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

Objectives: A disinhibition to transcranial magnetic stimulation (TMS) was observed in Restless Legs Syndrome (RLS), resulting in a hyperexcitability state [1]. The sensory complaints also suggest a central sensitization in RLS pathophysiology [2]. We probed clinical and neuroplastic role of inhibitory repetitive TMS (rTMS) over the primary motor (M1) and somatosensory cortices (S1) in idiopathic RLS. Materials: Resting motor threshold (rMT), motor evoked potentials (MEPs), central motor conduction time (CMCT) and cortical silent period (CSP) were recorded using a figure-of-eight coil from the first dorsal interosseus muscle of 13 RLS patients age-matched with 10 controls. Method: Participants, all right-handed, were randomly assigned to a stimulation sequence including, in differing order, motor, sensory, and sham stimulation. By using a stimulus intensity of 110% of rMT, a single evening session of low-frequency (1 Hz) rTMS over the 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-to-peak MEPs amplitude was also calculated at baseline (T0), after the first rTMS train (T1), and the whole procedure (T2). Results: At baseline, patients exhibited normal rMT, CMCT, MEPs latency and amplitude. CSP was shorter and remained shorter in patients than in controls after M1 and S1 stimulation. Clinically, patients reported a subjective improvement of initiating and maintaining sleep the night after S1-rTMS. Patients showed a decrease of rMT after S1-rTMS only, although the effect was smaller than in controls. Sham did not produce any variation. Smaller MEPs amplitude at T1 and T2 was found in all subjects, although this was significantly more pronounced in controls. Discussion: rTMS on S1-M1 connectivity may alleviate the clinical symptoms of RLS. Patients exhibited partial inhibitory rTMS-induced cortical plasticity over S1, and did not respond to M1 stimulation. TMS indexes of excitation and inhibition indicate an intracortical and cortico-spinal imbalance involving GABAergic and glutamatergic circuitries, and an impairment of the short-term mechanisms of cortical plasticity. The rTMS-induced activation of the dorsal striatum, with the consequent increase of dopamine release [3], may have contributed to the clinical and neurophysiological outcome. Conclusions: The distinctive TMS profile is useful for diagnosis and monitoring of RLS and it might be viewed as a target of novel drugs and non-invasive brain stimulation techniques modulating cortical networks.