Structural-Functional Correlates of Response to Pedunculopontine Stimulation in a Randomized Clinical Trial for Axial Symptoms of Parkinson’s Disease

Abstract

Background: Axial symptoms of Parkinson’s disease (PD) can be debilitating and are often refractory to conventional therapies such as dopamine replacement therapy and deep brain stimulation (DBS) of the subthalamic nuclei (STN). Objective: Evaluate the efficacy of bilateral DBS of the pedunculopontine nucleus area (PPNa) and investigate structural and physiological correlates of clinical response. Methods: A randomized, double-blind, cross-over clinical trial was employed to evaluate the efficacy of bilateral PPNa-DBS on axial symptoms. Lead positions and neuronal activity were evaluated with respect to clinical response. Connectomic cortical activation profiles were generated based on the volumes of tissue activated. Results: PPNa-DBS modestly improved (p = 0.057) axial symptoms in the medication-off condition, with greatest positive effects on gait symptoms (p = 0.027). Electrode placements towards the anterior commissure (ρ= 0.912; p = 0.011) or foramen caecum (ρ= 0.853; p = 0.031), near the 50% mark of the ponto-mesencephalic junction, yielded better therapeutic responses. Recording trajectories of patients with better therapeutic responses (i.e., more anterior electrode placements) had neurons with lower firing-rates (p = 0.003) and higher burst indexes (p = 0.007). Structural connectomic profiles implicated activation of fibers of the posterior parietal lobule which is involved in orienting behavior and locomotion. Conclusion: Bilateral PPNa-DBS influenced gait symptoms in patients with PD. Anatomical and physiological information may aid in localization of a favorable stimulation target.