Systems, methods and devices for peripheral neuromodulation for treating diseases related to overactive bladder

Abstract

To provide an effective treatment for treating a patient's voiding symptom with less side effects.SOLUTION: In some embodiments, systems and methods can include a wearable device with an electrically conductive skin interface that excites underlying nerves from a transcutaneous surface stimulator. The device may be sized for a range of user sizes with stimulation electrodes positioned to target appropriate nerves, such as the saphenous and / or tibial nerves. Transcutaneous afferent stimulation to one, two, or more peripheral nerves adjust the brain or spinal cord related to a bladder function.SELECTED DRAWING: Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 281,606, filed January 21, 2016, U.S. Provisional Application No. 62 / 352,462, filed June 20, 2016, and U.S. Provisional Application No. 62 / 365,326, filed July 21, 2016, each of which is incorporated herein by reference in its entirety. All applications in which a foreign or domestic priority claim is identified in an Application Data Sheet filed with this application are incorporated herein by reference pursuant to 37 CFR 1.57. [Technical field]

[0002] The present invention relates in some aspects to systems and methods for treating overactive bladder and related disorders. [Background technology]

[0003] Description of Related Art Overactive bladder (OAB) is a common condition affecting men and women with an estimated prevalence of 16% of the population, and a condition that will affect up to an estimated 500 million people by 2018. The total annual burden of OAB is projected to be US$3.9 billion in six countries (Canada, Germany, Italy, Spain, Sweden, and the UK). Symptoms of overactive bladder include an uncontrollable desire to urinate immediately, known as urgency, which may or may not be followed by urinary incontinence (incontinence), increased urination frequency, and / or nocturia. Nocturia is a medical condition that results in the person having to wake up to urinate one, two, three, or more times during the night. Lower urinary tract (LUT) dysfunction may be secondary to a variety of non-neurological or neurological causes, including stroke, spinal cord injury, multiple sclerosis, or neurodegenerative disorders such as Parkinson's disease. Standard treatment options for overactive bladder include behavioral strategies such as timed voiding or pelvic muscle training, or medications such as antimuscarinic or botulinum toxin injections into the bladder. Summary of the Invention [Problem to be solved by the invention]

[0004] However, oral medications can be poorly effective and have a high risk of adverse side effects leading to intolerance and frequent discontinuation. Effective treatments with fewer side effects are needed. [Means for solving the problem]

[0005] In some embodiments, disclosed herein is a method for treating a patient's urinary symptoms by dual percutaneous stimulation of the saphenous nerve and the posterior tibial nerve. The method may include, in some embodiments, positioning a first peripheral nerve effector on the patient's skin to stimulate the patient's saphenous nerve, positioning a second peripheral nerve effector on the patient's skin to stimulate the patient's posterior tibial nerve, delivering a first electrical nerve stimulation signal percutaneously to the saphenous nerve via the first peripheral nerve effector, delivering a second electrical nerve stimulation signal percutaneously to the posterior tibial nerve via the second peripheral nerve effector, receiving input regarding the patient's autonomic nervous system activity, and modifying at least one brain or spinal cord autonomic feedback loop related to bladder function based on the input to balance the activity of the patient's parasympathetic and sympathetic nervous systems. In some embodiments, the method does not utilize an implantable element and includes only percutaneous stimulation. The first peripheral nerve effector and the second peripheral nerve effector may both be positioned proximate to the patient's knee. The first electrical stimulation signal may be different from the second electrical stimulation signal. The first electrical stimulation signal may have a first frequency that is different from a second frequency of the second electrical stimulation signal. The first electrical stimulation signal may have a different amplitude from the second electrical stimulation signal. The first frequency or the second frequency may be, for example, about 10 Hz to about 20 Hz. The first or second frequency may be, for example, about 5 Hz to about 30 Hz. Receiving input related to the patient's autonomic nervous system activity may include any number of steps of receiving data from a sensor measuring the patient's autonomic nervous system activity, receiving data from a sensor measuring the patient's heart rate variability, measuring blood flow characteristics and receiving heart rate variability data from an optical sensor positioned proximate to a blood vessel proximate the patient's knee, receiving data from a sensor measuring the patient's galvanic skin response, receiving data related to the patient's voiding symptoms, and / or receiving data related to the patient's episodes of nocturia.

[0006] Also disclosed herein is a wearable device for dual percutaneous stimulation of the saphenous and posterior tibial nerves and treatment of urinary symptoms in a patient, which in some embodiments may include any number of features of a controller, a first peripheral nerve effector comprising at least one stimulating electrode configured to be positioned to percutaneously modulate the saphenous nerve, a second peripheral nerve effector comprising at least one stimulating electrode configured to be positioned to percutaneously modulate the posterior tibial nerve, and at least one biomedical sensor or data input source configured to provide feedback information. The controller may include a processor and memory for receiving feedback information from the sensor, and when executed by the processor, causes the device to adjust one or more parameters of the first electrical stimulus and the second electrical stimulus based at least in part on the feedback information, and / or deliver a first electrical stimulus to the saphenous nerve via a first peripheral nerve effector and a second electrical stimulus to the posterior tibial nerve via a second peripheral nerve effector to reduce voiding symptoms by modifying an autonomic feedback loop in the brain or spinal cord associated with bladder function to balance sympathetic and parasympathetic activity. In some embodiments, the device is not configured for implantation within the patient. The feedback information may include real-time feedback information. The first electrical stimulus may have a frequency, for example, from about 10 Hz to about 20 Hz. The second electrical stimulus may have a frequency, for example, from about 5 Hz to about 30 Hz. The feedback information may include autonomic nervous system activity of the patient. The feedback information may include heart rate variability. The feedback information may further include information regarding nocturia events of the patient. The feedback information may further include information regarding the patient's sleep state.

[0007] In some embodiments, disclosed herein is a method for treating a patient's urinary symptoms.The method may include any number of steps of: positioning a first electrode at a first location on a skin surface relative to a first afferent peripheral nerve; positioning a second electrode at a second location on a skin surface relative to a second afferent peripheral nerve; positioning a third electrode at a third location on a skin surface spaced apart from the first and second electrodes; delivering a first stimulus to the first peripheral nerve via the first electrode; and delivering a second stimulus to the second peripheral nerve via the second electrode.In some embodiments, the third electrode is a single common return electrode for the first and second electrodes. In some embodiments, the first electrode, the second electrode, and the third electrode are positioned such that the electric field between the first electrode and the third electrode passes through the first afferent peripheral nerve, and the electric field between the second electrode and the third electrode passes through the second afferent peripheral nerve. The first and second stimuli can modify at least one brain or spinal cord autonomic feedback loop associated with bladder function. In some embodiments, the first afferent peripheral nerve includes the posterior tibial nerve. In some embodiments, the second afferent peripheral nerve includes the saphenous nerve. The symptoms can include, for example, overactive bladder, nocturia, urgency, and / or frequency. In some embodiments, the first electrode, the second electrode, and the third electrode are all connected to a wearable device and positioned on the calf proximal to the patient's knee, distal to the patient's knee, ankle, and / or foot.

[0008] In some embodiments, disclosed herein is a method for treating a patient's urinary symptoms. The method may include any number of steps of: positioning a first electrode pair, which includes an anode and a cathode, at a first position on a skin surface relative to a first peripheral nerve; positioning a second electrode pair, which includes an anode and a cathode, at a second position on a skin surface relative to a second peripheral nerve; delivering a first stimulus to the first peripheral nerve via the first electrode pair; and delivering a second stimulus to the second peripheral nerve via the second electrode pair. In some embodiments, the first electrode pair and the second electrode pair are positioned such that the electric field between the first electrode pair passes through the first peripheral nerve, and the electric field between the second electrode pair passes through the second peripheral nerve. The first stimulus and the second stimulus can modify at least one brain or spinal cord autonomic feedback loop related to bladder function.

[0009] Further disclosed herein is a system for treating a urinary symptom of a patient, which in some embodiments may include any number of: a wearable housing configured to be positioned on the patient's calf proximate the patient's knee, a first electrode configured to be positioned at a first location on the skin surface relative to a first afferent peripheral nerve, a second electrode configured to be positioned at a second location on the skin surface relative to a second afferent peripheral nerve, a third electrode configured to be positioned at a third location on the skin surface spaced from the first and second electrodes, and a controller configured to deliver a first stimulus to the first peripheral nerve via the first electrode and a second stimulus to the second peripheral nerve via the second electrode to modify at least one brain or spinal cord autonomic feedback loop associated with bladder function. The third electrode may be a single common return electrode for the first and second electrodes. The first electrode, the second electrode, and the third electrode may be configured to be positioned such that an electric field between the first electrode and the third electrode passes through a first afferent peripheral nerve, and an electric field between the second electrode and the third electrode passes through a second afferent peripheral nerve. The wearable housing may be attached to each of the first electrode, the second electrode, and the third electrode. In some embodiments, the first afferent peripheral nerve is the posterior tibial nerve, and the second afferent peripheral nerve is the saphenous nerve.

[0010] Disclosed herein is a system for treating urinary symptoms in a patient, the system including any number of: a first electrode pair including an anode and a cathode and configured to be positioned at a first location on a skin surface relative to a first afferent peripheral nerve; a second electrode pair including an anode and a cathode and configured to be positioned at a second location on a skin surface relative to a second afferent peripheral nerve; and a controller configured to deliver a first stimulus to the first peripheral nerve via the first electrode pair and a second stimulus to the second peripheral nerve via the second electrode pair to modify at least one brain or spinal cord autonomic feedback loop associated with bladder function. The first electrode pair and the second electrode pair may be configured to be positioned such that an electric field between the first electrode pair passes through the first peripheral nerve and an electric field between the second electrode pair passes through the second peripheral nerve.

[0011] In some embodiments, disclosed herein is a wearable device for treating urinary symptoms of a patient.

[0012] The device may include any number of a controller, a first peripheral nerve effector comprising at least one stimulating electrode configured to be positioned to transcutaneously modulate a first afferent nerve pathway associated with bladder function, a second peripheral nerve effector comprising at least one stimulating electrode configured to be positioned to transcutaneously modulate a second afferent nerve pathway associated with bladder function, and at least one input source configured to provide feedback information. The controller may include a processor and memory for receiving real-time feedback information from an input source, and when executed by the processor, causes the device to adjust one or more parameters of a first electrical stimulus based at least in part on the feedback information, adjust one or more parameters of a second electrical stimulus based at least in part on feedback information separate from the first electrical stimulus, deliver a first electrical stimulus to a first afferent nerve pathway via a first peripheral nerve effector to reduce voiding symptoms by modifying a first brain or spinal cord autonomic feedback loop associated with bladder function, and deliver a second electrical stimulus to a second afferent nerve pathway via a second peripheral nerve effector to reduce voiding symptoms by modifying a second brain or spinal cord autonomic feedback loop associated with bladder function. By adjusting one or more parameters of the first electrical stimulus and the second electrical stimulus, activity of the sympathetic and parasympathetic nervous systems can be balanced.

