Restless leg syndrome or overactive nerve treatment

Abstract

To provide a system for treating Restless Leg Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) using high frequency (HF) electrostimulation.SOLUTION: The system includes means for selecting or receiving a subject presenting with RLS or PLMD. At least one electrostimulation electrode can be located at a location associated with at least one of, or at least one branch of, a sural nerve, a peroneal nerve, or a femoral nerve. The system includes means for delivery of HF electrostimulation to the subject, which include delivering AC electrostimulation of below-perception threshold and below-threshold at a frequency that exceeds 500 Hz and is less than 15,000 Hz to the location to help reduce or alleviate the one or more symptoms associated with RLS or PLMD. A charge-balanced controlled-current HF electrostimulation waveform can be used.SELECTED DRAWING: Figure 11B

Description

Technical Field

[0001] This disclosure relates generally, but not by way of limitation, to medical diagnostic and treatment devices and methods, and more specifically, but not limited thereto, to restless legs syndrome or hyperactive nerve treatment.

Background Art

[0002] Certain neurological disorders with troublesome symptoms can result from overactivity of sensory or other peripheral nerve fibers that can disrupt the quality of life. In particular, Restless Legs Syndrome (RLS) and Periodic Leg Movement Disorder (PLMD) are two such neurological conditions that can greatly affect the sleep of human patients. Patients with RLS (also called Willis-Ekbom Disease (WED)) may experience unpleasant tingling sensations in their lower extremities (legs). Such sensations can be immediately relieved by voluntarily moving the limbs, but doing so can potentially interfere with the ability of RLS patients to fall asleep. PLMD patients may experience spontaneous movements of the lower limbs during the sleep period. As a result, PLMD patients may wake up.

[0003] Patent Document 1 issued on April 27, 2015 to Burbank et al. relates to an apparatus and method for treating restless legs syndrome by providing mechanical counter-stimulus vibrations having a frequency between, for example, 50 Hz and 10 times per minute.

[0004] Patent Document 2 issued on March 5, 2015 to Elborno relates to an apparatus and method for treating essential tremor or restless legs syndrome using spinal cord stimulation. Patent Document 3 published on December 8, 2016 to Kent relates to a method and apparatus for treating restless legs syndrome using stimulation of the patient's sacral or lumbar region.

[0005] Patent Document 4 issued to Matsen on January 20, 2015 relates to a restless legs treatment device that uses a 25-volt generator to repeatedly cause certain muscle contractions (see lines 17-47, column 6 of Matsen's Patent Document 4).

[0006] Patent Document 5 issued to Lozano on August 10, 2010 relates to a system and method for treating movement disorders including restless legs syndrome, such as the use of cortical stimulation.

[0007] For patients diagnosed with primary RLS (i.e., not secondary to some other primary co-morbidity such as diabetes, neuropathy, etc., and in some cases RLS that can be treated individually on its own), the first line of treatment involves one or more of a change in behavior, a change in sleep, or exercise. The second line of treatment includes dopamine therapy or iron level management, or both. The third line of treatment includes one or more of anti-convulsants, off-label opioids, or benzodiazepines. In short, current treatment methods for RLS patients mainly involve pharmaceutical therapies that can have serious side effects.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

[0009] The inventor has found that restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) can be treated using high-frequency (HF) electrical stimulation. This may include selecting or accepting a subject presenting with RLS or PLMD. At least one electrical stimulation electrode is positioned at a location associated with at least one of the gastrocnemius nerve, peroneal nerve, or femoral nerve or at least one branch thereof. HF electrical stimulation is delivered to a subject to reduce or alleviate one or more symptoms associated with RLS or PLMD and may include delivering alternating current (AC) electrical stimulation below the perceptual threshold and below the threshold at a frequency higher than 500 Hz and less than 15,000 Hz. An electrically stimulating waveform of charge-balanced controlled current HF may be used. HF electrical stimulation may be configured to be performed without increasing blood flow to adjacent tissue.

[0010] The inventor has found, inter alia, that the electrical stimulation waveforms and techniques below the perceptual threshold and below the threshold of HF described herein act better than transcutaneous electrical neurostimulation (TENS) at low frequencies that are detected by RLS patients and actually make the symptoms of RLS patients more uncomfortable.

[0011] This summary is intended to provide an overview of certain matters of this patent application. It is not intended to provide an exclusive or exhaustive description of the invention. The detailed description is included to provide further information regarding this patent application. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In the drawings which are not necessarily drawn to scale, like reference numerals may describe like components in different figures. Similar reference numerals with different suffixes of letters may represent different instances of similar components. The drawings generally, by way of example, and not by way of limitation, illustrate various embodiments described herein.

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DETAILED DESCRIPTION OF THE INVENTION

[0013] Restless Legs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) can be treated using high frequency (HF) electrical stimulation. This may involve selecting or accepting a subject exhibiting RLS or PLMD. At least one electrical stimulation electrode is positioned at a location associated with at least one of the gastrocnemius nerve, peroneal nerve, or femoral nerve, or at least one branch thereof. HF electrical stimulation is delivered to the subject to reduce or alleviate one or more symptoms associated with RLS or PLMD, and may include delivering sub-sensory and sub-threshold AC electrical stimulation at a frequency higher than 500 Hz and less than 15,000 Hz. An electrically stimulating waveform of charge balanced control current HF may be used.

[0014] Pathophysiology of RLS Pharmacological treatment of RLS may, in certain cases, include dopamine replacement (e.g., levodopa), dopaminergic agents (e.g., ropinirole, pramipexole), or antispasmodic agents (e.g., gabapentin).

[0015] The approach of mechanical vibration pads is thought to be no more effective or superior to placebo. Many RLS patients may suffer from an exacerbation of the RLS disorder, which is a side effect of some RLS medications that may no longer cause symptoms of the RLS disorder in the lower limbs, or may be limited to only rest periods and sleep periods. As a result, many of these RLS-exacerbated patients may end up taking sleep medications or sedatives to manage their condition, along with possible additional side effects.

[0016] The pathophysiology that causes RLS in people may be hypothesized to include central dopamine deficiency. The dramatic and immediate therapeutic effect from levodopa may lead to the view that RLS patients may have significant brain dopamine deficiency. Investigations to demonstrate dopamine abnormalities in RLS have been more difficult and yielded surprising results than expected. Initial cerebrospinal fluid (CSF) analysis showed no difference between RLS patients and control patients with respect to major proteins related to dopamine. Repeated analysis of 3-orthymethyl dopamine (3-OMD) showed a significant increase in CSF in two independent samples (see Allen, Connor, & Hyland, 2009). Furthermore, the increase was correlated with homovanillic acid (HVA), a metabolite of dopamine. Considering the metabolic pathway from tyrosine hydroxylase to dopamine, the increase in both 3-OMD and HVA can best be explained as an increase in tyrosine hydroxylase activity that results in an increase in dopamine production.

[0017] The question has arisen as to how symptoms are alleviated when levodopa is administered and further increases dopamine, if dopamine in the brains of RLS patients is already abnormally increased. Resolving this apparent contradiction may involve recognizing that there is a strong circadian aspect to both dopamine activity and RLS symptoms.

[0018] Increased dopaminergic stimulation may potentially cause postsynaptic downregulation in both receptors and intracellular functions. Particularly in the case of more severe RLS, the general pattern of decreased D2 receptors may represent part of this response downregulation. However, dopamine has an obvious circadian activity pattern, decreasing in the evening and night and increasing in the morning. The postsynaptic cell regulation of RLS in response to increased dopamine stimulation may be sufficient during the day, but seems to overcompensate when dopamine levels are low between evening and night.

[0019] This may cause a relative dopamine deficiency between evening and night despite an overall increase in dopamine. Therefore, rather, the morning hyperalertness and the circadian pattern of RLS symptoms between evening and night with arousal may potentially interfere with the expected drowsiness of short and interrupted RLS sleep onset.

[0020] In short, the pathophysiology of RLS occurs in a wide range of locations and the body and may have multiple pathways to the disease. The pathophysiological findings of RLS help to guide the progress of treatment to emphasize the importance of reducing the risk of dopamine enhancement and developing better ways to manage RLS symptoms.

[0021] Pharmacological Treatment of RLS Dopaminergic agents may be a first-choice pharmacological therapy for RLS. Patients with serum ferritin values in the low to normal range may benefit from iron supplementation, similar to RLS patients receiving dopaminergic treatment where iron supplementation may prevent or reduce RLS exacerbation (Trenkwalder & Paulus, 2010).

[0022] Dopaminergic therapies for RLS may include dopaminergic drugs, and levodopa was the first dopaminergic drug used for RLS. Dopaminergic drugs are superior to levodopa in terms of efficacy parameters, and with these drugs, less RLS augmentation may occur than with levodopa. However, the dopaminergic side effect profile, which may include nausea, hypotension, or dizziness, may not be as severe with levodopa. The limitations of levodopa include both its lack of efficacy and RLS augmentation, with the latter occurring in 50 - 70% of RLS patients in long-term observational studies. Table 1 below shows a list of dopaminergic drugs for RLS treatment.

[0023]

Table 1

[0024] In RLS or PLMD patients reporting symptoms attributable to the upper limb, the femoral nerve and its direct peripheral extensions convey most of the sensory innervation from the rectus femoris and biceps femoris muscles behind the leg. Thus, the femoral nerve provides an additional target location for RLS electrical stimulation.

[0025] Example of the position of the peroneal nerve At least one electrode can be placed directly on the skin, preferably directly above or near the superficial peroneal nerve, for example, at the peroneal nerve target location (Figure 1C). At least one electrode can be placed directly below the landmark on the fibula, outside the knee under the lateral collateral ligament, or within 1-2 inches (2.54-5.08 cm) thereof. The second electrode can be placed such that there is a spacing of at least 1 inch (2.54 cm) from the end of the first electrode to the end of the second electrode. The second electrode can be placed along the length of the peroneal nerve, for example, further down the leg, or the second electrode can be placed directly above the tibia, such as about 1-2 inches (2.54-5.08 cm) below the first electrode. In one example, this second electrode can be placed directly below the medial collateral ligament on the tibial side, inside the knee, opposite the first electrode. Then, the electrical stimulation area can be modified, if desired, to extend between shorter or longer distances, for example, to reduce the perception by the patient.

[0026] In one example, two separate or different electrical stimulation areas can be applied, for example, in the leg below the knee, by using the second electrode on the tibia as a common return electrode to generate a modulated electrical stimulation area.

[0027] Position of the sural nerve At least one electrode can be disposed at the position of the peroneal nerve, for example, at a position between the lateral malleolus and the calcaneus on the outer side of the subject's foot, preferably on the skin directly above the peroneal nerve or on the outer side of the skin as close as possible to the peroneal nerve. As shown in FIG. 1B, a plurality of electrodes can be arranged along a portion of the length of the peroneal nerve, for example, having one electrode disposed immediately behind the bony mass of 2 cm of the lateral malleolus. Also, one or more additional electrodes can be included in two extended "wings" that extend, for example, approximately 1.0 to 1.5 inches (3.81 centimeters) laterally from the central electrode, so that these additional electrodes are positioned along the length of the peroneal nerve at an angle of 90 to 180 degrees with respect to the central electrode. For example, the first additional electrode can be disposed adjacent to the calcaneal tendon, and the second additional electrode can be disposed on the base of the lateral longitudinal arch on the outer side of the foot.

[0028] Position of the femoral nerve At least one electrode can be disposed at the position of the femoral nerve, for example, at a position approximately in the center of the "femoral triangle" surrounded by the inguinal ligament on the upper side, the sartorius muscle on the outer side, and the adductor longus muscle on the inner side, preferably on the skin directly above the femoral nerve or on the outer side of the skin as close as possible to the femoral nerve. In a plurality of examples that can include a plurality of electrodes, such additional electrodes can be positioned at a minimum interval of 1 inch with respect to the first electrode from electrode edge to electrode edge and configured to be arranged along the length of the femoral nerve.

