Changes in prefrontal cortical activity and turning in response to dopaminergic and cholinergic therapy in Parkinson's disease: A randomized cross-over trial

Introduction: Cholinergic dysfunction contributes to mobility deficits in Parkinson's disease (PD). People with PD rely on limited prefrontal executive-attentional resources for the control of locomotion, including turning. Cortical and behavioral responses to cholinergic augmentation during turning remains unclear. We examined prefrontal cortex (PFC) activity while turning-in-place and spatiotemporal measures of turns in response to usual dopaminergic medication and adjunct cholinergic augmentation. Methods: This study consisted of a single-site, randomized, double-blind crossover trial. Twenty PD participants were assessed in the levodopa-off state and then randomized to either levodopa + donepezil (5 mg) or levodopa + placebo treatments for two weeks followed by a 2-week washout before crossover. The primary outcome was change from off state in PFC activity while turning-in-place (assessed with functional near-infrared spectroscopy). Secondary outcomes were changes in spatiotemporal turning measures (assessed with body-worn inertial measurement units) and accuracy in the secondary task. Results: Nineteen participants completed the trial. While levodopa + placebo had no effect on PFC activity when turning-in-place with a dual-task, levodopa + donepezil led to a large reduction in PFC activity (effect size, −0.82). Spatiotemporal measures of turning improved with both treatments, with slightly greater effect sizes observed for levodopa + donepezil. Additionally, the accuracy in the concurrent cognitive task improved only with levodopa + donepezil (effect size, 0.63). Conclusion: The addition of cholinergic therapy with donepezil (5 mg/day for 2 weeks) to standard dopaminergic therapy reduced the burden on prefrontal executive-attentional resources while turning with a dual-task and improved secondary task accuracy and turning.