Delivering electrostimulation with drug therapy to treat restless legs syndrome

Abstract

This document describes a technique for evaluating therapy in patients with Restless Legs Syndrome (RLS). The technique can involve receiving a metric indicative of drug therapy administration and first sensor data that reflects leg movement or sleep quality during a desired relief period from RLS symptoms. A drug therapy efficacy indicator can be generated, such as based on the first sensor data and isolated from electrostimulation therapy effects. Such an indicator can assist a user or processes in evaluating the therapy's effectiveness for the patient. Such a technique can provide a systematic approach to assess the efficacy of drug therapy in managing RLS symptoms, enabling personalized treatment adjustments and improved patient outcomes.

Description

DELIVERING ELECTROSTIMULATION WITH DRUG THERAPY TOTREAT RESTLESS LEGS SYNDROMEPRIORITY

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 554,740, filed February 16, 2024, which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Restless Legs Syndrome (RLS) is a neurological condition that can impact sleep quality and overall quality of life for those affected. RLS can involve an urge to move the legs or uncomfortable sensations, each typically occurring during periods of rest or inactivity. This condition can cause sleep disturbances and can be addressed, e.g., via pharmacological interventions. Drug therapy for RLS can include dopamine agonists, opioids, or other medications aimed at alleviating symptoms.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] In the drawings, which are not necessarily drawn to scale, like numerals can describe similar components in different views. Like numerals having different letter suffixes can represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

[0004] FIG. 1 is a chart representing an iterative process of discovering interactions of various therapies with RLS symptoms.

[0005] FIG. 2 is a flowchart showing an example of a technique for electrostimulation during adjusting of medication for an RLS patient.

[0006] FIG. 3A is a chart showing exemplary approaches to delivering electrostimulation concurrent to drug therapy in attempt to reduce RLS symptoms.

[0007] FIG. 3B is a chart showing exemplary approaches to delivering electrostimulation concurrent to drug therapy in attempt to reduce RLS symptoms.

[0008] FIG. 4 depicts an example of a leg-wearable electrostimulation device.

[0009] FIG. 5A depicts an example of a leg-wearable electrostimulation device for wearing on a patient limb.

[0010] FIG. 5B depicts an example of leg-wearable electrostimulation device as worn on a patient limb.

[0011] FIG. 6 is a schematic diagram of an example of an electrostimulation electronics unit of an electrostimulation device.

[0012] FIG. 7 is a flowchart showing an example of a technique for delivering electrostimulation concurrent with adjusting a drug therapy.

[0013] FIG. 8 depicts a block diagram of an example of a machine.DETAILED DESCRIPTION

[0014] Restless Legs Syndrome (RLS) can significantly impact a patient's quality of life by disrupting sleeping patterns, e.g., leading to restless nights involving repeated involuntary leg movement. For example, sleep-related symptoms for patients with RLS, e.g., characterized by periodic limb movements (PLMs), can disrupt sleep quality and result in decreased sleep efficiency and excessive daytime sleepiness, e.g., leading to frequent nocturnal awakenings from to a perceived urge to move. Patients with RLS can also experience other symptoms such as tingling, burning, itching, and tugging sensations in the legs. Such symptoms can result in a significant reduction in quality of life, which can lead to decreases in daily activities and productivity and increases in depression and anxiety. Furthermore, the constant urge to move can cause individuals to experience fatigue and exhaustion, making it difficult for them to concentrate during the day. Approaches to mitigating symptoms of RLS can include drug therapy including administering at least one medication, e.g., a dopamine agonist (e.g., ropinirole, pramipexole), an opioid (e.g., methadone or oxycodone), an alpha- 2-delta ligand, a benzodiazepine, an anticonvulsant (e.g., gabapentin), an anti-seizure drug (e.g., levetiracetam), or a combination thereof. Approaches to treating RLS via drug therapy can raise concerns of a patient being medicated on long-term basis or for the patient to risk possible adverse side effects or dependencies. Further, some patients do not adequately respond to one or more medications for treating RLS.

[0015] One particular challenge to some drug therapy approaches for treating RLS is that a patient can become refractory over time to certain drugs. For example, dopaminergic drug therapy can lead to a tolerance of a primary medication (e.g., a dopamine agonist), involving that an RLS patient continually increase a dosage of the primary medication over time to maintain a similar therapeutic effect. In response to tolerance of the primary medication, a secondary medication (e.g., an anti-convulsant, an opioid, or a benzodiazepine) can be administered to the RLS patient, such as to supplement therapy as the primary medication becomes less effective or is downtitrated. However, certain secondary medications can involve especially undesirable side-effects, sometimes inhibiting a practicality of moving entirely to the second medication or further increasing a dosage of the secondary medication. Further, it can be difficult to effectively ween an RLS patient off certain medications, e.g., to supplement or replace a primary medication with a secondary medication or another therapy and without inducing or reintroducing undesired side effects. One reason for this is it can be challenging to predict an individualistic therapeutic effect, on any given particular patient, of downtitrating a medication. It can be similarly challenging to predict when a symptom (previously inhibited by a primary medication) will resurface following downtitration of the primary medication and to quickly mitigate the reemerging symptom via a secondary medication or therapy.

[0016] This document describes a technique to help overcome challenges of certain approaches to drug therapy by introducing a different, secondary therapy (e.g., electrostimulation) to help treat RLS. Such a technique can involve collecting and analyzing patient data, during application of the secondary therapy, to help mitigate symptom resurfacing, e.g., after reducing a primary medication. For example, the patient data can include sensor datafrom a leg-wearable electrostimulation device and the patient data can be indicative of a patient's leg movements or sleep quality during a target time period. This technique can help facilitate continuously and objectively monitoring of patient symptoms and adjusting of at least one therapy (e.g., a supplemental electrostimulation therapy) based on the monitored patient symptoms. Further, this technique can involve a generation of a drug therapy efficacy indicator, based on the sensor data, providing an objective measure of the drug's performance. In an example, the drug therapy efficacy indicator can be at least partially distinguishable from concurrent therapeutic effects of the supplemental electrostimulation therapy. Alternatively or additionally, altering drug therapy parameters based on the drug therapy efficacy indicator, such as via transdermal drug release, can help mitigate the challenge of dynamically adjusting treatment in response to real-time efficacy data. In an example, the drug therapy efficacy indicator can be provided to the patient or a healthcare provider, offering valuable insights that can guide treatment decisions, such as adjusting medication dosages or exploring additional treatment options. Such a technique can facilitate tailoring one or more therapies based on symptom severity, medication timing, and the integration of electrostimulation therapy, to help improve patient care and treatment outcomes.