[0029] The technology may include electrical stimulation that is specially configured to preferentially activate certain nerve fibers over other nerve fibers, for example, to suppress, treat, reduce, prevent, or avoid one or more RLS symptoms, additionally or alternatively. The electrical stimulation may be specially configured to be below the perceptual threshold (e.g., not so prominent as to affect the patient's ability to fall asleep or stay asleep). The electrical stimulation may be specially configured to be below the threshold (e.g., to avoid muscle activation in the patient that may interfere with the patient's ability to fall asleep or stay asleep). The electrical stimulation may be configured very differently from traditional low-frequency, centripetal, transcutaneous electrical nerve stimulation (TENS) that has no effect on or even exacerbates RLS symptoms, thereby worsening the RLS patient's ability to fall asleep. The technology may be applied in an open-loop manner, enabling patient control or titration, or may include closed-loop operation, for example, based on one or more sensed or received physiological parameters such as sleep stage.

[0030] Figure 1A shows an example of the ankle and foot regions of the lower limbs of an RLS patient, and shows the gastrocnemius nerve 100 and its branches 102A, 102B, 102C that can be specifically targeted, for example, by placing an electrical stimulation device in close proximity thereto to provide electrical stimulation set to suppress, reduce, or eliminate RLS symptoms.

[0031] FIG. 1B shows an example of a wearable external electrical stimulation device 104 disposed in extremely close proximity to a target gastrocnemius nerve 100 or its branches 102A - C, for example, to transmit transcutaneous electrical stimulation thereto. In this example, the electrical stimulation device 104 may include an adhesive patch 106 capable of carrying an electronic device unit 108 having, for example, separate or integrated electrodes 110A - B electrically connectable to the electronic device unit 108. FIG. 1B shows electrodes 110A - B disposed separately from the electronic device unit 108 on the patch 102, but one or both of the electrodes 110A - B (or additional electrode 110C (not shown)) may be disposed in the portion of the electronic device unit 108 facing the patient so as to remain in contact with the patient's skin through the opening of the adhesive patch 106. In one example, the electrical stimulation device 104 is attached or otherwise fixed or stabilized at a location on the outer or inner surface of the foot, such as near the posterior side of the leg near the outer side of the foot, like near the heel or behind and adjacent to the malleolar surface of the ankle.

[0032] FIG. 1C shows an example of a wearable external electrical stimulation device 104 disposed in close proximity to a target area 103 of a subject's peroneal nerve, such as in front of or to the side directly below the subject's knee, on a portion of the deep peroneal nerve. The wearable external electrical stimulation device 104 may alternatively or additionally be disposed in an area located further down the lower limb, such as on a portion of the superficial peroneal nerve capable of innervating one or more portions of the tibialis anterior muscle.

[0033] FIG. 1D shows an example of how a wearable external electrical stimulation device may be disposed in close proximity to a target area 106 of a target femoral nerve, such as in the upper region of the anterior thigh or a position slightly medial and in front of the knee.

[0034] At any of the desired target locations, the electrical stimulation device 104 can be additionally or alternatively arranged using wearable components or clothing, such as the electrical stimulation device 104 mounted by compression shorts or leggings, compression knee braces, ankle braces, socks, leggings, sleeves, etc.

[0035] Figure 2 shows an example of a specific mechanism of action specifically targeted by transmitting electrical stimulation adapted to a particular targeted location as described herein. However, as a first issue, it should be noted that the peripheral nerves are composed of bundles of multiple nerve subtypes that can be classified as type A, B, or C based on their corresponding conduction velocities and diameters as summarized in Table 2.

[0036]

Table 2

[0037] Without being bound by theory, reducing RLS symptoms can be thought to benefit from specially adjusted electrical stimulation that preferentially applies one or more nerve fibers at a specific target site, such as at the location of the gastrocnemius nerve, peroneal nerve, femoral nerve, or one of the nerve branches extending peripherally therefrom, as described with respect to Figure 2.

[0038] In FIG. 2, the left side shows a situation that is considered to exist in symptomatic RLS patients. The RLS symptoms are thought to be caused by irritative or hyperactive Alpha-delta and C fibers that can cause ectopic neural activity, which is recognized as a discomfort modulated by spinal 5-HT, opioid, or cannabinoid receptors. These receptors can be affected by preferentially applying (e.g., stimulating the activity of) Alpha-beta fibers that release the inhibitory neurotransmitter GABA to suppress this ectopic activity pattern.

[0039] In FIG. 2, the right side shows a situation that is considered to exist when electrical stimulation is properly adjusted and transmitted to appropriate target locations (e.g., to one or more of the gastrocnemius nerve, peroneal nerve, or femoral nerve, or to one or more branches extending to their peripheries). The adjusted electrical stimulation to these specifically selected one or more target nerve locations (e.g., one or more of the gastrocnemius nerve, peroneal nerve, or femoral nerve, or one or more branches extending to their peripheries) can activate faster-conducting Alpha-beta fibers and stimulate the production of GABA by spinal 5-HT, opioid, or cannabinoid receptors, thereby calming slower-conducting Alpha-Delta or C fibers and preventing the generation and transmission of excessive activity or irritative impulses by Alpha-Delta or C fibers.

[0040] One technique for evaluating the effectiveness of treating RLS symptoms is to perform a suggested immobilization test (SIT). In this case, the SIT test is performed before treatment is administered and can then continue or be repeated during or after treatment. As part of the SIT, multiple patients are asked to sit in bed with their backs straight and their legs extended outward while recording leg movement (e.g., using an accelerometer or other leg movement sensor) for, for example, 60 minutes and may be asked to score their discomfort on a scale from 0 to 10 every 10 minutes over the entire 60-minute period.

[0041] Figure 3 shows an example of experimental SIT data from severely affected RLS patients who were on medication (as opposed to those in the SIT trial who were off medication). The "baseline" SIT data shown in Figure 3 (without electrical stimulation applied) indicates that discomfort increased during the first 20 minutes of the SIT trial and then continued at a stable level of discomfort, approximately 60% of the maximum discomfort level for the remainder of the SIT trial. The "treatment" SIT data (with stimulation applied after the first 20 minutes) was obtained from the same patients the following night. Electrical stimulation was applied transcutaneously to both superficial peroneal nerves using hydrogel-coated transcutaneous electrodes connected to a constant current stimulator programmed to generate a waveform that stimulates the nerves with pulses of 80 - 100 microseconds duration and an inter-pulse interval of 240 - 250 microseconds. Electrical stimulation was initiated at 20 minutes. The patients reported near-instantaneous relief from the unpleasant sensations in their feet when the electrical stimulation treatment was initiated. The selected electrical stimulation waveform and amplitude were below the perceptual threshold (such that the patient could not distinguish whether the treatment had started or not) and below the threshold (such that muscle activation did not occur in the patient, as determined by visual twitching or other sensations reported by the patient). Electrical stimulation below the perceptual threshold and below the threshold can be particularly beneficial in the RLS applications of the present application, such as reducing the symptoms of RLS while avoiding or minimizing the patient's awareness of the applied electrical stimulation, so that the patient can comfortably fall asleep.

[0042] Figure 4 shows an example summarizing the SIT data results of "before" and "after" electrical stimulation of the superficial peroneal nerves in six RLS patients, all of whom met the criteria for "severe" RLS based on the International Restless Legs Syndrome Score (IRLSS) administered prior to recording. Figure 4 shows an example of the marked consistency in the reduction of unpleasant sensations associated with RLS in response to the initiation of electrical stimulation of the superficial peroneal nerves.

[0043] The electrical stimulation waveform can be specifically selected in terms of frequency, shape, and amplitude so as to, for example, as described herein with respect to FIG. 2, act to “gate” or block the input from the smaller diameter A-Delta and C fibers that transmit hyperactive and unpleasant sensations to the spinal cord in RLS patients, by activating the larger diameter A-Beta fibers. In one example, the controlled current electrical stimulation waveform can be, for example, a charge balanced rectangular wave current waveform having a current amplitude supplied at a controlled current level between 5 milliamperes and 30 milliamperes, or as used in a plurality of patients shown in FIG. 4 at a controlled current level between 11 milliamperes and 25 milliamperes.

[0044] The inventors have recognized, inter alia, that a high frequency (“HF”, for example a frequency between 500 Hz and 15000 Hz, and even more specifically between 4 kHz and 5 kHz) transcutaneous electrical stimulation current waveform is more preferable in this RLS application than a low frequency (“LF”, for example “150 Hz or less”) transcutaneous electrical nerve stimulation (TENS) waveform. This is because in RLS treatment applications, it has been observed to exacerbate RLS symptoms, so it is important to target these peripheral nerve fibers (such as the superficial peroneal nerve) with an electrical stimulation waveform below the threshold that causes muscle contraction and an electrical stimulation waveform below the perception threshold that causes the sharp sensation of electrical stimulation (such as most conventional LF sensory TENS waveforms, for example 150 Hz or less). Without being bound by theory, this may be due to RLS patients who have a strong hypersensitivity to any physical contact (tactile allodynia) when RLS symptoms are present and studied in the literature. Switching to an electrical stimulation waveform below the perception threshold at high frequencies (for example, 4000 Hz to 5000 Hz) has shown a significant improvement in RLS symptoms in some patients, as shown in the exemplary SIT data of FIG. 5.

[0045] Figure 5 shows an example of SIT data from a patient study where, in 20 minutes, it becomes the "Burst" TENS electrical stimulation waveform of conventional LF (150 Hz), and then directly switches to the electrical stimulation waveform of HF (4000 Hz to 5000 Hz) in 30 minutes. During the first 20 minutes of this SIT study (without electrical stimulation), the patient's discomfort increased from 0% to 80% of the maximum possible score. With LF TENS electrical stimulation, the patient's discomfort level actually increased to 90% of the maximum possible score. However, then, after the HF electrical stimulation was initiated, the patient's discomfort level decreased to 50% of the maximum possible score, showing a significant reduction compared to no electrical stimulation or LF TENS electrical stimulation.

[0046] Without being bound by theory, this rapid suppression of RLS symptoms using HF electrical stimulation is thought to be due to the selective application (e.g., activation by electrical stimulation) of A - Beta fibers of the target nerve that sequentially causes the release of GABA and blocks overactive A - Delta and C fibers, as described and explained above with respect to Figure 2. Detection waveforms indicating such selective activation can be obtained. This may involve recording the response resulting from electrical stimulation (such as using a nerve recording sense amplifier channel as described herein) and, if necessary, readjusting one or more parameters of the electrical stimulation to obtain a desired activation pattern, such as indicating the selective application of A - Beta fibers in the target nerve.

[0047] FIG. 6 conceptually shows an example of the resulting compound action potential (CAP) and the contribution of each nerve fiber subtype, which can be detected and recorded at a distance "L" from the location of the applied electrical stimulus along the length of the same nerve to which the electrical stimulus is applied. Detection at two different distances "L" from the electrical stimulation position is shown in the conceptual example of FIG. 6. At a larger separation distance "L", differences in conduction latency between different nerve fiber subtypes can contribute to a particular pattern indicating which subtype of nerve fiber was selectively or preferentially activated by a particular electrical stimulus, for example, with respect to one or more other nerve fiber subtypes.

[0048] For example, in FIG. 6, at a smaller distance "L" (e.g., about 1 inch or 25 mm), it may be difficult to observe each nerve fiber component contributing to the average CAP, taking into account the corresponding conduction velocity. However, when the detection / recording electrode is moved further along the length of the nerve from the electrical stimulation electrode, e.g., to a length "L" of about 80 mm or more, the separate nerve fiber components begin to appear on the CAP as individual peaks. This is conceptually shown in FIG. 6 for a period of about 60 ms after the electrical stimulation.

[0049] Based on the detected / recorded CAP, it is possible to construct or optimize one or more electrical stimulation waveforms to preferentially activate only a selected subset of fibers, such as A-Beta fibers. This method of detecting nerve fiber activation has been studied and reported in the technical literature. (e.g., Qing et al., IEEE Trans Neural Syst Rehabil Eng. November 2015, 23(6):936-45) FIG. 7 shows a conceptual example of how individual nerve fiber components can be detected. This can involve using a nerve recording amplifier system that can be connected to recording electrodes placed at one or more specific positions along the length of the nerve that is being stimulated upstream.

