Peripheral nerve stimulation for restless leg syndrome

Abstract

This invention discloses a system and method for treating patients with symptoms of restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using high-frequency stimulation by applying a high-frequency pulsed electrical stimulation therapeutic signal to the peroneal nerve or its branches, wherein the therapeutic signal is above the motor threshold of the muscles innervated by the peroneal nerve or its branches. Surface EMG (sEMG) responses to nerve stimulation can be used to assess a patient's response to nerve stimulation or to evaluate the efficacy of nerve stimulation, such as comparing various nerve stimulation parameter settings and selecting between these settings to achieve or balance one or more goals. The sEMG response can be obtained during muscle rest or during muscle activation.

Description

[0001] Priority requirements

[0002] This application claims priority to the following patent applications: (1) U.S. Provisional Application Serial No. 62 / 910,241, filed October 3, 2019, entitled “PERSONALIZED SCREENING OR TUNING FOR NEUROSTIMULATION”; and (2) U.S. Provisional Application Serial No. 62 / 706,525, filed August 22, 2020, entitled “SYSTEMSAND METHODS FOR PERIPHERAL NERVE STIMULATION FOR TREATMENT OF RESTLESS LEGSSYNDROME”, each of which is incorporated herein by reference.

[0003] Cross-reference to related applications

[0004] This application relates to U.S. Patent No. 10,342,977, filed July 9, 2019, which is a continuation of PCT / US2018 / 012631, filed January 5, 2018, and claims priority to U.S. Provisional Application Serial No. 62 / 442,798, filed January 5, 2017, and U.S. Provisional Application Serial No. 62 / 552,690, filed August 31, 2019. This application also relates to U.S. Provisional Application Serial No. 62 / 910,241, filed October 3, 2019, and U.S. Provisional Application Serial No. 63 / 016,052, filed April 27, 2020. All of the foregoing applications are incorporated herein by reference in their entirety. Technical Field

[0005] This disclosure relates to nerve stimulation, and more specifically to systems and methods for identifying, assessing, and treating patients with neurological disorders, including but not limited to restless legs syndrome (RLS) or periodic leg movement disorder (PLMD). This document also relates to personalized screening or adjustment of nerve stimulation, such as addressing overexcitation of one or more nerves or one or more associated symptoms. Background Technology

[0006] Electrical nerve stimulation can be used to treat one or more conditions, such as chronic or acute pain, epilepsy, depression, bladder disorders, or inflammatory conditions. The efficacy of electrical nerve stimulation signals in activating target nerves can vary significantly, particularly when the stimulation signal is delivered percutaneously (e.g., applied from external to internal or subcutaneous nerve targets), and also in recruiting specific nerve fibers to achieve the desired effect. Therefore, establishing safe and reliable nerve recruitment can be challenging, and the treatment of a specific lesion can depend on the type of nerve to be activated (e.g., central or peripheral nervous system), function (e.g., motor or sensory), and specific fibers (e.g., A-α, A-β, A-λ, B, or C type fibers).

[0007] Some neurological disorders can be attributed to overactivity of sensory or other peripheral nerve fibers, which can affect quality of life and / or the brain's processing of this neural activity. Restless legs syndrome (RLS) and periodic leg kinesiology (PLMD) fall into this category; they are two neurological disorders that can significantly affect sleep in human patients. Patients with RLS (also known as Willis-Ekbom disease (WED)) experience uncomfortable tingling sensations in the lower limbs (legs), which are less common in the upper limbs (arms). RLS is characterized by an uncontrollable urge to move the affected limb. This sensation is often temporarily relieved by voluntarily moving the limb, but doing so interferes with the patient's ability to fall asleep. Patients with PLMD experience spontaneous movements of the lower legs during sleep, which can cause them to wake up.

[0008] Moderate to severe recurrent spontaneous lumbar disc herniation (RLS) can be a debilitating sleep disorder. Many RLS patients do not respond to primary RLS medications, but there are few alternatives. For patients diagnosed with primary RLS (e.g., not secondary to other primary comorbidities such as diabetes, neuropathy, etc.), first-line treatment may involve one or more behavioral changes, sleep modifications, or physical exercise. Second-line treatment may involve dopaminergic therapy or iron management, or both. Dopaminergic therapy often leads to drug tolerance (called enhancement), requiring RLS patients to increase their dosage over time. Even at the highest safe dose, the efficacy of dopaminergic therapy decreases significantly. Third-line treatment may involve one or more anticonvulsants, off-label opioids, or benzodiazepines. Drug therapies, often part of the current treatment for RLS patients, can have serious side effects, including progressive worsening of RLS symptoms. There have been case reports of improved RLS symptoms in patients using implanted spinal cord stimulation (SCS) therapy to treat pain. However, the use of implantable medical devices poses significant additional risks to patients' health. These devices are unproven and very expensive, and therefore are not included in standard treatments. Consequently, patients and clinicians are very interested in low-risk medical device treatments as alternatives to drug therapies and medical implants. Summary of the Invention

[0009] The following is a simplified summary of one or more examples to provide a basic understanding of them. This summary is not a comprehensive overview of all the hypothetical examples, nor is it intended to identify key or decisive elements of all examples, nor to limit the scope of any or all examples. Its purpose is to present some concepts of one or more examples in a simplified form as an introduction to the more detailed descriptions that follow.

[0010] In one embodiment, the technology may include a method of treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation, the method comprising: coupling at least one first electrical stimulation electrode to at least a first external target body location of the patient near the peroneal nerve or a branch thereof; and delivering a first high-frequency pulsed electrical stimulation therapeutic signal to the at least first external target body location using the at least one first electrical stimulation electrode, wherein the pulse of the electrical stimulation therapeutic signal is defined by a plurality of parameters including a frequency between at least 500 Hz and 10,000 Hz and a current between 5 mA and 50 mA and wherein the electrical stimulation therapeutic signal is above a tonic motor threshold and below a pain threshold of at least one muscle innervated by the peroneal nerve or a branch thereof.

[0011] In one embodiment, the technology may include a method for determining stimulation parameters for non-invasive peripheral nerve stimulation therapy, the method comprising: coupling at least one first electrical stimulation electrode to a first external target body location of a patient near a peroneal nerve or its branches; coupling at least one first EMG sensing electrode to the skin of a patient near a muscle innervated by a peroneal nerve or its branches; delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches, wherein the pulse of the electrical stimulation test signal is defined by a plurality of parameters including a frequency at least between 500 Hz and 10,000 Hz and a current between 0 mA and 50 mA; and sensing the response of the muscle innervated by the peroneal nerve or its branches to the electrical stimulation. The process involves: testing the EMG activity of a signal; determining, based on the sensed EMG activity, whether the electrical stimulation test signal is above the muscle's tonic-motor threshold and below the patient's pain threshold; repeating the steps of delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches, sensing the muscle's EMG activity, and determining whether the electrical stimulation test signal is above the tonic-motor threshold and below the pain threshold, wherein each repetition of the electrical stimulation therapy for delivering the electrical stimulation test signal has at least one of a different frequency and a different current than the preceding electrical stimulation test signal; and selecting one of the electrical stimulation test signals above the tonic-motor threshold and below the pain threshold as the high-frequency pulsed electrical stimulation therapy signal.

[0012] In one embodiment, the technology may include a method for determining one or more patient thresholds for noninvasive peripheral nerve stimulation therapy, the method comprising: coupling at least one first electrical stimulation electrode to a first external target body location of the patient near a peroneal nerve or its branches; coupling at least one first EMG sensing electrode to the patient's skin near a muscle innervated by the peroneal nerve or its branches; delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches, wherein the pulse of the electrical stimulation test signal is defined by a plurality of parameters including a frequency at least between 500 Hz and 10,000 Hz and a current between 0 mA and 50 mA; sensing EMG activity of the muscle innervated by the peroneal nerve or its branches in response to the electrical stimulation test signal; determining, based on the sensed EMG activity, whether the electrical stimulation test signal is above a muscle tonic motor threshold and below a patient's pain threshold; and determining, based on patient feedback, whether the electrical stimulation test signal is above a sensory threshold. The procedure comprises the following steps: repeatedly delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches; sensing EMG activity of the muscle; determining whether the electrical stimulation test signal is above a tonic motor threshold and below a patient threshold; and determining, based on patient feedback, whether the electrical stimulation test signal is above a sensory threshold, a distraction threshold, a tolerance threshold, or a pain threshold, wherein each repetition of the electrical stimulation therapy for delivering the electrical stimulation test signal has at least one of a different frequency and a different current than the preceding electrical stimulation test signal; identifying a tonic motor threshold and at least one of a sensory threshold, a distraction threshold, a tolerance threshold, or a pain threshold; and performing a further action selected from: recording the identified threshold; selecting at least one high-frequency pulsed electrical stimulation test signal for application to the peroneal nerve or its branches; and identifying a change in at least one identified threshold relative to a previously determined threshold.

[0013] For the purpose of summarizing and providing additional overview, among other things, the inventors have identified that surface EMG (recordings from muscles attached to the innervating nerves being electrically stimulated) can provide good “feedback signals” or other indications, such as providing information about whether a non-invasive electrical nerve stimulation stimulus has produced the expected effect (or a “predictor feedback signal” or other predictive indicator of whether the stimulus will produce the expected effect). Furthermore, such surface EMG activity can be observed and recorded even before the subject has reported the presence of any stimulus, i.e., even when the stimulus is subsensory. Moreover, different patients can be observed exhibiting surface EMG signals in response to different combinations of one or more electrical stimulation parameters (e.g., frequency, pulse width, etc.), such that combinations of parameters can be established or adjusted in a way that can be used to increase or maximize the surface EMG activation response of a particular patient being observed.

[0014] Surface EMG signal information can be collected and used in one or more ways. For example, one or more electrical stimulation parameters (e.g., frequency, pulse width, etc.) can be changed, and the resulting surface EMG signals can be observed and used for purposes such as selecting one or more electrical stimulation settings or one or more electrical stimulation waveforms that best meet a specific goal, such as generating the most surface EMG activation for a particular subject while resulting in the minimum electrical stimulation power consumption (e.g., to reduce heat, extend battery life, etc.).

[0015] In another illustrative example, one or more electrical stimulation parameters (e.g., frequency, pulse width, etc.) can be varied, and the resulting surface EMG signal can be observed and used to select an electrical stimulation waveform, such as for use during a specific time of day, or during a specific time period corresponding to nighttime, for example, the nighttime objective during which the goal might be to maximize the surface EMG activation response to electrical stimulation while remaining below the subject's indicated distraction threshold. More specific and general examples are also described herein.

[0016] As mentioned above, electrical nerve stimulation (TENS) can be used to treat one or more conditions, such as chronic or acute pain, bladder disorders, or inflammatory conditions. The effectiveness of TENS varies significantly, especially when delivered percutaneously (through the skin) rather than using implanted electrodes. This is likely due to the increased variability of TENS, which may be due to one or more of the following: the device's location or placement on the patient's body; bioelectrical impedance, such as the patient's skin; or, in particular, the patient's subjective tolerance to higher TENS energy induction. For example, a review of TENS found a lack of consistency in research over the past decade, and that the efficacy of TENS varied between shown and unshown when used to treat pain (see https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC4186747 / ).

[0017] This subjective variability in the effectiveness of electrical stimulation can also exist in patients undergoing implantable sacral nerve stimulation, such as for the treatment of overactive bladder (OAB). In indications such as OAB, before a patient is deemed eligible for a permanent OAB electrical stimulation implant, this variability in therapeutic efficacy can be addressed by instructing the patient to first receive a temporary external electrical stimulation device, such as for use for an initial period, to assess the effectiveness of electrical stimulation using that temporary device. A similar protocol can be followed for patients eligible for implantable spinal cord stimulation (SCS) devices to treat pain. In one approach, the only standardized way to manage the dosage of electrical stimulation therapy is by controlling the output current (I) or voltage (V) to ensure that the frequency and pulse width of the waveform used for different patients are the same. However, this approach presents a unique challenge; for example, an electrical stimulation dose level that demonstrates therapeutic benefit in one patient may differ significantly from a dose level tolerated by another patient, or may be completely ineffective in a third patient.

[0018] Mechanistically, the purpose of electrical stimulation can be to electrically activate one or more nerve fibers to generate a desired neural response cascade, which can then trigger the resulting therapeutic effect. One approach to personalizing electrical stimulation therapy may require waiting to assess the presence or extent of the therapeutic effect, which may take weeks to occur and can be highly subjective (e.g., in the case of chronic pain). Another approach to personalizing electrical stimulation therapy is to measure the neural response, which can occur within milliseconds and can be measured more objectively compared to the resulting therapeutic effect. Given the speed of this neural response measurement technique, multiple electrical stimulation modalities (e.g., variations in amplitude, power, frequency, pulse width, etc.) can even be tested in a single outpatient visit, allowing for rapid personalization of electrical stimulation therapy.

[0019] Individual responses to medical treatments can vary. Therefore, response data-driven personalization of treatment has the potential to improve individual patient outcomes and reduce treatment costs for individuals or the whole population. Electro-neurostimulation (EMS) therapies have a particularly high potential to benefit from personalization compared to pharmacological therapies because these EMS therapies are not necessarily singular. Instead, the neurostimulation can be optimized or modulated, for example, by programmatically adjusting one or more parameters of the EMS. Some methods of such optimization can be expensive and slow and may require optimization by trained medical professionals based on the patient's subjective response to the expected therapeutic effect, such as observing this effect after the patient has used the product for a sufficiently long period (e.g., weeks or months). The inventors have recognized, among other things, that closed-loop or similar systems that can rapidly or even automatically modulate or optimize treatment can be extremely valuable in terms of saving time and money and improving individual patient outcomes. Furthermore, such systems can be used to rapidly predict and differentiate between “responder” patients (and “non-responder” patients) who will experience the benefits of a given therapy (and those who will not). In turn, such systems can help improve clinical outcomes, reduce costs, and increase the success rate of clinical trials.

[0020] One approach that can help improve the establishment, adjustment, or optimization of one or more parameters of a single (non-personalized) therapy may include, for example, determining whether all patients in a group, population, or subgroup should receive stimulation method 1 or stimulation method 2. For example, in vitro animal studies can be used to observe EMG signals, such as to demonstrate whether DC stimulation followed by AC stimulation elicits a better nerve block than AC stimulation alone, and this information can be used to select the desired approach for all patients in a group, population, or subgroup. In another approach, one or more evoked reflexes (e.g., flexor responses or sometimes referred to as flexion responses) in one or more human subjects may be used in conjunction with measured surface EMG signals in those subjects, such as to help identify the relative effectiveness of electrical stimulation in a particular human subject or a group of human subjects based on one or more electrical nerve stimulation parameters. For example, this approach can be used to help evaluate various frequencies of electrical nerve stimulation for a particular human subject or a group of human subjects. Raghunathan’s U.S. Patent No. 10,342,977 describes an exemplary example of the use of buckling response (such as in the context of an exemplary RLS use case), the entire contents of which are incorporated herein by reference, including its teachings on buckling response, which can be used in conjunction with the surface EMG signaling techniques described herein.

[0021] While these methods may be promising for improving single therapies, methods that do not use surface EMG signals may not always be suitable for in-patient screening or personalization of one or more electrical nerve stimulation parameters. This may be due to one or more factors, such as: (1) interference with the electrical nerve stimulation signal; (2) low amplitude of the measured flexion response; (3) the distance between the recorded flexion response and the actual neural target (e.g., in percutaneous applications); (4) the need for signal recording of the flexion response using multiple channels; (5) the random or inconsistent nature of the flexion response; and (6) the lack of automation and the resulting need for comprehensive technician training to interpret the flexion response. Therefore, using surface EMG data as an alternative or supplement to this technique for flexion response assessment may be useful, such as for patient screening, for establishing or modulating patient therapies, for evaluating the efficacy of therapies, or for one or more other purposes, as further explained elsewhere in this document. Attached Figure Description

[0022] To better understand the examples of the various descriptions, the following descriptions should be referred to in conjunction with the accompanying drawings, in which similar reference numerals indicate corresponding similar parts in all the drawings.

[0023] Figure 1 A system coupled to the right leg of a subject is shown, which is used to treat one or more symptoms of RLS or PLMD by applying an electrical stimulation signal to the peroneal nerve.

[0024] Figure 2 A system coupled to the left leg of a subject is shown, which is used to treat one or more symptoms of RLS or PLMD by applying an electrical stimulation signal to the peroneal nerve.

