Evaluating a motor progression connectivity model across Parkinson's disease stages

Abstract

Background: Stimulation of a specific site in the dorsolateral subthalamic nucleus (STN) was recently associated with slower motor progression in Parkinson's Disease (PD), based on the deep brain stimulation (DBS) in early-stage PD pilot clinical trial. Here, subject-level visualizations are presented of this early-stage PD dataset to further describe the relationship between active contacts and motor progression. This study also evaluates whether stimulation of the sweet spot and connectivity model associated with slower motor progression is also associated with improvements in long-term motor outcomes in patients with advanced-stage PD.

Methods: Active contacts of the early-stage PD cohort (N = 14) were analyzed alongside the degree of two-year motor progression. Sweet spot and connectivity models derived from the early-stage PD cohort were then used to determine how well they can estimate the variance in long-term motor outcomes in an independent STN-DBS cohort of advanced-stage PD patients (N = 29).

Results: In early-stage PD, proximity of stimulation to the dorsolateral STN was associated with slower motor progression. In advanced-stage PD, stimulation proximity to the early PD connectivity model and sweet spot were associated with better long-term motor outcomes (R = 0.60, P < 0.001; R = 0.37, P = 0.046, respectively).

Conclusions: Results suggest stimulation of a specific site in the dorsolateral STN is associated with both slower motor progression and long-term motor improvements in PD.

Keywords: Deep brain stimulation; Motor symptoms; Movement disorders; Parkinson’s disease; Subthalamic nucleus.

Fig. 1

Active contacts vs motor progression in the DBS in early-stage PD pilot clinical trial cohort. A–D Mirrored active contacts for the early DBS cohort are shown when dividing the cohort into two groups (yellow spheres = top responders; blue spheres = remaining subjects) at several motor progression thresholds (reported below each respective panel). E–G Clinical features of DBS subjects without motor progression whose active contacts are shown in panel B (yellow lines) vs the other DBS subjects (blue lines) and subjects randomized to the optimal drug therapy (ODT) control group (gray lines). Early DBS subjects without motor progression (E, yellow lines) required fewer PD medications (F) and lower stimulation amplitudes (G) Mean ± SEM

Fig. 2

Evaluating the early PD motor progression sweet spot and connectivity model in advanced-stage PD. The motor progression sweet spot (A–B) and connectivity model (C–D) identified in 14 early-stage PD patients [1] were each used to estimate long-term motor outcomes in an independent cohort of 29 standard of care PD patients. A The degree of overlap with the motor progression sweet spot identified from the early DBS cohort (i.e., “Sweet Spot Score”) significantly correlated with long-term UPDRS-III improvements (DBS duration at follow-up = 5.4 ± 2.0 years; Spearman’s R = 0.37, P = 0.046). B The motor progression sweet spot from [1]. STN is outlined in purple. Red nucleus is outlined in red. Bejanni line = white dashed line [27]. C The degree of stimulating positive tracts and not stimulating negative tracts identified from the early DBS cohort (i.e., the “Weighted Mean of Fiber R-Scores” of the Motor Progression Connectivity Model) significantly correlated with long-term UPDRS-III improvements (Spearman’s R = 0.60, P < 0.001). Two illustrative example patients are marked with colored circles in panel C and their stimulation volumes are shown in panel D (top responder example = green; poor responder example = red). D The motor progression connectivity model [1] consists of positive (orange) tracts originating from M1 and SMA and negative (cyan) tracts originating from pre-SMA and cerebellum