[0050] FIG. 8 shows a conceptual example of three different recording electrode waveforms. In the example of FIG. 8, the top waveform shows a reaction case that occurred when a specific nerve fiber type was not selectively or preferentially applied by an electrical stimulus. In FIG. 8, the middle waveform shows that the C fiber is an example of a reaction waveform that occurred when preferentially applied by an electrical stimulus, as indicated by the presence or predominance of the generated potential of the slower and lower frequency C fiber in the absence or omission of the generated potential of the faster and higher frequency A-Delta. The bottom waveform shows an example of a reaction waveform that occurred when the A-Delta fiber was preferentially applied by an electrical stimulus, as indicated by the presence or predominance of the generated potential of the faster and higher frequency A-Delta in the absence or omission of the generated potential of the slower and lower frequency C fiber.

[0051] In one example, the CAP can be detected, recorded, or measured. One or more parameters of the electrical stimulus can be adjusted or optimized to obtain a desired CAP response indicative of the preferential application of one or more specific nerve fiber subtypes, such as the selective application of A-Delta fibers, as described in the specification. The system can include a set of percutaneous electrodes for electrically stimulating a designated target location of a target nerve, such as a peripheral nerve of interest (e.g., peroneal, gastrocnemius, femoral, or a branch thereof), and recording electrodes disposed downstream of the target nerve or a branch thereof to record, for example, the resulting reaction signal.

[0052] In an illustrative and non-limiting example, first, a burst of electrical stimulation can be applied to a specific electrical stimulation location during a period (e.g., <10 milliseconds) specified at a particular frequency (e.g., a frequency between 4 and 5 kilohertz). Second, using a plurality of hydrogel recording electrodes placed at a specific distance from the electrical stimulation electrode location, the resulting CAP can be detected using an electrically connected neural amplifier channel. Third, the electrical stimulation intensity can be increased, for example, until the maximum resulting CAP amplitude is observed in the detected or recorded signal. Fourth, the contribution of one or more component A-Delta, A-Beta, or C fibers from those characteristic individual peaks can be detected and averaged, for example, over a plurality of bursts of electrical stimulation. Fifth, one or more electrical stimulation parameters can be adjusted, for example, to modify the plurality of amplitude peaks of the recorded CAP components for a lower intensity of electrical stimulation to preferentially apply a subset of one nerve fiber type over others.

[0053] Similarly, to detect whether a particular electrical stimulation waveform preferentially applies to a subset of one or more nerve fiber types over others, a device under test (DUT) of the electrical stimulation is applied to a test impedance representative of the nerve target to characterize, for example, the electrical stimulation waveform. The characterized electrical stimulation waveform can then be applied to the target nerve location to observe, for example, the resulting compound action potential (CAP) and components resulting from one or more nerve fiber types. Next, one or more parameters of the electrical stimulation waveform can be varied to determine, for example, whether a particularly emphasized component that occurred in response to the previously characterized electrical stimulation waveform decreases or disappears with respect to one or more other components of the resulting response waveform. For example, if one or more of the electrical stimulation parameters decreases the A-Delta component observed in the resulting CAP with respect to the C component of the resulting CAP, it is concluded that the characterized electrical stimulation waveform is particularly adjusted to preferentially apply to the A-Delta nerve fiber subtype over the C fiber subtype. Without being bound by theory, as described herein, this is desirable to release GABA in the dorsal horn of the spinal cord to help suppress or inhibit ectopic discharge activity from the targeted nerve and thereby reduce one or more restless legs syndrome (RLS) symptoms.

[0054] Without being bound by theory, as described herein with respect to FIG. 2, activation of larger diameter A-Beta fibers (or fibers of type II according to Lloyd's classification) has an inhibitory effect, for example, by promoting the release of GABA that suppresses activity from noxious stimuli transmitted by fibers (A-Delta and C fibers or types III and IV, respectively). This has been described with respect to FIG. 2 and confirmed by the inventor with clinical results obtained from patients with severe RLS symptoms.

[0055] In one example, a signaling cascade as described with respect to FIG. 2 can be achieved by activating one or more selected fibers (e.g., A-Beta, etc.) such as one or more peripheral nerves, such as the superficial peroneal nerve or the gastrocnemius nerve (or branches thereof), which exhibit a nearly instantaneous suppression of RLS symptoms. In one example, this can be set by using electrical stimulation of a carefully selected waveform, for example, in the frequency range of 500 Hz to 10,000 Hz, the pulse width in the range of 50 μS to 1 ms, and the current amplitude in the range of 1 to 30 mA.

[0056] In a particular example, clinical data were obtained by switching between a 150 Hz LF waveform and another 4,000 Hz HF waveform with a pulse width of 50 - 100 μs. This enabled a comparison of the effectiveness between the LF waveform and the HF waveform.

[0057] In another example, a randomly varying frequency waveform in the range of 4000 - 5000 Hz can be applied simultaneously with a second waveform that is, for example, 100 - 150 Hz away in frequency from the first waveform and also varies in the approximately same range of 4000 - 5000 Hz (e.g., the second frequency varies between 4100 - 5100 Hz).

[0058] FIG. 9A shows an example of SIT data where HF electrical stimulation is initiated after an initial 20 minutes to provide a nearly instantaneous suppression of RLS symptoms and then turned off again at 40 minutes, resulting in a recurrence of RLS symptoms, which is believed to provide the benefits of our proposed mechanism of action as described above with respect to FIG. 2.

[0059] FIG. 9B shows an example of electrical stimulation sensory comparison data of a typical low-frequency (LF) transcutaneous electrical nerve stimulation waveform compared to the (HF) transcutaneous electrical stimulation waveform according to the present technology in N = 5 healthy subjects.

[0060] The parameters of the HF electrical stimulation waveform can be carefully selected to compensate for the activation of the largest target nerve fibers relative to the minimum sensory perception threshold reported by the patient. As shown in FIG. 9B, in blinded experimental tests conducted on N = 5 healthy subjects, the HF electrical stimulation waveform was applied at a frequency selected between 4000 and 5000 Hz and was able to consistently supply a greater amount of current to the tissue before any sensation was reported by the patient, compared to a typical LF TENS waveform of 150 Hz or less. As shown in FIG. 9B, a similar difference is seen at the threshold at which the patient reported discomfort.

[0061] According to calculations based on waveform shape and pulse width, FIG. 9C shows that the HF waveform of the present technique (e.g., between 4000 and 5000 Hz) can inject 47 to 49 times more charge into the target tissue than conventional LF TENS (e.g., 150 Hz or less) before the electrical stimulation becomes perceptible or before it becomes uncomfortable.

[0062] Figures 9D and 9E show examples of the use of the flexor reflex (Fr) for electrical stimulation techniques (e.g., which can be used additionally or alternatively to the CAP technique described herein) to set or improve, for example, electrical stimulation waveform patterns in a patient undergoing treatment. The flexor or flexor reflex (Fr) is a neurophysiological tool used to evaluate the effectiveness of analgesic therapies, as described in the guidelines of the European Federation of Neurological Societies (EFNS). This Fr response is caused by electrical stimulation of a sensory nerve (e.g., the peroneal nerve) and can be recorded from the flexor muscles of the ipsilateral limb (e.g., the biceps femoris). The Fr includes an early response, the RII reflex (RIIr), and a late response, the RIII reflex (RIIIr). The RIIIr is a non-nociceptive A-beta fiber-mediated response, while the RIIIr is a high-threshold nociceptive A-delta fiber-mediated reflex, and the threshold of the RIIIr has been shown to correspond to the magnitude of the reflex related to the pain threshold and the level of pain perception. The RIIIr is a more stable and reliably measured reflex, and its amplitude correlates with the intensity of pain perception correlated with the amount of nociceptive A-Delta activation.

[0063] In one example, the lower limb flexion response can be obtained by transmitting transcutaneous electrical stimulation to the peroneal nerve via a plurality of surface electrodes applied behind the right lateral malleolus and recording the response from the ipsilateral brevis head of the biceps femoris. The stimulation includes a series of five electrical pulses (e.g., having a duration of 1 to 5 milliseconds at a frequency between 100 and 250 Hz) and can be delivered randomly or pseudo-randomly, such as at intervals between 5 and 20 seconds. Figure 9D shows a conceptual (not actual data) example of such a flexor reflex (Fr) response to a test electrical stimulation. The amount of stimulation current required to generate a reliable RIIIr waveform is recorded as the sensory threshold, and then the electrical stimulation can be adjusted to be below the perception threshold so that it is below the patient's sensory threshold and not felt by the patient.

[0064] When an HF electrical stimulation waveform is applied to a peripheral nerve (e.g., the superficial peroneal nerve), a decrease in the amplitude of the flexion reflex response (RIIIr component) is observed. Using a conceptual (not actual data) example showing how this can be measured, the results of the nerve activation suppression cascade described in FIG. 2 are shown.

[0065] In FIG. 10, the RLS treatment system 1000 can include a controller circuit 1002, a battery 1010, a power conversion circuit 1008, an electrical stimulation waveform generation circuit 1006, a user input device 102, and a plurality of patient electrodes 1014. In one example, the plurality of patient electrodes can include a plurality of external electrodes disposed on an adhesive skin patch, for example, for transcutaneous application of electrical stimulation energy. In one example, the plurality of patient electrodes includes implantable electrodes such as a nerve cuff that can be implanted to surround a target nerve (e.g., the gastrocnemius nerve) at a target location to dispose a plurality of electrodes at a desired location. A plurality of implantable electronics can be included on the nerve cuff for controlling, among other things, the delivery of electrical stimulation. The plurality of implantable electronics can be powered in whole or in part by RF or inductively coupled energy that can be wirelessly coupled from an external transcutaneous electrical transmission (TET) source to an energy receiving device on the plurality of implantable electronics.

[0066] The controller circuit 1002 can include, for example, a microprocessor, a microcontroller, a programmable logic circuit, etc. that are powered by a battery 1010 or other power source. The battery can be coupled to a power conversion circuit 1008 that includes, for example, a buck power conversion circuit, a boost power conversion circuit, a buck-boost power conversion circuit, or one or more of other inductive or capacitive or other circuits to convert the voltage and current of the battery to a desired output voltage and current for transmitting electrical stimulation to a subject via a plurality of patient electrodes 1014. The electrical stimulation waveform generation circuit 1006 can receive the power signal converted from the power conversion circuit 1008 and generate an appropriate electrical stimulation waveform such as an HF electrical stimulation waveform as described herein. For example, the electrical stimulation waveform generator can be configured by the controller circuit 1002 to generate an HF electrical stimulation control current waveform having a current amplitude that is controlled by the controller circuit 1002 and set to a desired level within a range of frequencies in the range of, for example, 4 kHz to 5 kHz and a range of desired levels in the range of 5 milliamperes to 30 milliamperes (e.g., levels of 5 mA, 10 mA, 15 mA, 20 mA, 25 mA, or 30 mA, or with finer resolution as needed).

[0067] In the example of FIG. 10 and the open-loop RLS treatment system 1000, the timer circuit 1004 is included in or coupled to the controller circuit 1002 and controls the period applied after the RLS electrical stimulation treatment is initiated, for example, by using a switch or other user input device 1012. After the "on" period set by the timer ends, the RLS electrical stimulation treatment is automatically turned off, thereby saving power drawn from the battery 1010. In one example, the timer period is the period expected for the patient to fall asleep with the aid of the RLS electrical stimulation treatment and can be, for example, a programmable or other specific treatment period value (e.g., 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, etc.). In one example, the treatment can be ramped down at the end of the timer rather than being suddenly turned off. The ramp-down period can be specified as a specific percentage of the treatment period (e.g., 10%, 20%, 30%, 40%, 50%, etc.). The timer circuit 1004 can include a clock circuit, for example, as described above, so that time is used to start an electrical stimulation treatment session such as an electrical stimulation treatment period value that is timed by the timer circuit 1004.

[0068] FIG. 11A shows an example of a closed-loop RLS electrical stimulation treatment system 1100, which is similar to the open-loop RLS electrical stimulation treatment system shown and described in FIG. 10. However, the timer 1004 can be replaced or enhanced by a sensor circuit 1104. The sensor circuit 1104 can be used to detect the patient's physiological or other similar parameters and to control the treatment using information regarding the parameters detected by the sensor circuit 1104.

