Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms
ABSTRACT
Study Objectives:
Restless legs syndrome (RLS) is a prevalent sleep disorder with limited treatment options. Bilateral high-frequency noninvasive peroneal nerve stimulation (NPNS) reduces RLS symptoms. Here, we sought to characterize the mechanism of action for NPNS and identify predictors of treatment response. We hypothesized that, similar to voluntary leg movements, NPNS reduces RLS symptoms by activating leg muscles.
Methods:
For 20 adults with moderate–severe RLS, we tested this hypothesis by recording surface electromyography (EMG) from the tibialis anterior leg muscle while administering NPNS at varying amplitudes to determine the minimum NPNS amplitude that evoked EMG activity (motor threshold) and maximal NPNS amplitude that was not distracting (therapeutic intensity level). Afterwards, participants self-administered NPNS (at the therapeutic intensity level) and sham control for 14 days, each in randomized order. Efficacy was defined as International RLS Study Group Rating Scale (IRLS) score difference for NPNS compared with sham.
Results:
NPNS consistently activated leg muscles; NPNS evoked EMG activity at the therapeutic intensity level for 19 of 20 participants (mean TIL: 26.6 mA, mean MT: 18.3 mA). Evoked EMG activity was tonic (not phasic) and sustained over time. Evoked EMG activity predicted efficacy; participants with lower motor thresholds had greater IRLS improvement (r = .45, P = .046). NPNS treatment did not interfere with self-reported sleep onset (NPNS: 16% of nights; sham: 11%; P = .629) and frequently improved self-reported sleep onset (NPNS: 52% of nights; sham: 15%; P = .002).
Conclusions:
These results demonstrate that NPNS reduces RLS symptoms by activating afferent pathways, thereby generating tonic and sustained leg muscle activity without interfering with sleep.
Clinical Trial Registration:
Registry: ClinicalTrials.gov; Name: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; URL: https://clinicaltrials.gov/ct2/show/NCT04700683; Identifier: NCT04700683.
Citation:
Charlesworth JD, Adlou B, Singh H, Buchfuhrer MJ. Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms. J Clin Sleep Med. 2023;19(7):1199–1209.
BRIEF SUMMARY
Current Knowledge/Study Rationale: The leading pharmacological treatments for restless legs syndrome are associated with low long-term efficacy and significant risks; a lower-risk treatment option would benefit patients with restless legs syndrome. Bilateral high-frequency noninvasive peroneal nerve stimulation is a novel lower-risk treatment for restless legs syndrome that has shown promising initial efficacy, but its mechanism of action has yet to be established.
Study Impact: Here, we characterize the mechanism of action for noninvasive peroneal nerve stimulation by showing that it activates specific neural pathways that lead to specific patterns of leg muscle activation while remaining compatible with sleep. This establishes a mechanistic distinction between noninvasive peroneal nerve stimulation and other technologies while also establishing a mechanistic similarity between noninvasive peroneal nerve stimulation and the types of voluntary leg movements that are known to reduce restless legs syndrome symptoms.
INTRODUCTION
Restless legs syndrome (RLS) is a neurologic condition and sleep disorder associated with a distressing and irresistible urge to move the legs.1 The symptoms of RLS are exacerbated by lying down, exhibit a circadian trend toward worsening in the evening or night, and interfere with sleep onset and maintenance.2,3 Whereas walking or voluntarily moving the legs can temporarily reduce daytime symptoms,1 these activities cannot be performed during sleep and thus are typically insufficient to reduce sleep disturbances. The significant reduction in sleep quality associated with RLS leads to quality-of-life degradation, daytime sleepiness, lack of productivity, and numerous downstream comorbidities.3,4 In the United States, an estimated 5 to 8 million adults experience clinically significant RLS with symptoms that present more than 3 nights per week and result in a significant degradation in sleep quality.5
Novel therapeutics are needed to address the population of patients with RLS who are inadequately treated with existing medications. RLS is primarily treated with dopamine agonist and alpha-2-delta ligand medications. Dopamine agonists initially provide consistent symptomatic relief, but long-term use often leads to augmentation, a paradoxical worsening of RLS symptoms.6 Whereas alpha-2-delta ligands do not result in augmentation, they are associated with side effects that limit tolerability, including daytime sleepiness, dizziness, and weight gain.7 For patients with RLS who become refractory to these classes of medication, there are no Food and Drug Administration–approved treatment options; off-label opioids have been recommended for refractory RLS in certain cases,7 but side effects can limit tolerability and response to the ongoing opioid epidemic has limited clinical adoption.
