Cortical Disinhibition in Parkinson's Disease

Claudia Ammann; Michele Dileone; Cristina Pagge; Valentina Catanzaro; David Mata-Marín; Frida Hernández-Fernández; Mariana H. G. Monje; Álvaro Sánchez-Ferro; Beatriz Fernández-Rodríguez; Carmen Gasca-Salas; Jorge U. Máñez-Miró; Raul Martínez-Fernández; Lydia Vela-Desojo; Fernando Alonso-Frech; Antonio Oliviero; José A. Obeso; Guglielmo Foffani

Disclosures

Brain. 2020;143(11):3408-3421. 

In This Article

Abstract and Introduction

Abstract

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease.

Introduction

The neuropathology of Parkinson's disease is primarily defined by the degeneration of dopaminergic nigrostriatal projection neurons (Fearnley and Lees, 1991; Kordower et al., 2013), which generates profound alterations in the neural activity of cortico-basal ganglia motor loops, leading to a dysfunctional motor output (Obeso et al., 2008). Motor deficits have been repeatedly associated with changes in the activity of the motor cortex, both in Parkinson's disease animal models (Doudet et al., 1990; Goldberg et al., 2002; Escola et al., 2003; Guo et al., 2015; Pasquereau et al., 2016; Chen et al., 2019; Hyland et al., 2019) and in patients with Parkinson's disease (Lefaucheur 2005; Monchi et al., 2007; Disbrow et al., 2013). A key regulator of cortical motor output is the balance between excitation and inhibition, which can be assessed in humans with transcranial magnetic stimulation (TMS) techniques (Kujirai et al., 1993; Chen, 2004). Despite decades of investigation, whether or not cortical inhibition is altered in Parkinson's disease remains unclear.

A common measure to explore inhibitory mechanisms is the short-interval intracortical inhibition (SICI) induced by paired-pulse TMS stimuli. This measure is modulated primarily—but not only—by drugs acting upon γ-aminobutyric acid type a (GABAa) receptors (Ziemann et al., 2015). Several studies have described reduced SICI (i.e. less inhibition) in the motor cortex of patients with Parkinson's disease (Ridding et al., 1995; Strafella et al., 2000; Cunic et al., 2002; Buhmann et al., 2004; Fierro et al., 2008; Barbin et al., 2013; Kaçar et al., 2013; Bologna et al., 2018). However, high variability exists, at least partly due to small sample sizes, methodological differences among studies, and uncontrolled putative confounding factors (e.g. conditioning and unconditioned stimulus intensities, level of muscle contraction, etc.). Indeed, a considerable number of studies have failed to replicate the alteration of SICI (Berardelli et al., 1996; MacKinnon et al., 2005; Chu et al., 2009; Vacherot et al., 2010; Kojovic et al., 2017; Ponzo et al., 2017; Guerra et al., 2019). Overall, the disagreement between studies raises serious doubts about the actual role of SICI in Parkinson's disease (Latorre et al., 2019). Furthermore, even if SICI is altered in Parkinson's disease, it might be an indirect consequence of a shift in the excitation/inhibition balance towards excitation rather than a genuine loss of inhibition (MacKinnon et al., 2005; Peurala et al., 2008; Ni et al., 2013; Shirota et al., 2019). Finally, whether and how the possible loss of motor cortex inhibition, if any, may reflect the clinical state of patients and the evolution of the disease remains unclear (Strafella et al., 2000; Bares et al., 2003; Barbin et al., 2013; Kojovic et al., 2015; Shirota et al., 2019).

To address these issues, here we studied a relatively large sample of patients with Parkinson's disease (n = 166), applying paired-pulse TMS protocols (Figure 1) to their most affected side compared to healthy control subjects (n = 40). All patients were studied OFF medication. All data were analysed with fully automatic procedures to avoid possible confirmation bias, and several potential confounding factors—i.e. age, gender, resting motor threshold (RMT), background of EMG activity and amplitude of motor evoked potential (MEP) elicited by the single-pulse test stimuli—were systematically considered and excluded. To gain mechanistic insight about the cortical circuits involved, we investigated SICI with conditioning stimuli of relatively low intensity (80% RMT), which maximizes inhibition (Kujirai et al., 1993; Ibañez et al., 2020), and we tested whether conditioning stimuli with equal low intensity affected short-interval intracortical facilitation (SICF) and intracortical facilitation (ICF) in the same patients. Finally, to investigate whether the alterations in the excitation/inhibition balance may change throughout the evolution of the disease, we grouped patients as levodopa-naïve (n = 57), non-dyskinetic (n = 50) or dyskinetic (n = 59). In a subset of patients (n = 145), we also examined the clinically less affected side. At clinical presentation, motor features are typically restricted to one side of the body. Accordingly, our dataset included a number of very early de novo drug-naïve patients with minimal parkinsonian features in the less affected side [lateralized Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) = 0 or 1, n = 23]. We specifically investigated the minimally symptomatic side of those patients to gain insight into the prodromal stage of Parkinson's disease.

Figure 1.

Experimental procedures. (A) Schematic experimental set-up using TMS on the primary motor cortex inducing MEPs in the contralateral first dorsal interosseous (FDI) muscle. MEPs were recorded through EMG from the relaxed FDI muscle using disposable surface electrodes. (B) Representative examples of MEPs induced by single-pulse and paired-pulse TMS techniques. CS = conditioning stimulus; TS = test stimulus.

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