Reduced left vmPFC-STN-related white matter integrity is associated with pre-surgical apathy in Parkinson's disease

Apathy is a common and disabling non-motor symptom in Parkinson's disease (PD) that can diminish the therapeutic benefit of subthalamic nucleus deep brain stimulation (STN-DBS). We previously demonstrated that co-stimulation of the left ventromedial prefrontal cortex (vmPFC) can alleviate apathy following levodopa withdrawal in PD patients treated with STN-DBS. Building on these findings, we investigated whether presurgical white matter integrity of the vmPFC-STN pathway constitutes a structural correlate of clinically significant apathy prior to DBS.

Preoperative T1-weighted and diffusion MRI data from 119 PD patients undergoing STN-DBS were analyzed. Based on Starkstein Apathy Scale (SAS) scores, patients were classified as apathetic (SAS ≥ 14; n = 67) or non-apathetic (n = 52). Fractional anisotropy (FA) maps were processed using FSL's Tract-Based Spatial Statistics pipeline. Voxel-wise group comparisons were performed with threshold-free cluster enhancement (5000 permutations), restricted to a bilateral vmPFC-STN mask derived from probabilistic tractography from the previously published cohort.

A significant cluster (74 voxels) within the left vmPFC-STN ROI showed reduced FA in apathetic patients (TFCE-corrected p = 0.0294). Post-hoc analyses revealed higher mean diffusivity (p = 0.0206) and radial diffusivity (p = 0.001) in the apathetic group, while axial diffusivity did not differ. Exploratory subset analysis suggested baseline vmPFC-STN integrity may influence apathy response to vmPFC DBS.

Clinically significant apathy in PD prior to STN-DBS is associated with reduced white matter integrity in the left internal capsule involving the broader left-sided vmPFC projection system. Identifying this structural substrate may contribute to future optimization of apathy management with STN-DBS.