l-DOPA and cortical associative plasticity in Parkinson’s disease

Clinical Neurophysiology xxx (2012) xxx–xxx

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Editorial L-DOPA

and cortical associative plasticity in Parkinson’s disease

Over the last decade, an increasing number of studies in humans have investigated long-term potentiation/depression (LTP/LTD)-like plasticity in primary motor cortex (M1) noninvasively by means of the paired associative stimulation (PAS) technique. PAS requires repetitive cortical and peripheral nerve stimuli (i.e. M1 and median nerve, respectively), delivered at specific interstimulus intervals (ISI). When M1 stimulation follows electric stimulation of the contralateral nerve at 21.5 or 25 ms ISI, the peak-to-peak amplitude of the motor evoked potentials (MEPs) recorded from intrinsic hand muscles increases, whereas after PAS at 10 ms, MEP amplitudes decrease for about 30– 60 min, reflecting LTP/LTD-like cortical associative plasticity (Stefan et al., 2000; Ziemann and Siebner, 2008; Suppa and Berardelli, 2012). Several studies have reported abnormally reduced responses to PAS in patients with PD, compared with healthy subjects, which points to decreased cortical associative plasticity in PD (Ueki et al., 2006; Morgante et al., 2006; Schwingenschuh et al., 2010). One previous study has instead reported enhanced PAS responses in PD patients, suggesting increased cortical associative plasticity in PD (Bagnato et al., 2006). A number of factors might have contributed to these contrasting results, including the clinical heterogeneity of the patient cohorts studied, the stage of the disease and possible confounders due to dopaminergic replacement (Bologna et al., 2012). A recent study testing responses to PAS from both hemispheres in ‘‘de novo’’ patients with PD and asymmetric symptoms has reported reduced PAS-induced LTP-like plasticity in the ‘‘more affected’’ hemisphere, and increased cortical associative plasticity in the ‘‘less-affected’’ hemisphere, thus suggesting compensatory functional sensorimotor reorganization in the early phase of PD (Kojovic et al., 2012). The varying degree of response to PAS in the ‘‘more affected’’ and ‘‘less affected’’ hemisphere in PD patients with asymmetric symptoms might at least partly explain the contrasting results in the previous PAS studies (Bagnato et al., 2006; Ueki et al., 2006; Morgante et al., 2006; Schwingenschuh et al., 2010). As regards possible confounders due to dopaminergic replacement on cortical associative plasticity in PD, it is worth noting that compelling evidence attributes a dose-dependent inverted ‘‘U-shape’’ effect to L-DOPA on cortical plasticity in both healthy subjects (Monte-Silva et al., 2010; Thirugnanasambandam et al., 2011) and parkinsonian patients (Huang et al., 2011). In addition, 12 h after drug withdrawal, the acute effects of L-DOPA on cortical plasticity in de novo as well as in chronically treated PD patients may differ significantly depending on the specific experimental condition tested (Bagnato et al., 2006; Ueki et al., 2006; Morgante et al., 2006; Schwingenschuh et al., 2010; Suppa et al., 2010, 2011; Huang et al., 2011; Kishore et al., 2012). Lastly, the influence of a LDOPA challenge 12 h after drug withdrawal may also vary depend-

