The role of Dopamine in Preparatory Inhibition: What can we learn from Parkinson’s disease?

• ¹ Institut de Neuroscience, Université Catholique de Louvain, Belgium
• ² Cliniques Universitaires Saint-Luc, Belgium
• ³ Université Catholique de Louvain, Belgium

Planning, initiating and executing movements correctly is one of the most important requirements to assure a smooth course within our daily lives. To do so, we depend on intact anatomical and functional connections, starting in the frontal cortex and ending in our muscles. This corticospinal tract – also called the “motor output pathway” – allows muscle activity to be regulated in an effective way by central neural structures. This pathway may thus lie at the basis of goal-oriented behaviour by being subject to not only facilitatory but also inhibitory influences, the latter being highly necessary to suppress any tendency towards inappropriate movements. In humans, the excitability of the corticospinal pathway can be investigated non-invasively: By applying single-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), one can elicit motor-evoked potentials (MEPs) measured by electromyography recorded in targeted contralateral muscles (Bestmann & Duque, 2016; Bestmann & Krakauer, 2015). The amplitude of elicited MEPs reflects the sum of all facilitatory and inhibitory inputs acting at the time of the TMS pulse and hence provides temporally precise and muscle-specific measures of the excitability of the motor output pathway (Hannah & Rothwell, 2017; Niemann, Wiegel, Kurz, Rothwell, & Leukel, 2018). Over the last years, TMS studies have revealed the existence of a profound suppression of corticospinal excitability when preparing a voluntary movement: when MEPs are elicited during action preparation, their amplitude is lower than when elicited at rest (Bestmann & Duque, 2016; Duque, Greenhouse, Labruna, & Ivry, 2017; Duque, Lew, Mazzocchio, Olivier, & Ivry, 2010). This phenomenon – called “preparatory inhibition” – still remains a matter of investigation and debate: neither its functional role as part of action preparation nor the neural structures at its basis have been clearly elucidated yet. Although some cortical regions have already been shown to play a role in preparatory inhibition (Badre & D'Esposito, 2009; Duque, Labruna, Verset, Olivier, & Ivry, 2012; Duque, Olivier, & Rushworth, 2013; Ebbesen & Brecht, 2017; Filevich, Kuhn, & Haggard, 2012; Mars et al., 2009; Tanji & Hoshi, 2008), the knowledge about the brain regions implicated in this phenomenon remains quite limited. Among other potential structures contributing to corticospinal inhibition during action preparation, interesting candidates are the basal ganglia (BG). Indeed, these subcortical structures are known to be able to inhibit the motor system via their action on the motor part of the thalamus (Parent & Hazrati, 1995a, 1995b; Wessel & Aron, 2017). Furthermore, they are known to be dysfunctional in hypokinetic disorders (characterised by insufficient movement) (Jahanshahi, Obeso, Baunez, Alegre, & Krack, 2015; Obeso et al., 2014; Wessel et al., 2016) like Parkinson’s disease (PD). This disease results from an alteration in the functioning of BG mainly due to a degeneration of dopaminergic neurons projecting to the dorsal striatum, the main input structure of the BG (Kalia & Lang, 2015; Poewe et al., 2017), which leads to the typical motor symptoms of PD. PD hence is classically treated by dopamine replacement therapy (Fox et al., 2018). Investigating preparatory inhibition in PD patients therefore represents a unique opportunity to study the role of BG and dopamine levels (within the BG) in the generation of motor inhibition during action preparation. In the present study, preparatory inhibition was assessed on two consecutive days in 8 PD patients (ON and OFF dopamine medication [L-DOPA]; randomized order) and 8 healthy control subjects. Participants had to perform an instructed-delay choice reaction-time task, in which a cue provided advance information about which index finger response to make (left or right). Importantly, they had to wait until the occurrence of an imperative signal to release their movement (Wilhelm, Grandjean, & Duque, 2017; Quoilin, Lambert, Jacob, Klein, & Duque, 2016). Single-pulse TMS was applied over both M1 while participants were performing the task, either during the inter-trial interval (TMSbaseline) or before the onset of the imperative signal, when they were preparing their response (TMSdelay). Preparatory inhibition was then assessed by expressing MEP amplitudes obtained at TMSdelay relatively to those obtained at TMSbaseline; motor inhibition was evident when the MEP amplitude probed at TMSdelay was lower compared to the one probed at TMSbaseline. Interestingly, since TMS was applied over the left and right M1 at a nearly simultaneous time (interval of 1 ms between the two impulses), MEPs could be obtained in both hands for each trial; this was done using a double-coil technique recently developed in our laboratory (Grandjean et al., 2018; Vassiliadis et al., 2018; Wilhelm, Quoilin, Petitjean, & Duque, 2016). Our preliminary results show a suppression of MEP amplitudes at TMSdelay compared to TMSbaseline, both in healthy control subjects and in PD patients. This confirms the presence of preparatory inhibition in healthy subjects and suggests the existence of a similar process in PD patients. Most importantly, L-DOPA medication appears to decrease both the strength of preparatory inhibition and its stability during action preparation, suggesting a central role of dopamine in the mechanisms at the very basis of preparatory inhibition. Data acquisition is still ongoing and additional analyses will be needed to shed more light on these preliminary results. LAY SUMMARY: Recent transcranial magnetic stimulation studies have shown that the motor output pathway shows a profound inhibition during the preparation of an action. This phenomenon, called “preparatory inhibition”, remains incompletely understood, as it is still unclear which neural structures support it and what function it exactly serves during action preparation. In the current study, we tested this preparatory inhibition in Parkinson’s disease (PD) patients and matched healthy control subjects. The aim was to better understand the role of basal ganglia (which are dysfunctional in PD) and the influence of dopamine replacement therapy on motor inhibition during action preparation.