[0017] FIG. 1 is a chart representing an iterative process of discovering interactions of various therapies with Restless Legs Syndrome (RLS) symptoms. For certain patients who have already experienced relief from symptoms of RLS via a pharmacological drug therapy (e.g., dopaminergic therapy), it can be desirable to reduce a dosage or frequency a medication included in the drug therapy. For example, long-term usage of a dopamine agonist, while initially providing short-term relief for RLS symptoms, can occasionally promote augmentation or eventual worsening of RLS symptoms. Also, certain drug therapies (e.g., dopaminergic medications, opioids, etc.) can involve undesired side effects. For example, table 1 shows a list of dopaminergic medications for RLS treatment, an exemplary daily dosage for treating RLS, and possible undesired side effects of each medication.

[0018] Table 1: Dopaminergic medications for RLS treatmentMedication Daily Dose Rate Possible Side EffectsLevodopa / dopa- 100 / 25-400 / 100 mg Diarrhea, nausea, decarboxylase dyspepsia, reduced inhibitor general drive, muscle weakness, somnolence, headachePramipexole 0.125-0.75 mg Nausea, dizziness, fatigue, somnolence, headache, orthostatic hypotensionRopinirole 0.25-4 mg Nausea, dizziness, fatigue, somnolence, headache, orthostatic hypotensionRotigotine 1-3 mg Nausea, dizziness,(transdermal patches) fatigue, somnolence, headache, orthostatic hypotension.Cabergoline 0.5 - 2.0 mg Nausea, dizziness, fatigue, somnolence, headache, orthostatic hypotension, cardiac valvular diseasePergolide 0.25-0.75 mg Nausea, dizziness fatigue, somnolence,headache, orthostatic hypotension, cardiac valvular disease

[0019] Downtitrating, such as reducing a dose (e.g., a specified portion) or dosage (e.g., number, frequency duration, or periodicity of doses) of the medication included in the drug therapy will generally cause resurfacing or reemergence of at least one RLS symptom that was previously mitigated by the medication at a prior titration. Thus, it can be desirable to supplement or replace the reduced medication with an alternative medication or therapy. For example, transcutaneous electrostimulation therapy can be introduced to the patient, following the downtitrating of the medication, to help offset the effect of the downtitration. Herein, “electrostimulation therapy” can refer to any suitable electrical stimulation, neurostimulation, or electrotherapy which is not a medication, but which can help alleviate or offset RLS symptoms. As described herein, “RLS Symptoms” can also include, refer to, or be interchangeably used with “Periodic Limb Movement Disorder (PLMD) Symptoms”. For example, similar or the same therapies described herein with respect to RLS can be applied to treat a symptom of PLMD, and in certain cases and RLS patient and a PLMD patient can exhibit similar or overlapping symptoms. Thus, although the present disclosure generally refers to RLS symptoms, it is not intended to be limiting or excluding of any symptoms of PLMD or other similar sleep disorders. Such electrical stimulation or electrotherapy can involve applying an electrical current or voltage to the patient to stimulate nerves, muscles, or other tissue. Such electrostimulation therapy can include or use an high frequency (HF) electrostimulation waveform at a frequency between about 500 Hz to about 10,000 Hz (or even more particularly, between about 3 KHz and about 5 kHz) and at a current between about 5 milliamps (mA) and about 50 mA, such as for treating Restless Legs Syndrome (RLS), such as described in Raghunathan U.S. Patent No. 10,242,977, which is hereby incorporated by reference herein in its entirety for its teaching of HF electrostimulation.

[0020] As shown by the sequence of steps 102, 104, 106, 108, and 110 of FIG. 1, it can be challenging to predict or forecast a resurfacing or reemergence of the at least one RLS symptom upon reducing the medication. For example, steps 102, 104, 106, 108, and 110 can represent a sequence of different sleep sessions in succession and can be characteristic of a “trial-and- error” approach to replacing at least a portion of medication with electrostimulation therapy. For example, steps 102, 104, 106, 108, and 110 can each occur across different nights, e.g., one or more steps occurring across consecutive nights. Also, steps 102, 104, 106, 108, and 110 can take place during select nights over the course of one or several months, e.g., according to a drug therapy plan. At 102, one or more patient symptoms can be observed, monitored, recorded, or otherwise received over a first sleep session. Based on the received one or more RLS symptoms, at 104 a drug therapy can be calculated and administered (e.g., at a full or peak dose or dosage) to help mitigate the symptoms exhibited in 102. For example, a healthcare provider can review the received one or more symptoms and prescribe a first titration (e.g., dose, dosage, etc.) based on the duration, timing, or severity of the one or more symptoms. In an example, step 104 can include one or more substeps for adjusting the first titration of the drug medication such that symptoms are adequately mitigated (e.g., RLS symptoms remain below a sleep threshold or a perception threshold) via the medication alone and without supplemental RLS therapy.

[0021] Optionally at step 106, an indication of the patient’s individualistic neural response to electrostimulation can be measured, e.g., to help calibrate the electrostimulation for a subsequent step (such as step 110). For example, one or more RLS or PLMD sensors (e.g., EMG, accelerometer, etc.) can be applied to monitor RLS or PLMD symptoms (e.g., remove, jerk, etc.) while a waveform generator implements electrostimulation. For example, an approach for personalizing electrostimulation therapy and measuring an individualistic neural response is described in Charlesworth U.S. Patent No. 11,103,691, which is incorporated by reference herein in its entirety. In an example, one or more parameters (frequency, current, duty cycle, etc.) of the electrostimulation waveform can be established or adjusted based on anindication of the patient’s individualistic neural response to the electrostimulation. Generally, the indication of the patient's neural response is measured during an absence of RLS symptoms, e.g., since the symptoms are repressed via the drug therapy. Alternatively, the indication of the patient's neural response can be measured within a duration where the patient is not fully experiencing the intended therapeutic effect of the medication (e.g., below a specified half-life of the medication).

[0022] At step 108, the medication of the drug therapy can be downtitrated, which can cause one or more RLS symptoms to resurface or reemerge. It can be challenging to predict the actual effect on RLS symptoms that a specified downtitration (e.g., whether reducing a dose, reducing a frequency, altering a type of medication, etc.) will elicit. Generally, as shown in step 108, reducing drug therapy involves monitoring, e.g., after commencing the downtitration, to determine when during an individual sleep session, the patient will experience symptoms attributable to the downtitration. A challenge with this approach is that the patient must experience the symptoms after the downtitration for these symptoms to be recognized and addressed, complicating reducing, replacing, or supplementing a drug therapy with an alternative therapy such as electrostimulation. Then, at step 110, a schedule and target parameters for electrostimulation can be determined based on the observed one or more RLS symptoms. The present inventors have recognized it would be advantageous to control medication downtitration and electrostimulation concurrently to help anticipate reemerging RLS symptoms and to help avoid a need to perform step 108.