Bilateral high-frequency noninvasive peroneal nerve stimulation (NPNS) is a low-risk wearable therapeutic device that has been shown to reduce RLS symptom severity when administered over the peroneal nerve at the head of the fibula bone. The efficacy of NPNS was previously established in a 3-center randomized controlled trial that enrolled 37 adults with primary moderate–severe RLS8; relative to sham control, NPNS reduced International RLS Study Group Rating Scale (IRLS) score and increased Clinical Global Impressions of Improvement (CGI-I) responder rate for both medication-naive and medication-refractory RLS.8 Furthermore, NPNS resulted in symptomatic relief that was both rapid and persistent, beginning within a single 30-minute stimulation session and persisting after the session is completed.8
Here, we sought to characterize the mechanism of action through which NPNS reduces RLS symptoms. We hypothesized that NPNS suppresses RLS symptoms by activating leg muscles, thereby mimicking the neural signals generated by voluntary leg movements. If this hypothesis is correct, then NPNS should induce activation of the tibialis anterior (TA) muscle, which is innervated by the peroneal nerve. To test this hypothesized mechanism of action, we analyzed surface electromyography (EMG) from the TA muscle during NPNS administration. The data for this analysis were collected during the randomized controlled trial summarized above.8
METHODS
Study protocol
Data were collected during a randomized, sham-controlled, participant-blinded clinical study conducted at 3 centers in the United States. This study was registered with ClinicalTrials.gov (NCT04700683) and the top-line results have been published previously.8 The protocol and informed consent were approved by a central institutional review board (IRB) and site-specific IRB as appropriate. To measure treatment response, the study used a crossover design wherein each participant was assigned to self-administer 14 days of active NPNS and 14 days of sham control in randomized order (Figure 1A). Participants were instructed to self-administer at least 1 full 30-minute therapy session at bedtime daily and were allowed to self-administer up to 3 additional sessions per day depending on RLS symptoms.
(A) Study design and participant disposition. (B) Positioning of stimulation and sensing electrodes. NPNS stimulation electrodes were positioned over the peroneal nerve at the head of the fibula, secured to the skin through an adhesive hydrogel electrode patch, and connected to the NPNS stimulator by a wired connector. EMG sensing electrodes were positioned over the belly of the tibialis anterior muscle a minimum of 1 inch distal to the NPNS stimulation electrodes. An EMG reference electrode was positioned over the patella. (C) Titration procedure. NPNS stimulation intensity (current, mA) is increased from 0 mA past the PT to the TT at a rate of approximately 0.5 mA per second. Then, NPNS intensity is lowered to the maximum level that is compatible with self-reported sleep onset (TIL) at a rate of approximately 0.1 mA per second and held constant at a TIL for a minimum of 30 seconds. EMG = electromyography, NPNS = noninvasive peroneal nerve stimulation, PT = perception threshold, RLS = restless legs syndrome, TIL = therapeutic intensity level, TT = tolerability threshold, wks = weeks.
To characterize the relationship between NPNS-evoked leg muscle activation and treatment response, a standardized EMG data-collection procedure was implemented as an exploratory assessment at 2 of the 3 clinical centers participating in the clinical trial, comprising a total of 20 participants. All analyses and data presented herein are specific to these 20 participants at these 2 clinical centers. EMG activity was measured from the TA muscle of the right leg (Figure 1B) during a controlled in-clinic titration procedure prior to in-home treatment (Figure 1C), which is described below.
Participants
The study recruited adults with moderate-to-severe primary RLS. Key inclusion criteria included IRLS total score ≥ 15 (moderate-to-severe RLS), symptoms primarily in the lower legs and/or feet, and symptoms primarily in the evening and night. The IRLS is a validated 10-item questionnaire that evaluates RLS severity on a range from 0 to 40 (mild: 1–10; moderate: 11–20; severe: 21–30; very severe: 31–40).9 Key exclusion criteria included unstable dosing of RLS medications, sleep medications, or antidepressants; untreated primary sleep disorders other than RLS; severe peripheral neuropathy; skin conditions affecting the stimulation site; and active medical device implants.
Investigational NPNS device
The investigational NPNS device administered in this study was developed by the study sponsor (Noctrix Health, Inc., Pleasanton, CA). For each leg, the bilateral NPNS system consisted of a battery-powered therapy unit connected by wires to a disposable adhesive hydrogel electrode patch (Figure 1B). The therapy units transmitted a high-frequency (4000 Hz) stimulation waveform at a configurable intensity ranging from 0 to 40 mA. The hydrogel electrode patch contained 2 rectangular electrodes spaced approximately 0.5 inches apart, each of which measured 2.0 inches × 1.3 inches. The NPNS system was applied over the head of the fibula bone so that the lateral electrode covered the common peroneal nerve at the position closest to the skin surface. During in-home use, the duration of each stimulation session was set to 30 minutes, after which stimulation automatically shut off.