[0025] Figure 3 An electrode pad for delivering an electrical stimulation signal to the peroneal nerve is shown, as well as a surface EMG sensing electrode for sensing the response induced by the electrical stimulation signal.

[0026] Figure 4 The calibration process for identifying one or more thresholds and the stimulation parameters for providing neurostimulation therapy to patients are shown.

[0027] Figures 5A to 5C The results show a comparison between NPNS therapy and sham stimulation in multiple patients treated with electrical stimulation.

[0028] Figure 6A and Figure 6B The results show a comparison of NPNS therapy versus sham stimulation applied during suggestive activity inhibition (SIT) trials in multiple patients with RLS symptoms.

[0029] Figure 7 This is a graph illustrating the relationship between setpoint intensity (current) and tonic motor threshold for multiple RLS patients.

[0030] Figure 8A and Figure 8B The figures show the relationship between the efficacy of NPNS therapy and the tonic-motor threshold and distraction threshold, respectively.

[0031] Figure 9 This is a diagram illustrating the sEMG response induced by electrical stimulation test signals for various electrode placement positions.

[0032] Figure 10A This is a conceptual model of RLS and an illustration of the role of leg movements.

[0033] Figure 10B A conceptual model of RLS and an illustration of the role of peroneal nerve electrical stimulation in helping to avoid leg movements.

[0034] Figure 11 The graphs are from experiments involving five different human participants and different EMG amplitudes at different frequencies of electrical nerve stimulation. Figures 1 to 9 The different studies shown.

[0035] Figure 12 The graphs obtained here are from experiments responding to changes in surface EMG amplitudes of electrical stimulation parameters. Different electrical nerve stimulation frequencies were provided to five different human subjects. Figure 11 The five study participants in the results shown were the same, that is, from the same... Figures 1 to 9 The different studies shown.

[0036] Figure 13 Experimental data illustrating the electrical nerve stimulation power to achieve surface EMG motor activation for each participant are presented.

[0037] Figure 14 Examples of techniques for testing various stimulation parameter settings and monitoring surface EMG responses are shown.

[0038] Figure 15 Possible electrical nerve stimulation waveforms with some different parameter settings are shown.

[0039] Figure 16 An example of a leg-worn sleeve device that may include EMG monitoring electrodes and electroneurostimulation electrodes is shown.

[0040] Figure 17 An exemplary example of an electrical nerve stimulation electrode grid is shown.

[0041] Figure 18An example of an architecture for onboard electronic circuitry that can be used to help implement or perform some of the disclosed techniques or methods is shown.

[0042] Figure 19 , Figure 20 and Figure 21 Experimental data comparing sEMG data during muscle activation with NPNS on and NPNS off are presented.

[0043] Figure 22 Examples of portions of this system are shown, such as those that can be used to perform one or more of the techniques described herein. Detailed Implementation

[0044] As used in this article, the “sensory threshold” refers to the lowest level of stimulation at which a pulsed electrical stimulation signal can be felt by a patient receiving the signal (represented by a specific combination of electrical stimulation parameters that define the pulsed electrical signal, such as pulse current, pulse width, pulse waveform, etc.).

[0045] The term "tonic muscle activation" refers to isometric muscle contraction or similar muscle activation that is sustained and consistent over time and does not induce periodic leg movements (e.g., clonic or jerky movements occurring at a rate exceeding once per minute). When measured by surface electromyography (sEMG) sensed from the skin above the activated muscle in a patient, sEMG activity induced by tonic activation is characterized by consistently higher amplitudes than baseline without significant transient changes in amplitude. The increase in muscle tone may (or may not) be apparent to the patient or observer, but rapid movements or jerks are not.

[0046] The term "phased muscle activation" refers to activation that causes periodic leg movements that are noticeable to the patient or observer and occur at least once per minute. Movements associated with phased muscle activation may manifest as twitches, kicks, or jerks, and the associated sEMG signals are characterized by sudden, brief (e.g., <1 second) large changes in amplitude.

[0047] The term "tonic motor threshold" refers to the minimum stimulation level (represented by a specific combination of electrical stimulation parameters defining the pulsed electrical stimulation signal, such as current, pulse width, pulse waveform, etc.) at which a pulsed electrical stimulation signal elicits definitive tonic muscle activation (as opposed to no muscle activation, segmental muscle activation, or a combination of tonic and segmental muscle activation) such that reducing one of the parameters defining the pulsed electrical stimulation signal will result in no tonic muscle activation in the muscle innervated by the electrical stimulation signal. If no stimulation level is generated that induces tonic muscle activation in the absence of segmental muscle activation, a tonic motor threshold cannot be defined.

[0048] The term "distraction threshold" refers to the highest level of electrical stimulation (represented by a specific combination of electrical stimulation parameters) that is comfortable, non-distracting, and compatible with a particular activity. For example, the sleep distraction threshold is the highest level of stimulation that is comfortable, non-distracting, and compatible with sleep, such that increasing one of the parameters defining the sleep distraction threshold would result in a stimulation level incompatible with sleep. The sleep distraction threshold can be established by one or more of the following: 1) the patient's subjective opinion (e.g., while awake and receiving an electrical stimulation test signal); 2) the adverse effects on the patient's sleep when receiving an electrical stimulation signal compared to no signal, such as A) an increased sleep latency (i.e., the time required for the patient to fall asleep), B) an increase in sleep fragmentation determined by one or more bodily parameters (such as sleep movement, EEG signals, heart rate signals, etc.), C) decreased sleep efficiency, D) a decrease in total sleep time, or E) an increase in wakefulness or arousal episodes after sleep onset. Other distraction thresholds (e.g., work distraction thresholds) can also be identified by testing the patient while they have a specific activity in mind or are performing that activity.

[0049] The term "tolerance threshold" refers to the highest level of stimulation a patient can tolerate within one minute, in their subjective opinion (represented by a specific combination of electrical stimulation parameters). The tolerance threshold is the level of stimulation that a patient experiences that is distracting or uncomfortable, but which can be tolerated for a short period without causing pain.

[0050] The term "pain threshold" refers to the minimum level of stimulation required to cause pain in a patient (represented by a specific combination of electrical stimulation parameters).

[0051] The term "electrical stimulation test signal" (ETS) refers to a pulsed electrical stimulation signal defined by multiple parameters (e.g., pulse current, pulse width, pulse waveform, etc.) applied to a body location near a target neural structure (e.g., the peroneal, sural, or femoral nerve or its branches) to determine a patient's response to the ETS. As a non-limiting example, the response may include the surface EMG (sEMG) response of the muscle innervated by the target neural structure to the ETS, and the patient's subjective perception of the response (e.g., the ETS is imperceptible, the ETS is perceptible but uncomfortable, the ETS is perceptible but not distracting, or the ETS is perceptible but tolerable).

[0052] The inventors have identified surface EMG (sEMG) as a feedback signal to determine whether an electrical stimulation signal is producing (or is likely to produce) the desired effect, determined from the muscles innervated by the nerves stimulated by the electrical stimulation signal, as part of a treatment regimen for one or more neurological disorders such as RLS or PLMD. Furthermore, many neurostimulation therapies require weeks or months to determine their effectiveness. Feedback from one or more bodily parameters (e.g., heart rate, respiratory rate, etc.) has been proposed as a potential indicator of efficacy. In many cases, these bodily parameters correlate poorly with efficacy. Conversely, the inventors have understood that, in the context of treating symptoms of RLS or PLMD using high-frequency pulsed electrical stimulation signals, there is a relatively good correlation between the tonic motor threshold for sustained tonic activation of muscles innervated by target peroneal nerve structures and therapeutic efficacy.

[0053] On one hand, sEMG can be used to identify one or more thresholds associated with providing effective electrical stimulation therapy to treat RLS symptoms. In one embodiment, an sEMG response to one or more electrical stimulation test signals (e.g., using sEMG sensing electrodes) can be determined, and this sEMG response is used to identify tonic-motor thresholds. In another embodiment, it can be based on a combination of... Figure 4 The proposed testing protocol delivers multiple electrical stimulation test signals, and the patient can provide a subjective response to the varying electrical stimulation test signals (e.g., verbal response or using an input device) to determine one or more of the distraction threshold, tolerance threshold, and pain threshold.

[0054] The one or more thresholds can be used in various implementations to perform a variety of tasks. In one implementation, one or more of these thresholds can be used to screen patients (e.g., identify potential responders and / or non-responders to NPNS therapy for treating RLS / PLMD). In another implementation, the one or more sEMG thresholds can be used to identify stimulation parameters that may be effective in relieving one or more RLS symptoms. In yet another implementation, the one or more sEMG thresholds can be used to modify treatment parameters, such as to help avoid neural adaptation or tolerance while maintaining effective relief of one or more RLS symptoms. In yet another implementation, the one or more sEMG thresholds can be used to control one or more electrical stimulation parameters, such as to achieve one or more additional goals, such as achieving increased or maximized therapeutic efficacy, minimizing or reducing power consumption while maintaining therapeutic efficacy, minimizing or reducing the temperature inside or near the electrical stimulation device, etc.

[0055] In some cases, sEMG activity can be observed and recorded even before the patient can sense the electrical stimulation signal being applied to the target neural structure (i.e., when the electrical stimulation signal is subsensory). Furthermore, different patients can be observed exhibiting different surface EMG (sEMG) signals in response to different combinations of one or more electrical stimulation parameters (e.g., frequency, pulse width, etc.). These different combinations of electrical stimulation parameters can be used to maximize or otherwise modulate the observed sEMG activation response in a particular patient. Because patient responses to specific electrical stimulation signals can vary significantly, specific electrical stimulation signal thresholds (e.g., sensory threshold, tonic-motor threshold, distraction threshold, pain threshold) may occur with a wide range of different parameter settings for different patients.

[0056] Surface EMG (sEMG) signals that capture the response of muscles to one or more electrical stimulation test signals (ETS) can be obtained in various ways. In one embodiment, the surface electrode may be externally coupled to the patient's skin near the muscle innervated by the nerve to be stimulated (e.g., located superficially on and adhered to the covered skin). In embodiments involving stimulation of the peroneal nerve or its branches in the patient's leg, at least one sensing electrode may be attached (e.g., using an adhesive hydrogel electrode) to one or more muscles, such as those selected from the tibialis anterior, extensor digitorum longus, peroneus third, extensor hallucis longus, peroneus longus, and peroneus brevis.

[0057] Data can be captured by sensing the sEMG activity of muscles dominated by the electrical stimulation test signal using at least one sensing electrode (e.g., using an electrode pair) during the application of an electrical stimulation signal. In one embodiment, data can be captured by using a fixed pulse width and pulse waveform and in a specified manner (such as in conjunction with Study 1 below). Figure 4 The discussion discusses varying the pulse current testing protocol to deliver multiple test electrical stimulation signals. Surface EMG data can be sensed and processed according to one or more specified protocols, and the patient can be queried or provided with input in response to the changing signals in various ways. Therefore, in one aspect, the system and method may include determining one or more of the aforementioned thresholds for a patient receiving the electrical stimulation signals.

[0058] In one aspect, the system and method can be used to treat patients with symptoms associated with RLS or PLMD using a high-frequency pulsed electrical stimulation signal applied to the peroneal nerve or its branches. The high-frequency electrical stimulation signal may include a frequency between 500 Hz and 15,000 Hz, more preferably 1 kHz to 10 kHz, and more preferably 2 kHz to 6 kHz, wherein the electrical stimulation signal is above the tonic motor threshold of at least one muscle innervated by the peroneal nerve or its branches, and below the pain threshold. In one embodiment, the electrical stimulation signal is below the distraction threshold. The system and method can be used to treat patients with symptoms associated with overactive peripheral nerves, such as using a first high-frequency pulsed electrical stimulation signal applied to a first nerve target on the patient's leg and a second high-frequency pulsed electrical stimulation signal applied to a second nerve target on the patient's arm. In one embodiment, the method is used to treat patients with symptoms associated with RLS or PLMD, wherein the first nerve target is selected from one of the peroneal nerve or its branches, the sural nerve or its branches, and the femoral nerve or its branches, and the second nerve target is selected from one of the ulnar nerve or its branches and the radial nerve or its branches. The high-frequency electrical stimulation therapy signal may include frequencies between 500 Hz and 15,000 Hz, more preferably 1 kHz to 10 kHz, and even more preferably 2 kHz to 6 kHz, wherein a first high-frequency electrical stimulation therapy signal is higher than the tonic motor threshold of at least one muscle innervated by one of the peroneal nerve or its branches, the sural nerve or its branches, and the femoral nerve or its branches, and a second high-frequency electrical stimulation therapy signal is higher than the tonic motor threshold of one of the ulnar nerve or its branches and the radial nerve or its branches. In one embodiment, the electrical stimulation signal is lower than the distraction threshold.

[0059] Study 1 - RLS treatment using HF stimulation above the stress threshold

[0060] experiment

[0061] To address the significant unmet need for treatment of RLS, a study was conducted to evaluate the feasibility of using a noninvasive peripheral nerve stimulation (NPNS) system to stimulate nerve fibers in the lower leg as a target body location subjectively associated with RLS symptoms. This study was a randomized, participant-blinded, crossover feasibility study conducted at three clinical sites in the United States. Inclusion criteria were a diagnosis of primary RLS, moderate to severe RLS symptoms (defined as those scoring at least 15 on the International RLS Severity Scale), age 18 years or older, symptoms primarily in the lower leg and / or foot, and predominantly occurring in the evening or night. Patients included those who were medication-naïve (i.e., had never taken medication to treat their RLS symptoms), those who had previously taken RLS medication, and those who were drug-resistant. Exclusion criteria included patients with an active implantable medical device, epilepsy, skin conditions affecting device placement, severe peripheral neuropathy, unstable dosage of RLS medication, medication exacerbating RLS symptoms, or uncontrolled sleep apnea / insomnia unrelated to RLS.

[0062] The severity of patients' RLS was initially assessed using the International Restless Legs Syndrome (IRLS) Scale. After identifying patients with a score of at least 15, thirty-nine (39) patients were randomly assigned in a 1:1 ratio to two groups in a crossover trial. One group received two weeks of NPNS treatment followed by a two-week crossover of sham stimulation, while the other group received two weeks of sham stimulation followed by a two-week crossover of NPNS treatment. Thirty-five patients completed both interventions 1 and 2.

[0063] The median age of all patients was 55.7 years, with 46% being male and 54% being female. The mean IRLS score at enrollment was 24.0, the mean age at onset of RLS was 34.4 years, and the mean duration of symptoms was 20.9 years. Of the 39 patients enrolled, 14 (36%) had never received RLS medication, 4 (10%) had discontinued RLS medication, and 21 (54%) were currently taking RLS medication but were refractory, consistent with the predictive effect of an IRLS score of 15 or higher.

[0064] refer to Figures 1 to 3 System 100 provides a wearable, non-implantable stimulator unit 110 for generating therapeutic electrical pulses, which is coupled to a wearable external patch 120 (1.3 inches × 2.1 inches) having adhesive hydrogel electrodes for delivering electrical pulses to the peroneal nerve. The wearable external patch 120 ( Figure 1 and Figure 2 Hydrogel electrode pairs are provided on (in) Figures 1 to 3 (Not visible in the middle). Figure 1A system 100 coupled to the subject's left leg is shown, while Figure 2 A system 100 coupled to the right leg of a subject is shown.

[0065] A separate system (stimulator unit 110 and patch 120) is externally placed on each leg to provide bilateral percutaneous stimulation of the superficial peroneal nerves on the left and right sides. Each patch 120 is superficially positioned below each knee, above the fibular head, and adjacent to (i.e., close to) the common peroneal nerve. The patches 120 are positioned parallel to the medial-lateral axis, with their shorter dimensions positioned on the distal-proximal axis. The upper lateral corner of each patch is positioned to cover a portion of the fibular head, with one gel electrode (not shown) above the main portion of the superficial peroneal nerve on the left or right side, and another electrode (not shown) above the area innervated by the superficial peroneal nerve to the tibialis anterior muscle.

