Corticospinal suppression underlying intact movement preparation fades in late Parkinson’s disease

Abstract

In Parkinson's disease, neurophysiological abnormalities within the primary motor cortex have been shown to contribute to cardinal symptoms such as bradykinesia, but the exact modalities are still uncertain. Here, we propose that such impairment could involve alterations of mechanisms shaping motor activity specifically during voluntary movement preparation. Indeed, several past studies in healthy populations have suggested that a strong suppression of corticospinal excitability, called ''preparatory suppression'', propels movement execution by increasing motor neural gain. Thus, we hypothesized that a gradual alteration to this mechanism may contribute to progressive motor slowness in Parkinson's disease. We also predicted a benefit of dopamine medication in restoring correct motor neural activity during action preparation. To test these hypotheses, we investigated preparatory suppression on two consecutive days in 29 Parkinson's disease patients (ON and OFF medication) and 29 matched healthy controls. Single-pulse transcranial magnetic stimulation was applied over both primary motor cortices, eliciting concurrent motor-evoked potentials in the two hands, while subjects were either at rest or prepared a left- or right-hand response in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing the amplitude of motor potentials evoked during movement preparation relative to those obtained at rest. These neurophysiological measures were cross-analysed with task behaviour and clinical data. Contrary to healthy controls, Parkinson's disease patients showed a lack of preparatory suppression, which appeared to depend on disease progression, but not on dopamine medication. Indeed, in relatively early disease stages, patients still exhibited partial preparatory suppression, while in later stages, they lacked it completely and even exhibited a tendency for corticospinal facilitation in the hand selected for movement execution. As expected, patients also showed increasing motor handicap with disease progression as well as a decreased movement velocity during the task, but such findings did not directly correlate with levels of preparatory suppression in our cohort. While dopamine medication had no effect on the latter, it did however globally reduce raw corticospinal excitability in the dominant hand. Taken together, our results are in line with the idea that a lack of corticospinal suppression during movement preparation in Parkinson's disease slows down response execution and illustrate the importance of considering disease stages in such investigations; they also suggest differential roles of dopamine in shaping corticospinal output in those patients. Our findings thus support the use of task-related functional markers such as preparatory suppression in future studies on motor impairment in Parkinson's disease.

Corticospinal excitability reductions during action preparation and action stopping in humans: Different sides of the same inhibitory coin?

“…Finally, a recent study investigating preparatory CSE in Parkinson's disease revealed a lack of spTMS MEP reductions in patients compared to healthy controls (Wilhelm et al, 2022). Interestingly, the degree of altered preparatory CSE reductions was found to increase with disease duration and tended to correlate with motor impairments, suggesting a potential association between preparatory CSE and motor impairments (Wilhelm et al, 2022).…”

From Inhibition to Excitation and Why: The Role of Temporal Urgency in Modulating Corticospinal Activity

“…In conditions like Parkinson's disease (PD), which is associated with cognitive dysfunction and can affect patients early on(Dirnberger & Jahanshahi, 2013), there is some evidence supporting this idea. More relevant to our conceptual model, recent work byWilhelm et al (2022) found that PD patients display reduced CS suppression during movement preparation in comparison to healthy control individuals. Relatedly, alcohol dependent individuals and binge drinkers, who commonly show abnormalities in prefrontal networks, show a similar impairment of CS suppression during action preparation(Grandjean…”