Titration procedure
The titration procedure was used to individualize the stimulation intensity for each participant to provide a balance of efficacy and sleep compatibility. This procedure was motivated by the assumption that higher intensities are more likely to be efficacious, whereas lower intensities are more likely to be compatible with sleep. Based on this principle, the titration procedure sought to identify the highest intensity that would be compatible with sleep.
In the titration procedure, stimulation intensity was adjusted within the range of 0 to 40 mA while soliciting self-reported feedback from the participant (Figure 1C). Participants sat in a chair with feet on the floor and were instructed to keep their legs motionless throughout the procedure to minimize signals from voluntary muscle activation. Self-reported feedback was solicited to establish the minimum intensity with noticeable stimulation-evoked sensations (perception threshold [PT]), the maximum tolerable level (tolerability threshold [TT]), and the maximum level that was compatible with self-reported sleep onset (therapeutic intensity level [TIL]). First, intensity (current, mA) was increased monotonically from 0 mA to TT (Figure 1C). Second, intensity was gradually reduced from TT by 1 mA every 10 seconds until the participant stated that stimulation intensity would not interfere with their ability to fall asleep; this intensity was defined as the TIL (Figure 1C). Finally, intensity was held constant at the TIL for 30 seconds to collect additional EMG data at the TIL (Figure 1C). During EMG recording, titration was completed either once (participants 1–8) or twice (participants 9–20); when completed twice, data from the 2 runs were averaged.
Following the titration procedure, the TIL was programmed into the devices to define the stimulation intensity during in-home treatment. For both active NPNS and sham control, stimulation output automatically ramped up to a value slightly below the TIL within the first 20 seconds of therapy, after which participants were instructed to press the “+” controller twice to increase stimulation intensity to the TIL. For active NPNS, stimulation intensity remained at the TIL for the remainder of the 30-minute session. For sham control, stimulation intensity immediately ramped down from TIL to 0 mA and stayed at 0 mA for the remainder of the 30-minute session. Participants were instructed to maintain stimulation intensity at the TIL for most sessions but were permitted to increase intensity by 2–4 mA (eg, for severe RLS symptoms) or reduce intensity by 2–4 mA (eg, for mild RLS symptoms).
EMG data collection and analysis
EMG data were collected to test the hypothesis that NPNS activates leg muscles. During the titration procedure, surface EMG data were collected from the TA muscle of the right leg using a Shimmer3 EMG system (Shimmer Sensing, Dublin, Ireland) with a sampling rate of 512 Hz. Sensing electrodes were placed over the belly of the TA at a minimum of 1 inch distal to the distal edge of the stimulation electrodes and the reference electrode was placed on the patella (Figure 1B); repositionable electrodes measuring 1.56 inches by 1.25 inches (Red Dot monitoring electrodes, 3M Health Care, St. Paul, MN) were used for both sensing and reference. Data were high-pass filtered at 5 Hz, rectified, and smoothed with a 1-second rolling average. During the monotonic increase in NPNS stimulation intensity from 0 mA to TT, the motor threshold (MT) was defined as the stimulation intensity corresponding to the point in time when the EMG envelope first exceeded the noise floor and continued to exceed the noise floor with further increases in intensity (Figure 2); thus, the motor threshold corresponded to the minimal NPNS intensity that activated leg muscles. The evoked amplitude was defined as the difference between the EMG noise floor and the median EMG amplitude during the 30 seconds that stimulation intensity was held constant at the TIL during the titration procedure (Figure 2); thus, the evoked amplitude corresponded to the magnitude of NPNS-evoked leg muscle activation associated with therapy. For consistency with prior work,10 the relative MT was also normalized as a ratio of TIL and as a ratio of PT.
NPNS amplitude (mA) is shown in black and rectified filtered EMG signal (µV) is shown in blue. NPNS amplitude was gradually increased from 0 mA (NPNS on, t = 28 s) to the tolerability threshold (40 mA, t = 102 s), reduced to the TIL (32 mA), and held constant at TIL for 30 seconds (NPNS at TIL, t = 130–160 s). The average EMG signal amplitude during the 30 seconds at TIL was 6.81 µV and thus the magnitude of evoked EMG activity over the EMG noise floor (2.17 µV) was 4.64 µV. For NPNS amplitudes greater than or equal to 13 mA (t = 44 s), EMG signal amplitude was consistently elevated above the noise floor; this threshold for NPNS-evoked EMG activity is termed the motor threshold (green). EMG = electromyography, NPNS = noninvasive peroneal nerve stimulation, TIL = therapeutic intensity level.