[0066] Patients in this study were instructed to self-administer an NPNS electrical stimulation signal to both legs for 30 minutes before bedtime for 14 consecutive days. In addition to bedtime stimulation, patients were allowed to self-administer the NPNS multiple times as needed, either earlier in the day or after falling asleep at night (e.g., upon waking with RLS symptoms). The system provides a high-frequency electrical stimulation signal using a charge-balanced, controlled current, a rectangular pulse at a frequency of 4000 Hz and a pulse width of 125 μs, and a current ranging from 15 mA to 40 mA. This current was set to the patient's distraction threshold (the highest current that makes the aforementioned 4000 Hz waveform comfortable and compatible with sleep). Because different distraction thresholds vary significantly, a distraction threshold was determined for each patient via an automated electrical stimulation test signal (ETS) process, in which the electrical stimulation test signal is applied to the patient and, as described below... Figure 4 The discussion focuses on determining various thresholds, including a distraction threshold. Electrical stimulation signals (different from the test signal) are continuously delivered during the 30-minute treatment period. Therefore, the duty cycle (stimulation on time divided by the sum of stimulation on and off times) during the 30-minute electrical stimulation treatment is 100%.

[0067] The applicant has come to understand that EMG activity (particularly sEMG activity indicating tonic activation of at least one muscle controlled by electrical stimulation therapy) is associated with the efficacy of alleviating RLS symptoms. Figure 3 A wearable external patch 120 coupled to the patient's right leg is shown, such as Figure 2 As shown, it is used to deliver an electrical stimulation test signal (ETS) or an electrical stimulation therapy signal to the peroneal nerve or its branches. Figure 3 Also shown are sEMG electrodes 310, 320 for sensing sEMG responses to ETS or electrical stimulation therapy signals.

[0068] Figure 4The calibration procedure used to determine the distraction threshold and other thresholds for each patient in this study is shown. Starting with an initial current of 0 mA (410), the current value was increased at a rate of 1 mA / 2 seconds (line 420) to the highest current level that the patient indicated could tolerate for 1 minute (430), after which the current value was gradually decreased at a rate of 1 mA / 10 seconds (area 440) to the highest level that the patient indicated was not distracting and compatible with sleep (450), which was designated as the distraction threshold. The current value was held at the distraction threshold (450) for at least 30 seconds, and then decreased to 0 mA within 10 seconds.

[0069] For each 30-minute electrical stimulation treatment session in active treatment mode, the electrical stimulation signal rises to approximately the calibrated distraction threshold current within 30 seconds, remains at the calibrated distraction threshold parameter for 29.5 minutes, drops to 0 mA in the final 10 seconds, and automatically shuts off. Patients receiving sham stimulation receive an electrical stimulation signal that rises within the initial 30-second period, but then drops to 0 mA within 10 seconds and remains at 0 mA for the remainder of the 30-minute sham treatment period.

[0070] Those skilled in the art, benefiting from this disclosure, will understand that the distraction threshold depends on a combination of multiple parameters, and that changing other parameters (e.g., pulse width) will also change the corresponding current setting. Therefore, in some embodiments (not shown), the threshold setting process may involve changing two parameters (e.g., current and pulse width), three parameters (e.g., current, pulse width, and frequency), or four or more parameters. While such a threshold setting process is more complex than… Figure 4 The process of simply gradually / changing the current setting, as shown, is more complex and time-consuming; however, according to this disclosure, such a threshold setting process can be enabled without excessive experimentation. A programming application (not shown) has been developed for use on a handheld computing device (e.g., a mobile phone, tablet, etc.) wirelessly coupled to the stimulator unit 110, and this programming application is used to automatically implement the test signal process for establishing the distraction threshold.

[0071] effect

[0072] This study compared the responses of patients receiving this NPNS regimen with those receiving the same sham device. Specifically, in the second week of device use, NPNS resulted in a 6.64-point reduction in RLS severity as measured by the IRLS scale relative to baseline IRLS at the start of the study. This reduction exceeded the minimum clinically significant reduction of 3.0 points on the IRLS scale and was also significantly greater than the 3.15-point reduction associated with sham stimulation. Figure 5A As shown.

[0073] Furthermore, NPNS resulted in a statistically significant increase in response rate (i.e., the percentage of study participants with a clinically significant response on the patient-rated CGI-I scale). Figure 5B As shown, 66% of participants responded to NPNS, compared to 17% who responded to sham stimuli.

[0074] Finally, NPNS dramatically reduced the severity of RLS, measured by the Numerical Rating Scale (NRS) score of patient-reported RLS symptom severity. Patients rated their RLS symptoms using the NRS before, during, and after 30-minute stimulation each night. The NRS was managed in a summary format after every 14-day treatment period and also in a daily format via an online questionnaire. For bi-weekly and per-purpose NRS assessments, NPNS resulted in a statistically significant reduction in mean RLS severity during and after stimulation, thus indicating that NPNS dramatically reduced RLS symptoms immediately after stimulation. Figure 5C ).

[0075] SIT Data

[0076] To further investigate the patients' response time to stimulation, we employed the Suggestive Activity Inhibition Test (SIT), a 60-minute protocol designed to exacerbate and measure RLS symptoms. Consistent with the SIT protocol described by Garcia-Borreguero et al., participants were instructed to sit in a fixed position but were allowed to move their legs to the extent desired to relieve RLS symptoms. Each patient completed three SIT procedures during a separate lab visit: one without treatment at the start of the study (baseline), one with 60 minutes of concurrent NPNS stimulation immediately after 2 weeks of NPNS therapy, and another with 60 minutes of concurrent sham therapy immediately after 2 weeks of sham therapy.

[0077] During SIT, NPNS reduced subjective scores for RLS severity. For example... Figure 6A As shown, NPNS (data line 610) reduced the NRS score for RLS discomfort relative to baseline (data line 620) and showed a strong but not significant trend toward reducing NRS scores relative to spurious stimulation (data line 630). There was no indication that the effect of NPNS diminished over time. On the contrary, the reduction in NRS appeared to persist throughout the 60-minute process. NPNS also reduced leg movement during SIT. A 3-axis accelerometer was positioned on the lateral malleolus of each ankle and used to measure total leg movement during the SIT procedure. Data was collected at 25 Hz and high-pass filtered at 1 Hz to eliminate gravity and sensor drift. During the SIT test, acceleration metrics were calculated for every 10-minute segment (calculated as x).2 y 2 and z 2 The sum of the square root of the two legs is used, but the data from the last 5 minutes of the 60-minute period is discarded. The data from the left and right legs are averaged at each time point. For example... Figure 6B As shown, NPNS (data line 640) reduced total leg acceleration relative to baseline (data line 650) and relative to sham stimulation (data line 660).

[0078] Drug-resistant patients and drug-free patients

[0079] Both drug-resistant and untreated participants showed similar responses to the NPNS. In the drug-resistant cohort, the NPNS demonstrated a statistically significant reduction in IRLS (7.30 points) compared to the 3.45 points reduction in IRLS achieved with the sham stimulus, and also showed a statistically significant higher response rate. In terms of magnitude, the untreated cohort showed similar NPNS responses in IRLS as the full study population (7.08 vs. 6.64), and similar response rates in CGI-I (64%) as the full study population (66%). Due to the small sample size (n=12), the comparisons with the sham stimulus were close but did not reach statistical significance.

[0080] EMG data

[0081] To investigate the physiological mechanisms of NPNS-based relief of RLS symptoms, sEMG measurements of the tibialis anterior (TA) muscle were performed on some patients during stimulus intensity calibration. The tibialis anterior is a large, superficial muscle innervated by the peroneal nerve, which is the putative neural target for NPNS in Study 1. Stimulus activation was used to induce tonic muscle activation but not segmental muscle activation (tonic motor threshold). Figure 4 I 运动 The minimum stimulus intensity was compared to the intensity setting (“setpoint”) used for home stimulation, which is set to the maximum comfortable and non-distracting intensity (distraction threshold). Figure 4 I 分心 On average, the motor stress threshold was 7.2 mA lower than the set point (18.2 mA vs. 25.4 mA). Furthermore, 87% of participants had a motor stress threshold below the set point. Figure 7 This means that the NPNS at the set point generated motor activation in most patients. It is noteworthy that the EMG activity induced by the stimulus was tonic, rather than phased.

[0082] The applicant understands that the tonic motor threshold is related to efficacy. Specifically, the lower the intensity of the electrical stimulation signal applied to the peroneal nerve that induces tonic activity in the tibialis anterior muscle, the greater the likelihood that the patient will respond to treatment and achieve relief of RLS or PLMD symptoms. In other words, the lower the tonic motor threshold (e.g., the lower the current setting required to induce tonic sEMG activity in the tibialis anterior muscle for a series of electrical stimulation test signals with a fixed pulse width and waveform), the greater the likelihood that NPNS will provide relief for the patient's RLS symptoms. Without being bound by theory, this may be because peripheral nerves are more sensitive to NPNS delivered via the methods described above, such as possibly due to the nature of the nerve fibers, the nature of the tissue layer between the electrode and the nerve fiber, and / or the positioning of the electrode relative to the nerve. Therefore, Figure 7 The data suggest that exercise activation may contribute to the physiological mechanisms of NPNS relief.

[0083] Overall results

[0084] The results of Study 1 suggest that, on the basis of nighttime use, NPNS has the potential to reduce and alleviate RLS symptoms. IRLS is a recognized indicator of RLS severity, and the observed reduction of 6.64 points was significantly greater than the minimum clinically significant difference of 3.0 points. Regular use of NPNS appears to be important for maintaining RLS symptom relief. There was no evidence that the sham stimulation arm or the treatment arm had a delaying effect on the other arm. The response during sham stimulation was the same regardless of whether it occurred before or after active treatment; therefore, NPNS appears to be more likely to act as a treatment than a cure.

[0085] Safety results showed that patients tolerated NPNS well during the 2-week study period.

[0086] Measured by IRLS and CGI-I, both drug-naïve and drug-resistant RLS patients experienced a similar reduction in RLS severity. While drug-naïve patients have access to several FDA-approved medications, they may hesitate to do so due to the well-characterized and potentially debilitating side effects of these drugs. Opioids are the most common option for drug-resistant RLS patients, but many patients and clinicians hesitate to use them due to the widely publicized long-term outcomes associated with abuse, dependence, and addiction. Therefore, NPNS can provide a viable alternative for many patients who are not well managed with current standard treatments.

[0087] Study 1 suggests that symptom relief may not be immediate but may gradually emerge during the 30-minute NPNS stimulation. Results from each NRS rating scale (daily, pooled, SIT) indicate that the reduction in RLS symptoms after 30 minutes of stimulation was greater than during the initial 30 minutes of stimulation. For the daily and pooled NRS results, the increased relief after stimulation termination could be explained by the 30-minute stimulation duration. However, during the SIT, the stimulation lasted 60 minutes, and there was still a trend towards increased relief after 30 minutes. In summary, these data suggest a gradual relief physiological mechanism that takes time to develop but persists thereafter.

[0088] Proper electrode placement can significantly contribute to efficacy. The stimulating electrodes are positioned above the common peroneal nerve, which provides sensory and motor innervation to the lower leg and foot (the body regions most commonly associated with subjective RLS symptoms). Free from theoretical constraints, possible mechanisms of action may include the gating theory, where activation of sensory fibers in the peroneal nerve inhibits pathological neural signals at the spinal cord level. However, furthermore, the pathological basis of RLS may reside primarily in the brain rather than the spinal cord or peripheral nervous system. Therefore, the NPNS may also transmit signals via ascending sensory pathways, thereby inhibiting pathological neural signals in the thalamus, somatosensory cortex, limbic system, or other brain regions.

[0089] Stimulation parameters may also contribute to tolerability and efficacy. The stimulation parameters in Study 1 were designed and calibrated to deliver maximum stimulation intensity while allowing for comfortable self-administration without distracting sensory disturbances. In contrast, alternative neurostimulation methods such as spinal cord stimulation or TENS devices can cause distracting sensory disturbances, which could potentially interfere with sleep onset and thus hinder bedtime use.

[0090] The applicant also investigated the relationship between the efficacy of NPNS and sham stimulation in reducing IRLS scores in certain patients. Figure 8A This is a graph illustrating the relationship between the stimulation efficacy for multiple patients and the tonic motor threshold of each patient as determined by sEMG measurements. Figure 8A Each point in the graph represents a patient, and the X-axis value corresponds to the tonic-motor threshold I, which indicates the patient's stress response. 运动 (That is, the current (mA) value used to induce sustained tonic activity in the tibialis anterior muscle), the current value in Figure 4The values ​​were obtained during the short (approximately 5 minutes) calibration / threshold determination process shown and discussed above. The Y-axis value at each point indicates the reduction in the patient's IRLS score at the end of the two-week treatment period compared to sham stimulation over two weeks. Patients with lower Y-axis values ​​indicate that the treatment provided a greater improvement than sham stimulation compared to patients with higher Y-axis values ​​(i.e., lower Y-axis values ​​indicate higher treatment efficacy). Line 810 is a least-squares fit to the data points and indicates that the lower the tonic motor threshold used by the patient to induce tonic activation of the tibialis anterior muscle, the higher the efficacy. As stated above and without being bound by theory, this is likely because peripheral nerves are more sensitive to NPNS delivered via the methods described above, due to the nature of the nerve fibers, the nature of the tissue layer between the electrode and the nerve fiber, and / or the positioning of the electrode relative to the nerve. Therefore, Figure 8A This indicates that in one implementation, a short (approximately 5-minute) calibration process that identifies a patient's tonic-motor threshold can be used to identify patients with a higher likelihood of receiving NPNS treatment benefits. In another implementation, Figure 8A The minimum stimulus intensity that indicates the likelihood of providing a therapeutic response (e.g., the minimum current value for a fixed pulse width and waveform), i.e., the tonic motion threshold current It. 运动 .

[0091] Figure 8B The stimulation effect is related to sEMG activation at the patient's distraction threshold (EMG). 分心 A diagram illustrating the relationship between the distraction threshold and the threshold value. Figure 4 The measurements were taken during a time period indicated by 450. (Compared to...) Figure 8A Similarly, each point in the figure represents a patient, and the Y-axis values ​​also indicate the reduction in IRLS scores at the end of the two-week treatment period compared to the two-week sham stimulation. Figure 8B The X-axis in the diagram represents the... Figure 4 The magnitude of sEMG activation of the tibialis anterior muscle occurring at the distraction threshold during the short calibration process. Line 820 is a least-squares fit of the data points and demonstrates that the greater the sEMG activation for a given patient (i.e., the stronger the tonic activation in the tibialis anterior muscle for stimulation at the distraction threshold (i.e., the treatment setting), the greater the likelihood that the patient will experience higher efficacy (i.e., the greater the reduction in IRLS compared to sham stimulation). Figure 8B This indicates activity at the distraction threshold (the highest electrical stimulation setting that may be used to treat patients during sleep), thus suggesting that the greater the tonic activity that can be elicited by the electrical stimulation therapy signal, the greater the potential efficacy.

[0092] Figure 9 This demonstrates how sEMG responses to electrical stimulation test signals can be used to identify wearable patches (e.g., patch 120). Figure 1When is the correct positioning achieved? As shown in four different photographs, each involving a different patch (and therefore a hydrogel electrode) position relative to the target nerve, compared to other positions where the electrode is far from or not close to the target nerve (920, 930, and 940), when the electrode innervates the target nerve ( Figure 9 When the electrode is placed on the superficial peroneal nerve (in the middle part of the nerve), a test signal applied to this nerve will elicit a significantly higher sEMG response (910). Generally, the farther the electrode is placed from the target nerve, the lower the sEMG response to the nerve-innervated muscles; only when the electrode is close to the target nerve will the response be significantly increased. Therefore, the implementation scheme includes using the response to the electrical stimulation test signal applied to the electrode patch to ensure the correct placement of wearable electrode patches for treating RLS or PLMD symptoms.

[0093] Given the sensory hypersensitivity sometimes associated with RLS and PLMD, patients using this system may be sensitive to very mild discomfort. Therefore, many patients will not use the system if it causes them discomfort. It is desirable to make the stimulator unit, which includes the system electronics and software / firmware, as well as the wearable patch, as small, light, and non-bulky as possible. Due to the need for size reduction, in some designs, the power supply and circuit board, confined to a small space and used to deliver high-frequency electrical pulses, may create potential heating problems within the stimulation unit. If the temperature rises significantly above the patient's body temperature, discomfort may cause the patient to discontinue use. Because small power supplies and circuit boards may be required, for patients requiring high power consumption (e.g., higher frequencies or relatively high current pulses in patients with high tonic-motor thresholds or distractibility thresholds), some implementations may include systems and methods that monitor one or more parameters of the system and can modify one or more stimulation parameters, such as to optimize one or more goals (e.g., power consumption) in addition to or in conjunction with therapeutic efficacy.