[0013] In some embodiments, the systems and methods may include a wearable device having a conductive skin interface that excites underlying nerves from a transcutaneous surface stimulator. The device may be sized for a range of user sizes with stimulation electrodes positioned to target appropriate nerves, such as the devices described in U.S. Pat. No. 9,452,287 to Rosenbluth et al., WO 2015 / 187712 to Wong et al., and PCT / US2016 / 037080, each of which is incorporated herein by reference.

[0014] The present invention, in some embodiments, describes a wearable system that uses transcutaneous sensory stimulation to improve symptoms of overactive bladder and urinary incontinence. In some embodiments, a key element of this system is that it can improve the effectiveness of peripheral nerve stimulation for routine home use by avoiding the inconvenience of frequent outpatient visits and the invasive aspects of using percutaneous penetrating tibial or sacral nerve stimulation. Some embodiments can advantageously utilize transcutaneous neuromodulation of peripheral afferent nerve pathways to non-invasively affect brain or spinal cord pathways related to physiology such as bladder function.

[0015] A wearable form of chronic peripheral nerve stimulation that is easily integrated into an individual's life and allows for full mobility and ease of use could improve the efficacy of urological neuromodulation. However, home use of a percutaneous penetration system can be inconvenient for the patient and technically challenging. Percutaneous neuromodulation is a more suitable modality for home use, but is currently limited by its form factor, depending on the need for chronic daily use. Furthermore, the addition of a responsiveness aspect and a more frequent use aspect could greatly improve the efficacy and comfort of such devices for chronic use.

[0016] The effects of peripheral nerve stimulation on bladder function may occur only during the period of active stimulation or may persist longer than the stimulation period after stimulation has ended. Various mechanisms, such as modulation of the micturition reflex or induction of brain or spinal plasticity, may be involved in these experimental and clinical observations. Furthermore, the onset of the stimulation effect may occur acutely (e.g., during or immediately after treatment) or chronically only after several stimulation sessions. For example, in patient-related outcomes, the effects of percutaneous tibial and / or saphenous nerve stimulation are evaluated 4-6 weeks after the initiation of weekly stimulation sessions. Depending on the underlying mechanism and the time course of the beneficial effect, stimulation may require delivery continuously, as in sacral nerve stimulation, in discrete scheduled sessions, or in an on-demand conditional form. Conditioned stimulation may rely either on the patient's control to identify urgency or on automatic detection of involuntary detrusor contractions (IDCs) responsible for the evolution to urgent symptoms or frank incontinence.

[0017] Several peripheral nerves, including the tibial, pudendal, and dorsal genital nerves, whose acute and chronic effects on bladder function have been documented in animal and human experimental studies, can be selected as targets for urinary neuromodulation. The saphenous nerve can acutely reduce bladder hyperexcitability. The saphenous nerve is a purely sensory nerve that innervates the skin of the medial crura. The proximity of the saphenous nerve to the skin surface makes it an advantageous target for transcutaneous stimulation. Selective stimulation of the tibial and saphenous nerves can reduce symptoms of overactive bladder. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 illustrates non-limiting structures and pathways associated with bladder function. [Figure 1A] FIG. 1 illustrates example stimulation waveforms according to some embodiments of the present invention. [Figure 1B] FIG. 1 illustrates example stimulation waveforms according to some embodiments of the present invention. [Diagram 2]FIG. 1 is a schematic diagram illustrating a flow chart incorporating a stimulation protocol according to some embodiments of the present invention. [Diagram 3] 1A-1D illustrate a calf band stimulator device configured to be positioned adjacent to the knee, according to some embodiments of the present invention. [Figure 4A] 1 illustrates an ankle stimulator device according to some embodiments of the present invention. [Figure 4B] 1 illustrates an ankle stimulator device according to some embodiments of the present invention. [Figure 5A] FIG. 1 illustrates non-limiting embodiments of potential electrode placement locations for neurostimulation. [Figure 5B] FIG. 1 illustrates non-limiting embodiments of potential electrode placement locations for neurostimulation. [Figure 5C] FIG. 1 illustrates non-limiting embodiments of potential electrode placement locations for neurostimulation. [Figure 6] 1A-1D illustrate a stimulation device having adhesive electrodes according to some embodiments of the present invention. [Figure 7] 1A-1D illustrate a stimulation device having adhesive electrodes according to some embodiments of the present invention. [Figure 8] FIG. 1 illustrates a thin bandage-like electrode that may be attached to a patient according to some embodiments of the present invention. [Figure 9] FIG. 1 illustrates an embodiment of a distal saphenous nerve sensing and / or stimulation technique. [Figure 10] FIG. 1 illustrates a stimulation device including a housing, according to some embodiments of the present invention. [Figure 10A] FIG. 1 illustrates an embodiment of an electrode array having individually addressable elements. [Figure 10B] FIG. 1 illustrates one embodiment of a stimulation system including a wearable device at the ankle or other desired anatomical location, as well as implanted stimulation electrodes around a target nerve. [Figure 11A] FIG. 1 illustrates how systems and methods for peripheral nerve stimulation may be provided that target one, two, or more individual nerves. [Figure 11B] FIG. 1 illustrates how systems and methods for peripheral nerve stimulation may be provided that target one, two, or more individual nerves. [Figure 11C] FIG. 1 illustrates how systems and methods for peripheral nerve stimulation may be provided that target one, two, or more individual nerves. [Figure 11D] FIG. 1 illustrates how systems and methods for peripheral nerve stimulation may be provided that target one, two, or more individual nerves. [Figure 11E] FIG. 1 illustrates how systems and methods for peripheral nerve stimulation may be provided that target one, two, or more individual nerves. [Figure 12A] FIG. 1 illustrates how systems and methods for peripheral nerve stimulation may be provided that target one, two, or more individual nerves. [Figure 12] FIG. 1 illustrates how electrodes may be arranged on a wearable band (or sleeve) that may be circumferential or non-circumferential and may be worn around the ankle, knee, leg, or other body part, in accordance with some embodiments of the present invention. [Figure 13] FIG. 1 illustrates how electrodes may be arranged on a wearable band (or sleeve) that may be circumferential or non-circumferential and may be worn around the ankle, knee, leg, or other body part, in accordance with some embodiments of the present invention. [Figure 14] FIG. 1 illustrates an embodiment of a stimulation system having at least three electrodes that can be configured to separately stimulate multiple nerves. [Figure 15] FIG. 1 illustrates an embodiment of a stimulation system having at least three electrodes that can be configured to separately stimulate multiple nerves. [Figure 16A] FIG. 1 illustrates clinical data related to saphenous nerve stimulation, according to some embodiments of the present invention. [Figure 16B] FIG. 1 illustrates clinical data related to saphenous nerve stimulation, according to some embodiments of the present invention. [Figure 16C]FIG. 1 illustrates clinical data related to saphenous nerve stimulation, according to some embodiments of the present invention. [Figure 17A] FIG. 1 illustrates clinical data regarding tibial nerve stimulation, according to some embodiments of the present invention. [Figure 17B] FIG. 1 illustrates clinical data regarding tibial nerve stimulation, according to some embodiments of the present invention. [Figure 17C] FIG. 1 illustrates clinical data regarding tibial nerve stimulation, according to some embodiments of the present invention. [Figure 17D] FIG. 1 illustrates clinical data regarding tibial nerve stimulation, according to some embodiments of the present invention. [Figure 17E] FIG. 1 illustrates clinical data regarding tibial nerve stimulation, according to some embodiments of the present invention. [Figure 17F] FIG. 1 illustrates clinical data regarding tibial nerve stimulation, according to some embodiments of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] As used herein, the terms "stimulate" and "stimulator" generally refer to the delivery of a signal, stimulus, or impulse to the nerve tissue of a target region. The effect of such stimulation on neuronal activity is referred to as "modulation," but for brevity, the terms "stimulate" and "modulate" and variations thereof may be used interchangeably herein. The effect of delivering a signal to the nerve tissue may be an excitatory or inhibitory effect, and may enhance acute and / or long-term changes in neuronal activity. For example, the effect of "stimulating" or "modulating" the nerve tissue may include one or more of the following effects: (a) depolarizing the neuron so that it fires an action potential; (b) hyperpolarizing the neuron to inhibit action potentials; (c) depleting the ion stores of the neuron to inhibit firing action potentials; (d) altering with proprioceptive input; (e) affecting muscle contraction; (f) affecting changes in neurotransmitter release or uptake; or (g) inhibiting firing. "Proprioception" refers to the sense of the relative position of one's own body parts, or the force used to move a body part. Proprioception may otherwise be referred to as somatosensation, kinesthetic sensation, or tactile sensation. "Proprioceptors" are receptors that provide proprioceptive information to the nervous system, and include stretch receptors in muscles, joints, ligaments, and tendons as well as receptors for pressure, temperature, light, and sound. An "effector" is the mechanism by which a device modulates a target nerve. For example, an "effector" could be electrical stimulation of a nerve or mechanical stimulation of a proprioceptor.

[0020] "Electrical stimulation" refers to the application of electrical signals to the soft tissues and nerves of a target area. "Cloud" refers to a network of computer communications that uses Internet-like real-time protocols to analyze, display, and interact with data across distributed devices.

[0021] Some forms of treatment for the control of urinary symptoms include electrical neuromodulation, including percutaneous and / or percutaneous penetrating peripheral nerve stimulation and / or implanted pudendal or sacral nerve stimulation. Neuromodulation of the urinary system can be very effective in controlling lower urinary tract symptoms. In some embodiments, modulation of the micturition reflex can be achieved by stimulation of lumbosacral afferents. Sacral neuromodulation can involve surgical placement of an implant at the level of the S3 sacral foramen and can be very effective and durable, but requires an invasive procedure. Stimulation can be continuous and open-loop. Sacral stimulation can lead to modulation of the micturition reflex at the spinal or spinal column level. Sacral nerve stimulation is considered relatively long-lasting, but is invasive, and side effects include buttock, leg or pelvic pain, lead site infection, and negative changes in urinary, bowel or sexual function. Complications associated with the device include battery failure, lead migration, or loss of efficacy requiring device revision or explantation.

[0022] In some cases, modulation of bladder dysfunction may be achieved using intermittent tibial nerve stimulation. Acute effects of stimulation may include improvements in cystometry measurements, including bladder capacity. Stimulation may be performed, for example, with percutaneous needle electrodes in weekly 30-minute sessions. Because stimulation is not continuous, there may be carryover effects. The effects of percutaneous penetrating tibial nerve stimulation may be maintained, for example, after 12 weeks, but continuous monthly scheduled sessions may be required thereafter to maintain efficacy. Stimulation of the posterior tibial nerve may result in spinal root L4-S3 stimulation inhibiting bladder activity, although it is unclear whether spinal reflexes or brain networks are involved in the effect. The presence of carryover effects after a period of stimulation suggests plasticity mechanisms at either the spinal or brain levels.

[0023] Transcutaneous stimulation of one, two or more target nerves of interest, such as saphenous and / or tibial nerve stimulation, can control urinary incontinence symptoms with varying levels of success.However, in some embodiments, transcutaneous stimulation may be preferred.The feasibility of stimulation at home has been limited by device form factor and the limited programming flexibility of current devices.