Characterization of NPNS-evoked EMG activity was performed to determine the pathway through which NPNS activates leg muscles. This was primarily of interest because it had implications for the sleep compatibility of NPNS therapy, based on the assumption that tonic and sustained muscle activity was more likely to be sleep compatible than phasic or jerky muscle activation. Tonic scores and sustained scores were calculated for the 19 (out of 20) participants with evoked motor activity at the TIL. Tonic scores were calculated by first measuring the rolling coefficient of variability (standard deviation [SD]/mean) of the EMG signal, with a 1-second window, for the 30-second period where stimulation intensity was held constant at TIL during the titration procedure, and then quantifying the percentage of time that the rolling coefficient of variability of the EMG signal was less than 1.0 (ie, SD < mean). The results of this analysis were robust to changes in the duration of the rolling window. Sustained scores were calculated by first measuring the noise floor for the EMG signal prior to the titration procedure and then quantifying, for the 30-second period where stimulation intensity was held constant at TIL during the titration procedure, the percentage of time when EMG signal amplitude was at least 50% greater than the noise floor. The results of this analysis were robust to adjusting this threshold from 25% greater than the noise floor to 100% greater than the noise floor.
Relationship between NPNS muscle activity and efficacy
To determine if NPNS-evoked muscle activity was related to NPNS treatment response, we measured the relationship between evoked muscle activity and efficacy. Treatment efficacy was assessed using the IRLS9 total score and Patient Global Impressions of Improvement (PGI-I) patient-rated outcome measures. The IRLS total score ranges from 0 to 40, where higher scores indicate more severe RLS symptoms. The IRLS was assessed at study entry and at the end of each 14-day treatment period. The PGI-I ranges from 1 to 7, where lower scores indicate improvements in RLS and higher scores indicate worsening of RLS. The PGI-I was assessed at the end of each 14-day treatment period relative to study entry. For evaluating relationships between evoked EMG activity and efficacy, the IRLS was selected as the efficacy metric because it allows for greater range of discrete scores (0 to 40) and because data were available for all 20 participants for the IRLS compared with 16 participants for the PGI-I. Therapeutic efficacy for each participant was quantified as the IRLS difference, the difference in IRLS score for active NPNS treatment relative to sham control. Consistent with convention, responders were defined as participants with an IRLS difference greater than or equal to 3 for treatment relative to sham.11
Compatibility with sleep onset
During the titration procedure, the TIL was chosen based on participant attestation that it would be consistently compatible with administration during sleep. To test if this was the case during in-home use, at the end of the 14-night in-home use of active NPNS and sham control, participants were asked to quantify the number of nights the devices interfered with falling asleep, the number of nights the devices helped with falling asleep, and the number of nights they experienced RLS symptoms. Electronic usage logs recorded by the NPNS devices were used to establish the actual number of nights when the devices were used.
Statistical analysis
Means were compared using 2-tailed t tests, paired when appropriate, with an alpha level of 0.05 against the null hypothesis of no relationship. Correlation coefficients were assessed using linear regression t tests, with an alpha level of 0.05 against the null hypothesis of a slope of zero.
RESULTS
Of the 43 total participants enrolled in NCT04700683,8 surface EMG activity was collected and analyzed for 20 participants at 2 of the 3 clinical centers. The participant characteristics and efficacy results for these 20 participants are summarized below. Twelve of these participants were randomized to active NPNS followed by sham control and the remaining 8 were assigned to sham control followed by active NPNS (Figure 1A). The average IRLS score at study entry was 24.6 (SD: 3.9), the average age was 52.8 years (SD: 11.4), 50% were female, 50% were male, 75% were medication-refractory, and 25% were medication-naive. The complete safety and efficacy results for all 43 participants have been presented previously8; for the 20 participants analyzed here, IRLS total score changed by –4.8 (SD: 1.1) points during active NPNS treatment compared with –0.3 (SD: 0.7) points during sham control, and the PGI-I responder rate was 75% during active NPNS treatment compared with 0% during sham control.
NPNS-evoked motor activity
First, we tested if NPNS consistently activated leg muscles at TILs, as would be expected if NPNS reduces RLS symptoms by activating leg muscles. For each participant, EMG activity was measured from the TA muscle as stimulation intensity was increased during the titration procedure (see Methods for details). Figure 2 illustrates a representative EMG signal during the titration procedure; consistent NPNS-evoked EMG activity first appears when stimulation intensity reaches 13 mA (MT = 13 mA), the amplitude of NPNS-evoked EMG activity gradually increases as stimulation intensity is further increased, and the magnitude of NPNS-evoked EMG activity at the TIL (TIL = 32 mA) is 4.64 µV above the noise floor. Therefore, for this participant, the TIL exceeded the MT and stimulation at the TIL evoked TA muscle activity.
