Effects of levodopa on motor and cerebellar network connectivity in Parkinson's disease.

Background: Levodopa is the most effective treatment for motor symptoms in Parkinson's disease (PD), but its therapeutic mechanisms and effects on resting-state functional connectivity (FC) remain incompletely understood. This study aims to investigate the acute impact of levodopa on FC within motor-related networks in PD.

Methods: Twenty-seven patients with PD underwent resting-state functional magnetic resonance imaging on 2 consecutive days under OFF and ON dopaminergic therapy conditions. Ten age-matched healthy controls were included for comparison. FC analyses targeted 57 regions of interest (ROIs) across the basal ganglia, motor cortex, and cerebellum, assessed using ROI-to-ROI connectivity and graph theory.

Results: Levodopa altered FC in motor circuits, with six connections increasing and seven decreasing. Key changes involved enhanced FC between the right globus pallidus externa and left pre-supplementary motor area, and reduced FC between the right cerebellum 10 and bilateral primary motor cortex. These changes were correlated with improvements in UPDRS-III scores. Graph metrics revealed increased clustering in the right cerebellar Crus I and reduced global efficiency in the left primary motor cortex.

Conclusions: Levodopa modulates FC in motor-related networks in PD, enhancing cerebellar and PPN connectivity while reducing cortical coupling. These changes, reflected in graph-theoretical metrics, suggest a shift from global integration toward a more modular and locally segregated organization. This reconfiguration may underlie levodopa's therapeutic effects on motor symptoms.