[0094] In one implementation, the system can monitor one or more system and / or efficacy parameters, which can be used as feedback to adjust one or more electrical stimulation parameters, or to start, stop, or resume treatment to achieve one or more goals. As a non-limiting example, the system can monitor power consumption or remaining available power, the highest temperature within the system (e.g., in the pulse generator or processor), and the impedance of the patient's body tissues (which may indicate that the hydrogel electrodes are degrading, that skin cells are accumulating and causing increased impedance, or other problems indicating the need to replace the wearable patch). As a non-limiting example, the system may monitor or calculate one or more system or body parameters related to therapeutic efficacy, such as: patient movement (e.g., calculated from a three-dimensional accelerometer for short or long time scales during or after sleep or treatment); sEMG activity indicating muscle activation levels (including changes in muscle activation over time that may indicate increased or decreased efficacy or neural adaptation) or how much the response to electrical stimulation of the therapeutic stimulus elicited in the tibialis anterior or other muscles is above or below a tonic motor threshold; and patient feedback, such as signals from the patient (e.g., via manual or wireless input) indicating that the stimulus is above or below a target threshold, such as a sensory threshold, tonic motor threshold, distraction threshold, tolerance threshold, or pain threshold.

[0095] One or more of the aforementioned system parameters and / or efficacy parameters can be used as input to one or more system processors and / or algorithms, such as for altering one or more operating parameters to achieve one or more objectives, such as, but not limited to: avoiding neural adaptation or tolerance, ensuring sufficient power in a planned or ongoing treatment protocol, compensating for high impedance, reducing temperature, and avoiding patient discomfort. In one embodiment, one or more parameters of the electrical stimulation treatment signal can be adjusted randomly or pseudo-randomly or at programmed time intervals to provide different electrical signals that are always kept at or near a distraction threshold, such as to avoid neural adaptation. In one embodiment, adaptation can be avoided by repeatedly or periodically altering one or more parameters of the electrical stimulation treatment parameters, such as by alternating between signals at or slightly above a tonic motor threshold (and below a distraction threshold) and signals at or near a distraction threshold. In yet another embodiment, the electrical stimulation parameters can be repeatedly or periodically altered by providing stimulation above a distraction threshold but below a tolerance threshold for a short duration (e.g., 5 or 10 seconds). In one embodiment, Figure 4 The calibration process can be repeated repeatedly or periodically (e.g., every month) or when certain events (e.g., reduced efficacy) occur, such as to help re-establish optimal electrical stimulation therapy parameters.

[0096] In one implementation, one or more electrical stimulation therapy parameters can be modified (e.g., by temporarily or repeatedly or periodically reducing and then restoring a programmed current or pulse width), such as based on planned power consumption, to help ensure sufficient power for stimulation throughout the night for patients with severe RLS symptoms. In one implementation, a high-temperature indicator within the system can be used to reduce the pulse current, pulse width, or pulse frequency, or to disable stimulation for a predetermined period of time, or to provide a longer ramp time.

[0097] In one implementation, patient input (e.g., from a patient application on a personal computing device) can be used to modify one or more electrical stimulation therapies (e.g., increase or decrease stimulation intensity), to respond to repetitive or periodic cues (e.g., provide RLS symptom scores), or to record patient comments on the system's operation or use and therapeutic efficacy. While such specific implementations may be complex and time-consuming, those skilled in the art may be able to implement the aforementioned functions and / or structures thanks to this disclosure and the foregoing related applications.

[0098] In one embodiment, the system and method may include treating a patient with symptoms associated with RLS or PLMD using a first high-frequency pulsed electrical stimulation therapeutic signal applied to a first nerve target on the patient's leg and a second high-frequency pulsed electrical stimulation therapeutic signal applied to a second nerve target on the patient's arm, wherein the first high-frequency electrical stimulation therapeutic signal and the second high-frequency electrical stimulation therapeutic signal are respectively above the tonic motor threshold of the muscles innervated by the first nerve target and the second nerve target.

[0099] Disorder of excessive excitation of the nervous system:

[0100] To summarize and expand upon the above description, there are certain conditions that can lead to overexcitation of one or more nerves, such as causing one or more sensations of pain or discomfort, which can significantly impact a patient's quality of life. Examples may include restless legs syndrome (RLS), nocturnal myalgia, overactive bladder (OAB), myalgia, dystonia, tension headache, pruritus, sciatica, temporomandibular joint disorder (TMJ), chronic pain, Parkinson's disease, or Huntington's disease. This approach, which uses a consistent and reproducible paradigm (such as potentially including the use of surface EMG signals) to deliver personalized electrical stimulation to the patient, can help improve treatment efficacy and may additionally or alternatively help allow for a reduction or minimization of the amount of charge delivered to the patient, thereby improving power efficiency and thus extending battery life, reducing heat dissipation, etc.

[0101] Restless legs syndrome (RLS)

[0102] Restless legs syndrome (RLS) (also known as Willis-Ekbom disease (WED)) is a common sleep-related movement disorder characterized by frequent, unpleasant, or uncomfortable urges to move the legs during periods of inactivity, particularly at night, which can be temporarily relieved by movement. Current treatments for RLS primarily include pharmacological therapy, including dopamine supplements (levodopa), dopamine medications (ropinirole, pramipexole), and (in some cases) anticonvulsants such as gabapentin. Other treatment options may include the use of a mechanical vibration pad, but this may be ineffective except as a placebo.

[0103] Overactive neural activity in the peripheral nervous system and / or spinal cord is thought to contribute to the pathophysiology of RLS. Spontaneous leg movements naturally lead to relief of RLS symptoms, which can be explained by mechanisms such as gating theory, where proprioceptive signals triggered by leg movements inhibit pathologically overactive neural signals before they reach the brain. However, voluntary leg movements are incompatible with sleep. Systems such as vibrating mattresses or TENS or NEMS devices can generate signals similar to voluntary leg movements, but can also produce similar distractions that are incompatible with sleep.

[0104] U.S. Patent No. 10,342,977, published on July 19, 2019, by Shriram Raghunathan and entitled “Restless Leg Syndrome or Overactive Nerve Treatment,” describes a technique for treating RLS symptoms to provide therapeutic benefits such as no distracting side effects, which is incorporated herein by reference. For example, U.S. Patent No. 10,342,977 describes a method that employs one or more high-frequency electrical stimulation waveforms that may have different effects on different nerve fiber types, thus allowing patients to tolerate higher and more therapeutic levels of electrical nerve stimulation without disrupting their natural ability to fall asleep. For example, activation of one or more nerve fibers of the peroneal nerve allows excitation of sensory and proprioceptive nerve fibers, resulting in gating inhibition of peripheral and / or spinal cord overexcitation in RLS patients, and thus reducing the sensory impulse to move their legs. Unbound by theory, Figure 10A and Figure 10B This conceptually demonstrates how voluntary leg movements can alleviate RLS symptoms (see...). Figure 10A (such as through gating inhibition and / or distraction mechanisms) and through high-frequency electrical stimulation of the common peroneal nerve ( Figure 10B Examples of how this difference can help suppress RLS symptoms such as leg movements (thus allowing for better sleep onset and sleep quality).

[0105] The inventors have observed, among other things, that when induced by one or more therapeutic waveforms below a “distraction threshold” that allow the patient to comfortably fall asleep, electrical nerve stimulation waveforms that produce greater involuntary motor fiber activation (e.g., recorded by surface electromyography or sEMG activity) at rest are associated with higher therapeutic efficacy. This distraction threshold can be determined by asking subjects about their tolerance or comfort with a particular waveform. Furthermore, the inventors have observed that the frequency and pulse width of the electrical nerve stimulation used to induce this motor response can vary between patients.

[0106] The following Figure 11 The graphs are from experiments involving five different human subjects and EMG amplitudes at different electrical nerve stimulation frequencies (2000 Hz, 4000 Hz, 6000 Hz). Figures 1 to 9 The different studies shown. Figure 11 This illustrates an example of the maximum level of below-distraction threshold motor activation generated among five study participants by electrical nerve stimulation waveforms varying at frequencies (2000 Hz, 4000 Hz, 6000 Hz). Participants 1 through 4 exhibited motor activation, while participant 5 did not. Therefore, participant 5 may not be a suitable candidate for treatment during sleep and could be excluded during patient screening (e.g., as a “non-responder”), as illustrative examples of variations in electrical stimulation parameters can be based on surface EMG signals responding to electrical stimulation at different frequencies. Participants 1, 2, 3, and 4 all exhibited significantly higher motor activation at specific frequencies, but this “optimal” frequency varied among the participants. The optimal frequency was 6000 Hz for participants 1 and 4, 4000 Hz for participant 3, and 2000 Hz for participant 2.

[0107] While most patients with recurrent neuralgia (RLS) experience their strongest RLS symptoms when attempting to fall asleep at night, many also experience symptoms during the day, with those symptoms being particularly pronounced at night. Furthermore, many other symptoms associated with hyperactive neural activity are more or most pronounced during the day. Therefore, we also used surface EMG signal activity to clinically assess the relative efficacy of electroneurostimulation waveforms at higher, daytime-related patient thresholds (i.e., the patient's "discomfort threshold"). For all participants, the "distraction threshold" at which patients were able to fall asleep was lower than the "discomfort threshold" at which the same patient was willing to tolerate electroneurostimulation treatment while awake (e.g., performing one or more daily activities). We observed similar differences in EMG signals responding to different frequencies of electroneurostimulation at the patient's discomfort threshold, suggesting that this method of using surface EMG signals as an indicator of the efficacy or efficiency of electroneurostimulation response can also be useful, for example, for selecting or modulating the titration of daytime electroneurostimulation.

[0108] Figure 12 The graphs obtained from experiments responding to changes in surface EMG amplitudes with varying electrical stimulation parameters are shown below. Different electrical nerve stimulation frequencies (2000 Hz, 4000 Hz, 6000 Hz) were provided to five different human participants. Figure 12 The maximum motor activation level, determined by surface EMG below the patient's discomfort threshold, is shown by applying electrical stimulation waveforms varying in selected parameters. Here, the frequencies (2000 Hz, 4000 Hz, 6000 Hz) of the five study participants are compared with... Figure 11 The results shown are identical to those studied. Participants 1 through 5 all exhibited motor activation. Therefore, based on these EMG signal responses to different neurostimulation outcomes, patient screening would result in all participants being considered suitable candidates for daytime electrical stimulation therapy. Based on the different motor activations based on surface EMG signals between different electrical neurostimulation frequencies, Participant 1 will be assigned to an electrical stimulation frequency of 6000 Hz, Participant 2 will be assigned to 2000 Hz, Participant 3 will be assigned to 4000 Hz, Participant 4 may be assigned to any of these three electrical stimulation frequencies, such as selection based on relative power limitations, and Participant 5 may be assigned to either 2000 Hz or 6000 Hz, such as selection based on relative power limitations.

[0109] like Figure 12The experimental results showed that participants 1 through 4 all exhibited motor activation below the patient's distraction threshold as determined by surface EMG signals, but only participants 1 and 3 exhibited motor activation below their corresponding patient distraction thresholds at multiple electrical stimulation frequencies. Therefore, relative power consumption can be used as a consideration or target, such as in determining which electrical stimulation frequency to deliver to participants 1 and 3. Alternatively, the magnitude of sEMG activation at the distraction threshold can be used as a consideration or target, such as... Figure 8B As discussed in the description.

[0110] Figure 13 Experimental data illustrating the electrical stimulation power required to achieve surface EMG motor activation for each participant are presented. For participant 1, the difference in electrical stimulation power was not significant across different stimulation frequencies. For participant 3, the lower electrical stimulation power required at a stimulation frequency of 2000 Hz relative to that required at a stimulation frequency of 4000 Hz could be used as a basis for automatically selecting or otherwise selecting 2000 Hz as the electrical stimulation frequency.

[0111] Personalization method examples

[0112] In illustrative examples, one or more recording electrodes for sEMG can be placed in desired locations, such as near the bulge or thickest part of a muscle innervated by a specific nerve being electrically stimulated. In the case of treating RLS, as described in U.S. Patent No. 10,342,977, two sEMG recording electrodes can be located at the bulge of the tibialis anterior (TA) muscle on the leg being stimulated, one sEMG reference electrode can be placed on the patella, and two electrical nerve stimulation electrodes can be placed along the length of the common peroneal nerve on the transverse side of the leg, covering the fibular head, below the patella.

[0113] Surface electromyography (sEMG) can be recorded from the bulge of the TA muscle, such as by sampling at frequencies below the electrical nerve stimulation frequency (e.g., sampling at 512 Hz for the experiment described above, where the electrical nerve stimulation frequencies are 2000 Hz, 4000 Hz, and 6000 Hz). The resulting recorded sEMG waveforms can be processed, such as amplified, bandpass filtered (e.g., between 1 Hz and 512 Hz), rectified, smoothed (e.g., using rolling average, filtering, or other smoothing time windows between 1 second and 5 seconds (including endpoints), and monitored.

[0114] In illustrative examples, for instance, to help ensure the maximum efficacy of electrical nerve stimulation used "during sleep," the amplitude of the electrical nerve stimulation waveform can be gradually increased for each electrical nerve stimulation setting (e.g., using one or more parameters, which may include pulse width, inter-pulse interval, etc.), such as until it reaches the patient's "distraction threshold," at which the subject reports that the electrical nerve stimulation is too distracting for the patient to fall asleep.

[0115] In another illustrative example, such as to help ensure the maximum effectiveness of electrical nerve stimulation during the day, for each electrical nerve stimulation setting (e.g., using one or more parameters, which may include pulse width, inter-pulse interval, etc.), the amplitude of the electrical nerve stimulation waveform may be gradually increased, such as until it reaches the patient's "discomfort threshold," at which the subject reports that the electrical nerve stimulation cannot be comfortably tolerated.

[0116] In another illustrative example, such as to help reduce the power, voltage, or current of the electrical nerve stimulation, for each stimulation setting (e.g., using one or more parameters, which may include pulse width, inter-pulse interval, etc.), the amplitude of the electrical nerve stimulation waveform may be gradually increased, such as until the rectified EMG signal is observed to consistently exceed the baseline EMG signal (before the application of electrical nerve stimulation) by a specified factor (e.g., 2 times) for a specified time period (e.g., a 15-second time period).

[0117] In one or more of these exemplary examples above, the electrical nerve stimulation parameter settings can be recorded by the system, and the next set of electrical nerve stimulation parameters in the aggregated list of such sets can be used to repeat the process, such as to explore various permutations or combinations of electrical nerve stimulation parameter settings.

[0118] For the time period corresponding to the exploration of electrical nerve stimulation parameters, the patient can be instructed to remain still to avoid voluntary muscle activation. The EMG system can be configured to provide an algorithm or other means to detect one or more high levels of voluntary muscle activation via the sEMG signal, and in any such case, to signal the patient, clinician, or technician to restart the stimulation parameter exploration procedure. The algorithm can also “take up” or store the raw EMG signal in the 1Hz-512Hz range, amplified and bandpass filtered, but neither rectified nor smoothed.

[0119] A first potential goal in exploring electrostimulation parameters could be to find an electrostimulation waveform setting that produces the maximum increase in resting sEMG signal (e.g., from pre-stimulation baseline values) while remaining below a patient distraction (or discomfort) threshold. This particular selected electrostimulation waveform can then be programmed into the electrostimulation therapy device and is considered to represent the most effective electrostimulation waveform to be delivered for that particular patient.

[0120] A second potential (additional or alternative) goal in exploring electrical nerve stimulation parameters could be to find the most power-efficient (or current- or voltage-efficient) stimulation waveform setting that produces a clinically relevant increase in the resting sEMG signal (from baseline) while remaining below the patient's distraction (or discomfort) threshold. This selected electrical nerve stimulation waveform can then be programmed into the treatment device and can help provide the most power-efficient therapeutic electrical nerve stimulation waveform to be delivered to that particular patient. Power efficiency can also reduce the heat generated by the device, which in turn can help to use the device in a way that is more comfortable for the patient.

[0121] A third potential (additional or alternative) goal of exploring electroneurostimulation parameters could be for patient screening, such as helping to identify one or more “unresponsive” patients who do not show clinically relevant enlargements in resting sEMG signals while remaining below a distraction (or discomfort) threshold, and excluding them from eligibility for clinical trials or from being prescribed such electroneurostimulation devices.

