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Background  The primary motor cortex (M1) is a critical node in Parkinson’s disease (PD)-related motor circuitry; however, the functional roles of its subregions are poorly understood. In this study, we investigated changes in the functional connectivity patterns of M1 subregions and their relationships to improved clinical symptoms following levodopa administration.    Methods  Thirty-six PD patients and 37 healthy controls (HCs) were enrolled. A formal levodopa challenge test was conducted in the PD group, and the Unified Parkinson’s Disease Rating Scale motor section (UPDRS-III) was assessed before (off state) and 1 h after administration of levodopa (on state). The PD group underwent resting-state functional magnetic resonance imaging in both off and on states, whereas the HC group was scanned once. We used the Human Brainnetome Atlas template to subdivide M1 into twelve regions of interest (ROIs). Functional connectivity (FC) was compared between PD on and off states [paired  t -test, voxel-level  p  < 0.001, cluster-level  p  < 0.05, Gaussian random field (GRF) correction] and between patients and HC (two-sample  t -test voxel-level  p  < 0.001, cluster-level  p  < 0.05). Correlations between ΔFC (differences in FC between PD off and on states) and clinical symptom improvements were examined.    Results  There was decreased FC between the right caudal dorsolateral area 6 and the anterior cingulate gyrus (ACC), the right upper limb region and the left medial dorsal thalamus (mdTHA), as well as increased FC between the left tongue and larynx region and the left medial frontal gyrus. ΔFC between the right caudal dorsolateral area 6 and ACC was positively correlated with improvements in UPDRS-III total scores as well as the rigidity (item 22) and bradykinesia (items 23–26 and 31) subscores. ΔFC between the right upper limb region and left thalamus was positively correlated with improvements in the left upper limb tremor (items 20c and 21b) and postural tremor (item 21b) subscores.    Conclusions  Our results reveal novel information regarding the underlying mechanisms in the motor circuits in the M1 and a promising way to explore the internal function of the M1 in PD patients. Notably, M1 is a potential therapeutic target in PD, and the exploration of its subregions provides a basis and a source of new insights for clinical intervention and precise drug treatment.

Levodopa Changes Functional Connectivity Patterns in Subregions of the Primary Motor Cortex in Patients With Parkinson’s Disease