Neurophysiological Correlates of Gait in the Human Basal Ganglia and the PPN Region in Parkinson's Disease

Rene Molina, Chris J Hass, Kristen Sowalsky, Abigail C Schmitt, Enrico Opri, Jaime A Roper, Daniel Martinez-Ramirez, Christopher W Hess, Kelly D Foote, Michael S Okun, Aysegul Gunduz, Rene Molina, Chris J Hass, Kristen Sowalsky, Abigail C Schmitt, Enrico Opri, Jaime A Roper, Daniel Martinez-Ramirez, Christopher W Hess, Kelly D Foote, Michael S Okun, Aysegul Gunduz

Abstract

This study aimed to characterize the neurophysiological correlates of gait in the human pedunculopontine nucleus (PPN) region and the globus pallidus internus (GPi) in Parkinson's disease (PD) cohort. Though much is known about the PPN region through animal studies, there are limited physiological recordings from ambulatory humans. The PPN has recently garnered interest as a potential deep brain stimulation (DBS) target for improving gait and freezing of gait (FoG) in PD. We used bidirectional neurostimulators to record from the human PPN region and GPi in a small cohort of severely affected PD subjects with FoG despite optimized dopaminergic medications. Five subjects, with confirmed on-dopaminergic medication FoG, were implanted with bilateral GPi and bilateral PPN region DBS electrodes. Electrophysiological recordings were obtained during various gait tasks for 5 months postoperatively in both the off- and on-medication conditions (obtained during the no stimulation condition). The results revealed suppression of low beta power in the GPi and a 1-8 Hz modulation in the PPN region which correlated with human gait. The PPN feature correlated with walking speed. GPi beta desynchronization and PPN low-frequency synchronization were observed as subjects progressed from rest to ambulatory tasks. Our findings add to our understanding of the neurophysiology underpinning gait and will likely contribute to the development of novel therapies for abnormal gait in PD. Clinical Trial Registration: Clinicaltrials.gov identifier; NCT02318927.

Keywords: DBS; Parkinson’s disease (PD); brainstem; deep brain stimulation; deep brain stimulation (DBS); gait.

Copyright © 2020 Molina, Hass, Sowalsky, Schmitt, Opri, Roper, Martinez-Ramirez, Hess, Foote, Okun and Gunduz.

Figures

Figure 1
Figure 1
Pedunculopontine nucleus (PPN) lead localization methods. (A) MRI-CT co-registered images of each subject. The “active contact” marks the center of the bipolar electrode configuration that yielded the feature most correlated with gait. The left panels show T1 inverted axial views of the active contact (orange) and the contralateral lead (blue). The right panels show T2 sagittal views of the active contact. (B) Leads normalized to MNI space using Lead-deep brain stimulation (DBS). All leads are shown with a red dot that roughly defines the location of the PPN.
Figure 2
Figure 2
Globus pallidus internus (GPi) response to medication. (A) Power spectral density of GPi signals from Subject 1, OFF, and ON levodopa medication during various baseline and gait tasks. (B) Bar plots of raw decrease in GPi beta power during sitting (8–20 Hz). (C) Bar plots of each subject’s percent improvement in UPDRS III score from OFF medication to ON medication during sitting. The red line marks a 30% improvement, a commonly employed clinical benchmark for medication responsiveness.
Figure 3
Figure 3
PPN and GPi response to gait tasks in the on medication condition. (A) Logarithmic power spectral density of PPN signal power in a single subject during various balance and gait-related tasks. (B,C) Single-subject (log normalized to standing) demonstrating PPN low frequency and GPi beta modulation with gait onset shown as boxplots. Significance bars indicate that tasks that statistically could be differentiated from gait every month (p < 0.001). Panel (D) Shows the temporal evolution of neural signatures with gait initiation and the spectrogram from the same subject as (A) averaged across gait initiation trials in one session. This subject exhibited a beta peak while at rest, and this beta peak decreased with gait initiation, while the PPN modulated in response to walking in the 1–8 Hz spectral band. The outlined bands show the dissipation of the beta rhythm in the GPi while the PPN feature bands modulated at the onset of gait.
Figure 4
Figure 4
PPN low-frequency feature compared against gait metrics. The mean walking speed of subjects 1, 2, and 5 are plotted against their averaged normalized power in the 1–8 Hz PPN feature band. Each regression is performed by subject and within the same medication condition, for a total of six regressions. Each point represents a trial. Error bars are shown as dotted parabolas following the trend line. *p < 0.1.

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