[0122] exist Figure 14 In the test example shown, one or more electrical nerve stimulation waveform parameters can be selected or changed, such as a table of possible permutations or combinations of one or more pulse width (PW) and interpulse interval (used to derive frequency f), as shown below. Figure 15 An illustrative example is shown.

[0123] exist Figure 15 In the diagram, electrical nerve stimulation waveforms A through C illustrate three different arrangements of electrical nerve stimulation waveforms, representing charge-balanced electrical nerve stimulation settings with different stimulation pulse widths (PWs) in the illustrated example. All PWs are at the same stimulation frequency (f), and none of these are required. By scanning these different electrical nerve stimulation waveform settings, this testing method can be designed to identify the optimal waveform for a specific, single, or combined goal, such as minimizing charge injection, maximizing sEMG activation, or achieving one or both goals while ensuring patient comfort and / or without distraction.

[0124] exist Figure 14 At position 1402, various electrical nerve stimulation parameters can be tested. At position 1404, the recording electrode (E1) can be placed at the desired location on the patient's anatomical surface, such as on the tibialis anterior muscle. The stimulation electrode (E2) can be placed at the desired location on the patient's anatomical surface, such as along and above the patient's common peroneal nerve.

[0125] At 1406, a neural stimulation setting (e.g., a combination of neural stimulation parameters) can be selected in the memory circuit, such as by selecting from a stored table, and may include various neural stimulation settings, such as different arrangements or combinations of neural stimulation parameters.

[0126] At 1408, stimulation can be initiated with selected neural stimulation settings, such as by gradually increasing the amplitude of the neural stimulation to a specified amplitude level.

[0127] At 1410, the surface EMG signal response to neural stimulation can be monitored from the recording electrode (E1).

[0128] At 1412, the patient can be monitored or questioned (e.g., via a patient interface device) to determine if the patient is experiencing discomfort caused by nerve stimulation. If so, the flow can proceed to 1416; otherwise, the flow can proceed to 1414.

[0129] At 1414, the surface EMG signal can be processed and monitored, and compared with a threshold, such as to determine whether the indication derived from the surface EMG signal intersects with the threshold. If so, the procedure can proceed to 1416; otherwise, the procedure can proceed to 1408 to continue gradually increasing the stimulus amplitude.

[0130] At point 1416, a stimulation setting indicating discomfort can be recorded and stored in the memory circuitry. A stimulation setting that causes the surface EMG signal indication to intersect with a threshold can also be recorded at this step of the process. The process can then return to point 1406, for example, to select another neural stimulation setting, involving a different set of neural stimulation parameters. In this way, various neural stimulation settings stored in the table can be tested sequentially. A linear progression through the table can be used, or binary search or other rule-based or other logical techniques to determine the next neural stimulation setting to be tested can be used.

[0131] Applicability of the technology to one or more other indications

[0132] While the examples above focus on optimizing one or more electrical stimulation waveforms, such as to treat one or more symptoms of restless legs syndrome (RLS), similar approaches can be used to optimize one or more electrical stimulation therapies for one or more other indications, such as by targeting different neuromuscular combinations. Some examples are included in Table 1 below.

[0133] Table 1: Examples of other indications for target nerves and muscles in samples

[0134]

[0135]

[0136] The applicability of the technology to one or more other methods of neural stimulation, such as reducing one or more side effects.

[0137] Although Table 1 above focuses on the use of electroneurostimulation for the treatment of various conditions associated with overactive muscles, there are other electroneurostimulation techniques for which the described testing methods may be useful.

[0138] In this context, this testing method can be used to select or optimize one or more neurostimulation techniques that may have the unintended side effect of activating one or more muscles. For example, vagus nerve stimulation used to treat epilepsy can lead to activation of the pharyngeal muscles, as these muscles are innervated by branches of the vagus nerve.

[0139] In examples such as those where muscle activation is correlated with therapeutic efficacy, this technique can be used to identify one or more stimulation parameter settings that lead to greater muscle activation (e.g., while remaining below the threshold of patient discomfort or distraction) and thus greater therapeutic efficacy.

[0140] In another example, such as where muscle activation is an undesirable side effect, this technique can be used to identify one or more therapeutic stimulation parameter settings that minimize or reduce this undesirable side effect.

[0141] Automated devices and systems for waveform personalization

[0142] In applications of this technical example for optimizing electrostimulation therapy (such as treating RLS), a leg-worn sleeve device may include a built-in EMG monitoring electrode and an electrode grid having a plurality of electroneurogenic electrodes, the built-in EMG monitoring electrode being positioned above the tibialis anterior (TA) muscle when worn, the plurality of electroneurogenic electrodes covering a portion along the length of the common peroneal nerve, such as... Figure 16 As shown in the example. The sleeve may also include battery-powered electronic circuitry, such as circuitry that can be configured to communicate wirelessly with an external computing or display device, such as an external computing or display device that can be used in conjunction with the sleeve to provide signal processing or user interface capabilities.

[0143] Figure 17 An exemplary example of an electro-neurostimulation electrode grid, such as having nine electrodes, is shown, which can be placed externally on the patient's skin, for example, at a location above and near the patient's common peroneal nerve.

[0144] Once the desired electro-neural stimulation waveform is identified, the electro-neural stimulation electrode grid can be used to modify the selected electrodes, such as to allow the automatic selection of the most effective stimulation electrode pair, which, for example, uses the selected electro-neural stimulation waveform to generate the maximum sEMG signal for electrical stimulation. Similarly, onboard electronics can be additionally or alternatively used to help determine the optimal electro-neural stimulation electrode pair, such as by detecting the skin contact location presenting the lowest impedance.

[0145] Figure 18 An example of an architecture for onboard electronic circuitry that can be used to assist in the implementation or execution of the disclosed techniques or methods is shown. Figure 18 In this system, system 1800 may include or be coupled to a grid of stimulating electrodes 1810, for example, for percutaneous delivery of high-frequency electrical nerve stimulation to an external location, such as the superficial peroneal nerve of a patient. Stimulation delivery may be controlled by stimulation controller circuitry 1814 (such as a microcontroller, FPGA, or other suitable circuitry). Stimulation controller circuitry 1814 may also provide one or more control signals to stimulation electrode selector / multiplexer circuitry 1812, such as selecting a specific combination of stimulating electrodes from the stimulation electrode grid 1810 to deliver electrical nerve stimulation to the patient. Recording electrode 1802 may receive a responsive surface EMG signal, which may be routed through isolation and bandpass or other filtering circuitry 1804 and then to amplifier 1806. The surface EMG signal response may be digitized and further processed by processor circuitry 1808 and then transmitted to a local or remote user device via wireless communication unit 1816. A battery 1818 and power management circuitry 1820 may also be provided.

[0146] In an exemplary example, surface EMG signals from the tibialis anterior muscle can be detected, such as via two or more recording electrodes. The obtained surface EMG signals can first be filtered (e.g., by isolation and filtering circuitry) and amplified (e.g., by an amplifier), then digitized and processed or analyzed by onboard processor circuitry. The processor can also control electrical stimulation controller circuitry, which can be configured to generate a constant current or programmed to provide additional outputs for one or more electroneurostimulation therapy settings selected by the processor. A multiplexer can then be used to select the programmed electrode pairs, such as from a grid of available electrodes. The processor can also include transmitter or transceiver circuitry, which can be configured to communicate wirelessly (e.g., via Bluetooth or WiFi) or otherwise with an external display or processing unit (e.g., for further processing or displaying results of parameter optimization or information associated with electroneurostimulation.

[0147] Applications can be provided on the patient's or caregiver's smartphone, such as those that help guide the user through step-by-step sequences to help identify or determine which electrical nerve stimulation waveforms and electrode locations are most effective for the specific patient.

[0148] Examples of sEMG responses to neural stimulation used in conjunction with muscle activation

[0149] In one example, the above-described sEMG-based NPNS personalization could involve measuring sEMG during NPNS delivery within a controlled protocol involving routine muscle activation. Routine muscle activation can be voluntary or involuntary. The controlled protocol can involve one or more muscles associated with a neural or neuromuscular target (or its antagonist) of the NPNS. This approach could include measuring the routine sEMG response associated with muscle activation. The system could be used to measure the degree to which this sEMG response is modulated via NPNS relative to baseline (without NPNS), where such modulation of the sEMG response can be an increase in sEMG signal amplitude, a decrease in sEMG signal amplitude, or a change in the duration of sEMG response signal artifacts. Some illustrative examples are described below.

[0150] Example 1: Voluntary staged buckling

[0151] In this method, patients or subjects can be instructed to repeatedly perform controlled movements. For example, subjects can be instructed to perform the designated movement multiple times at baseline (without NPNS delivery) and during each parameter setting of the NPNS being tested to reduce variability. sEMG responses can be measured on the muscles associated with (or antagonistic to) the designated movement. Parameters of the designated movement (including effort and time intervals between each instance of movement) can be selected to minimize fatigue and ensure that movement-induced sEMG activity remains relatively constant over time without NPNS delivery. NPNS can be applied to block experimental designs, and sEMG activity during NPNS opening can be compared to sEMG activity during NPNS closing.

[0152] More specifically, the subject can be instructed to dorsiflex their foot toward the subject's knee. The NPNS can be applied above the subject's peroneal nerve, and sEMG can be measured above the subject's tibialis anterior muscle. For example, the subject can be instructed to flex their toes toward the knee with consistent time and force (dorsiflexion), such as 6 repetitions per set, with less than 1 second of rest between each repetition and approximately 10 seconds of rest between sets. This will induce an sEMG signal in the tibialis anterior muscle during dorsiflexion, the amplitude of which is stable at baseline (during NPNS-OFF). This sEMG signal in the tibialis anterior muscle can be smoothed (e.g., using a low-pass filter) and rectified, and the maximum sEMG amplitude for each dorsiflexion can be recorded as a single point.

[0153] Figures 19 to 21 This indicates the experimental data obtained using this method. The peak EMG amplitude of the staggered backbend block will be compared between the NPNS-on and NPNS-off states. For example... Figures 19 to 21 The data shown indicates that, in this example, NPNS reduced the sEMG amplitude of the tibialis anterior muscle.

[0154] Figure 19 This is a graph showing the experimental data of sEMG amplitude compared to the time periods when NPNS is on or off. Figure 19 This sEMG activity in the tibialis anterior muscle during repetitive foot dorsiflexion is shown. Figure 19 The smoothed sEMG traces and peak sEMG activity for each backbend are marked with circles.

[0155] Figure 20 yes Figure 19 The graph showing the peak sEMG amplitude of the same experimental data compared to the NPNS state illustrates... Figure 19 Peak sEMG activity for each dorsiflexion. Figure 20 As can be seen, the peak sEMG amplitude during dorsiflexion decreases during NPNS.

[0156] Figure 21 This is a graphical representation of experimental data on peak sEMG amplitudes under various stimulation conditions and parameters during foot dorsiflexion (e.g., no stimulation, high-frequency and low-intensity stimulation, high-frequency and high-intensity simulation, no stimulation, low-frequency stimulation, no stimulation). Therefore, Figure 21 Peak sEMG activity of foot dorsiflexion is shown during adjustment of stimulation parameters, including high frequency (4000 Hz) and low frequency (<500 Hz). Figure 21 As can be seen, the sEMG amplitude during dorsiflexion and high-frequency NPNS is modulated (reduced) in a manner that depends on the intensity of high-frequency NPNS but does not occur with low-frequency stimulation or in the absence of stimulation. It is believed that the amount of this sEMG amplitude modulation (reduction) during dorsiflexion (or other controlled muscle activation) and high-frequency NPNS can be used as an indicator of neurostimulation responsiveness or efficacy in a specific patient, such as for assessing and comparing different NPNS parameter settings.

[0157] Example 2: Involuntary staged reflexes

[0158] In this method, the patient or subject can be instructed to relax their muscles. Muscle reflexes can be repeatedly induced by applying staged electrical stimulation (e.g., Hoffman reflex) to sensory fibers associated with the muscle spindle or by applying staged forces to the muscle spindle, such as to induce stretch reflexes (e.g., knee-jerk reflex). Surface EMG (sEMG) signals can be measured on the muscle associated with the reflex (or the antagonistic muscle). Parameters of reflex induction (including amplitude and time interval between each reflex instance) can be selected to minimize fatigue, thus keeping reflex-induced sEMG activity relatively constant over time in the absence of NPNS. NPNS can be applied to designs such as block experiments, and sEMG activity during NPNS block opening can be compared to sEMG activity during NPN block closing.

[0159] Example 3: Voluntary isometric buckling

[0160] In this method, a patient or subject can be instructed to tonically activate muscles via isometric flexion. For example, this could include tonic activation of muscles by pushing against a fixed object or pulling a rope attached to the fixed object. Surface EMG (sEMG) can be measured on the muscles associated with (or antagonistic to) isometric flexion. The effort and duration of the protocol can be selected to minimize fatigue, thus keeping sEMG activity relatively constant over time in the absence of NPNS. NPNS can be applied to a block experimental design, and sEMG activity during NPNS opening can be compared to sEMG activity during NPNS closing.

[0161] In various examples 1 to 3, the system may include an electrical stimulation unit having a response signal measurement unit and controller circuitry for measuring signals related to muscle activation, such as one or more of the following physiological signals:

[0162] a. EMG activity of muscles, such as that which can be measured by sEMG or invasive EMG;

[0163] b. Force, such as that which can be measured by a force gauge or other device; or

[0164] c. Motion, such as that which can be measured by one or more of an IMU, accelerometer, gyroscope, or video.

[0165] While therapeutic NPNS is associated with increased stress-induced sEMG activity at rest, during these controlled protocols, therapeutic NPNS may lead to a decrease, increase, or modulation of protocol-induced sEMG activity. In these examples, NPNS-based differences in this physiological signal can be used to predict the strength of the therapeutic response to various combinations of NPNS parameters (personalized / optimized) and / or the response to NPNS in various patients (patient selection).

[0166] Figure 22Examples of portions of the system 2200 are shown, such as those used to perform one or more techniques described herein. System 2200 may include an electrical stimulation unit 2210. The electrical stimulation unit 2210 may include or be coupled to electrical stimulation electrodes 2250, which may be placed or fixed at an external location, such as that for delivering high-frequency NPNS to a subject, as described herein. The electrical stimulation unit 2210 may include or be coupled to a power source 2205, which may be used to provide electrical energy available for delivering NPNS, including delivery to various circuitry for generating NPNS or to controller circuitry for performing one or more algorithms or for performing signal processing. The electrical stimulation unit 2210 may include or be coupled to a power regulator circuitry 2212, which is configured to receive energy from the power source 2205 and regulate power for delivery to other circuitry included in or coupled to the electrical stimulation control unit 2210. An electrical stimulation generator 2230 may be configured to generate high-frequency NPNS electrical stimulation pulses, as described herein, for delivery to a subject via the electrical stimulation electrodes 2250. The electrical stimulation controller 2220 circuitry can control the timing and electrical stimulation parameters (e.g., amplitude, frequency, pulse width, duty cycle, electrode selection, etc.) of the NPNS electrical stimulation generated by the electrical stimulation generator 2230. The electrical stimulation unit 2210 may include an impedance detection circuit 2240, which may be configured to detect the load impedance or electrode-skin interface impedance at one or more electrical stimulation electrodes 2250, and this impedance information may be provided to the electrical stimulation controller, for example, for selecting or adjusting electrical stimulation parameters or control algorithm parameters, which may be based in part on this detected impedance, for example, automatically or in a closed-loop manner. The electrical stimulation unit 2210 may include an electrical stimulation testing unit 2218, which may include circuitry configured to test or compare the efficacy of NPNS under various electrical stimulation parameter settings, such as for selecting specific settings for combinations of electrical stimulation parameters, such as based on responsiveness or efficacy, as described herein. The electrical stimulation unit 2210 may include one or both of the communication interface 2216 circuitry or the transceiver 2214 circuitry, such as to allow wired or wireless communication with the local or remote user interface device 2290, such as for use by a patient or other subject to provide feedback on a particular NPNS instance or event, such as for determining pain or discomfort thresholds, distraction thresholds or other patient feedback or patient input information.