[0024] In some embodiments, more continuous stimulation at the level of the tibial and / or saphenous nerves may potentially improve the efficacy of peripheral nerve stimulation for disorders such as urinary incontinence. Implantable percutaneous penetrating tibial nerve stimulators may be effective and safe. Some embodiments may use a stimulation frequency of, for example, about 1 kHz to about 100 kHz, 1 Hz to about 100 Hz, about 1 Hz to about 50 Hz, about 5 Hz to about 30 Hz, or about 10 Hz to about 20 Hz at or below the sensory threshold or below the motor contraction threshold that is tolerable to the patient for a certain period of time, for example, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, or about 60 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, or at least about 60 minutes, or for a period of about 20 minutes or less, about 30 minutes or less, about 40 minutes or less, about 50 minutes or less, or about 60 minutes or less. Varying the regularity of stimulation and frequency of the stimulation waveform may improve tolerance or efficacy in some cases. Increasing the frequency of stimulation may be more effective but may require a more chronic, at-home portable system to provide continuous transcutaneous stimulation throughout the day.

[0025] Stimulating at intensities below the sensory threshold or at high frequencies (e.g., about 1 kHz to about 100 kHz) can avoid the discomfort (tingling, numbness, pain) that can be associated with peripheral nerve stimulation. Because the exact electrode location, size and surface contact have a large effect on the stimulation level and the anatomical structures receiving the stimulation, the sensory threshold may need to be calibrated for each patient and each session. This calibration may be done by the user manually setting the stimulation parameters or by otherwise indicating their sensory threshold. Another possible embodiment is for the device to automatically sweep through a series of stimulation parameters and for the patient to select the most comfortable set of parameter values. Another possible embodiment is for the patient to select from a set of previously selected parameter values ​​that provided effective and comfortable stimulation.

[0026] In some embodiments, disclosed herein is a peripheral nerve stimulation device that improves disorders including, but not limited to, urinary dysfunction. Stimulation can target one, two, three, or more nerves associated with bladder function. Nerves can include, for example, the tibial nerve or posterior tibial nerve, which can branch into the medial and lateral plantar nerve branches and the calcaneal nerve. The saphenous nerve is a cutaneous branch of the femoral nerve. Other nerves include, for example, the pudendal nerve, pelvic nerve, dorsal genital nerve, external anal sphincter, and dorsal genital nerve. In some embodiments, the posterior tibial nerve can be stimulated percutaneously in a manner similar to percutaneous penetrating tibial nerve stimulation, but in a non-invasive and more chronic manner. In some embodiments, the systems and methods include only percutaneous elements without implantable and / or percutaneous penetrating elements.

[0027] Without being limited by theory, the voluntary control of the bladder may be largely through the autonomic nervous system (ANS). The ANS maintains a balance that may be important for the normal function of the body's organs. For example, the hypogastric nerve (sympathetic) and the pelvic nerve (parasympathetic) work together to transmit information about bladder filling to the brain and enable the relaxation contraction mechanism that controls urination. Figure 1 shows non-limiting structures and pathways related to bladder function.

[0028] Activation of the pontine micturition center (PMC) results in parasympathetic activation of the bladder, which then contracts the bladder muscles and relaxes the urethral muscles. The command to micturition is terminated when CNS structures, including the periaqueductal gray (PAG), receive the signal that the bladder is no longer full.

[0029] Inappropriate activation and inhibition of the parasympathetic and sympathetic nervous systems can result in bladder fullness, urgency, discomfort, and / or involuntary urination. Peripheral stimulation affecting autonomic activity can be used to modulate or interrupt the micturition reflex circuit to correct abnormal bladder function. This modulation can be achieved, for example, by stimulation of the saphenous nerve, the tibial nerve, or a combination of the two. In some embodiments, the systems and methods use stimulation schemes designed to dephase, override, or interrupt the abnormal network. In some embodiments, the systems and methods use stimulation schemes designed to restore balance between sympathetic and parasympathetic activity of the micturition reflex loop. Advantageously, certain embodiments utilize transcutaneous afferent stimulation of one, two, or more peripheral nerves to modulate brain or spinal pathways related to bladder function, and / or organs or target sites remote from the stimulation site(s).

[0030] Generally, sympathetic fibers originate from the T11-L2 segments of the spinal cord, and parasympathetic fibers originate from the S2-S4 spinal segments. The sympathetic fibers pass through the hypogastric nerve and inferior mesenteric artery ganglion, and the parasympathetic fibers travel within the pelvic nerves and plexuses. In some cases, the effective frequency band of this parasympathetic modulation may be, for example, a frequency band of approximately 10-20 Hz, while the frequency band of sympathetic modulation may in some cases be as high as 30 Hz or as low as 5 Hz. Without being limited by theory, in some cases, higher frequencies may provide comfort benefits, and lower frequencies may provide more adequate protection benefits.

[0031] In some embodiments, the systems and methods include stimulation parameters including frequency and spatial selectivity on the surface of the distal limb to selectively modulate and balance the sympathetic and parasympathetic nervous systems.

[0032] Without being limited by theory, stimulation of a first target nerve, such as the saphenous nerve, may provide sympathetic regulation of the bladder circuit. Specifically, electrical stimulation tuned to excite large myelinated fibers in a target nerve, such as the saphenous nerve, may provide somatic afferent input to the lumbar plexus via sympathetic input to the bladder circuit via the hypogastric nerve. The sympathetic nerve releases norepinephrine, activating beta-adrenergic receptors to relax the detrusor muscle of the bladder and activating alpha-adrenergic receptors to contract the intrinsic urethral sphincter. Relaxing the bladder and contracting the intrinsic sphincter may provide comfort during the filling and storage phases of the bladder cycle. Stimulation of a second target nerve, such as the tibial nerve, may provide parasympathetic regulation of the bladder circuit. Specifically, electrical stimulation tuned to excite the large myelinated fibers of the tibial nerve provides somatic afferent input to the sacral micturition center, the sacral plexus, via parasympathetic input to the bladder circuit via the pelvic nerves through the release of cholinergic transmitters. There may also be input from somatic efferent nerves of the pelvic floor to the external urethral sphincter, modulating the afferent sensation of bladder filling. Due to the extensively connected circuit-based mechanisms of these circuits, all of the above mechanisms can, in some embodiments, modulate the central cortical micturition center and the pontine micturition center, which modulate and time their signals.

[0033] The system can execute pre-specified program options that vary stimulation parameters and target one or more nerves individually or in combination to improve a particular patient's overactive bladder symptoms, whether the challenge is primarily daytime urgency, nighttime awakenings (nocturia), or incontinence. Alternatively, the system can be closed loop on a number of parameters including subject's symptom history including nighttime awakening events or manually entered voiding displayed on the on-board device or a secondary device, direct detection of sympathetic and parasympathetic activity in the bladder or entire circuit including HRV and galvanic skin response, and / or closed loop based on previous device use, e.g., pure sympathetic excitation can be augmented by brief periods of parasympathetic balance.

[0034] In some embodiments, the neurostimulation may be synergistically combined with one, two, or more medications for overactive bladder, including, but not limited to, anticholinergics (e.g., oxybutynin, tolterodine, trospium, darifenacin, solifenancin, and / or fesoterodine), beta-3 adrenergic agonists (e.g., mirabegron), anticonvulsants (e.g., flavoxate), and / or antidepressants (e.g., tricyclic antidepressants such as desipramine or imipramine), hormonal agents (e.g., estrogen and / or progesterone), or botulinum toxin.

[0035] The use of chronic non-invasive stimulation may involve specific waveform characteristics to comfortably excite sensory neurons. The frequency of stimulation used may be, for example, about 1 Hz to about 500 Hz (e.g., about 5 Hz to about 30 Hz, e.g., about 10 Hz to about 20 Hz, etc.), or about 1 kHz to about 100 kHz, to preferentially affect the appropriate targets. In some embodiments, the waveform may be biphasic rectangular or charge-balanced to minimize skin irritation, as shown diagrammatically in FIG. 1A. In some embodiments, the waveform may be asymmetric, particularly when stimulating one, two, three, or more nerves, as described, for example, in U.S. Provisional Patent Application No. 62 / 360,265, filed July 8, 2016, the entire contents of which are incorporated herein by reference. In some embodiments, the waveform shape and rising edge may be modified to enhance patient comfort and tolerance of the treatment. In some embodiments, the waveform may include a high frequency sine wave within a rectangular signal, as shown in FIG. 1B. The interval between opposing waveforms may be adjusted to a value that allows for charge balance, so that the excitatory effect of the first waveform cannot be immediately countered by the second waveform, but the charge at the interface can be balanced to reduce skin irritation and increase comfort. In some cases, an interval of 0 microseconds to 300 microseconds is effective. The amplitude of the waveforms may be adjusted to be perceptible, above the minimum sensory threshold, but not intolerable to the patient.

[0036] In some embodiments, the effector can be excitatory to the nerve. In other embodiments, the effector can be inhibitory to the nerve. In some embodiments, the system can be used to excite the nerve during some portions of the treatment and inhibit the nerve during other portions of the treatment.

[0037] In some embodiments, waveforms, including those described herein, may be modified over time to minimize certain effects such as habituation. One way to reduce habituation is to modify the frequency, pulse width, or amplitude of the stimulation. For example, randomization or pseudorandomization of parameters such as frequency or pulse width can reduce habituation. Using a Gaussian distribution for randomization may be effective in some cases and may be used with waveforms such as stochastic waveforms. Another way to reduce habituation is to lower the frequency below a certain threshold to which humans tend not to habituate, such as about 60 Hz or less, about 55 Hz or less, about 50 Hz or less, about 45 Hz or less, or about 40 Hz or less.

[0038] Varying other parameters, such as amplitude, can be a way to improve the comfort of the waveform. For example, the amplitude of the stimulation can be adjusted based on the threshold required to generate strong sensations and paresthesia without inducing motor contractions. Muscle excitation can lead to unpleasant muscle cramping sensations in some embodiments. The amplitude can also be adjusted to an appropriate and comfortable value depending on the person's position or movement throughout the session.

[0039] The stimulation waveforms described herein may be applied continuously to a target nerve, such as the tibial and / or saphenous nerve, or may be shaped in a manner adapted to apply stimulation of various durations, or by adjusting the characteristics of the stimulation waveform, including, but not limited to, amplitude, frequency, and pulse width, in response to different inputs of the system. In some embodiments, the system may include closed-loop control, using one or more signals measured by the device or feedback input to the device by the patient or physician, to adjust the stimulation to enhance efficacy. The signals or inputs may include, for example, any number of sensors on the device or connected to the digital ecosystem, assessment of autonomic function, reflex loop integrity, or excitability using heart rate variability, measurement of muscle sympathetic nerve activity (MSNA), and / or measurement of the h-reflex by sending a stimulation signal and measuring the response using EMG. In some embodiments, the signals or inputs may further include a sleep sensor set, including, but not limited to, an accelerometer, a gyroscope, an infrared-based motion sensor, and / or a pressure sensor under the mattress, to measure nighttime movement as a measure of nocturia events. For example, a patient can wear the stimulator while sleeping, and treatment can be initiated by nighttime restlessness that is indicative of an upcoming nocturia event. A motion sensor set (e.g., accelerometer, IR-based motion sensor, etc.) can measure the rapid back and forth movement of the legs that is typically seen when a person feels urgency. An EEG headband can be used to measure different sleep states. Patient and / or physician input can provide feedback of the effectiveness of and / or satisfaction with the treatment to the device or another connected device. Also, the use of the stimulator can be tracked, and a particular stimulation program (e.g., a specified set of stimulation parameters) can be altered based on symptoms exhibited by the patient or the results of the treatment.