[0023] FIG. 2 is a flowchart showing an example of a technique 200 for electrostimulation during adjusting of a medication for an RLS patient. The technique 200 can be implemented using one or more devices or systems described herein, such as the electrostimulation therapy system 400 of FIG. 4, the electrostimulation electronics unit 404 of FIG. 6, the processor 802 of FIG. 8, etc. Two particular patient responses can be difficult to predict during adjusting of the medication and to at least partially supplant it with electrostimulation. First, it can be difficult to identify therapeutic gaps during a sleep session after reducing drug therapy, such that they can be addressedvia electrostimulation before symptom onset. Second, it can be difficult to calibrate an electrostimulation waveform (e.g., to "prime" the waveform for filling the therapeutic gaps) without feedback related to the impact of the waveform on RLS symptoms. This is because typically, during such calibration, the patient is not experiencing symptoms and instead is relieved via the drug therapy. The present exemplary technique helps predict such patient responses. For example, the technique can involve receiving a drug therapy metric indicative of administering a drug (e.g., a timing, dose, dosage, indication of downtitration, etc.). Sensor data can be received during a target time period, and a drug therapy efficacy indicator can be generated based on the first sensor data and for the patient corresponding to the target time period. Here, the drug therapy efficacy indicator can be distinguishable (e.g., able to be differentiated or generated in isolation) from therapeutic effects of electrostimulation therapy. The drug therapy efficacy indicator can then be provided to a user or process for assisting in evaluating therapy to the patient. Such a technique can incorporate a plurality of known variables (e.g., data from one or more of inputs 204, 206, 208, and 210 of FIG. 2) available before adjusting of the medication. Also, the technique can also incorporate physiological or patient-subjective feedback (e.g., one or more of inputs 216, 218, and 220), e.g., received concurrent with or following the adjusting of the medication.

[0024] At operation 202, data, including at least one drug therapy metric or electrostimulation calibration data, can be received before a present medication adjustment, such as a downtitration. For example, the drug therapy metric can include information about the type of medication the patient is taking for RLS, such as any of a type of medication 204, a minimal quantal dose 206 of the medication, or a typical or expected half-life 208 of the medication. For example, the type of medication 204 can include, e.g., a dopamine agonist (e.g., ropinirole, pramipexole), another dopaminergic medication (e.g., as listed above in table 1), an opioid (e.g., methadone or oxycodone), an alpha-2-delta ligand, a benzodiazepine, an anticonvulsant (e.g., gabapentin), an anti-seizure drug (e.g., levetiracetam), or a combination thereof. The minimal quantal dose 206 can be a smallest-intended division ofa medication (e.g., a 5 milligram (mg) can be broken in half once, such as via physician instruction and by a user, and have a minimal quantal dose 206 of about 2.5mg). The drug therapy metric can also include an indication of a duration of electrostimulation relief 210 which can be determined via a baseline calibration of the electrostimulation waveform (e.g., as described respect to step 106 of FIG. 1. For example, the indication of the duration of electrostimulation relief 210 can include a patient-specific to electrostimulation (e.g., from a diagnostic test) and can be used to help determine how long the electrostimulation would provide relief from RLS symptoms. In an example, the indication of the duration of electrostimulation relief 210 can be collected or received during a time where the patient is not experiencing RLS symptoms or RLS symptoms are concurrently mitigated via a drug therapy. Additional information such as a present dose of the medication, the time of a most recent dose of the medication, a cumulative amount of the medication administered over a given time period, etc. can also be included within the drug therapy metric. Information about the RLS patient's susceptibility to RLS or reactivity to a previously administered medication can also be considered within the drug therapy metric. The drug therapy metric can additionally include an age, weight, sex, body-type, body mass index (BMI), RLS index, or information about a prior sleep quality or duration of neuromodulation for a particular patient. In an example, the drug therapy metric can be received prior to any specified downward adjustment of the medication (e.g., a specified downtitration from a previous night). Here, the drug therapy metric can be used to help establish a patient- specific electrostimulation therapy baseline which can adjusted downstream based on later feedback and data. For example, the patient-specific electrostimulation therapy baseline can factor a plurality of inputs, such as any of 204, 206, 208, and 210, to help “prime” electrostimulation therapy parameters or to predict (e.g., provide a relatively rough approximation) a severity or timing of symptom reemergence for a particular patient.

[0025] At operation 212, medication adjustment can be commenced. In an example, the medication adjustment 212 can include triggering a message to a user or a physician that a patient-specific electrostimulation therapy baselinehas been determined and that medication adjustment may be commenced. The medication adjustment 212 can also include receiving an indication that medication adjustment has commenced, such as via a patient-accessible user input or a command from software exclusively accessible by a physician or a pharmacy technician. Alternatively or additionally, at operation 212 the technique 200 can include actually triggering or controlling release of a specified dose of the medication (e.g., via a transdermal drug releasing patch, a prescribed dose-metered drug dispensing system, or other medication compliance system). In an example, controlling the specified dose of the medication via a transdermal drug releasing patch can include modulating a permeability of the transdermal drug delivery unit or generating a drug release waveform (e.g., via an electrostimulation device) configured to establish a voltage gradient and to modulate transdermal drug release to the patient. Also, the medication adjustment 212 can also include providing or generating a notification, vibration, or signal, which can, e.g., cue a patient to take medication, or warn them that medication is beginning to be released.

[0026] At operation 214, feedback data, e.g., concurrent with the prior medication adjustment 212, can be received. Generally, the feedback data is indicative of a sleep quality, leg movement during sleep, or other RLS symptom indication and corresponds with or correlates with the the medication adjustment 212. The feedback data can include sensor data 216 (e.g., motion data, accelerometer data, internal measurement unit (IMU) data, heart rate variability (HRV) data, electrode impedance data, etc.). For example, an approach for receiving sensor data indicative of a sleep quality or leg movement during sleep is described in Charlesworth U.S. Patent No. 11,878,166, which is incorporated by reference herein in its entirety. Sensor data 216 can also include electroencephalographic (EEG) data, electromyogram (EMGs) data, eye movement (EOG) data, respiratory data, or features arising from a polysomnography (PSG) sleep assessment.

[0027] The feedback data can also include patient-subjective feedback 218, such as a rating, ranking, or other characterization of a sleep quality or an estimate of a time frame in which the patient is experiencing undesired leg movements during a time which the patient desires to sleep. For example, thepatient-subjective feedback 218 can include patient-reported information about leg movements during sleep (e.g., patient goes to bed at 9:00 PM; at 10:00 PM she begins experiencing significant symptoms or difficulties; and then her symptoms are mitigated or settle around 3:30 am). The patient- subjective feedback 218 can also include include a reporting of a patient's sleep quality (e.g., a choice between two or more statements, such as “my sleep was terrible last night”; or, “I woke up refreshed and comfortable”). Additionally, or alternatively, the patient-subjective feedback 218 can include sleep study measurement data (e.g., a sleep diary or observational records), or be gathered via a standardized inventory (e.g., Restless Legs Syndrome Quality of Life Questionnaire (RLSQoL)).

