrode leads.

[0088] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured to determine the breakthrough signature while concurrently delivering the electrical stimulation at the first and / or second levels.

[0089] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the first and second levels of stimulation may be configured to preemptively stop an incontinence event, such as a urinary incontinence event or a fecal incontinence event. The first and second levels of stimulation may be configured to stop an urge urinary incontinence event and a stress urinary incontinence event. The first and second levels of stimulation may be delivered to a pudendal nerve or tissue near the pudendal nerve of the patient, and / or a sacral nerve or tissue near the sacral nerve of the patient. In some embodiments, the first and second levels of stimulation may be configured to treat pain or sexual dysfunction.

[0090] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured to use a machine learning and / or artificial intelligence trained classifier model to determine the breakthrough signature. In some embodiments, the system (e.g., processor) or method disclosed herein may be configured to determine the breakthrough signature in response to, for example, a sensor reading exceeding (or falling below) a predetermined threshold.

[0091] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured to determine a second and / or third breakthrough signature of a patient. The second breakthrough signaturemay comprise a postural change of the patient. The third breakthrough signature may comprise a patient notification. The system (e.g., processor) or method disclosed herein may be further configured to provide at least three levels of stimulation including the first level, the second level, and a third level. The third level may be a second background level. The system (e.g., processor) or method disclosed herein may be further configured to output stimulation at the first or third background level (for example, based on a time of a day, user setting, etc.) unless the second level is triggered.

[0092] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that determining the breakthrough signature, the second breakthrough signature, and / or a fourth breakthrough signature may comprise responding to a combination of data of two or more sensors.

[0093] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the second level of stimulation may be configured to cause contraction of muscles surrounding urethra to restore a natural orientation of the urethra. Restoring the natural orientation of the urethra may comprise restoring a kink in a location between proximal and distal ends of the urethra through contraction of a distal portion of the urethra to bend the distal portion of the urethra away from a longitudinal axis of the urethra extending along a portion of the urethra proximal to the distal portion of the urethra. The contraction of the muscles may further comprise contraction of smooth muscles surrounding the urethra to improve a tone along a length of the urethra. In some embodiments, the system (e.g., processor) or method disclosed herein may be configured to adjust a parameter value of the second level based on whether a mixed continence patient is urge predominant or stress predominant.

[0094] In some embodiments, a system to deliver personalized neuromodulation using breakthrough signatures (e.g., to treat a pelvic condition including but not limited to incontinence, pain, sexual dysfunction, etc.) is provided. The system may include an implantable pulse generator including a processor. The processor may be configured to execute instructions stored on a non-transitory computer readable storage medium to generate an electrical stimulation of different levels. The system may further include one or more electrode leads in electrical communication with the processor. The one or more electrode leads may comprise at least one stimulation electrode configured to deliver the electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve of a patient). The processor may be further configured to be triggered from a background level of electrical stimulation to a different level of electrical stimulation in response to determining a breakthrough signature. The processor may be further configured to determine the breakthrough signature using a machine learning and / or artificial intelligence classifier trained on a labelled set of patient-specific data. The trained classifier may be optimized for one or more predetermined metrics, wherein the one or more metrics comprise an F-1 score, an F-2 score, or classification area under the curve (AUG).

[0095] In some embodiments, a method for delivering personalized neuromodulation using breakthrough signatures (e.g., to treat a pelvic condition including but not limited to incontinence, pain, sexual dysfunction, etc.) is provided. The method may include providing electrical stimulation of at least first and second levels to one or more electrode leads. The one or more electrode leads may comprise at least one stimulation electrode configured to deliver the electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve of a patient). The method may further include delivering a background level of electrical stimulation. The background level may be the first level of electrical stimulation. The method may further include determining a breakthrough signature using amachine learning and / or artificial intelligence trained classifier. The classifier may be trained on a labelled set of patientspecific data and optimized for one or more predetermined metrics. The one or more metrics may comprise an F-1 score, an F-2 score, or classification area under the curve (AUG). The method may further include delivering the second level of electrical stimulation in response to determining the breakthrough signature. The second level may be different than the first level.

[0096] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the patient-specific data comprises readings from one or more sensors. The one or more sensors may comprise a motion or posture sensor, and the readings may be indicative of a patient input on the implantable pulse generator or a postural change, respectively. In some embodiments, the one or more sensors may comprise a bioelectrical sensor, and the readings may be indicative of a muscle contraction. In some embodiments, the patientspecific data may be labelled based on whether any leakage occurred during its collection. In some embodiments, the patient-specific data may be labelled based on patient or clinician input.

[0097] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the one or more predetermined metrics may further comprise sensitivity or specificity.

[0098] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the classifier may be biased based on one or more patient-specific objectives to accept a higher false positive rate or a higher false negative rate. The classifier may be biased depending on a time of a day. A bias point of the classifier may be adjustable by the patient. In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the classifier meets a threshold classifier score.

[0099] In some embodiments, the system (e.g., processor) or method disclosed herein may be configured such that the personalized neuromodulation may be configured to preemptively stop an incontinence event, such as a urinary incontinence event or a fecal incontinence event. The personalized neuromodulation may be configured to preemptively stop an urge urinary incontinence event and a stress urinary incontinence event. The personalized neuromodulation may be delivered to a pudendal nerve or tissue near the pudendal nerve of the patient, and / or a sacral nerve or tissue near the sacral nerve of the patient. In some embodiments, the personalized neuromodulation may be configured to treat pain or sexual dysfunction.

[0100] In some embodiments, a method for delivering personalized neuromodulation using one or more input modes (e.g., to treat a pelvic condition including but not limited to incontinence, pain, sexual dysfunction, etc.) is provided. The method may include providing at least two levels of electrical stimulation to one or more electrode leads. The one or more electrode leads may comprise at least one stimulation electrode configured to deliver the electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve of a patient). A first level of electrical stimulation may be a first background level. A second level of electrical stimulation may be triggered by determining a breakthrough signature. The second level may be different than the first level. The method may further include providing a first machine learning and / or artificial intelligence classifier trained on patient-specific data of a first input mode. The first input mode may be used for determining a first breakthrough signature. The first classifier may be configured to determine the first breakthrough signature. The first breakthrough signature may comprise a muscle contraction of a patient. The method may further include evaluating the first classifier based on a first threshold classifier score. The method may further include disabling the first input mode in response to the first threshold classifier score not beingmet and enabling a second input mode. The second input mode may be used for determining a second breakthrough signature. The second breakthrough signature may comprise a postural change of the patient and / or a patient notification.

[0101] In some embodiments, the method disclosed herein may further include retraining and revaluating the classifier at least one more time on the patient-specific data of the first input mode in response to the threshold classifier score not being met and before disabling the first input mode.

[0102] In some embodiments, the method disclosed herein may be configured such that the first input mode may use one or more bioelectrical sensors. The one or more bioelectrical sensors may be located on one or more electrode leads implanted in the patient's body.

[0103] In some embodiments, the method disclosed herein may be configured such that the postural change may be determined by a posture sensor located on an implantable pulse generator implanted in the patient's body. The patient notification may comprise a tap on an implantable pulse generator implanted in the subject's body. The tap may be detected by a motion sensor (or another sensor such as a pressure sensor) located on the implantable pulse generator.

[0104] In some embodiments, the method disclosed herein may further include providing a second classifier trained on patient-specific data of the second input mode and evaluating the second classifier based on a second threshold classifier score. The method may further include disabling the second input mode if the second threshold classifier score is not reached and defaulting to a third input mode. The third input mode may be used to determine a third breakthrough signature. The third breakthrough signature may comprise a time of a day and / or a manual patient action. The manual patient action may comprise a button push.

[0105] In some embodiments, the method disclosed herein may be configured such that the personalized neuromodulation may be configured to preemptively stop an incontinence event, such as a urinary incontinence event or a fecal incontinence event. The personalized neuromodulation may be configured to preemptively stop an urge urinary incontinence event and a stress urinary incontinence event. The personalized neuromodulation may be delivered to a pudendal nerve or tissue near the pudendal nerve of the patient, and / or a sacral nerve or tissue near the sacral nerve of the patient. In some embodiments, the personalized neuromodulation may be configured to treat pain or sexual dysfunction.

[0106] In some embodiments, a neuromodulation system configured to deliver neuromodulation using bilaterally implanted electrode leads (such as to treat a pelvic condition of a patient including but not limited to incontinence, pain, sexual dysfunction, etc.) is provided. The system may include an implantable pulse generator including a processor. The processor may be configured to execute instructions stored on a non-transitory computer readable storage medium to generate an electrical stimulation of at least first and second levels. The first level may be a first background level. The second level may be triggered by a breakthrough signature. The second level may be different from the first level. The system may further include one or more first electrode leads implanted in a first lateral side of the patient and one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side. The first and second electrode leads may be in electrical communication with the processor. The one or more first electrode leads may include at least one stimulation electrode configured to deliver the electrical stimulation (e.g., to a target nerve or tissue adjacent to the target nerve on the first lateral side of the patient). The oneor more first electrode leads and the one or more second electrode leads may include a first and second sensing electrode, respectively. The first and second sensing electrodes may form a sensing dipole. The sensing dipole may be configured to measure bioelectrical signals (e.g., across the bilaterally implanted leads in the patient). The system (e.g., processor) may be further configured to determine a breakthrough signature of a patient using the sensing dipole of the bilaterally implanted electrode leads. The breakthrough signature may comprise a muscle contraction of the patient. The system (e.g., processor) may be further configured to cause at least one stimulation electrode to output stimulation at the second level (e.g., to the target nerve or tissue adjacent to the target nerve on the first lateral side) when the second level is triggered.BRIEF DESCRIPTION OF THE DRAWINGS

[0107] Several features of the disclosure are set forth with particularity in the claims. A better understanding of the features and advantages of various embodiment can be obtained by reference to the following detailed description that sets forth illustrative non-limiting embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings described below. Features from one figure may be combined with features of other figures.

[0108] Figure 1A illustrates a block diagram of an example neuromodulation system of the present disclosure.

[0109] Figure 1 B illustrates a block diagram of another example neuromodulation system of the present disclosure.

[0110] Figure 1C illustrates an example implantable pulse generator of the neuromodulation system.

[0111] Figure 1D illustrates an example controller of the neuromodulation system.

[0112] Figure 1E illustrates an example electrode lead of the neuromodulation system.

[0113] Figure 1F illustrates an example second electrode lead of two-lead neuromodulation system embodiments of which are disclosed herein.

[0114] Figure 1G illustrates schematically communications among the neuromodulation system disclosed herein and with another device.

[0115] Figure 2A illustrates an example frontal plane schematic of the anatomy and implanted IPG in an individual.

[0116] Figure 2B illustrates an example frontal plane schematic of the anatomy and implanted leads and IPG in an individual, showing a bilateral lead placement at the pudendal nerve.

[0117] Figure 2C illustrates a first example sagittal plane schematic of one lateral side of the anatomy and implanted leads and IPG in an individual.

[0118] Figure 2D illustrates a second example unilateral sagittal plane schematic of one lateral side of the anatomy and implanted leads and IPG in an individual.

[0119] Figure 3 illustrates schematically certain lower urinary tract physiology of a continent female and females with different types of incontinence.

[0120] Figure 4 is a flowchart illustrating an example process of patient-activated adaptive stimulation by the neuromodulation system disclosed herein.

[0121] Figure 5 is a table showing example physiological changes induced by a first operation mode and a second operation mode of the neuromodulation system disclosed herein.

[0122] Figure 6 is a flowchart illustrating an example process of determining a patient-specific stimulating parameter using the neuromodulation system disclosed from a perspective of the IPG.

[0123] Figure 7 is a flowchart illustrating an example process of determining a patient-specific stimulating parameter using the neuromodulation system disclosed from a perspective of the IPG or an external processor in communication with the IPG.

[0124] Figure 8 is a flowchart illustrating an example training program implemented by the IPG of the neuromodulation system disclosed herein.

[0125] Figures 9A-9C illustrate examples of EMG graphs when different parts of the pudendal nerve is stimulated according to some embodiments.

[0126] Figure 10 illustrates time-wise aligned graphs of EMG data and stimulation program change according to some embodiments.

[0127] Figure 11 A illustrates an example electrode lead configuration for monopolar stimulation.

[0128] Figure 11 B illustrates an example electrode lead configuration for bipolar stimulation.

[0129] Figure 11C illustrates an example bilateral electrode lead configuration for bipolar sensing on the left side of the patient.

[0130] Figure 11D illustrates an example bilateral electrode lead configuration for bipolar sensing on the right side of the patient.

[0131] Figure 11E illustrates an example bilateral electrode lead configuration for bipolar sensing across two leads on each side of the patient.

[0132] Figure 11 F illustrates an example bilateral electrode lead configuration for bipolar sensing on each of the two leads on each side of the patient.

[0133] Figure 12 is a flowchart illustrating an example process of bilateral sensing-activated adaptive stimulation by the neuromodulation system disclosed herein.

[0134] Figure 13 is a flowchart illustrating an example process of determining a patient-specific stimulating parameter for each lateral side of the patient using the neuromodulation system disclosed from a perspective of the IPG.

[0135] Figure 14 is a flowchart illustrating an example classifier training program implemented by the neuromodulation system disclosed herein.

[0136] Figure 15 is a flowchart illustrating an example process of switching input modes based on a threshold classifier score implemented by the neuromodulation system disclosed herein.

[0137] Figures 16A and 16B illustrate example signal data including evoked responses before and after performing a sample-and-hold method.

[0138] Figure 17 illustrates example signal detection using an example dual threshold algorithm.DETAILED DESCRIPTION

[0139] Electrical stimulation has clinical application in providing treatment and / or management of a variety of clinical conditions, for example within the pelvic region. For example, electrical stimulation may be used totreat urinary incontinence, fecal incontinence, pain, sexual dysfunction, or any combination thereof medical condition and / or diseases within the pelvic region. In one embodiment, pelvic organ prolapse is treated. In one embodiment, restless leg syndrome and / or restless genital syndrome are treated separately or when there is co-morbidity with overactive bladder. In some embodiments, symptoms or episodes are prevented through use of the technology described herein. For example, through patient engagement, feedback, neural retraining, or tissue strengthening, or combinations thereof, an incontinence episode can be treated or otherwise ameliorated through prevention of one or more actual episode. In another example, through bilateral stimulation and / or sensing capabilities, adaptive stimulation with flexible sensor input(s) selections and personalized trained machine learning classifiers for determining breakthrough signatures, personalized patient-controlled thresholds, or combinations thereof, an incontinence episode can be treated or otherwise ameliorated through prevention of one or more actual episode. In several embodiments, any one or more of bilateral stimulation and / or sensing, machine learning and / or artificial intelligence trained classifiers, or combinations thereof disclosed herein may be used with any one or more of the feedforward patient engagement, feedback, neural retraining, tissue strengthening, time-dependent programming, adaptive stimulation with flexible sensor input(s) selections for determining breakthrough signatures, personalized thresholds, additional patient safety and / or comfort features, or combinations thereof as described herein, and in PCT Application No. XXXX / XXX.XXX [Attorney Docket No. AMBTX.041WO] titled "TIME-DEPENDENT ADAPTIVE NEUROMODULATION SYSTEM,” filed on the same day as the present application, which is hereby incorporated by reference in its entirety.

[0140] Although certain devices, systems, and methods are described herein with respect to the pelvic region to prevent, treat and / or manage pelvic conditions, the devices, systems, and methods can be used in other regions of the body or to treat other conditions. The implantable devices may be implanted in other regions of the body and / or to treat other conditions. In some embodiments, electrode lead(s) of the implantable devices may be implanted in the spinal region, for example to treat chronic or incidental pain. The electrode lead(s) may be implanted in or near the spine to treat, for example, pain (e.g., the spinal cord region caudal of the occiput or other spinal regions). In other embodiments, the electrode lead(s) may be implanted near peripheral or cranial nerves, and / or may monitor and / or sense brain activity. For example, lead(s) may be implanted near the vagus nerve (e.g., in the facial / cranial region) for treatment of several disorders, including but not limited to balance issues, headache, migraines, etc. In several embodiments, restless leg syndrome is treated.Embodiments of Neuromodulation Systems

[0141] Provided herein are methods, devices, and systems for aiding an incontinence patient, for example, in improving personalization of therapy, detection of biomarkers and biopotential breakthrough signatures, and / or other advantages including but not limited to advantages disclosed herein.

[0142] Figure 1A illustrates an example neuromodulation system 10A. The system 10A may include devices that may be implanted in the body 2 of an individual, comprising or consisting essentially of at least one electrode lead 102 (for example, two electrode leads or more, such as three, four, etc.) and an implantable pulse generator (IPG) 108. The at least one electrode lead 102 may be coupled to the IPG 108, for example, via wire(s).

[0143] Figure 1B illustrates an example neuromodulation system 10B. The system 10B may include devices that may be implanted in the body 2 of an individual, comprising or consisting essentially of at least two electrode leads 102, 104 (for example, two electrode leads or more, such as three, four, etc.) and an implantable pulsegenerator (IPG) 108. At least one electrode lead, for example, at least two electrode leads 102, 104 may be coupled to the IPG 108, for example, via wire(s).

[0144] Figure 1C illustrates a non-limiting example of the IPG 108. The IPG 108 may be implanted anywhere in the body 2 of the individual in or near the pelvic region. For example, the IPG 108 may be implanted in buttock fat, a leg, the abdomen, etc. Figure 1E illustrates a non-limiting example of an electrode lead 102. Figure 1F illustrates a non-limiting example of a second electrode lead 104 for bilateral stimulation, according to embodiments. The neuromodulation system 10A, 10B may further include a controller 110 that may be external to the body 2 of the individual. The controller 110 may be used by the patient or another user. The controller 110 and the IPG 108 may be in wireless communication via wireless communication hardware. FIG. 1D illustrates a non-limiting example of the controller 110.

[0145] The communication hardware may implement any suitable wireless communication protocols, including but not limited to those disclosed herein. Non-limiting examples of wireless communication protocol may include Wireless Fidelity (WIFI), Bluetooth, Zigbee, Near Field Communication (NFC), Z-wave, Long Range (LoRa), Cellular Networks (e.g., 4G LTE, 5G, etc.). In some implementations, the wireless communication between the controller 110 and the IPG 108 is via a Medical Implant Communication System (MICS). The wireless communication between the controller 110 and the IPG 108 may be in a frequency band between about 300 MHz to about 500 MHz, or about 400 MHz to about 499 MHz, or about 401 MHz to about 406 MHz, or about 402 MHz to about 405 MHz, or about 413 MHz to about 419 MHz, or about 426 MHz to about 432 MHz, or about 438 MHz to about 444 MHz, or about 451 MHz to about 457 MHz, or a smaller range within any of the defined ranges, or another range defined by any of the values between 300 MHz to 500 MHz. The frequency band between about 300 MHz and about 500 MHz may improve device security and reliability when data is transmitted to support diagnostic or therapeutic functions associated with medical implant devices. In some implementations, the maximum distance between the controller 110 and the IPG 108 for wireless communication may be less than about 4.0 m, or about 3.8 m, or about 3.6 m, or about 3.4 m, or about 3.2 m, or about 3.0 m, or about 2.8 m, or about 2.6 m, or about 2.4 m, or about 2.2 m, or about 2 m, or a distance within a range defined by any of these values.

[0146] The IPG 108 may include a processor 122, which may execute software or instructions stored on a non-transitory computer readable storage medium to generate an electrical stimulation pattern according to a stimulation program (also referred to as a "mode”). In some embodiments, the processor 122 may be a microprocessor. In some implementations, the processor 122 may include a clock and a memory device for recording and storing data. The processor 122 may further include hardware and / or software modules for controlling the electrical stimulation generated by an actuator of the IPG 108. The processor 122 may further include hardware and / or software modules for analyzing signals from one or more sensors 124 and / or sensing electrodes, and / or other sensors described elsewhere in the present disclosure. In some implementations, at least some of the processing for the IPG 108 may be completed on a server, cloud, or other dedicated computing clusters.

[0147] The IPG 108 may include a power source 126. The power source 126 may be a battery, which may be a lithium polymer ion battery, lithium iodine, lithium manganese dioxide, lithium carbon monofluoride, or any combination thereof. The battery may be rechargeable. In some implementations, recharging can be via a wireless charger, including but not limited to an inductive charger. The wireless charger may be placed on the torso of theindividual over the location of the IPG 108 to perform wireless charging. In some implementations, the wireless charger may be secured to a recharge belt and holster to hold the wireless charger in the correct position. The wireless charger, when connected to the controller 110 (wirelessly or in a wired connection), may connect to the IPG 108 to charge the battery in the IPG 108. In some implementations, the maximum distance between the wireless charger and the IPG 108 during charging may be less than about 3.0 cm, or about 2.8 cm, or about 2.6 cm, or about 2.4 cm, or about 2.2 cm, or about 2.0 cm, or about 1.8 cm, or about 1.6 cm, or about 1.4 cm, or about 1.2 cm, or about 1.0 cm, or a distance within a range defined by any of these values. Alternatively, the battery power source may be a single use.

[0148] In some embodiments, the battery may last at least about 24 hour, about 48 hours, about 72 hours, about 96 hours, about 120 hours, or longer after each charge, or a duration within a range defined by any of these values. As described elsewhere in the present disclosure, the battery life may be improved so that the patient needs not charge the IPG 108 after several hours of use or daily, which may be inconvenient. As also described elsewhere in the present disclosure, the battery saving features do not sacrifice accuracy in adaptive stimulation in some embodiments. In some implementations, the system may include a cost function including power requirements and may optimize the stimulation algorithm for the total cost function inclusive of maximizing symptom management, while minimizing power usage and side-effects. In some implementations, the system may use machine learning and / or artificial intelligence to optimize the stimulation based on any of the inputs described herein, e.g., power requirements, battery level, etc.

[0149] The electrical stimulation current generated by the IPG 108 may be delivered to one or more electrodes at or near a distal end of the at least one electrode lead 102 and / or a distal end of the electrode lead 104. In some embodiments, the electrode leads 102, 104 may be coupled to an actuator circuitry of the IPG 108. As shown in Figures 1A, 1 B, 1D, and 1E, each electrode lead (e.g., the electrode lead 102, the second electrode lead 104, etc.) may be a quadripolar lead. The electrode lead 102 may include four electrodes 132, 134, 136, 138 along a distal end of the lead 102. The second electrode lead 104 may include four electrodes 131, 133, 135, 137 along a distal end of the lead 104. In some implementations, each lead may include more than four electrodes (for example, five, six, seven, eight, nine, ten, eleven, twelve, or more) or fewer than four electrodes (for example, one, two, or three).

[0150] The remainder of the electrode lead 102, 104 other than at the electrodes may be insulated. A proximal end of the electrode lead 102 may be connected to the IPG 108 via a wire (also referred to as a "lead body”). In the illustrated example as shown in Figures 1E and 1F, the electrodes may be numbered and may be coupled to the respective connection point in the IPG 108 having the same number (see Figure 1C). The IPG 108 as shown in Figure 1C may couple to two electrode leads, which may include the electrode lead 102 and second electrode lead 104 as shown in Figures 1 E and 1F respectively. In some implementations, the electrodes 132, 134, 136, 138 on the electrode lead 102 may be labeled as Nos. 1, 2, 3, and 4; and the electrodes 131, 133, 135, 137 on the second electrode lead 104 may be labeled as Nos. 5, 6, 7, and 8. Similar numberings of the electrodes may be used in software used to program or configure the system, which is described elsewhere in the present disclosure.