[0167] The electrical stimulation unit 2210 may include or be coupled to the sEMG sensing and analysis unit 2260, whose circuitry may be implemented on a microprocessor, microcontroller, or controller circuitry that may be included in or coupled to the electrical stimulation unit 2210. The sEMG sensing and analysis unit 2260 may be coupled to the sEMG sensing electrode 2270, which may be fixed to a muscle (or antagonistic muscle) innervated by a target nerve of the NPNS, as described elsewhere herein. The sEMG sensing and analysis unit 2260 may include an sEMG tonic activation detection unit 2266, which may include, for example, a buffer amplifier, integrator or other sEMG signal filtering or analog or digital signal processing circuitry, analog-to-digital converter circuitry, peak amplitude detection circuitry, comparator circuitry, or other suitable circuitry for performing the sEMG tonic activation detection techniques described herein. The sEMG threshold detection unit 2268 may include circuitry configured to determine thresholds for tonic muscle activation, pain, discomfort, distraction, etc., as described herein. The sEMG processor 162 may include controller circuitry or signal processing circuitry, such as for executing coded instructions for determining sEMG signal amplitude, peak value, duration, patient threshold, etc., as described herein. The sEMG recording unit 2264 may include memory circuitry and other circuitry, such as for storing sEMG responses to various NPNS instances, such as those provided under different parameter settings or electrode selections, for example, for comparison to determine optimal or other desired NPNS parameter settings or electrode selections, or for switching between different parameter settings or electrode selections, such as to improve efficiency, save power, or achieve one or more other objectives.

[0168] Overview and further description of various aspects of this disclosure

[0169] The following list of numbered aspects is intended to highlight but not limit or impose requirements on various aspects of this disclosure, such as those that can be used alone or in combination to provide one or more of a system, method, apparatus, or readable medium for performing the methods or articles of manufacture according to this disclosure.

[0170] Aspect 1 may include a system, apparatus, device, method, device-readable medium, article of manufacture, etc., which may include or use (or may be combined with one or more other aspects to include or use) a system for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. This aspect may include or use at least one electrical stimulation electrode, which may be configured to be positioned at a first external target body location near the peroneal nerve or its branches. This aspect may also include or use an externally non-implantable electrical stimulation unit, which may be coupled to at least one electrical stimulation electrode, for example for generating a first high-frequency pulsed electrical stimulation signal and applying it to the peroneal nerve or its branches, the first high-frequency pulsed electrical stimulation signal may include a frequency in the range of 500 Hz to 15,000 Hz, such as generating tonic sEMG activity or modulating phased sEMG activity in at least one muscle innervated by the peroneal nerve.

[0171] Aspect 2 may include or use, or may be combined with the subject matter of aspect 1, to include or use at least one parameter setting of the first high-frequency pulsed electrical stimulation signal specified at least in part based on the observed surface electromyography (sEMG) signal.

[0172] Aspect 3 may include or use, or may be combined with the subject matter of Aspect 1 or 2, to include or use at least one parameter setting of the first high-frequency pulsed electrical stimulation signal that is at least partially based on patient feedback, specified as less than at least one of a pain threshold or a distraction threshold. For example, this may be based on a subjective determination by the patient, which may be provided to the system by the patient via a user interface device, such as those described herein.

[0173] Aspect 4 may include or use, or may be combined with, the subject matter of any of Aspects 1 to 3 to include or use at least one parameter setting of the first high-frequency pulsed electrical stimulation signal that can be configured to allow for different designations based on the time of day or other indications of whether the patient is or is expected to be awake or asleep. For example, this may include a clock or sleep detector or other form of NPNS that the system may use to provide a higher level of NPNS during the day / awake period than during the night / sleep period (e.g., allowing distraction but not discomfort).

[0174] Aspect 5 may include or use, or may be combined with, the subject matter of any of aspects 1 to 4 to include or use the observed sEMG signal from at least one muscle innervated by the peroneal nerve of the same patient to which the first high-frequency pulsed electrical stimulation signal is delivered. For example, this may allow patient-specific NPNS customization or personalization such as achieving or balancing one or more goals, such as efficacy, energy saving, etc. Alternatively, population-based or similar subpopulation-based NPNS customization or personalization may be achieved using the techniques of this disclosure.

[0175] Aspect 6 may include or use, or may be combined with, the subject matter of any of Aspects 1 through 5 to include or use an electrical stimulation unit comprising or coupled to controller circuitry, such controller circuitry being configured to determine whether a first high-frequency pulsed electrical stimulation signal produces tonic sEMG activity or the degree of such tonic sEMG activity (e.g., sEMG signal amplitude) in an observed sEMG signal from the same patient. For example, this information may be used to determine the patient's responsiveness to the NPNS, the efficacy of the NPNS, or to compare various parameter settings to select appropriate NPNS parameter settings, such as based on one or more objectives. For example, the peak amplitude of the sEMG signal may be used, where the muscle is at rest, or controlled muscle activation may be used, as described elsewhere herein.

[0176] Aspect 7 may include or use, or may be combined with, the subject matter of any of Aspects 1 to 6 to include or use, an electrical stimulation unit comprising or coupled to controller circuitry that may be configured to store one or more indications of sEMG activity, such as different settings of the at least one parameter corresponding to a first high-frequency pulsed electrical stimulation signal. For example, this information may be used to compare the efficacy of various NPNS settings, which may be used alone or in conjunction with other information to achieve or balance one or more objectives (e.g., efficacy, power consumption, etc.).

[0177] Aspect 8 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 7 to include or use, an electrical stimulation unit comprising or coupled to a controller circuit that may be configured to select the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal, such as selection based on a comparison of corresponding sEMG activities under different settings.

[0178] Aspect 9 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 8 to include or use, an electrical stimulation unit that includes or is coupled to controller circuitry that may be configured to record indications of baseline sEMG activity obtained without providing the patient with a first high-frequency pulse electrical stimulation signal.

[0179] Aspect 10 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 9 to include or use, a controller circuit configured to characterize the patient’s neurostimulation responsiveness, such as characterization based at least in part on changes in the patient’s observed sEMG activity in response to a first high-frequency pulsed electrical stimulation signal relative to baseline sEMG activity.

[0180] Aspect 11 may include or use, or may be combined with, the subject matter of any of aspects 1 to 10 to include or use controller circuitry configured to characterize the neurostimulation responsiveness at least in part based on at least one of a tonic motor activation threshold, a distraction threshold, or a pain threshold, which are determined using one or more parameter settings of a first high-frequency pulsed electrical stimulation signal. For example, the tonic motor activation threshold may be determined using an sEMG signal, and the distraction threshold and pain threshold may be determined using subjective patient feedback, such as via a user interface device that may be provided to the patient.

[0181] Aspect 12 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 11 to include or use the electrical stimulation unit, which includes or is coupled to controller circuitry, which may include or be coupled to a communication interface, such as for receiving patient feedback or other input from the user, such as for use in selecting or determining one or more of a first high-frequency pulsed electrical stimulation signal or its parameters.

[0182] Aspect 13 may include or use, or may be combined with the subject matter of any one of aspects 1 to 12, to include or use at least one sEMG signaling electrode, such as being configured to be located in association with or capable of being located in relation to at least one muscle innervated by the peroneal nerve of the same patient to which the at least one electrical stimulation electrode delivers a first high-frequency pulse electrical stimulation signal.

[0183] Aspect 14 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 13 to include or use at least one electrical stimulation electrode capable of being positioned at a first external target body location near the peroneal nerve or its branches, the at least one electrical stimulation electrode comprising: at least one first electrical stimulation electrode configured for positioning at a first external target body location near the right peroneal nerve or its branches on the patient's right leg; and at least one second electrical stimulation electrode configured for positioning at a second external target body location near the left peroneal nerve or its branches on the patient's left leg. The electrical stimulation unit may be configured to generate a first high-frequency pulsed electrical stimulation signal and a second high-frequency pulsed electrical stimulation signal, the first high-frequency pulsed electrical stimulation signal being delivered using the at least one first electrical stimulation electrode to the right peroneal nerve or its branches to generate or modulate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the right peroneal nerve, and the second high-frequency pulsed electrical stimulation signal being delivered using the at least one second electrical stimulation electrode to the left peroneal nerve or its branches to generate or modulate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the left peroneal nerve. For example, this can be used to provide bilateral stimulation, bilateral sEMG monitoring, or both.

[0184] Aspect 15 may include or use, or may be combined with the subject matter of any of aspects 1 to 14, to include or use pulses of the electrical stimulation unit configured to repeatedly deliver the first high-frequency pulsed electrical stimulation signal, such as by increasing the energy level in a ramp manner, such as increasing toward a target energy level.

[0185] Aspect 16 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 15 to include or use an arrangement of multiple electrodes, wherein the electrical stimulation unit may include or may be coupled to controller circuitry configured to select one or more electrodes from the plurality of electrodes, such as based at least in part on observed sEMG activity in response to test electrical stimulation signals delivered to a patient via different electrodes of the plurality of electrodes, and to use the selected one or more electrodes, such as to apply therapeutic electrical stimulation signals to the patient.

[0186] Aspect 17 may include or use, or may be combined with, the subject matter of any of aspects 1 to 16 to include or use the electrical stimulation unit including or coupled to controller circuitry configured to, for example, at least one parameter setting for specifying a first high-frequency pulsed electrical stimulation signal, such as modulation of phased sEMG activity at least in part based on observed sEMG signals, such as muscle activation in conjunction with at least one muscle innervated by the peroneal nerve. For example, this may include controlled muscle activation, such as dorsiflexion or other techniques described herein.

[0187] Aspect 18 may include or use, or may be combined with, the subject matter of any of aspects 1 to 17 to include or use the electrical stimulation unit coupled to the at least one electrical stimulation electrode, such as for delivering a first high-frequency pulsed electrical stimulation signal to a patient and for detecting reactive sEMG signals from the patient using the same at least one electrical stimulation electrode. Alternatively, an electrode different from the electrode used for NPNS or other electrical stimulation may be used for sEMG sensing.

[0188] Aspect 19 may include or use, or may be combined with the subject matter of any of Aspects 1 to 18, to include or use a method for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. The method may include delivering a first high-frequency pulsed electrical stimulation signal defined by a plurality of parameters, including frequencies in the range of 500 Hz to 15,000 Hz, to a first external target body location near the peroneal nerve or its branches. The method may also include generating tonic sEMG activity or modulating phased sEMG activity in at least one muscle innervated by the peroneal nerve. The method may also optionally include establishing or adjusting at least one parameter setting of the first high-frequency pulsed electrical stimulation signal based at least in part on observed surface electromyography (sEMG) signals.

[0189] Aspect 20 may include or use, or may be combined with the subject matter of any one of aspects 1 to 19, to include or use at least one parameter setting of the first high-frequency pulsed electrical stimulation signal that is at least partially based on patient feedback, such as being less than at least one of a pain threshold or a distraction threshold.

[0190] Aspect 21 may include or use, or may be combined with the subject matter of any of aspects 1 to 20, to include or use at least one parameter setting of a first high-frequency pulsed electrical stimulation signal that can be specified differently, such as based on the time of day or other indications of whether the patient is or is expected to be awake or asleep.

[0191] Aspect 22 may include or use, or may be combined with, the subject matter of any of aspects 1 to 21 to include or use the observed sEMG signal from at least one muscle innervated by the peroneal nerve of the same patient to which the first high-frequency pulsed electrical stimulation signal is delivered.

[0192] Aspect 23 may include or use, or may be combined with the subject matter of any of aspects 1 to 22, to include or use the at least one parameter setting for selecting the first high-frequency pulsed electrical stimulation signal, such as selection based on a comparison of sEMG activity generated in response to multiple different high-frequency pulsed electrical stimulation test signals (e.g., under different settings such as one or more neural stimulation parameters).

[0193] Aspect 24 may include or use, or may be combined with, the subject matter of any of aspects 1 to 23 to include or use characterization of a patient’s neurostimulation responsiveness, such as characterization based at least in part on changes in observed patient sEMG activity relative to baseline sEMG activity, such as sEMG activity generated in response to a first high-frequency pulsed electrical stimulation signal.

[0194] Aspect 25 may include or use, or may be combined with, the subject matter of any of aspects 1 to 24 to include or use a characterization of a patient’s neurostimulation responsiveness, such as being based at least in part on at least one of a tonic motor activation threshold, a distraction threshold, or a pain threshold, which may be determined using a plurality of different high-frequency pulsed electrical stimulation test signals (e.g., differences in one or more parameter settings corresponding to a first high-frequency pulsed electrical stimulation signal).

[0195] Aspect 26 may include or use, or may be combined with, the subject matter of any of aspects 1 to 25 to include or use, bilateral electrical stimulation of the patient’s legs.

[0196] Aspect 27 may include or use, or may be combined with, the subject matter of any of aspects 1 to 26 to include or use one or more electrodes selected from an arrangement of multiple electrodes, such as selection based at least in part on observed sEMG activity in response to test electrical stimulation signals delivered to the patient via different electrodes of the plurality of electrodes, and application of therapeutic electrical stimulation signals to the patient using the selected one or more electrodes.

[0197] Aspect 28 may include or use, or may be combined with the subject matter of any of aspects 1 to 27, to include or use the at least one parameter setting specifying the first high-frequency pulsed electrical stimulation signal, such as being specified at least in part based on the modulation of tonic sEMG activity in the observed sEMG signal, such as muscle activation along with at least one muscle innervated by the peroneal nerve.

[0198] Aspect 29 may include or use, or may be combined with the subject matter of any of Aspects 1 to 28, to include or use a system for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. The system may include: at least one electrical stimulation electrode configured to be positioned at a first external target body location near the peroneal nerve or its branches; and an external, non-implantable electrical stimulation unit coupled to the at least one electrical stimulation electrode for generating and applying a first high-frequency pulsed electrical stimulation signal to the peroneal nerve or its branches, the first high-frequency pulsed electrical stimulation signal including frequencies in the range of 500 Hz to 15,000 Hz, wherein the electrical stimulation unit includes or is coupled to controller circuitry configured to specify at least one parameter setting of the first high-frequency pulsed electrical stimulation signal, the specification (1) being at least partially based on reactive surface electromyography (sEMG) of the observed same patient. (1) a signal, such as for generating tonic sEMG activity or modulating phased sEMG activity in at least one muscle innervated by the peroneal nerve, and (2) specifying at least one parameter setting of the first high-frequency pulsed electrical stimulation signal to be less than at least one of a pain threshold or a distraction threshold, at least in part based on patient feedback, wherein the controller circuit is configured to select the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal based on a comparison of corresponding sEMG activities under different settings; and at least one sEMG signal electrode is capable of being located in association with at least one muscle innervated by the peroneal nerve of the same patient to which the at least one electrical stimulation electrode delivers the first high-frequency pulsed electrical stimulation signal.

[0199] Aspect 30 may include or use, or may be combined with the subject matter of any of aspects 1 to 29, to include or use a method for characterizing the neurostimulation responsiveness of a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. The method may include delivering a first high-frequency pulsed electrical stimulation signal to a first external target body location near the peroneal nerve or its branches, the first high-frequency pulsed electrical stimulation signal including frequencies in the range of 500 Hz to 15,000 Hz, such as for generating or modulating tonic sEMG activity in at least one muscle innervated by the peroneal nerve. The method may also include characterizing the patient's neurostimulation responsiveness based at least in part on (1) observed changes in the patient's sEMG activity in response to the delivered first high-frequency pulsed electrical stimulation signal relative to baseline sEMG activity, and (2) at least one of a tonic motor activation threshold, a distraction threshold, or a pain threshold determined using one or more parameter settings of the first high-frequency pulsed electrical stimulation signal.

[0200] Aspect 31 may include or use, or may be combined with the subject matter of any of aspects 1 to 30, to include or use a method of treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using applied high-frequency stimulation. The method may include positioning at least one electrical stimulation electrode on the patient's body at a first external location associated with at least one nerve selected from the patient's peroneal nerve or its branches, sural nerve or its branches, or femoral nerve or its branches. The method may also include delivering an electrical stimulation signal to the first external location to reduce or alleviate one or more symptoms associated with RLS or PLMD, wherein the electrical stimulation signal comprises a pulsed electrical signal characterized by a plurality of parameters including a pulse frequency between 500 Hz and 15,000 Hz (inclusive), wherein the electrical stimulation signal is capable of producing at least one, or both: (1) tonic sEMG activation in muscles innervated by the at least one nerve; or (2) inhibition of the patient's muscle excitability during autonomic muscle activation, such as dorsiflexion.

