Cued and self-paced action in Parkinson's disease

In our life we encounter many stimuli to which we need to react and act upon. The orchestration of these processes is vital for survival and is often impaired in the context of movement disorders. In Parkinson's disease (PD), progressive degeneration of midbrain dopaminergic neurons leads to increasing difficulty in action initiation.

What makes this clinically fascinating is a phenomenon that looks almost paradoxical. Give a patient an external cue — a sound, a line drawn on the floor to step over — and movement that was locked can suddenly release. This has led to the compelling hypothesis that self-initiated actions depend heavily on dopamine and on basal ganglia circuitry, while actions triggered by an external cue can recruit the brain differently, along a route the disease has spared. If that is right, it would explain why cueing works, and it would say something fundamental about how the brain decides to move.

The goal of this project is to understand the neurobiological underpinnings of the cueing phenomenon in PD. For this, I worked on the optimization of a novel head-fixed behavioral task where mice are trained to initiate and sustain locomotion on top of a rotating disk. The task was organized in blocks where self-paced movement initiation is rewarded, alternating with blocks where a reward is given only if movement initiation follows an auditory cue.

In the experiments I performed, I demonstrated that in a state of acute hypodopaminergia (to mimic that of PD patients), mice initiate less and with less vigour, but the number of initiations upon cue onset is maintained, despite the overall decrease in the total number of initiations. These results hint that the initiation of learned self-paced and cued movements might engage motor circuitry in distinct ways, as hypothesized.

This project is still ongoing in the lab and has since been funded by an ERC grant.