Disabling levodopa-induced dyskinesia in Parkinson’s disease: the role of sleep

Background:

During wake and sleep, synaptic strength is regulated by counterbalancing homeostatic processes. Specifically, during wake, synaptic upscaling is followed by selective downscaling mechanisms during slow wave sleep (SWS). Patients with levodopa-induced dyskinesia (LID) have been observed to have changes in SWS. Furthermore, a pathologically sustained slow wave activity (SWA) during SWS, which is known to be the marker and effector of the downscaling process, is observed in PD patients with LID. The disruption of the SWA-mediated normalization of cortical plasticity is associated with the development of LID.

Leading hypothesis:

The lack of an apparent decrease in SWA content throughout the night in LID patients could be due to impaired SWA-mediated downscaling or a lower build-up, resulting in a flooring effect. Previous findings support the first hypothesis. To confirm this hypothesis, we aim to investigate the build-up process during wake. Specifically, we hypothesize that dyskinetic patients may exhibit greater theta activity in the morning due to impaired downscaling function, and that this amount would remain relatively stable throughout the day.

Specific aims:

Our observational case-control study includes three groups of PD patients at different stages of the disease and healthy control subjects. We will perform Hd-EEG recordings early in the morning, after a whole night of sleep, and later in the evening. We will compare the amount of theta activity and its increment between the two recordings between groups. Furthermore, we will explore the downscaling process in the same subjects by performing whole-night polysomnographic recordings. This will help us to have a comprehensive understanding of both the build-up and downscaling mechanisms. We will also evaluate the relationship between the amount of theta activity, the performance of the subjects at cognitive tasks, and their clinical features.

Expected value:

Investigating the association between the build-up process, the downscaling process, and LID would help establish a causal relationship between an alteration in this homeostatic process and the development of a disabling treatment-related complication. This project is of great interest for understanding the fundamental pathophysiological features of PD and has great potential to provide new directions in the clinical treatment of LID. Furthermore, investigating the link between EEG theta and SWA will help to clarify to what extent EEG theta reflects encoding-related synaptic upscaling.