Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients Elias Paolo Casula a, 1 , Mario Stampanoni Bassi a, b, 1 , Maria Concetta Pellicciari a, c , Viviana Ponzo a , Domenica Veniero a , Antonella Peppe a , Livia Brusa d , Paolo Stanzione d, e , Carlo Caltagirone a, b, d , Alessandro Stefani d , Giacomo Koch a, b, e, * a Non-Invasive Brain Stimulation Unit, Neurologia Clinica e Comportamentale, Fondazione Santa Lucia IRCCS, Rome, Italy b Department of System Medicine, Policlinico di Tor Vergata, Rome, Italy c Cognitive Neuroscience Section, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy d Department of Neurology, Sant’Eugenio Hospital, Rome, Italy e Stroke Unit, Policlinico Tor Vergata, Rome, Italy article info Article history: Received 29 May 2016 Received in revised form 5 September 2016 Accepted 14 October 2016 Keywords: Parkinson DBS L-dopa TMS EEG abstract Background: The effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood. Objectives: By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients. Methods: PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group. Results: STN-DBS enhanced early global TMS-evoked activity (~45e80ms) and high-alpha TMS-evoked oscillations (11e13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (~80e130ms) and beta TMS-evoked oscillations (13e30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values. Conclusions: Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity. © 2016 Elsevier Ltd. All rights reserved. 1. Introduction Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) represents an effective therapy in Parkinson's disease (PD). STN- DBS may exert its control on motor cortical activity through the modulation of basal ganglia-thalamo-cortical pathways, influ- encing intracortical inhibitory mechanisms. In particular, it is of interest to understand whether STN-DBS determines peculiar ef- fects on motor cortical activity, eventually different from those induced by L-Dopa (LD). It has been proposed that in the motor cortex STN-DBS has profound effect on the activity of specific intracortical circuits. Previous TMS studies showed consistently that STN-DBS restores mainly GABA-A dependent short intra- cortical inhibition (SICI) circuit closer to normal levels [1,2]. On the other hand, STN-DBS seems less effective in modulating late inhibitory processes such as long intracortical inhibition (LICI) [3] and cortical silent period (CSP) [3,4]. Previous works showed that STN-DBS alone has no effects on SP duration [1,3,4], but increases CSP duration if coupled with LD therapy [2]. This is consistent with previous work in PD patients not treated with STN-DBS showing * Corresponding author. Non invasive Brain Stimulation Unit, Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Fondazione S. Lucia, Via Ardeatina, 306, 00179, Rome, Italy. E-mail address: g.koch@hsantalucia.it (G. Koch). 1 These authors contributed equally to this work. Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis http://dx.doi.org/10.1016/j.parkreldis.2016.10.009 1353-8020/© 2016 Elsevier Ltd. All rights reserved. Parkinsonism and Related Disorders xxx (2016) 1e7 Please cite this article in press as: E.P. Casula, et al., Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.009