Encoding type, medication, and deep brain stimulation differentially affect memory-guided sequential reaching movements in Parkinson's disease

Abstract

Memory-guided movements, vital to daily activities, are especially impaired in Parkinson's disease (PD). However, studies examining the effects of how information is encoded in memory and the effects of common treatments of PD, such as medication and subthalamic nucleus deep brain stimulation (STN-DBS), on memory-guided movements are uncommon and their findings are equivocal. We designed two memory-guided sequential reaching tasks, peripheral-vision or proprioception encoded, to investigate the effects of encoding type (peripheral-vision vs. proprioception), medication (on- vs. off-), STN-DBS (on- vs. off-, while off-medication), and compared STN-DBS vs. medication on reaching amplitude, error, and velocity. We collected data from 16 (analyzed n = 7) participants with PD, pre- and post-STN-DBS surgery, and 17 (analyzed n = 14) healthy controls. We had four important findings. First, encoding type differentially affected reaching performance: peripheral-vision reaches were faster and more accurate. Also, encoding type differentially affected reaching deficits in PD compared to healthy controls: peripheral-vision reaches manifested larger deficits in amplitude. Second, the effect of medication depended on encoding type: medication had no effect on amplitude, but reduced error for both encoding types, and increased velocity only during peripheral-vision encoding. Third, the effect of STN-DBS depended on encoding type: STN-DBS increased amplitude for both encoding types, increased error during proprioception encoding, and increased velocity for both encoding types. Fourth, STN-DBS was superior to medication with respect to increasing amplitude and velocity, whereas medication was superior to STN-DBS with respect to reducing error. We discuss our findings in the context of the previous literature and consider mechanisms for the differential effects of medication and STN-DBS.

Keywords: Parkinson's disease; encoding; peripheral-vision levodopa; proprioception; subthalamic nucleus deep brain stimulation (STN-DBS).

Figure 1

(A) Peripheral-visual encoding task divided into the encoding and execution phases. Encoding phase: The participant fixated on the central fixation LED (solid central circle) while placing their right index finger on a stand immediately below the central fixation LED. The target LED (solid peripheral circle) flashed in 3 different locations sequentially. The participant encoded the target location and sequence with their peripheral vision. Execution phase: The flashing of the central fixation LED cued the start of the execution phase (unfilled central circle). The participant remained fixated on the central fixation LED. The participant pointed to the remembered targets (unfilled circles) as accurately as possible in the order presented. The time series below the cartoon show the central fixation LED (Fix LED), target LED (Tar LED), horizontal and vertical eye position (Hor Eye Pos, Ver Eye Pos, respectively), tangential eye velocity (Tan Eye Vel), horizontal and vertical finger position (Hor Fing Pos, Ver Fing Pos, respectively), and tangential finger velocity (Tan Fing Vel). Figures are aligned to the execution cue at 8 s. (B) Proprioceptive encoding task divided into the encoding and execution phases. The participant (gray shirt) was blindfolded for the entire task therefor no eye movement traces are shown. Encoding phase: The experimenter (in white) held the participant's (in gray) relaxed right arm at the elbow and wrist while placing their right index finger on a stand immediately below the central fixation LED (solid central circle). The experimenter guided the participant's arm to each of the three sequential targets (solid peripheral circles) ensuring that the participant's pointer finger touched the target LED. The participant encoded the target location and sequence proprioceptively. The experimenter then guided the participant's index finger back to the stand and the participant regained active control of their limb. Execution phase: An oral cue from the experimenter initiated the execution phase. The participant pointed to the remembered targets (unfilled circles, see inset) as accurately as possible in the order presented. The time series below the cartoon show the central fixation LED (Fix LED), the target LED (Tar LED), the horizontal finger position (Hor Fing Pos), the vertical finger position (Ver Fing Pos), and tangential finger velocities (Tan Fing Vel). Figures are aligned to the execution cue at 9 s. Reaching primarily occurred in the horizontal and vertical dimension; therefore, only these traces are shown.

Figure 2

Shows the participant flow in the healthy control group and the Parkinson's disease group.