[0069] For example, when the RLS electrical stimulation therapy system 1100 is worn on a patient's foot or lower limb, the sensor circuit 1104 may include an accelerometer or other motion sensor configured to detect the movement of the patient's leg. Information regarding the detected leg movement may be used by the controller circuit 1002 to control the parameters of the electrical stimulation. For example, if a symptomatic RLS lower limb spasm or movement of a threshold number is detected within a specific first detection period (e.g., within a period specified as 1 minute, 2 minutes, 5 minutes, or 20 minutes, etc.), the electrical stimulation may be initiated. This helps, for example, in automatically starting (or increasing) the treatment to relieve symptoms and assist the patient in sleeping in PLMD patients who experience leg spasms or movements during sleep. In one example, when the RLS lower limb spasm or movement is not detected within a specific second detection period (e.g., within a period specified as 1 minute, 2 minutes, 5 minutes, or 20 minutes, etc.), the electrical stimulation may be turned off (or tapered down or ramped off). In one example, the amplitude of the electrical stimulation may be increased when RLS spasms or movements are detected within a specific third detection period during which the RLS electrical stimulation therapy was provided (e.g., lasting beyond a period that can be specified as 5 minutes, 10 minutes, etc.).

[0070] In one example, the sensor circuit 1104 includes a heart rate variability (HRV)-based or other sleep sensor and is configured to, for example, detect whether the patient has fallen asleep and then turn off (or taper down or ramp off) the electrical stimulation, or detect the sleep stage and adjust the electrical stimulation parameters based on the patient's sleep stage. The sleep sensor may be used, for example, in combination with an accelerometer to detect leg spasms or movements while the subject is asleep and automatically turn on (or increase) the electrical stimulation therapy in response. This helps, for example, in automatically starting (or increasing) the treatment to relieve symptoms and assist the patient in sleeping in PLMD patients who experience leg spasms or movements during sleep.

[0071] FIG. 11B shows an example of a block diagram of a plurality of portions of an RLS electrical stimulation system 1110 configured to generate a controlled current waveform (e.g., a specific constant current amplitude AC electrical stimulation) with a variable impedance present at an interface between, for example, a plurality of electrical stimulation electrodes 1014 and the skin or other tissue of a patient contacted by such a plurality of electrical stimulation electrodes 1014.

[0072] In FIG. 11B, the power management circuit 1118 can be electrically connected to a power source such as one or more rechargeable batteries or other battery 1110, or alternatively (e.g., wirelessly) interfaced. The power management circuit 1118 can monitor a battery usability indication such that it can provide information regarding the amount of charge remaining in the battery 1110 or other indication of available usage time. The power management circuit 1118 can provide a warning or trigger one or more automatic recharges (e.g., wireless or otherwise) of the battery 1110 when a programmable, specifiable, or other threshold is exceeded or otherwise.

[0073] The battery 1110 is electrically connected to, or otherwise (e.g., via the power management circuit 1118) interfaced with, a buck-boost converter circuit 1120 that can generate a programmable output DC voltage (e.g., 12V, 20V, 30V, or other specific DC output voltage). The required DC output voltage can be determined by the controller circuit 1002 based on, for example, a detected load impedance that varies due to, for example, a varying electrode-tissue interface impedance. The load impedance can be measured using an impedance detection circuit 1119. The impedance detection circuit 1119 can include, for example, one or more current detection resistors that can detect current at the electrodes. The current detected by the current detection resistor can be converted to a voltage signal by the current detection resistor. The resulting voltage signal can be received at one or more inputs of an amplifier 1122 and buffered or amplified by the voltage amplifier 1122. The resulting buffered or amplified voltage signal can be digitized, for example, by an analog-to-digital converter (ADC) circuit included in or connected to the controller circuit 1002.

[0074] The controller 1002 can use the detected load impedance, which can be used by the controller 1002 in combination with other information, to determine, for example, the magnitude of the DC output voltage of the buck-boost converter 1120 required to generate a desired electrical stimulation, and to conserve battery power while providing or maximizing the therapeutic effect of the electrical stimulation. The controller 1002 can set one or more patterns of the desired electrical stimulation, for example, by using one or more stored electrical stimulation waveform parameters generated by the controller 1002. The controller 1002 can use one or more stored electrical stimulation parameters to generate one or more analog electrical stimulation control voltage waveforms, for example, using a digital-to-analog (D / A) converter 1106.

[0075] One or more resulting generated analog electrical stimulation control voltage waveforms are converted to a proportional, controlled, load-independent current, including, for example, using one or more operational amplifier-based current pumps 1108. The resulting control current electrical stimulation signal can be routed to the desired corresponding electrode 1014. Such routing can include using a multiplexer or switch matrix 1116. In one example, switch matrix 1116 includes one or more single-pole double-thrown (SPDT) switches as shown in the example of FIG. 11B, which switches can be operated and controlled by controller 1002 to selectively interface the control current electrical stimulation signal with tissue at one or more target locations using, for example, a plurality of electrode contacts 1014 to achieve charge balance or to direct the polarity of the electrical stimulation, the direction of the generated electrical stimulation region to adjust or optimize the electrical stimulation waveform.

[0076] In one example, controller 1002 can interface with a two-way or other wireless communication circuit 1017 that includes a transceiver circuit that follows a protocol such as Wi-Fi or Bluetooth to communicate with or exchange information with, for example, a local external unit or a remote server. Also, user input module 1012 is configured to interface with controller 1002 and includes one or more aids for interacting with the patient, caregiver, or other user, such as one or more push buttons or LED lights, for example, to communicate information, provide one or more status updates, or turn the RLS electrical stimulation system 1110 or one or more of its components on or off.

[0077] One or more portions of the example shown in FIG. 11B can be combined with one or more portions of the example shown in FIG. 11A, one or more portions of the example shown in FIG. 10, or one or more portions of one or more other examples as shown or described herein.

[0078] FIG. 11C is a flowchart generally showing an example of multiple parts of a method 1130 as may be performed using an RLS electrical stimulation system 1130. At 1132, one or more electrical stimulation parameters may be set, such as by programming such information into a memory storage device within or coupled to the controller circuit 1002. Examples of such multiple electrical stimulation parameters may include one or more of amplitude, frequency, pulse width, duty cycle, pulse repetition frequency, etc. At 1134, a test electrical stimulation waveform may be transmitted to the subject, such as via the multiple electrodes 1014. At 1136, a load impedance or a component thereof, such as an electrode-skin interface impedance, may be calculated using a detected impedance signal that is measurable, for example, by the controller circuit 1002 using an impedance measurement circuit 1119 and bufferable or amplifiable by an amplification circuit 1122. Such impedance may be determined by outputting a known voltage amplitude signal and measuring the response current signal (or vice versa). At 1138, the response signal data or the calculated impedance data may be logged, for example, by storing it in a memory location such as within the controller circuit 1002. At 1140, determining whether the measured electrode-skin interface impedance is outside a particular “normal” range may include using one or more comparison circuits within the controller circuit 1002 or elsewhere, where, for example, one or more reference values for comparison are provided to set a normal impedance range. If the measured impedance data is determined to be outside the normal range, at 1142, a warning may be issued to the patient or other user, such as to prompt replacement of the electrode 1014, and an error state may be recorded in the controller circuit 1117 or communicated to a local or remote interface device or server system.Rather, at 1140, if the measured impedance data is determined to be within the normal range, at 1144, the measured impedance data may be recorded in the controller circuit 1117 or communicated to a local or remote interface device or server system.

[0079] In FIG. 11C, after the skin - electrode interface impedance is calculated at 1136, at 1146, this information can be used to set the DC output voltage provided by the boost - converter circuit 1120 for use, for example, in generating an appropriate HF electrical stimulation waveform as described with reference to FIG. 11B. At 1148, the generated HF electrical stimulation waveform can be applied to the patient via a plurality of electrodes 1014. At 1150, the generated HF electrical stimulation waveform can be measured. This can include measuring the HF electrical stimulation waveform current, for example, by measuring the voltage across the sense resistor to provide a measurement value indicative of the electrical stimulation waveform current. At 1152, the measured value of the electrical stimulation value is compared with a saturation threshold value and can include using a comparator included within, for example, the controller circuit 1102. If the result of the comparison indicates the presence of a saturation condition, at 1154, the DC output voltage of the boost - converter circuit 1120 can be increased for subsequent application of electrical stimulation energy. Otherwise, the DC output voltage of the boost - converter can be maintained for subsequent application of electrical stimulation energy.

[0080] FIG. 12 illustrates an example of a technique 1200 that uses one or more sensor circuits 1104 or user input device 102, or both, to control RLS electrical stimulation therapy delivery, such as by a closed-loop RLS electrical stimulation therapy system 1100. At 1202, to control RLS therapy delivery, for example, one or more of user inputs are received (1202A) by a controller circuit 1002, a 3D accelerometer input is received (1202B), a sensed heart rate (HR) or respiratory input signal is received (1202C), a sensed skin impedance input signal is received (1202D), and used, for example, at 1204 to determine whether a patient is attempting to fall asleep or, at 1206, whether the onset of sleep has been detected.

[0081] For example, in 1202A, to communicate to the system 1100 that the patient intends to go to sleep, the user may activate a switch or provide other user input. Sleep detection may be performed by the controller circuit 1002 by, for example, using information from a 3D accelerometer in 1202B to determine the patient's posture (e.g., upright vs. supine) or the position of the patient's lower limbs, or by determining whether leg movements indicate RLS symptoms such as leg cramps or movements, or are consistent with sleep. The heart rate is detected (e.g., via a plurality of patient electrodes 1014 or via separate electrodes arranged or positioned to contact the patient), and a heart rate variability (HRV) parameter may be calculated from the heart rate signal detected by the controller circuit 1002. HRV may be used to detect sleep or to detect a particular sleep state. The respiration (breathing) signal may be detected (e.g., via a plurality of patient electrodes 1014 or via separate electrodes arranged or positioned to contact the patient) by detecting respiration using an impedance sensor that adjusts the detected impedance. Sleep stage information may be extracted from the respiration signal, for example, by signal processing performed by the controller circuit 1002. Sleep stage information may be obtained, for example, by interfacing with a plurality of other sleep monitoring products to which the patient communicates this information, such as the controller circuit 1002. The skin impedance sensor is used to detect frequency-dependent impedance using a plurality of patient electrodes 1014 or other changes in skin impedance, for example, by processing information such as that performed by the controller circuit 1002, and can provide information regarding, for example, the sleep stage of the subject.

[0082] An autonomic balance sensor or indicator can be used to detect the state of balance between a subject's sympathetic and parasympathetic nervous systems. Such information can be used to adjust electrical stimulation parameters. This can include adjusting the electrical stimulation level to provide a higher level of electrical stimulation corresponding to a higher level of sympathetic nervous system assertion as compared to an assertion of the parasympathetic nervous system.

[0083] A posture sensor is used to detect the state of a patient's posture, and that information can be used to adjust one or more electrical stimulation parameters. For example, in a patient who has RLS symptoms that worsen when the patient is trying to lie flat (e.g., in an airplane seat) as opposed to when the patient is trying to lie horizontally in a supine position, such posture information is used to increase the titration of electrical stimulation therapy when the latter case occurs as compared to when the former case occurs.

[0084] At 1204, it can be determined whether the patient / user is attempting to fall asleep. For example, at 1202A, the user can activate a switch or provide other user input to signal to the system 1100 that the patient is attempting to fall asleep. In one example, the patient's transition to a supine position can be used as an indicator that the patient is attempting to fall asleep.