[0151] The stimulation programs may be set by a healthcare provider on an external device. Turning to Figure 1G, the external device 20 is in communication with the controller 110 or directly with the IPG 108. The external device 20 may include a desktop, a laptop, a tablet, a smartphone, a wearable device, and / or the like. The programs may be transmitted (e.g., wirelessly or optionally via a wired connection) to the IPG 108 from the externaldevice 20. A user (including but not limited to a clinician or a patient) may modify or set electrical stimulation parameters via the external device 20 via a wireless communication between the external device 20 and the IPG 108. Alternatively, the user may modify or set electrical stimulation parameters via the user interface 114 of the controller 110. The electrical stimulation parameters that may be adjusted may include frequency, amplitude, pulse width, or any combinations thereof. In some implementations, the system may use machine learning and / or artificial intelligence to automatically determine and set stimulation programs and / or parameters based on any of the inputs described herein, e.g., sensor data, time of day, etc. The usage data may be stored on the IPG 108. Alternatively or additionally, the usage data may be transmitted from the IPG 108 to the controller 110, the external device 20, and / or a remote server (e.g., a data repository, a cloud, etc.). In some implementations, the usage data may be transmitted from the IPG 108 to the controller 110 and / or the external device 20 during charging of the power source on the IPG 108. The data received by the external device 20 and / or the remote server may be accessible by the clinician. In some cases, the data transmission during recharging may reduce the patient's frequency of re-visits to the clinician's office.

[0152] The electrical stimulation may be delivered to the nerve (for example, the pudendal nerve and / or the sacral nerve) or tissue adjacent to the nerve via one or more of the electrodes 132, 134, 136, 138 of the electrode lead 102 and / or the electrodes 131, 133, 135, 137 of the second electrode lead 104 functioning as stimulating electrodes. The system 10B may include two electrode leads 102, 104 for stimulating nerves on two sides of the body, i.e., bilateral stimulation, or additional electrode leads for stimulating a nerve at two sites on the same side of the body. Depending on the indication, the length of the wire or lead body may vary. In some cases, bilateral leads may have different lengths for the lead body. The length of the lead contralateral to the IPG may be greater than the length of the lead ipsilateral to the IPG. In some cases, having a bilateral approach, the difference between the length of a first lead body and a second lead body may be between about 100 mm and 200 mm. In some cases, the difference between the length of two bilateral lead bodies may be about 100 mm, about 110 mm, about 120 mm, about 130 mm, about 140 mm, about 150 mm, about 160 mm, about 170 mm, about 180 mm, about 190 mm, about 200 mm, or a length in a range defined by any of these values.

[0153] One or more of the electrodes 132, 134, 136, 138 in the lead 102 and / or the electrodes 131, 133, 135, 137 in the lead 104 may function as stimulating electrodes to deliver various amounts of voltage, current, and / or power. The electrodes may be designed to deliver a voltage of about 10V per electrode. The electrodes may be designed to deliver a voltage of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 V per electrode. In some embodiments, the electrodes may be designed to deliver a voltage of at most about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 V per electrode. The electrodes may be designed to deliver a voltage of about 1 to about 50 V per electrode, about 1 to about 40 V per electrode, about 1 to about 30 V per electrode, or about 1 to about 20 V per electrode. The electrodes may be designed to deliver a current of about 10mA per electrode. In some embodiments, the electrodes may be designed to deliver a current of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mA per electrode. The electrodes may be designed to deliver a current of at most about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mA per electrode. The electrodes may be designed to deliver a current of about 1 to about 50 mA per electrode, about 1 to about 40 mA per electrode, about 1 to about 30 mA per electrode, or about 1 to about 20 mA per electrode. The electrodes may be designed to deliver a power (VA) of about 0.1 W per electrode. In some embodiments, the electrodesmay be designed to deliver a power (VA) of at least about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, or 5 W per electrode. In some embodiments, the electrodes may be designed to deliver a power (VA) of at most about 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 W per electrode. The electrodes may be designed to deliver a power (VA) of about 0.01 to about 10W per electrode, about 0.01 to about 5W per electrode, or about 0.01 to about 1 W per electrode. The electrodes may be designed to deliver stimulation with a pulse width of about 1 pis to about 1000 pis. In some embodiments, the electrodes may be designed to deliver stimulation with a pulse width of at least about 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 pis, or any value in a range defined by these values.

[0154] Another one or more of the four (or more) electrodes 132, 134, 136, 138 in the lead 102 and / or the four (or more) electrodes 131, 133, 135, 137 in the lead 104 may function as sensing electrodes. In some implementations, the sensing electrodes may include bioelectrical sensing electrodes. In some implementations, a biopotential across two sensing electrodes may be measured. In some implementations, the sensing electrodes may sense an Electromyography (EMG) signal. The EMG signal may be analyzed to determine whether a contraction (or relaxation, or any other muscle activity) of at least one pelvic muscle, a sphincter muscle, an abdominal muscle, or another muscle (e.g., leg muscle, glute muscle, etc.) has occurred. In some implementations, the strength of the EMG signal may indicate that a contraction of a muscle has occurred. The data collected by the sensing electrodes may be stored on a memory device of the IPG 108. The memory device may be part of the processor 122. In some implementations, the processor 122 may process the data to determine whether a contraction of a certain muscle has occurred. In some embodiments, the data collected by the sensing electrodes may be fed into a biopotential classifier of the IPG processor 122 (described elsewhere herein) for determining whether a different stimulation program needs to be activated. In some implementations, the IPG 108 may include an amplifier 125, e.g., a biopotential amplifier, comprising amplifier circuitry to amplify the signal from the sensing electrodes prior to feeding into the classifier. In some implementations, the processor 122 may transmit the data collected by the sensing electrodes to the controller 110 and / or to the external device 20 (e.g., a laptop, a desktop, a tablet, a smartphone, watch or other wearable, etc.). In some implementations, the controller 110 or the other device that receives the data may process the data to determine whether a contraction of a certain muscle has occurred.

[0155] In some implementations, the IPG 108 may activate sensing only when the IPG is not running any stimulation program. In those embodiments, during a stimulation program, the user input in the form of a tap on the location of the IPG 108 detected by a motion or posture sensor (which is described in greater details elsewhere in the present disclosure) may trigger a different stimulation program. As referred to herein, a "tap” (or "taps” or "tapping”) may refer to tap(s) on the portion of patient's body overlying the IPG (e.g., a tap on the skin of the abdomen if the IPG is implanted in the abdomen), rather than a tap directly onto the IPG case. In some implementations, the IPG 108 may alternate between a sensing program and a stimulation program. In some implementations, the IPG 108 may run a stimulation program to generate stimulation while receiving data at the sensing electrodes during the stimulation program. In some embodiments, concurrent stimulation and sensing during a stimulation program may include stop sensing when a pulse of the electrical stimulation is generated, and enable sensing in between the pulses. Concurrent stimulation and sensing may improve the accuracy in detecting a breakthrough signature (described elsewhere in the present disclosure) from the patient to change the stimulation program or mode. Additionally, or alternatively, one ormore sensors may be positioned on one or more leads, for example, two or more leads 102, 104, including but not limited to a motion / posture sensor, a pressure sensor, a global positioning system (GPS), etc. In one embodiment, one or more leads, for example, two or more leads 102, 104, do not include sensors other than the sensing electrodes disclosed herein. In one embodiment, only motion, posture, or motion and posture sensor(s) are included.

[0156] As shown in Figure 1A, the IPG 108 can include one or more sensors 124, including but not limited to a motion / posture sensor, a pressure sensor, a global positioning system (GPS), etc. e.g., 1, 2, 3, 4 or more sensors, which may be on one lead, more than one leads, and / or on locations others than a lead). The motion / posture sensor can detect the individual's movement and / or posture. The motion / posture sensor may include an accelerometer, a gyroscope, and / or a magnetometer. In some implementations, the motion / posture sensor may include a three-axis accelerometer. Data from the one or more sensors 124 (including but not limited to a motion or posture sensor, or a combined motion / posture sensor) may be used by the processor 122 of the IPG 108 (or another controller) to control switching between different stimulation programs, as described in greater detail elsewhere in the present disclosure. In some implementations, data from the one or more sensors 124 on the IPG 108, the sensing electrodes and / or one or more sensors in the one or more leads 102, or any combinations thereof may be used for determining whether the IPG 108 should switch to a different stimulation program. In some implementations, data from the one or more sensors 124 on the IPG 108, the sensing electrodes, and / or one or more sensors in the one or more leads 102, or any combinations thereof may be used for determining whether the IPG 108 should disable certain sensors and / or switch to a different adaptive mode, as described in greater detail elsewhere in the present disclosure. In some implementations, a sensor of a first input mode may cooperate with one or more other sensors of another input mode to provide multimodal sensing with improved specificity when performing any of the functions described herein with respect to sensing.

[0157] The controller 110 may include a user interface 114, for example, buttons, switches, graphic user interface on a touch screen, etc. The controller 110 may optionally include a display screen. Figure 1D illustrates a non-limiting example of the controller 110. The controller 110 may optionally be in communication with an external device (e.g., not necessarily part of the neuromodulation system 10) (see Figure 1G), for example, a computer, a tablet, a smartphone, watch or other wearable, and the like. The external device may run software as described elsewhere in the present disclosure that can be used to program the IPG 108. The communication between the controller 110 and the external device may be via a wired or wireless connection. When connected, the controller 110 may transmit data to the other / external device and / or receive data from the other / external device. Alternatively, the IPG 108 may establish wireless communication with the external device other than the controller 110 to allow transmission and receiving of data between the IPG 108 and the external device.

[0158] In several embodiments, one or more stimulation parameters (e.g., frequency, amplitude, pulse width, duration, timing etc.) or locations of stimulation are varied automatically (e.g., using machine learning and / or artificial intelligence) to reduce or prevent habituation and / or to facilitate patient tolerance (if for example, the patient feels any discomfort from stimulation). In some embodiments, stimulation parameters or locations are controlled by the patient to reduce or prevent habituation and / or to facilitate patient tolerance. Varying stimulation includes, for example, reducing stimulation by 25%-95% or stopping stimulation for a time period. As described elsewhere in the present disclosure, several embodiments may include other safety and / or comfort features in addition to varying stimulation.

[0159] In several embodiments, the system may support monophasic and / or biphasic stimulation pulses. Monophasic stimulation may use passive recharge. Biphasic stimulation may use active recharge. Monophasic stimulation may deliver a pulse in only one direction leading to charge accumulation at the electrode-tissue interface. Monophasic stimulation may rely on passive recharge, which may be a waiting period allowing the accumulated charge to dissipate before delivering the next pulse. Biphasic stimulation may deliver a pulse in one direction followed by one or more reverse pulses in an opposite direction, e.g., up to 3 reverse pulses. The one or more reverse pulses serve as an active recharge to balance the charge. The contact output for each electrode may be independently controllable and can receive a portion of the set total charge, as disclosed elsewhere herein. The system 10 may use time-division multiplexing to divide the stimulation waveform into a series of interlaced high-speed pulses. The current may be distributed across multiple electrodes using time-division multiplexing, e.g., by splitting delivered charge between contacts based on a time sequence. The system may be capable of pulse width modulation, allowing for adjustability of the percentage of the total charge delivered by each electrode. These features may allow for shaping of the electric field and improving stimulation precision, which may enhance therapy personalization and reduce unwanted side effects.Lead Placements

[0160] In some implementations, at least one electrode lead can be implanted on a nerve or tissue adjacent to the nerve that serve one or more muscles used for treating urinary or fecal incontinence. The at least one electrode lead may comprise at least one stimulation electrode and / or at least one sensing electrode. In some implementations, the at least one electrode lead may comprise the at least one stimulation electrode and the at least one sensing electrode on the same side of the body to provide unilateral stimulation and sensing capabilities.

[0161] In some implementations, at least two electrode leads can be implanted on a nerve or tissue adjacent to the nerve that serve one or more muscles used for treating urinary or fecal incontinence. The leads may be implanted bilaterally, such that one of the at least two electrode leads is implanted on one lateral side of the body, and another one of the at least two electrode leads is implanted on the other lateral side of the body. A midline may divide the body of a patient into two lateral sides, which can be referred to as a left side and a right side.

[0162] The lead(s) may be placed to target the pudendal nerve and / or the sacral nerve or tissue adjacent to the nerve(s). The pudendal nerve stimulation may inhibit the bladder corresponding to innervation provided from three sacral levels, S2, S3, and S4. Thus, the pudendal nerve stimulation may have a stronger inhibition than other target nerves, for example sacral nerve stimulation, because stimulation of a sacral nerve is typically delivered at a single level for stimulation, as described in greater detail elsewhere in the present disclosure. In some embodiments, the pudendal nerve is stimulated at 2, 3 or more places, but stimulation at a single level of the pudendal nerve is also contemplated.

[0163] In some embodiments, one or more leads may be placed to target the pudendal nerve and / or the sacral nerve (or other nerve(s) or tissue adjacent to the nerve(s)) on one lateral side of the body, and one or more leads may be placed to target the pudendal nerve and / or the sacral nerve (or other nerve(s) or tissue adjacent to the nerve(s)) on the other lateral side of the body. For example, one or more leads may target the pudendal nerve and sacral nerve on one side of the body, and one or more different leads may target only the pudendal nerve on the other side of the body.

[0164] In one embodiment, the lead(s) are placed to only target the pudendal nerve or tissue adjacent to the pudendal nerve, not other nerves. In one embodiment, only the pudendal nerve or tissue adjacent to the pudendal nerve, but not other nerves, is stimulated. In another embodiment, a combination of only two nerves are stimulated (e.g., the pudendal nerve and the sacral nerve).

[0165] In some embodiments, at least one lead with 1-6 electrodes (e.g., 4 electrodes) is placed an appropriate distance away from another lead having 1-6 electrodes (e.g., 4 electrodes). This distance may be bilateral with respect to the midline. The electrodes on each lead may be capable of sensing or stimulating, or both.

[0166] Figures 2A-2D illustrate the anatomical path desired for lead placements in some implementations. Figure 2A shows the IPG 208 placed in a pocket in the buttock fat overlying the gluteal muscles. In other embodiments, the IPG 208 may be placed at or near the abdomen. Figure 2A also shows a bilateral view of the right pudendal nerve 210 and left pudendal nerve 212. Figure 2A shows the iliac crest 222, intergluteal cleft 236, greater trochanter 238 of the femur, ischial tuberosity 240 of the pelvis, and gluteal fold 242. Figure 2A also shows a portion of the path of the pudendal nerve 210, 212 from a posterior view arising from S2-S4 and converging to form the pudendal nerve 210, 212.

[0167] According to embodiments, one electrode lead may be placed on each side of the body at a nerve that serves one or more muscles controlling or used for urination or bowel movement, resulting in a bilateral placement. The lead may be placed at any suitable locations on the nerve, such as a trunk lead, or a lead at another location on the nerve. In some instances, a trunk lead electrode stimulation may lead to higher external anal sphincter (EAS) EMG amplitudes compared to an anterior lead electrode stimulation, indicating better therapy efficacy being delivered to the patient. In some implementations, both leads may be trunk leads. For example, bilateral stimulation of the pudendal nerve may allow for better control and / or effectiveness in treating urinary or fecal incontinence than unilateral stimulation. Figure 2B shows a schematic of a bilateral lead placement at the pudendal nerve 210, 212. A first lead 202 may be positioned in the right side of the body at the trunk of the right pudendal nerve 210. A second lead 204 may be positioned contralateral to the first lead 202, in the left side of the body at the trunk of the left pudendal nerve 212. The first and second leads 204, 202 may be tunneled through the gluteal region to connect to a unilateral IPG 208. The length of the lead contralateral to the IPG may be greater than the length of the lead ipsilateral to the IPG. As illustrated by Figure 2B, the second lead 204 may be longer than the first lead 202. For example, the length of the second lead 204 may be about 550 mm and the length of the first lead 202 may be about 400 mm. The difference between the length of the second lead 204 and the first lead 202 may be between about 100 mm and 200 mm. For example, the difference between the length of two bilateral leads may be about 100 mm, about 110 mm, about 120 mm, about 130 mm, about 140 mm, about 150 mm, about 160 mm, about 170 mm, about 180 mm, about 190 mm, about 200 mm, or a length in a range defined by any of these values.

[0168] In some cases, one or more leads may be placed on each side of the body at one or more nerve that serves one or more muscles controlling or used for urination or bowel movement. Figure 2C shows a schematic of the anatomy and the disposition of leads and IPG in an individual on a right side of the body. Figure 2C shows iliac crest 222 of the ileum, gluteus minimus 224, piriformis 206, sacrotuberous ligament 228, pudendal nerve 210, and sciatic nerve 211. The leads 202, 204 may be placed on one or more locations along the length of the right pudendal nerve 210 and / or the sciatic nerve 211 on one side of the body. The wires 203 of the leads 202, 204 may be connectedto the IPG 208. The placement of the leads 202, 204 on the pudendal nerve may be verified and fixed before their wires 203 are connected to the IPG 208. In some cases, one or more leads may be placed on two different sections of a nerve on one side of the body, e.g. right and / or left. Figure 2D shows two leads 202, 204, each lead with four electrodes (shown as dark circles), placed on two different sections of the right pudendal nerve 210 on the right side of the body. The wires 203 of the leads 202 and 204 may be connected to the IPG 208. Shown in Figure 2D are the inferior gluteal nerve 234, pudendal nerve 210, obturator internus 216, sacrotuberous ligament 228, posterior femoral cutaneous nerve 220, gluteus medius 232, gluteus minimus 224, piriformis 206, quadratus femoris 244, gluteus maximus 230, and sciatic nerve 211.

[0169] In some implementations, robotic arm(s) and / or robotic control may be used for placement and / or manipulation of the IPG and / or the lead during implantation. In some cases, stereotactic guidance may be used for manually and / or robotically-assisted placement and / or manipulation of the IPG and / or the lead during implantation.Feedforward Patient Engagement with Operation Modes

[0170] Described herein are devices, systems, and methods that may, among other features, prevent an episode of incontinence in an individual by providing electrical nerve stimulation. The episode of incontinence may include urinary incontinence, fecal incontinence, or any combination thereof. The devices, systems and methods disclosed herein may treat one or more sub-types of incontinence. Common sub-types of incontinence may include urge incontinence, stress incontinence, overflow incontinence, or mixed incontinence, which are described in greater detail elsewhere in the present disclosure. One advantage of several embodiments is the ability to treat both urge and stress incontinence, and to personalize therapy depending on whether a patient is urge or stress predominant.

[0171] As shown in Figure 3, during filling, the bladder of a continent female 302 may be quiet (not in contraction and / or not overactive) and the external urethral sphincter may be closed. Individuals with urge incontinence have a strong and sudden need to urinate immediately, often leaving them with insufficient time to reach a bathroom. The urge may be due to the premature contraction of the bladder (also known as an overactive bladder) of the urge incontinent patient 304 or due to relaxation of the internal urethral sphincter. As shown in Figure 3, the external urethral sphincter of the urge incontinent patient 304 may be closed. Stress urinary incontinence is usually due to a poorly functioning urethral sphincter muscle or hypermobility of the urethra or bladder neck. As shown in Figure 3, the bladder of a stress incontinent patient 306 may be quiet, but the external urethral sphincter may be insufficiently closed. As a result, the patient 306 may experience a urinary leak during activities such as coughing, sneezing, laughing, lifting, exercise, moving from a sitting position to a standing position, or other stress events, which increases the abdominal pressure. Mixed urinary incontinence (MUI) may involve features of stress and urge incontinence. As shown in Figure 3, an MUI patient 308 may have both an overactive bladder and an insufficiently closed external urethral sphincter during filling of the bladder.

[0172] Several embodiments advantageously provide multiple operation modes that can be effective in reducing both urge incontinence events and stress incontinence events. Several embodiments disclosed herein may include adaptive nerve stimulation (for example, pudendal nerve stimulation) that may toggle between a first operation mode and a second operation mode. The system in the second mode may provide more enhanced stimulation current (e.g., higher intensity, increased charge delivery per unit time) than the first mode. In one example, the first mode is a basal stimulation mode and the second mode is a boost stimulation mode. The first and secondmodes may differ in at least one stimulation parameter. Examples of such stimulation parameters may include but are not limited to frequency, pulse width, amplitude, or any combinations thereof. In some embodiments, the second mode may include a higher frequency in the stimulating electrical current than the first mode. In some embodiments, the second mode may include a higher pulse width than the first mode. In several implementations, the pulse width may range from about 60 microseconds to about 400 microseconds, or about 80 microseconds to about 350 microseconds, or about 100 microseconds or about 300 microseconds, or about 120 microseconds to about 250 microseconds, or about 140 microseconds or about 200 microseconds, or any pulse width within a range defined by these values. In some implementations, the system may use machine learning and / or artificial intelligence to automatically determine and set stimulation parameters (e.g., frequency, amplitude, pulse width, duration, or combinations thereof) based on any of the inputs described herein, e.g., sensor data, for any of the operation modes described herein.

[0173] According to several embodiments, dual stimulation is provided such that the second stimulation is higher in one, two or all of frequency, pulse width, and amplitude (as compared to the first stimulation). The second stimulation is controlled by the patient in some embodiments by, for example, a patient movement (squeezing of muscles, tapping the device, or using an external device to control stimulation, such as a smartphone, wearable, or other device). In some embodiments, the system may use machine learning and / or artificial intelligence for determining when the second stimulation should be activated and / or automatically triggering the second stimulation. For example, system may be programmed to use artificial intelligence along with one or more sensors to determine an indicator of an incontinence event (a fullness of the bladder, and / or patient activity, etc.) and determine that the second stimulation should be triggered. The second stimulation may only last seconds, while the first stimulation may be hours. In some embodiments, when triggered, the second stimulation may last for about one second to about one minutes, or about several seconds to about 30 seconds, or about 2-5 seconds, or about 30-60 seconds, or a duration within a range defined by any of these values. In some implementations, a duration of less than ten seconds may be effective for preemptively stopping a stress event. In some implementations, a duration of about 30 seconds may be effective for preemptively stopping an urge event (e.g., lasting for a duration long enough for a person to reach the toilet). In some embodiments, the second stimulation is applied for a total of 30 seconds to 60 minutes per day. In some embodiments, the second stimulation may be triggered at least about 5 times to about 25 times per day, or at least about 10 times to about 20 times per day, or a number of times within a range defined by these values.

[0174] In some embodiments, the second stimulation has a ramp up from the first stimulation and / or a ramp down from the first stimulation, so that one, two or all of frequency, pulse width, and amplitude increase and / or decrease gradually.

[0175] In one embodiment, tri-level stimulation is provided, where a third stimulation is provided. The third stimulation level may be for inactive states, such as sleep, and may be lower than the first stimulation or have a different stimulation pattern. Alternatively, a third stimulation level may be lower than the second stimulation level to address a patient's needs and / or to reduce habituation. The third stimulation level may be constant or varied.

[0176] In some implementations, the first mode may include a frequency of about 1 Hz to about 50 Hz, or a stimulating frequency of about 2 Hz, about 4 Hz, about 6 Hz, about 8 Hz, about 10 Hz, about 12 Hz, about 14 Hz, about 16 Hz, about 18 Hz, about 20 Hz, about 22 Hz, about 24 Hz, about 26 Hz, about 28 Hz, about 30 Hz, about 32 Hz, about 34 Hz, about 36 Hz, about 38 Hz, about 40 Hz, about 42 Hz, about 44 Hz, about 46 Hz, about 48 Hz, orabout 50 Hz, or any frequency within a range defined by these values. In some implementations, the first mode may include a frequency of about 1 Hz to about 150 Hz, or a stimulating frequency of about 5 Hz, about 10 Hz, about 15 Hz, about 20 Hz, about 25 Hz, about 30 Hz, about 35 Hz, about 40 Hz, about 45 Hz, about 50 Hz, about 65 Hz, about 70 Hz, about 75 Hz, about 80 Hz, about 85 Hz, about 90 Hz, about 95 Hz, about 100 Hz, about 105 Hz, about 110 Hz, about 115 Hz, about 120 Hz, about 125 Hz, about 130 Hz, about 135 Hz, about 140 Hz, about 145 Hz, or about 150 Hz, or any frequency within a range defined by these values.