[0040] In some embodiments, the stimulator may be part of a system with sensors to assess sleep states and adjust stimulation based on the wearer's sleep state. The sensors may include motion sensors (e.g., body-worn accelerometers and gyroscopes, or wireless motion tracking sensors via video or infrared), temperature sensors to measure body temperature, pressure sensors under the mattress to measure motion, heart rate sensors to measure HRV, sensors to measure sympathetic and parasympathetic activity, and / or EEG sensors to measure brain activity to assess the wearer's sleep state. For example, if a nocturia event occurs during slow wave sleep, where parasympathetic activity may be elevated, stimulation parameters are adjusted to affect parasympathetic activity and vice versa for sympathetic activity.

[0041] In some embodiments, a first stimulation frequency may be applied to obtain a short-term effect, and a second stimulation frequency different from the first stimulation frequency (e.g., higher or lower) may be applied to obtain a long-term effect. For example, 10 Hz stimulation may provide a short-term effect, and in some cases, 20 Hz stimulation may provide a long-term effect. As an example, 10 Hz stimulation may be applied early in treatment (e.g., 3 weeks) for acute treatment, followed by 20 Hz stimulation for long-term maintenance or disease treatment, or vice versa depending on the desired clinical outcome. In some embodiments, specific sympathetic and / or parasympathetic targets and circuits may be specifically targeted to regulate upward or downward sympathetic and / or parasympathetic nervous activity depending on the patient's underlying autonomic nervous system activity. For example, as disclosed elsewhere herein, the use of data and / or sensors that directly or indirectly measure sympathetic and / or parasympathetic nervous system activity may be utilized as closed-loop feedback input to a hardware and / or software controller to modify stimulation parameters, e.g., in real time.

[0042] In some embodiments, the treatment (e.g., stimulation) may be applied for about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or more, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, or more, or for about 5 minutes or less, about 10 minutes or less, about 15 minutes or less, about 30 minutes or less, about 45 minutes or less, about 1 hour or less, about 2 hours or less, about 3 hours or less, about 4 hours or less, about 5 hours or less, about 6 hours or less, or more. In some embodiments, the patient is treated at night, such as during sleep, and / or upon awakening. Treatment may be repeated daily or weekly once, twice, three times, four times, five times or more, every other day, every third day, weekly, or at other intervals depending on the desired clinical result.

[0043] In some embodiments, the responsiveness may depend on different time periods. For example, the patient or physician (or algorithm) may pre-schedule different onset treatment sessions throughout the day, and the device may apply treatment stimuli at different times of the day. In one example, treatment is administered at regular or irregular intervals during the day, at a frequency associated with typical urination volume. In treating nocturia, stimulation may be timed to regular intervals while the person is asleep. In some embodiments, a stimulation scheme is applied to restore autonomic dysfunction based on natural circadian patterns of sympathetic or parasympathetic activity. Treatment may further occur at irregular intervals input by a human or predicted by machine learning from the previous day's urination incidents. In some embodiments, a first frequency (e.g., 10Hz or 20Hz) treatment may be applied in the morning for acute daytime relief, and a second, different higher or lower frequency (e.g., 20Hz or 10Hz) treatment may be administered before bed for longer nighttime relief.

[0044] In some embodiments, the responsiveness may be activity dependent. For example, in nocturia, a motion sensor such as an accelerometer or gyroscope may sense whether a person is awake, which may indicate a potential desired urination. During that time, the device may be turned on to apply the appropriate stimulation. In some embodiments, once urination is over, the device may be turned off.

[0045] In some embodiments, the responsiveness of the stimuli may depend on one, two, or more sensors housed within the device to collect, store, and analyze biological measures of the wearer, such as, but not limited to, movement (e.g., accelerometers, gyroscopes, magnetometers, flexion sensors), ground reaction forces or foot pressure (force sensors or pressure insoles), muscle activity (e.g., EMG), cardiovascular measures (e.g., heart rate, heart rate variability (HRV)), skin conductance (e.g., skin conductance response, galvanic skin response), respiration rate, skin temperature, and sleep state (e.g., awake, light sleep, deep sleep, REM). Using standard statistical analysis techniques such as logistic regression or naive Bayes classifiers, these biological measures may be analyzed to assess the wearer's activity state, such as sedentary or active, stress level, and / or bladder fluid volume, which may serve as predictors of increased urinary urgency.

[0046] Sympathetic and parasympathetic activity may be measured by several methods, including microneurography (MSNA), catecholamine testing, heart rate, HRV, or galvanic skin response. HRV may provide a rapid and valid approximation of autonomic activity in the body. HRV may be determined by analyzing the time interval between heartbeats (also known as RR intervals). Heart rate may be accurately obtained, for example, via a recording device such as a chest strap or finger sensor. The difference between successive RR intervals may indicate the state of cardiac health and autonomic activity. Generally speaking, the healthier the heart, the greater the variability between successive RR intervals. This beat-to-beat data may be used to indicate the level of sympathetic and parasympathetic activity of an individual. With frequency domain analysis, heartbeat frequencies may be separated into distinct bands. In most cases, high frequency signals (approximately 0.15-0.4 Hz) reflect parasympathetic activity, while low frequency signals (approximately 0.04-0.15 Hz) represent a mix of sympathetic and parasympathetic activity. Therefore, taking the ratio of high frequency (HF) signal to low frequency (LF) signal gives an approximation of sympathetic tone. In some embodiments, HRV can be analyzed under time domain method, geometric domain method, in addition to frequency domain method, for example. In some embodiments, an increase in heart rate variability can indicate an increase in parasympathetic response and / or a decrease in sympathetic response. A decrease in heart rate variability can mean a decrease in parasympathetic response and / or an increase in sympathetic response. In some embodiments, the system can sense an increase or decrease in HRV of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, about 100% or more, or more than about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, about 100% or more, from a baseline value (or a target value for a desired HRV value) and set changes in one, two or more stimulation modality parameters accordingly.In some embodiments, the one, two, or more stimulation modalities may be configured to regulate, for example, increased or decreased stimulation to one or more nerves (e.g., peripheral nerves) associated with the sympathetic and / or parasympathetic nervous systems, and a response to treatment may be ascertained by sensing an increase or decrease in parasympathetic or sympathetic tone, including, but not limited to, an increase or decrease in HRV, a change in the high frequency component of HRV, or a change in the ratio of high frequency to low frequency components of HRV.

[0047] In some embodiments, the balance of parasympathetic and sympathetic activity of the bladder reflex loop may be assessed by frequency analysis of heart rate variability measured with pulse plethysmography using an LED light source and optical sensor located within a device that measures fluctuations in light levels due to blood flow targeting one of the major blood vessels around the knee, which may include one or more of the femoral artery and vein, the popliteal artery and vein, the posterior tibial artery and vein, the anterior tibial artery and vein, and / or the descending genicular artery and vein.

[0048] A significant source of error in optical measurement of heart rate is motion artifacts due to relative motion between the optical sensor and the blood vessel being measured. In some embodiments, the optical heart rate sensor has an adhesive on the side of the housing that contacts the wearer's skin to reduce the relative motion between the sensor and the target blood vessel.

[0049] In some embodiments, one, two, or more additional sensors, including electrical sensors in contact with the wearer's skin to measure cardiac activity or pressure sensors to measure vascular changes, are disposed within the device and used in conjunction with the optical sensor to improve the fidelity of the heart rate measurement.

[0050] In some embodiments, the systems and devices have memory and a processor to extract RR intervals from the sensor data, calculate the variability of the RR intervals, transform the data into the frequency domain, and calculate high frequency signals, low frequency signals, and ratios of high frequency signals to low frequency signals.

[0051] In some embodiments, the heart rate sensor stores the collected data for a period of time to ensure proper collection of data for heart rate variability calculations, which period of time may be between 1 and 60 seconds and may extend up to 10 minutes.

[0052] In some embodiments, a sensor such as an electrode can be used to measure skin potential, also known as galvanic skin response or skin conductance. Galvanic skin response is the change in electrical resistance of the skin caused by emotional stress, which can be measured, for example, with a sensitive galvanometer. Without being limited by theory, skin resistance changes depending on the state of the sweat glands in the skin. Sweating is controlled by the sympathetic nervous system, and skin conductance can be an indicator of psychological or physiological arousal. When the sympathetic nervous system is in a high arousal state, sweat gland activity also increases, which increases skin conductance. In this way, skin conductance can be a measure of emotional and sympathetic responses that can be measured, and feedback data can be sent to a controller that adjusts stimulation, for example, to reduce sympathetic nervous system activity. Other non-limiting parameters related to sympathetic and / or parasympathetic nervous system activity that may be sensed include, for example, sweating during particular times of the day and / or night, sleep state as detected, for example, by an EEG headband (to determine times when sympathetic and / or parasympathetic activity is particularly high or low, potentially correlating sleep states such as stages 1, 2, 3, 4, or REM with nocturia), and / or movement.

[0053] The device may further respond to the number of episodes, including overactive bladder: if more episodes occur in a day, treatment may be increased, for example, by increasing the amplitude of stimulation, duration of stimulation, or number of treatment sessions.

[0054] The number of episodes of symptoms such as overactive bladder can be detected in various ways to control the stimulation applied by the system and device. In some embodiments, the patient can input events related to symptoms of overactive bladder, including but not limited to bladder voiding events, urgency events, or incontinence events, on a mobile device. In some embodiments, location services on the device, such as GPS, can detect when a person enters a building or restroom.

[0055] In some embodiments, information regarding bladder voiding may be combined with an understanding of the amount of fluid consumed by a person to better apply the desired amount of therapy. For example, more bladder voiding is expected on days when an individual consumes more beverages. FIG. 2 is a schematic diagram of a flow chart incorporating a stimulation protocol, according to some embodiments of the present invention. The time, amount, and type of beverage consumed by a patient per day may be recorded manually, as shown in box 200, or electronically, as in a software application. Knowing when and what was consumed may be used to predict when and how much the person's bladder must void, and a therapeutic dose may be applied accordingly. Information regarding the processing time of a certain amount of fluid in the human body may be used to predict through literature research, along with additional information from the patient (e.g., gender, weight, height, and possibly bladder size measured using an initial pelvic ultrasound procedure). The processing and integration of this data (shown in box 202) to predict the required amount of therapy and timing may be performed within a single device or using another separate device, such as a mobile phone. In this manner, the stimuli 204 may be applied accordingly based on the number of episodes a person experiences.

[0056] One way to record the time and type of beverage consumed is by a journal or diary, for example on a smartphone, tablet, or other device. Another way to accomplish this is by using a device such as a smart cup that identifies the type and amount of beverage consumed in a day and syncs this information to a system or device. This information can advantageously be an automated journal of the amount of liquid consumed in a day.