[0085] At 1204, if the patient / user is trying to fall asleep, at 1208, RLS electrical stimulation therapy can be initiated or, if already in progress, can be continued. Otherwise, at 1204, if the patient / user is not trying to fall asleep, the process flow can proceed to "1210" which tapers off and stops any ongoing RLS electrical stimulation therapy (if any). At 1208, the initiation of RLS treatment can include, in one example, starting the treatment using an initial set of electrical stimulation parameter values that include a set of electrical stimulation parameters selected and stored based on previous effectiveness in the patient. Such effectiveness can be determined by user survey input that ranks effectiveness or by detecting the severity (quantity) of RLS symptoms over time (e.g., leg cramps or movements) after starting an RLS electrical stimulation therapy session. Also, the plurality of electrical stimulation parameter values can be selected based on, for example, the sleep stage (e.g., N1 - N4, REM / NREM, etc.) detected by the controller circuit 1002 using one of a plurality of on - board sensors 1104 that can communicate with the controller circuit 1002 or using a different sleep monitoring device available to the patient. As an example, the controller circuit 1002 can select electrical stimulation parameter values optimized for lower perception when a light or initial sleep stage is detected, such as to prevent any sleep disturbances in the patient.

[0086] At 1206, if sleep is detected after starting the electrical stimulation therapy, the process flow can continue to 1210, for example, by stopping the electrical stimulation or tapering the therapeutic electrical stimulation energy in a direction to stop it thereafter. This can help conserve power while the subject is sleeping and avoid unnecessary treatment. Otherwise, at 1206, if sleep is not detected after starting the electrical stimulation therapy, then the process flow can return to 1208 to continue the electrical stimulation therapy until, for example, sleep onset can be detected at 1206.

[0087] Figure 13 shows an example of a technique 1300 similar to the technique 1200 shown and described in Figure 12, and is modified to address the occurrence of foot cramping or movement symptoms that may occur after a subject who may have PLMD falls asleep. In the example of Figure 13, the technique 1300 can proceed as described with respect to Figure 12 until sleep is detected at 1206.

[0088] At 1206, when sleep is detected, monitoring continues until a specified period (e.g., 10 minutes, 15 minutes, or 20 minutes) has elapsed, with no leg movement or less than a specified threshold amount of leg movement during and over the specified period, after which the process flow proceeds to 1210 and the electrostimulation treatment can be discontinued or tapered off and discontinued. However, in PLMD patients, there is a possibility of recurrence of leg cramping or movement events while the subject is sleeping, so the process flow returns from 1210 to 1206, continues to monitor the patient for sleep at 1206, and then can monitor leg movement during sleep at 1302. If such monitoring indicates that the patient has woken up, at 1208, the RLS electrostimulation treatment can be restarted. If such monitoring indicates that the patient is continuing to sleep but has experienced a sufficient degree of leg cramping or movement during such sleep, at 1208, the electrostimulation treatment can be restarted. Otherwise, the ongoing electrostimulation is tapered off and stopped at 1210, further sleep can be monitored at 1206, and further leg movement can be monitored at 1302.

[0089] FIG. 14 shows an example in which one or more open-loop RLS electrical stimulation systems 1000 or one or more closed-loop RLS electrical stimulation systems 1100, or both, can be communicatively coupled to a remote server 1402 via a cloud or communication network 1404 or the like. This can include optionally using a repeater or other local interface device 1406 to establish a Bluetooth or other low-power wireless connection with the local RLS electrical stimulation systems 1000, 1100, for example, to interface with the remote server 1402.

[0090] The remote server 1402 can be used for logging, processing, or analyzing data from individual RLS electrical stimulation system 1000, 1100 instances associated with corresponding patients. The remote server 1402 can include, for example, a library of patient data including waveforms and efficacy data from previous events of various patients. The remote server 1402 includes a neural network, artificial intelligence, or machine learning system that uses efficacy data for waveforms used in various patients to obtain various results, and can, for example, propose specific electrical stimulation waveforms or electrical stimulation parameters for a specific patient based on previous data from the patient or a population of patients. Such a proposal can be based at least in part on the similarity of one or more features between the target patient and a plurality of patients within the patient population included in the library.

[0091] FIG. 15 includes an example of a stabilizer that carries or holds all or a plurality of parts of, for example, the RLS electrical stimulation systems 1000, 1100 in a predetermined position. In FIG. 15, the stabilizer may include, for example, a spandex or other elastic wearable and removable knee sleeve that includes an elastic patellar opening formed therein to allow the patient's patella to protrude therefrom. A disposable or other removable patch carries or holds the integrated electronics of the RLS electrical stimulation systems 1000, 1100 and also includes an integrated hydrogel or other electrodes that can contact the patient's skin through corresponding openings in the knee sleeve corresponding to one or more desired positions of the target nerve to which electrical stimulation is transmitted, for example, for RLS treatment. Thus, positioning relative to the target nerve position is facilitated by using the patient's patella as a landmark that serves as a reference for positioning the sleeve and can help to properly place the electrodes in the desired position relative to the corresponding target nerve position.

[0092] FIG. 16A shows an example of a multi-layer of the various layers of a disposable or other removable patch 1600 as shown in FIG. 15 for use with a knee sleeve. In this example, the most proximal (closest to the patient) layer 1602 may include a peel-off layer on an adhesive lower layer having a plurality of electrode cutouts. The next closest layer 1604 may include a plurality of hydrogel pockets or electrodes shaped and arranged similar to the cutouts of layer 1602. The next closest layer 1606 may include or carry an electronics unit of the RLS electrical stimulation systems 1000, 1100, including conductive traces for providing electrical contact and connection to the electrodes of layer 1604 or one or more other components. The next closest layer 1608 may include, for example, a flexible battery and antenna with electrical connection to the lower electronics unit carried by the lower layer 1606. The next closest layer 1610 may be the farthest layer and may include an electrically insulating top layer that is joined at least around its perimeter to one or more underlying layers. In one example, the electronics unit may be removable from the other components using a clasp or locking mechanism that allows for reuse of the electronics unit along with disposal of the other components of the patch.

[0093] FIG. 16B shows an example of a plurality of portions of a stabilizer including, for example, a multi-layer disposable or other user attachable and removable patch 1620, which is separately attachable to a removable (e.g., optionally reusable) electronic device unit 1640 (FIG. 15C) and can be optionally used with the knee sleeve shown in FIG. 15. Patch 1620 is shown as being sized, shaped, or otherwise configured to be particularly suitable for placement targeting the peroneal nerve or the femoral nerve, such as for transmitting a targeted electrical stimulation. Removable patch 1620 may include an uppermost layer 1622A, an intermediate layer 1622B, and a lowermost layer 1622C. These layers may be similarly shaped to each other such that when stacked, they define a circular, flared out, or other flared end or lobe. These ends may be interconnected by a rectangle or other strip of a desired length, such as to obtain a desired positioning of the electrodes. A plurality of electrodes may be appropriately spaced at desired positions at a plurality of ends or at appropriate positions on the interconnecting strip, such as for transmitting electrical stimulation to a nerve location of interest (e.g., the femoral nerve, the peroneal nerve, the sural nerve, or one or more branches thereof). Including a return electrode 1624C at an appropriate position in the central portion of the interconnecting strip can provide a return electrode position close to the electrodes at the ends that can target the desired electrical stimulation nerve target position, safely away from other nerves, such as to help avoid unwanted electrical stimulation of such other nerves (e.g., in a peroneal nerve targeting arrangement). In the lowermost layer 1622C, a plurality of electrodes 1624 may include a plurality of hydrogel pockets carried at selected positions of the lowermost layer 1622C at one or more desired positions of one or more of the plurality of ends of the lowermost layer 1622C or along the interconnecting strip of the lowermost layer 1622C, such as for contacting the underlying muscle. The hydrogel carried within such a plurality of hydrogel pockets associated with the plurality of electrodes 1624 can be conductive. This can help provide a low electrode-skin interface impedance for the plurality of electrodes 1624.

[0094] The intermediate layer 1622B can include vias 1626, 1627, and conductive traces 1628, for example, at one of its plurality of ends, to interconnect the plurality of electrodes 1624 to corresponding metals or other conductive contact portions 1630 on the top layer 1622A or to one of the plurality of electrodes 1624 on the bottom layer 1622C. The removable electronic device unit 1640 (FIG. 16C) is attached to the top layer 1622A, for example, using a corresponding plurality of contact portions that coincide with the positions of the plurality of contact portions 1630. The plurality of contact portions on the removable electronic device unit 1640 (FIG. 16C) can be magnetized to apply a magnetic attraction force to the plurality of contact portions 1630 on the top layer 1622A. This magnetic attraction force holds the removable electronic device unit 1640 (FIG. 16C) in a fixed position relative to the top layer 1622A and can self-align the removable electronic device unit 1640 (FIG. 16C) to the appropriate plurality of contact portions of the top layer 1622A.

[0095] FIG. 16C shows an example of the arrangement of the removable patch 1620 of FIG. 16B at the peroneal nerve target position just below the knee in the front portion of the lower limb, having a removable electronic device unit 1640 magnetically or otherwise attached to the removable patch 1620.

[0096] FIG. 16B shows an example of multiple portions of a stabilizer that include a multi-layer disposable or other removable patch 1660, similar to the patch 1620 shown in FIG. 16B. As compared to the three electrodes of the patch 1620 shown in FIG. 16B, the patch 1660 is shown to include five electrodes. In the example of FIG. 16D, the multiple ends can include flared circular or other lobes that extend laterally in opposite directions from each end of the patch 1660. The removable electronic device unit 1640 is magnetically self-aligning or otherwise attached to one of these lobes, providing aligned contacts between the multiple contacts on the removable electronic device unit 1640 similar to the arrangement of the multiple contacts 1630 shown in FIG. 16C.

[0097] FIG. 16E shows an example of the arrangement of the removable patch 1660 of FIG. 16D at the location of the peroneal nerve just below the knee in the front portion of the lower limb, having a removable electronic device unit 1640 magnetically or otherwise attached to the removable patch 1660.

[0098] FIG. 16F shows an example of a local external interface device 1670 that is used to charge or recharge one or more removable electronic device units 1640 that are removable wirelessly or otherwise, for example, by plugging into an AC wall outlet power supply, or to wirelessly communicate data between a cellular phone application and one or more removable electronic device units 1640, for example, for further communication with a remote server, via Bluetooth.

[0099] FIG. 16G shows an example of a block diagram of a local external interface device 1670. The local external interface device may include or be coupled to a controller circuit 1672 that is interfacable with a memory interface circuit 1680 that includes or is coupled to a power management circuit 1674, a battery charging management circuit 1676, a wireless communication transceiver circuit 1678, and an external memory drive interface circuit 1682. The power management circuit includes an AC / DC conversion circuit and a buck converter, a boost converter, a buck-boost converter, or other DC-DC power conversion circuit, and can generate an appropriate supply voltage for charging or recharging one or more electronic device units 1640, for example, via the battery charging management circuit 1676.

[0100] As an alternative to the selective application of specific nerve fiber types, HF electrical stimulation can be used to stimulate GABA production, thereby calming the leg spasms or motor symptoms of RLS or PLMD and blocking the transmission to the spinal cord of the target nerve (e.g., the peroneal nerve, femoral nerve, or gastrocnemius nerve, or one or more of their branches, or one or more of other nerve targets). This can be carried out to interrupt, suppress, or calm the RLS or other leg spasms or motor symptoms. For example, an AC waveform can be applied directly to the nerve using a cuff electrode wound around it, such as for applying an HF electrical stimulation waveform to the nerve.

[0101] In one example of the present technology, such nerve transmission blocking is achieved by transcutaneously modulating a desired high-frequency blocking signal onto a low-frequency carrier signal, and can effectively prevent the transmission of electrical signals along the nerve without the need for an implanted electrode or device.

[0102] Figure 17 shows an example of a transdermal drug delivery patch. In an example of the present technology, transmission interruption is obtained or assisted by applying a transdermal drug or chemical delivery patch using a local anesthetic (e.g., lidocaine, bupivacaine, capsaicin), for example, triggered to contact and penetrate the skin at activation, etc., by an electrical trigger signal generated by an on-board electronic device carried by the transdermal drug delivery patch. In the example of Figure 17, the patch may include, for example, a release adhesive layer closest to the body containing a local anesthetic. The next layer closer to the body may include an insulating layer having cutouts, etc., to enable contact with a plurality of electrodes that control the release of the chemical agent. The more distal layer may include, for example, a removable electronic device module configured to control the release of the chemical agent to interrupt neurotransmission between the spinal cord and a target nerve site (e.g., one or more of the peroneal nerve, femoral nerve, sural nerve, or one or more of their branches, or other nerve targets) to reduce one or more RLS symptoms such as muscle spasms and movements in the leg.