Stimulation at the TIL consistently evoked muscle activity. For 19 of 20 participants, the MT was less than or equal to the TIL, indicating that stimulation at the TIL evoked TA muscle activity (Figure 3A). The average TIL (mean: 26.6 mA; SD: 4.1 mA; range: 16–32 mA) was 45% greater than the average MT (mean: 18.3 mA; SD: 5.5 mA; range: 9–30 mA), a difference of +8.3 mA (P < .0001). For the 19 participants with evoked activity at the TIL, the mean evoked amplitude was 7.4 µV above the noise floor (SD: 5.8 µV; range: 1.7–19.8 µV). As shown in Figure 3B, the ratio of MT to TIL ranged from 0.33 to 1.07 (mean: 0.69; SD: 0.19). These results indicate that NPNS consistently activates leg muscles at TILs, consistent with the hypothesis that NPNS reduces RLS symptoms by activating leg muscles.
(A) MT and TIL values for each participant. (B) Histogram of the ratio of TIL to MT for each participant. Each bin represents participants with MT:TIL values less than or equal to the bin value (eg, bin 1.0 represents participants with 0.9 < MT:TIL ≤ 1.0). MT = motor threshold, TIL = therapeutic intensity level.
Relationship between NPNS-evoked motor activation and efficacy
Next, we tested if differences in NPNS leg muscle activation across participants predicted differences in efficacy, as would be expected if NPNS reduces RLS symptoms by activating leg muscles. To test this, we measured the relationship between NPNS-evoked MTs and efficacy; lower MTs indicate that NPNS more easily generates muscle activation and thus should be associated with greater efficacy if the hypothesized mechanism is correct. Efficacy was expressed as the difference between the IRLS score for active NPNS treatment compared with sham control (IRLS difference); since IRLS score reduction represents RLS improvement, a more negative IRLS difference represents greater efficacy. The NPNS-evoked MT for each participant was expressed as a ratio of the corresponding TIL (MT:TIL), as shown in Figure 3B. There was a statistically significant positive correlation between MT:TIL and IRLS difference (r = .45, P = .046), indicating that lower MTs were associated with greater IRLS reduction and thus greater efficacy (Figure 4A). Furthermore, participants with MTs below 15 mA had a greater IRLS difference (–7.7; n = 6) than participants with MTs between 15 mA and 20 mA (–4.2; n = 6) or MTs above 20 mA (–2.4; n = 8). In summary, lower NPNS-evoked MTs predicted greater efficacy.
Each data point corresponds to a single participant. Dotted gray lines indicate linear regression lines of best fit. (A) Relationship between MT expressed as a ratio of TIL and difference in IRLS total score for active NPNS relative to sham control (IRLS difference). (B) Relationship between MT expressed as a ratio of PT and difference in IRLS total score for active NPNS relative to sham control (IRLS difference). IRLS = International RLS Study Group Rating Scale, MT = motor threshold, NPNS = noninvasive peroneal nerve stimulation, PT = perception threshold, TIL = therapeutic intensity level.
Next, we assessed the robustness of the observed relationship between NPNS-evoked motor activation and efficacy. Expressing MTs as ratios of PTs (MT:PT) instead of TILs (MT:TIL) resulted in a similar correlation with IRLS difference (r = .46, P = .042), further confirming this predictive relationship (Figure 4B). Notably, the correlation between IRLS and MT (r = .37) was much greater than the correlation between IRLS and TIL (r = .06) or IRLS and PT (r = .07), indicating that low MT values were uniquely predictive of efficacy—as opposed to high TIL or PT values. We also compared NPNS-evoked motor activation for IRLS responders compared with nonresponders. IRLS responders were defined as participants for whom IRLS total score was lower during active NPNS relative to sham control by a margin of 3 points or greater, indicating a clinically significant reduction in RLS severity during active NPNS relative to sham.11 Compared with nonresponders (n = 10), responders (n = 10) had a lower average MT (15.8 mA vs 20.7 mA; P = .042) and a lower MT:TIL (0.61 vs 0.77; P = .058) (Table 1). Notably, the relationships between low MT and high efficacy could not be explained by underlying differences in TIL, age, calf circumference, or body mass index between responders and nonresponders (Table 1). In addition to the MT, we also found that the amplitude of NPNS-evoked muscle activation was positively correlated with IRLS difference (r = .35, P = .128). Together, these results confirm a robust and uniquely predictive relationship between NPNS-evoked TA muscle activity and NPNS therapeutic efficacy, such that lower MTs for evoked TA activity predict greater therapeutic efficacy.
