Developing a longitudinal framework to explore how deep brain stimulation parameters influence cognitive decline in Parkinson’s disease

Abstract

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for motor symptoms in Parkinson’s disease (PD), yet its e!ects on cognitive function remain less understood. This study develops a workflow within Lead-DBS environment to automatically compute volumes of tissue activated (VTAs) across multiple postoperative timepoints. In addition, it analyzes these data by assessing whether stimulation parameters are associated with cognitive decline following STN-DBS. A structured dataset of 64 PD patients who underwent STN-DBS was used, which included a complete cognitive performance assessed with the Mattis Dementia Rating Scale (MDRS) and stimulation data across five postoperative time points. The developed pipeline enabled automatic VTA generation from stimulation parameters and organized patient data in a structure compatible with Lead-DBS. This allowed for the computation of stimulation overlap with the specific STN subregions at each timepoint. To explore potential associations with cognitive change, patients were clustered based on their longitudinal Mattis trajectories. Two distinct subgroups were identified: one showing stable or improved cognitive scores, and another exhibiting progressive decline. Linear mixed-e!ects models confirmed a significant divergence in cognitive outcomes between these groups over time. Although stimulation overlap with STN subregions did not di!er significantly between clusters, the declining group showed a consistent trend toward greater overlap in the motor and associative territories. Exploratory sweetspot analyses gave further information regarding voxel-wise distribution of the sweet and sour spots. Despite limitations such as a relatively small sample size and the absence of genetic data, this study demonstrates the feasibility of longitudinal VTA analysis using Lead DBS. Although no robust evidence between stimulation and cognitive decline was found in this cohort, subtle trends suggest a potential relationship that cannot be completely discarded. Future work should integrate this approach with more ad- vanced voxel-wise and connectivity-based methods to better understand the neural mechanisms underlying cognitive outcomes in DBS-treated patients.