Modulatory Effect of Levodopa on the Basal Ganglia-Cerebellum Connectivity in Parkinson’s Disease

Abstract Levodopa has remained the mainstay of medical therapy for Parkinson’s disease since its development in the 1980s. However, long-term medication use is associated with declining clinical efficacy and the emergence of motor complications. Unveiling the effects of levodopa on brain functional reorganisation at a relatively early treatment phase is therefore imperative to inform the optimisation of Parkinson’s therapeutics. In this study, we comprehensively investigated levodopa’s modulation on the resting-state functional connectivity in the cortico- basal ganglia-cerebellum system at regional and network levels, with dual cross-sectional and longitudinal designs. The data was extracted from the Parkinson’s Progression Marker Initiative (PPMI) dataset. The cross-sectional patient groups comprised 17 Parkinson’s patients on stable levodopa medication and 15 drug-naïve patients, while the longitudinal set included 14 Parkinson’s patients measured at both drug-naïve and levodopa-medicated conditions. With nodes defined across cortical, basal ganglia, and cerebellar networks, we conducted univariate comparisons of the internodal connectivity strength between the medication conditions using nonparametric permutation. At the network level, we computed multivariate combinations of individual connections within and between the networks, followed by an assessment of their discriminative capabilities on patients’ medication classes using supervised machine learning. The univariate seed-based approach showed no statistically significant effect of levodopa in either dataset. However, the network connectivity pattern between basal ganglia and the cerebellum displayed a robust classification power in the longitudinal dataset and a similar trend was observed in the cross-sectional. The role of the cerebellum is often overlooked in previous functional integration investigations of Parkinson’s disease and levodopa effects. Considering the recent evidence suggesting the bidirectional communications between the cerebellum and basal ganglia networks, our study provides further insight into the importance of inter-network functional connectivity in Parkinson’s, as well as in the functional and plastic processes following levodopa medication.