Andrea Guerra1, Antonio Suppa2, Valentina D'Onofrio3, Flavio Di Stasio1, Francesco Asci3, Giovanni Fabbrini2, Alfredo Berardelli4. 1. IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy. 2. IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy; Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università 30, 00185, Rome, Italy. 3. Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università 30, 00185, Rome, Italy. 4. IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy; Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università 30, 00185, Rome, Italy. Electronic address: alfredo.berardelli@uniroma1.it.
Abstract
BACKGROUND: Animal models of Parkinson's Disease (PD) demonstrated increased facilitatory cortico-striatal activity, reflecting overactive glutamatergic neurotransmission and contributing to the pathophysiology of l-dopa induced dyskinesias (LIDs). OBJECTIVE: To assess different facilitatory intracortical circuits in the primary motor cortex (M1) in patients with PD and LIDs by means of a combination of transcranial magnetic stimulation (TMS) protocols. METHODS: We tested the Input/Output (I/O) curve, intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) at baseline (T0), 'OFF' and 'ON' state, in 20 PD patients with LIDs. The same parameters were examined after 2 weeks of chronic intake of 50 mg (T1) and 100 mg/day (T2) of safinamide. Finally, we tested SICF in a further group of patients without LIDs. RESULTS: At T0, patients with LIDs showed increased I/O curve steepness, which was partly ameliorated by l-dopa. These patients also had normal ICF, and abnormally increased SICF, which did not change with l-dopa. Safinamide improved the I/O curve both at T1 and T2, it reduced SICF at T1 and normalized this measure at T2. In patients with PD and LIDs, SICF correlated with the severity of dyskinesia. In patients without LIDs, SICF was less prominently abnormal and responsive to l-dopa. CONCLUSIONS: Patients with PD and LIDs have abnormal cortical facilitation, possibly suggesting overactive glutamatergic neurotransmission in specific circuits within M1. Although not responsive to l-dopa, this dysfunction is restored by the anti-glutamatergic properties of safinamide 100 mg. The results suggest that the abnormal cortical facilitation in M1 contributes to the pathophysiology of LIDs.
BACKGROUND: Animal models of Parkinson's Disease (PD) demonstrated increased facilitatory cortico-striatal activity, reflecting overactive glutamatergic neurotransmission and contributing to the pathophysiology of l-dopa induced dyskinesias (LIDs). OBJECTIVE: To assess different facilitatory intracortical circuits in the primary motor cortex (M1) in patients with PD and LIDs by means of a combination of transcranial magnetic stimulation (TMS) protocols. METHODS: We tested the Input/Output (I/O) curve, intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) at baseline (T0), 'OFF' and 'ON' state, in 20 PDpatients with LIDs. The same parameters were examined after 2 weeks of chronic intake of 50 mg (T1) and 100 mg/day (T2) of safinamide. Finally, we tested SICF in a further group of patients without LIDs. RESULTS: At T0, patients with LIDs showed increased I/O curve steepness, which was partly ameliorated by l-dopa. These patients also had normal ICF, and abnormally increased SICF, which did not change with l-dopa. Safinamide improved the I/O curve both at T1 and T2, it reduced SICF at T1 and normalized this measure at T2. In patients with PD and LIDs, SICF correlated with the severity of dyskinesia. In patients without LIDs, SICF was less prominently abnormal and responsive to l-dopa. CONCLUSIONS:Patients with PD and LIDs have abnormal cortical facilitation, possibly suggesting overactive glutamatergic neurotransmission in specific circuits within M1. Although not responsive to l-dopa, this dysfunction is restored by the anti-glutamatergic properties of safinamide 100 mg. The results suggest that the abnormal cortical facilitation in M1 contributes to the pathophysiology of LIDs.
Authors: Robert Chen; Alfredo Berardelli; Amitabh Bhattacharya; Matteo Bologna; Kai-Hsiang Stanley Chen; Alfonso Fasano; Rick C Helmich; William D Hutchison; Nitish Kamble; Andrea A Kühn; Antonella Macerollo; Wolf-Julian Neumann; Pramod Kumar Pal; Giulia Paparella; Antonio Suppa; Kaviraja Udupa Journal: Clin Neurophysiol Pract Date: 2022-06-30