| IRLS Responders (n = 10) | IRLS Nonresponders (n = 10) | P | |
|---|---|---|---|
| NPNS-evoked motor activation | |||
| MT, mA | 15.8 (4.1) | 20.7 (5.8) | .042 |
| MT:TIL ratio | 0.61 (0.17) | 0.77 (0.17) | .058 |
| Other features | |||
| TIL, mA | 26.2 (4.0) | 26.9 (4.3) | .712 |
| Age, y | 53.1 (12.5) | 52.4 (10.7) | .895 |
| Calf circumference, inches | 15.1 (2.4) | 15.4 (1.3) | .730 |
| Body mass index, kg/m2 | 29.7 (7.9) | 27.6 (5.6) | .502 |
Characterization of NPNS-evoked motor activation
Having established a relationship between NPNS-evoked motor activity and NPNS efficacy, we characterized the pathway through which NPNS evokes motor activation. In principle, since the peroneal nerve contains both motor and sensory fibers, peroneal nerve stimulation could evoke efferent motor activation through direct activation of motor fibers or afferent motor activation through activation of sensory fibers, leading to reflexive muscle activation (Figure 5).12,13 This is an important distinction because it has implications for the sleep compatibility of NPNS therapy. Whereas afferent motor stimulation typically evokes tonic and sustained increases in muscle tone that could be compatible with sleep, efferent motor stimulation typically evokes phasic muscle twitches and jerky movements that could interfere with sleep (eg, Figure 6, “3–4”).12
Diagram illustrating the proposed mechanism of action. The peroneal nerve (gray) contains high-threshold proprioceptive afferent nerve fibers (red), low-threshold proprioceptive afferents (green), and motoneurons (blue) that innervate the tibialis anterior leg muscle (orange). In RLS, (1) activation of high-threshold proprioceptive afferent nerve fibers contributes to the symptoms of focal akathisia (discomfort and restlessness) in the legs and (2) activation of low-threshold proprioceptive afferents through walking or standing activates inhibitory interneurons in the spinal cord (black) that suppress the transmission of signals from the high-threshold proprioceptive afferent nerve fibers to the brain, thereby suppressing these RLS symptoms, as previously proposed.21 Here, we show that (3) NPNS directly activates low-threshold proprioceptive afferents and (4) NPNS evokes tibialis anterior motor activity through the afferent Hoffman reflex pathway, thereby generating additional low-threshold proprioceptive afferent signals resulting from muscle activation. NPNS = noninvasive peroneal nerve stimulation, RLS = restless legs syndrome.
Diagram illustrating potential EMG response patterns evoked by electrical stimulation. In this hypothetical example, stimulation (1) evokes tonic and sustained motor activation, stimulation (2) evokes tonic but not sustained activation, stimulation (3) evokes sustained but not tonic activation, and stimulation (4) evokes activation that is neither tonic nor sustained. Dotted vertical lines denote beginning and end of the electrical stimulation patterns that lead to each of the potential EMG response patterns. EMG = electromyography, NPNS = noninvasive peroneal nerve stimulation.
To distinguish between these pathways, we assessed the extent to which NPNS-evoked motor activity was tonic and sustained, characteristics of afferent motor activation. To assess the tonic nature of NPNS-evoked motor activity, we calculated that the percentage of time that the time-windowed coefficient of variability of NPNS-evoked EMG activity was less than 1 (tonic score; see Methods for details). Based on this definition, purely tonic activation (eg, Figure 6, “1”) would have a tonic score of 100%, whereas partially phasic activation would have a lower score (eg, Figure 6, “3–4”). For the 19 participants with evoked EMG activity at the TIL, the average tonic score was 97% and median tonic score was 100%. To assess the sustained nature of NPNS-evoked motor activity, we calculated the percentage of time that the amplitude of NPNS-evoked EMG activity was elevated more than 50% above the noise floor (sustained score; see Methods for details). Based on this definition, purely sustained activation (eg, Figure 6, “1”) would have a sustained score of 100%, whereas less fully sustained activation would have a lower score (eg, Figure 6, “2”). For the 19 participants with evoked EMG activity at the TIL, the average sustained score was 84% and the median sustained score was 100%. Figure 2 illustrates evoked motor activity for a representative participant with a tonic score of 100% and a sustained score of 100%.
Having shown that NPNS-evoked motor activity was tonic and sustained, we sought to determine if these characteristics were predictive of therapeutic response, as defined by IRLS difference. The IRLS difference was –7.2 for participants with a tonic score of 100% compared with –0.3 for participants with a tonic score less than 100% (P = .021), and the correlation coefficient between the tonic score and IRLS difference was 0.35. The IRLS difference was –6.6 for participants with a sustained score of 100% compared with –1.3 for participants with a sustained score less than 100% (P = .085), and the correlation coefficient between the sustained score and IRLS difference was 0.35. In summary, tonic and sustained motor activation predicted greater therapeutic efficacy. Together, these results suggest that NPNS reduces RLS symptoms by evoking motor activity through the afferent pathway, not the efferent pathway.
