Association between the functional connectivity of ventral tegmental area-prefrontal network and pure apathy in Parkinson's disease: a cross-sectional study

Background: Apathy, characterized by diminished goal-directed behaviors, frequently occurs in patients with Parkinson's disease (PD). The dopamine-releasing neurons of the ventral tegmental area (VTA) have been closely related to this behavioral disruption and project widely to the corticolimbic areas, yet their functional and structural connectivity in regard to other brain regions remain unknown in patients with PD and pure apathy (PD-PA). This study thus aimed to characterize the alterations of functional connectivity (FC) of the VTA and white matter structural connectivity in PD-PA. Methods:<bold> </bold>In this study, 29 patients with PD-PA, 37 with PD but not pure apathy (PD-NPA), and 28 matched healthy controls (HCs) underwent T1-weighted, resting state functional magnetic resonance imaging, and diffusion tensor imaging scans. Patients of this cross-sectional retrospective study were consecutively recruited from The First Affiliated Hospital of Nanjing Medical University between April 2017 and October 2021. Meanwhile, HCs were consecutively recruited from the local community and the Health Examination Center of our hospital. An analysis of covariance and a general linear model were respectively conducted to investigate the functional and structural connectivity among three groups. The tract-based spatial statistics (TBSS) approach was used to investigate the white matter structural connectivity. Results:<bold> </bold>Patients with PD-PA showed reduced FC of the VTA with the left medial superior frontal gyrus (SFGmed) when compared to the patients with PD-NPA [t=-3.67; voxel-level P<0.001; cluster-level family-wise error-corrected P (P-FWE)<0.05]. Relative to the HCs, patients with PD-PA demonstrated reduced FC of the VTA with the left SFGmed (t=-4.98; voxel-level P<0.001; cluster-level P-FWE<0.05), right orbital superior frontal gyrus (SFGorb) (t=-5.08; voxel-level P<0.001; cluster-level P-FWE<0.05), and right middle frontal gyrus (MFG) (t=-5.08; voxel-level P<0.001; cluster-level P-FWE<0.05). Moreover, the reductions in VTA FC with the left SFGmed were associated with severe apathy symptoms in patients with PD-PA (r=-0.600; P=0.003). However, a TBSS approach did not reveal any significant differences in fiber tracts between the three groups. Conclusions:<bold> </bold>This study identified reduced FC within the mesocortical network (VTA-SFGmed) of patients with PD-PA. These findings may provide valuable information for administering neuromodulation therapies in the alleviation of apathy symptoms in those with PD.