[0103] Figure 18 shows an alternative closed-loop ultrasonic embodiment that supplies ultrasonic energy to one or more targeted nerve locations (e.g., femoral nerve, peroneal nerve, or sural nerve) described herein. In this example, electrical energy can be converted to ultrasonic energy, such as by using a piezoelectric transducer tuned to the ultrasonic frequency and driven by an ultrasonic frequency electrical pulse generation circuit.

[0104] In one example, in combination with the HF RLS electrical stimulation described herein, ultrasonic energy can be transmitted to the subject's targeted nerve location. In one example, nerve ablation (e.g., by use of RF heating or use of a cryogenic agent) can be used additionally or alternatively to block one or more targeted nerve locations (e.g., femoral nerve, peroneal nerve, or sural nerve) described herein.

[0105] Figures 19A-19B show an example of a method of using the HF RLS electrical stimulation treatment described herein, along with a drug therapy that titrates the drug therapy downward stepwise as the HF RLS electrical stimulation treatment increases, for example. In one example, this approach can be used to find an appropriate pharmaceutical treatment level that can avoid RLS exacerbation or other pharmaceutical side effects, or to wean subjects off of drug therapy completely.

[0106] Patients suffering from RLS may complain about symptoms that are present or become present at night or at bedtime, thereby preventing the patient from falling asleep. Sleep onset latency can be defined as the amount of time it takes to achieve the transition from full wakefulness to sleep, such as the lightest non-REM sleep stage. RLS patients may have extremely long sleep latencies, which can be improved using the treatment methods described herein.

[0107] As described herein, actigraphic recording, measurement of sympathetic nervous system tone (e.g., heart rate, or particularly heart rate variability), and measurement of sleep such as EEG are used to identify when a patient wakes, walks, sleeps, or falls asleep, and may be used to appropriately initiate and stop or adjust to an appropriate level for treatment as described herein.

[0108] Figure 20 shows an example of a technique used to turn on and off an HF RLS electrical stimulation therapy as described herein. A patient can initiate therapy at bedtime, such as by activating a switch or other user interface device. In addition to therapy, monitoring of activity and sleep can be initiated. If the onset of sleep is detected, the therapy can be stopped or paused, for example, until the detection of waking up, and further activity or sleep can be monitored to resume the therapy. If sleep is not detected, or if sufficient lower limb motor activity is detected, the therapy can be continued or increased. A sleep quality report can be created using information from a sleep sensor, which can include, for example, using information regarding the therapy delivered.

[0109] Nerve adaptation and relief Neural stimulation therapy, especially when continuously used, as in the case of multiple devices having multiple implanted electrical stimulation electrodes, may have a reduced effectiveness over an extended period. Such neural accommodation or tolerance may be due to neural reorganization (plasticity) or attenuation of end-organ responsiveness. Neural plasticity is the change in the structure, function, and composition of neurons in response to new experiences. The present RLS electrical stimulation therapy system and techniques can include specific features that can help make it less susceptible to such a decrease in efficacy over long-term habitual use.

[0110] First, the present RLS electrical stimulation therapy system can be configured to be used only during the period in which RLS symptoms are present (e.g., typically, within several hours or nights out of a week). In an open-loop configuration, this can include the use of a timer, a clock with time information, or both. In a closed-loop configuration, this can include, for example, the use of one or more sensors as described herein to detect when RLS or PLMD symptoms (e.g., over-assertion of sympathetic tone in heart rate variability (HRV) or other indications of autonomic balance) are present, or to detect physiological indicators indicative of sensitivity or exacerbation to RLS or PLMD symptoms, and can be used, for example, to control the initiation, titration, or adjustment of electrical stimulation therapy based on such sensor information, alone or in combination with a timer, time information, or both. Since the RLS electrical stimulation application time is limited, there is a limited range of neural adaptation due to plasticity.

[0111] Second, the present RLS electrical stimulation therapy system has its controller circuit 1002 configured to provide waveform variability or adaptation, which helps counter the potential for neural adaptation. This can include modulating one or more electrical stimulation waveform parameters such as one or more of pulse width, amplitude, frequency, or burst mode or burst interval.

[0112] FIG. 21 shows an example of an RLS electrical stimulation waveform that can be generated by the RLS electrical stimulation therapy system of the present application. One or more of the electrical stimulation parameters can be changed over time, for example, from an initial setting. A plurality of examples of electrical stimulation parameters that can be set or adjusted can include, for the square wave electrical stimulation waveform of FIG. 21, a positive amplitude (A1), a positive pulse width (PW1), a negative amplitude (A2), a negative pulse width (PW2), and an off period (tOFF) between successive electrical stimulation pulses.

[0113] Figures 22 and 23 show multiple examples of waveform patterns specifically configured to suppress or prevent short-term neural adaptation. Figure 22 shows a gradual increase (e.g., during the ramp-on of the ramp period) or decrease (e.g., during the ramp-off of the ramp period), or both, of one or more parameters (amplitude A1, A2, or both, or pulse width PW1, PW2, or both) while maintaining charge-balanced electrostimulation as needed until the desired therapeutic dose is reached. In addition to being useful for suppressing neural adaptation, the gradual increase or decrease can help further reduce or avoid the perception of RLS therapeutic electrostimulation. The therapeutic stimulation waveform may also be separated by "off" periods (burst-off) between multiple bursts, as shown in Figure 22. This can help further reduce the application of any repetitive pattern to the target nerve while still maintaining the therapeutic effect.

[0114] Figure 23 shows a technique in which the primary electrical stimulation waveform is separated by "off" periods (burst-off), during which smaller secondary bursts of electrical stimulation therapy are applied, for example, as microbursts. The smaller the secondary burst of the therapy, the less charge can be injected into the nerve, for example, by using a decrease in amplitude, a decrease in pulse width, or a change in frequency.

[0115] In addition to or instead of this, the RLS electrical stimulation treatment waveform can be varied in a fixed frequency range around the center frequency (e.g., 4000 Hz) in each burst so as to further reduce, for example, an accommodation-related decrease associated with the perception of a therapeutic effect or a detected adaptation. These operations can be triggered by user input of an RLS discomfort score or automatically triggered by an RLS electrical stimulation system controller circuit that reviews collected sensor data indicative of symptoms or related physiological factors of RLS or PLMD, such as, for example, such leg movements, usage time per night, amplitude settings, and improvement in the reported IRLSS score. The RLS electrical stimulation waveform parameters can be modified, for example, to ensure a continuous decrease in the measured flexion response from the patient in order to maintain RLS electrical stimulation below the perception threshold. For example, if the amplitude of the flexion response (Fr-III) increases over time with the use of RLS electrical stimulation treatment, one or more of the RLS electrical stimulation treatment parameters are reprogrammed to help facilitate or ensure this continuous minimization of the flexion response as shown in FIG. 24. Additionally or alternatively, an interferential current type of treatment approach can be used within the HF frequency range to help suppress, sedate, or prevent neural adaptation.

[0116] Various notes and aspects Although this specification has referred to RLS and RLS treatment, including HF RLF electrical stimulation treatment, the techniques herein for detecting or treating RLS are also applicable to PLMD in which similar symptoms (single contractions or movements of the legs) occur during sleep.

[0117] A non-limiting list of numbered aspects of the particular matter of this application is presented below. Aspect 1 may include or use a particular matter (such as an apparatus, a system, a device, a method, a means for performing an operation, or a device-readable medium including a plurality of instructions that cause a device to perform an operation when executed by the device), for example, may include providing treatment for one or more symptoms associated with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) including the use of applied high-frequency electrical stimulation. This may include positioning at least one electrical stimulation electrode at a position associated with at least one of the gastrocnemius nerve, the peroneal nerve, or the femoral nerve of a subject having RLS or PLMD, or at least one of their branches. Next, the electrical stimulation can be transmitted to that position to help reduce or alleviate one or more symptoms associated with RLS or PLMD.

[0118] Aspect 2 may include or use the particular matters of Aspect 1, or optionally combined, and include or use transmitting sub-perceptual threshold (e.g., imperceptible) AC high-frequency (HF) electrical stimulation below threshold (e.g., with muscles not activated), for example, at an HF frequency higher than 500 Hz and less than 15,000 Hz to reduce or alleviate one or more symptoms associated with RLS or PLMD.

[0119] Aspect 3 may include or use one or more particular matters of Aspects 1 - 2, or optionally combined, and transmitting the electrical stimulation may include transmitting a controlled current electrical stimulation.

[0120] Aspect 4 may include or use one or more particular matters of Aspects 1 - 3, or optionally combined, and transmitting the controlled current electrical stimulation may include transmitting at a controlled current level between 5 milliamperes and 30 milliamperes.

[0121] Aspect 5 may include or use one or more specific matters of Aspects 1 to 4, or be arbitrarily combined, and transmitting an electrical stimulation may include transmitting a charge-balanced AC electrical stimulation. For example, this may include a positive waveform portion that transmits an amount of charge balanced by a negative waveform portion.

[0122] Aspect 6 may include or use one or more specific matters of Aspects 1 to 5, or be arbitrarily combined, and may include, for example, transmitting an electrical stimulation at a frequency between 4 kHz and 5 kHz.

[0123] Aspect 7 may include or use one or more specific matters of Aspects 1 to 6, or be arbitrarily combined, and may include, for example, transmitting an electrical stimulation below the perception threshold that is set or adjusted to a level that is not felt by the subject and does not cause muscle contraction in the subject.

[0124] Aspect 8 may include or use one or more specific matters of Aspects 1 to 7, or be arbitrarily combined, and transmitting an electrical stimulation may include, for example, using a waveform that preferentially activates A-Beta fibers over other nerve fiber types at the target nerve location.

[0125] Aspect 9 may include or use one or more specific matters of Aspects 1 to 8, or be arbitrarily combined, and may include, for example, transmitting an electrical stimulation using a waveform selected to (e.g., preferentially) activate A-Beta fibers to help release GABA and suppress overactive A-Delta fibers, C fibers, or both.

[0126] Aspect 10 may include or use one or more specific matters of Aspects 1 to 9, or be arbitrarily combined, and may include, for example, transmitting a controlled current electrical stimulation using an energy level or other electrical stimulation characteristic value set or adjusted based on the measured electrode-skin interface impedance.

[0127] Aspect 11 may include using an electrical stimulation waveform that includes or uses one or more specific items of Aspects 1 - 10, or optionally combined, to produce a measured compound action potential (CAP) that results in a higher amplitude ratio of A - Beta fibers to C - fiber components recorded along a nerve or a branch thereof, such as a relevant one of the gastrocnemius nerve, peroneal nerve, or femoral nerve, compared to the amplitude ratio from the recorded response to a reference electrical stimulation waveform having a frequency of 150 Hz, recorded at a distance (e.g., extending peripherally) from an electrical stimulation electrode.

[0128] Aspect 12 may include transmitting an electrically - stimulated setting or adjustment, for example, based on a measured load impedance or a component thereof (e.g., electrode - skin interface impedance), including or using one or more specific items of Aspects 1 - 11, or optionally combined.

[0129] Aspect 13 may include selecting or accepting a subject presenting with RLS or PLMD, including or using one or more specific items of Aspects 1 - 12, or optionally combined. Additionally, this may optionally include, for example, selecting a subject who does not exhibit at least one of peripheral neuropathy above the subject's legs or enhanced RLS.

[0130] Aspect 14 may be automatically triggered or adjusted, for example, in response to a sensor or other indication of the subject's RLS symptoms, including or using one or more specific items of Aspects 1 - 13, or optionally combined.

[0131] Aspect 15 may include transmitting an electrically - stimulated setting that is automatically triggered or adjusted, for example, in response to a sensor or other indication of the subject's PLMD symptoms, including or using one or more specific items of Aspects 1 - 14, or optionally combined.

[0132] Aspect 16 may include or use one or more of the specific matters of Aspects 1 to 15, or be arbitrarily combined, and may include transmitting an electrically-stimulating impulse that is automatically triggered or adjusted in response to time information (e.g., from a clock or timer circuit).

