Functional motor network abnormalities associated with levodopa-induced dyskinesia in Parkinson's disease: A systematic review

Parkinson's disease (PD) can be effectively treated with levodopa and dopamine agonists but leads to levodopainduced dyskinesia (LID) in most patients in the long run. Various functional brain mapping techniques are used to explore alterations in motor networks associated with LID. This pre-registered review (PROSPERO: CRD42022320830) summarizes the motor network abnormalities reported in functional brain mapping studies of patients with LID. We included studies using functional MRI, EEG, PET, SPECT, or TMS and included at least 10 LID patients. For completeness, we included studies of 5-9 patients with LID in a table. Some of these were also incorporated into the review if other studies used the same method. Thirty studies met our pre-defined criteria. Patients with LID showed stronger motor-related activation and functional connectivity of motor and premotor cortical areas and the putamen after levodopa intake relative to PD patients without LID. Decreased activation was found in the right inferior frontal cortex. TMS studies showed increased cortical excitability and blunted cortical plasticity in patients with LID, while "inhibitory" repetitive TMS of prefrontal motor control areas and cerebellum produced transient anti-dyskinetic effects. Overall, sample sizes were small, the number of studies per mapping modality was limited, and most studies lacked independent replication. The alterations associated with LID encompass changes in functional activity, connectivity, cortical excitability, and plasticity in motor execution and motor control networks. A comprehensive understanding of how LID manifests at the motor network level will guide the future development of stimulation-based network therapies for LID.