[0057] Bladder control and comfort require a delicate balance of sympathetic, parasympathetic, somatic efferent and afferent innervation of the bladder reflex circuit.In some embodiments, a variable frequency stimulator is electrically connected with three or more electrodes to target at least two nerves that provide sympathetic, parasympathetic and somatosensory input to the bladder reflex circuit.In some embodiments, the device is placed in a knee strap that is attached just below the knee with a fastening mechanism to hold the device firmly to the body.In some embodiments, electrodes made of adhesive hydrogel are placed in the housing of the device to allow the device to adhere to the wearer's skin.

[0058] In some embodiments, as shown diagrammatically in FIG. 3, the neurostimulator may be designed in a calf band 357 with a stimulator housing 359 configured to be attached to the calf band 357 and positioned just distal to the knee to percutaneously stimulate the posterior tibial nerve and the saphenous nerve. As shown in FIGS. 4A-4B, the neurostimulator may include an ankle brace or anklet 400 or an ankle brace (shown in FIG. 4B) with a stimulator box 402 (shown in FIG. 4A). This form factor may be further extended to, for example, socks, shoes, boots, or stockings. These form factors may be advantageous in some cases, as they are compact and do not necessarily interfere with walking. Electrodes may be incorporated into clothing, for example, in the form of conductive polymers or silver fabric. In some embodiments, dry electrodes may be utilized, such as dry electrodes including a conductive backing layer (e.g., a metal foil material disposed on a flexible polymer substrate) and a skin contact layer disposed on the conductive backing layer, which may include, for example, a polymeric, plastic, or rubber material, and a conductive filler material (e.g., a powder, a particulate material, a metal, carbon, mixtures thereof, or a porous material treated with a conductive coating) substantially uniformly dispersed throughout the silicone, plastic, or rubber material. In some embodiments, the skin contact layer has a skin-facing surface that is not coated with a hydrogel or liquid.

[0059] In some embodiments, the brace or sock weave can be designed to fit closely to the knee, calf, ankle, or other desired area of ​​the device, similar to the weave of a commonly found ankle-length sock. Electrodes can also be made from, for example, conventional hydrogels. Adhesive electrodes may require fastening elements such as clasps or Velcro® to prevent the device from slipping easily on the foot. In some embodiments, for example, knee, calf, ankle brace or anklet embodiments can be extended to electrode locations on the top (dorsal) or bottom (ventral) surface of the foot. In some cases, socks with electrodes on the sole can be used with an electronic module located near the ankle through the sock.

[0060] FIG. 5A illustrates a non-limiting embodiment of potential electrode placement locations for neural stimulation. FIG. 5B illustrates a non-limiting embodiment of potential electrode placement locations for neural stimulation. FIG. 5C illustrates a non-limiting embodiment of potential electrode placement locations for neural stimulation. Sensor systems, including those disclosed herein, can communicate to the stimulator 502 wired or wirelessly. The placement of the electrodes on the tibial stimulator can vary with the electrodes 500 attached along the tibial nerve (FIG. 5A), on the bottom of the foot (FIG. 5C), or on either side of the ankle or on the side attached to the stimulator (FIG. 5B).

[0061] In some embodiments, as shown in the embodiment of Figures 6-7, when the electrodes 606 are adhesive, a bandage-like device 600 can be created that wraps around a body part, e.g., a limb, circumferentially or non-circumferentially. The strips can be any shape, including circular, square, rectangular, triangular, or other shapes. In some cases, the electronics can be placed inside a removable housing 602 that can be removably attached to the site 604 from the entire device 600 when the consumable is discarded. Figure 6 is a bottom view of the device 600 and Figure 7 is a top view of the device 600.

[0062] In another embodiment, a thin bandage-like electrode 802 may be attached to the patient, as shown in FIG. 8. Power may be coupled from a battery source, such as a knee band, thigh band, calf band, anklet 800, or sock, loosely wrapped around the target body area, such as the knee or ankle, or placed on the side of a shoe generally near the electrode. In some embodiments, power may be delivered wirelessly to the electrode 802, for example, via inductive charging. This configuration may be advantageous in some embodiments in that the consumable may be very thin, enhancing the comfort of the skin interface even if the consumable is very sticky (which is similar to an adhesive bandage). This embodiment may also be adapted for use where the electrode bandage is placed on the bottom of the foot. In some cases, the electronics may be placed / fastened to the top or sole of the shoe.

[0063] In addition to or instead of the tibial nerve, several peripheral nerves, including the pudendal nerve and the dorsal genital nerve, which have acute and / or chronic effects on bladder function in animal and human experimental studies, may serve as targets for urinary neuromodulation. Saphenous nerve stimulation can acutely or chronically reduce bladder hyperexcitability. The saphenous nerve is a purely sensory nerve that innervates the skin of the medial leg. The proximity of the saphenous nerve to the skin surface makes it an advantageous target for transcutaneous stimulation in some embodiments. In some embodiments, selective stimulation of the saphenous nerve can advantageously reduce overactive bladder symptoms. In some embodiments, peripheral nerves can be separately targeted with specific same or different frequencies to demonstrate acute or chronic relief of overactive bladder symptoms and / or to modify sympathetic and / or parasympathetic activity.

[0064] The effect of peripheral nerve stimulation on bladder function may, in some embodiments, occur only during the period of active stimulation or may persist longer than the stimulation period after stimulation has ceased. Using the systems and methods disclosed herein, different mechanisms may be triggered, such as modulation of the micturition reflex or induction of brain and / or spinal plasticity. Furthermore, in some cases, the onset of the effect of stimulation may occur only after several stimulation sessions, either acutely or chronically. For example, the effect of percutaneous or percutaneous penetrating tibial nerve stimulation on patient-related outcomes is, in some embodiments, evaluated 4-6 weeks after the initiation of weekly stimulation sessions. Depending on the underlying mechanism and the time course of beneficial effects, stimulation may require delivery continuously, as with sacral nerve stimulation, in discrete scheduled sessions, or in an on-demand conditional form. Conditional stimulation may rely either on patient control to identify urgency or on automatic detection of involuntary detrusor contractions (IDCs) responsible for the evolution to urgency symptoms or frank incontinence.

[0065] Conditioned stimulation of the dorsal genital nerve and / or pudendal nerve may be advantageous in some embodiments. Alternatively or additionally, continuous stimulation may be utilized to control bladder symptoms. In some embodiments, benefits of conditioned stimulation may include customized symptom control, improved battery life, and reduced risk of habituation with continuous stimulation. A patient-controlled conditioned stimulation device for overactive bladder may be effective in suppressing urge symptoms before progression to incontinence.

[0066] The stimulation frequency may vary depending on the desired clinical outcome. In some embodiments, relatively high frequencies may be used, such as about 10 Hz to about 33 Hz, about 10 Hz to about 30 Hz, about 10 Hz to about 20 Hz, or about 20 Hz to about 33 Hz, or about 10 Hz, about 15 Hz, about 20 Hz, about 25 Hz, about 30 Hz, about 33 Hz, about 35 Hz, or more, or at least about 10 Hz, at least about 15 Hz, at least about 20 Hz, at least about 25 Hz, at least about 30 Hz, at least about 33 Hz, at least about 35 Hz, or more. The stimulation frequency may further be tailored to the particular nerve being targeted. In some embodiments, a slower stimulation rate, such as 2 Hz, may have an excitatory effect on bladder function and may worsen incontinence. However, in some embodiments, frequencies of about 10 Hz, about 9 Hz, about 8 Hz, about 7 Hz, about 6 Hz, about 5 Hz, about 4 Hz, about 3 Hz, about 2 Hz, or about 1 Hz may be utilized. In some embodiments, the stimulation frequency may be within a kHz range, such as, for example, about 1 kHz to about 100 kHz, for example, about 10 kHz to about 50 kHz. The stimulation may be regular, irregular, or random in some embodiments. In some embodiments, the frequency or frequencies of one, two, or more nerves may be selected from, for example, about 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, 11 Hz, 12 Hz, 13 Hz, 14 Hz, 15 Hz, 16 Hz, 17 Hz, 18 Hz, 19 Hz, 20 Hz, 21 Hz, 22 Hz, 23 Hz, 24 Hz, 25 Hz, 26 Hz, 27 Hz, 28 Hz, 29 Hz, 30 Hz, 35 Hz, 40 Hz, 45 Hz, 50 Hz. In some embodiments, two or more of the same or different frequencies or frequency ranges may be applied to the same or different target nerves.

[0067] The exact location of stimulation in the leg may vary depending on the desired target. For example, the tibial nerve may be stimulated at the level of the ankle or behind the knee. The saphenous nerve area is on the medial leg, so in some cases, stimulation of the nerve may be performed near the ankle or knee.

[0068] In some embodiments, stimulation of the saphenous nerve may be used in place of or in conjunction with tibial nerve stimulation to treat overactive bladder and / or urinary incontinence. The saphenous nerve runs up the upper leg, down along the inside of the knee, down along the tibia side of the lower leg, where it splits into two branches that continue down the tibia to the ankle and a branch that runs in front of the ankle and down the inside of the foot.

[0069] In some embodiments, a stimulator worn around the ankle or leg or knee or leg may be used to stimulate the saphenous nerve, and optionally the tibial nerve. In other embodiments, the stimulator may be worn around any other part of the leg or foot to stimulate the saphenous nerve at other locations. The electrode(s) of the stimulator may be placed in proximity to or on the saphenous nerve.

[0070] In some embodiments, the stimulation is electrical and may be applied percutaneously using electrodes placed on the patient's skin. In some embodiments, the stimulation of the saphenous nerve may be patient-actuated. In some embodiments, the stimulation of the saphenous nerve may be automatic and / or patient-actuated. In some embodiments, the stimulation of the saphenous nerve may be solely patient-actuated, meaning that stimulation is only applied while the patient is awake. If stimulation while the patient is asleep is desired, an automated stimulation therapy may be performed.

[0071] FIG. 9 illustrates an embodiment of a distal saphenous nerve sensing and / or stimulation technique. In some embodiments, treatment may be performed in supine, upright, or sitting positions. In some embodiments, rod electrodes (e.g., 3 cm) may be used. The reference electrode (R) may be positioned slightly anterior to the highest eminence of the medial malleolus between the malleolus and the tibialis anterior tendon. The active electrode (A) may be positioned slightly medial in close proximity to the tibialis anterior tendon. A return electrode, such as a ground electrode (G), may be placed, for example, between the recording electrode and the cathode. With respect to the stimulation point (S), the cathode (C) may be placed, for example, 14 cm proximal to the active electrode deep to the medial border of the tibia. The anode (A) may be, for example, proximal. In some embodiments, device settings may include any of the following: sensitivity-2-5 μV / division, low frequency filter-20 Hz, high frequency filter-2 kHz, sweep speed-1 ms / division. In some embodiments, the L3 and L4 nerve roots passing through the posterior part of the lumbosacral plexus may be tested. In some embodiments, a sensing element and its associated components such as a reference electrode (R) may not be required.

[0072] In some embodiments, a device for stimulating one, two, or more nerves is shown diagrammatically in FIG. 10. The device 10 may include a housing 20, one, two, or more effectors 30, a power source 50, and / or a controller 40. In some embodiments, the device further includes one or more sensors 70. The effectors may include a pulse generator and electrodes for delivering electrical stimulation, and / or may be a mechanical stimulator for delivering mechanical stimulation, such as, for example, a vibration stimulus. The sensors may include, for example, an accelerometer, a gyroscope, and electrodes for measuring electrical activity, including neural and muscular activity.

