Impact of PSA- versus STN-DBS on effective connectivity in Parkinson’s disease – a 3.0T resting-state fMRI study

Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment for advanced Parkinson's disease (PD), whereas the posterior subthalamic area (PSA) has been proposed as an alternative target for tremor-dominant cases. However, their underlying therapeutic mechanisms have not been directly compared. Leveraging the single-trajectory dual-target DBS technique, this work utilizes high-field 3.0 T resting-state functional magnetic resonance imaging data and spectral dynamic causal modeling to investigate the differential modulatory effects of PSA and STN stimulation on effective connectivity within both cortico-basal ganglia and cerebello-thalamo-cortical networks. We show that both PSA and STN stimulation suppress cortico-cerebellar connectivity and cortico-subthalamic hyperdirect connectivity, while enhancing STN self-inhibition. Compared with STN stimulation, PSA stimulation provides a greater reduction in cortico-cerebellar coupling but a greater increase in striato-STN connectivity. Moreover, changes in hyperdirect pathway coupling correlate with motor improvement in response to both PSA and STN stimulation. Furthermore, hyperdirect pathway and cerebellar connectivity were significantly associated with motor impairment and resting tremor severity, respectively, regardless of hemisphere or DBS target. Taken together, these findings suggest that PSA and STN stimulation share common network-level mechanisms but differ in their relative modulation of cortico-cerebellar pathway. The present study may offer theoretical guidance for future individualized DBS targeting in treating tremor-dominant PD.