[0133] Aspect 17 may include or use one or more of the specific matters of Aspects 1 to 16, or be arbitrarily combined, and may include transmitting an electrically-stimulating impulse that is automatically triggered or adjusted in response to, for example, a sensor of the subject's posture or other instructions.

[0134] Aspect 18 may include or use one or more of the specific matters of Aspects 1 to 17, or be arbitrarily combined, and may include transmitting an electrically-stimulating impulse that is automatically triggered or adjusted in response to, for example, a sensor of the subject's sleep state or sleep stage or other instructions.

[0135] Aspect 19 may include or use one or more of the specific matters of Aspects 1 to 18, or be arbitrarily combined, and may include transmitting an electrically-stimulating impulse that is automatically triggered or adjusted in response to, for example, a sensor of the subject's autonomic balance (e.g., heart rate variability (HRV), etc.) or other instructions.

[0136] Aspect 20 may include or use one or more of the specific matters of Aspects 1 to 19, or be arbitrarily combined, and may include transmitting an electrically-stimulating impulse that is automatically triggered or adjusted in response to, for example, one or more sensors of the movement of the subject's leg or foot (e.g., from an accelerometer) or other instructions.

[0137] Aspect 21 may include or use one or more of the specific matters of Aspects 1 to 20, or be arbitrarily combined, and may include transmitting an electrically-stimulating impulse that is automatically triggered or adjusted in response to, for example, an instruction for the subject's drug treatment. For example, in a RLS electro-stimulating treatment plan, the electro-stimulating energy level can be gradually increased over a period of time long enough to gradually reduce the RLS drug treatment for the subject.

[0138] Aspect 22 may include or use one or more specific items of Aspects 1-21, or be arbitrarily combined, for example, using information about the electrical stimulation transmitted (or the physiological response to the electrical stimulation transmitted) to affect the drug treatment of the subject. For example, this may include transmitting electrical stimulation, measuring a flexion response or a compound action potential (CAP) response, and determining whether or how to titrate one or more drugs administered to the patient using such physiological response information.

[0139] Aspect 23 may include or use one or more specific items of Aspects 1-22, or be arbitrarily combined, for example, communicating information about the electrical stimulation transmitted, its effectiveness (such as physiological parameters measured in relation to providing treatment), or one or more symptoms (such as leg movement, sleep state, etc.) to a local or remote external device (such as a local interface device or a remote server device).

[0140] Aspect 24 may include or use one or more specific items of Aspects 1-23, or be arbitrarily combined, for example, placing the electrical stimulation electrode at an external location related to the gastrocnemius nerve or at least one of its branches (such as a branch extending to a directly connected peripheral).

[0141] Aspect 25 may include or use one or more specific items of Aspects 1-24, or be arbitrarily combined, for example, placing the external electrical stimulation electrode at a location related to the peroneal nerve or at least one of its branches (such as a branch extending to a directly connected peripheral).

[0142] Aspect 26 may include or use one or more specific items of Aspects 1-25, or be arbitrarily combined, and may include, for example, arranging an electrical stimulation electrode at an external position related to the femoral nerve or at least one of its branches (for example, a branch extending to a directly connected periphery).

[0143] Aspect 27 may include or use one or more specific items of Aspects 1-26, or be arbitrarily combined, and may include, for example, arranging an electrical stimulation electrode at an external position on or near the subject's knee.

[0144] Aspect 28 may include or use one or more specific items of Aspects 1-27, or be arbitrarily combined, and may include arranging an electrical stimulation electrode, for example, by attaching a knee sleeve around the subject's leg at the subject's knee.

[0145] Aspect 29 may include or use one or more specific items of Aspects 1-28, or be arbitrarily combined, and may include, for example, arranging an electrical stimulation electrode at an external position on or near the subject's heel.

[0146] Aspect 30 may include or use one or more specific items of Aspects 1-29, or be arbitrarily combined, and may include, for example, arranging an electrical stimulation electrode at an external position on or near the peroneal nerve just below the tibial tuberosity at the front of the subject's lower limb under the patella.

[0147] Aspect 31 may include or use one or more specific items of Aspects 1-31, or be arbitrarily combined, and may include, for example, transmitting electrical stimulation triggered in response to at least one of the symptoms, times, posture instructions, sleep state instructions, autonomic balance instructions, or leg or foot movement instructions of RLS or PLMD.

[0148] Aspect 32 may include or use one or more specific items of Aspects 1-31, or be arbitrarily combined, and may include, for example, transcutaneously transmitting electrical stimulation via external electrodes placed on a subject.

[0149] Aspect 33 may include or use one or more specific items of Aspects 1-32, or be arbitrarily combined, and may include, for example, treating one or more symptoms associated with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using the applied electrical stimulation. This may include positioning at least one electrical stimulation electrode at a position associated with at least one of the gastrocnemius nerve, peroneal nerve, or femoral nerve, or at least one of their branches. It may include transmitting sub-threshold AC electrical stimulation below the perceptual threshold using a waveform configured to provide a measured compound action potential (CAP) obtained as a result of having an increased amplitude ratio of A-Beta fibers to the C fiber component recorded at the distance from the electrical stimulation electrode along the relevant one of the gastrocnemius nerve, peroneal nerve, or femoral nerve with respect to a reference electrical stimulation waveform of 150 Hz.

[0150] Aspect 34 may include or use one or more specific items of Aspects 1-33, or be arbitrarily combined, and may include, for example, treating one or more symptoms associated with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using the applied high-frequency electrical stimulation. The electrical stimulation electrodes are positioned at a position associated with at least one of the gastrocnemius nerve, peroneal nerve, or femoral nerve, or at least one of their branches. Sub-threshold AC electrical stimulation below the perceptual threshold is transmitted using a waveform set to release GABA so as to provide a higher measured increase in GABA as a result compared to any increase in GABA resulting from a reference electrical stimulation waveform of 150 Hz, for example.

[0151] Aspect 35 may include or use one or more of the specific matters of Aspects 1 to 34, or be arbitrarily combined, and for example, may include or use a device for treating one or more symptoms related to restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using high-frequency electrical stimulation. The device may include or be coupled to a plurality of external electrical stimulation electrodes configured to be attached to a subject at a position related to at least one of, for example, the gastrocnemius nerve, the peroneal nerve, or the femoral nerve, or at least one branch thereof (for example, a directly connected terminal or a distally extending bifurcation) to transmit electrical stimulation thereto. The electrical stimulation generation circuit may be applied to or coupled to the plurality of electrical stimulation electrodes to generate electrical stimulation for transmission by the plurality of electrical stimulation electrodes. For example, the controller circuit may be coupled to the electrical stimulation generation circuit to control at least one parameter of the electrical stimulation, for example.

[0152] Aspect 36 may include or use one or more of the specific matters of Aspects 1 to 35, or be arbitrarily combined, and for example, may include or use an electrical stimulation generation circuit including an alternating current (AC) electrical stimulation generation circuit below the perception threshold and below the threshold, coupled to the plurality of electrical stimulation electrodes to transmit electrical stimulation at a frequency greater than 500 Hz and less than 15,000 Hz at that position to help reduce or alleviate one or more symptoms related to RLS or PLMD.

[0153] Aspect 37 may include or use one or more of the specific matters of Aspects 1 to 36, or be arbitrarily combined, and for example, may include or use an electrical stimulation generation circuit having a control current circuit configured to control the electrical stimulation current, such as at a current level between 5 milliamperes and 30 milliamperes.

[0154] Aspect 38 may include or use one or more of the specific matters of Aspects 1 to 37, or be arbitrarily combined, and for example, may include or use an electrical stimulation generation circuit configured to provide a controlled current electrical stimulation waveform having a frequency between 4 kHz and 5 kHz.

[0155] Aspect 39 may include or use one or more specific items of Aspects 1 to 38, or be arbitrarily combined, and may include or use a stabilizer that, for example, holds at least a part of the device at a target position.

[0156] Aspect 40 may include or use one or more specific items of Aspects 1 to 39, or be arbitrarily combined, and may include or use a stabilizer that includes a skin patch configured to be attached to a subject at a position where electrical stimulation is transmitted.

[0157] Aspect 41 may include or use one or more specific items of Aspects 1 to 40, or be arbitrarily combined, and may include or use a stabilizer that includes a wearable sleeve configured to hold a device at a position where electrical stimulation is transmitted.

[0158] Aspect 42 may include or use one or more specific items of Aspects 1 to 41, or be arbitrarily combined, and may include or use a user interface coupled to a controller circuit to trigger or adjust electrical stimulation in response to at least one of, for example, symptoms of RLS or PLMD, time, posture instructions, sleep state instructions, autonomic balance instructions, or leg or foot movement instructions.

[0159] Aspect 43 may include or use one or more specific items of Aspects 1 to 42, or be arbitrarily combined, and may include or use a sensor coupled to a controller circuit to trigger or adjust electrical stimulation in response to at least one of, for example, symptoms of RLS or PLMD, time, posture instructions, sleep state instructions, autonomic balance instructions, or leg or foot movement instructions.

[0160] Aspect 44 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 43, and may include or use, for example, an accelerometer configured to detect the movement of at least a part of a subject (e.g., the movement of the legs or feet).

[0161] Aspect 45 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 44, and may include or use, for example, a sensor including a clock circuit that provides a time display.

[0162] Aspect 46 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 45, and may include or use, for example, a posture sensor configured to detect the posture of a subject (e.g., standing upright, lying down, etc.).

[0163] Aspect 47 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 46, and may include or use, for example, a sleep sensor configured to indicate the sleep state of a subject.

[0164] Aspect 48 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 47, and may include or use, for example, a sensor including an automatic balance indicator configured to provide information regarding at least one of the sympathetic nervous tension or parasympathetic nervous tension of a subject.

[0165] Aspect 49 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 48, and may include or use, for example, a sensor including an impedance sensor configured to provide information about the impedance of a subject or the impedance related to the subject to a controller circuit in order to adjust the parameters of an electrical stimulus accordingly.

[0166] Aspect 50 may include or use one or more specific matters of Aspects 1 to 49, or optionally be combined, and include or use, for example, a controller circuit configured to initiate or adjust parameters of electrical stimulation using information about the drug treatment of a subject.

[0167] Aspect 51 may include or use one or more specific matters of Aspects 1 to 50, or optionally be combined, and include or use, for example, a transceiver circuit configured to communicate information about transmitted electrical stimulation, one or more effective physiological parameters thereof, or one or more symptoms to a local or remote external device.

[0168] Aspect 52 may include or use one or more specific matters of Aspects 1 to 51, or optionally be combined, and include or use, for example, a plurality of electrical stimulation electrodes carried on an adhesive patch.

[0169] Aspect 53 may include or use one or more specific matters of Aspects 1 to 52, or optionally be combined, and include or use, for example, an adhesive patch configured to be used only once before discarding the patch.

[0170] Aspect 54 may include or use one or more specific matters of Aspects 1 to 53, or optionally be combined, and include or use, for example, a device further including a battery also carried by an electronic circuit or an adhesive patch.

[0171] Aspect 55 may include or use one or more of the specific matters of Aspects 1 to 54, or be arbitrarily combined, and for example, may include or use a device that treats one or more symptoms related to restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) by using electrical stimulation at the position of the gastrocnemius nerve behind and below the ankle of a human subject. The device may include or use, for example, a wearable patch including a plurality of external electrical stimulation electrodes including a plurality of electrical contact portions within a first configuration that is configured to be fixed to the subject at the position of the gastrocnemius nerve and receives signals from an electrical stimulation electronic device unit that is user-wearable and user-detachable from the patch.

[0172] Aspect 56 may include or use one or more of the specific matters of Aspects 1 to 55, or be arbitrarily combined, and for example, may include or use a patch sized and shaped to fit on the outer side of the foot between the ankle and the heel of a human subject.

[0173] Aspect 57 may include or use one or more of the specific matters of Aspects 1 to 56, or be arbitrarily combined, and for example, may include or use a patch including a central lobe that receives (optionally additionally carrying electrical stimulation electrodes) an electrical stimulation electronic device unit and a plurality of wing portions extending from the central lobe carrying corresponding plurality of electrical stimulation electrodes that contact the skin of the subject.