[0073] In some embodiments, as shown in Fig. 10A, the device may include a two- or three-dimensional array of electrodes 1000 so that stimulation can be targeted. The elements 1002 may be individually addressable so that the location of stimulation can be adjusted on the fly or for each session such as electronic referencing. Alternatively, the elements may be configured for an individual user, such as a mechanical configuration in which electrode connections are cut or joined to customize the device.

[0074] FIG. 10B illustrates an embodiment of a stimulation system 1001 including a wearable device 1010 at the ankle or other desired anatomical location and an implanted stimulation electrode 1020 around a target nerve 1030, such as the tibial nerve. In another embodiment, the wearable device may be a component of a stimulation system including subcutaneous, percutaneous, and / or percutaneous penetrating elements. For example, the wearable device may communicate with and power and control the implanted stimulation device. Additionally, the implanted electrode may be powered by a rechargeable battery housed within an implant and charged wirelessly from an external power source or the wearable device. Alternatively, the wearable device may include a guidance array used to direct the location of a percutaneous needle in either a patient-directed location or in a medical setting.

[0075] In some embodiments, the implanted electrodes that stimulate the nerves can be powered by an external stimulation unit, and the stimulation pulses are directly coupled to the electrodes and nerves using capacitive or inductive coupling. In some embodiments, the wearable device can communicate with an external computer or device (e.g., tablet, smartphone, smartwatch, or custom base station) to store data. The communication between the wearable device and the external device can be a direct connection, a physical connection, or by wireless communication connection, such as Bluetooth, Wi-Fi, Zigbee, GSM, or mobile. In some embodiments, the system communicates with an external portable computing device, such as a smartphone through an app, or other mobile digital interaction. The device can be used to track relevant event information entered by the user or automatically obtained from biological sensors, such as time since last urination and water intake, or biometric data that predicts the onset of an upcoming urinary incontinence or urgency symptom. This information can be used to close the loop to adjust stimulation parameters (waveform, amplitude, on / off) or to suggest user behavior.

[0076] In some embodiments, the wearable device may have a GPS or similar device to track the wearer's location and assess activity. GPS measurements may be combined with a mapping or location system to determine the context of the wearer's activity (e.g., whether they are at the gym or at the office) or to determine elevation changes during a particular activity, such as running or cycling.

[0077] In some embodiments, the wearable device can track parameters related to the stimulation administered by the stimulation unit, including stimulation time, duration of the stimulation session, and power used by the stimulation unit. This data can be stored in memory within the wearable device, processed by the wearable device, and / or transmitted to an external computing device.

[0078] The stimulation unit may use switches or electrical sensors to detect electrode connection, i.e., (1) to ensure that proper unique electrodes that communicate a unique code, e.g., via RFID, are installed (e.g., not using a different or incorrect type of electrode), (2) to regulate the number of times each electrode is used to prevent overuse, and / or (3) to prevent use of a device without electrodes to prevent mild shocks.

[0079] In some embodiments, the system may include features to enhance skin comfort. One solution is to use a high frequency carrier (e.g., 1 kHz or higher) over a low frequency heartbeat (10-200 Hz), or to position the electrodes so that the interaction of the two waveforms combines to produce the low frequency heartbeat.

[0080] In some embodiments, systems and methods of peripheral nerve stimulation may be provided that target one, two, or more individual nerves, as shown in FIGS. 11A-11E. In some embodiments, the system 10 may allow for customization and optimization of transcutaneous electrical therapy to an individual. In particular, the device 10 described is a device for electrical stimulation of one, two, or more nerves. For example, a two electrode embodiment may be used to stimulate the tibial and / or saphenous nerves. In some embodiments, targeting these specific nerves and utilizing appropriately customized stimulation may result in more effective treatment. In some embodiments, the target nerves may include nerves in the leg, such as the tibial and / or saphenous nerves, which may be used to treat overactive bladder. In some embodiments, the device 10 may be configured to be worn on the leg, knee, or ankle, and may be formed of a housing 12 and a band 14 or sleeve. In some embodiments, electronics and sensors located within the housing 12 may measure signs of bladder filling or other symptoms of overactive bladder, as described herein. The electronics may include, for example, a pulse generator, a controller, and one, two, or more sensors, such as an accelerometer and / or a gyroscope, and / or electrodes for measuring neural activity. Electrical contacts and / or traces in the band 14 and / or housing 12 transmit stimulation waveforms from the pulse generator to the electrodes 16, which may be disposable. The location of the contacts in the band 12 may be positioned to target specific nerves, such as the tibial nerve and / or the saphenous nerve, or other nerves, including those disclosed herein. The housing 12 may further have a digital display screen to provide feedback regarding stimulation and sensor data to the wearer of the device.

[0081] In some embodiments, disclosed herein is a dual nerve stimulator configured to be positioned just below the knee to target the saphenous and posterior tibial nerves, including a sensor to measure slow changes in heart rate variability to assess autonomic dysfunction (e.g., to balance sympathetic and parasympathetic activity), and / or an accelerometer to measure overall activity, with the targeted nerves and stimulation frequency controlled based on sensor data. Stimulation of each of the targeted nerves can be individually turned on or off, and stimulation frequency can be individually adjusted, if necessary, to provide acute or chronic relief of symptoms resulting from disorders such as overactive bladder.

[0082] In some embodiments, the therapeutic device 10 may be a wearable device including an electronic box or housing 12 that houses a stimulator or pulse generator 18, a sensor 20, and other associated electronics such as a controller or processor 22 for executing instructions, a memory 24 for storing instructions, a user interface 26 that may include a display and buttons, a communication module 28, a battery 30 that may be rechargeable, and optionally an induction coil 32 for charging the battery 30. The device 10 may further include, for example, a band or sleeve to hold all the components together and secure the device around an individual's leg, knee, foot, or ankle. The device may include, for example, a pair of electrodes on the band or sleeve.

[0083] Further system and device embodiments are shown in Figures 12 and 13, where the electrodes may be circumferential or non-circumferential electrodes and may be disposed on a wearable band (or sleeve) that may be worn around the ankle, knee, leg or other body part. The wearable band may include a removable / separable controller as further described in International Application No. PCT / US2016 / 37080, entitled "SYSTEMS AND METHOD FOR PERIPHERAL NERVE STIMULATION TO TREAT TREMOR WITH DETACHABLE TERHAPY AND MONITORING UNITS," the entire contents of which are incorporated herein by reference. As shown, the wearable band has two electrodes that may be used to stimulate up to two nerves. However, other embodiments may have N electrodes for stimulating N or fewer nerves, or N+1 electrodes for stimulating N nerves (e.g., two electrodes for stimulating one nerve, three electrodes for stimulating two nerves, or four electrodes for stimulating three nerves).

[0084] FIG. 12 shows a wearable band 800 with disposable electrodes 802, 804. The disposable electrodes 802, 804 may be disposed on a strip 806 that may be coated or covered with a conductive hydrogel and may be removably attached to the wearable band 800, which may have a receptacle 808 for receiving the strip 806. The strip 806 and band 800 may have electrical contacts and flexible circuits so that the electrodes are electrically connected to a controller 810. To accommodate different body part sizes, the disposable strip 806 may be provided with different electrode spacings. This allows one band size to accommodate users with different body part sizes. Because hydrogel may dry out, hydrogel-coated electrodes are more suitable for use with removable electrodes that may be placed and replaced periodically, for example, every 1, 2, 3, 4, 5, 6, or 7 days, as shown in FIG. 12.

[0085] In some embodiments, stimulation of three or more electrodes may be used to stimulate two or more nerves. As shown in FIG. 12A, in some embodiments, the electronic and electrical circuitry 1200 used to drive the array may include adjustable switches that can connect individual electrodes 1202 to either one of two contacts 1204, 1206 of the stimulator 1208 for a predetermined time by opening or closing a switch 1210 for each channel. To prevent current surges that may cause damage or discomfort, each channel may include a DC blocking circuit 1212 since charge balance may be important to prevent skin irritation and burning, and may be individually current limited by a current IO limiter 1214. This current limit may be set to a predetermined tolerable threshold for a particular patient or patient population.

[0086] There are many transistor circuits or components such as polyfuses to limit or cut off current to certain nodes. These circuits and their components such as stimulators, switches, and current limiters can be controlled by the microprocessor 1216 in real time and / or can be programmable. A 15 switch matrix allows multiple electrodes to be connected to the same stimulator contact at a given time for maximum flexibility. Additionally, electrodes can be switched between the positive and negative contacts of the stimulator to generate bipolar pulses.

[0087] 13 illustrates an embodiment of a wearable band 900 having embedded electrodes 902, 904. The embedded electrodes 902, 904 may be dry electrodes that communicate electrically with a separable controller 910 via a flexible circuit embedded in the band. In some cases, dry electrodes may be more suitable for long-term use electrodes that may be used for several months, such as at least one month, two months, or three months, before the band needs replacing. In some embodiments, the band may be a disposable band that may be used for a relatively long period of time before replacing.

[0088] In some embodiments, disclosed herein are systems and methods for stimulating multiple nerves for the treatment of disorders including, but not limited to, overactive bladder. Stimulation of two, three, or more nerves, such as the saphenous nerve and the tibial nerve, may be used to treat disorders such as overactive bladder. Dual nerve stimulation may synergistically enhance the efficacy of treatment in some cases, for example, by synergistically combining the effects of saphenous nerve stimulation and tibial nerve stimulation. In some embodiments, including those disclosed in connection with Figures 14 and 15 below, the system may be configured to separately control the stimulation of a first target nerve (including stimulation parameters such as frequency and other parameters listed herein) and the stimulation of a second target nerve. That is, the first target nerve and the second target nerve may be stimulated with the same or different parameters, and may be stimulated simultaneously or alternately, or otherwise. In some embodiments, the stimulation system may include multiple independent stimulation circuits, or a common circuit with a controller configured to switch between stimulation parameters of one, two, or more nerves.

[0089] In some embodiments, as shown diagrammatically in FIG. 14, the system 1400 may use three electrodes: a first electrode 1404 positioned over a first nerve, e.g., the tibial nerve 1402; a second electrode 1406 positioned over a second nerve, e.g., the saphenous nerve 1408; and a third electrode 1410 positioned opposite the first two electrodes 1404, 1406, e.g., on the outside of the leg. This third electrode 1410 serves as a common cathode for the other two electrodes 1404, 1406. The three electrodes 1404, 1406, 1410 may be oriented such that the electric field between each of the first two electrodes 1404, 1406 and the common cathode 1410 passes through the tibial nerve 1402 and the saphenous nerve 1408, respectively.

[0090] Another possible configuration, shown in Figure 15, utilizes four electrodes. Similar to the embodiment shown in Figure 14, three channels are used: a first channel targeting the tibial nerve 1402, a second channel targeting the saphenous nerve 1408, and a channel serving as a common cathode 1410. However, the cathode of the electronics is split between two common electrodes 1411, 1413, each serving as the cathode for the other two electrodes 1404, 1406. Thus, the first electrode 1404 is positioned above the tibial nerve 1402, the first cathode electrode 1411 is positioned directly below it, the second electrode 1406 is positioned above the saphenous nerve 1408, and the second common electrode 1413 is positioned directly below it. Each electrode pair 1404, 1411 and 1406, 1413 can be oriented such that the electric field between the two electrodes (the electrode over the nerve and its respective common electrode) passes through the intended nerve (e.g., the tibial nerve or saphenous nerve).

