N-of-1 tissue activation modeling reveals regional subthalamic stimulation predicting verbal fluency decline in Parkinson disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) effectively treats Parkinson disease (PD) motor symptoms. However, STN DBS commonly leads to declines in verbal fluency (VF). This study aimed to identify STN stimulation regions that optimize motor benefits while minimizing negative impacts on phonemic (PVF) and semantic verbal fluency (SVF). 40 PD patients who underwent bilateral STN DBS (72 implants) were retrospectively analyzed. Individualized volume of tissue activation (VTA) models were utilized to comprehensively assess stimulation spread and STN activation. Regional VTA-STN overlap and external activation, as well as active contact position, were correlated with PVF and SVF outcomes using regression and Wilcoxon tests to determine the effect of stimulation location on VF. Motor speech outcome was also evaluated. Patients significantly declined in both PVF (p = 0.0001) and SVF (p = 0.008) post-DBS. PVF decline was significantly associated with more activation in the dorsal region of the left STN (p = 0.031). SVF decline correlated with significantly less activation in the anterior region outside the right STN (p = 0.036) and more posterior active contacts relative to the right STN centroid (p = 0.042). No significant impact of DBS on motor speech outcome or its relationship to stimulation location was observed. Utilizing individualized VTA models provided insights into specific stimulation regions potentially affecting VF. These findings underscore the importance of precise STN DBS targeting in surgical planning and clinical programming to balance motor benefits with the preservation of cognitive speech functions in PD patients.