Neurodegeneration epicenters: Distinct network mechanisms of dopaminergic treatment in Parkinson's disease.

Parkinson's disease exhibits heterogeneous spatiotemporal patterns of neurodegeneration. Dopaminergic therapy improves motor symptoms by modulating brain function in affected regions, yet whether the neural mechanisms through which dopaminergic therapy exerts its effects are linked to this heterogeneity of neurodegeneration remains unclear. A connectivity-based epicenter framework combined with spectral dynamic causal modeling was applied to resting-state functional magnetic resonance imaging data from 160 drug-naïve Parkinson's disease patients and 174 healthy controls to identify subtype-specific degenerative epicenters and characterize directional interactions among affected regions. Ninety-seven patients additionally underwent an acute levodopa challenge to evaluate how dopaminergic modulation influences these interactions and relates to symptom improvements. Two distinct Parkinson's disease subtypes were identified: subtype 1 was characterized by degenerative epicenters predominantly located in subcortical and cerebellar regions, whereas subtype 2 exhibited epicenters primarily involving cortical regions. Both subtypes exhibited widespread dysregulation of directional interactions among epicenter regions relative to healthy controls. Levodopa treatment partially reversed these network abnormalities in a manner specific to each subtype, notably within cerebellar vermis in subtype 1 and frontal cortex in subtype 2. Symptom improvements were linked to distinct network interactions: in subtype 1, tremor correlated with the thalamus, midbrain nuclei, and cerebellar vermis, whereas bradykinesia primarily involved the cerebellar vermis; in subtype 2, rigidity improvements mapped to frontal cortex and limbic regions, and bradykinesia to limbic regions. These findings suggest that Parkinson's disease involves distinct epicenter networks in each subtype, with widespread directional dysregulation contributing to symptom diversity in patients. Levodopa treatment selectively modulates these network interactions, shedding light on the mechanisms underlying treatment heterogeneity and guiding precision-targeted therapeutic strategies.