[0028] The feedback data can further include medication administration data 220. For example, the medication administration data 220 can be a self-report of a patient's compliance with drug therapy (e.g., a patient may respond when they administer a medication during a specific day: “8: 10 am medication”; or, “I forgot to take my pills but I took them the following day immediately when I remembered”). Medication administration data 220 can also include measured data (e.g., a medication dispensed meter or data from or monitoring an element of the patient's bodily fluids (e.g., blood glucose measurements, blood plasma, etc.). Such data can further be analyzed with a model characterized by a parametric pharmacokinetic model or a non-parametric metabolic pharmacokinetic model to help determine an absorption or other metric of a patient’s medication intake.

[0029] At operation 222, at least one RLS symptom can be predicted or forecasted during sleep, e.g., based at least in part on the feedback data of operation 214 and the received, pre-adjustment data from operation 202. In an example, such prediction can be performed without concurrent or present measurement of a patient's electrostimulation-therapy effectiveness. The RLS symptom prediction can be performed, e.g., using an artificial neural-network, logistic regression analysis, a hidden Markov model, a multivariable regression model, a k-nearest neighbors (KNN) algorithm, or a combination thereof. The RLS symptom prediction can be performed, e.g., via using the feedback data to help adjust a hypothetical patient-specific electrostimulationtherapy baseline generated from the pre-adjustment data at operation 202. In an example, the prediction can yield a rough approximation (e.g., a bestestimate or maximum likelihood estimator based on the data) of when during a sleep session a patient will experience undesired leg movements or other another sleep disruption. For example, the prediction can include identifying a session time interval, based on a least one of the feedback data (e.g., the sensor data 216, the patient-subjective feedback 218, the medication administration data at 220) and patient-derived feedback or patient physiological parameters. Here, identifying a session time interval can include, e.g., predicting a time window in which the patient can experience a therapeutic significant quantity of leg movements or sleep disturbances. Herein, a “therapeutic significant quality of leg movements’' can be defined as indicative of an RLS patient experiencing leg movements during a sleep session e.g., about 25-50 occurrences of leg movement or, e.g., including a leg movement or series of continuous leg movements having a duration beyond about 15 seconds.

[0030] In an example the prediction can be based on real-time differences between sensor data from the patient at different target times before the sleep session. In an example, the differences can include or involve comparisons of modeled data input against live sensor data which provides hysteresis to capture waning effects of medication (e.g., as the dosage the medication decreases or symptom intensity increases) or anticipate reemerging symptoms (which can occur after a medication fades in concentration or structure). Optionally, upon identification of the time window, operation 222 can establish or adjust one or more electrostimulation therapy parameters for delivering electrostimulation therapy at the target window identified. In an example, the established or adjusted one or more electrostimulation therapy parameters can be provided even before the moment in which the undesired leg movements or RLS symptoms emerge or are experienced by the patient (e.g., as determined via session time interval), such that the RLS patient can avoid an impact of symptom onset on sleep quality.

[0031] At operation 224, the technique 200 can involve recommending, based on the predicted RLS symptom, an additional change in medication dose(e.g., a change in the rate of downtitration) or a change in the one or more electrostimulation therapy parameters. For example, the recommending the additional change can include displaying the recommendation (e.g., on a user interface) to a patient-user or a physician. Alternatively or additionally, the recommendation can include transmitting the recommendation to a physician, pharmacy, or other medical database e.g., via a secure communication network. The recommendation can itself involve one or more dosages, dosages at specific target windows before or after an individual sleep session, or particular intervals or schedules in which the dosage is recommended. In an example, the recommending the dosage can involve providing a least one dosage as a fixed dosage or as a function of patient-derived data or time after the medication adjustment via operation 212. The dosage provided can also be based on a previously recorded or predicted severity or mitigability of RLS symptom based on the drug therapy metric from operation 202. In an example, the one or more dosages to potentially provide can be ranked based on their expected effectiveness in minimizing or tolerating RLS symptoms for a particular patient before being provided or administered. In an example, the recommendation at operation 224 can include providing increased electrostimulation waveform intensity during predicted symptomatic time window or during a time from otherwise corresponding with leg motion (a time frame mentioned or indicated in feedback collected for a particular patient). Optionally, following the recommendation at operation 224, the medication can be adjusted according to the recommendation and the technique 200 can involve recycling through operations 212, 214, 222, and 224 once again. For example, operations 212, 214, 222, and 224 can be performed repeatedly in a loop or continuously during an individual sleep session of the patient.

[0032] FIG. 3 A and FIG. 3B are each charts showing exemplary approaches to delivering electrostimulation concurrent to drug therapy in attempt to reduce RLS symptoms. Such approaches can include one or more operations from the technique 200 as described above with respect to FIG. 2. FIG. 3A and FIG. 3B each represent responses for different respective patients. Each chart in FIG. 3 A and FIG. 3B depicts three separate timelines: a baseline 310,316, a first approach 312, 318, and a second approach 314, 320. Each separate timeline can each occur during a separate day or a separate sleep session, and the timelines 310, 312, and 314 or 316, 318, and 320 can occur as a sequence of sleep sessions or consecutive sessions. In FIG. 3A and FIG. 3B, the height (y axis) of each of the drug therapy, RLS symptoms, and electrostimulation can represent a relative magnitude (e.g., intensity, dose etc.) of each respective condition. Approaches characterized by FIG. 3A and FIG. 3B can show patient-specific responses to various therapy measures, and such responses can vary greatly from patient to patient based on a specific patient's physiology, drug tolerance, and sleep patterns / schedules.

[0033] As shown in FIG. 3 A, at the baseline 310 a drug dose (e.g., before downtitration of the medication) can include about 10 milligrams (mg) of a medication (e.g., Methadone) daily, e.g., specified as a dosage of about 5 milligrams administered at or near a first time (e.g., at about 5:00 pm) and about 5 milligrams administered at or near a second time (e.g., at about 10:00 pm). As shown in the timeline at baseline 310, such a drug dosage as a sole therapy for RLS can essentially mitigate all RLS symptoms during the time frame (e.g., an individual sleep session). The first approach 312 to downtitrating the medication can involve reducing the dosage of the medication from about 10 mg daily to about 5 mg daily, e.g., specified as about 2.5 mg administered at or near the first time and about 2.5 mg administered at or near the second time. During the first approach 312 and after commencing downtitrating of the medication, electrostimulation can be administered, e.g., after an onset of RLS symptoms. For example, the electrostimulation can be administered at a third time (e.g., about 6:00 pm) between the first time and the second time. In an example, such a first approach 312 can result in RLS symptoms generally occurring from about 7:00 pm and until about 10:00 pm. Such prolonged occurrence of RLS symptoms can be distracting and even unacceptable for certain RLS patients.