[0177] In some implementations, the second mode may include a frequency of about 50 Hz to about 1,000 Hz, or about 100 Hz to about 800 Hz, or about 200 Hz to about 500 Hz, or a stimulating frequency of about 50 Hz, about 60 Hz, about 70 Hz, about 80 Hz, about 90 Hz, about 100 Hz, about 110 Hz, about 120 Hz, about 130 Hz, about 140 Hz, about 150 Hz, about 160 Hz, about 170 Hz, about 180 Hz, about 190 Hz, about 200 Hz, about 210 Hz, about 220 Hz, about 230 Hz, about 240 Hz, or about 250 Hz, or any frequency within a range defined by those values. In some implementations, the second mode may include a frequency of about 1 Hz to 10 kHz, or a stimulating frequency of about 500 Hz, about 1,000 Hz, about 1,500 Hz, about 2,000 Hz, about 2,500 Hz, about 3,000 Hz, about 3,500 Hz, about 4,000 Hz, about 4,500 Hz, about 5,000 Hz, about 6,500 Hz, about 7,000 Hz, about 7,500 Hz, about 8,000 Hz, about 8,500 Hz, about 9,000 Hz, about 9,500 Hz, or about 10,000 Hz, or any frequency within a range defined by these values.

[0178] The toggle between the first mode and the second mode may be controlled by the patient to improve patient outcome. For example, the patient may be an MUI patient. The requirement of the patient conscious engagement to enter the second mode may allow the patients to be in greater control over their bladder. As shown in Figure 4, the processor of the IPG disclosed herein may be operating in the first mode at step 402. The processor of the IPG may receive a user input at step 404. The processor of the IPG may enter the second mode in response to the user input and operate in the second mode at step 406. The processor may operate in the second mode for a certain period of time prior to returning to the first mode at step 408. In some implementations, the patient may be able to toggle between the second mode and the first mode. For example, the patient may provide a user input, e.g., one or more taps, to return back to a first mode with a decreased level of stimulation from a second mode with increased stimulation.

[0179] The patient may have control over the timing of step 404, that is, when to activate the second mode. In some implementations, the patient may activate the second mode (for example, by implementing the process as shown in Figure 4) prior to an incontinence event, such as prior to moving from sitting to standing up, coughing, sneezing, laughing, exercising, getting out of the car to open the door upon arrival at home, etc. In some cases, the incontinence event may be a stress event. In other words, the activation of the second mode may include a feedforward control, which uses measurement of a disturbance input (user input prior to an incontinence event) to control a manipulated input (the operation mode). In some cases, the patient may be able to activate the second mode during an incontinence event to reduce the severity of the incontinence event as it occurs.

[0180] In physiotherapy for incontinent patients, patients may be taught to identify the stress event and contract the pelvic floor before the event. The neuromodulation system can allow preemptive engagement by the patient in a more automated way. Some stress incontinent patients, for example, one out of three stress incontinent patients, are unable to voluntarily squeeze the pelvic floor. The requirement of patient activation of the second methodmay initiate the continence reflexes (including but not limited to the guarding reflex) to automatically kick in without having to wait for the body to start those reflexes. Thus, the feedforward control of the neuromodulation system disclosed herein may allow earlier identification of a stress event and preemptively activate the second mode so the patient can have preemptive contraction prior to a leak or before any physiological symptom associated with stress incontinence. In one embodiment, this is more advantageous than a passive implanted device with a feedback loop, which may activate delivery of stimulation when receiving an input that an incontinence event is actually occurring (rather than preemptively stopping an incontinence event before it occurs). Passive or closed feedback without patient activation is provided in one embodiment, where such systems might benefit a particular patient who does not wish to be, or is physically unable to be, engaged in the process. In one embodiment, a partially or fully implantable closed-loop bioelectrical therapy that can access and target the pudendal nerve (or tissue adjacent to the pudendal nerve) is provided that regulates the urge to void the bladder and increases resistance to urine leakage caused by activities such as coughing or lifting. In another embodiment, the bioelectrical therapy is not entirely an automated closed-loop system, but instead provides the option for user-controlled stimulation.

[0181] In some implementations, the first mode may be an automated mode. In some instances, the processor of the IPG may implement the first mode automatically or as a default operation mode in the absence of a user input to activate the second mode. In some implementations, the neuromodulation system disclosed herein may allow the processor of the IPG to operate in different modes at different time of the day and / or intervals based on user settings. In some instances, the neuromodulation system may provide a combination of an automated mode and a patient-activated mode. The combination of the automated mode and the patient-activated mode may benefit a patient with mixed incontinence.

[0182] In some instances, the user input may be in the form of a tap on the IPG implanted inside the patient's body, a squeeze of the pelvic floor muscles and / or the anal sphincter by the patient, and / or the patient crossing her legs (which may result in pressure change in the pelvic floor region). The advantage of squeezing of the pelvic floor muscles and / or the anal sphincter is that the squeeze may be more discrete than the tap and not visible to others, further giving the patients the psychological comfort and control when using the neuromodulation system disclosed herein. The tap on the IPG and / or the patient crossing her legs may provide more options for patients to activate the second mode. Certain patients may prefer the tap and / or the crossing of legs instead of the squeeze and / or may have weaker control of their pelvic floor muscles (which will be described in greater detail elsewhere in the present disclosure). In some cases, the user input may be the patient engaging any muscle in the pelvic region and / or near the pelvic region, e.g., leg muscles, glute muscles, etc. For example, the user input may include a contraction of a hamstring muscle.

[0183] In some implementations, the processor of the IPG may operate in different modes based on (for example, only or entirely) user inputs detected by one or more motion / posture sensors of the IPG. In those implementations, the one or more leads may or may not include sensing electrode(s) as disclosed herein. For example, the motion / posture sensors of the IPG may be configured to detect one or more taps, specific sequences of taps, rapid changes in acceleration, postural changes, and / or physical activities performed by the patient. Non-limiting examples of physical activities may include coughing, sneezing, jumping, jogging, etc. In some embodiments, the physical activities configured to be detected by the motion / posture sensor may include activities that tend to cause anincontinence event in a particular patient. The IPG may be programmed to operate in a specific mode and / or switch between modes based on the detected user input. In some embodiments, the detected user input may be detection of increased activity in a certain axis of movement. For example, the IPG may be programmed to detect user inputs from data collected by a motion / posture sensor of the IPG using methods for detecting breakthrough signatures disclosed herein, e.g., trained classifiers, autocorrelation, pattern matching, etc. The IPG may be programmed to apply different levels of stimulation, and in some cases, different durations of stimulation, based on the detected user input. In some embodiments, a user input detected by the motion / posture sensor can cause the processor of the IPG to move from a first mode to a second mode. For example, the first user input may be a tap or any other motion or posture change detected by the motion / posture sensor of the IPG disclosed herein. In some embodiments, a second user input detected by the motion / posture sensor can cause the processor of the IPG to move from a second mode back to a first mode. The second user input may be different from the first user input, such as a double tap, a series of taps, movement of the IPG, etc. In some embodiments, the motion / posture sensor may detect inactivity to move from a second mode back to a first mode. The amount of time required for patient movement to remain below a set threshold for the system to register inactivity may be adjusted. The first and second modes may be different in at least one parameter, as disclosed herein. The adaptive stimulation based on user inputs detected by motion / posture sensors may be more power efficient than detection of biomarkers requiring continuous real-time sensing of bioelectrical signals. In some embodiments, the processor of the IPG may operate in different modes based on user inputs detected by the one or more motion / posture sensors and pre-programmed mode changes based on time-dependent parameters, such as time of the day, time of the week, time of the month, etc.

[0184] In some embodiments, the preemptive patient engagement or the user input is a patient conscious act only to trigger the second stimulation mode. In those embodiments, the patient conscious act itself is not a physiological response to prevent an incontinence event. Rather, it is the stimulation in the second mode that prevents the incontinence event as disclosed herein. In some embodiments, the system disclosed herein may not need to sense a parameter associated with a physiological response associated with the onset of an incontinence event.

[0185] The preemptive patient engagement, that is, ability of the patient to control the timing of the activation of the second mode, may give the control of the bladder back to the patient. In some embodiments, the neuromodulation system may change the patients' behavior. The patients may feel that they are actively participating in the therapy and personalizing the therapy with the second mode, which can improve psychosomatic well-being of the patient. The feedforward control involving the patient is more advantageous than current products on the market, which may be a passive implanted device without any conscious participation by the patient, because the patients have the autonomy to control the device and / or participate in the therapy. With the neuromodulation system disclosed herein, the patients may feel that they have regained control of their bladder.

[0186] Alternatively or additionally, the system disclosed herein may include an open-loop configuration. In the open-loop configuration, the healthcare provider may set the electrical stimulation parameters, for example, through a graphical user interface on a remote device (which may be the controller 110 and / or an external device disclosed herein). The patient with the IPG 108 and one or more leads 102 implanted may modify or set electrical stimulation parameters via the remote device disclosed herein, for example, an external input device (e.g., amobile phone, a watch or other wearable device, a tablet, a computer, etc.) via a wireless and / or wired communication with the IPG 108, or the controller 110. In some cases, the electrical stimulation parameters that may be adjusted comprise frequency, amplitude, pulse width, or any combination thereof.

[0187] Alternatively or additionally, the system disclosed herein may include a closed-loop configuration. In the closed-loop configuration, the processor 122 of the IPG 108 and / or the controller 110 analyze signals from the sensors on the IPG 108 and / or the leads 102 disclosed herein to administer an electrical stimulation pattern. The signals may include an EMG signal, a pressure sensor signal, a motion / posture sensor signal, and / or any combinations thereof. In some instances, the measured EMG and / or pressure sensor signals may be analyzed to detect the onset of a stress incontinence event or a level of innate myoelectric electrical activity. In some instances, the pressure sensor signals and / or the motion / posture sensor signals may be analyzed to detect rapid acceleration, shock, posture-orientation, movement of interested body parts, or any combination thereof, which may also indicate the onset of a stress incontinence event. In some examples, these stress events may be caused by events such as coughing, laughing, jumping, etc. Once detected the IPG 108 may provide an electrical stimulation pattern to prevent micturition or uncontrolled defecation. In some cases, the threshold level for detecting a stress incontinence event may be modified and adjusted by the healthcare professional and / or the patient via graphical user interface on the controller 110 and / or an external device disclosed herein via wireless communication and / or a wired connection. In some embodiments, the closed-loop configuration may use machine learning and / or artificial intelligence to determine, based on signals from the one or more sensors on the IPG 108 or any other inputs described herein, the onset of a stress incontinence event.

[0188] The open-loop configuration and / or closed-loop configuration may augment the preemptive patient engagement for activating the second mode. As described herein, the preemptive patient engagement may allow the patient to activate the second mode prior to the onset of an incontinence event or before any physiological response to an incontinence event has occurred. In some instances, when the patient has failed to initiate a preemptive patient engagement user input, the closed-loop configurations may automatically activate the second mode based at least on the signals disclosed herein, which may detect the onset of an incontinence event. In one embodiment, the neuromodulation system includes an automated first mode and a patient-activated second mode without including an automated closed-loop configuration for activating the second mode or an automated open loop configuration.

[0189] In some instances, the patients may experience fewer stress incontinence events and / or fewer urge incontinence events after having used the neuromodulation system disclosed herein for a period of time. If the patients are enabled to take control of the problem that has previously generated fear and shame and that the patients previously had no control of, the patients' brains may be activated in a way that promotes continence. The control of the physiological process related to continence may alter the brain circuits of the patients that previously resulted in incontinence, or worsened incontinence. As described elsewhere in the present disclosure, the neuromodulation system disclosed herein may also provide training to help the patient relearn the control of muscles associated with continence.

[0190] While the second mode may provider greater immediate physiological effect in reducing urge and / or stress incontinence events than the first mode, the patients may not need the neuromodulation system to be constantly in the second mode in order to be in control of their bladders. Moreover, keeping the external urethralsphincter in prolonged state of titanic contract (which may require the system to be operating in the second mode) may be undesirable as doing so may lead to voiding problems and / or agitate the bladder. Activating the second mode only when the patient wants it to be activated may reduce voiding difficulties and have less disturbance of the bladder, while preventing amplification of the urge sensation by direct inhibition of an overactive bladder. The requirement of patient activation to enter the second mode may also prevent habituation that may occur as a result of constant current stimulation at an enhanced level (e.g., higher intensity), which may cause changes in the tissue impedance around the nerve in the vicinity of the electrodes. The changes may be, for example, due to fibrosis around the stimulating electrodes, and / or other chronic effects. As will be described in greater detail elsewhere in the present disclosure, the requirement of patient action of the second mode may also facilitate behavioral changes, rehabilitation, and / or relearning of the preemptive reflexes, including but not limited to the guarding reflex.

[0191] In several embodiments, adaptive nerve stimulation disclosed herein (e.g., pudendal nerve stimulation) may treat patients with unmet clinical needs, including patients with mixed urinary incontinence (MUI) failing first-line therapies (e.g., bladder training and / or pelvic floor muscle training) and / or patients with urge urinary incontinence (UUI) failing first and second line therapies (e.g., sacral neuromodulation with or without botulinum toxin injection). Patients with UUI failing second line therapies may be considered to have severe refractory UUI. In some cases, those patients may be implanted with the system disclosed herein, including the IPG and two quadripolar electrode leads. In some embodiments, the leads may be placed on the trunk (e.g., the Alcock's canal) and anterior pudendal nerve (e.g., a distal pudendal nerve) using radiological guidance and intraoperative electromyography (EMG) of the pelvic floor muscles (PFM) and external anal sphincter (EAS). Specific EMG findings associated with the adaptive stimulation disclosed herein may provide confirmation of correct placement during the implantation surgery.

[0192] As described elsewhere in the present disclosure, the lead and electrode combinations for stimulation may be user configurable. Different lead and electrode combinations for stimulation may result in slight variability in the EMG activity of the PFM. Additionally, or alternatively, as shown in Figures 9A-9C, stimulation (e.g., at a current of about 2 mA) on different parts of the pudendal nerve may show isolated PFM activity, concurrent PFM and EAS activity, and EAS activity alone. Figures 9A-9C each illustrate examples of the EMG activity when a different part of the pudendal nerve is stimulated.

[0193] The control of the adaptive stimulation may be voluntary and / or automated control. In some embodiments, the stimulation may be monophasic (e.g., with a pulse width of about 200 pis) stimulation. The first mode (also referred to as a basal mode) may include a frequency at about 15 Hz. The second mode (also referred to as an adaptive mode or a boost mode) may include a frequency at about 40 Hz. The motion or posture sensor (e.g., an accelerometer) may detect a patient-actuated tap on the location of the IPG, which may cause the stimulation to change from the first mode to the second mode. In some examples, the detection of the tap may be based on inertial detection. Patients may actively engage the second mode many times during the day in response to feelings of urgency.

[0194] Additionally or alternatively, certain physiological biomarkers of pelvic neuromuscular activity (e.g., in the EMG signal) may be detected real-time, in vivo. These EMG findings may be used for adaptive stimulation because reflexes mediated by sphincter contraction may have a role in bladder control. As described elsewhere in the present disclosure, these biomarkers may indicate that the patient has squeezed a pelvic floor muscle (or othermuscles), which can cause the IPG to switch from operating in the first mode to the second mode. In some cases, the biomarkers may result from the patient engaging any muscles outside of the pelvic region, e.g., leg muscles, gluteal muscles, etc. Figure 10 illustrates, in the top graph, the amplitude of an example raw EMG waveform, which includes periods of greater amplitude that may correspond to actions that may result in contraction of a pelvic floor muscle (or other muscles). In the illustrated embodiment, those actions may include the patient coughing, performing the Valsalva maneuver (e.g., blowing nose, sneezing, straining during a bowel movement, playing a wind instrument), and squeezing the pelvic floor muscle. In some instances, those actions may include stress events. The middle graph of Figure 10 illustrates the extracted envelop of the raw EMG waveform. In some embodiments, signal processing circuitry and / or software embedded in the IPG may extract the envelop to more clearly discriminate those actions from background activity. In some embodiments, a patient-specific classifier embedded in the IPG may set a threshold (e.g., amplitude threshold or otherwise) at which the system may switch from operating in the first mode to the second mode. The bottom graph in Figure 10 illustrates the change in stimulation program from the basal mode to the boost mode in response to the actions detected (that is, the threshold exceeded) via analysis of the EMG signal.

[0195] Some embodiments disclosed herein may include reviewing the patient outcomes at a desired time period post therapy (e.g., 1, 3, 6 months, 12 months, etc.) and adjusting therapy or recalibrating based on such reviewed outcomes. Such outcomes include but are not limited to: safety (primary outcome), surgical feasibility, physiological (e.g., urodynamic testing) and / or clinical efficacy (e.g., voiding diaries, questionnaires, etc.). In some instances, positive results from voiding diaries may be confirmed by quality of life questionnaires (e.g., dropping by one or more severity categories in the quality of life questionnaires such as the ICIQ GAB OoL and / or the ICIQ Ul SF). In some instances, pudendal nerve stimulation disclosed herein may lead to immediate and sustained (for example, up to about six months) effects on bladder and urethral physiology.

[0196] The introduction of a patient activated adaptive stimulation mode disclosed herein may contribute to the positive clinical effect. The tap-induced activation may provide a decrease in urgency and additional time to reach a toilet in time. The EMG-signal based stimulation may additionally or alternatively support patients at any time during the day.

[0197] In some implementations, MUI patients using the adaptive stimulation disclosed herein may regain complete continence. Some of those MUI patients may previously experience from about 3 to about 8 incontinence events / day, and may have no incontinence event throughout the day by using the adaptive stimulation disclosed herein. In some implementations, MUI patients may show improvement by about 90% after using the adaptive stimulation disclosed herein. In some implementations, MUI patients may show improvement by reducing the number of incontinence events / day from about 4-5 to about 0-0.5, or about 0.4, after using the adaptive stimulation disclosed herein. In some implementations, MUI patients may experience a better response with both electrode leads activated than with a single lead. As described elsewhere in the present disclosure, patients may switch off one lead due to discomfort. In some cases, the improvement from stimulation with leads may drop when one lead was switched off for a period of time. In some examples, the drop in improvement may be about 20% to about 25%, or about 23%. In some embodiments, the improvements disclosed herein may last for at least about six months.

[0198] In some implementations, a refractory urge urinary incontinence (rUUl) patient using the adaptive stimulation disclosed herein may regain complete continence. Some of those rUUl patients may previouslyexperience from about 3 to about 4 incontinence events / day, and may have no incontinence event throughout the day by using the adaptive stimulation disclosed herein. In some implementations, rUUl patients may show improvement by greater than about 50% after using the adaptive stimulation disclosed herein. In some implementations, rUUl patients may show improvement by reducing the number of incontinence events / day from about 5-6 to about 1 to about 3, after using the adaptive stimulation disclosed herein. In some embodiments, the improvements disclosed herein may last for at least about six months.

[0199] In addition to its effect on incontinence, the adaptive stimulation disclosed herein in several embodiments has an immediate and / or sustained positive effects on bladder capacity. In some embodiments, a patient who has used the adaptive stimulation disclosed herein for a period of time may show a significant increase in mean baseline MCC with basal stimulation (as compared to their measured MCC before being stimulated with embodiments described herein). Additionally, the patient's MCC may show further increments with adaptive stimulation. In some example, a patient may start with a baseline MCC of about 196 ml to about 200 ml. With the basal stimulation, the MCC may be increased to about 325 ml to about 328 ml. With the boost or adaptive stimulation, the MCC may be increased to about 360 ml to about 363 ml.

[0200] Using a first stimulation type (e.g., basal stimulation) according to several embodiments described herein increases a patient's baseline MCC (as measured pre-stimulation) by 25-70% (e.g., 25-50%, 50-70%, 60-70%, and overlapping ranges therein). Using a second stimulation type (e.g., boost stimulation) according to several embodiments described herein increases a patient's baseline MCC (as measured pre-stimulation) by 70-100% or more (e.g., 70-80%, 70-90%, 80-100%, and overlapping ranges therein). Using boost stimulation according to several embodiments described herein provides increases of 5-20% as compared to basal stimulation (e.g., 5-10%, 5-15%, 10-20%, and overlapping ranges therein).

[0201] In some embodiments, provided herein are systems and methods to increase a baseline MCC by 25-70% after a first stimulation (e.g., basal stimulation) and by 75-100% after a second stimulation (e.g., boost stimulation). Such increased capacity may be temporary or sustained over a period of days, weeks, months and years. In one embodiment, the increase in MCC with the first stimulation is sustained over at least 6 months and the increase in MCC with the second stimulation is temporary or more short-lived (e.g., days). In some embodiments, a patient who has used the adaptive stimulation disclosed herein may show increased baseline bladder capacity by about 25% to about 50% with the first stimulation (e.g., immediately post-operatively or soon after). In some embodiments, a patient who has used the adaptive stimulation disclosed herein may show increased baseline bladder capacity by about 50% to about 80% with the second stimulation (e.g., immediately post-operatively or soon after). In some embodiments, a patient who has used the adaptive stimulation disclosed herein may show increased baseline bladder capacity by about 35% to about 70% with the first stimulation after usage for a period of time (e.g., about 4 months to about 8 months). In some embodiments, a patient who has used the adaptive stimulation disclosed herein may show increased baseline bladder capacity by about 55% to about 90% with the second stimulation after usage for a period of time (e.g., about 4 months to about 8 months).

[0202] In some embodiments, provided herein are systems and methods to improve incontinence of mixed urinary incontinence (MUI) patients by 20-100% (e.g., 23-100%, 20-90%, and overlapping ranges therein). Insome embodiments, the systems and methods disclosed herein reduce incontinence events of MUI patients by 20-100% (e.g., 23-100%, 20-90%, and overlapping ranges therein).

[0203] In some embodiments, provided herein are systems and methods to improve incontinence of refractory urge urinary incontinence (rUUl) patients by 15-100% (e.g., 15-50%, 15-80%, 50-100%, and overlapping ranges therein). In some embodiments, the systems and methods herein reduce incontinence events of rUUl patients by 15-100% (e.g., 15-50%, 15-80%, 50-100%, and overlapping ranges therein).

[0204] In some embodiments, stimulating using two leads according to several embodiments described herein increases effectiveness in improving incontinence by about 20-25% compared with stimulating using a single lead. In some embodiments, stimulating using two leads according to several embodiments described herein reduces incontinence events by about 20-25% compared with stimulating using a single lead.Improvement in Urethral or Lower Urinary Tract Support

[0205] In some implementations, the multiple operation modes may provide a holistic urethral function support by activating different parts of the lower urinary tract. With stimulation in the first mode and / or the second mode, immediate effects may be observed on lower urinary tract functions (e.g., during urodynamics) during stimulation, such as increased maximal bladder capacity, and / or increased resting urethral pressure.

[0206] The likely physiological responses from the stimulation in the first mode and / or the second mode are summarized in Figure 5. The stimulation in the first mode may inhibit the bladder due to afferent activity at the S2, S3, and / or S4 level of the pudendal nerve. As also shown in Figure 5, the system in the first mode may improve urethral function by activating the striated muscle complexes surrounding the urethra at different levels. The stimulation in the first mode may lead to activation of the external urethral sphincter to actively restrict the opening of the urethra (for example, if the stimulation amplitude, frequency, and / or pulse width are lower in the first mode). The stimulation in the first mode may activate striated muscles surrounding the urethra to restore the natural orientation of the urethra. The stimulation in the first mode may also increase smooth muscle activity of the urethra to improve tone along the length of the urethra. The stimulation in the first mode may activate the pelvic floor muscles to provide further urethral support. The combination of any of those physiological responses may as a whole improve urethral support to prevent a leak.

[0207] As also shown in Figure 5, the stimulation in the second mode may cause a more forceful and sustained contraction (for example, a tetanic contraction) of the external urethral sphincter to completely close the urethra at the external urethral sphincter. In some implementations, a tetanic contraction may include contraction sustained for about 30 seconds, or about one minute, or any duration within a range defined by those values. In some implementations, a tetanic contraction may include contraction sustained for about 3 seconds, or about 4 seconds, or about 5 seconds, or about 10 seconds, or about 20 seconds, or about 30 seconds, or any duration within a range defined by those values. In some implementations, a tetanic contraction may include contraction sustained for a first time period followed by another contraction sustained for a second time period, with a brief muscle relaxation period (e.g. less than about 1 second, or less than about 0.5 second, or less than about 0.3 second, or less than 0.1 second, etc. or any duration within a range defined by those numbers), such that the first time period and the second time period combined may be at least about 20 seconds, or about 30 seconds, or about 40 seconds, or about 50 seconds, or about 60 seconds, or any duration within a range defined by those values. The complete closure of the urethra mayprevent leak in a stress event at the external urethral sphincter. The stimulation in the first mode may be below the threshold for causing a tetanic contraction of the external urethral sphincter. The stimulation in the second mode may also cause greater inhibition of the premature contraction of the bladder.

