Walking exercise alters pedunculopontine nucleus connectivity in Parkinson's disease in a dose-dependent manner

Jiayue Cai; Aiping Liu; Yuheng Wang; Sun Nee Tan; Taylor Chomiak; Jacqueline Burt; Richard Camicioli; Bin Hu; Martin J McKeown; Fang Ba

doi:10.3389/fnins.2022.930810

Walking exercise alters pedunculopontine nucleus connectivity in Parkinson's disease in a dose-dependent manner

Front Neurosci. 2022 Aug 9:16:930810. doi: 10.3389/fnins.2022.930810. eCollection 2022.

Authors

Jiayue Cai^{1

2}, Aiping Liu³, Yuheng Wang⁴, Sun Nee Tan⁵, Taylor Chomiak⁶, Jacqueline Burt⁷, Richard Camicioli⁷, Bin Hu⁶, Martin J McKeown², Fang Ba⁷

Affiliations

¹ School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, China.
² Division of Neurology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.
³ Department of Electronic Science and Technology, University of Science and Technology of China, Hefei, China.
⁴ School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada.
⁵ Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada.
⁶ Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
⁷ Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Abstract

Background: Gait disturbances are critical motor symptoms in Parkinson's disease (PD). The mechanisms of gait impairment in PD are not entirely understood but likely involve changes in the Pedunculopontine Nucleus (PPN), a critical locomotion center, and its associated connections. Exercise is universally accepted as helpful in PD, but the extent and intensity of exercise required for plastic changes are unclear.

Methods: Twenty-seven PD subjects participated in a 3-month gait training intervention. Clinical assessments and resting-state functional magnetic resonance imaging were performed at baseline and 3 months after exercise. Functional connectivity of PPN was assessed by combining the methods of partial least squares, conditional dependence and partial correlation. In addition, paired t-tests were used to examine the effect of exercise on PPN functional connectivity and clinical measures, and Pearson's correlation was used to assess the association between altered PPN functional connectivity and clinical measures.

Results: Exercise significantly improved Unified Parkinson's Disease Rating Scale-III (UPDRS-III). A significant increase in right PPN functional connectivity was observed after exercise, which did not correlate with motor improvement. However, the decrease in left PPN functional connectivity significantly correlated with the improvement in UPDRS-III and was linearly related to both number of walks and the duration of walks. In addition, exercise induced a significant increase in the laterality of PPN connectivity strength, which correlated with motor improvement.

Conclusion: PPN functional connectivity is modifiable by walking exercise in both a dose-independent (right PPN and laterality of PPN connectivity strength) and dose-dependent (left PPN) manner. The PPN may contribute to pathological and compensatory processes in PD gait control. The observed gait improvement by walking exercise is most likely due to the reversal of the maladaptive compensatory mechanism. Altered PPN functional connectivity can be a marker for exercise-induced motor improvement in PD.

Keywords: Parkinson’s disease; fMRI; functional connectivity; pedunculopontine nucleus; walking exercise.