Objective: To examine the long-term effect of chronic treatment with safinamide 100 mg/day on specific Transcranial Magnetic Stimulation (TMS) measures of primary motor cortex (M1) excitability and plasticity in patients with Parkinson’s disease (PD).

Background: We have recently demonstrated that patients with PD have an abnormal Short Interval Intracortical Facilitation (SICF) reflecting a pathological enhancement in glutamatergic transmission in M1. Those abnormalities can be restored by a short-term treatment with safinamide at 100 mg/day which is thought to reduce glutamatergic transmission via blockade of voltage-gated sodium channels.

Method: 25 patients with PD underwent 3 separate experimental sessions: before starting safinamide (T0), after 2 weeks of safinamide 100 mg/day (T1) and after 12 months of safinamide 100 mg/day (T2). In each session patients were tested in both OFF and ON conditions. The clinical evaluation of motor signs and dyskinesias included MDS-UPDRS-III and UDysRS-III, respectively. The neurophysiological measures of M1 excitability included various TMS protocols such as Input/output curve, Short Interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF) and SICF. In a subgroup of 15 patients, as a measure of M1 plasticity, we examined and compared Motor Evoked Potentials (MEPs) amplitudes before and after intermittent Theta Burst Stimulation (iTBS).

Results: Patients had comparable scores at UPDRS-III and UDysRS-III at T0-T1-T2, indicating overall clinical stability over one-year of follow-up. In PD patients safinamide 100 mg/day restored the abnormally enhanced SICF at both T1 and T2 timepoints. Concerning plasticity measures, safinamide improved responses to iTBS at T1 and T2. Our data showed a significant correlation between the amount of drug-induced changes in  SICF and in responses to iTBS at T2.

Conclusion: Our results overall support the pathophysiological role of abnormally enhanced glutamatergic transmission in M1 in patients with PD. Safinamide at 100 mg/day induces a short-term as well as a long-term improvement of excitability and plasticity measures in M1 in patients with PD. These results support the antiglutamatergic effect of the drug when given at 100 mg/day.

References: [1] Sciaccaluga M, Mazzocchetti P, Bastioli G, Ghiglieri V, Cardinale A, Mosci P, et al. Effects of safinamide on the glutamatergic striatal network in experimental Parkinson’s disease. Neuropharmacology 2020;170:108024. [2] Guerra A, Suppa A, D’Onofrio V, Di Stasio F, Asci F, Fabbrini G, et al. Abnormal cortical facilitation and L-dopa-induced dyskinesia in Parkinson’s disease. Brain Stimulation 2019;12:1517–25. [3] Ziemann U. I-waves in motor cortex revisited. Exp Brain Res 2020;238:1601–10.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/long-term-effect-of-safinamide-on-primary-motor-cortex-excitability-and-plasticity-in-parkinsons-disease-a-tms-study/