Compatibility with sleep onset
Since NPNS-evoked motor activity was tonic and sustained, as opposed to phasic and jerky, we further hypothesized that NPNS could be compatible with administration during sleep. To test this, participants were asked whether NPNS interfered with sleep onset on each night of in-home treatment (Table 2). Participants reported that NPNS interfered with falling asleep on 2.3 nights in the 14-night period (16%) compared with 1.6 nights for sham (11%), which was not a significant difference (P = .629). Next, participants were asked whether NPNS helped with falling sleep on each night of in-home treatment (Table 2). Participants reported that active NPNS helped with falling asleep 7.3 nights in the 14-night period (52%) compared with 2.2 nights for sham (15%), which was statistically significant (P = .002). In summary, NPNS significantly improved self-reported sleep onset and did not interfere with self-reported sleep onset.
| Number of nights (out of 14 total) | Active NPNS | Sham Control | P |
|---|---|---|---|
| NPNS usage | 12.2 | 10.2 | .150 |
| RLS symptoms | 8.5 | 10.1 | .347 |
| NPNS helped with falling asleep | 7.3 | 2.2 | .002 |
| NPNS interfered with falling asleep | 2.3 | 1.6 | .629 |
Relationship between efficacy and RLS severity
Next, we tested whether NPNS efficacy was dependent on RLS severity. This analysis was of interest because voluntary leg movements tend to provide less complete relief for participants with more severe RLS.9 For this analysis, we included all participants in the modified intention-to-treat population of the study (n = 37) to provide maximal statistical power. NPNS efficacy was defined as IRLS difference and RLS severity was defined as baseline IRLS. We found no correlation between baseline IRLS and IRLS difference (r = .02, P = .910). These results indicate that NPNS-induced leg muscle activation provides relief of RLS symptoms, irrespective of RLS severity.
DISCUSSION
Together, these results suggest that NPNS activates afferent peroneal nerve fibers to evoke increases in TA muscle tone, thereby reducing RLS symptoms while maintaining compatibility with sleep. NPNS and voluntary leg movements both lead to leg muscle activation and relief of RLS symptoms, suggesting a similar mechanism of action. However, NPNS confers 2 clinically significant advantages. First, NPNS can be used at bedtime without interfering with sleep onset (Table 2), whereas voluntary leg movements are incompatible with sleep. Second, NPNS remains similarly efficacious for severe RLS, in contrast to leg movements.9
NPNS activates leg muscles and thus is fundamentally different from technologies that rely on sensory counterstimulation. Mechanical vibration devices activate mechanoreceptors in the dermis but do not directly activate nerves,14 whereas NPNS directly activates the peroneal nerve with sufficient potency to evoke muscle activity. The relatively weak signals triggered by mechanical vibration may explain why this approach does not reduce RLS symptom severity,14 whereas NPNS reduces RLS symptom severity to a clinically significant degree.8 Transcutaneous electrical stimulation devices use sensory counterstimulation and in some forms can induce abrupt muscle twitches but do not result in tonic increases in muscle activity.15 In summary, NPNS uniquely delivers nerve stimulation to evoke tonic muscle activity while remaining compatible with sleep.
One limitation of these findings is the sample size. The data set was limited to 20 of 43 total participants at 2 of 3 participating clinical centers, thereby limiting the statistical power. Whereas this sample size was sufficient to demonstrate that NPNS-evoked muscle activity predicts therapeutic response, it is possible that a larger sample size could have detected additional nuances of EMG activity that are also associated with the therapeutic response. For example, the amplitude of NPNS-evoked muscle activity and the sustained nature of NPNS-evoked muscle activity (sustained score) were positively correlated with IRLS differences but did not reach statistical significance; future research with a larger sample size could focus on establishing these relationships.
The high-frequency and high-amplitude waveform transmitted by NPNS may contribute to its efficacy and tolerability for the treatment of RLS. Whereas transcutaneous electrical stimulation devices transmit waveforms with frequencies below 100 Hz and root-mean-squared amplitude below 1 mA,15 NPNS transmits a stimulation frequency of 4000 Hz and root-mean-squared amplitude above 10 mA. Due to frequency-dependent nerve fiber activation, stimulation frequencies above 1 kHz (such as NPNS) tend to be more comfortable than frequencies below 100 Hz (such as transcutaneous electrical stimulation),16 likely contributing to the sleep compatibility of NPNS. Additionally, stimulation frequencies in the 1–10-kHz range are associated with an optimally low ratio of the MT to the PT (MT:PT),10,16 meaning that motor activity can be activated with less noticeable sensations, which is also favorable for compatibility with sleep. Our results here further indicate that low MT:PT values are correlated with therapeutic efficacy, suggesting an additional advantage of stimulation frequencies in the 1–10-kHz range. The relatively high frequency of NPNS also likely contributes to its primarily afferent mechanism of action,17,18 as described below.
