Reaching to proprioceptively defined targets in Parkinson's disease: effects of deep brain stimulation therapy

Abstract

Deep brain stimulation of the subthalamic nucleus (STN DBS) provides a unique window into human brain function since it can reversibly alter the functioning of specific brain circuits. Basal ganglia-cortical circuits are thought to be excessively noisy in patients with Parkinson's disease (PD), based in part on the lack of specificity of proprioceptive signals in basal ganglia-thalamic-cortical circuits in monkey models of the disease. PD patients are known to have deficits in proprioception, but the effects are often subtle, with paradigms typically restricted to one or two joint movements in a plane. Moreover, the effects of STN DBS on proprioception are virtually unexplored. We tested the following hypotheses: first, that PD patients will show substantial deficits in unconstrained, multi-joint proprioception, and, second, that STN DBS will improve multi-joint proprioception. Twelve PD patients with bilaterally implanted electrodes in the subthalamic nucleus and 12 age-matched healthy subjects were asked to position the left hand at a location that was proprioceptively defined in 3D space with the right hand. In a second condition, subjects were provided visual feedback during the task so that they were not forced to rely on proprioception. Overall, with STN DBS switched off, PD patients showed significantly larger proprioceptive localization errors, and greater variability in endpoint localizations than the control subjects. Visual feedback partially normalized PD performance, and demonstrated that the errors in proprioceptive localization were not simply due to a difficulty in executing the movements or in remembering target locations. Switching STN DBS on significantly reduced localization errors from those of control subjects when patients moved without visual feedback relative to when they moved with visual feedback (when proprioception was not required). However, this reduction in localization errors without vision came at the cost of increased localization variability.

Fig. 1

(A) Schematic diagram of the subject’s position and the five target locations shown in slightly rotated side view. Four targets (up, down, left, and right) formed a diamond (40-cm diagonal length) in a frontal plane, centered in the subject’s midline. A back target (back) was located 15 cm farther away from the first target plane along the subject’s midline. (B) The three main error measures. 3D error is the absolute distance in space of the final finger position from the target for each trial. Constant error is the distance of the mean of the endpoints to the target, and variable error is the dispersion of the endpoints around the endpoint mean location (see Methods).

Fig. 2

Peak tangential velocity of the hand during the reach averaged across vision conditions for the five targets. Error lines combine standard errors of the mean within and across subjects. The inset shows a frontal projection of the target space. Controls exhibit the fastest reaches, PD patients Off STN DBS the slowest, and patients On STN DBS show intermediate speeds. Thus, PD patients, as expected, show bradykinesia, which is significantly improved with STN DBS.

Fig. 3

Endpoint distributions of a representative control subject (top row) and a PD patient when STN DBS was switched off (middle row) and switched on (bottom row). Both front and side views are shown. Within each view, the no vision condition is on the left (first and third columns) and the vision condition is on the right (second and fourth columns). The large (10-cm diameter) circles represent the five targets with unique colors, and filled dots are individual trial endpoints with matching colors. Target size is enlarged for clarity. Scale bar = 10 cm. Note the markedly increased localization errors of the PD patient, particularly when vision was occluded and when STN DBS was switched off.

Fig. 4

3D error, constant error, and variable errors across targets. Filled circles (upper set, solid lines) indicate no-vision, and open circles (lower set, dashed lines) indicate vision. All error lines indicate standard errors combined within and across subjects. 3D error (A) and constant error (B) show similar patterns. Without vision, control subjects had the smallest errors, STN DBS On patients had intermediate errors, and STN DBS Off patients had the largest errors. With vision, errors are markedly reduced for all groups. Controls subjects still have the smallest errors, but the error difference between control subjects and STN DBS Off patients is reduced from that of no vision. (C) Variable errors are smaller than constant errors, and show a different pattern within the PD group. Without vision, control subjects have the smallest variable errors, but unlike for 3D and constant errors, STN DBS Off patients have intermediate errors while STN DBS On patients have the largest errors. With vision, errors are reduced and similar across groups, although PD patients have slightly higher errors than control subjects.

Fig. 5

Difference in error across the vision conditions (no vision minus vision). Increasing values indicate increasingly larger errors in the no vision than vision condition, implying increased difficulty in localizing the limb using proprioception. Whisker bars indicate 95% confidence intervals across subjects. Asterisks indicate a significant difference between groups (p < 0.05). (A) 3D errors show disproportionately increased localization errors for STN DBS Off patients than control subjects when vision is occluded; this deficit is partially reversed when STN DBS is turned on. (B) Constant errors show the same pattern although the group difference is significant only for STN DBS On versus Off. (C) Variable errors show a small increase for STN DBS Off patients over that of control subjects, which is exacerbated by switching DBS on.

Fig. 6

Constant error in the superior–inferior direction to each of the five targets separately for all subjects with STN DBS On and Off. Positive values are upward. Error lines represent standard errors over trials, the line is a least square fit within each target, and the shaded region represents 95% confidence of the fit. Constant error in the superior–inferior direction for the three targets at central height (left, back and right) show very little variability across UPDRS. However, the upper target shows an increasing downward deflection and the lower an increasing upward deflection with increasing UPDRS scores.