Longitudinal changes in effective connectivity associated with worsening freezing of gait in Parkinson's disease: a...

Freezing of gait (FOG) is a key contributor to gait impairment in people with Parkinson's disease (PD). Previously, we found freezing-specific increased effective connectivity from the dorsolateral prefrontal cortex (DLPFC) to the mesencephalic locomotor region (MLR), but it is yet unknown whether effective connectivity changes with FOG progression.

The primary objective of this study was to evaluate effective connectivity changes in freezers over time and their association with gray matter structural alterations.

In this longitudinal study, spanning 2 years, we analyzed 51 patients (27 freezers and 24 non-freezers) for the main effective connectivity, and 88 patients (44 freezers and 44 non-freezers) and 37 age-matched healthy controls for structural volume analysis. Spectral dynamic causal modeling (DCM) with hierarchical empirical Bayes approaches was performed.

Freezers reported a significant worsening of FOG over time. Longitudinally, abnormally increased functional connectivity was observed between the bilateral cerebellar lobule VIIb and the MLR. Spectral DCM revealed that the previously identified increase in DLPFC-to-MLR effective connectivity was lost at follow-up. In contrast, an increased inhibitory effective connectivity from the left cerebellar lobule VIIb to the right MLR emerged (posterior probability > 0.99). This was associated with slower FOG progression, but not with structural volume changes.

We found that the pattern of FOG-related effective connectivity changed over time, characterized by increasing inhibitory connectivity from the cerebellum to MLR, while frontal compensatory influences were no longer apparent. Future study needs to focus on how compensatory cortical mechanisms could be optimized to counteract FOG progression.

This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR 000036570) on 22 April 2019.