[0174] Aspect 58 may include or use one or more of the specific matters of Aspects 1 to 57, or be arbitrarily combined, and for example, may include or use an electrical stimulation electronic device unit including a plurality of electrical contact portions in a second configuration that matches the first configuration of the patch.

[0175] Aspect 59 may include or use one or more of the specific matters of Aspects 1 to 58, or be arbitrarily combined, and for example, may include or use one or more electrical contact portions of a magnetized patch that attract similarly arranged plurality of contact portions of the electrical stimulation electronic device unit.

[0176] Aspect 60 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 59, for example, a lower layer carrying a plurality of hydrogel electrodes, an upper layer including a plurality of electrical contacts for interfacing with an electronic device unit, and an intermediate layer that provides electrical connection to the plurality of hydrogel electrodes supported by the lower layer and the plurality of electrical contacts included in the upper layer.

[0177] Aspect 61 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 60, for example, using electrical stimulation at the position of the peroneal nerve below the patella and the tibial tuberosity in the front part of the lower limb of a human subject to treat one or more symptoms associated with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD). The device may include, for example, a plurality of external electrical stimulation electrodes configured to be fixed to the subject at the position of the peroneal nerve, and may include or use a wearable patch including a plurality of electrical contacts in a first configuration that receives signals from an electrical stimulation electronic device unit that is user-wearable and user-detachable from a patch.

[0178] Aspect 62 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 61, for example, including or using a wearable patch that includes a plurality of electrodes at each end of the patch for placement at opposing outer and inner positions on the tibia, and the plurality of electrical contacts in the first configuration are disposed at one of the plurality of ends of the patch.

[0179] Aspect 63 may include or use, or optionally combine, one or more specific matters of Aspects 1 to 62, for example, including or using a feedback electrode disposed to be located in front of the tibia when the electrodes at one of the plurality of ends of the patch are disposed outside or inside on the peroneal nerve target.

[0180] Aspect 64 includes or uses one or more of the specific matters of Aspects 1 to 63, or optionally combines them, and includes or uses, for example, a patch including a plurality of lobes extending in opposite directions at each end of the patch, each lobe carrying an electrode.

[0181] Aspect 65 includes or uses one or more of the specific matters of Aspects 1 to 64, or optionally combines them, and includes or uses, for example, a lower layer carrying a plurality of hydrogel electrodes, an upper layer including a plurality of electrical contacts for interfacing with an electronic device unit, and an intermediate layer providing electrical connection to the plurality of hydrogel electrodes carried by the lower layer and the plurality of electrical contacts included in the upper layer, and may include or use a patch including or using the same.

[0182] Aspect 66 includes or uses one or more of the specific matters of Aspects 1 to 65, or optionally combines them, and includes or uses, for example, a device for treating one or more symptoms associated with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using electrical stimulation at the position of the femoral nerve in front of the upper part of the femur of a human subject. The device includes a plurality of external electrical stimulation electrodes configured to be fixed to the subject at the position of the peroneal nerve, and may include or use a wearable patch including a plurality of electrical contacts in a first configuration that receives signals from an electrical stimulation electronic device unit that is user-wearable and user-detachable from the patch.

[0183] Aspect 67 includes or uses one or more of the specific matters of Aspects 1 to 66, or optionally combines them, and includes or uses, for example, including or using a wearable patch that includes a plurality of electrodes at each end of the patch for placement at opposing outer and inner positions on the thigh, and the plurality of electrical contacts in the first configuration are disposed at one of the plurality of ends of the patch.

[0184] Aspect 68 includes or uses one or more of the specific matters of Aspects 1 to 67, or optionally combines them. For example, including or using a wearable patch may include a feedback electrode arranged to be located in front of the femur when an electrode at one of the plurality of ends of the patch is arranged outside or inside on the target of the femoral nerve.

[0185] Aspect 69 includes or uses one or more of the specific matters of Aspects 1 to 68, or optionally combines them. For example, including or using a patch that includes a plurality of lobes extending in opposite directions at each end of the patch, and each lobe may carry an electrode.

[0186] Aspect 70 includes or uses one or more of the specific matters of Aspects 1 to 69, or optionally combines them. For example, it may include or use a lower layer carrying a plurality of hydrogel electrodes, an upper layer including a plurality of electrical contacts for interfacing with an electronic device unit, and an intermediate layer providing electrical connection to the plurality of hydrogel electrodes supported by the lower layer and the plurality of electrical contacts included in the upper layer.

[0187] The above description includes references to the accompanying drawings that form part of the detailed description. The drawings show, by way of example, a plurality of specific embodiments in which the present invention can be implemented. These embodiments are also referred to herein as "aspects" or "examples". Such a plurality of examples may include a plurality of elements in addition to those illustrated or described. However, the inventors also contemplate a plurality of examples in which only these elements illustrated or described are provided. Furthermore, the inventors also contemplate a plurality of examples using any combination or substitution of the plurality of elements (or one or more of their aspects) illustrated or described with respect to a particular example (or one or more of its aspects), or with respect to other examples (or one or more of their aspects) illustrated or described herein.

[0188] If there is a conflicting usage between this specification and any document incorporated by reference, the usage in this specification is used. As is common in patent documents, in this specification the term "a" or "an" is used to include one or more, independent of any other instance or usage of "at least one" or "one or more". In this specification, the term "or" is used to indicate an exclusive "or", and "A or B" includes, unless otherwise specified, "not A but B", "not B but A", and "A and B". In this specification, the terms "including" and "in which" are used as ordinary English equivalents of the corresponding terms "comprising" and "wherein". Also, in the appended claims, the terms "including" and "comprising" are used without limitation, i.e., a system, apparatus, article, composition, formulation, or process that includes a plurality of elements in addition to those recited after such terms in a claim is still considered to be within the scope of that claim. Further, in the appended claims, terms such as "first", "second", and "third" are used merely as labels and are not intended to impose numerical requirements on their objects.

[0189] Geometric terms such as "parallel", "perpendicular", "circular", or "square" are not intended to require absolute mathematical precision unless the context indicates otherwise. Instead, such geometric terms are allowed to vary by manufacturing or equivalent functionality. For example, if an element is described as "circular" or "substantially circular", components that are not exactly circular (e.g., those that are slightly oval or faceted polygonal) are also included in this specification.

[0190] Multiple examples of the methods described herein may be implemented, at least in part, mechanically or by computer. Some examples may include a computer-readable medium or a machine-readable medium encoded with a plurality of instructions operable to configure an electronic device to perform a plurality of methods as described in the above examples. Implementations of such methods may include code such as microcode, assembly language code, high-level language code, and the like. Such code may include a plurality of computer-readable instructions for performing various methods. The code may form part of a computer program product. Further, in one example, the code may be tangibly stored on one or more volatile, non-transitory, or non-volatile tangible computer-readable media, such as during execution or at other times. Multiple examples of such tangible computer-readable media may include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memory (RAM), read only memory (ROM), and the like.

[0191] The above description is illustrative and not restrictive. For example, the above-described multiple examples (or one or more aspects thereof) may be used in combination with each other. Upon consideration of the above description, other embodiments may be used by, for example, those skilled in the art. The abstract is provided to comply with 37 C.F.R. §1.72(b) and enable the reader to quickly ascertain the nature of the technical disclosure. The abstract is submitted with the understanding that it is not to be used to interpret or limit the scope or meaning of the claims. Also, in the above detailed description, various features may be grouped together to simplify the disclosure. This should not be construed as intending that the disclosed functions not claimed are essential to any of the claims. Rather, the subject matter of the invention may lie in less than all of the features of a particular disclosed embodiment. Accordingly, the appended claims are incorporated into the detailed description as examples or embodiments, and each claim stands on its own as an independent embodiment, and such multiple embodiments are considered to be combinable with each other in various combinations or permutations. The scope of the present invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. 1. A neurostimulation therapy system for treating a patient having one or more symptoms associated with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) using high frequency electrical stimulation, comprising: a wearable device including an electrical stimulation electronics unit including or coupled to first and second skin electrodes for delivering electrical stimulation therapy signals to the patient at a sensory nerve for at least one of the patient's tibialis anterior region, gastrocnemius region, rectus femoris, and biceps femoris, the electrical stimulation therapy signals being delivered at a frequency of 500 Hz to 15,000 Hz and a current of 5 mA to 30 mA to induce responsive neural activation in the sensory nerve for the patient's tibialis anterior region, gastrocnemius region, rectus femoris, and biceps femoris; A system comprising: a controller circuit included in or coupled to the electrical stimulation electronics unit, the controller circuit configured to set or adjust electrical stimulation therapy signal parameters.

2. 10. The system of claim 1, wherein the controller circuitry is configured to set or adjust the electrical stimulation therapy signal parameters based on one or more of a measured physiological parameter, a set of user symptoms, and a user survey.

3. The system of claim 2 , wherein one or more of the measured physiological parameters, the set of user symptoms, and the user survey relate to at least one of RLS and PLMD.

4. 10. The system of claim 1, wherein the controller circuitry is configured to detect a sleep stage of the patient and set or adjust the electrical stimulation therapy signal parameters based on the detected sleep stage of the patient.

5. The controller circuit includes:

10. The system of claim 1, configured to coordinate triggering or adjustment of at least one of an electrical stimulation therapy or a drug therapy based on an indication that the other is being administered to the patient.

6. a transceiver circuit configured to communicate information regarding the delivered electrical stimulation therapy signal, electrical stimulation therapy efficacy, or one or more symptoms to a remote external device; 6. The system of claim 5, wherein the controller circuitry is configured to coordinate triggering or adjustment of drug therapy for the patient based on information about the delivered electrical stimuli or a physiological response to the delivered electrical stimuli.

7. 1. A transceiver circuit comprising: Indication of downward titration of drug therapy; the transceiver circuitry configured to communicate sensor data including at least one of an actigraphic recording corresponding to the downward titration of the drug treatment, a measurement of sympathetic tone, a measurement of sleep, and an electroencephalogram (EEG); The system of claim 1 , wherein the controller circuitry is configured to adjust electrical stimulation parameters of the electrical stimulation therapy signal based on the sensor data.

8. at least one of a neural network, an artificial intelligence model, and a machine learning system; At least one of the neural network, the artificial intelligence model, and the machine learning system: receiving efficacy data including one or more of a measured physiological parameter, a set of user symptoms, or a user survey; using the efficacy data to determine desired electrical stimulation therapy signal parameters; The system of claim 1 , configured to: communicate the desired electrical stimulation therapy signal parameters to the controller circuit.

9. 10. The system of claim 1, comprising an electrical stimulation generating circuit configured to deliver the electrical stimulation therapy signal having a frequency between 4 kHz and 5 kHz.

10. 10. The system of claim 1, further comprising a user interface coupled to the controller circuit for triggering or adjusting the electrical stimulation therapy signal in response to at least one of a sleep disorder symptom, a time of day, an indication of posture, an indication of sleep state, an indication of autonomic balance, or an indication of leg or foot movement.

11. 10. The system of claim 1, further comprising a sensor including an impedance sensor configured to provide information regarding an impedance associated with the patient to the controller circuit for adjusting parameters of the electrical stimulation therapy signal in response to information regarding an impedance associated with the patient.

12. 10. The system of claim 1, wherein the controller circuitry is configured to set or adjust parameters of the electrical stimulation therapy signal using information regarding a drug dosage of the patient's drug therapy.

13. The system includes a sleeve wearable on the patient; 2. The system of claim 1, wherein the sleeve includes the first and second skin electrodes configured to be secured to the patient at the patient's leg and a plurality of electrical contacts in a first configuration to receive signals from the electrical stimulation electronics unit.

14. 14. The system of claim 13, further comprising the electrical stimulation electronics unit including a plurality of electrical contacts in a second configuration that matches the first configuration.

15. 2. The system of claim 1, wherein the sensory nerves for the patient's tibialis anterior region, the gastrocnemius region, the rectus femoris, and the biceps femoris include at least one of the sural nerve, the peroneal nerve, and the femoral nerve, or at least one branch thereof.

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