[0034] The second approach 314 to downtitrating the medication can involve reducing the dose of medication from about 10 mg daily to about 5 mg daily, e.g., specified as a dosage of about 5 mg administered at or near the first time and about 0 mg administered at or near the second time. During the secondapproach 314 and after commencing downtitrating of the medication, electrostimulation can be administered, e.g., at or near the second time or rapidly (e.g., in less than about 5 minutes) after an onset of RLS symptoms. Here, the combination of the downtitrated medication (at or near the first time) and the electrostimulation (at or near the second time) can generally mitigate RLS symptoms such that RLS symptoms only occur under a specified threshold (e.g., less than 20 minutes), such as from about 10:15 pm to about 10:30 pm. As indicated by the second approach 314, replacing a medication with electrostimulation can be more effective at RLS symptom mitigation when occurring later at night, e.g., when the patient has reached a certain sleep stage. The temporal relationship between when electrostimulation occurs during the sleep session can be fine-tuned to match each individual patient's sleep patterns for more optimal RLS symptom mitigation.

[0035] As shown in FIG. 3B, at the baseline 316 a drug dose (e.g., before downtitration of the medication) can include about 15 milligrams (mg) of the medication daily, e.g., specified as a dosage of about 5 milligrams administered at or near a first time (e.g., at about 8:00 am), about 5 mg administered at or near a second time (e.g., at about 3:00 pm), and about 5 mg administered at a third time (e.g., at about 10:00 pm). As shown in the timeline at baseline 316, such a drug dosage as a sole therapy for RLS can essentially mitigate all RLS symptoms during the time frame (e.g., an individual sleep session). The first approach 318 to downtitrating the medication can involve reducing the dosage of the medication from about 15 mg daily to about 10 mg daily, e.g., specified as about 5 mg administered at or near the first time, about 5 mg administered at or near the second time, and about 0 mg administered at or near the third time. During the first approach 316 and after commencing downtitrating of the medication, electrostimulation can be administered, e.g., at or near the third time or after an onset of RLS symptoms. For example, the electrostimulation can cause RLS symptom relief for a time period between about 60 minutes (min) and about 90 min during the timeline of the first approach 316. In an example and as depicted in FIG. 3B, such an approach can lead to recurring RLS symptoms can not being entirely mitigated by the electrostimulation therapy. In some circumstances, such anoccurrence of RLS symptoms can be distracting and even unacceptable for certain RLS patients. In other circumstances, such relief provided by the electrostimulation after the onset of RLS symptoms can be tolerable or acceptable to adequately treat RLS or maintain a sleep quality of the patient during downtitrating of the medication.

[0036] The second approach 320 to downtitrating the medication can involve reducing the dose of the medication from about 15 mg daily to about 10 mg daily, e.g., specified as a dosage of about 5 mg administered at or near the first time, about 0 mg administered at or near the second time, and about 5 mg administered at or near the third time. During the second approach 320 and after commencing downtitrating of the medication, electrostimulation can be administered, e.g., at or near the second time and rapidly (e.g., in less than about 5 minutes) after an onset of RLS symptoms. For example, the electrostimulation can cause RLS symptom relief for a time period between about 60 minutes (min) and about 90 min during the timeline of the second approach 320. Also, as shown in FIG. 3B, the electrostimulation can be administered a plurality of times (e.g., twice) during the second sleep session, e.g., at about 4:00 pm and at about 7:00 pm. Here, the combination of the downtitrated medication (at or near the first time and third time, respectively) and the electrostimulation (at or near the second time) can generally mitigate RLS symptoms such that RLS symptoms only occur under a specified threshold (e.g., less than 20 minutes). As indicated by the second approach 320, replacing a medication with electrostimulation can be more effective at RLS symptom mitigation when occurring directly between a plurality of drug administrations and can be even more effective at RLS symptom mitigation during a patient's waking state.

[0037] FIG. 4 depicts a perspective view of a wearable electrostimulation device. In an example, an electrostimulation therapy system 400 can include a wearable electrostimulation device 402, an electrostimulation electronics unit 404, and one or more electrostimulation electrodes 406. The wearable electrostimulation device 402 can function to deliver electrostimulation therapy to skin of a subject via the electrode pads 410 which help form the electrodes 406. In an example, the electrode pads 410 can be removablycouplable to the wearable electrostimulation device 402. The electrode pads 410 can each be attached to a pairing surface 422 of the wearable electrostimulation device 402. The pairing surface 422 can include the electrode terminal 408 e.g., disposed therein, and the electrode terminal 408 can be electrically connected to the electrostimulation electronics unit 404. In an example, two or more electrode pads 410 are each paired to corresponding pairing surfaces 422 including one electrode terminals 408. In another example, one electrode pad 410 can be paired to an electrode pairing surface 422 containing more than one electrode terminal 408, or one electrode pad can span multiple electrode pairing surfaces 422 containing one or more electrode terminals 408. The electrode pad 410 can be removed for, e.g., hygienic maintenance, electrode maintenance such as rehydrating, or disposal.

[0038] The wearable electrostimulation device 402 can be worn by the subject and can include or use the electrostimulation electronics unit 404 coupled to the electrodes 402, such as for transcutaneously delivering an electrostimulation waveform. The wearable electrostimulation device 402 can be sized and shaped to be able to be attached or held to a body location of the subject, e.g., a leg, arm, foot, waist, neck, head, or chest of the subject. In an example, the wearable electrostimulation device 402 can include or use a strap to help hold the electrodes 406 to the skin of the subject. While electrodes are generally described herein with a focus on providing electrostimulation to a subject, the electrodes can alternatively or additionally be used such as to help detect or measure one or more biosignals or biopotentials from the subject. A particular electrode 406 can include or use an electrode terminal 408 and an electrode pad 410. For example, the electrode terminal 408 can receive a capacitively-coupled (e.g., coupled using series DC-blocking capacitors, e.g., in a charge-balanced arrangement) electrostimulation waveform from the electrostimulation electronics unit 404, and can deliver a resulting electrostimulation waveform to the skin of the subject, such as via the electrode pad 410. In an example, multiple electrodes, such as two electrodes 406, can be used. For a bipolar electrode example having two electrodes 406, this can a first electrode that can serve as an anode and a second electrode, such as which can serve as a cathode. Also, a pluralityof electrodes 406 can be arranged to form a multi-electrode group, matrix, or array such as for one or both of sensing or for delivering the electrostimulation waveform to the skin of the subject. In an example, each electrode terminal 408 can be an electrode contact fixed to the wearable electrostimulation device 402 and each corresponding electrode pad 410 can be removably couplable to the device 402. In other examples, the electrode pad can be fixed to the wearable electrostimulation device 402. Because the current density of the electrostimulation waveform at the electrode terminal 408 may be larger than desired, the electrode pad 410 can include an embedded or other arrangement of electrical conductors that can help distribute the electrostimulation waveform current over a larger effective surface area for delivery to the subject at the skin-electrode interface. The electrode pad can be formed of a hydrogel, a hydrophilic polymer such as polyvinyl alcohol (PVA), carbon, textiles, or other types of conductive or dielectric gels, polymers, or textiles.