[0208] Striated muscles may include the sphincter urethrae. Contraction of the sphincter urethrae may provide a closure of the external urethral sphincter. In some implementations, the stimulation in the first mode may not reach the threshold needed to cause a tetanic contraction of the external urethral sphincter to completely close the urethra at the external urethral sphincter. In some implementations, the stimulation in the first mode may not reach the threshold to cause any contraction of the external urethral sphincter. In the second mode, the stimulation may reach or exceed a threshold for causing a tetanic contraction of the external urethral sphincter.

[0209] The striated muscles may further include two parts distal to the sphincter urethrae, the compressor urethrae and urethrovaginal sphincter. These two parts may be located on an anterior side of the urethra. In some instances, when the compressor urethrae and urethrovaginal sphincter (and optionally the pelvic floor muscles) contract, the urethra may be pulled backward toward the anal area, similar to a tape pulling the urethra upwards, thereby providing a passive closure of the urethra. Said differently, when contracted, the compressor urethrae and urethrovaginal sphincter (and optionally the pelvic floor muscles) may pull down a distal part of the urethra as a result of the urethra being fixed by the pubourethral ligaments. As a result, the urethra may form a kink, also referred to as the "knee” (e.g., during a stress event). The distal part of the urethra may be bent away from the longitudinal axis of the urethra as defined by a remainder of the urethra, that is, the length of the urethra from the bladder up to the knee.

[0210] A kink (or knee) may be commonly present in the urethra. The knee may be in a location more proximal to the distal part of the urethra, for example, at approximately 60% to approximately 80%, of the urethral length (starting from the proximal end of the urethra that extends from the bladder 704, or approximately 65%, or approximately 68%, or approximately 70%, or approximately 72%, or approximately 74%, or approximately 75%, or approximately 78%, or any other percentage in a range defined by those values. The knee may be helpful for preventing leakage of fluid from the urethra. In some people, the knee may not be present and / or may straighten to some extent in a manner that causes or correlates with incontinence. Thus, several embodiments disclosed herein are directed to restoring the knee (e.g., the proper angle of the knee bend). Several embodiments change the location of urethral kinking to treat incontinence. For example, to the extent that the further (e.g., more distal) urethral kinking is from the mid urethra, the higher the likelihood of incontinence (such as urodynamic stress incontinence), then several embodiments are configured to move the kink closer to the mid urethra (e.g., less distal) using for example the stimulation as disclosed herein.

[0211] When the bladder experiences an external pressure, such as abdominal pressure when one coughs or in other events (including but not limited to stress events) or other types of external pressure disclosed herein, the knee may contribute to passively closing the distal part of the urethra by increasing the maximum urethral pressure (MUP). The knee may be located in a high pressure zone, with the MUP situated at approximately 50% of the urethral length, or approximately 40%, or approximately 45%, or approximately 51%, or approximately 52%, or approximately 53%, or approximately 54%, or approximately 55%, or any percentage within a range defined by those values.

[0212] For patient with incontinence, the kink (knee) may no longer be present, and / or the closing force of the knee may be insufficient to counter the pressure from the bladder (e.g., bent to a less extent, having the location of the knee changed, etc.). The stimulation in the first mode may activate the striated muscles surrounding the urethra and / or the pelvic floor muscles, which may restore the natural orientation, such as by changing the axis of the urethra and / or by restoring or supporting the knee.

[0213] The stimulation in the first mode may additionally or alternatively activate the smooth muscles surrounding the urethra. The smooth muscles may include fibers running longitudinally along the length of the urethra. The smooth muscles that surround the urethra may have an intrinsic ability to contract and may be excited when there is a deformation of the smooth muscle cell. When a somatic nerve (e.g., the pudendal nerve) is stimulated, the forms of the smooth muscles may change to contract, which may rotate the axis of the urethra and / or improve the tone along the length of the urethra, thereby further supporting closure of the of the urethra to prevent leak.

[0214] In some implementations, the stimulation in the first mode and / or the second mode (or other modes) may affect the membrane potential of the peripheral nerve to increase or decrease the probability of an action potential occurring. In some cases, the stimulation disclosed herein may affect the calcium ion channel, the sodium ion channel, the potassium channel, and / or the like to affect the membrane potential. In some embodiments, electrical stimulation disclosed herein may affect noradrenaline from the sympathetic pathway. In some embodiments, electrical stimulation as described herein affect the acetylcholine pathway. For example, muscarinic receptors may be blocked. In some embodiments, the release, activity and / or reuptake of acetylcholine (or other neurotransmitter) may be modulated (e.g., decreased or increased) via electrical stimulation of, for example, the pudendal nerve or other tissue.

[0215] In some implementations, the stimulation in the first mode and / or the second mode (or other modes) may immediately improve urethral function (including but not limited to reducing stress incontinence events) without causing difficulty in voiding. When the bladder contracts to void, the axis of the urethra may change due to contraction of the longitudinal smooth muscles. If the knee in the urethra is permanently maintained, the patient may experience difficulty in voiding. However, with the stimulation in the first mode using the neuromodulation system of the present disclosure, the contraction of the striated and / or smooth muscles surrounding the urethra may be overridden during voiding. The stimulation in the first mode may only cause contraction of the striated and / or smooth muscles when needed, such as when the patient needs to hold the pee.

[0216] In some implementations, the immediate urethral support by the stimulation in the first mode and / or the second mode (or other modes) may be confirmed or observed by various methods. For example, changes in the axis of the urethra may be measured from a transperineal ultrasound of the urethra. As another example, an increase in the MUP and functional urethral length may be determined using urethra pressure profilometry . As yet another example, EMG signal of the external urethral sphincter activity and / or pelvic floor muscle activity may be monitored to evaluate muscle contraction at the sphincter and / or the pelvic floor. The EMG signal may be a raw signal and / or a processed signal, for example, the root mean square or other signal features, which may indicate the strength of contraction of the external urethral sphincter and / or the pelvic floor muscles.Personalized Stimulation

[0217] In some implementations, the stimulating parameter value of the first mode may be patient specific. The stimulating parameter may be strong enough to cause contractions of the striated and / or smooth muscle surrounding the urethra in a particular individual as described elsewhere in the present disclosure).

[0218] Across the spectrum of a mixture of MUI sub-types, some patients may be more urge predominant and others may be more stress predominant. The system can provide optimization and personalization of the treatment by implementing an algorithm for determining the patient-specific stimulating parameter. In some implementations, the system may test each patient within a certain range of the stimulating parameter to determine the appropriate parameter value. In one example, the patient can be tested with low stimulating frequencies ranging from 3 Hz to 14 Hz in increments (such as in 1 Hz increments). In some instances, the range may vary depending on whether the patient is urge predominant or stress predominant. In some implementations, the system may start from a default parameter, monitor an initial response (for example, a bioelectrical signal), and iteratively increase or decrease the parameter value in small increments or decrements. Before starting a treatment, patient's incontinence sub-type may be characterized based on relative frequencies of urge versus stress incontinence events, which may be determined from patient history and / or responses to patient questionnaire. In some implementations, algorithms implementing machine learning and / or artificial intelligence may be used for determining the patient-specific stimulating parameter based on any of the inputs described herein.

[0219] Figure 6 illustrates an example titrating process performed by the processor of the IPG. At step 802, the processor may output a stimulating electric current of a first parameter value. In some implementations, the first parameter may be a default parameter for all patients. In some instances, the first parameter may be a default frequency value. For example, the default frequency value may be 10 Hz, 11 Hz, 12 Hz, 13 Hz, 14 Hz, 15 Hz, 16 Hz, 17 Hz, or 18 Hz.

[0220] At step 804, the processor may receive data from one or more sensing electrodes. The data may include a bioelectrical signal indicative of the patient response to the stimulation current at the first parameter value. In one example, the bioelectrical signal may include an EMG signal. At step 808, the processor may adjust the parameter from the first parameter value to a new parameter meter. For example, the parameter value may be lowered in response to more innervation being detected at step 804, or be increased in response to insufficient innervation being detected.

[0221] In another example, the processor of the IPG may optionally receive input from an external controller at step 806. The input may include patient medical history and / or responses to patient questionnaire that may be used to characterize whether the patient, who may be an MUI patient, is urge or stress predominant. In response to an appropriate innervation being detected, the processor may maintain the first or default parameter value as the patient-specific parameter value. In response to the patient being urge predominant and a higher level of innervation being detected at the first or default parameter value, the processor may decrease the parameter level in small increments based on the data from the one or more sensing electrodes until the appropriate innervation is detected. In response to the patient being stress predominant and an insufficient level of innervation being detected at the first or default parameter value, the processor may increase the parameter level in small increments based on the data from the one or more sensing electrodes until the appropriate innervation is detected. In someimplementations, the processor may optionally transmit the patient specific parameter value to the external controller at step 810.

[0222] The external controller may include the patient controller (such as the controller 110 of Figure 1 A or 1 B), or any device on which a software of the neuromodulation system disclosed herein may be run (for example, a computer, a tablet, a smartphone, watch or other wearable, etc.).

[0223] Figure 7 illustrates an example titrating process that may be performed by an external controller or the processor of the IPG. The external controller may be the patient controller 110 or another device as disclosed herein that may communicate with the IPG or the patient controller. At step 900, the external controller or the processor of the IPG may receive sensing electrodes data. At step 902, the external controller or the processor of the IPG may receive incontinence sub-type data. The incontinence sub-type data may be derived from patient medical records and / or responses to patient questionnaire, which may include questions about relative frequencies of urge versus stress incontinence events. In some implementations, the external controller may display the questionnaire and receive patient responses to the questionnaire using patient inputs of the external controller.

[0224] At decision step 904, the external controller may determine whether an innervation threshold has been reached based on the sensing electrodes data. If the innervation threshold is reached, at step 912, the external controller or the processor of the IPG may output instructions to maintain the current parameter value and may then proceed at to end the titration process at step 914.

[0225] If the innervation threshold is not reached, at decision step 906, the external controller or the processor of the IPG may determine whether the patient is urge or stress predominant based on the incontinence subtype data. In response to the patient being urge predominant, at step 908, the external controller or the processor of the IPG may output instructions to adjust the parameter in a first manner (for example, by decreasing in a small decrement). In response to the patient being stress predominant, at step 910, the external controller or the processor of the IPG may output instructions to adjust the parameter in a second manner (for example, by increasing in small increment). The external controller or the processor of the IPG may return to step 900 from step 908 or step 910 to continue the titration process.

[0226] In some instances, the parameter may include frequency. If the patient is urge predominant, a frequency in the range of about 1 Hz to about 18 Hz, or about 2 Hz to about 16 Hz, or about 3 Hz to about 14Hz may be used. The small decrement may be 0.5 Hz, 1 Hz, or 2 Hz. If the patient is stress predominant, a frequency in the range of about 10 Hz to about 50 Hz, or about 12 Hz to about 45 Hz, or about 14 Hz to about 40 Hz may be used. The small increment may be 0.5 Hz, 1 Hz, or 2 Hz.

[0227] In some embodiments, the patient-specific stimulation parameters may be different for a certain patient based on the aim of the therapy. In case of treatment of incontinence, for example, the subtype of MUI may be one factor for determining the stimulation parameters. In the case of rehabilitation, at certain "training” hours, for regeneration of nerve and / or muscle activities, and / or for pain control, the stimulation parameters may be different for the same patient.Retraining Muscle Control for Continence

[0228] A person with normal continence control may contract the pelvic floor in response to an increase in the abdominal pressure. In some implementations, the second mode of the neuromodulation system may include asubfunction to output a stimulation that can reproduce the pre-contraction trigger. As explained elsewhere in the present disclosure, many incontinent patients, particularly the stress incontinent patients, at all or in a coordinated pattern, have lost the ability or have never learned to voluntarily contract or effectively contract the pelvic floor muscles or the sphincters. Physiotherapy for urinary incontinence may include rehabilitation exercises (for example, Kegel exercises) or use of nerve stimulation electrode introduced into the patient's pelvic floor to excite the pelvic floor muscles. These physiotherapy treatments may teach the patients to contract before the actual stress events until the preemptive contraction becomes reflexive again to the patient. The sub-function of the second mode may automate the re-education of the pelvic floor muscles in their normal state and / or to restore the normal function of the pelvic floor muscles, in addition to providing stimulation that restore nerve activity to reduce urge and / or stress incontinence events.

[0229] In some implementations, after the patient has activated the second mode, the system may output stimulation that results in a forceful (e.g., tetanic) contraction of the pelvic floor muscles. The patient may learn how it feels when the pelvic floor contracts under stimulation of the electric current. In some implementations, the neuromodulation system may include a training mode. The training mode may be a subfunction of the second mode that is patient activated. The training mode may be a separate mode from the first operation mode and the second operation mode. In some instances, in the training mode, the system may output a stimulating electric current of the same parameter(s) as when the system is operating in the second mode.

[0230] Figure 8 illustrates an example training mode that may be implemented by the processor of the IPG disclosed herein. At step 1000, the processor may receive a user input. In some implementations, the user input may be the same as the user input for activating the second mode as described elsewhere in the present disclosure. In other implementations, the user input may differ from the user input for activating the second mode. For example, the user input for the training mode may not include the squeeze of the pelvic floor muscles as the patients using the training mode may not be able to squeeze or adequately squeeze the pelvic floor muscles to active the training mode. In some instances, the user input for the training mode may include a double tap on the IPG or otherwise. At step 1002, the processor may enter the training mode. At step 1004, the processor may generate the stimulating electrical current. The stimulating current may cause a tetanic contraction of the pelvic floor muscles that can be felt by the patient.

[0231] In some implementations, the processor may generate the current at certain intervals for a certain period of time. For example, the interval may be about every 10 second, or about every 15 seconds, or about every 20 seconds, or about every 25 seconds, or about every 30 seconds, or about every 35 seconds, or about every 40 seconds, or about every 45 seconds, or about every 50 seconds, or about every 55 seconds, or about every 60 seconds, or an interval within a range defined by any of those values. For example, the period of time for the intermittent stimulation generation may be about 2 minutes, or about 3 minutes, or about 4 minutes, or about 5 minutes, or about 6 minutes, or about 7 minutes, or about 8 minutes, or about 9 minutes, or about 10 minutes, or about 11 minutes, or about 12 minutes, or about 13 minutes, or about 14 minutes, or about 15 minutes, or any duration within a range defined by those values.

[0232] The patient may learn to squeeze based on how it felt when the pelvic floor muscles contracted under stimulation. In some instances, the patient may learn to squeeze after every current generation. In some instances, the patient may learn to squeeze after the intermittent stimulation current has stopped. The processor ofthe IPG may optionally monitor the squeeze based on the bioelectrical signal from the at least one sensing electrodes. Patients with well-placed lead(s) at or near a target nerve may have a perception that electrical stimulation from the lead(s) is causing a contraction of their muscles. The patient may then try to replicate the feeling after experiencing a muscle contraction caused by the electrical stimulation. For example, a well-placed lead near a pudendal nerve may be a lead with electrodes having a sensory amplitude of less than 1 mA. For example, a well-placed lead may cause a response in a specific area of a patient with a stimulation current of less than 3 mA, less than 2 mA, or less than 1 mA, etc.. The response from a well-placed lead may be a tingling or buzzing feeling at a relatively low stimulation current. As the current is increased, the response may become a contraction. For example, the response may be a midline sensation that feels like a contraction. A well-placed lead may allow a patient to more dominantly feel a muscle contraction in response to electrical stimulation, rather than just feeling the electrical stimulation itself.

[0233] In step 1010, the IPG may record the training data and / or transmit the training data to an external controller or device. The training data may include, for example but not limited to, the date and / or time when the training mode was activated, and / or how well the patient was able to squeeze. The external controller or device may include the patient controller disclosed herein, or a computer, tablet, smartphone, watch or other wearable, server (local and / or remote, cloud), etc.

[0234] In some instances, the contraction of the pelvic floor muscles may provide direct haptic or tactile feedback to the patient such that the system may not include other forms of feedback to remind the patient that the contraction has happened. Optionally, at step 1006, the system may output vibration, haptic, tactile, visual, and / or auditory feedback to the patient to allow the patient to understand that the pelvic floor has contracted. In some cases, at optional step 1006, the system may output stimulatory feedback, e.g., a unique stimulation pattern recognizable by the patient to provide feedback. In some cases, stimulatory feedback may have different stimulation parameters than a background level of stimulation to cause a different sensation than the background level which the patient can recognize, but not extreme enough to cause pain. Alternatively, the training mode may not output stimulation (that is, omitting step 1004), but may instruct the patient to vol ition ally try to contract a pelvic floor muscle. The vibration, haptic, tactile, visual, stimulatory, and / or auditory feedback at step 1006 may be output to the patient when the system senses a bioelectrical signal (such as the EMG signal) indicative of the pelvic floor muscle contraction, such that the patient may associate her efforts with a pelvic floor muscle contraction. The additional feedback may help the patient associate the feeling with pelvic floor contraction. In some implementations, the system may receive patient feedback at 1008. The patient feedback may include the bioelectrical signal and / or other forms of feedback. For example, the patient may provide user feedback via user input on an external device or external controller in communication of the IPG. The user feedback may include the patient confirming that an attempt to squeeze the pelvic floor muscles has been made.

[0235] In some instances, the training mode of the neuromodulation system may be used independently to help the patient regain the reflexes against incontinence. In some instances, the training mode may be used in combination with physiotherapy and / or incontinence medication to further improve patient outcome. In several embodiments, the training mode or the various neuromodulation systems described herein provided sustained results such that a patient, over time, may need to use the system on a less frequent basis to achieve the same therapeutic results. For example, a patient may only need to use the system once a day to achieve all-day relief or alonger therapeutic effect. As another example after 6-18 months of consistent use, a patient may only need neurostimulation on an intermittent basis thereafter (e.g., at a usage level of 20-50% of what was used previously). In one embodiment, the patient may achieve a therapeutic effect (e.g., reduced incontinence) even when the system is not in use.

[0236] Alternatively or additionally, the training mode may facilitate associative learning by operant conditioning. The patients may learn directly from pairing device activation with their experience of preventing and / or controlling incontinence. Incontinence may be an aversive bodily outcome. If, by feeling the activation of the system (stimulation and pelvic floor contraction), the patient feels that this prevents an incontinence episode, the patient may learn by negative reinforcement of behavior. Similarly, the ability to restore normal life activities may be positively reinforcing. Over time, patients may associatively learn by operant conditioning that feeling or experiencing certain patterns of device activation is beneficial. In some cases, the patient may be more tolerant of the stimulation. The patient may self-optimize therapy based on the associative learning. For example, the patient may trigger the second mode more frequently and / or increase the stimulation level.

[0237] In several embodiments, the training mode may be adapted to prevent incontinence of a patient immediately after a surgery (e.g., radical prostatectomy) or child delivery, or other trauma that may lead to incontinence. The adapted training mode may incorporate any of the features of the training mode disclosed herein, but may be less invasive and / or more temporary than the training mode disclosed herein. In some embodiments, the adapted training mode may provide nerve and / or muscle regeneration.

[0238] After the surgery, child delivery, or other trauma that may lead to incontinence, the adapted training mode may provide the stimulation at certain intervals for a certain period of time. For example, the interval may be about every 10 second, or about every 15 seconds, or about every 20 seconds, or about every 25 seconds, or about every 30 seconds, or about every 35 seconds, or about every 40 seconds, or about every 45 seconds, or about every 50 seconds, or about every 55 seconds, or about every 60 seconds, or an interval within a range defined by any of those values. For example, the period of time for the intermittent stimulation generation may be about 2 minutes, or about 3 minutes, or about 4 minutes, or about 5 minutes, or about 6 minutes, or about 7 minutes, or about 8 minutes, or about 9 minutes, or about 10 minutes, or about 11 minutes, or about 12 minutes, or about 13 minutes, or about 14 minutes, or about 15 minutes, or any duration within a range defined by those values.

[0239] Several embodiments of the training mode disclosed herein include use of augmented reality (AR) and / or virtual reality (VR). In the training mode, the neuromodulation system disclosed herein may be paired with AR and / or VR eyewear and / or headset, including but not limited to any off-the-shelf ARA / R eyewear or headset, or other suitable ARA / R eyewear or headset. The ARA / R eyewear or headset may allow a user to visualize, for example, anatomy of the lower urinary tract or bowels, graphics and / or icons providing feedback as described herein, usage and / or training statistics in any visual format, and / or any other visual representation that can aid the user in retraining muscle control and / or continence reflexes.Bilateral Stimulation and Sensing

[0240] Described herein are devices, systems, and methods that may, among other features, prevent an episode of incontinence in an individual by providing electrical nerve stimulation. The episode of incontinence may include urinary incontinence, fecal incontinence, or any combination thereof. The devices, systems and methodsdisclosed herein may treat one or more sub-types of incontinence. Common sub-types of incontinence may include urge incontinence, stress incontinence, overflow incontinence, or mixed incontinence, which are described in greater detail elsewhere in the present disclosure. One advantage of several embodiments is the ability to treat both urge and stress incontinence, and to allow for stimulation and / or sensing on both sides of the patient's body to improve overall therapy.

[0241] Stimulation using bilaterally placed electrode leads (also referred to as "bilateral stimulation”) may be provide by the embodiments disclosed herein. Several embodiments advantageously provide bilateral stimulation. Stimulation may be provided by the leads on a first lateral side and sensing may be provided by the leads on a second lateral side of the patient, which is described in greater detail herein with reference to Figure 12. In other words, in some embodiments, "bilateral stimulation” as disclosed herein may not necessarily include providing stimulation by leads on both lateral sides. In some embodiments, stimulation may be provided by leads on both lateral sides, simultaneously or in an alternating manner. Stimulation on the first lateral side and stimulation on the second lateral side may include one or more different parameters (e.g., frequency, amplitude, duration, pulse width, etc.). Simultaneous stimulation on both lateral sides may include a phase difference between stimulation on the first lateral side and stimulation on the second lateral side. In some embodiments, sensing may use one lead on the first lateral side and another lead on the second lateral side. In some embodiments, at least one lead with 1-6 electrodes (e.g., 4 electrodes) is placed an appropriate distance away from another lead having 1-6 electrodes (e.g., 4 electrodes). This distance may be bilateral with respect to the midline. The electrodes on each lead may be capable of sensing or stimulating, or both.

[0242] The system disclosed herein may deliver stimulation to both lateral sides of the patient. In some embodiments, the stimulation delivered to both lateral sides of a patient may work together, e.g., synergistically, to result in a desired or an enhanced therapeutic effect. The stimulation level on each side may be lower than the stimulation level required if stimulation is provided only on one side. In some embodiments, the system may deliver stimulation to each lateral side at different times, e.g. non-overlapping stimulation periods or cycles. In some embodiments, the system may deliver stimulation to each lateral side simultaneously, e.g., at least partially overlapping stimulation periods or cycles). The system may be configured to deliver bilateral stimulation via one or more electrode leads implanted on each side of the patient. The electrode leads may comprise one or more stimulation electrodes at a target tissue, such as the pudendal and / or sacral nerve or tissue adjacent to the nerve(s). The one or more leads on each side of the patient may deliver stimulation to target tissue sites proximate the same nerve on each side or different nerves on each side. For example, the IPG 108 may deliver bilateral stimulation to a patient by delivering stimulation to both a left and a right portion of the same nerve. Additionally, or alternatively, the IPG 108 may deliver bilateral stimulation to a patient by delivering stimulation to a left portion of a first nerve and a right portion of a second nerve different than the first nerve. In some embodiments, the stimulation may be delivered to one lateral side while anodally blocking the other side, to treat lateralized conditions, e.g., pain on one side of the body. Bilateral stimulation may be beneficial for causing an effect on muscles that are bilaterally innervated. For example, the external anal sphincter may be bilaterally innervated, such that stimulating on a side of the body may cause a stronger contraction on that side of the body compared to an opposite side of the body. In some cases, stimulation on one side of a bilaterally innervatedmuscle may cause an ipsilateral response with shorter latency and a contralateral response with larger latency, which may indicate a reflexive response on the contralateral side due to the stimulation.