[0091] A 4-week proof-of-concept (POC) study of percutaneous saphenous nerve stimulation was conducted, enrolling seven subjects. Eligibility was confirmed using the industry standard OAB-V8 screening and one week of baseline data. Subjects were treated with 60 minutes of saphenous nerve stimulation daily. Data collected included a voiding diary three days per week, and four weeks of scheduled ICIQ-SF and OAB-Q patient assessments. Study data are shown in Figures 16A-C. Figure 16A is a bar graph showing patient response after one week of daily treatment, which is faster than the four-week response reported for percutaneous penetrating stimulation. All subjects improved, and four subjects with mild to moderate incontinence symptoms saw near complete relief of incontinence. Figure 16B shows that nocturia also generally improved. Figure 16C shows results from the OAB-q scale, an established scale of quality of life in overactive bladder, demonstrating a clinically significant (e.g., ≥10 points) improvement in QOL.

[0092] A 4-week proof-of-concept (POC) study of percutaneous transtibial nerve stimulation was conducted, with four subjects enrolled. Eligibility was confirmed using industry-standard OAB-V8 screening and one week of baseline data. Subjects were treated with 60 minutes of tibial nerve stimulation daily. Data collected included frequency, incontinence, and nocturia data. Study data is shown in Figures 17A-17F. Figure 17A shows a table of subject baseline parameters including 24-hour OAB-V8 score, frequency, incontinence, and nocturia rates. Figure 17B shows a table of responder rates for nocturia, incontinence, and frequency. Figure 17C shows a table of improvement in voiding parameters including frequency, incontinence, and nocturia. As shown in the graphs in Figures 17D, 17E, and 17F, the number of frequency episodes per 24 hours, the number of incontinence episodes per 24 hours, and the number of nocturia episodes per 24 hours generally improve with stimulation. In this specification, when a feature or element is referred to as "on" another feature or element, it means that the feature or element may be directly on the other feature or element, or there may be intervening features and / or elements as well. On the other hand, when a feature or element is referred to as "directly on" another feature or element, it means that there are no intervening features or elements. Furthermore, when a feature or element is referred to as "connected," "attached," or "coupled" to another feature or element, it will be understood that the feature or element may be directly connected, attached, or coupled to the other feature or element, or there may be intervening features or elements. On the other hand, when a feature or element is referred to as "directly connected," "directly attached," or "directly coupled" to another feature or element, there are no intervening features or elements. Although described or illustrated with respect to one embodiment, the features and elements so described or illustrated are applicable to other embodiments. Those skilled in the art will further understand that a reference to a structure or feature being located "adjacent" another feature may have portions that overlap or underlie the adjacent feature.

[0093] The terms used herein are for the purpose of describing particular embodiments only and are not limiting of the present invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural unless the context clearly indicates otherwise. As used herein, the terms "comprises" and / or "comprising" specify the presence of the stated features, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0094] Spatially relative terms such as "under," "below," "lower," "over," "upper," and the like may be used herein to facilitate describing the relationship of an element or feature to another element(s) or feature(s) as depicted in the drawings. It will be understood that the spatially relative terms are intended to include different orientations of the device in use or operation in addition to the orientation depicted in the drawings. For example, if a device in the drawings is inverted, an element described as being "below" or "directly below" another element or feature would be oriented "above" the other element or feature. Thus, the exemplary term "below" can include both an upward and downward orientation. The device may be oriented in another direction (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein may be interpreted accordingly. Similarly, unless otherwise noted, terms such as "upward," "downward," "vertical," "horizontal," and the like are used herein for descriptive purposes only.

[0095] The terms "first" and "second" may be used herein to describe various features / elements (including steps), but these features / elements should not be limited by these terms unless otherwise specified. These terms may be used to distinguish one feature / element from another. Thus, a first feature / element described below can be referred to as a second feature / element, and similarly, a second feature / element described below can be referred to as a first feature / element without departing from the teachings of the invention.

[0096] Throughout this specification and the appended claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" mean that various components may be used together in methods and articles (e.g., compositions and devices and apparatus that include methods). For example, the term "comprising" will be understood to imply the inclusion of any recited elements or steps but not the exclusion of other elements or steps.

[0097] All numbers, including those used in the examples, when used in the specification and claims, unless expressly stated otherwise, may be read as if they are preceded by the word "about" or "approximately", even if not expressly indicated. The phrase "about" or "approximately" may be used when describing a magnitude and / or location to indicate that the stated value and / or location is within a reasonable expected range of values ​​and / or locations. For example, a numerical value may have a value of + / -0.1% of the stated value (or range of values), + / -1% of the stated value (or range of values), + / -2% of the stated value (or range of values), + / -5% of the stated value (or range of values), + / -10% of the stated value (or range of values), etc. Any numerical value provided herein should be understood to include "about" or "approximately" that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all subranges subsumed therein. As would be well understood by one of ordinary skill in the art, when a value is disclosed, it is also understood that "less than or equal to that value," "more than or equal to that value," and possible ranges between those values ​​are also disclosed. For example, when a value "X" is disclosed, "less than or equal to X" and "more than or equal to X" (e.g., X is a numeric value) are also disclosed. It is also understood that throughout this application, data is provided in a number of different formats, and this data represents endpoints and starting points, and ranges for any combination of data points. For example, when a specific data point "10" and a specific data point "15" are disclosed, the ranges from 10 to 15, above 10 and above 15, above 10 and above 15, below 10 and below 15, below 10 and below 15, and equal to 10 and 15, are also considered to be disclosed. It is also understood that each unit between two specific units is also disclosed. For example, when 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0098] Although various embodiments have been described above, any of a number of modifications may be made to the various embodiments without departing from the scope of the invention as set forth in the claims. For example, the order in which the various method steps described are performed is often changed in alternative embodiments, and in other alternative embodiments, one or more method steps may be skipped entirely. The methods disclosed herein include specific actions taken by a practitioner, but may also include any instruction of these actions by a third party, either explicitly or implicitly. For example, an action such as "stimulate a peripheral nerve" includes "instructing stimulation of a peripheral nerve." Any feature of the various device and system embodiments may be included in some embodiments and not in other embodiments. Thus, the above description is provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention as set forth in the claims.

[0099] The examples and descriptions contained herein are illustrative, not limiting, of specific embodiments in which the subject matter may be practiced. As noted above, other embodiments may be utilized and derived, and structural and logical substitutions and changes may be made without departing from the scope of the present disclosure. Such embodiments of the subject matter of the present invention may be referred to herein, individually or collectively, by the term "invention" when in fact more than one is disclosed, merely for convenience, and without any voluntary attempt to limit the scope of the present application to any one invention or inventive concept. Thus, although specific embodiments have been illustrated and described herein, any configuration calculated to achieve the same purpose may be substituted for the specific embodiment shown. The present disclosure is intended to encompass any and all adaptations or modifications of the various embodiments. Combinations of the above embodiments, as well as other embodiments not specifically described herein, will be apparent to those skilled in the art upon reviewing the above description.

Claims

1. 1. A method of treating urinary symptoms in a patient by dual percutaneous stimulation of the saphenous nerve and the posterior tibial nerve, comprising: positioning a first peripheral nerve effector on the patient's skin to stimulate the patient's saphenous nerve; positioning a second peripheral nerve effector on the patient's skin to stimulate the patient's posterior tibial nerve; delivering a first electrical nerve stimulation signal percutaneously to the saphenous nerve via the first peripheral nerve effector; delivering a second electrical nerve stimulation signal percutaneously to the posterior tibial nerve via the second peripheral nerve effector; receiving input related to autonomic nervous system activity of the patient; modifying at least one brain or spinal cord autonomic feedback loop associated with bladder function based on the input to balance activity of the patient's parasympathetic and sympathetic nervous systems; Including, The method does not utilize an implantable element and involves only transcutaneous stimulation.

2. The method of claim 1 , wherein the first peripheral nerve effector and the second peripheral nerve effector are both positioned proximate to the patient's knee.

3. The method of claim 1 or claim 2, wherein the first electrical stimulation signal is different from the second electrical stimulation signal.

4. 3. The method of claim 1 or claim 2, wherein the first electrical stimulation signal has a first frequency that is different from a second frequency of the second electrical stimulation signal.

5. The method of claim 1 or claim 2, wherein the first electrical stimulation signal has a different amplitude than the second electrical stimulation signal.

6. The method of claim 4 , wherein the first frequency is between about 5 Hz and about 30 Hz.

7. The method of claim 4 , wherein the second frequency is between about 10 Hz and about 20 Hz.

8. 3. The method of claim 1 or claim 2, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data from a sensor that measures the patient's autonomic nervous system activity.

9. 3. The method of claim 1 or claim 2, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data from a sensor measuring the patient's heart rate variability.

10. 3. The method of claim 1 or claim 2, wherein receiving input related to the patient's autonomic nervous system activity comprises measuring blood flow characteristics and receiving heart rate variability data from an optical sensor positioned proximate a blood vessel proximate the patient's knee.

11. 3. The method of claim 1 or claim 2, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data from a sensor that measures the patient's galvanic skin response.

12. 3. The method of claim 1 or claim 2, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data related to the patient's urinary symptoms.

13. 3. The method of claim 1 or claim 2, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data related to the patient's episodes of nocturia.

14. 1. A wearable device for dual percutaneous stimulation of the saphenous nerve and the posterior tibial nerve to treat urinary symptoms in a patient, comprising: A controller; a first peripheral nerve effector including at least one stimulation electrode configured to be positioned to percutaneously modulate the saphenous nerve; a second peripheral nerve effector including at least one stimulation electrode configured to be positioned to percutaneously modulate the posterior tibial nerve; at least one biomedical sensor or data input source configured to provide feedback information; Equipped with The controller comprises a processor and memory for receiving the feedback information from the sensor, and when executed by the processor, causes the device to: adjusting one or more parameters of the first electrical stimulus and the second electrical stimulus based at least in part on the feedback information; and delivering the first electrical stimulus to the saphenous nerve via the first peripheral nerve effector and the second electrical stimulus to the posterior tibial nerve via the second peripheral nerve effector to modify an autonomic feedback loop in the brain or spinal cord associated with bladder function to balance sympathetic and parasympathetic activity, thereby reducing urinary symptoms; A wearable device, wherein the device is not configured for implantation within the patient's body.

15. The device of claim 14 , wherein the feedback information comprises real-time feedback information.

16. 15. The device of claim 14, wherein the first electrical stimulus has a frequency of about 5 Hz to about 30 Hz.

17. 15. The device of claim 14, wherein the second electrical stimulus has a frequency of about 10 Hz to about 20 Hz.

18. The device of claim 14 , wherein the feedback information includes the patient's autonomic nervous system activity.

19. The device of claim 18 , wherein the feedback information comprises heart rate variability.

20. A device according to any of claims 14 to 19, wherein the feedback information comprises information relating to the patient's nocturia events.

