Effects of deep brain stimulation in the subthalamic nucleus or globus pallidus internus on step initiation in Parkinson disease: laboratory investigation

Abstract

Object: Difficulty with step initiation, called "start hesitation," is related to gait bradykinesia and is an early hallmark of gait freezing in Parkinson disease (PD). Authors of this study investigated the effects of deep brain stimulation (DBS) and levodopa on step initiation before and 6 months after DBS surgery in 29 patients with PD who were randomized to either the bilateral subthalamic nucleus (STN) or globus pallidus internus (GPi) as the DBS site.

Methods: The authors measured the amplitude and duration of anticipatory postural adjustments (APAs), the feed-forward postural preparation that precedes the onset of voluntary step initiation, based on center-of-pressure displacements on a force plate. They also measured the length and velocity of the first step using a motion analysis system to study kinematics. Some of the patients (22) were from a large, multicenter, double-blind clinical trial, and all patients in the study (29, PD-DBS group) were randomized to DBS in either the bilateral STN (15 patients) or bilateral GPi (14 patients). Differences in step initiation were investigated in 2 conditions before surgery (off/on levodopa) and in 4 conditions after surgery (off/on levodopa combined with off/on DBS). Twenty-eight elderly healthy control volunteers (CTRL group) were also tested, and 9 control volunteers with PD who met the criteria for DBS (PD-C group) were tested at baseline and 6 months later.

Results: Patients in the PD-DBS group had smaller amplitudes and longer durations of APAs compared with those in the 28 healthy control volunteers in all conditions. Before surgery, APAs improved with levodopa. After surgery, the APAs were significantly worse than in the best-treatment state before surgery (DOPA condition), and responsiveness to levodopa decreased. No differences in APAs were detected between the STN and GPi groups. A comparison with PD control volunteers who did not undergo DBS surgery confirmed that a deterioration in step preparation was not related to disease progression. Step length and velocity were smaller in the PD-DBS group than in controls in all conditions. Before surgery, levodopa improved the length and velocity of the first step. Both step length and velocity were unchanged in the best-treatment state before surgery (DOPA condition) as compared with after surgery (DBS+DOPA), with only step velocity in the STN group getting worse after surgery.

Conclusions: Six months of DBS in the STN or GPi impaired anticipatory postural preparation for step initiation, the opposite effect as with levodopa. Deep brain stimulation disrupted postural preparation more than step execution, suggesting independent motor pathways for preparation and execution of gait. Although turning the stimulators on after surgery combined with levodopa benefited the postural preparation to step, a comparison of pre- and postsurgery conditions suggests that either the surgery itself or 6 months of continuous stimulation may lead to an alteration of circuits or plastic changes that impair step initiation.

Figures

Figure 1

Anticipatory postural adjustments (APA). A) Representative time-series of lateral CoP excursion. B) Bar graph demonstrating Peak-CoP, i.e. peak of lateral CoP excursion during APA. C) Bar graph showing APA duration, i.e. the time necessary to take the first step from APA onset. Data are represented as means ± standard errors of the means. Horizontal lines in B and C represent values for healthy control group. * p

Figure 2

Anticipatory postural adjustment amplitude post-surgery compared to pre-surgery. A: Graph demonstrating OFF states to investigate surgery effect; B Graph showing the ON levodopa states to compare best medical management states before and after surgery. Means ± standard errors of the means and single subject values are represented. * p

Figure 3

Bar graphs showing APA amplitude (A) and APA duration (B) in the PD control group, evaluated at baseline and 6 months later. * p

Figure 4

Bar graphs showing kinematics of the first step: A) Step Length, B) Step Velocity. Data are represented as means ± standard errors of the means. Horizontal lines represent values for healthy control group. * p