The Sequence Effect Worsens over Time in Parkinson’s disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation

Background The sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open and closed-loop deep brain stimulation in people with PD. Objective To investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) and closed-loop deep brain stimulation (DBS). Methods Twenty-one people with PD with bilateral STN DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS. Results The sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and even further improvement on closed-loop DBS. Conclusions Sequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open and closed-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and that closed-loop DBS may offer added improvement.