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

Emmanuelle Wilhelm1, 2*, Caroline Quoilin1, Gerard Derosiere1, Vincent Leroux3, Brice Virlee3, Anne Jeanjean2 and Julie Duque1*
  • 1 Institute of NeuroScience, Université Catholique de Louvain, Belgium
  • 2 Cliniques Universitaires Saint-Luc, Belgium
  • 3 Catholic University of 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 [1, 2]. 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 [3, 4]. 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 [1, 5, 6]. 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 [7-13], taken together, 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 [14-16]. Furthermore, they are known to be dysfunctional in hypokinetic disorders (characterised by insufficient movement) [17-19] 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 [20, 21], which leads to the typical motor symptoms of PD. PD hence is classically treated by dopamine replacement therapy (DRT) [22]. 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 11 PD patients (ON and OFF dopamine replacement therapy; randomized order) and 11 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 [23, 24]. Single-pulse TMS was applied over both M1 while participants were performing the task, either during the inter-trial interval (baseline) or before the onset of the imperative signal, when they were preparing their response (delay). 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), for each trial MEPs could be obtained in both hands; this was done using a double-coil technique recently developed in our laboratory [25-27]. Our preliminary results show that PD patients with a relatively short disease duration (4 ± 1.3 y) exhibited MEP suppression during action preparation, similarly to healthy subjects. However, preparatory inhibition was less obvious in PD patients with a long disease duration (12.3 ± 2.3 y). In fact, in those patients, MEPs were only suppressed when the finger was not selected for the response. Interestingly, the lack of suppression found in the selected finger was even worse in the presence of DRT, especially in the dominant hand, where MEPs became facilitated. Taken together, those results confirm the presence of preparatory inhibition in healthy subjects, as previously shown in the literature. This phenomenon is also evident in PD patients, but seems to decline throughout the disease. Most importantly, DRT medication appears to decrease the strength of preparatory inhibition, especially in the dominant hand, suggesting a role of dopamine in the mechanisms at the very basis of preparatory inhibition.

Acknowledgements

This work was supported by grants from the “Fonds Spéciaux de Recherche” (FSR) of the Université catholique de Louvain, the Belgian National Funds for Scientific Research (FRS – FNRS: MIS F.4512.14) and the “Fondation Médicale Reine Elisabeth” (FMRE). EW is a doctorate student supported by the L'Oréal-UNESCO "For Women in Science" program and the FRS – FNRS. CQ and GD are postdoctoral fellows supported by the FRS – FNRS.

References

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Keywords: Transcranial Magnetic Stimulation, Parkinson's disease, Dopamine, motor control, Basal Ganglia

Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019.

Presentation Type: Poster presentation

Topic: Behavioral/Systems Neuroscience

Citation: Wilhelm E, Quoilin C, Derosiere G, Leroux V, Virlee B, Jeanjean A and Duque J (2019). The role of Dopamine in Preparatory Inhibition: What can we learn from Parkinson’s disease?. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00053

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Received: 24 Apr 2019; Published Online: 27 Sep 2019.

* Correspondence:
MD. Emmanuelle Wilhelm, Institute of NeuroScience, Université Catholique de Louvain, Louvain-la-Neuve, Walloon Brabant, 1200 Brussels, Belgium, emmanuelle.wilhelm@uclouvain.be
Prof. Julie Duque, Institute of NeuroScience, Université Catholique de Louvain, Louvain-la-Neuve, Walloon Brabant, 1200 Brussels, Belgium, julie.duque@uclouvain.be