Our data suggest that NPNS primarily evokes afferent—not efferent—muscle activation. Efferent activation involves direct activation of motor fibers, whereas afferent activation involves activation of proprioceptive fibers in the peroneal nerve trunk, leading to reflexive motor activation through a monosynaptic reflex in the spinal cord termed the Hoffman reflex or H-reflex (Figure 5).13,19 Here, we show that the average NPNS TIL is 45% greater than the MT, in the ideal range for inducing primarily afferent motor activation.19 Furthermore, we show that NPNS evokes primarily tonic and sustained motor activation, characteristic of afferent but not efferent muscle activation. Whereas efferent activation fatigues rapidly and is phase-locked to the pulse rate of the stimulus,10,12 afferent activation can evoke stable increases in muscle tone.10,12,18 This stable pattern of tonic muscle activation is likely less distracting and thereby may contribute to the observed sleep compatibility of NPNS; therefore, we propose that future reports should refer to this specific technology as Tonic Motor Activation to differentiate it from other potential forms of NPNS.
The proposed mechanism of action for NPNS is consistent with previously hypothesized mechanisms of RLS pathophysiology. Specifically, prior reports have hypothesized that the distressing RLS symptoms of focal akathisia (discomfort and restlessness) in the lower extremities are mediated by high-threshold proprioceptive fibers of the nerves that innervate the lower extremities, such as the peroneal nerve (Figure 5, “1”).20 It has been further proposed that voluntary leg muscle activation—associated with walking or standing—activates low-threshold proprioceptive afferents of the same nerves, thereby inhibiting signaling of the pathological high-threshold fibers and thus relieving RLS symptoms (Figure 5, “2”).20 Our data here suggest that NPNS also activates these therapeutic low-threshold proprioceptive afferents through 2 pathways. First, NPNS directly stimulates these nerve fibers (Figure 5, “3”). Second, through the Hoffman reflex,13,19 NPNS evokes TA muscle activation (Figure 5, “4”), which naturally triggers additional activation of low-threshold proprioceptive afferents. These dual pathways may contribute to the potency of NPNS for relieving RLS symptoms.
The proposed mechanism of action for NPNS is also consistent with brain-centric hypotheses of RLS pathophysiology. RLS is associated with brain iron deficiency, which leads to dopamine dysregulation that is thought to disrupt both corticothalamic21–23 and spinal processing.20 As a result, the RLS symptoms of discomfort and restlessness may result from an increase in the amount of high-threshold proprioceptive signals transmitted to the brain,20 a change in how the brain processes such somatosensory signals,21,22 or both. Either way, suppression of high-threshold proprioceptive signals by NPNS before they reach the brain would be expected to reduce RLS symptoms of discomfort and restlessness.
For patients with RLS, NPNS may have a similar physiological effect to surgically implanted epidural spinal cord stimulation (SCS). Although SCS is not indicated for RLS, some patients with SCS implants for chronic pain also happen to have comorbid RLS. A series of case studies with this patient population has demonstrated dramatic reductions in RLS symptoms during SCS activation.24,25 Whereas SCS is designed to suppress high-threshold pain signals in the spinal cord to suppress chronic pain, it is possible that SCS also suppresses high-threshold proprioceptive signals to suppress RLS symptoms. Although SCS is not likely to gain traction as a treatment for RLS, due to the cost and requirement for surgical implantation, it could provide a means to further investigate mechanistic hypotheses.
In summary, NPNS uses a unique approach of Tonic Motor Activation to substantially reduce RLS symptoms while being compatible with sleep. The specific frequency, amplitude, positioning, and bilateral nature of this technology appear to be important for its ability to evoke afferent motor activation at sleep-compatible intensity levels, and therefore contribute to its tolerability and therapeutic efficacy.
DISCLOSURE STATEMENT
All authors have seen and approved the manuscript. Work for this study was performed at (1) Mark J. Buchfuhrer private practice, Downey, CA; (2) Sleep Medicine Specialists of California, San Ramon, CA; and (3) Noctrix Health, Inc., Oakland, CA. Study execution was performed at institutions 1 and 2. Project conception, analysis, and manuscript preparation performed at institution 3. Dr. Buchfuhrer is a consultant and scientific advisor for Noctrix Health, Inc.; Dr. Singh is a consultant for Noctrix Health, Inc.; Mr. Adlou is a former employee and current consultant for Noctrix Health, Inc.; Dr. Charlesworth is currently employed by Noctrix Health, Inc.; Dr. Charlesworth has received financial support from National Institutes of Health (NIH) R44NS117294 for work unrelated to this study.
ABBREVIATIONS
| EMG | electromyography |
| IRLS | International RLS Study Group Rating Scale |
| MT | motor threshold |
| NPNS | noninvasive peroneal nerve stimulation |
| PGI-I | Patient Global Impressions of Improvement |
| PT | perception threshold |
| RLS | restless legs syndrome |
| SCS | spinal cord stimulation |
| SD | standard deviation |
| TA | tibialis anterior |
| TIL | therapeutic intensity level |
| TT | tolerability threshold |
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