21. The device according to any one of claims 14 to 19, wherein the feedback information comprises information regarding a patient's sleep state.

22. 1. A method of treating urinary symptoms in a patient by dual percutaneous stimulation of the saphenous nerve and the posterior tibial nerve, comprising: Providing a wearable device according to any one of claims 14 to 21; positioning a first peripheral nerve effector on the patient's skin to stimulate the patient's saphenous nerve; positioning a second peripheral nerve effector on the patient's skin to stimulate the patient's posterior tibial nerve; delivering a first electrical nerve stimulation signal percutaneously to the saphenous nerve via the first peripheral nerve effector; delivering a second electrical nerve stimulation signal percutaneously to the posterior tibial nerve via the second peripheral nerve effector; receiving input related to autonomic nervous system activity of the patient; modifying at least one brain or spinal cord autonomic feedback loop associated with bladder function based on the input to balance activity of the patient's parasympathetic and sympathetic nervous systems; Including, The method does not utilize an implantable element and involves only transcutaneous stimulation.

23. Use of a device as described in any one of claims 14 to 21 for modifying at least one brain or spinal cord autonomic feedback loop associated with bladder function based on said input to balance activity of the patient's parasympathetic and sympathetic nervous systems.

24. 1. A method of treating a urinary symptom in a patient, comprising: positioning a first electrode at a first location on a skin surface relative to a first afferent peripheral nerve; positioning a second electrode at a second location on the skin surface relative to a second afferent peripheral nerve; positioning a third electrode at a third location on the skin surface spaced from the first electrode and the second electrode; delivering a first stimulus to the first peripheral nerve via the first electrode; delivering a second stimulus to the second peripheral nerve via the second electrode. Including, the third electrode being a single common return electrode for the first and second electrodes; the first electrode, the second electrode, and the third electrode are positioned such that an electric field between the first electrode and the third electrode passes through the first peripheral afferent nerve, and an electric field between the second electrode and the third electrode passes through the second peripheral afferent nerve; The method, wherein the first stimulus and the second stimulus modify at least one brain or spinal cord autonomic feedback loop associated with bladder function.

25. 25. The method of claim 24, wherein the first afferent peripheral nerve includes the posterior tibial nerve.

26. 26. The method of claim 24 or claim 25, wherein the second afferent peripheral nerve comprises the saphenous nerve.

27. The method according to any one of claims 24 to 26, wherein the condition comprises overactive bladder.

28. The method according to any one of claims 24 to 26, wherein the symptom comprises nocturia.

29. The method according to any one of claims 24 to 26, wherein the symptoms include urinary urgency.

30. The method according to any one of claims 24 to 26, wherein the symptom comprises frequent urination.

31. 31. The method of any of claims 24 to 30, wherein the first electrode, the second electrode, and the third electrode are all connected to a wearable device and positioned on the patient's calf proximate to and distal to the knee.

32. The method of any of claims 24 to 30, wherein the first electrode, second electrode, and third electrode are all connected to a wearable device and positioned adjacent to the patient's ankle.

33. The method of any of claims 24 to 30, wherein the first electrode, the second electrode, and the third electrode are all connected to a wearable device and positioned in proximity to a foot of the patient.

34. 1. A method of treating a urinary symptom in a patient, comprising: positioning a first electrode pair including an anode and a cathode at a first location on a skin surface relative to a first peripheral nerve; positioning a second electrode pair including an anode and a cathode at a second location on the skin surface relative to a second peripheral nerve; delivering a first stimulus to the first peripheral nerve via the first electrode pair; delivering a second stimulus to the second peripheral nerve via the second electrode pair; Including, the first electrode pair and the second electrode pair are positioned such that an electric field between the first electrode pair passes through the first peripheral nerve and an electric field between the second electrode pair passes through the second peripheral nerve; The method, wherein the first stimulus and the second stimulus modify at least one brain or spinal cord autonomic feedback loop associated with bladder function.

35. 1. A system for treating a urinary symptom of a patient, comprising: a wearable housing configured to be positioned on the patient's calf adjacent the patient's knee; a first electrode configured to be positioned at a first location on the skin surface relative to a first afferent peripheral nerve; a second electrode configured to be positioned at a second location on the skin surface relative to a second afferent peripheral nerve; a third electrode configured to be positioned at a third location on the skin surface spaced from the first electrode and the second electrode; a controller configured to deliver a first stimulus to the first peripheral nerve via the first electrode and a second stimulus to the second peripheral nerve through the second electrode to modify at least one brain or spinal cord autonomic feedback loop associated with bladder function; Equipped with the third electrode being a single common return electrode for the first and second electrodes; the first electrode, the second electrode, and the third electrode are configured to be positioned such that an electric field between the first electrode and the third electrode passes through the first peripheral afferent nerve and an electric field between the second electrode and the third electrode passes through the second peripheral afferent nerve; The wearable housing is attached to each of the first electrode, the second electrode, and the third electrode.

36. 36. The system of claim 35, wherein the first peripheral afferent nerve is the posterior tibial nerve and the second peripheral afferent nerve is the saphenous nerve.

37. 1. A system for treating a urinary symptom of a patient, comprising: a first electrode pair configured to be positioned at a first location on the skin surface relative to a first afferent peripheral nerve; a second electrode pair configured to be positioned at a second location on the skin surface relative to a second peripheral afferent nerve; a controller configured to deliver a first stimulus to the first peripheral nerve via the first electrode pair and a second stimulus to the second peripheral nerve via the second electrode pair to modify at least one brain or spinal cord autonomic feedback loop associated with bladder function; Equipped with The system, wherein the first electrode pair and the second electrode pair are configured to be positioned such that an electric field between the first electrode pair passes through the first peripheral nerve and an electric field between the second electrode pair passes through the second peripheral nerve.

38. 1. A wearable device for treating urinary symptoms of a patient, comprising: A controller; a first peripheral nerve effector including at least one stimulation electrode configured to be positioned to transcutaneously modulate a first afferent nerve pathway associated with bladder function; a second peripheral nerve effector including at least one stimulation electrode configured to be positioned to transcutaneously modulate a second afferent nerve pathway associated with bladder function; and at least one input source configured to provide feedback information; Equipped with The controller comprises a processor and memory for receiving real-time feedback information from the input sources, and when executed by the processor, causes the device to: adjusting one or more parameters of the first electrical stimulus based at least in part on the feedback information; adjusting one or more parameters of a second electrical stimulus based at least in part on the feedback information separate from the first electrical stimulus; delivering a first electrical stimulus to a first afferent neural pathway via the first peripheral nerve effector to reduce voiding symptoms by modifying a first brain or spinal cord autonomic feedback loop associated with bladder function; and delivering the second electrical stimulus to a second afferent neural pathway via the second peripheral nerve effector to reduce voiding symptoms by modifying a second brain or spinal cord autonomic feedback loop associated with bladder function; A wearable device, wherein adjusting one or more parameters of the first electrical stimulus and the second electrical stimulus contributes to balancing activity of the sympathetic nervous system and the parasympathetic nervous system.

39. 1. A method of treating urinary symptoms in a patient by dual percutaneous stimulation of the saphenous nerve and the posterior tibial nerve, comprising: positioning a first peripheral nerve effector on the patient's skin to stimulate the patient's saphenous nerve; positioning a second peripheral nerve effector on the patient's skin to stimulate the patient's posterior tibial nerve; delivering a first electrical nerve stimulation signal percutaneously to the saphenous nerve via the first peripheral nerve effector; delivering a second electrical nerve stimulation signal percutaneously to the posterior tibial nerve via the second peripheral nerve effector; receiving input related to autonomic nervous system activity of the patient; modifying at least one brain or spinal cord autonomic feedback loop associated with bladder function based on said input to balance activity of the patient's parasympathetic and sympathetic nervous systems. Including, The method does not utilize an implantable element and involves only transcutaneous stimulation.

40. 40. The method of claim 39, wherein the first peripheral nerve effector and the second peripheral nerve effector are both positioned proximate the patient's knee.

41. The method of any of claims 39 to 40, wherein the first electrical stimulation signal is different from the second electrical stimulation signal.

42. 42. The method of any of claims 39 to 41, wherein the first electrical stimulation signal has a first frequency that is different from a second frequency of the second electrical stimulation signal.

43. The method of any of claims 39 to 42, wherein the first electrical stimulation signal has a different amplitude than the second electrical stimulation signal.

44. 43. The method of claim 42, wherein the first frequency is between about 10 Hz and about 20 Hz.

45. 43. The method of claim 42, wherein the second frequency is between about 5 Hz and about 30 Hz.

46. 46. ​​A method according to any of claims 39 to 45, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data from a sensor measuring the patient's autonomic nervous system activity.

47. 47. A method according to any of claims 39 to 46, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data from a sensor measuring the patient's heart rate variability.

48. 48. The method of claim 39, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving heart rate variability data from an optical sensor measuring blood flow characteristics and positioned adjacent a blood vessel adjacent the patient's knee.

49. 49. A method according to any of claims 39 to 48, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data from a sensor measuring the patient's galvanic skin response.

50. 50. A method according to any of claims 39 to 49, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data related to the patient's urinary symptoms.

51. 51. A method according to any one of claims 39 to 50, wherein receiving input related to the patient's autonomic nervous system activity comprises receiving data related to the patient's episodes of nocturia.

52. 1. A wearable device for dual percutaneous stimulation of the saphenous nerve and the posterior tibial nerve to treat urinary symptoms in a patient, comprising: A controller; a first peripheral nerve effector including at least one stimulation electrode configured to be positioned to percutaneously modulate the saphenous nerve; a second peripheral nerve effector including at least one stimulation electrode configured to be positioned to percutaneously modulate the posterior tibial nerve; at least one biomedical sensor or data input source configured to provide feedback information; Equipped with The controller comprises a processor and memory for receiving the feedback information from the sensor, and when executed by the processor, causes the device to: adjusting one or more parameters of the first electrical stimulus and the second electrical stimulus based at least in part on the feedback information; and delivering the first electrical stimulus to the saphenous nerve via the first peripheral nerve effector and the second electrical stimulus to the posterior tibial nerve via the second peripheral nerve effector to modify an autonomic feedback loop in the brain or spinal cord associated with bladder function to balance sympathetic and parasympathetic activity, thereby reducing urinary symptoms; A wearable device, wherein the device is not configured for implantation within the patient.

53. 53. The device of claim 52, wherein the feedback information comprises real-time feedback information.

54. 54. The device of claim 52 or claim 53, wherein the first electrical stimulus has a frequency of about 10 Hz to about 20 Hz.

55. 55. A device as described in any of claims 52 to 54, wherein the second electrical stimulus has a frequency of about 5 Hz to about 30 Hz.

56. A device according to any of claims 52 to 55, wherein the feedback information comprises the patient's autonomic nervous system activity.

57. A device according to any of claims 52 to 56, wherein the feedback information comprises heart rate variability.

58. A device according to any of claims 52 to 57, wherein the feedback information comprises information relating to nocturia events of the patient.

59. A device according to any of claims 52 to 58, wherein the feedback information comprises information regarding the patient's sleep state.

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