[0243] The system disclosed herein may also have bilateral sensing capabilities on both lateral sides of the patient. The system may provide sensing capabilities via one or more leads on each side of the patient comprising one or more sensing electrodes. The one or more sensing electrodes may comprise bioelectrical sensing electrodes. In some implementations, a biopotential across two sensing electrodes may be measured. For example, the sensing electrodes may sense an electromyography (EMG) signal. The sensing may occur concurrently with the stimulation. For example, the system may deliver stimulation on one side lateral side of the body, while sensing on the other lateral side of the body (with more details disclosed herein with reference to Figure 12). Additionally, or alternatively, the system may concurrently deliver stimulation and sense on the same side of the body. In some cases, the system may sense across two bilateral leads placed on opposite sides of the body, while concurrently delivering stimulation on one or both sides. An electrode lead may comprise one or more stimulation electrodes and one or more sensing electrodes on the same lead. Each of the electrodes on an electrode lead may be configured to deliver stimulation or for bioelectrical sensing, although an electrode may not perform the two functions at the same time.

[0244] The system disclosed herein may include an open-loop configuration. In the open-loop configuration, the healthcare provider may set the electrical stimulation parameters, for example, through a graphical user interface on a remote device (which may be the controller 110 and / or an external device disclosed herein). The patient with the IPG 108 and one or more leads 102 implanted may modify or set electrical stimulation parameters via the remote device disclosed herein, for example, an external input device (e.g., a mobile phone, a watch or other wearable device, a tablet, a computer, etc.) via a wireless and / or wired communication with the IPG 108, or the controller 110. In some cases, the electrical stimulation parameters that may be adjusted comprise frequency, amplitude, pulse width, or any combination thereof.

[0245] Alternatively, or additionally, the system disclosed herein may include a closed-loop configuration. In the closed-loop configuration, the processor 122 of the IPG 108 and / or the controller 110 analyze signals from the sensors on the IPG 108 and / or the leads 102, 104 disclosed herein to administer an electrical stimulation pattern. The signals may include an EMG signal, a pressure sensor signal, a motion / posture sensor signal, and / or any combinations thereof. In some instances, the measured EMG and / or pressure sensor signals may be analyzed to detect the onset of a stress incontinence event or a level of innate myoelectric electrical activity. In some instances, the pressure sensor signals and / or the motion / posture sensor signals may be analyzed to detect rapid acceleration, shock, posture-orientation, movement of interested body parts, or any combination thereof, which may also indicate the onset of a stress incontinence event. In some examples, these stress events may be caused by events such as coughing, laughing, jumping, etc. Once detected the IPG 108 may provide an electrical stimulation pattern to prevent micturition or uncontrolled defecation. In some cases, the threshold level for detecting a stress incontinence event may be modified and adjusted by the healthcare professional and / or the patient via graphical user interface on the controller 110 and / or an external device disclosed herein via wireless communication and / or a wired connection.

[0246] The system disclosed herein can allow multiple stimulation programs to be saved to the IPG processor 108. In some instances, predefined thresholds, which may include specific biomarkers, may be defined by a clinician using a software program on the external device disclosed herein. The predefined thresholds may beadjusted when the patient revisits the clinician and / or when the external device running the software program establishes communication with the IPG. In some cases, other stimulation parameters (e.g., frequency, amplitude, pulse width, duration, safety / comfort features, etc.) may be defined by a clinician using the software program. The parameters may be adjusted by the clinician when the patient revisits the clinic and / or when the external device disclosed herein running the software program establishes communication with the IPG. In some instances, certain parameters may be adjusted by the patient using the controller and / or an external device disclosed herein.

[0247] The system disclosed herein may allow for adaptive stimulation. The IPG processor 108 may receive one or more breakthrough signature inputs, for adaptive stimulation. In some embodiments, a breakthrough signature input may include detection of a postural change of the patient. In some embodiments, a breakthrough signature input may include detection of patient inactivity. In some embodiments, a breakthrough signature input may include detection of a muscle contraction. For example, a breakthrough signature input may include detection of a cough, a sneeze, or any other event that may cause acute changes to abdominal pressure. In some embodiments, a breakthrough signature input may include detection of a muscle relaxation. In some embodiments, a breakthrough signature input may include detection of a patient notification. For example, the breakthrough signature may include detection of one or more taps, or a specific pattern of taps, on the implantable pulse generator implanted in the patient's body. In some embodiments, the breakthrough signature inputs may be determined using any of the sensors disclosed herein, and / or via the controller (see, e.g., controller 110) or an external device disclosed herein. For example, a motion or posture sensor disclosed herein may facilitate providing the breakthrough signature inputs relating to a postural change of the patient or the detection of a patient notification. As another example, a bioelectrical sensor may facilitate providing the breakthrough signature input relating to detection of a muscle contraction. In some implementation, one of the breakthrough signatures may include a geographical location change, a pressure change, etc. In some embodiments, the breakthrough signature may be based on a combination of sensor inputs, for example, the motion or posture sensor input and the bioelectrical sensor input. In one example, the motion or posture sensor input may indicate that the patient is sleeping, but the bioelectrical sensor input indicates increased activity, which may indicate a muscle contraction. As another example, the breakthrough signature indicating a stress urinary incontinence event may include a combination of a motion sensor input (e.g., indicating a motion shock) and a bioelectrical sensor input (e.g., indicating a muscle contraction). Depending on the adaptive profile(s) assigned to be activated, the IPG processor 108 may operate automatically switch from an assigned background program to a different stimulation program upon receiving one or more of the breakthrough signature inputs disclosed herein. In other words, the sensors disclosed herein can provide multiple independent actions in detecting one or more breakthrough signatures, and / or be merged for greater specificity in detecting other breakthrough signatures.

[0248] Additional details of adaptive stimulation will now be described. Adaptive stimulation can be effective in improving reduction of both urge incontinence events and stress incontinence events. Several embodiments disclosed herein may include adaptive nerve stimulation (for example, pudendal nerve stimulation) that may toggle between a first, background level and a second, higher level. The background level and the higher level may include different stimulation programs. In one example, the background level is a basal stimulation, and the higher level is a boost stimulation. The background and higher levels may differ in at least one stimulation parameter. Examples of such stimulation parameters may include but are not limited to frequency, pulse width, amplitude, or any combinationsthereof. In some embodiments, the higher level may include a higher frequency in the stimulating electrical current than the background level. According to several embodiments, the higher level stimulation is higher in one, two or all of frequency, pulse width, and amplitude (as compared to any background level assigned to certain time). In some embodiments, the higher level of stimulation may be delivered using a different electrode configuration, e.g., a different set of electrodes on the leads, than the background level. The set of electrodes used for the higher level may stimulate a different part of the target nerve than the set of electrodes used for the background level. In some implementations, the system may use machine learning and / or artificial intelligence to automatically determine and set stimulation parameters (e.g., frequency, amplitude, pulse width, duration, or combinations thereof) based on any of the inputs described herein, e.g., sensor data, for any of the operation modes described herein.

[0249] In some implementations, the background or higher level includes a fixed pulse width and / or a fixed amplitude. In some implementations, the background or higher level may include variable pulse widths and / or variable amplitudes. In some embodiments, the higher level has a ramp up from the background level and / or a ramp down from the background level, so that one, two or all of frequency, pulse width, and amplitude increase and / or decrease gradually.

[0250] In one embodiment, tri-level stimulation is provided in adaptive stimulation, where a third stimulation program is provided with a third, highest level stimulation that is higher than the second level. The third stimulation level may be higher than the second stimulation level to address a patent's needs and / or to reduce habituation. The third stimulation level may be constant or varied. In some implementations, the second stimulation level may be triggered by determining a breakthrough signature from the bioelectric sensor (e.g., when the patient squeezes a muscle), and the third stimulation level may be triggered when the readings from the motion or posture sensor indicate that the event is a severe event, such as a severe refractory urge incontinence. In some implementations, more than three levels of stimulation may be provided in adaptive stimulation.

[0251] In some implementations, the first, background level may include a frequency of about 1 Hz to about 50 Hz, or a stimulating frequency of about 2 Hz, about 4 Hz, about 6 Hz, about 8 Hz, about 10 Hz, about 12 Hz, about 14 Hz, about 16 Hz, about 18 Hz, about 20 Hz, about 22 Hz, about 24 Hz, about 26 Hz, about 28 Hz, about 30 Hz, about 32 Hz, about 34 Hz, about 36 Hz, about 38 Hz, about 40 Hz, about 42 Hz, about 44 Hz, about 46 Hz, about 48 Hz, or about 50 Hz, or any frequency within a range defined by these values. In some implementations, the first mode may include a frequency of about 1 Hz to about 150 Hz, or a stimulating frequency of about 5 Hz, about 10 Hz, about 15 Hz, about 20 Hz, about 25 Hz, about 30 Hz, about 35 Hz, about 40 Hz, about 45 Hz, about 50 Hz, about 65 Hz, about 70 Hz, about 75 Hz, about 80 Hz, about 85 Hz, about 90 Hz, about 95 Hz, about 100 Hz, about 105 Hz, about 110 Hz, about 115 Hz, about 120 Hz, about 125 Hz, about 130 Hz, about 135 Hz, about 140 Hz, about 145 Hz, or about 150 Hz, or any frequency within a range defined by these values.

[0252] In some implementations, the second, higher level may include a frequency of about 50 Hz to about 1,000 Hz, or about 100 Hz to about 800 Hz, or about 200 Hz to about 500 Hz, or a stimulating frequency of about 50 Hz, about 60 Hz, about 70 Hz, about 80 Hz, about 90 Hz, about 100 Hz, about 110 Hz, about 120 Hz, about 130 Hz, about 140 Hz, about 150 Hz, about 160 Hz, about 170 Hz, about 180 Hz, about 190 Hz, about 200 Hz, about 210 Hz, about 220 Hz, about 230 Hz, about 240 Hz, or about 250 Hz, or any frequency within a range defined by those values. In some implementations, the second mode may include a frequency of about 1 Hz to 10 kHz, or a stimulatingfrequency of about 500 Hz, about 1,000 Hz, about 1,500 Hz, about 2,000 Hz, about 2,500 Hz, about 3,000 Hz, about 3,500 Hz, about 4,000 Hz, about 4,500 Hz, about 5,000 Hz, about 6,500 Hz, about 7,000 Hz, about 7,500 Hz, about 8,000 Hz, about 8,500 Hz, about 9,000 Hz, about 9,500 Hz, or about 10,000 Hz, or any frequency within a range defined by these values.

[0253] As disclosed herein with the breakthrough signatures, the second stimulation is controlled by a breakthrough signature from the patient in some embodiments by, for example, a voluntary and / or involuntary patient movement (squeezing of muscles, engaging in certain physical activities including but not limited to heavy coughing, laughing, heavy movements, or tapping the device, or using an external device to control stimulation, such as a smartphone, wearable, or other device). The breakthrough signature may be detected by the motion or posture sensor, the bioelectrical sensor, or another sensor disclosed herein, or any combinations of sensors disclosed herein. In some implementations, one sensor may detect the breakthrough signature using different adaptive profiles, which is described elsewhere in the present disclosure. In some embodiments, the second stimulation may be triggered based on a location of the patient, for example, by the patient arriving at home. The location of the patient may be determined by a GPS sensor, which may be embedded on the IPG or the one or more leads, or a GPS signal from the patient's cellphone or wearable transmitted to the IPG.

[0254] In some instances, the processor of the IPG may implement the background level automatically based on the program assignment input in the absence of a breakthrough signature for increasing to the higher level and / or in the presence of a breakthrough signature for returning to the background level. For example, a breakthrough signature for returning to the background level may include a detection of patient inactivity for a certain time period. In some cases, the length of the time period for inactivity to register as a breakthrough signature may be adjusted.

[0255] The higher level may be run for only a few seconds, while the background level may be run for hours. In some embodiments, when triggered, the higher level is applied for about one second to about one minute, or about several seconds to about 30 seconds, or about 2-5 seconds, or about 30-60 seconds, or a duration within a range defined by any of these values. In some implementations, a duration of less than ten seconds may be effective for preemptively stopping a stress event. In some implementations, a duration of about 30 seconds may be effective for preemptively stopping an urge event (e.g., lasting for a duration long enough for a person to reach the toilet). In some embodiments, the second stimulation is applied for a total of 30 seconds to 60 minutes per day. In some embodiments, the second stimulation may be triggered at least about 5 times to about 25 times per day, or at least about 10 times to about 20 times per day, or any number of times within a range defined by these values.

[0256] A clinician may select the best electrode lead for stimulation. Bilateral nerves, e.g., the pudendal nerve or sacral nerve, may have asymmetrical function, such that one side of a bilateral nerve may not provide the same function as the other. Thus, a preferential lead for electrical stimulation may be chosen based on measured bioelectrical responses. The clinician may select the best electrode(s) on each lead for stimulation to achieve the best therapeutic effect. In one example, electrode(s) may be selected for stimulation corresponding to a lead implanted close to the nerve trunk. In another example, electrode(s) may be selected for stimulation corresponding to a lead implanted at the branches of a nerve and pelvic floor, or another location along the pudendal nerve or sacral nerve. In some embodiments, the clinician may determine the best electrode based on electrode responses received during the implantation surgery, urodynamics study, and / or the clinic visits. Figures 11A-11F illustrate example electrode leadconfigurations. Figures 11A-11F illustrate visual representations of the electrode leads 1102, 1104, electrodes 1131-1138, and the IPG 1108 as shown in an example software program for configuring the neuromodulation system. In some implementations of the software program, the electrodes 1132, 1134, 1136, 1138 on the electrode lead 1102 may be labeled as Nos. 1 , 2, 3, and 4, respectively; and the electrodes 1131 , 1133, 1135, 1137 on the second electrode lead 1104 may be labeled as Nos. 5, 6, 7, and 8, respectively. The clinician may select a monopolar stimulation (using the selected electrode 1137 and the IPG 1108 as the cathode and anode, respectively), such as shown in Figure 11 A, or bipolar stimulation (using two electrodes 1135, 1137, which may be from the same lead or different leads), such as shown in Figure 11 B. In some embodiments, monopolar stimulation may use multiple electrodes as the cathodes and the IPG as the anode. In some embodiments, the best lead for stimulation and / or the best electrode(s) on the lead for stimulation may be selected by the patient, or automatically by the system. For example, the system may deliver stimulation to all the electrode contacts, one by one, and sense the corresponding bioelectrical response. The system may then determine the electrode(s) that elicit the best response, and thereby configure those electrode(s) for stimulation. This "self-evaluation” process of determining the best electrode(s) for stimulation may occur at a moment when little to no muscle activity is occurring, e.g., at night when the patient is sleeping. In some implementations, the system may use machine learning and / or artificial intelligence to automatically determine and / or select the best lead(s) and / or the best electrode(s) for stimulation at any given time based on any of the inputs described herein.

[0257] In some embodiments, the automated selection of leads and / or electrodes for stimulation may be performed by measuring evoked responses. The system may use one or more sensing electrodes to determine, at each electrode, if a certain level of stimulation evokes a response from a patient at the pelvic floor, the external anal sphincter, and / or another pelvic muscle. For example, the system may perform an automated sweep of each electrode to determine a minimum stimulation parameter, e.g., amplitude, frequency, pulse width, etc., for generating an evoked response from stimulating at each electrode. The system may automatically select the best stimulation electrode(s) using a machine learning and / or artificial intelligence algorithm for optimizing one or more metrics. For example, the system may determine a ratio of the strength of the evoked response, e.g., a biopotential signal amplitude, to a stimulation parameter, e.g., amplitude, frequency, etc. A higher (or lower) ratio of evoked response to stimulation may indicate a better electrode for stimulation. The automated selection of stimulation electrodes at set time intervals may allow for reduced habituation in therapy, e.g., by automatically changing the electrodes and / or stimulation parameters.

[0258] In some embodiments, a biopotential breakthrough signature for adaptive stimulation may be detected by a bioelectrical sensor. The bioelectrical sensor may comprise one or more sensing electrodes on an electrode lead. According to embodiments, at least one electrode lead may be implanted on each lateral side of the patient's body. As shown in Figure 11C, the electrode lead 1102 may be implanted on the left side of the body, and the electrode lead 1104 may be implanted on the right side of the body. Each of the electrode leads on either side of the body may have at least one stimulation electrode and at least one sensing electrode. Figure 11C illustrates two leads showing the sensing dipole selection, which is electrodes 1132 and 1138 of the left side lead, in the illustrated embodiment. The biopotential can be measured between any combination of two of the four electrodes on one lead, or two of eight electrodes in a two-lead configuration. For example, as shown in Figure 11D, the electrodes 1133 and 1135 of the right sided lead may comprise a sensing dipole section. In some implementations, as shown in Figure 11 E, two electrodes across the two leads, e.g., electrodes 1132 and 1135 (which may be implanted on different sides of thebody), may be selected as sensing dipoles. In some cases, as shown in Figure 11F, each lead in a bilateral configuration may comprise a sensing dipole section, e.g., electrodes 1136 and 1138 of lead 1102 and electrodes 1133 and 1135 of lead 1104. For some patients, if stimulation is more effective using one of the electrodes selected for sensing, another electrode may be assigned for sensing. Thus, the arrangement for electrodes assigned for sensing and electrodes assigned for stimulation may be patient-specific.

[0259] The clinician may select the best electrodes for sensing. For example, a wider spacing between sensing electrodes can capture a stronger signal by detecting from a larger muscle area, but can pick up signals from nearby muscles and may be more prone to noise. A closer spacing between electrodes can be more focused on a specific muscle area, improving spatial precision and reducing background noise and stimulation artifacts, but generating smaller signals. In some implementations, the system may use machine learning and / or artificial intelligence to automatically determine and / or select the best lead(s) and / or the best electrode(s) for sensing at any given time.

[0260] A biomarker, as referred to herein, may be a characteristic of one or more bioelectrical signals (e.g., band power, amplitude, etc.) that is indicative of a particular patient state and / or particular neuromuscular activity. Certain physiological biomarkers of pelvic neuromuscular activity (e.g., in the EMG signal) may be detected real-time, in vivo. These EMG findings may be used for adaptive stimulation because reflexes mediated by sphincter contraction may have a role in bladder control. As described elsewhere in the present disclosure, these biomarkers may indicate that the patient has squeezed a pelvic floor muscle (or other muscles), which can cause the IPG to switch from operating at a background level to a higher level. Figure 10 illustrates, in the top graph, the amplitude of an example raw EMG waveform, which includes periods of greater amplitude that may correspond to actions that may result in contraction of a pelvic floor muscle (or other muscles). In the illustrated embodiment, those actions may include the patient coughing, performing the Valsalva maneuver (e.g., blowing nose, sneezing, straining during a bowel movement, playing a wind instrument), and squeezing the pelvic floor muscle. In some instances, those actions may include stress events. The middle graph of Figure 10 illustrates the extracted envelope of the raw EMG waveform. In some embodiments, signal processing circuitry and / or software embedded in the IPG may extract the envelop to more clearly discriminate those actions from background activity. In some embodiments, a patient-specific classifier embedded in the IPG may set a threshold (e.g., amplitude threshold or otherwise) at which the system may switch from operating in the background level to the higher level. The bottom graph in Figure 10 illustrates the change in stimulation program from the basal mode to the boost mode in response to the actions detected (that is, the threshold exceeded) via analysis of the EMG signal.

[0261] The system disclosed herein may provide for concurrent stimulation and sensing, which may allow for real-time monitoring of patient neuromuscular activity while simultaneously delivering stimulation therapy. Concurrent stimulation and sensing may enable personalized treatment based on patient-specific responses to allow tailored stimulation programs, e.g., sense adaptive stimulation. Concurrent stimulation and sensing may also facilitate adaptive stimulation therapy based on physiological responses and maximize the collected usable biopotential data for improving understanding of the therapy.

[0262] However, in some instances, it may be difficult to distinguish a biomarker from bioelectrical signals that were sensed while stimulation was simultaneously being delivered. For example, the triggering of a higher level of stimulation as a response to a first biopotential breakthrough signature may result in the stimulationcontaminating the sensed signal, e.g., stimulation artifacts. The contamination may prevent further recognition of biomarkers during the delivery of stimulation, which may render the system blind to a patient's condition and the effectiveness of the stimulation. For example, it may be unclear whether the event causing the breakthrough signature has passed and the higher level of stimulation is no longer needed, or if continued stimulation and / or an even higher level of stimulation is needed. In some instances, when stimulation is increased in response to detection of a biomarker, the increased stimulation may cause an unintended reentrant loop. A reentrant loop may refer to a "self-triggering” scenario when a higher level of stimulation is triggered by a first detection of a biomarker, resulting in a transient response due to the increased stimulation coupled in the sensed signal. The contaminated sensed signal may result in false detection of a biomarker to continue to trigger further stimulation, such that the system enters a reentrant loop and is no longer responsive to actual physiological changes. Some embodiments disclosed herein may provide stimulation using a lead on one lateral side of the patient and sensing using another lead on the other lateral side of the patient to reduce the effect of stimulation on concurrent sensing.

[0263] The bilateral neuromodulation system disclosed herein, by having stimulation and sensing on opposite lateral sides of the body, may advantageously provide flexibility in stimulation and sensing, for example, during adaptive closed-loop stimulation. The tissue that generates biomarkers may be at or near the tissue targeted for stimulation. For example, delivering stimulation using an electrode lead may lead to local muscle contractions ipsilateral to the electrode lead. Thus, in some cases, sensing with the same electrode lead used for delivering stimulation may cause a reentrant loop in the feedback loop. In some cases, sensing on the side ipsilateral to which stimulation is delivered may cause a reentrant loop. The bilateral placement of electrode leads each having at least one stimulation electrode and at least one sensing electrode may allow for concurrent stimulation and sensing while reducing the occurrence of reentrant loops. For example, an electrode lead on one side may be used primarily to deliver stimulation, while an electrode lead on the opposite side may be used primarily for sensing. In another example, sensing may occur across two bilateral leads, thus reducing the possibility of reentrant loops, as discussed elsewhere in the present disclosure.

[0264] Figure 12 illustrates an example process of bilateral sensing-activated adaptive stimulation by the neuromodulation system disclosed herein. As shown in Figure 12, the processor of the IPG disclosed herein may be delivering stimulation to a first lead on a first lateral side in a first mode, e.g., a background stimulation level of a certain frequency, at step 1202. The system may sense one or more signals on a second lateral side, opposite the first side, at step 1204. The sensing can include receiving one or more biopotential signals, e.g. EMG signals. The sensing may be performed by one or more electrodes on a lead implanted in the second side. Although the delivering step 1202 and sensing step 1204 are presented sequentially in the flow chart, the sensing may be occurring concurrently with the delivery of stimulation to the first lead. In some cases, the electrical stimulation may be delivered continuously while sensing is performed intermittently. In some cases, sensing may be performed continuously while stimulation is performed intermittently. In some cases, both sensing and stimulation are performed intermittently. In some cases, both sensing and stimulation are performed continuously, such that they are concurrent. The system may determine a biopotential breakthrough signature, at step 1206. The system may deliver stimulation to the first lead on the first side in a second mode, e.g., a higher level of stimulation, at step 1208. In some cases, the sensing of step 1204 may be performed continuously through step 1208. Advantageously, the system may be able to concurrently stimulate at ahigher level on one side of the patient and sense on the other side of the patient to reduce contamination of the sensed signals and avoid reentrant loops.

