Clinical and neuroplastic effect of inhibitory rTMS on the sensory-motor cortical areas in RLS: a proof of concept study

Objective: A disinhibition to transcranial magnetic stimulation (TMS) was observed in Restless Legs Syndrome (RLS), resulting in a hyperexcitability state. The sensory complaints also suggest a central sensitization in RLS pathophysiology. We probed inhibitory repetitive TMS (rTMS) over the primary motor (M1) and somatosensory cortices (S1) in idiopathic RLS. Methods: Resting motor threshold (rMT), motor evoked potentials (MEPs), central motor conduction time, and cortical silent period (CSP) were recorded from 13 RLS patients age-matched with 10 controls. Participants, all right-handed, were randomly assigned to motor, sensory, and sham stimulation. A single evening session of low-frequency (1 Hz) rTMS over left M1, left S1, and sham was performed in different days. In each session, 20 rTMS trains were delivered, with 50 stimuli for each train, and an intertrain interval of 30 s (1,000 stimuli in total). Clinical and TMS measures were repeated after every stimulation modality. Median peak-topeak MEPs amplitude was calculated at baseline, after the first rTMS train (T1), and the whole procedure (T2). Results: CSP was shorter at baseline and remained shorter in patients than in controls after M1 and S1 stimulation. Patients reported a subjective improvement of initiating and maintaining sleep the night after S1-rTMS. They also showed a decrease of rMT after S1-rTMS only, although the effect was smaller than in controls. Sham did not produce variations. Smaller MEPs amplitude at T1 and T2 was found, although this was significantly more pronounced in controls. Discussion: rTMS on S1-M1 connectivity may alleviate RLS symptoms. Patients exhibited partial inhibitory rTMS-induced cortical plasticity over S1 and did not respond to M1 stimulation. Data suggests an involvement of both GABA and glutamate, and an impairment of short-term mechanisms of neuroplasticity. These findings are useful for diagnosis, monitoring, and design of novel drugs or neuromodulatory stimulation techniques in RLS.