Success and Failure With the Antidyskinetic Effect of Globus Pallidus Internus Deep Brain Stimulation: A Sweet Spot and Connectivity Analysis in the CSP-468 Cohort

OBJECTIVES: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) can reduce levodopa-induced dyskinesias, yet GPi targeting sometimes fails or worsens them, suggesting distinct prokinetic/antikinetic circuit mechanisms. Using the broad globus pallidus (GP) sampling from the Veteran Affairs Cooperative Study Program 468 (CSP-468) trial, we sought to identify stimulation zones and connectivity maps that predict dyskinesia outcomes in patients treated with GPi-DBS. MATERIALS AND METHODS: Data were drawn from the multicenter, randomized CSP-468 study which compared subthalamic nucleus with GPi-DBS in Parkinson disease. Postoperative imaging from patients treated with bilateral GPi-DBS with substantial presurgical dyskinesia (n = 69) was analyzed to relate lead location to change in hours of dyskinesia at six months postop. Cranial Suite and LeadDBSv3.0 enabled nonlinear registration to Montreal Neurologic Institute space and generation of volumes-of-tissue-activated (VTAs). Patients were pseudorandomly divided into model or hold-out cohorts. Outcome-weighted VTAs in the model cohort were used to derive above-average (sweet spot) and below-average (suboptimal) stimulation zones through t-tests. Outcome-weighted structural fibers were identified using the Parkinson Progressive Marker Initiative connectome. Normative resting state functional magnetic resonance imaging (rsfMRI) connectivity maps were generated using patient VTAs and the Brain Genomics Superstruct Project-1000 connectome, visualizing regions with significant synchrony differences between patients with improved vs worsened dyskinesias. All models were tested on the hold-out cohort. CONCLUSIONS: This analysis identified stimulation zones and connectivity that predict dyskinesia outcomes in an independent cohort, underscoring the relevance of the (sub)ventral GPi, Ansa Lenticularis, and supplementary motor area or premotor networks.