[0265] The bilateral placement of electrode leads may allow for alternating stimulation of both lateral sides of the patient. The alternating bilateral stimulation may be non-overlapping, such that both sides of the patient are never stimulated at the same time. In some cases, the alternating bilateral stimulation may be at least partially overlapping, such that both sides of the patient are stimulated at the same time for a portion of the stimulation period, but not the entire stimulation period. In some cases, the alternating bilateral stimulation may apply to adaptive stimulation, as described elsewhere in the present disclosure. For example, when both sides of the patient are in a background stimulation level, the triggering of a higher level of stimulation from the background level of stimulation may alternate between each side of the patient. In some embodiments, the bilateral placement of electrode leads may allow for cycling of a higher or enhanced level of stimulation on one side of the patient at pre-determined time intervals. For example, the one side of the patient may have an electrode lead cycling between a higher or enhanced level of stimulation and a background level and / or no stimulation every two minutes, while the other side of the patient may have an electrode lead delivering a constant background level of stimulation. The cycling of a higher or enhanced level of stimulation may alternate between bilateral leads on each side of the patient. The alternating stimulation between bilateral leads, as described herein with respect to adaptive stimulation, cycling, etc., may occur at pre-determined time intervals, e.g., every 30 minutes.

[0266] The alternating bilateral stimulation may comprise delivering stimulation to each side with a phase difference. In some cases, constant stimulation of tissue may cause habituation, which may refer to a decreased response due to the tissue becoming used to the repeated stimulation. In some cases, constant stimulation of tissue may cause fatigue, which may refer to a decreased response due to physical exhaustion of the tissue. For example, the pelvic floor muscle may experience fatigue after being stimulated for long periods of time. In some cases, constant stimulation of tissue may cause habituation and / or fatigue. Thus, the bilateral stimulation may comprise delivering stimulation to each lateral side with a phase difference to avoid habituation and / or fatigue. In some embodiments implementing adaptive stimulation, the higher level of stimulation may be activated on each side of the patient with a phase difference. The higher level of stimulation on each side may be at least partially overlapping so that at least one side of the patient is always under the higher level of stimulation.

[0267] In some embodiments, the bilateral placement of leads may allow for bioelectrical sensing across two leads on either side of the patient. In most cases, the physiological events of interest, e.g., muscle contractions, will happen bilaterally in a patient. For example, a pelvic squeeze or a cough may result in muscle contractions in the pelvic floor occurring bilaterally. On the other hand, a response to stimulation, e.g., a contraction, may be greater on an ipsilateral side than a contralateral side. Thus, in some cases, sensing across bilateral leads may allow the system to more accurately distinguish the sensed signals corresponding to physiological events of interest versus contaminated signals due to stimulation, thereby reducing the occurrence of re-entrant loops. The sensing across bilateral leads may also provide a broad field of sensing to achieve an optimal stimulation configuration. In some cases, simultaneous sensing on both lateral sides may reduce the occurrence of re-entrant loops, by allowing the system to distinguish between physiological events of interest and responses from stimulation.

[0268] Figure 13 illustrates an example titrating process performed by the processor of the IPG. At step 1302, the processor may deliver bilateral stimulation to a first lead and a second lead at a first parameter value. The second lead may be contralateral to the first lead. In some implementations, the first parameter may be a default parameter for all patients. In some instances, the first parameter may be a default frequency value. For example, the default frequency value may be 10 Hz, 11 Hz, 12 Hz, 13 Hz, 14 Hz, 15 Hz, 16 Hz, 17 Hz, or 18 Hz.

[0269] At step 1304, the processor may receive data from one or more sensing electrodes on each of the first lead and the second lead. The data may include a bioelectrical signal indicative of the patient response to the stimulation current at the first parameter value. In one example, the bioelectrical signal may include an EMG signal. At step 1308, the processor may adjust the parameter from the first parameter value to a new parameter meter. For example, the parameter value may be lowered in response to more innervation being detected at step 1304, or be increased in response to insufficient innervation being detected. The processor may separately adjust the stimulation parameter on each of the first and the second lead based on the sensing data collected from one or both of the sides.

[0270] In another example, the processor of the IPG may optionally receive input from an external controller at step 1306. The input may include patient medical history and / or responses to patient questionnaire that may be used to characterize whether the patient, who may be an MUI patient, is urge or stress predominant. In response to an appropriate innervation being detected, the processor may maintain the first or default parameter value as the patient-specific parameter value. In response to the patient being urge predominant and a higher level of innervation being detected at the first or default parameter value, the processor may decrease the parameter level in small increments based on the data from the one or more sensing electrodes until the appropriate innervation is detected. In response to the patient being stress predominant and an insufficient level of innervation being detected at the first or default parameter value, the processor may increase the parameter level in small increments based on the data from the one or more sensing electrodes until the appropriate innervation is detected. In some implementations, the processor may optionally transmit the patient specific parameter value to the external controller at step 1310.

[0271] The external controller may include the patient controller (such as the controller 110 of Figure 1 A or 1 B), or any device on which a software of the neuromodulation system disclosed herein may be run (for example, a computer, a tablet, a smartphone, watch or other wearable, etc.).

[0272] In several embodiments, any one or more of the feedforward patient engagement, feedback, neural retraining, or tissue strengthening, time-dependent programming, adaptive stimulation with flexible sensor input(s) selections for determining breakthrough signatures, personalized thresholds, additional patient safety and / or comfort features, or combinations thereof as described herein, and in PCT Application No. CCXXXX / XXX.XXX [Attorney Docket No. AMBTX.041WO] titled "TIME-DEPENDENT ADAPTIVE NEUROMODULATION SYSTEM,” filed on the same day as the present application, which is hereby incorporated by reference in its entirety, can be used with the bilateral stimulation and sensing disclosed herein.Trained Classifiers for Adaptive Stimulation

[0273] In some embodiments, the thresholds for entering the higher level of stimulation from the background level may be patient specific or personalized. For example, one person's tapping may result in a different reading from the motion sensor than another person's tapping. As another example, the EMG signal from one person squeezing the pelvic floor or other muscles may be different from another person squeezing the same muscles.

[0274] In some implementations, the threshold for what is considered the patient movement and / or posture that may trigger the higher level may be determined by asking patient to perform the different types of breakthrough signatures described herein after the IPG and the lead(s) have been implanted in the patient. Patientspecific data including but not limited to readings from the sensors disclosed herein (including but not limited to the motion or posture sensor and the bioelectrical sensor) as the patient is performing those breakthrough signatures may be recorded. The appropriate threshold for a particular patient performing a particular breakthrough signature may be determined based on the readings collected. In some embodiments, the sensor readings may be analyzed in the time domain and / or the frequency domain to identify features in the sensor readings that may be indicative of the particular breakthrough signature performed by the patient. The features may include time-domain features, frequency domain features, statistical features, and any combinations thereof. The patient-specific data may include readings from sensors as the patient performs daily activities to provide examples of background signals that do not warrant the higher level of stimulation.

[0275] In some instances, a classifier may be trained with the collected readings to improve accuracy in detection of the breakthrough signature, as described elsewhere in the present disclosure. The classifiers may include an inertial classifier based on motion and / or posture data, or a biopotential classifier based on bioelectrical signal data. In some cases, the classifier may automatically output recommendations of an adaptive profile configuration based on the sensor data. In some embodiments, the classifiers can be optimized using a machine learning algorithm. In one example, the process implemented by the machine learning algorithm may include Bayesian Optimization to search the classifier space and look to optimize it against a cost function (e.g., F-1 score for classifier versus power required).

[0276] In some cases, the classifiers, such as the inertial classifier and the biopotential classifier, may include machine learning classifiers. One or more machine learning algorithms may be used to construct the machine learning and / or artificial intelligence model, such as support vector machines. For example, machine learning and / or artificial intelligence algorithms or other statistical algorithms may be used such as alternating decision trees (ADTree), decision stumps, functional trees (FT), logistic model trees (LMT), logistic regression, random forests (if), receiver operational characteristic curves (ROC), linear regression, extreme gradient boosting (xgb), classification and regression trees, support vector machines (SVM), generalized additive model using splines (e.g., gamSpline), glmnet, multivariate adaptive regression splint (earth), neural network, k-means clustering, or any other suitable machine learning algorithm or statistical algorithm. One or more algorithms may be used together to generate an ensemble method, wherein the ensemble method may be optimized using a machine learning ensemble meta-algorithm such as boosting (e.g., AdaBoost, LPBoost, TotalBoost, BrownBoost, MadaBoost, LogitBoost, etc.) to reduce bias and / or variance.

[0277] In some embodiments, the machine learning and / or artificial intelligence algorithm may include a constrained machine learning and / or artificial intelligence algorithm configured to run on microprocessors. In some cases, the machine learning and / or artificial intelligence algorithm may operate within a Tiny ML framework. In some instances, the machine learning and / or artificial intelligence algorithm may be trained offline. The offline training may be completed on a server, cloud, or other dedicated computing clusters. In some cases, the trained machine learningand / or artificial intelligence algorithm may then be downloaded, deployed, and / or imported into the IPG to iteratively improve upon the IPG and system performance, for example, in preventing incontinent events.

[0278] In some cases, the one or more machine learning and / or artificial intelligence models may be trained on raw and / or processed signals measured by the IPG, sensors, and systems disclosed herein. In some cases, the processed signals may include original raw signals that have been filtered to optimize the signal -to-noise ratio of the raw signal. In some cases, the filter may include a high-pass, low-pass, band-pass, notch, or any combination thereof filters. In some instances, the one or more machine learning and / or artificial intelligence models may alternatively, or in addition to, be trained on user feedback regarding whether or not the stimulation parameters prevented an incontinent event, and / or whether such parameters caused any discomfort. In some embodiments, the filters may be adjusted to save power. In some embodiments, the classifiers may be adjusted to save power. In one example, the use of a simpler classifier structure may double the battery lifetime.

[0279] Figure 14 illustrates an example process for building a machine learning classifier for adaptive stimulation. At step 1402, the system may provide labelled patient-specific data for training the classifier. The patientspecific data may include readings from the sensors disclosed herein (including but not limited to the motion or posture sensor, e.g., accelerometer, and the bioelectrical sensor, e.g., EMG sensing electrodes). The labelled data may be used to train an inertial classifier or a biopotential classifier, as described elsewhere in the present disclosure. For example, the patient may be asked to perform various activities, e.g., walking, running, coughing, squatting, etc. In some implementations, the daily activities of the patient may be recorded, and patient-specific data may be gathered continuously while the patient performs the activities throughout the day. The data may be labelled based on the activity that was being performed while it was collected. In some implementations, the data may be labelled by whether a stress event actually occurred during the activity, e.g., observing if any leakage occurred. In some implementations, the data may be labelled by whether pain or sexual dysfunction occurred. In some implementations, the data may be labelled by whether or not a higher level should be triggered, e.g., based on likelihood of an activity causing a stress event. For example, data collected while the patient is coughing or squatting may be labelled as requiring a higher level of stimulation. In another example, data collected while the patient stands up, sits down, or is gently walking may be labelled as not requiring a higher level of stimulation. The labelling process may be performed using patient or clinician input. For example, the patient may decide that they do not want stimulation to be triggered during a certain activity.

[0280] At step 1404, the classifier may be trained using the labelled patient-specific data. The classifier may be trained using machine learning optimization routines for one or more relevant metrics. An objective function may be specified with desired attributes for optimizing the classifier. For example, the objective function may be based on improving on one or more classification metrics, such as classification area under the curve (AUG), F-1 score, F-2 score, sensitivity, specificity, or some combination thereof, etc. In some cases, a cost may be associated with the optimization, such as the power utilization or some other downside associated with the desired attributes. The machine learning algorithm(s) may be designed and trained to optimize the specified objective function.

[0281] In some implementations, the classifier may use autocorrelation. Autocorrelation may refer to the analysis of time-dependent data to measure the correlation of a signal with a time delayed version of the signal. Autocorrelation may be used to determine repeating patterns or periodic components in a signal. The classifier mayuse autocorrelation of bioelectrical signals to more readily distinguish a breakthrough signature, e.g., muscle activity, from transient artifacts.

[0282] In some implementations, the classifier may use pattern matching. Pattern matching may include directing the patient to perform certain tasks in a clinic and extracting envelopes from the collected data. The envelopes may have a specific pattern corresponding to the activity performed by the patient, which may be used for pattern detection by the classifier.

[0283] In some implementations, the classifier may optionally be biased based on one or more patientspecific objectives, at step 1406. In some cases, the system may be programmed to assign a specified bias point on the receiver operating characteristic (ROC) curve of the classifier. The ROC curve plots the true positive rate (TPR) against the false positive rate (FPR) at each threshold setting. The bias point may represent a selected threshold for the classifier to decide when to trigger a higher level of stimulation. In some cases, the patient may want to bias the classifier in a different way to either accept more false positives (FP) or accept more false negatives (F N) . For example, the patient may prefer to accept more false positives, i.e., a higher FPR, to make sure that the higher level of stimulation is triggered at all necessary times, e.g., during a stress event, to ensure that no leakage occurs. Thus, in this example, the bias point in the ROC curve may be moved to the right, such that the classifier increasingly accepts false positives and penalizes false negatives. In an alternative example, the patient may prefer to accept more false negatives, i.e. a lower TPR, because they may not like the sensation of the boosted stimulation. Thus, in this example, the bias point in the ROC curve may be moved to the left, such that the classifier increasingly penalizes false positives and accepts false negatives.

[0284] The bias point of the classifier may be an adjustable parameter, either automatically or by manual control. In some implementations, the bias point of the classifier may be automatically adjusted based on the time of day. For example, the patient may want the classifier to accept more false negatives at nighttime when they are at home and able to deal with a leakage event and reduce discomfort while sleeping. In another non-limiting example, the patient may want the classifier to accept more false positives over false negatives during the daytime in order to ensure that they do not experience a leakage event in a public setting, even if they have to deal with the discomfort of the stimulation. However, in some cases, the patient may want the classifier to accept more false positives at night and accept more false negatives in the day. In some cases, the classifier may be biased differently throughout the day, e.g., by the hour, based on the patient's specific daily schedule and preferences.

[0285] In some implementations, the classifier may use an algorithm using a dual threshold and / or timing threshold. The classifier may be selective of specific activities of interest performed by the patient, e.g., a squeeze, a cough, etc., while avoiding other activities, e.g., light walking, standing, etc. The activities of interest and not of interest may vary between specific patients and classifiers. Since the raw data collected by the motion / posture sensor and / or the biopotential sensors may have a large bandwidth, differentiating between the data from different activities based only on frequency may be difficult, as a frequency content of different activities may be similar. Similarly, using only a single lower threshold for power for activity detection may cause the classifier to respond to some activities with high power signals, which the patient may not be interested in. For example, walking may result in high power signals with shorter duration, and squeezing may result in lower power signals with longer duration. To distinguish between these activities, the classifier may use a dual threshold, e.g., a first, lower threshold and a second, higherthreshold. In some cases, the classifier may additionally, or alternatively, use a timing threshold, which may be set to a minimum value for detecting an activity of interest while being longer than transient signals or signals from activities not of interest (e.g., walking). The first, lower threshold may be set to the minimum level for detecting a signal of interest (e.g., from a squeeze). The second, upper threshold may be set to the maximum level for detecting the signal of interest. The first and second thresholds and / or the time threshold may be set manually, or automatically (e.g., using machine learning and / or artificial intelligence), based on patient-specific data and / or the activities of interest. Figure 17 illustrates an example of signal detection from walking, squeezing, and squeezing while walking, respectively, using a dual threshold algorithm, according to embodiments. The raw data may be filtered to extract an envelope. As shown in Figure 17, the signals from squeezing may be between the upper and lower threshold for longer than the time threshold (e.g., 300 samples), such that a different level of stimulation is activated. On the other hand, as shown in Figure 17, the signals from walking may be rejected by the dual threshold algorithm and a different level of stimulation may not be activated.

[0286] In some implementations, the inertial classifier and / or the biopotential classifier may be configured using a software program. The software program may comprise a configuration assistant for a clinician to build a patient-specific classifier. The patient-specific classifier may use patient-specific thresholds for sensor data, e.g., accelerometer data or EMG signals, that will activate a different mode of stimulation. For example, in the case of a biopotential classifier, the goal of the configuration assistant may be to create a patient-specific classifier to activate a different stimulation mode after a volitional pelvis floor contraction. The clinician may direct the patient to follow certain directions prompted by the configuration assistant, e.g., on a display device. For example, in the case of a biopotential classifier, the configuration assistant may prompt the patient to perform a sequence of pelvic floor squeezes, e.g., squeeze in 3 seconds, relax, squeeze again, etc. In the example of configuring a biopotential classifier, the clinician may first identify the optimal sensing electrodes by streaming raw data, asking the patient to perform a task such as a squeeze, and identifying a bipolar electrode pair with the greatest signal-to-noise ratio. In some cases, the system may automatically determine the optimal sensing electrodes using machine learning and / or artificial intelligence algorithms.

[0287] Motion / posture sensors and / or bioelectrical sensors may collect data as the patient performs the prompted tasks, and the configuration assistant may automatically label the data. There may be separate configuration assistants for different classifiers, e.g., an inertial classifier or a biopotential classifier, with each configuration assistant having different prompted tasks for the patients to perform. The patient may be able to see the collected data displayed on a display device, e.g., a screen. The patient visualization of the data may allow for better data collection during the configuration process, as a patient may be able to observe how their activities are registered by the sensors, and may be able to adjust or correct how they are performing the tasks accordingly. For example, the patient may be directed to perform multiple squeezes in different positions, e.g., 3-5 squeezes while sitting and / or standing, with a relaxing period in between each squeeze, or to walk for a certain amount of time, e.g., 15 seconds. Once the data are collected and labelled, the configuration assistant may use a machine learning and / or artificial intelligence algorithm, e.g., Bayesian Optimization, to optimize one or more fine-tune parameters for filtering the raw signal data for classification. For example, the one or more parameters may include amplitude and / or smoothing of the data. The machine learning and / or artificial intelligence algorithm may determine and set a threshold for activating a different level, or mode, of stimulation. In some cases, the clinician may adjust the threshold manually, e.g., using aslider in the software program, to fine-tune the classifier based on their observations and / or the patient's preferences. The configuration assistant may be personalized between patients, for example, by asking the patient to perform a different set of tasks depending on which activities are more likely to result in incontinence events for that specific patient. For example, a patient may fill out a survey for understanding which activities specifically lead to incontinence events prior to undergoing the configuration assistant process and the configuration assistant may be adjusted accordingly.

[0288] In some implementations, the classifier may be trained using patient-specific data collected from a loop recorder. The patient may be implanted with a loop recorder for extended monitoring of biopotential signals in the patient, e.g., in a pelvic region of the patient. The loop recorder may collect data from a patient as the patient goes through their regular life performing daily activities. The loop recorder may assist with collection of patient-specific data and labelling the data for training a classifier. For example, the patient may be directed to provide a user input, e.g., a tap or sequence of taps, to the system whenever experiencing symptoms of an incontinence event. The user inputs may be used to label the data from the loop recorder, and the labelled data may be used for training the classifier, as described elsewhere herein.

[0289] In some implementations, a threshold classifier score may be determined for the stimulation therapy. The threshold classifier score may be a prerequisite to implementing the trained classifier into the adaptive stimulation described herein. For example, if the classifier is trained with the patient-specific data but the classifier scores lower than the specified minimally acceptable classifier score, then the system may be instructed to no longer use the classifier for adaptive stimulation. In some cases, a trained biopotential classifier may fail to achieve the minimally acceptable classifier score because the data from sensed signals may be contaminated by too many artifacts or because a signal characteristic adequately differentiating the data could not be identified.

[0290] Figure 15 illustrates an example programming flow for switching input modes using trained classifiers of the neuromodulation system disclosed herein. In some embodiments, the system may be programmed to start in a first input mode of the highest complexity, e.g., a bioelectrical input mode. At step 1502, the system may provide a trained classifier for a first input mode. At step 1504, the system may evaluate the trained classifier based on a threshold classifier score. For example, the threshold classifier score may comprise an F-1 score, F-2 score, or an AUG. The system may evaluate the trained classifier by comparing a score of the classifier to the threshold classifier score. In some cases, the trained classifier may meet the threshold classifier score if a score of the classifier exceeds the threshold classifier score. In some embodiments, the trained classifier may meet the threshold classifier score if a score of the classifier is lower than the threshold classifier score. In some embodiments, the trained classifier may meet the threshold classifier score if a score of the classifier is the same as the threshold classifier score. In some implementations, evaluating the classifier may optionally comprise retraining and reevaluating the classifier one or more times. If the threshold classifier score cannot be met in a certain input mode, the system may default to a input mode of a lower complexity. If the threshold classifier score is met, the system may implement the trained classifier in the first input mode, at step 1506. If the threshold classifier score is not met, then the system may be programmed to disable the first input mode feature and move to a second input mode, at step 1508. The second input mode may be of a lower complexity than the first input mode. For example, the system may be programmed to disable the bioelectrical sensing input mode and switch to an inertial input mode, such as a tap and / or accelerometer mode. In some cases, atrained classifier of the second input mode may optionally be evaluated and switched using the same process. For example, if the classifier for the second input mode (e.g., inertial) fails, the system may default to a third input mode of even lower complexity, such as pre-programmed scheduled stimulation or manual activation. In some implementations, the system may be programmed to start in a first input mode of lower complexity, e.g., an inertial input mode using a motion / posture sensor, and move to a second and / or third input mode of higher complexity, e.g., a bioelectrical input mode. In some embodiments, the inertial input mode may be of a higher complexity than a bioelectrical input mode.

[0291] The thresholds for the classifier determining when to enter and / or exit a higher level of stimulation may be adjustable, as described elsewhere in the present disclosure. In some embodiments, the system may provide a patient control feature for allowing the patient to adjust a threshold. The threshold may be adjusted for either of a motion adaptive or sense adaptive profile. For example, if a patient experiences that the system triggers the higher level of stimulation too often for their preference, the patient may increase the threshold required to activate the higher level of stimulation. Thus, the patient may be able to fine tune the sensitivity of the machine learning algorithm based on their experience and preferences. The patient may be able to adjust a sensitivity threshold in the clinic, via telehealth, or otherwise remotely, e.g., at home. In some embodiments, a patient may be able to provide a user input detectable by a sensor, e.g., a motion / posture sensor and / or a bioelectrical sensor, to disable an input mode. For example, the patient may be able to perform specific sequence of taps, or any other action, in order to enable and / or disable a specific input mode.

[0292] In some implementations, the threshold for determining a breakthrough signature for any given classifier may be manually set by the clinician. The clinician may observe readings from the sensors disclosed herein (including but not limited to the motion or posture sensor and the bioelectrical sensor) while asking patient to perform the different types of breakthrough signatures described herein. The clinician may then determine an appropriate threshold based on the observations. For example, the clinician may manually operate a slider for setting a threshold for a particular patient performing a particular breakthrough signature based on the collected readings. The clinician may adjust the threshold using the slider in an iterative process to determine an appropriate threshold for detecting a specific breakthrough signature.

[0293] In some implementations, the system may be able to automatically select the best electrodes for stimulation and the optimal stimulation parameters for said electrodes through evoked responses, as described elsewhere herein. In some implementations, the purposeful generation of evoked responses, e.g., for therapy and / or for automated electrode stimulation configuration, may interfere with the ability of the biopotential classifier to determine a breakthrough signature, as disclosed elsewhere herein. This may be because the evoked responses have a frequency that overlaps the biopotential signal frequency, or because some evoked responses can have a relatively large amplitude. The biopotential classifier may not be able to filter evoked responses from the biopotential signal data, which may cause the system to become locked at a higher level of stimulation. In some cases, to solve this issue, the system may perform a sample and hold method. The system may have an accurate timing of when stimulation is being delivered. Based on the timing, the system may take a biopotential signal data sample prior to stimulation and hold the signal data at the sampled value for a set duration of time after the stimulation is delivered. The sample and hold method may allow for the biopotential classifier to ignore the evoked responses and avoid a self-triggering scenario.Figures 16A and 16B illustrate example artifact-filled signals from evoked responses 1602 and the corresponding signal envelopes before and after using a sample-and-hold method, according to embodiments.Incontinence

[0294] Described herein are devices, systems, and methods to prevent, treat, or otherwise ameliorate an episode of incontinence in an individual in need thereof by providing electrical stimulation, such as neurostimulation. The episode of incontinence may include urinary incontinence, fecal incontinence, or any combination thereof. The devices, systems and methods disclosed herein may treat a sub-type of incontinence. The sub-type of incontinence may include urge incontinence, stress incontinence, overflow incontinence, or mixed incontinence.

