Bilateral high-frequency noninvasive peroneal nerve stimulation evokes tonic leg muscle activation for sleep-compatible reduction of restless legs syndrome symptoms.

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, MT) and maximal NPNS amplitude that was not distracting (therapeutic intensity level, TIL). Afterwards, participants self-administered NPNS (at the TIL) 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 to sham.

RESULTS: NPNS consistently activated leg muscles; NPNS evoked EMG activity at the therapeutic intensity level for 19 of 20 participants (mean TIL: 26.6mA, mean MT: 18.3mA). 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=0.45, P=0.046). NPNS treatment did not interfere with self-reported sleep onset (NPNS: 16% of nights, sham: 11%, P=0.629) and frequently improved self-reported sleep onset (NPNS: 52% of nights, sham: 15%, P=0.002).

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; Title: Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome; Identifier: NCT04700683; URL: https://clinicaltrials.gov/ct2/show/NCT04700683.