[0039] The electrode terminal 408 can supply an alternating current (AC) electrostimulation waveform for delivery to the skin by the electrode 406. The electrostimulation waveform can be supplied by the electrode terminal 408 at a frequency between about 500 Hz to about 10 kHz such as for treating Restless Legs Syndrome (RLS). The wearable electrostimulation device 402 can include or use capacitive coupling such as to inhibit a direct current (DC) waveform at the electrode terminal 408 while communicating an AC waveform. In an example, the capacitive coupling includes one or more capacitors included in series between each electrode terminal 408 and the electrostimulation electronics unit 404. The one or more capacitors can also be included in series between each electrode terminal 408 and the battery of the electrostimulation electronics unit 404. The electrostimulation waveform can be delivered from the electrode terminal 408 to the skin through the electrode pad 410 disposed therebetween.

[0040] FIG. 5A and FIG. 5B each depict an example of a leg-wearable electrostimulation device for wearing on a patient limb. In an example, the leg-wearable wearable electrostimulation device 402 can be sized, shaped, and components arranged thereon for wear on a patient's leg. For example, the device 402 can be worn on a lower region (e.g., at or below a knee) of a patientleg, e.g., for transcutaneous stimulation at or near a nerve target including one of the peroneal nerve, the sural nerve, or a branch thereof. The device can 402 can also be worn on an upper region (e.g., above a knee) of a patient leg for transcutaneous stimulation at or near the femoral nerve or a branch thereof. For example, the electrode pads 410 can adhere to a patient skin such that an electrostimulation waveform from the terminals 408 is coupled to the patient skin and the electrodes 406 deliver an electrostimulation waveform to the nerve target. In an example, the electrostimulation electronics unit 404 can be sized, shaped, and otherwise configured to close to the patient leg. For example, the electrostimulation electronics unit 404 can include circuitry for generating the waveform while remaining adequate in terms of form factor, energy efficiency, and heat dissipation, for wear directly on a patient's bare leg-

[0041] FIG. 6 is a schematic representation of portions of an example of a wearable electrostimulation device. An example wearable electrostimulation device can include an electrostimulation electronics unit 404, electrode terminals 408, and electrode pads 410. The electrostimulation electronics unit 404 can be configured to produce a controlled-current waveform (e.g., specified constant current amplitude AC electrostimulations) across a varying impedance present at an interface between the electrostimulation electrodes 406 and the skin or other tissue of the subject contacted by such electrostimulation electrodes 406.

[0042] The electrostimulation electronics unit 404 can include a first amplifier Al 621 and a second amplifier A2 622 arranged to supply an electrostimulation waveform to first and second electrode terminals 408. In an example, the first amplifier Al 621 can include transconductance amplifier that can produce a first output waveform with a controlled or constant current and the second amplifier A2 can include a voltage amplifier that can produce a different second output waveform with a controlled or constant voltage. By driving the electrostimulation electrodes 406 via separate amplifiers, Al 621 and A2 622, the waveforms at the electrode terminals 408 can be smoothly controlled to be responsive to sudden changes in load impedance without introducing oscillations, e.g., caused by other approaches including twoconstant-current amplifiers counteracting each other through a capacitive load.

[0043] The electrostimulation electronics unit 404 can also include a first impedance detection circuit 607, e.g., configured for measuring or receiving an indication of a change in load impedance or an electrode-skin interface impedance at or near one or more of the electrostimulation electrodes 603. To help produce a constant-current output at the electrode terminals 408, the first impedance detection circuit 607 can provide a negative feedback loop from the output current of the first amplifier Al 621, the second amplifier A2 622, or both back to the first amplifier Al 621. In an example, the output current can be sensed by one or more sense resistors included in the first impedance detection circuit 607. The electrostimulation electronics unit 404 can also include or use waveform generation circuitry 614 included in or coupled to the controller circuitry 610. In an example, the waveform generation circuitry 614 can include waveform modulation circuitry or at least one waveform modulation component. Here, the waveform generation circuitry 614 can adjust, in response to a detected or measured indication of a threshold change in impedance, at least one parameter of the at least one HF electrostimulation waveform to adjust a current of the electrostimulation waveform. In an example, the battery can be electrically connected or otherwise interfaced to a step-up power converter circuit, e.g., including power management circuitry 608 and step-up converter circuitry 613, such as can generate a programmable output DC voltage (e.g., 12V, 20V, 30V, or other specified DC output voltage. The DC output voltage needed can be determined by the controller circuit 610.

[0044] The controller circuitry 610 can use information (e.g., accelerometer, sEMG, or temperature data) such as to determine the magnitude of the DC output voltage of the step-up converter circuitry 613 needed to generate the desired electrostimulations, such as to conserve battery power while providing or maximizing therapeutic efficacy of the electrostimulations. The controller circuitry 610 can establish one or more patterns of the desired electrostimulation, such as by using one or more stored electrostimulation waveform parameters that can be generated by the controller circuitry 610. The controller circuitry 610 can use the one or more stored electrostimulationparameters, such as to generate one or more analog electrostimulation control voltage waveforms, such as using a digital-to -analog (D / A) converter. The resulting one or more generated analog electrostimulation control voltage waveforms can be converted to a proportionate, controlled, load-independent current. The resulting controlled-current electrostimulation waveform can be routed, e.g., via an electrode interface, to a desired corresponding electrode terminal 408 and distributed to the skin of a subject via the corresponding electrode 406.

[0045] The electrostimulation electronics unit 404 can also include a second impedance detection circuit 609, e.g., configured for measuring or receiving an indication of a change in load impedance or an electrode-skin interface impedance at or near one or more of the electrostimulation electrodes 606. Such impedance information, e.g., including respective first and second indications of different first and second impedances, can be provided to processor / controller circuitry 610 for electrostimulation waveform parameter selection or adjustment. In an example, the second impedance detection circuit 319 can include one or more current sensing resistors, such as can sense a current at the electrodes.

[0046] In an example, the electrostimulation electronics unit can generate and deliver an electrostimulation waveform at a specified first current between 5 mA and 50mA. For example, the specified first current can be within a range of about 25mA and about 35mA. The specified first current can be determined based on an efficacy of a particular current at treating at least one symptom of RLS or determined tolerance of the subject. The specified first current can also be a benchmark or target current, and the benchmark current can be adjusted during an electrostimulation therapy session independent from the waveform generation circuitry 614 which facilitates constant-current output.

[0047] FIG. 7 is a flowchart showing an example of a technique 700 for delivering electrostimulation concurrent with adjusting a drug therapy. The technique 700 can be implemented using one or more devices or systems described herein, such as the electrostimulation therapy system 400 of FIG. 4,the electrostimulation electronics unit 404 of FIG. 6, the processor 802 of FIG. 8, etc.