[0201] Aspect 32 may include or use, or may be combined with, the subject matter of any of aspects 1 to 31 to include or use, a method of treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. The method may include: coupling at least one first electrical stimulation electrode to at least a first external target body location of the patient near the peroneal nerve or its branches; and delivering a first high-frequency pulsed electrical stimulation therapeutic signal to the at least first external target body location using the at least one first electrical stimulation electrode. The pulse of the electrical stimulation therapeutic signal may be defined by a plurality of parameters including a frequency at least between 500 Hz and 15,000 Hz and a current between 5 mA and 100 mA, and wherein the electrical stimulation therapeutic signal is above a tonic motor threshold and below a pain threshold for at least one muscle innervated by the peroneal nerve or its branches.

[0202] Aspect 33 may include or use, or may be combined with the subject matter of any one of aspects 1 to 32, to include or use the electrical stimulation therapeutic signal below at least one of the tolerance threshold and the distraction threshold.

[0203] Aspect 34 may include or use, or may be combined with, the subject of any of aspects 1 to 33 to include or use the distraction threshold as a threshold of maximum stimulation at which the patient is not distracted when falling asleep during a sleep period.

[0204] Aspect 35 may include or use, or may be combined with the subject matter of any of aspects 1 to 34, to include or use pulses configured not to generate phased muscle activity in the at least one muscle innervated by the peroneal nerve or its branches.

[0205] Aspect 36 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 35 to include or use delivery of a first high-frequency pulsed electrical stimulation therapeutic signal, the delivery comprising applying a charge-balanced AC controlled current pulse to the at least first external target body location, and controlling or adjusting the current, such as by means of a measured load impedance or a component thereof.

[0206] Aspect 37 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 36 to include or use positioning at least one EMG sensing electrode on the patient’s skin near the at least one muscle innervated by the peroneal nerve or its branches; delivering an electrical stimulation test signal to the at least one first electrical stimulation electrode, wherein the pulse of the electrical stimulation therapy is defined by a plurality of parameters, including a frequency between at least 500 Hz and 10,000 Hz and a current between 0 mA and 50 mA; sensing EMG activity induced by the electrical stimulation test signal in at least one muscle innervated by at least one of the sural nerve and the peroneal nerve; determining whether the electrical stimulation test signal is above a tonic motor threshold and below a pain threshold; repeating the steps of delivering the electrical stimulation test signal, sensing EMG activity, and determining whether the electrical stimulation test signal is above a tonic motor threshold and below a pain threshold, wherein each repetition of the electrical stimulation therapy pulse for delivering the electrical stimulation test signal has at least one of a different frequency and a different current than the immediately preceding electrical stimulation test signal; and selecting one of the electrical stimulation test signals as a first high-frequency pulsed electrical stimulation therapy signal.

[0207] Aspect 38 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 37 to include or use delivery of an electrical stimulation test signal, the delivery of which may include delivery of an electrical stimulation test signal having a first current value, and wherein each repetitive step of delivery of the electrical stimulation test signal may include applying an electrical stimulation signal having a current higher than that of the immediately preceding electrical stimulation test signal.

[0208] Aspect 39 may include or use, or may be combined with, the subject matter of any of aspects 1 to 38 to include or use a repetitive step of delivering an electrical stimulation test signal, the repetitive step comprising applying a series of electrical stimulation test signals, wherein the current value of the test signal increases at a rate from 1 mA / 0.25 sec to 1 mA / 15 sec.

[0209] Aspect 40 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 39 to include or use at least one of the following muscles innervated by the peroneal nerve or its branches: tibialis anterior, extensor digitorum longus, peroneus tertiary, extensor hallucis longus, peroneus longus, and peroneus brevis.

[0210] Aspect 41 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 40 to include or use monitoring at least one physical parameter selected from body movement, cardiac parameters, respiratory parameters, and neurological parameters; determining whether the patient is asleep or awake; if the patient is asleep: processing the at least one physical parameter; and if the physical parameter indicates either wakefulness or the possibility of wakefulness while the patient is asleep, adjusting the electrical stimulation treatment signal.

[0211] Aspect 42 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 41 to include or use coupling at least one first electrical stimulation electrode to at least one first external target body location, the coupling comprising: coupling at least one first electrical stimulation electrode to a first external target body location on the patient's left leg near the left peroneal nerve or a branch thereof; and coupling at least one second electrical stimulation electrode to a second external target body location on the patient's right leg near the right peroneal nerve or a branch thereof; and wherein delivering a first high-frequency pulsed electrical stimulation therapeutic signal comprises using the at least one first electrical stimulation electrode to apply a frequency and a pulsed electrical stimulation signal having a frequency between 500 Hz and 15,000 Hz. The method further comprises delivering a first electrical stimulation therapeutic signal with a current between 5 mA and 100 mA to the left peroneal nerve or its branches, the first electrical stimulation therapeutic signal inducing tonic activation in at least one muscle innervated by the left peroneal nerve or its branches and below a pain threshold, the method further comprising delivering a second high-frequency pulsed electrical stimulation therapeutic signal having a frequency between 500 Hz and 15,000 Hz and a current between 5 mA and 100 mA to the right peroneal nerve or its branches using at least one second electrical stimulation electrode, the second electrical stimulation therapeutic signal inducing tonic activation in at least one muscle innervated by the right peroneal nerve or its branches and below a pain threshold.

[0212] Aspect 43 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 42 to include or use coupling at least one first electrical stimulation electrode to at least one first external target body location, the coupling comprising coupling at least one first electrical stimulation electrode to the first external target body location on the patient's leg near the peroneal nerve or its branches, and wherein delivering the first high-frequency pulsed electrical stimulation therapeutic signal comprises using the at least one first electrical stimulation electrode to deliver a first electrical stimulation therapeutic signal having a frequency between 500 Hz and 15,000 Hz and a current between 5 mA and 100 mA to the peroneal nerve or its branches, the first electrical stimulation therapeutic signal being delivered to at least one area innervated by the peroneal nerve or its branches. The method further includes: coupling at least one second electrical stimulation electrode to at least a second external target body location on the patient's arm near one of the ulnar nerve or its branches and the radial nerve or its branches; and using the at least one second electrical stimulation electrode to deliver a second high-frequency pulsed electrical stimulation therapeutic signal having a frequency between 500 Hz and 15,000 Hz and a current between 5 mA and 100 mA to one of the ulnar nerve or its branches and the radial nerve or its branches, the second electrical stimulation therapeutic signal inducing tonic activation in at least one muscle innervated by the ulnar nerve or its branches and the radial nerve or its branches, and below a pain threshold.

[0213] Aspect 44 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 43 to include or use the first external target location being the skin surface superficial to the peroneal nerve or its branches.

[0214] Aspect 45 may include or use, or may be combined with, the subject of any of aspects 1 to 44 to include or use the sleep period as the time between the patient's bedtime and expected wake-up time.

[0215] Aspect 46 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 45 to include or use at least one first stimulating electrode positioned such that its proximal edge overlaps with the fibular head above the superficial peroneal nerve.

[0216] Aspect 47 may include or use, or may be combined with, the subject matter of any of aspects 1 to 46 to include or use at least a second electrode positioned inside the at least one first electrode at a distance of about half an inch from the first electrode, the at least second electrode overlapping the distal region of the tibialis anterior muscle.

[0217] Aspect 48 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 47 to include or use, a method for determining stimulation parameters for noninvasive peripheral nerve stimulation therapy, the method comprising: coupling at least one first electrical stimulation electrode to a patient's body location near a first external target point adjacent to the peroneal nerve or its branches; coupling at least one first EMG sensing electrode to the patient's skin adjacent to a muscle innervated by the peroneal nerve or its branches; delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches, wherein the pulse of the electrical stimulation test signal is defined by a plurality of parameters including a frequency between at least 500 Hz and 15,000 Hz and a current between 0 mA and 100 mA; sensing the nerve innervated by the peroneal nerve or its branches. The procedure involves: responding to the EMG activity of the muscle in response to the electrical stimulation test signal; determining, based on the sensed EMG activity, whether the electrical stimulation test signal is above the muscle's tonic motor threshold and below the patient's pain threshold; repeatedly delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches, sensing the muscle's EMG activity, and determining whether the electrical stimulation test signal is above the tonic motor threshold and below the pain threshold, wherein each repetition of the electrical stimulation therapy for delivering the electrical stimulation test signal has at least one of a different frequency and a different current than the immediately preceding electrical stimulation test signal; and selecting one of the electrical stimulation test signals above the tonic motor threshold and below the pain threshold as the high-frequency pulsed electrical stimulation therapy signal.

[0218] Aspect 49 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 48 to include or use: for each step of delivering a high-frequency pulsed electrical stimulation test signal, determining whether the electrical stimulation test signal is at or near a distraction threshold; selecting one of the high-frequency pulsed electrical stimulation test signals that is above a tonic-motor threshold, below a distraction threshold, and below a pain threshold as a high-frequency pulsed electrical stimulation treatment signal; and applying the selected high-frequency pulsed electrical stimulation test signal as a high-frequency pulsed electrical stimulation treatment signal to a first external target body location during a first time period.

[0219] Aspect 50 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 49 to include or use, a method for determining one or more patient thresholds for non-invasive peripheral nerve stimulation therapy, the method comprising: coupling at least one first electrical stimulation electrode to a first external target body location of the patient near a peroneal nerve or a branch thereof; coupling at least one first EMG sensing electrode to the patient's skin near a muscle innervated by the peroneal nerve or a branch thereof; delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or a branch thereof, wherein the pulse of the electrical stimulation test signal is defined by a plurality of parameters including a frequency at least between 500 Hz and 15,000 Hz and a current between 0 mA and 100 mA; sensing EMG activity of the muscle innervated by the peroneal nerve or a branch thereof in response to the electrical stimulation test signal; determining, based on the sensed EMG activity, whether the electrical stimulation test signal is above a muscle tonic movement threshold and below a patient's pain threshold; and determining, based on patient feedback, whether the electrical stimulation... The steps include: determining whether the electrical stimulation test signal is higher than one or more of a sensory threshold, a distraction threshold, a tolerance threshold, or a pain threshold; repeatedly delivering a high-frequency pulsed electrical stimulation test signal to the peroneal nerve or its branches, sensing EMG activity of the muscle, determining whether the electrical stimulation test signal is higher than a tonic motor threshold and lower than a patient threshold, and determining whether the electrical stimulation test signal is higher than one or more of a sensory threshold, a distraction threshold, a tolerance threshold, or a pain threshold based on patient feedback, wherein each repetition of the electrical stimulation therapy for delivering the electrical stimulation test signal has at least one of a different frequency and a different current than the immediately preceding electrical stimulation test signal; identifying the tonic motor threshold and at least one of the sensory threshold, a distraction threshold, a tolerance threshold, or a pain threshold; and performing a further action selected from: recording the identified threshold; selecting one of the high-frequency pulsed electrical stimulation test signals for application to the peroneal nerve or its branches; and identifying a change in one of the identified thresholds relative to a previously determined threshold.

[0220] Aspect 51 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 50 to include or use delivery of a high-frequency pulsed electrical stimulation test signal, the delivery of which may include delivery of an electrical stimulation test signal having a first current value, and wherein each repetitive step of delivery of the electrical stimulation test signal includes applying an electrical stimulation signal having a current higher than that of the immediately preceding electrical stimulation test signal.

[0221] Aspect 52 may include or use, or may be combined with, the subject matter of any of aspects 1 to 51 to include or use a repetitive step of delivering an electrical stimulation test signal, the repetitive step comprising applying a series of electrical stimulation test signals, wherein the current value of the test signal increases at a rate from 1 mA / 0.25 sec to 1 mA / 15 sec.

[0222] Aspect 53 may include or use, or may be combined with, the subject matter of any of aspects 1 to 52 to include or use, a system for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. The system may include: at least one electrical stimulation electrode located at a first external target body location near the peroneal nerve or its branches; and an external electrical stimulation unit coupled to the at least one electrical stimulation electrode, the electrical stimulation unit comprising: an electrical stimulation signal generator that generates a first high-frequency pulsed electrical stimulation therapeutic signal having a frequency from 500 Hz to 15,000 Hz and a current of at least 5 mA, and applying the first high-frequency electrical stimulation therapeutic signal to the peroneal nerve or its branches using the at least one electrical stimulation electrode to generate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the peroneal nerve.

[0223] Aspect 54 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 53 to include or use, wherein during the application of a first high-frequency pulsed electrical stimulation therapeutic signal, the first high-frequency pulsed electrical stimulation therapeutic signal generates tonic sEMG activity in the at least one muscle innervated by the peroneal nerve, the tonic sEMG activity exceeding, for a specified time period, a specified amount of baseline sEMG activity in the at least one muscle in the absence of the first high-frequency pulsed electrical stimulation therapeutic signal, the specified amount of which is selected from at least 50%, at least 100%, and at least 200%, and the specified time period is selected from at least 5 seconds, at least 10 seconds, at least 15 seconds, and at least 30 seconds.

[0224] Aspect 55 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 54 to include or use a first high-frequency pulsed electrical stimulation therapeutic signal defined by a plurality of parameters, the plurality of parameters including a frequency of at least 500 Hz to 10,000 Hz.

[0225] Aspect 56 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 55 to include or use a first high-frequency pulsed electrical stimulation therapeutic signal comprising a current amplitude from 5 mA to 50 mA.

[0226] Aspect 57 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 56 to include or use at least one of the following muscles innervated by the peroneal nerve or its branches: tibialis anterior, extensor digitorum longus, peroneus tertiary, extensor hallucis longus, peroneus longus, and peroneus brevis.

[0227] Aspect 58 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 57 to include or use, an external electrical stimulation unit further comprising: at least one surface EMG (sEMG) electrode coupled to a second external target body location near at least one muscle innervated by the peroneal nerve or its branches, wherein the at least one surface EMG recording electrode senses sEMG activity in the at least one muscle and generates an sEMG signal indicating the sEMG activity sensed in the at least one muscle; and an sEMG processor receiving the sEMG signal from the at least one sEMG electrode and analyzing the sEMG signal received during the application of a first high-frequency electrical stimulation signal to the at least one muscle or within 500 milliseconds after the application is terminated, to determine whether the first high-frequency pulsed electrical stimulation signal generates tonic sEMG activity in the at least one muscle innervated by the peroneal nerve.

[0228] Aspect 59 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 58 to include or use an electrical stimulation testing unit that causes an external electrical stimulation signal unit to generate a plurality of electrical stimulation test signals having frequencies from 500 Hz to 15,000 Hz and currents of at least 5 mA, and to sequentially apply each of the plurality of electrical stimulation test signals to the peroneal nerve or a branch thereof using at least one electrical stimulation electrode; and an sEMG tonic activation detection unit that causes an sEMG processor to receive sEMG signals from the at least one sEMG electrode during each of the plurality of electrical stimulation test signals being applied to the peroneal nerve or a branch thereof, for analyzing each of the plurality of electrical stimulation test signals. The method comprises: receiving sEMG signals during application to the peroneal nerve or its branches; determining whether each electrical stimulation test signal generates tonic sEMG activity in the at least one muscle innervated by the peroneal nerve; and determining the magnitude of any such tonic sEMG activity generated by each electrical stimulation test signal; and at least one of a recording unit and a transceiver unit, the recording unit being used to store whether each of the plurality of electrical stimulation test signals generates tonic sEMG activity in the at least one muscle, and to store the magnitude of any such tonic sEMG activity; and the transceiver unit being used to transmit to the user whether each of the plurality of electrical stimulation test signals generates tonic sEMG activity in the at least one muscle.

[0229] Aspect 60 may include or use, or may be combined with, the subject matter of any of aspects 1 to 59 to include or use each electrical stimulation test signal following the first electrical stimulation test signal to include a current with a higher current than the immediately preceding electrical stimulation test signal.

[0230] Aspect 61 may include or use, or may be combined with the subject matter of any of aspects 1 to 60, to include or use a communication interface for receiving input from a user who selects one of the plurality of electrical stimulation test signals as a first high-frequency pulse electrical stimulation therapy signal.

[0231] Aspect 62 may include or use, or may be combined with the subject matter of any one of aspects 1 to 60, to include or use each of the plurality of electrical stimulation test signals applied to the peroneal nerve or its branches on the patient's leg when the patient's leg is in a state selected from immobility, performing voluntary dorsiflexion, or performing an involuntary reflex.

