Pathogenesis and Intervention Strategies for Motor Complications in Parkinson's Disease

Parkinsons disease (PD) and its motor complications, including levodopa-induced dyskinesia and end-of-dose off periods, profoundly diminish patient quality of life. Despite extensive research, the underlying biological mechanisms of these fluctuations remain only partially understood. In this Review, we integrate clinical and experimental evidence demonstrating that intermittent dopaminergic therapy drives remodeling of basal ganglia circuits, induces maladaptive alterations in corticostriatal synaptic plasticity, and sustains chronic neuroinflammation through microglial activation. We examine the prevalence and clinical manifestations of dyskinesia and off phenomena, then critically compare three principal intervention domains: optimized pharmacotherapy with continuous-release formulations and adjunctive agents, deep brain stimulation targeting the subthalamic nucleus or globus pallidus interna, and structured rehabilitation programs encompassing balance, gait training, strength exercises and neurofeedback. Across diverse studies, continuous drug delivery yields more stable motor control, deep brain stimulation reduces fluctuations and dyskinesia, and early, personalized rehabilitation enhances gait and posture. We further show that combining these approaches produces synergistic improvements that exceed those achieved by any single strategy. Finally, we propose a precision medicine framework that stratifies patients by demographic and molecular biomarkers to guide the timing and sequence of multimodal treatments, charting a path toward truly personalized management of PD motor complications.