ing on the different stages of PD. The long-lasting pharmacological effects of L-DOPA in the early phases of the disease might imply that patients should not be considered ‘‘off’’ therapy after only 12 h following drug withdrawal. The present issue of Clinical Neurophysiology includes a study by Kacˇar et al. (2013) that sheds light on the influence of L-DOPA on cortical associative plasticity in patients with PD. The main aim of the study (Kacˇar et al., in this issue) was to evaluate a possible confounding effect of chronic exposure to L-DOPA in patients with advanced PD. For this purpose, Kacˇar et al. (2013) compared responses to facilitatory PAS in two cohorts of advanced PD patients: the first group included chronically and optimally treated patients (Hoehn & Yahr – H&Y: 2.4; Unified Parkinson’s Disease Rating scale – UPDRS: 30.6; Disease Duration: 5 years, range 2– 15 years), while the second group included patients with advanced PD (H&Y: 2; UPDRS: 31.5; Disease Duration: 2.6 years, range 1– 8 years) who had never taken dopaminergic drugs owing to various socio-economic reasons. Both PD cohorts were comparable in terms of clinical and demographic features, including age, age at disease onset, disease severity and disease duration, and both included patients without any cognitive and motor side effects or complications. Kacˇar et al. (2013) found that facilitatory responses to PAS were reduced in both cohorts of chronically treated and drug naïve parkinsonian patients when compared with healthy subjects. Hence, their study suggests that, in advanced PD, cortical associative plasticity is impaired regardless of previous chronic exposure to L-DOPA. In addition, the altered cortical associative plasticity observed in PD cannot be restored by an acute L-DOPA challenge. The study by Kacˇar et al. (2013) also focused on another important issue, i.e. whether cortical associative plasticity in advanced PD depends on baseline M1 excitability, as has been suggested in studies on healthy human subjects (Ziemann and Siebner, 2008). In PD, several studies have demonstrated a number of abnormalities in M1 excitability, including increased corticospinal excitability (i.e. the steepness of the input–output curve), reduced short-latency intracortical inhibition, enhanced long-interval intracortical inhibition, shortened cortical silent period, and reduced long-latency afferent inhibition (Chen et al., 2008; Berardelli et al., 2008). Hence, when previous PAS studies on PD are compared, it should be borne in mind that differences in baseline excitability might have influenced the degree of cortical plasticity induced by PAS. Accordingly, the study by Kacˇar et al. (2013) also included extensive and detailed measurements of baseline excitability performed by applying a number of single and paired pulse TMS techniques. The authors found that the degree of short-latency intracortical inhibition and the steepness of the input–output curve were both reduced at baseline in chronically treated as well as in drug naïve patients,

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Editorial / Clinical Neurophysiology xxx (2012) xxx–xxx

compared with healthy controls, and that the extent of the abnormalities was similar in both groups. This finding indicates that chronic exposure to L-DOPA does not significantly affect the extent of M1 excitability abnormalities in PD and suggests that the response to PAS in PD does not merely reflect baseline abnormalities in excitability. Yet another aim of the study by Kacˇar et al. (2013) was to verify whether PAS affects the excitability of specific M1 intracortical circuits, including those mediating short-latency intracortical inhibition and the input–output curve, and whether PAS-induced changes differ in drug naïve and in chronically treated parkinsonian patients. By comparing M1 excitability before and at different time points after PAS, the authors found that PAS left the abnormal M1 excitability observed at baseline unchanged in both groups of parkinsonian patients, with the exception of a drop in intracortical facilitation in drug naïve patients 30 min after PAS. Lastly, Kacˇar et al. (2013) assessed the possible correlation between clinical (i.e. UPDRS sub-items for bradykinesia, rigidity and tremor) and neurophysiological (i.e. excitability and plasticity variables) features in the two cohorts of PD patients. No correlation between the clinical and neurophysiological variables emerged in either group of patients. Overall, these findings suggest that chronic exposure to L-DOPA in advanced PD does not significantly influence abnormalities in M1 excitability and plasticity and that an acute L-DOPA challenge fails to restore such abnormalities. In conclusion, the study by Kacˇar et al. (2013) confirms and extends previous observations supporting the hypothesis that impaired cortical associative plasticity in PD occurs in the early phase of the disease and does not reflect chronic exposure to LDOPA. Whether impaired cortical associative plasticity reflects a primary or compensatory phenomena adopted in the motor system to improve motor symptoms in PD is, instead, a question that has yet to be clarified. References Bagnato S, Agostino R, Modugno N, Quartarone A, Berardelli A. Plasticity of the motor cortex in Parkinson’s disease patients on and off therapy. Mov Disord 2006;21:639–45. Berardelli A, Abbruzzese G, Chen R, Orth M, Ridding MC, Stinear C, et al. Consensus paper on short-interval intracortical inhibition and other transcranial magnetic stimulation intracortical paradigms in movement disorders. Brain Stimul 2008;1:183–91. Bologna M, Conte A, Suppa A, Berardelli A. Motor cortex plasticity in Parkinson’s disease: advances and controversies. Clin Neurophysiol 2012;123:640–1. Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119:504–32. Huang YZ, Rothwell JC, Lu CS, Chuang WL, Chen RS. Abnormal bidirectional plasticity-like effects in Parkinson’s disease. Brain 2011;134:2312–20.

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Antonio Suppa Matteo Bologna IRCCS Neuromed Institute, Italy Alfredo Berardelli Department of Neurology and Psychiatry and Neuromed Institute, ‘‘Sapienza’’ University of Rome, Viale dell’Università 30, 00185 Rome, Italy Tel./fax: +39 06 49914700 E-mail address: [email protected]