Figure 3

Top row: Box plots overlaid with violin plots of observed reaching amplitude (A), error (B), and velocity (C) for PD OFF Medication (OFF MEDS, purple) and Healthy Controls (HC, pink). The boxplot shows the 25th, 50th, and 75th percentiles (horizontal black lines), filled white circle represents the mean, and filled black circles are outliers. Bottom row: Linear mixed model estimated mean ± SE of reaching amplitude (D), error (E), and velocity (F) for PD OFF Medication (OFF MEDS, purple) and Healthy Controls (HC, pink) for the peripheral-vision encoding and proprioception encoding. (D) Asterisk (*) and double-s (§) indicate statistically significant smaller amplitudes during peripheral-vision relative to proprioception encoding for the PD OFF MEDS (purple) and HC (pink) groups respectively. Double dagger (‡) indicates statistically significant lower amplitudes in PD OFF MEDS relative to HC, only during peripheral-vision encoding. (E) Yen (¥) indicates statistically significant main effect of encoding type, i.e., averaging across groups, peripheral-vision reaches were lower in error relative to proprioception reaches. (F) Asterisk (*) and double-s (§) indicate statistically significant faster velocities during peripheral-vision relative to proprioception encoding in PD OFF MEDS (purple) and HC (pink) groups, respectively. The trends seen in the observed data in the top row are replicated in the estimated means in the bottom row and those differences that are statistically significant are illustrated with symbols.

Figure 4

Top row: Box plots overlaid with violin plots of observed reaching amplitude (A), error (B), and velocity (C) for PD OFF Medication (OFF MEDS, purple) and PD ON Medication (ON MEDS, blue). The boxplot shows the 25th, 50th, and 75th percentiles (horizontal black lines), filled white circle represents the mean, and filled black circles are outliers. Bottom row: Linear mixed model estimated mean ± SE of reaching amplitude (D), error (E), and velocity (F) for PD ON Medication (ON MEDS, blue), and OFF Medication (OFF MEDS, purple) for the peripheral-vision and proprioception encoding. (D) Medication had no effect on amplitude for both encoding types. (E) Dagger (†) indicates a statistically significant main effect of medication, i.e., averaging across encoding types, ON MEDS reduced error relative to OFF MEDS. (F) Double dagger (‡) indicates statistically significant increase in velocity while ON MEDS relative to OFF MEDS, only during peripheral-visual encoding. The trends seen in the observed data in the top row are replicated in the estimated means in the bottom row and those differences that are statistically significant are illustrated with symbols.

Figure 5

Top row: Box plots overlaid with violin plots of observed reaching amplitude (A), error (B), and velocity (C) for PD OFF bilateral STN-DBS (OFF DBS, striped purple) and ON bilateral STN-DBS (ON DBS, striped blue). The boxplot shows the 25th, 50th, and 75th percentiles (horizontal black lines), filled white circle represents the mean, and filled black circles are outliers. Bottom row: Linear mixed model estimated mean ± SE of reaching amplitude (D), error (E), and velocity (F) for PD ON bilateral STN-DBS (ON DBS, dashed blue), and OFF bilateral STN-DBS (OFF DBS, dashed purple) for the peripheral-vision and proprioception encoding. All STN-DBS testing was conducted while OFF medication. (D) Dagger (†) indicates a statistically significant main effect of STN-DBS, i.e., averaging across encoding types, ON DBS increased amplitude relative to OFF DBS. (E) Double dagger (‡) indicates statistically significant increase in error while ON DBS relative to OFF DBS, only during proprioception encoding. (F) Dagger (†) indicates a statistically significant main effect of STN-DBS, i.e., averaging across encoding types, ON DBS increased velocity relative to OFF DBS.

Figure 6

Top row: Box plots overlaid with violin plots of observed reaching amplitude (A), error (B), and velocity (C) for PD ON Medication pre-surgery (ON MEDS, blue) and PD ON bilateral STN-DBS post-surgery (ON DBS, striped blue). The boxplot shows the 25th, 50th, and 75th percentiles (horizontal black lines), filled white circle represents the mean, and filled black circles are outliers. Bottom row: Linear mixed model estimated mean ± SE of reaching amplitude (D), error (E), and velocity (F) for PD participants ON Medication pre-surgery (solid light blue) and ON bilateral STN-DBS post-surgery (dashed light blue) for the peripheral-vision and proprioception encoding. All STN-DBS testing was conducted while OFF medication. (D) Dagger (†) indicates a statistically significant main effect of treatment, i.e., averaging across encoding types, ON DBS increased amplitude relative to ON MEDS. (E) Dagger (†) indicates a statistically significant main effect of treatment, i.e., averaging across encoding types, ON DBS increased error relative to ON MEDS. (F) Double dagger (‡) indicates statistically significant increase in velocity while ON DBS relative to ON MEDS, only during proprioception encoding.

Figure 7

Mean ± SE (gray bars and orange error bars) of MDS-UPDRS Motor Scores for PD participants pre-surgery while OFF and ON anti-parkinsonian medication and post-surgery while OFF and ON STN-DBS. Overlaid open circles and connecting lines show MDS-UPDRS Motor Scores of each participant. All STN-DBS testing was conducted while OFF medication. All post-surgery data was collected following 12-h overnight withdrawal from anti-Parkinsonian medication.