[0295] Urinary incontinence may be categorized into one of four main types: urge incontinence, stress incontinence, overflow incontinence, and mixed incontinence. Urge incontinence is often due to an overactive bladder (OAB). Individuals with urge incontinence have a strong and sudden need to urinate immediately, often leaving them with insufficient time to reach a bathroom. Stress urinary incontinence (SUI) is usually due to a poorly functioning urethral sphincter muscle or hypermobility of the urethra or bladder neck. An individual may experience stress incontinence during activities such as coughing, sneezing, laughing, lifting, or exercise. Overflow incontinence may typically be due to poor bladder contraction or blockage of the urethra. Mixed urinary incontinence (MUI) may involve features of stress and urge incontinence. Incontinence often involves neurological issues, including but not limited to impaired nerve conduction between the brain and / or the affected muscles, and nervous system conditions or injuries (e.g., multiple sclerosis or stroke), or mental confusion. Other causes of incontinence include but are not limited to weakness of pelvic or urethral muscles and pelvic prolapse.

[0296] Fecal incontinence, also referred to as bowel incontinence, is the loss of bowel control, causing an individual to pass stool unexpectedly from the rectum. Fecal incontinence is usually categorized into three main types: urge incontinence, passive incontinence and post-defecatory leakage (or a combination thereof). Individuals with urge incontinence have a strong and sudden need to defecate immediately, often leaving them with insufficient time to reach a bathroom. Passive fecal incontinence is when an individual passes feces without conscious awareness. Individuals suffering from passive incontinence have poor conscious control of their bowel movements and stool can pass without their knowledge. Post-defecatory leakage typically occurs due to incomplete evacuation of stool leaving residual stool to leak through a compromised sphincter mechanism. Incontinence often involves neurological issues, including but not limited to impaired nerve conduction between the brain and / or the affected muscles, and nervous system conditions or injuries (e.g., multiple sclerosis or stroke), or mental confusion. Causes of fecal incontinence include but are not limited to nerve damage, anal sphincter muscle damage, obstructed defecation, constipation, diarrhea, surgery, loss of rectum storage capacity, rectal prolapse, and rectocele.

[0297] Electrical stimulation of muscles may be used to treat incontinence by training the pelvic floor muscles thereby improving strength and function of the muscle to control over urination and defecation. In some cases, electrical stimulation may target the sacral nerve (or tissue adjacent to the nerve) to improve control over urination and defecation. In some cases, the electrical stimulation approaches may benefit from stimulation of an alternate target, such as the pudendal nerve.

[0298] Existing electrical stimulation approaches may be capable of delivering only a predetermined stimulation protocol and may not be able to adapt to the condition and circumstances of the individual during a particularepisode of incontinence. This may result in overstimulation or under stimulation of the target tissue (e.g., nerve and / or tissue adjacent to the nerve), resulting in inadequate control over muscles involved in urination or bowel movements. Usually, traditional approaches to treating incontinence may not be able to mimic sufficiently an innate human response (e.g., reflex) to prevent an incontinence episode and may be insufficient. Individuals who have an incontinence episode may experience insufficient preventative response. The preventative response may include a muscle contraction of at least one pelvic floor muscle to prevent a leakage event in response to an increased intra-abdominal pressure. Individuals who experience stress incontinence may exhibit a delayed response in preventing an incontinence episode in response to a stress event. In some cases, individuals may experience stress incontinence related to urethral hypermobility (e.g., insufficient support) that may lead to an increased pressure transmitted to the bladder and subsequently an incontinence event.

[0299] A lack of voluntary control over micturition, defecation, incontinence, or any combination thereof is a problem that can impact quality of life and cause social embarrassment. Urinary and fecal incontinence may affect individuals of all ages. Usually, older individuals may exhibit a greater probability of incontinence with varied pathophysiology. Urinary incontinence, or loss of bladder control, and fecal incontinence, loss of control of bowel movements, often relate to neurological issues. Both urinary incontinence and fecal incontinence may involve injury, weakness, or overactivity of the pelvic floor muscles, including but not limited to the urethral and anal sphincter, and the nerves that innervate these muscles and involved organs, such as the bladder, rectum, or anus.

[0300] To treat or reduce symptoms of incontinence, electrical stimulation of the muscle, sacral nerve, and / or other pelvic nerves (e.g., the pudendal nerve) involved in incontinence has been used to improve control over micturition and bowel movements targeting the pudendal nerve, provides an improved approach to treating incontinence. Often, the pudendal nerve contributes to motor functions and mediating volitional contraction of the urethral and anal sphincter muscles in the preservation of continence. Targeting of the pudendal nerve (or tissue adjacent to the pudendal nerve) may be combined with a closed-loop capability in some cases with time-dependent and / or dynamic adaptive control to provide a more effective treatment for incontinence. In some cases, individuals may control stimulation by a pelvic squeeze, wherein receiving a threshold EMG signal from the pelvic floor may activate electrical stimulation.

[0301] Current electrical stimulation therapies may include sacral neuromodulation (SNM) that may provide fixed patterns of stimulation to treat "urge” (the sudden need to urinate), but such stimulation may be unable to respond to the more common "stress” incontinent events, such as coughing, sneezing, and lifting. While SNM may reduce the frequency of incontinence episodes, the success of SNM may be limited in scope {e.g., not a cure) and may decrease over time. Furthermore, SNM may not be suitable to treat individuals having stress incontinence or mixed urinary incontinence (with stress and urge incontinence). SNM may have high long-term costs in management of the electrical stimulation device and may require high level of skill and precision from the surgeon to place the lead on the sacral nerve. As such, targeting another nerve (such as the pudendal nerve as described herein), may provide an improved approach to treating incontinence.

[0302] Pudendal nerve stimulation may provide a more effective treatment for individuals having incontinence than SNM. In some cases, pudendal nerve stimulation may be an effective treatment for incontinence in individuals where SNM has failed. PNS may be more powerful than SNM because the pudendal nerve enters the spinalcord through S2, S3, and S4, while SNM only acts upon the S3 root. Pudendal nerve stimulation may provide an effective treatment for urinary incontinence. In some cases, the pudendal nerve may be an effective continence target for closed loop stimulation. The neuromodulation system disclosed herein may address the problems of existing electrical stimulation therapies disclosed herein and / or other problems. In some embodiments, severe refractory urge incontinence is treated, which involves involuntary urine leakage resulting from a sudden and strong urge to urinate, which is considered refractory when there is no response to behavioral therapies or at least two medications.

[0303] Electrical stimulation as described herein may be used to treat incontinence instead of, or combined with, a pharmaceutical therapy. In several embodiments, a reduced drug dosage may be needed when combined with stimulation, thus reducing the side effects associated with a higher drug dose. Thus, the synergies of the combined approach may reduce reliance on medication, which in turn can reduce certain undesired side effects (including but not limited to dry mouth, dry eyes, constipation, cognitive side effects, etc.). In some embodiments, electrical stimulation as described herein is used with muscarinic receptor antagonists. In some embodiments, electrical stimulation as described herein is used with an anticholinergic drug. In some embodiments, electrical stimulation as described herein is used with one or more of fesoterodine, mirabegron, oxybutynin, solifenacin, tolterodine, trospium, and similar compounds. In some embodiments, electrical stimulation as described herein is used with botulinum toxin, hormones (such as estrogen), tricyclics, serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. By reducing side effects of drugs (e.g., with reduced dosages), drugs may be tolerated for a longer period of time and / or patient compliance may increase. In some embodiments, the combined use of electrical stimulation with pharmacologic therapy has synergistic effects. Electrical stimulation and drugs may both affect the acetylcholine pathway with beneficial, synergistic results according to several embodiments. For example, a drug may block muscarinic receptors while the stimulation may modulate neurotransmission, thus working together in a cooperative manner.

[0304] In several embodiments, kits are provided that comprise the generators and devices described herein, and optionally include battery charging devices and instructions for use.Pain Control

[0305] The devices, systems, methods, and / or kits, described elsewhere herein, may treat pain in the pelvic region. Chronic pelvic pain (CPP) can impact quality of life, often causing episodes of severe discomfort and exacerbating pain. Common symptoms of CPP include but are not limited to neuropathic symptoms like paresthesia, numbness, burning, lancinating pain, in the pelvic, anus and / or genitals. Episodes of pain associated with CPP may frequently occur with sitting, urinating, defecating, or sexual intercourse and may be exacerbated with these activities. Approaches to treat CPP by electrically stimulating a large section of the affected area (e.g., pelvic area) or transcutaneously may have limited success at alleviating the symptoms of pain. As such, targeting specific nerves for electrical stimulation that is adapted to the individual's pain response may provide a highly efficacious treatment for CPP and other pain symptoms.

[0306] Many electrical nerve stimulation approaches currently used deliver a preset stimulation protocol (e.g., open-loop configuration) and usually are not able to adapt to the changing parameters of pain experienced by the individual. Pudendal nerve stimulation may provide an effective treatment for chronic pain. In some cases, the inability to adapt the stimulation can result in overstimulating or under stimulating the target area and lead to inefficient or inadequate pain management. Moreover, because treatments usually do not adapt to the changing parameters ofpain, existing pain management often requires patient-actuation during bouts of exacerbating pain to provide pain relief. Therefore, it would be highly beneficial to provide electrical stimulation to peripheral nerve targets that adapt to innate feedback from the subject as conditions change (e.g., a closed-loop configuration). The time-dependent adaptive stimulation provided by the neuromodulation system disclosed herein may address the problems of existing electrical stimulation therapies for pain control and / or other problems. The patient can activate the electrical stimulation mode when needed using the system disclosed herein.

[0307] The systems, methods, and devices, described herein are directed to treating episodes of pain associated with chronic pelvic pain (CPP) or other conditions resulting in pelvic pain using peripheral nerve stimulation. In some embodiments, the systems, methods, and devices, comprise a closed-loop configuration. In some embodiments, adapted stimulation to the target nerves are provided by an implanted stimulator with an underlying physiological rationale comprising: (a) stimulating motor fibers to alter end organ muscle activity where peripheral pain is driven by spasm and / or hypertonicity (e.g., pelvic floor myalgia, some cases of bladder pain syndrome, and urethral pain associated with motor modulation); (b) stimulating larger diameter afferent fibers to modulate spinal gating of nociceptive signaling from peripheral foci of pain generation (e.g., interstitial cystitis, coccygodynia, and pelvic myalgia); (c) blocking nerve conduction (e.g., anodal block, in pudendal neuralgia (pudendal nerve entrapment)) to (I) directly block disease-related peripherally driven pain, and (ii) block noxious effects associated with providing the adapted stimulation, which facilitates higher charge delivery for therapeutic benefit; and any combination thereof.

[0308] Described herein are targeting one or more peripheral nerves based on the etiology of the pain condition with adapted electrical stimulation to reduce pain experienced by an individual. The stimulator electrodes may target different nerves (e.g., a first stimulator targeting a sacral nerve and a second stimulator targeting a pudendal nerve). In some embodiments, stimulating multiple nerves within the pelvic area may broaden the field of treatment in pain syndromes having diffuse areas of pain. In some embodiments, targeting the sacral nerve may stimulate or modulate the autonomic nervous system that contributes to the pain. In some embodiments, the electrical stimulation may be adapted to provide blocking and stimulation of electrical nerve signals on the same nerve. In some embodiments, stimulator electrodes may target one or more locations along a single nerve. Targeting multiple points along a single nerve may allow for improved control in the closed-loop modulation (e.g., a first stimulator implanted at or adjacent to a first anatomical site of a pudendal nerve and a second stimulator implanted at or adjacent to a second anatomical site of the pudendal nerve). In some embodiments, targeting a single nerve at multiple sites may permit both blocking and stimulation on the same nerve. In some embodiments, one, two or three branches of the pudendal nerve are stimulated. When two or more branches are stimulated, they may be stimulated simultaneously or in sequence. The same stimulation parameters may be used for two or more branches, or different stimulation parameters may be used.

[0309] In some embodiments, pudendal neuralgia, such as pudendal nerve entrapment, is treated using the electrical stimulation described herein. Use of a first stimulation level at or near the pudendal nerve with or without another stimulation level is used for such treatment in some embodiments. When additional modes are used, a patient may be able to activate a higher frequency, amplitude and / or pulse width or otherwise boost stimulation at, for example, the onset of pain and / or when the patient is about to engage in an activity that would otherwise likely cause pain.

[0310] Electrical stimulation as described herein may be used for pain in lieu of, or combined with, a pharmaceutical therapy. In several embodiments, a reduced drug dosage may be needed when combined with stimulation, thus reducing the side effects associated with a higher drug dose. Thus, the synergies of the combined approach may reduce reliance on pain medication, which in turn can reduce undesired side effects of opioids and other drugs (e.g., Gl issues, bleeding, constipation, addiction, etc.). By reducing side effects of drugs (e.g., with reduced dosages), drugs may be tolerated for a longer period of time and / or patient compliance may increase.Sexual Dysfunction

[0311] The devices, systems, methods, and / or kits, described elsewhere herein, may treat sexual dysfunction of a subject. Sexual dysfunction can impact quality of life and may prevent a person from experiencing satisfaction from a sexual activity. Generally, sexual dysfunction may be classified as a desire disorder (lack of sexual desire or interest in sex), an arousal disorder (inability to become physically aroused or excited during sexual activity, an orgasm disorder (delay or absence of orgasm), or a pain disorder (pain during intercourse), or a combination of these disorders. Sexual dysfunction may involve physical and psychological causes. Although sexual dysfunction may be treated using medication, a mechanical aid, psychotherapy, and behavioral treatments, such treatments may have undesired side effects, suffer from patient non-compliance, or are ineffective. For example, sexual dysfunction with a physical cause may be treated more effectively using several embodiments described herein.

[0312] A number of symptoms are associated with sexual dysfunction. In both men and women, symptoms of sexual dysfunction include but are not limited to a lack of interest in or desire for sex, inability to become aroused, and pain with intercourse. In women, some symptoms associated with sexual dysfunction include but are not limited to inability to achieve orgasm, inadequate vaginal lubrication before and during intercourse, and inability to relax the pelvic floor muscles surrounding the vagina to allow intercourse. In men, some symptoms associated with sexual dysfunction include but are not limited to erectile dysfunction (ED), retarded ejaculation, and premature ejaculation. ED may refer to the inability to achieve or maintain an erection suitable for intercourse. A retarded ejaculation may refer to absent or delayed ejaculation despite sufficient sexual stimulation. Premature ejaculation may refer to an inability to control the timing of ejaculation.

[0313] ED is the most common form of sexual dysfunction in men. It is estimated that 322 million men worldwide will be affected by ED by 2025. ED has various etiologies, including but not limited to vascular, hormonal, and neurogenic causes. Individuals having neurogenic causes of ED include individuals with spinal cord injuries (SCI) and men after radical prostatectomy. Global incidence of SCI ranges from 40-80 new case per million of population per year, with 20-30 million men affected in the U.S. alone. A significant proportion of SCI individuals experiencing ED are young, where ED may significantly affect the quality of life.

[0314] To achieve an erection of the erectile tissue, contributions from both nervous and vascular components may be needed. A normal erection may rely on two reflex loops, pudendo-cavernosal reflex loop (for tumescence) and bulbocavernosus reflex loop (for rigidity). An adequate nerve activity may include release of nitric oxide (NO), leading to increase in cGMP, which in turn induce smooth muscle relaxation in the penile corpora. The nervous arrangement for an erection may be complex and may rely on both the somatic nervous systems (via pudendal nerve (PN)) and autonomic nervous systems (via cavernous nerve (CN)).

[0315] In some embodiments, the technology described herein (e.g., electrical stimulation such as neurostimulation) works synergistically with other therapies. For example, in some embodiments, sexual dysfunction is treated using neuromodulation and one or more of medication, mechanical aid, psychotherapy, and behavioral treatments. In some cases, the medication, also referred herein as medicament, includes a hormone, injection, pill, patch, or cream.

[0316] With respect to ED, examples include but are not limited to a phosphodiesterase type 5 (PDE5) inhibitor to increase blood flow to the penis; or injection papaverine, phentolamine, and / or Prostaglandin E1 (PGE1) at or near the erectile tissue. Often, PDE5 inhibitors are a first line treatment and include but are not limited to sildenafil, tadalafil, vardenafil, avanafil, lodenafil, udenafil, and mirodenafil. Although PDE5 inhibitors are effective in treating sexual function, discontinuation rates may be high, reported as high as 50% after 1-2 years of use. Intracavernosal injections with papaverine, phentolamine, and / or PGE1 may be administered to the patient if medication is ineffective. In some cases, intracavernosal injections may result in a high incidence of adverse effects, such as priapism, injection site pain, bruising. In some cases, high incidences of adverse effects lead to patient non-compliance. Mechanical aids include but are not limited to vacuum devices, penile implants, vaginal dilators, and vibrators. In some cases, penile prosthesis implantation may result in significant complications, such as infection, erosion and pain. As such, the effectiveness of certain treatment may be limited, especially for sexual dysfunction with a physical etiology and when patient compliance or response drops. Thus, in several embodiments, the use of electrical stimulation, such as neurostimulation, is advantageous alone or when used in combination with other therapies. In such combined approaches, the undesired side effects of other therapies may be reduced or eliminated. For example, when electrical stimulation is combined with a pharmaceutical therapy, a reduced drug dose may be needed, thus reducing the side effects associated with a higher dose.

[0317] Several embodiments overcome difficulty in treating sexual dysfunction due to the complex organization of the nervous system involved in sexual function, such as erection, including but not limited to access to the pudendal and / or cavernous nerves. In several embodiments, electrical stimulation using electrodes at multiple nerves involved in sexual function, such as pudendal and cavernous nerves, may restore sexual function, such as erection. Electrical stimulation at both pudendal and cavernous nerves may be able to treat sexual dysfunction due to neurogenic (e.g., spinal cord injury, post-prostatectomy) or combined neurogenic / vascular etiology (e.g., diabetes mellitus, idiopathic). In some cases, the erection produced by electrostimulation may be potentiated by PDE5 inhibitor (PDE5i). In some cases, the mechanisms of action may be directly linked to PDE5i as PDE5i inhibits the degradation of the CGM by inhibiting NOS. Advantageously, in one embodiment, side effects from stimulation of somatic nerves are reduced because, for example, stimulation is strategically delivered in locations where the proportion of somatic nerves is low (e.g., surrounding the prostate apex, where somatic nerves represent approximately less than 5% of the autonomic nerves).

[0318] According to several embodiments, sexual dysfunction is treated by targeted peripheral stimulation and restoration and / or augmentation of reflex activity involved in sexual function. Adapted stimulation to the target tissue (e.g., nerve and / or tissue around the nerve) may be provided by an implanted stimulator with an underlying physiological rationale to target both somatic nervous system (e.g., PN) and autonomic nervous system (e.g., CN), which are is involved in erection and sexual function. In some embodiments, adapted stimulation to the target nervesmay be provided by an implanted stimulator to target an autonomic nerve (e.g., CN), a somatic nerve (e.g., PN), or a combination thereof. The devices, systems, and methods described herein may be configured to restore erection in case of neurogenic (e.g., spinal cord injury, post-prostatectomy) and combined neurogenic / vascular etiology (e.g., diabetes mellitus, idiopathic). In some embodiments, the systems, methods, and devices may comprise a closed-loop configuration or another configuration disclosed herein for providing the electrical stimulation.

[0319] Electrical stimulation as described herein may be used for sexual dysfunction in lieu of, or combined with, a pharmaceutical therapy, such as hormone therapy, ED drugs, etc. In several embodiments, a reduced drug dosage may be needed when combined with electrical stimulation, thus reducing the side effects associated with a higher drug dose. Side effects include but are not limited to flushing, headaches, heartburn, priapism, vision changes, and cardiac issues. By reducing side effects of drugs (e.g., with reduced dosages), drugs may be tolerated for a longer period of time and / or patient compliance may increase.

[0320] Restless leg syndrome, restless genital syndrome, and other somatosensory dysfunctions may also be treated using the electrical stimulation described herein. Nerve stimulation of the pudendal nerve and / or nerves or other tissue surrounding the pudendal nerve is used to treat these conditions in some embodiments using the components and parameters described herein.

[0321] Several embodiments of the electrical stimulation described herein involve nerve stimulation. In some embodiments, one or more nerves are stimulated together with other tissue types. Vibrations or vibratory stimulation, acoustic (ultrasound) stimulation, and / or other mechanical stimulation may be provided in conjunction with or instead of the electrical stimulation described herein. For example, in several embodiments, for the disclosure herein that describes electrodes and electrical stimulation, the term electrode can be replaced by effector, transducer, delivery element; and the term electrical stimulation can be replaced by vibratory, ultrasound, and / or mechanical stimulation or delivery.

[0322] In several embodiments, any one or more of the feedforward patient engagement, feedback, neural retraining, or tissue strengthening, or combinations thereof as described herein can be used with any one or more of bilateral stimulation and sensing, trained classifiers, or combinations thereof disclosed herein. In several embodiments, any one or more of the using time-dependent programming, adaptive stimulation with flexible sensor input(s) selections for determining breakthrough signatures, personalized thresholds, additional patient safety and / or comfort features, or combinations thereof as described herein, and in PCT Application No. XXXX / XXX.XXX [Attorney Docket No. AMBTX.041WO] titled "TIME-DEPENDENT ADAPTIVE NEUROMODULATION SYSTEM,” filed on the same day as the present application, which is hereby incorporated by reference in its entirety, can be used with any one or more of bilateral stimulation and sensing, trained classifiers, or combinations thereof disclosed herein.

[0323] As used herein throughout this application, the terms "treatment”, "treating”, or "therapy” are used in reference to an intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to reduction, eradication, or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the reduction, eradication, or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includesdelaying, preventing, or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0324] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0325] As used in the specification and claims, the singular forms "a”, "an” and "the” include plural references unless the context clearly dictates otherwise. For example, the term "a sample” includes a plurality of samples, including mixtures thereof and phrases such as "a device configured to” are intended to include one or more recited devices. Such one or more recited devices can also be collectively configured to carry out the stated recitations. For example, "a processor configured to carry out recitations A, B and C” can include a first processor configured to carry out recitation A working in conjunction with a second processor configured to carry out recitations B and C.

[0326] The terms "approximately,” "about,” and "substantially” as used herein represent an amount close to the stated amount that still performs a desired function or achieves a desired result. For example, the terms "approximately”, "about”, and "substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1% of, within less than 0.1% of, and within less than 0.01% of the stated amount.

[0327] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0328] While certain embodiments of the present disclosure have been shown and described herein, such embodiments are provided by way of example only. The phrases "in one (or some) implementations”, "in one (or some) instances”, "in one (or some) cases” shall mean "in one (or some) embodiments”. It should be understood that various alternatives within the scope of the embodiments disclosed herein (such as structural and functional equivalents) described herein may be employed.

[0329] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0330] The terms "comprising,” "including,” "having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations, and so forth. Also, the term "or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term "or” means one, some, or all of the elements in the list. Further, the term "each,”as used herein, in addition to having its ordinary meaning, can mean any subset of a set of elements to which the term "each” is applied. In several embodiments, the systems and methods may consist or consist essentially of the features and steps recited.

[0331] Conditional language used herein, such as, among others, "can,” "might,” "may,” "for example,” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain examples include, while other examples do not include, certain features, elements and / or states. Thus, such conditional language is not generally intended to imply that features, elements and / or states are in any way required for one or more examples or that one or more examples necessarily include logic for deciding, with or without author input or prompting, whether these features, elements and / or states are included or are to be performed in any particular example.

[0332] Disjunctive language such as the phrase "at least one of X, Y, or Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to present that an item, term, etc., may be either X, Y, or Z, or any combination thereof (for example, X, Y, and / or Z). Thus, such disjunctive language is not generally intended to, and should not, imply that certain examples require at least one of X, at least one of Y, or at least one of Z to each be present.

