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.

Keywords: Deep brain stimulation; Parkinson’s disease; pedunculopontine nucleus.

Fig. 1

Randomized double-blind cross-over study design. The patients were brought in for baseline evaluations preoperatively. The operation was followed by a two-month familiarization phase with stimulation OFF, and to account for possible micro-lesions effects. At two months postoperatively, the patients visited for a postoperative evaluation, randomization of stimulation settings, and titration of the stimulation settings. At four months postoperatively, the patients visited again for the first treatment evaluation, cross-over, and stimulation titration. The second treatment evaluation, marking the end of the study, was performed at six months postoperatively.

Fig. 2

A) Lead placement correlates, and B) single-unit recordings. A) MRI results suggest that more anterior lead placements were favorable. B) Single-unit recordings show two clusters of neurons (cluster-1 being faster and more regular versus cluster-2 being slower and less regular). Neurons resembling cluster-2 were more prominent in recording trajectories of patients with more anterior electrode placements (who had better therapeutic responses).

Fig. 3

Lead locations and groupwise structural and functional connectomic profiles. A, B) Reconstructions of all electrodes, C, D) fibers traversing the groupwise VTA, and E) structural and F) functional connectivity profiles.