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

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.

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.

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.

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.