[0232] Aspect 63 may include or use, or may be combined with, the subject matter of any one of aspects 1 to 62 to include or use at least one electrical stimulation electrode located at a first external target body location near the peroneal nerve or its branches, the at least one electrical stimulation electrode comprising: at least one first electrical stimulation electrode located on the patient's right leg at a first external target body location near the right peroneal nerve or its branches; and at least one second electrical stimulation electrode located on the patient's left leg at a second external target body location near the left peroneal nerve or its branches, and wherein the electrical stimulation signal generator generates an electrical signal having a frequency from 500 Hz to 15,000 Hz and at least 5 mA. The method involves generating a first high-frequency pulsed electrical stimulation treatment signal and applying the first high-frequency electrical stimulation treatment signal to the right peroneal nerve or its branches using at least one first electrical stimulation electrode to generate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the right peroneal nerve; and generating a second high-frequency pulsed electrical stimulation treatment signal having a frequency from 500 Hz to 15,000 Hz and a current of at least 5 mA, and applying the second high-frequency electrical stimulation treatment signal to the left peroneal nerve or its branches using at least one second electrical stimulation electrode to generate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the left peroneal nerve.

[0233] Aspect 64 may include or use, or may be combined with, the subject matter of any of aspects 1 to 63 to include or use, a system for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation. The system may include: at least one electrical stimulation electrode located at a first external target body location near a peroneal nerve or its branches; at least one surface EMG (sEMG) electrode coupled to a second external target body location near at least one muscle innervated by a peroneal nerve or its branches, wherein the at least one surface EMG recording electrode senses sEMG activity in the at least one muscle and generates an sEMG signal indicating the sensed sEMG activity in the at least one muscle; and an external electrical stimulation unit coupled to the at least one electrical stimulation electrode, the external electrical stimulation unit including an electrical stimulation signal generator, the electrical stimulation... A signal generator generates a first high-frequency pulsed electrical stimulation therapeutic signal having a frequency from 500 Hz to 15,000 Hz and a current of at least 5 mA, and applies the first high-frequency electrical stimulation therapeutic signal to the peroneal nerve or its branches using at least one electrical stimulation electrode to generate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the peroneal nerve; an electrical stimulation testing unit causes an external electrical stimulation signal unit to generate multiple electrical stimulation test signals having a frequency from 500 Hz to 15,000 Hz and a current of at least 5 mA, and applies the multiple electrical stimulation test signals using at least one electrical stimulation electrode to generate the signal. Each of the plurality of electrical stimulation test signals is sequentially applied to the peroneal nerve or a branch thereof; a user device for receiving input indicative of the patient's perception of each of the plurality of electrical stimulation test signals, each of the plurality of electrical stimulation test signals being associated with at least one of pain, tolerance, and distraction during the patient's sleep during a sleep period; an sEMG threshold detection unit, for each of the plurality of electrical stimulation test signals, receiving: 1) an sEMG signal from the at least one sEMG electrode, and 2) input indicative of the patient's perception from the user device; and analyzing the sEMG signal. The device includes an input indicating the patient's perception, and determines one or more of a tonic motor threshold, a pain threshold, a tolerance threshold, and a distraction threshold based on the sEMG signal and the input indicating the patient's perception; and at least one of a recording unit and a transceiver unit, the recording unit being used to store whether each of the plurality of electrical stimulation test signals generates tonic sEMG activity in the at least one muscle, and to store the magnitude of any such tonic sEMG activity, the transceiver unit being used to send at least one of the tonic motor threshold, pain threshold, tolerance threshold, and distraction threshold to the user device user.

[0234] Other implementation plans

[0235] This technology can also be used to optimize or personalize other neurostimulation techniques that stimulate the nerves that innervate muscles, including vagus nerve stimulators for epilepsy (pharyngeal muscles) and spinal nerve stimulators for chronic pain.

[0236] The detailed description above, taken in conjunction with the accompanying drawings, is intended as a description of various configurations and not as representing the only configuration in which the concepts described herein can be practiced. This detailed description includes specific details to provide a thorough understanding of the various concepts. However, it will be apparent to those skilled in the art that these concepts can be practiced without these specific details. In some cases, well-known structures and components are shown in block diagram form to avoid obscuring these concepts.

[0237] Examples of systems and methods for identifying, assessing, and treating patients with hyperexcitatory or hyperactive nerves are presented with reference to various electronic devices and methods described in the following detailed description and illustrated in the accompanying drawings by various blocks, components, circuits, steps, processes, algorithms, etc. (collectively, “elements”). These elements may be implemented using electronic hardware, computer software, firmware, or other forms of executable computer code, or any combination thereof. Whether these elements are implemented as hardware or software depends on the specific application and the design constraints imposed on the system as a whole.

[0238] For example, one or more processors can be used to implement elements, any part of elements, or any combination of elements in various electronic systems. Examples of processors include microprocessors, microcontrollers, graphics processing units (GPUs), central processing units (CPUs), application processors, digital signal processors (DSPs), reduced instruction set computing (RISC) processors, system-on-a-chip (SoCs), baseband processors, field-programmable gate arrays (FPGAs), programmable logic devices (PLDs), state machines, gated logic, discrete hardware circuits, and other suitable hardware configured to perform the various functions described throughout this disclosure. One or more processors in a processing system can execute software. Software should be interpreted broadly as instructions, instruction sets, code, code segments, program code, programs, subroutines, software components, application programs, software applications, software packages, routines, subroutines, objects, executable files, threads of execution, procedures, functions, etc., whether referring to software, firmware, middleware, microcode, hardware description languages, or others.

[0239] Therefore, in one or more examples, the functions described in certain methods and systems for treating patients with overexcited or hyperactive nerves can be implemented in hardware, software, or any combination thereof. If implemented in software, these functions can be stored as one or more instructions or code on or encoded on a computer-readable medium. A computer-readable medium can include transient or non-transitory computer storage media for carrying or having computer-executable instructions or data structures stored thereon. Both transient and non-transitory storage media can be any available medium that can be accessed by a computer as part of a processing system. By way of example and not limitation, such computer-readable media can include random access memory (RAM), read-only memory (ROM), electrically erasable programmable ROM (EEPROM), optical disc storage, magnetic disk storage, other magnetic storage devices, combinations of computer-readable media of the foregoing types, or any other medium that can be used to store computer-executable code in the form of computer-accessible instructions or data structures. Furthermore, when information is transmitted or provided to a computer via a network or other communication connection (hardwired, wireless, or a combination thereof), the computer or processing system correctly identifies that connection as a transient or non-transitory storage medium, depending on the specific medium. Therefore, any such connection is properly referred to as a computer-readable medium. Combinations of the aforementioned media should also be included within the scope of computer-readable media. Non-transitory computer-readable media do not include the signal itself or the air interface.

Claims

1. A system for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation, said system comprising: At least one electrical stimulation electrode configured to be positioned at a first external target body location near the peroneal nerve or its branches; and An externally non-implantable electrical stimulation unit, coupled to the at least one electrical stimulation electrode, is used to generate a first high-frequency pulsed electrical stimulation signal and apply it to the peroneal nerve or its branches, the first high-frequency pulsed electrical stimulation signal including frequencies in the range of 500 Hz to 15,000 Hz, thereby achieving at least one of the following: generating tonic surface electromyographic activity, i.e., tonic sEMG activity, in response to the electrical stimulation signal in at least one muscle innervated by the peroneal nerve, or regulating phased sEMG activity in response to the electrical stimulation signal in response to the electrical stimulation signal, and using at least one of the reactive tonic sEMG activity or the reactive regulated phased sEMG activity as the observed sEMG signal to determine a threshold and control at least one parameter setting of the first high-frequency pulsed electrical stimulation signal.

2. The system of claim 1, wherein, based at least in part on patient feedback, the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal is specified to be less than at least one of a pain threshold or a distraction threshold.

3. The system of claim 1 or 2, wherein the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal is configured to allow being specified differently based on the time of day or other indications of whether the patient is or is expected to be awake or asleep.

4. The system of claim 1 or 2, wherein the observed sEMG signal originates from at least one muscle innervated by the peroneal nerve of the same patient to which the first high-frequency pulsed electrical stimulation signal is delivered.

5. The system of claim 1 or 2, wherein the electrical stimulation unit includes or is coupled to a controller circuit configured to determine whether the first high-frequency pulsed electrical stimulation signal produces tonic sEMG activity or the degree of tonic sEMG activity in the observed sEMG signal from the same patient.

6. The system of claim 1 or 2, wherein the electrical stimulation unit includes or is coupled to a controller circuit configured to store indications of the reactivity of the sEMG activity, the indications corresponding to different settings of the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal.

7. The system of claim 1 or 2, wherein the electrical stimulation unit includes or is coupled to a controller circuit configured to select at least one parameter setting of the first high-frequency pulsed electrical stimulation signal based on a comparison of the sEMG activity of reactivity under different settings.

8. The system of claim 1 or 2, wherein the electrical stimulation unit includes or is coupled to a controller circuit configured to record an indication of baseline sEMG activity obtained without providing the patient with the first high-frequency pulsed electrical stimulation signal.

9. The system of claim 8, wherein the controller circuitry is configured to characterize the patient’s neurostimulation responsiveness at least in part based on the change in the patient’s sEMG activity relative to the baseline sEMG activity in response to the first high-frequency pulsed electrical stimulation signal.

10. The system of claim 9, wherein the controller circuitry is configured to characterize the neural stimulation responsiveness at least in part based on at least one of a tonic motor activation threshold, a distraction threshold, or a pain threshold, the tonic motor activation threshold, the distraction threshold, or the pain threshold being determined using at least one parameter setting of the first high-frequency pulsed electrical stimulation signal.

11. The system of claim 1 or 2, wherein the electrical stimulation unit is coupled to the at least one electrical stimulation electrode for generating a first high-frequency pulsed electrical stimulation signal and applying it to the peroneal nerve or its branches, the first high-frequency pulsed electrical stimulation signal including frequencies in the range of 500 Hz to 15,000 Hz, thereby generating tonic sEMG activity in at least one muscle innervated by the peroneal nerve.

12. The system of claim 1 or 2, further comprising at least one observed sEMG signal electrode, the at least one observed sEMG signal electrode being configured to be located in association with at least one muscle innervated by the peroneal nerve of the same patient to which the at least one electrical stimulation electrode delivers the first high-frequency pulsed electrical stimulation signal.

13. The system of claim 1 or 2, wherein the at least one electrical stimulation electrode is capable of being positioned at a first external target body location near the peroneal nerve or its branches, the at least one electrical stimulation electrode comprising: At least one first electrical stimulation electrode is configured to be positioned on the patient's right leg at a first external target body location near the right peroneal nerve or its branches; and At least one second electrical stimulation electrode is configured to be positioned on the patient's left leg at a second external target body location near the left peroneal nerve or its branches; and The electrical stimulation unit generates a first high-frequency pulsed electrical stimulation signal and a second high-frequency pulsed electrical stimulation signal. The first high-frequency pulsed electrical stimulation signal is delivered to the right peroneal nerve or its branches using the at least one first electrical stimulation electrode to generate or modulate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the right peroneal nerve. The second high-frequency pulsed electrical stimulation signal is delivered to the left peroneal nerve or its branches using the at least one second electrical stimulation electrode to generate or modulate tonic surface electromyography (sEMG) activity in at least one muscle innervated by the left peroneal nerve.

14. The system of claim 1 or 2, wherein the electrical stimulation unit is configured to repeatedly deliver pulses of the first high-frequency pulsed electrical stimulation signal in a manner that ramps up the energy level toward a target energy level.

15. The system of claim 1 or 2, comprising an arrangement of a plurality of electrodes, wherein the electrical stimulation unit includes or is coupled to controller circuitry configured to select one or more electrodes from the plurality of electrodes based at least in part on the sEMG activity in response to the responsiveness of the test electrical stimulation signal delivered to the patient via different electrodes of the plurality of electrodes, and to apply a therapeutic electrical stimulation signal to the patient using the selected one or more electrodes.

16. The system of claim 1 or 2, wherein the electrical stimulation unit includes or is coupled to a controller circuit configured to specify the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal based at least in part on the modulation of phased sEMG activity in the observed sEMG signal in conjunction with muscle activation of the at least one muscle innervated by the peroneal nerve.

17. The system of claim 1 or 2, wherein the electrical stimulation unit is coupled to the at least one electrical stimulation electrode for delivering the first high-frequency pulsed electrical stimulation signal to the patient and for detecting the observed sEMG signal from the patient using the same at least one electrical stimulation electrode.

18. A system for treating a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation, the system comprising processor circuitry configured to: A first high-frequency pulsed electrical stimulation signal defined by multiple parameters is delivered to a first external target body location near the peroneal nerve or its branches, the multiple parameters including frequencies in the range of 500 Hz to 15,000 Hz; The delivered first high-frequency pulsed electrical stimulation signal is used to generate tonic surface electromyographic activity, i.e., tonic sEMG activity, and / or modulated phased sEMG activity in at least one muscle innervated by the peroneal nerve; and At least one of the tense sEMG activity or the regulated phased sEMG activity is used as the observed sEMG signal to determine the threshold and control at least one parameter setting of the first high-frequency pulsed electrical stimulation signal.

19. The system of claim 18, wherein the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal is specified to be less than at least one of a pain threshold or a distraction threshold, based at least in part on patient feedback.

20. The system of claim 18 or 19, wherein the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal can be specified differently based on the time of day or other indications of whether the patient is or is expected to be awake or asleep.

21. The system of claim 18 or 19, wherein the observed sEMG signal is obtained from at least one muscle innervated by the peroneal nerve of the same patient to which the first high-frequency pulsed electrical stimulation signal is delivered.

22. The system of claim 18 or 19, wherein the processor circuitry is configured to select the at least one parameter setting of the first high-frequency pulsed electrical stimulation signal based on a comparison of sEMG activities generated in response to a plurality of different high-frequency pulsed electrical stimulation test signals.

23. The system of claim 18 or 19, wherein the processor circuitry is further configured to characterize the patient’s neurostimulation responsiveness at least in part based on the observed change in the patient’s sEMG activity in response to the first high-frequency pulsed electrical stimulation signal relative to baseline sEMG activity.

24. The system of claim 23, wherein the processor circuitry is configured to characterize the patient’s neurostimulation responsiveness at least in part based on at least one of a tonic motor activation threshold, a distraction threshold, or a pain threshold, the tonic motor activation threshold, the distraction threshold, or the pain threshold being determined using a plurality of different high-frequency pulsed electrical stimulation test signals.

25. The system of claim 18 or 19, wherein the processor circuitry is further configured to perform control to provide bilateral electrical stimulation to the patient's legs.

26. The system of claim 18 or 19, wherein the processor circuitry is further configured to select one or more electrodes from the arrangement of the plurality of electrodes based at least in part on observed sEMG activity in response to test electrical stimulation signals delivered to the patient via different electrodes of the plurality of electrodes, and to apply therapeutic electrical stimulation signals to the patient using the selected one or more electrodes.

27. The system of claim 18, wherein the processor circuitry is further configured to specify at least one parameter setting of the first high-frequency pulsed electrical stimulation signal based at least in part on the modulation of phased sEMG activity in the observed sEMG signal in conjunction with muscle activation of the at least one muscle innervated by the peroneal nerve.

28. A system for characterizing the neurostimulation responsiveness of a patient with one or more symptoms associated with at least one of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) using applied high-frequency electrical stimulation, the system comprising processor circuitry configured to: Delivering a first high-frequency pulsed electrical stimulation signal to a first external target body location near the peroneal nerve or its branches, the first high-frequency pulsed electrical stimulation signal including frequencies in the range of 500 Hz to 15,000 Hz, for generating or modulating tonic sEMG activity in at least one muscle innervated by the peroneal nerve; and The neurostimulation responsiveness of the patient is characterized at least in part based on (1) the observed changes in the patient’s sEMG activity in response to the delivered first high-frequency pulse electrical stimulation signal relative to baseline sEMG activity.

29. The system of claim 28, wherein the processor circuitry is configured to characterize the patient’s neurostimulation responsiveness at least in part based on at least one of a tonic motor activation threshold, a distraction threshold, or a pain threshold, the tonic motor activation threshold, the distraction threshold, or the pain threshold being determined using one or more parameter settings of the first high-frequency pulsed electrical stimulation signal.

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