[0048] At 702, a drug therapy metric, indicative of administering a drug, can be received. For example, the drug therapy metric can also include specific details such as the type of drug, the timing of administration, dose or dosage, duration of effect, and any titration information, such as an indication of a downward titration.

[0049] At 704, first sensor data can be received, the data indicative of leg movement or a sleep quality of the patient during a target time period for which relief from at least one of an RLS symptom is desired. In an example, such data collection is performed during the absence of electrostimulation administration, ensuring that the evaluation of the drug therapy is not influenced by other treatments.

[0050] At 706, a drug therapy efficacy indicator for the patient can be generated based on the first sensor data. The drug therapy efficacy indicator can correspond to the target time period. In an example, the drug therapy efficacy indicator can be generated in isolation from therapeutic effects of electrostimulation therapy. This drug therapy efficacy indicator can provide a detailed characterization of the patient's response to the drug therapy, such as multiple time fractions of the target time period or symptom severity. The drug therapy efficacy indicator can also include a composite indicator characterizing both the time fractions and symptom severity.

[0051] At 708, the drug therapy efficacy indicator can be provided to a user or process for assisting in evaluating therapy to the patient. In an example, the technique 700 can include generating a treatment protocol for drug or electrostimulation administration. Such a protocol can be informed by the drug therapy efficacy indicator and can include electrostimulation titration strategies to provide a high-frequency (HF) electrostimulation waveform, or an adjustment of the waveform based on an incline in symptom suppression efficacy. The technique 700 can also include establishing or adjusting the timing or duration of individual electrostimulation deliveries within the target time period, ensuring that the therapy is tailored to the periods when relief from symptoms is most needed or desired. In an example, the technique 700can include establishing or adjusting delivery parameters for a HF electrostimulation waveform based on the drug therapy metric and the sensor data. Also, based on a threshold composite efficacy indicator, one or more parameters of the drug therapy treatment can be altered. For example, the technique 700 can include controlling transdermal drug release from a unit locatable on the patient, modulating the unit's permeability, or generating a drug release waveform to establish a voltage gradient.

[0052] FIG. 8 illustrates generally an example of a block diagram of a machine 801 upon which any one or more of the techniques (e.g., methodologies) discussed herein may perform in accordance with some examples. In alternative embodiments, the machine 801 may operate as a standalone device or may be connected (e.g., networked) to other machines. In a networked deployment, the machine 801 may operate in the capacity of a server machine, a client machine, or both in server-client network environments. In an example, the machine 801 may act as a peer machine in peer-to-peer (P2P) (or other distributed) network environment. The machine 801 may be a personal computer (PC), a tablet PC, a set-top box (STB), a personal digital assistant (PDA), a mobile telephone, a web appliance, a network router, switch or bridge, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken by that machine. Further, while only a single machine is illustrated, the term “machine” shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein, such as cloud computing, software as a service (SaaS), other computer cluster configurations.

[0053] Examples, as described herein, may include, or may operate on, logic or a number of components, modules, or mechanisms. Modules are tangible entities (e.g., hardware) capable of performing specified operations when operating. A module includes hardware. In an example, the hardware may be specifically configured to carry out a specific operation (e.g., hardwired). In an example, the hardware may include configurable execution units (e.g., transistors, circuits, etc.) and a computer readable medium containinginstructions, where the instructions configure the execution units to carry out a specific operation when in operation. The configuring may occur under the direction of the executions units or a loading mechanism. Accordingly, the execution units are communicatively coupled to the computer readable medium when the device is operating. In this example, the execution units may be a member of more than one module. For example, under operation, the execution units may be configured by a first set of instructions to implement a first module at one point in time and reconfigured by a second set of instructions to implement a second module.

[0054] Machine (e.g., computer system) 801 may include a hardware processor 802 (e.g., a central processing unit (CPU), a graphics processing unit (GPU), a hardware processor core, or any combination thereof), a main memory 803 and a static memory 804, some or all of which may communicate with each other via an interlink (e.g., bus) 805. The machine 801 may further include a display unit 806, an alphanumeric input device 807 (e.g., a keyboard), and a user interface (UI) navigation device 808 (e.g., a mouse). In an example, the display unit 806, alphanumeric input device 807 and ui navigation device 808 may be a touch screen display. The machine 801 may additionally include a storage device (e.g., drive unit) 809, a signal generation device 810 (e.g., a speaker), a network interface device 811, and one or more sensors 812, such as a global positioning system (GPS) sensor, compass, accelerometer, or other sensor. The machine 801 may include an output controller 816, such as a serial (e.g., universal serial bus (USB), parallel, or other wired or wireless (e.g., infrared (IR), near field communication (NFC), etc.) connection to communicate or control one or more peripheral devices (e.g., a printer, card reader, etc.).

[0055] The storage device 809 may include a machine readable medium 813 that is non-transitory on which is stored one or more sets of data structures or instructions 814 (e.g., software) embodying or utilized by any one or more of the techniques or functions described herein. The instructions 814 may also reside, completely or at least partially, within the main memory 803, within static memory 804, or within the hardware processor 802 during execution thereof by the machine 801. In an example, one or any combination of thehardware processor 802, the main memory 803, the static memory 804, or the storage device 809 may constitute machine readable media.

[0056] While the machine readable medium 813 is illustrated as a single medium, the term “machine readable medium” may include a single medium or multiple media (e.g., a centralized or distributed database, or associated caches and servers) configured to store the one or more instructions 814.

[0057] The term “machine readable medium” may include any medium that is capable of storing, encoding, or carrying instructions for execution by the machine 801 and that cause the machine 801 to perform any one or more of the techniques of the present disclosure, or that is capable of storing, encoding or carrying data structures used by or associated with such instructions. Nonlimiting machine-readable medium examples may include solid-state memories, and optical and magnetic media. Specific examples of machine- readable media may include: non-volatile memory, such as semiconductor memory devices (e.g., Electrically Programmable Read-Only Memory (EPROM), Electrically Erasable Programmable Read-Only Memory (EEPROM)) and flash memory devices; magnetic disks, such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD- ROM disks.

[0058] The instructions 814 may further be transmitted or received over a communications network 815 using a transmission medium via the network interface device 811 utilizing any one of a number of transfer protocols (e.g., frame relay, internet protocol (IP), transmission control protocol (TCP), user datagram protocol (UDP), hypertext transfer protocol (HTTP), etc.). Example communication networks may include a local area network (LAN), a wide area network (WAN), a packet data network (e.g., the Internet), mobile telephone networks (e.g., cellular networks), Plain Old Telephone (POTS) networks, and wireless data networks (e.g., Institute of Electrical and Electronics Engineers (IEEE) 802.11 family of standards known as Wi-Fi®, IEEE 802.16 family of standards known as WiMax®), IEEE 802.15.4 family of standards, peer-to- peer (P2P) networks, among others. In an example, the network interface device 811 may include one or more physical jacks (e.g., Ethernet, coaxial, or phone jacks) or one or more antennas to connect to the communicationsnetwork 815. In an example, the network interface device 811 may include a plurality of antennas to wirelessly communicate using at least one of singleinput multiple-output (SIMO), multiple-input multiple-output (MIMO), or multiple-input single-output (MISO) techniques. The term “transmission medium” shall be taken to include any intangible medium that is capable of storing, encoding or carrying instructions for execution by the machine 801, and includes digital or analog communications signals or other intangible medium to facilitate communication of such software.

