Levodopa induced dyskinesia severity is linked to distinct microstructural alterations in nigrostriatal and brainwide neural circuits

Dopaminergic replacement therapy via L-DOPA is the major medical therapy for Parkinsons Disease. Long-term L-DOPA administration is known to cause dyskinetic movements, L-DOPA Induced Dyskinesia (LID). It remains unclear if the LID related, maladaptive changes in brain structure/function are localized to neural circuits within the nigrostriatal DA system or have brainwide impact. We employed multi-shell diffusion magnetic resonance imaging and correlational tractography to investigate structural brain networks associated with daily administration of L-DOPA and the development of LID in the unilateral 6-hydroxydopamine rat model. 53% of rats receiving L-DOPA therapy developed severe LID. Tractography found brainwide statistical maps positively and negatively associated with LID severity highlighted by bilateral neural circuits contained in the lesioned nigrostriatal system as well as others including the cerebellum and prefrontal cortex. These results suggest that systemic dysfuntion in brainwide neural circuits forms the mechanistic basis the maladaptive changes underlying LID.