[0333] Methods described herein also include an instruction to perform such method (or a step of such method) and systems may include instructions for use.

[0334] Many other variations than those described herein will be apparent from this disclosure. For example, certain acts, events, or functions of any of the algorithms described herein can be performed in a different sequence, can be added, merged, or left out altogether (for example, not all described acts or events are necessary for the practice of the algorithms). Moreover, acts or events can be performed concurrently, for example, through multithreaded processing, interrupt processing, or multiple processors or processor cores or on other parallel architectures, rather than sequentially. In addition, different tasks or processes can be performed by different machines and / or computing systems that can function together.

[0335] It is to be understood that not necessarily all such advantages can be achieved in accordance with any particular example of the examples disclosed herein. Thus, the examples disclosed herein can be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other advantages as may be taught or suggested herein.

[0336] The various illustrative logical blocks, modules, and algorithm steps described in connection with the examples disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality can be implemented in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure.

[0337] The various illustrative logical blocks and modules described in connection with the examples disclosed herein can be implemented or performed by a machine, such as a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or otherprogrammable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general purpose processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, or state machine, combinations of the same, or the like. A processor can include electrical circuit or digital logic circuit configured to process computer-executable instructions. In another example, a processor can include an FPGA or other programmable device that performs logic operations without processing computer-executable instructions. A processor can also be implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. A computing environment can include any type of computer system, including, but not limited to, a computer system based on a microprocessor, a mainframe computer, a digital signal processor, a portable computing device, a device controller, or a computational engine within an appliance, to name a few.

[0338] The steps of a method, process, or algorithm described in connection with the examples disclosed herein can be embodied directly in hardware, in a software module stored in one or more memory devices and executed by one or more processors, or in a combination of the two. A software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of non-transitory computer-readable storage medium, media, or physical computer storage known in the art. An example storage medium can be coupled to the processor such that the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integral to the processor. The storage medium can be volatile or nonvolatile. The processor and the storage medium can reside in an ASIC.

Claims

WHAT IS CLAIMED IS:

1. A neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency nerve stimulation through active patient engagement, the system comprising:an implantable pulse generator comprising an actuator and a processor, wherein the processor is configured to control the actuator to generate at least a dual frequency nerve stimulation,wherein the dual frequency nerve stimulation comprises a first stimulation and a second stimulation; andone or more electrode leads in electrical communication with the processor and configured to deliver at least the first stimulation or the second stimulation to a target nerve or tissue adjacent to the target nerve of a patient,wherein the second stimulation comprises a higher frequency than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation,wherein the second stimulation is activated in response to the implantable pulse generator detecting the patient's active engagement of the implantable pulse generator,wherein the second stimulation is configured to enhance stimulation at the target nerve or tissue adjacent to the target nerve; andwherein activating the second stimulation in response to the patient's active engagement of the implantable pulse generator is configured to reduce or prevent habituation.

2. The system of Claim 1, wherein the reduction or prevention of habituation facilitates a therapeutic effect without having to further increase the frequency of the second stimulation.

3. The system of Claim 1, wherein the patient's active engagement of the implantable pulse generator is a feedforward input.

4. The system of Claim 1 , wherein the at least dual frequency nerves stimulation works synergistically with a pharmaceutical therapy.

5. The system of Claim 1 , wherein the at least dual frequency nerves stimulation reduces one or more side effects of a pharmaceutical therapy.

6. The system of Claim 1, wherein the frequency value of the at least first or second stimulation is determined using artificial intelligence.

7. The system of any of Claims 1-6, wherein the implantable pulse generator further comprises at least one sensor.

8. The system of Claim 7, wherein the at least one sensor comprises a motion sensor.

9. The system of Claim 8, wherein the motion sensor is an accelerometer.

10. The system of Claim 7, wherein the at least one sensor is configured to transmit sensed data to a remote server.

11. The system of any of Claims 1-6, wherein the first or second stimulation is administered based on artificial intelligence determination of the patient's activities.

12. The system of any of Claims 1-6, wherein the patient's active engagement of the implantable pulse generator is not a physiological response associated with the onset of the incontinence event.

13. The system of any of Claims 1-6, wherein the processor is configured to allow the patient to control timing of activation of the second stimulation.

14. The system of any of Claims 1-6, wherein the processor is configured to control the actuator to generate the stimulation of a default parameter value and adjust the parameter value based on whether a mixed continence patient is urge predominant or stress predominant.

15. The system of any of Claims 1-6, wherein the one or more electrode leads further comprise at least one sensing electrode configured to detect a signal indicative of muscle activity.

16. The system of Claim 15, wherein an output of the at least one sensing electrode is configured to indicate when the patient has squeezed the at least one pelvic floor muscle, wherein the patient squeezing the least one pelvic floor muscle is configured to switch the processor from the first mode to the second mode to stop the stress urinary incontinence event.

17. The system of Claim 16, wherein the processor further comprises a biopotential classifier configured to determine whether the patient has squeezed the at least one pelvic floor muscle, the biopotential classifier being trained by artificial intelligence.

18. A neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency nerve stimulation through active patient engagement, the system comprising:an implantable pulse generator comprising a processor, wherein the processor is configured to generate at least a dual frequency nerve stimulation,wherein the dual frequency nerve stimulation comprises a first stimulation and a second stimulation; andone or more electrode leads in electrical communication with the processor and configured to deliver at least the first stimulation or the second stimulation to a target nerve or tissue adjacent to the target nerve of a patient,wherein the second stimulation comprises a higher frequency than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation,wherein the second stimulation is activated in response to a sensor in communication with the implantable pulse generator detecting the patient's active engagement of the implantable pulse generator, andwherein the second stimulation is configured to enhance stimulation at the target nerve or tissue adjacent to the target nerve.

19. The system of Claim 18, wherein activating the second stimulation in response to the patient's active engagement of the sensor in communication with the implantable pulse generator is configured to reduce or prevent habituation20. The system of Claim 18, wherein the patient's active engagement of the implantable pulse generator is a feedforward input.

21. The system of Claim 18, wherein the at least dual frequency nerves stimulation works synergistically with or reduces one or more side effects of a pharmaceutical therapy.

22. The system of Claim 18, wherein the sensor comprises a motion sensor within the implantable pulse generator.

23. The system of Claim 18, wherein the frequency value of the at least first or second stimulation is determined using artificial intelligence.

24. The system of Claim 18, wherein the sensor is configured to transmit sensed data to a remote server.

25. The system of Claim 24, wherein the first or second stimulation is administered based on artificial intelligence determination of the patient's activities.

26. The system of any of Claims 18-25, wherein the at least one sensor comprises a motion sensor.

27. The system of Claim 26, wherein the motion sensor is an accelerometer.

28. The system of any of Claims 18-25, wherein the patient's active engagement of the implantable pulse generator is not a physiological response associated with the onset of the incontinence event.

29. The system of any of Claims 18-25, wherein the processor is configured to allow the patient to control timing of activation of the second stimulation.

30. The system of any of Claims 18-25, wherein the processor is configured to control the actuator to generate the stimulation of a default parameter value and adjust the parameter value based on whether a mixed continence patient is urge predominant or stress predominant.

31. The system of Claim 30, wherein the processor is configured to increase from the default parameter value in response to the mixed continent patient being stress predominant.

32. The system of Claim 30, wherein the processor is configured to decrease from the default parameter value in response to the mixed continent patient being urge predominant.

33. The system of any of Claims 18-25, wherein the one or more electrode leads further comprise at least one sensing electrode configured to detect a signal indicative of muscle activity.

34. The system of any of the preceding claims, wherein the first stimulation is below a threshold configured to cause a tetanic contraction of muscles and the second stimulation meets or exceeds the threshold configured to cause the tetanic contraction of the muscles.

35. The system of any of the preceding claims, wherein the second stimulation is configured to cause closure of the patient's urethra.

36. A neuromodulation system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency nerve stimulation through active patient engagement, the system comprising:an implantable pulse generator comprising an actuator, a motion sensor, and a processor, wherein the processor is configured to control the actuator to generate at least a dual frequency nerve stimulation, wherein the dual frequency nerve stimulation comprises a first stimulation and a second stimulation; andone or more electrode leads in electrical communication with the processor and configured to deliver at least the first stimulation or the second stimulation to a target nerve or tissue adjacent to the target nerve of a patient,wherein the second stimulation comprises a higher frequency than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation,wherein the processor is configured to control the actuator to generate the first or second stimulation of a default frequency value and adjust the frequency value based on whether a mixed continence patient is urge predominant or stress predominant,wherein the second stimulation is activated in response to the motion sensor of the implantable pulse generator detecting the patient's active engagement of the implantable pulse generator, andwherein the second stimulation is configured to enhance stimulation at the target nerve or tissue adjacent to the target nerve.

37. A system configured to reduce or prevent habituation of nerve stimulation and to deliver at least dual frequency stimulation through active patient engagement, the system comprising:at least one processor configured to generate at least a dual frequency nerve stimulation, wherein the dual frequency stimulation comprises a first stimulation and a second stimulation; and one or more effectors to deliver the stimulation to a target nerve or tissue adjacent to the target nerve of a patient, andwherein the second stimulation comprises a higher frequency than the first stimulation, thereby providing enhanced stimulation compared to the first stimulation,wherein the second stimulation is activated in response to a sensor in communication with the processor detecting the patient's active engagement of the system,wherein the effectors comprise one or more of a transducer, piezoelectric element, electrode, or other stimulation delivery mean, or a combination thereof; andwherein the at least dual frequency stimulation comprises one or more of vibratory, ultrasound, mechanical, electrical stimulation, or a combination thereof, andwherein the second stimulation is configured to treat a condition,wherein the condition is optionally incontinence, a pelvic disorder, pain, or sexual dysfunction.

38. A generator configured to provide at least dual stimulation to tissue, wherein the dual stimulation comprises a first stimulation and a second stimulation, wherein the second stimulation provides a different parameter than the first stimulation, thereby providing enhanced stimulation, and wherein the second stimulation is activated when the generator or a sensor detects the patient's active engagement of the generator or the sensor, wherein the different parameter comprises one or more of frequency, intensity, pulse width, and / or amplitude, wherein the generator or sensor are partially or fully implantable or non-implantable.

39. The use of any of the systems or generators according to the preceding claims for the treatment of incontinence, sexual dysfunction, pelvic disorders, and / or pain.

40. A device for charging any of the systems or generators according to the preceding claims, wherein the device comprises an inductive battery charger.

41. A neuromodulation system configured to deliver a patient-specific electrical current to a pudendal nerve or tissue adjacent to the pudendal nerve of a patient, the system comprising:an implantable pulse generator including a processor, the processor configured to execute software stored on a non-transitory computer readable storage medium to generate a stimulating electrical current; and-n-one or more electrode leads in electrical communication with the processor, the one or more electrode leads comprising at least one sensing electrode and at least one stimulating electrode, wherein the at least one stimulating electrode is configured to deliver the stimulating electrical current to the pudendal nerve or tissue adjacent the pudendal nerve of the patient,wherein the at least one sensing electrode is configured to detect a signal indicative of muscle activity,wherein the processor is configured to execute software stored on a non-transitory computer readable storage medium to determine a patient-specific parameter value of the stimulating electrical current based at least in part on the signal output by the at least one sensing electrode and a sub-type of continence of the patient,wherein the signal is indicative of the muscle activity in response to the stimulating electrical current, andwherein the stimulating electrical current of the predetermined parameter value is configured to cause contraction of muscles surrounding urethra to restore a natural orientation of the urethra.

42. A method of delivering personalized neurostimulation to a patient to restore a natural orientation of a urethra of the patient using a neuromodulation system including an implantable pulse generator and one or more electrodes in electrical communication with the processor, the method comprising:using a processor of the implantable pulse generator:determining a patient-specific stimulation parameter value based at least in part on a subtype of incontinence of the patient; andgenerating the stimulating electrical current of the patient-specific stimulation parameter value such that the one or more electrodes leads can deliver the stimulating electrical current to a pudendal nerve or tissue adjacent the pudendal nerve of the patient,wherein the stimulating electrical current of the patient-specific stimulation parameter value is configured to cause contraction of muscles surrounding urethra to restore the natural orientation of the urethra.

43. A neuromodulation system configured to provide a training program to an incontinence patient who is unable to voluntarily squeeze pelvic floor muscles prior to or in response to a stress incontinence event, the system comprising:an implantable pulse generator including a processor, the processor configured to generate a stimulating electrical current; andone or more electrode leads in electrical communication with the processor;wherein the processor is configured to execute software stored on a non-transitory computer readable storage medium to operate a training mode in response to a user input,wherein, when in the training mode, the processor is configured to generate a stimulating electrical current such that the one or more electrode leads are configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of the patient,wherein the stimulating electrical current is configured to cause contraction of the pelvic floor muscles such that the patient can learn how it feels when the pelvic floor muscles contract under stimulation, and wherein the processor is configured to generate the stimulating electrical current at a predetermined interval for a predefined period of time in the training mode.

44. A method of training a user who is unable to voluntarily squeeze pelvic floor muscles prior to a stress incontinence event, the method comprising:(I) electrically stimulating a target nerve or tissue in the pelvic region sufficient to cause contraction of the pelvic floor muscles,(II) notifying the user that said electrical stimulation is occurring, optionally through an audible, visual or tactile signal so that the user registers the contraction of the pelvic floor muscles, (ill) reducing or stopping the electrical stimulation; and(iv) repeating steps (I) and (II) at least twice to train the user to contact the pelvic floor muscles voluntarily without electrical stimulation.

45. A method of preventing incontinence of a patient immediately after a surgery or child delivery, the method comprising:(I) immediately after a surgery or child delivery, electrically stimulating a target nerve or tissue to cause nerve and / or muscle regeneration,(II) reducing or stopping the electrical stimulation; and(ill) repeating steps (I) and (II) at least twice to prevent incontinence without electrical stimulation.

46. A neuromodulation system configured to prevent incontinence of a patient immediately after a surgery or child delivery, the system comprising:an implantable pulse generator including a processor, the processor configured to generate a stimulating electrical current; andone or more electrode leads in electrical communication with the processor;wherein the processor is configured to execute software stored on a non-transitory computer readable storage medium to operate a training mode in response to a user input,wherein, when in the training mode, the processor is configured to, immediately after a surgery or child delivery, generate a stimulating electrical current such that the one or more electrode leads are configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of a patient to cause nerve and / or muscle regeneration, andwherein the processor is configured to generate the stimulating electrical current at a predetermined interval for a predefined period of time in the training mode.

47. A neuromodulation system configured to deliver patient-controlled adaptive nerve stimulation, the system comprising:an implantable pulse generator including a processor, the processor configured to execute software stored on a non-transitory computer readable storage medium to generate a stimulating electrical current; andone or more electrode leads in electrical communication with the processor and configured to deliver the stimulating electrical current to a target nerve or tissue adjacent to the target nerve of a patient, wherein the processor is further configured to operate in a first mode or a second mode, the first mode and the second mode differing in at least one stimulating parameter,wherein the stimulating electrical current in the first mode is below a threshold to cause a tetanic contraction of muscles and the stimulating electrical current in the second mode meets or exceeds the threshold to cause the tetanic contraction of the muscles,wherein the processor is further configured to switch from the first mode to the second mode in response to a user input, andwherein the user input comprises a tap on the implantable pulse generator or the patient squeezing at least one pelvic floor muscle prior to an onset of a stress incontinence event.

48. A method for delivering patient-controlled adaptive nerve stimulation, the method comprising:operating in a first mode by outputting a stimulating electrical current below a threshold to cause a tetanic contraction of muscles, wherein the stimulating electrical current is delivered to a target nerve or tissue adjacent to the target nerve of a patient; andin response to a user input, switching from the first mode to a second mode,wherein the first mode and the second mode differ in at least one stimulating parameter, wherein the stimulating electrical current in the second mode meets or exceeds the threshold to cause the tetanic contraction of the muscles, andwherein the user input comprises a tap on an implantable pulse generator or the patient squeezing at least one pelvic floor muscle prior to an onset of a stress incontinence event.

49. A neuromodulation system configured to deliver patient-controlled adaptive nerve stimulation, the system comprising:an implantable pulse generator including a processor and a motion / posture sensor, the processor configured to execute software stored on a non-transitory computer readable storage medium to generate a stimulating electrical current; andone or more electrode leads in electrical communication with the processor,wherein the one or more electrode leads comprises at least one sensing electrode and at least one stimulating electrode,wherein the at least one stimulating electrode is configured to deliver the stimulating electrical current to a target nerve or tissue adjacent the target nerve of a patient, wherein the at least one sensing electrode is configured to detect a signal indicative of muscle activity,wherein the processor is configured to operate in a first mode or a second mode, the first mode and the second mode differing in at least one stimulating parameter,wherein the stimulating electrical current in the first mode is below a threshold configured to cause a tetanic contraction of muscles and the stimulating electrical current in the second mode meets or exceeds the threshold configured to cause the tetanic contraction of the muscles,wherein the processor is configured to switch from the first mode to the second mode in response to a user input, the user input configured to be detected by the motion / posture sensor or the at least one sensing electrode,wherein the second mode is configured to preemptively stop a stress incontinence event.

50. A method for delivering patient-controlled adaptive nerve stimulation, the method comprising:operating in a first mode by outputting a stimulating electrical current below a threshold to cause a tetanic contraction of muscles, wherein the stimulating electrical current is delivered to a target nerve or tissue adjacent to the target nerve of a patient; andin response to a user input, switching from the first mode to a second mode, the user input configured to be detected a motion / posture sensor or at least one sensing electrode,wherein the first mode and the second mode differ in at least one stimulating parameter, wherein the stimulating electrical current in the second mode meets or exceeds the threshold to cause the tetanic contraction of the muscles, andwherein the second mode is configured to preemptively stop a stress incontinence event.

51. A neuromodulation system configured to deliver neuromodulation using bilaterally implanted electrode leads to treat a pelvic condition of a patient, the system comprising:an implantable pulse generator including a processor, the processor configured to execute instructions stored on a non-transitory computer readable storage medium to generate an electrical stimulation of at least first and second levels, wherein the first level is a first background level and the second level is triggered by a breakthrough signature, the second level being different from the first level; and one or more first electrode leads implanted in a first lateral side of the patient and one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side, the first and second electrode leads in electrical communication with the processor;wherein the one or more first electrode leads comprise at least one stimulation electrode configured to deliver the electrical stimulation to a target nerve or tissue adjacent to the target nerve on the first lateral side of the patient;wherein the one or more second electrode leads comprise at least one sensing electrode configured to measure bioelectrical signals from the second lateral side of the patient; andwherein the processor is further configured to:determine a breakthrough signature of a patient using the at least one sensing electrode on the second lateral side, wherein the breakthrough signature comprises a muscle contraction of the patient; andcause the at least one stimulation electrode to output stimulation at the second level to the target nerve or tissue adjacent to the target nerve on the first lateral side when the second level is triggered.

52. A method of delivering neuromodulation using bilaterally implanted electrode leads to treat a pelvic condition, the method comprising:providing one or more first electrode leads implanted in a first lateral side of a patient, wherein the one or more first electrode leads comprise at least one stimulation electrode configured to deliver electrical stimulation to a target nerve or tissue adjacent to the target nerve on the first lateral side of the patient; providing one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side, wherein the one or more second electrode leads comprise at least one sensing electrode configured to measure bioelectrical signals from the second lateral side of the patient;determining a breakthrough signature of a patient using the at least one sensing electrode on the second lateral side, wherein the breakthrough signature comprises a muscle contraction of the patient; providing at least first and second levels of electrical stimulation to the at least one stimulation electrode on the first lateral side;wherein the first level is a first background level, and the second level is triggered by the breakthrough signature, the second level being different than the first level; andcausing the at least one stimulation electrode to output electrical stimulation at the second level to the target nerve or tissue adjacent to the target nerve on the first lateral side when the second level is triggered.

53. The method of Claim 52, for delivering personalized neuromodulation using a plurality of breakthrough signatures, the method further comprising:determining a second breakthrough signature of a patient;determining a third breakthrough signature of the patient;wherein the second breakthrough signature comprises a postural change of the patient, wherein the third breakthrough signature comprises patient notification;providing at least three levels of stimulation including the first level, the second level, and a third level,wherein a third level is a second background level, andoutputting stimulation at the first or third background level based at least in part on a time of a day unless the second level is triggered.

54. A system configured to deliver personalized neuromodulation using breakthrough signatures, the system comprising:an implantable pulse generator including a processor, the processor configured to execute instructions stored on a non-transitory computer readable storage medium to generate an electrical stimulation of different levels; andone or more electrode leads in electrical communication with the processor,wherein the one or more electrode leads comprise at least one stimulation electrode configured to deliver the electrical stimulation to a target nerve or tissue adjacent to the target nerve of a patient, wherein the processor is further configured to be triggered from a background level of electrical stimulation to a different level of electrical stimulation in response to determining a breakthrough signature, andwherein the processor is configured to determine the breakthrough signature using a machine learning and / or artificial intelligence classifier trained on a labelled set of patient-specific data and optimized for one or more predetermined metrics, wherein the one or more metrics comprise an F-1 score, an F-2 score, or classification area under the curve (AUG).

55. A method for delivering personalized neuromodulation using breakthrough signatures to treat a pelvic condition, the method comprising:providing electrical stimulation of at least first and second levels to one or more electrode leads comprising at least one stimulation electrode configured to deliver the electrical stimulation to a target nerve or tissue adjacent to the target nerve of a patient;delivering a background level of electrical stimulation, wherein the background level is the first level; determining a breakthrough signature using a machine learning and / or artificial intelligence trained classifier;delivering the second level of electrical stimulation in response to determining the breakthrough signature,wherein the second level is different than the first level, andwherein the classifier is trained on a labelled set of patient-specific data and optimized for one or more predetermined metrics, wherein the one or more metrics comprise an F-1 score, an F-2 score, or classification area under the curve (AUG).

56. A method for delivering personalized neuromodulation using one or more input modes to treat a pelvic condition, the method comprising:providing at least two levels of electrical stimulation to one or more electrode leads comprising at least one stimulation electrode configured to deliver the electrical stimulation to a target nerve or tissue adjacent to the target nerve of a patient;wherein a first level is a first background level, a second level is triggered by determining a breakthrough signature, and wherein the second level is different than the first level;providing a first machine learning and / or artificial intelligence classifier trained on patient-specific data of a first input mode, the classifier configured to determine a first breakthrough signature;evaluating the first classifier based on a first threshold classifier score; anddisabling the first input mode in response to the first threshold classifier score not being met and enabling a second input mode,wherein the first input mode is used for determining the first breakthrough signature comprising a muscle contraction of a patient, andwherein the second input mode is used for determining a second breakthrough signature comprising a postural change of the patient and / or a patient notification.

57. A neuromodulation system configured to deliver neuromodulation using bilaterally implanted electrode leads to treat a pelvic condition of a patient, the system comprising:an implantable pulse generator including a processor, the processor configured to execute instructions stored on a non-transitory computer readable storage medium to generate an electricalstimulation of at least first and second levels, wherein the first level is a first background level and the second level is triggered by a breakthrough signature, the second level being different from the first level; and one or more first electrode leads implanted in a first lateral side of the patient and one or more second electrode leads implanted in a second lateral side of the patient opposite the first lateral side;wherein the one or more first electrode leads comprise at least one stimulation electrode configured to deliver the electrical stimulation to a target nerve or tissue adjacent to the target nerve on the first lateral side of the patient,wherein the one or more first electrode leads comprise a first sensing electrode and the one or more second electrode leads comprise a second sensing electrode, wherein the first and second sensing electrodes form a sensing dipole configured to measure bioelectrical signals across the bilaterally implanted electrode leads; andwherein the processor is further configured to:determine a breakthrough signature of a patient using the sensing dipole of the bilaterally implanted electrode leads, wherein the breakthrough signature comprises a muscle contraction of the patient; andcause the at least one stimulation electrode to output stimulation at the second level to the target nerve or tissue adjacent to the target nerve on the first lateral side when the second level is triggered.

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