[0059] The following, non-limiting examples, detail certain aspects of the present subject matter to solve the challenges and provide the benefits discussed herein, among others.

[0060] The above Detailed Description can include references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention can be practiced. These embodiments are also referred to herein as “examples.” Such examples can include elements in addition to those shown or described. However, the present inventors also contemplate examples in which only those elements shown or described are provided. Moreover, the present inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0061] In the event of inconsistent usages between this document and any documents so incorporated by reference, the usage in this document controls. In this document, the terms “including” and “in which” are used as the plain- English equivalents of the respective terms “comprising” and “wherein.” Also, in the following claims, the terms “including” and “comprising” are open-ended, that is, a system, device, article, composition, formulation, or process that can include elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim.

[0062] In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” In this document, the term “or” is used to refer to a nonexclusive or, such that “A or B” can include “A but not B,” “B but not A,” and “A and B,” unless otherwise indicated. In this document, the terms “including” and “in which” are used as the plain- English equivalents of the respective terms “comprising” and “wherein.” Also, in the following claims, the terms “including” and “comprising” are open-ended, that is, a system, device, article, composition, formulation, or process that can include elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.

[0063] The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) can be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided to comply with 37 C.F.R. §1.72(b), to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features can be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter can lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMSWhat is claimed is:

1. A computing device for evaluating therapy for a Restless Legs Syndrome (RLS) or Periodic Limb Movement Disorder (PLMD) patient, the computing device including a processor and a memory device, the memory device including instructions that, when executed by the processor, cause the computing device to: receive a drug therapy metric indicative of administering a drug; receive first sensor data indicative of leg movement or sleep quality of the patient during a target time period, for which relief from at least one of an RLS or PLMD symptom is desired; generate, based on the first sensor data and the drug therapy metric, a drug therapy efficacy indicator for the patient corresponding to the target time period, the drug therapy efficacy indicator generated in isolation from therapeutic effects of electrostimulation therapy; and provide the drug therapy efficacy indicator to a user or process for assisting in evaluating therapy to the patient.

2. The computing device of claim 1, wherein the generated drug therapy efficacy indicator is determined based on sensor data received during an absence of electrostimulation administration.

3. The computing device of claim 1, wherein the memory device includes instructions that, when executed by the processor, cause the computing device to generate, based on the drug therapy efficacy indicator, at least one of a drug or electrostimulation dosing treatment protocol for providing relief from the at least one of the RLS or PLMD symptom during the target time period.

4. The computing device of claim 1, wherein the drug therapy efficacy indicator individually characterizes multiple time fractions of the target time period for which relief from at least one of an RLS or PLMD symptom is5. The computing device of claim 1, wherein the drug therapy efficacy indicator characterizes at least one of an RLS or PLMD symptom severity during the target time period.

6. The computing device of claim 1, wherein the drug therapy efficacy indicator includes a composite indicator characterizing: one or more fractions of the target time period for which relief from at least one of an RLS or PLMD symptom is desired; and an RLS or PLMD symptom severity during the target time period.

7. The computing device of claim 1, wherein the drug therapy metric indicative of administering the drug includes a metric indicating a downward titration of the drug.

8. The computing device of claim 1, wherein the drug therapy metric indicative of administering the drug includes at least one of a drug type, a drug administration timing, a drug with a different duration of effect, or a drug dosage of a specified drug.

9. The computing device of claim 8, comprising: estimating an actual decay rate of the specified drug, based on the first sensor data indicative of a sleep quality or leg movement of the patient during the target time period; and generating a treatment protocol for at least one of drug or electrostimulation administration, based on the estimated actual decay rate.

10. The computing device of claim 8, comprising: estimating a decline in symptom suppression efficacy of the specified drug, based on the first sensor data indicative of a sleep quality of the patient during the target time period; and generating a treatment protocol for an electrostimulation administration, the treatment protocol including a first electrostimulation titration, in response to the estimated decline of symptom suppression efficacy of the specified drug, to provide a high-frequency (HF) electrostimulation waveform having a frequency within a range of 500 hertz(Hz) to 10,000 Hz, the waveform to limit the at least one symptom of RLS or PLMD.

11. The computing device of claim 10, the memory device including instructions that, when executed by the processor, cause the computing device to: estimate an incline in symptom suppression efficacy of the specified drug; wherein generating the treatment protocol for the electrostimulation administration includes a second electrostimulation titration to decrease or interrupt electrostimulation based on the estimated incline in symptom suppression efficacy of the specified drug.

12. The computing device of claim 1, the memory device including instructions that, when executed by the processor, cause the computing device to establish or adjust a delivery parameter of a high-frequency (HF) electrostimulation waveform based on the drug therapy metric and the first sensor data.

13. The computing device of claim 12, wherein the memory device includes instructions that, when executed by the processor, cause the computing device to: receive second sensor data corresponding with leg movement of the patient following an electrostimulation delivery of the established or adjusted HF electrostimulation waveform; and generate, based on the first and second sensor data, an electrostimulation efficacy indicator of the electrostimulation delivery in improving the sleep quality or reducing the leg movements of the patient.

14. The computing device of claim 13, wherein the memory device includes instructions that, when executed by the processor, cause the computing device to: determine a threshold composite efficacy indicator, based on the electrostimulation efficacy indicator and the drug therapy efficacy indicator; andalter, based on the composite efficacy indicator, at least one parameter of a drug therapy treatment.

15. The computing device of claim 14, wherein altering the at least one parameter of the drug therapy treatment includes controlling a transdermal drug release from a transdermal drug delivery unit locatable on the patient.

16. The computing device of claim 15, wherein controlling the transdermal drug release includes modulating a permeability of the transdermal drug delivery unit to modulate transdermal drug release to the patient.

17. The computing device of claim 15, wherein controlling the transdermal drug release includes generating a drug release waveform configured to establish a voltage gradient to modulate transdermal drug release to the patient.

18. The computing device of claim 12, wherein the establishing or adjusting the delivery parameter includes establishing or adjusting at least one of a timing or a duration of an individual electrostimulation delivery within target time period for which relief from at least one of an RLS or PLMD symptom is desired.

19. The computing device of claim 1, wherein the target time period is within a first half-life of the administering of the drug.

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