Disruption in proprioception from long-term thalamic deep brain stimulation: a pilot study

Abstract

Deep brain stimulation (DBS) is an excellent treatment for tremor and is generally thought to be reversible by turning off stimulation. For tremor, DBS is implanted in the ventrointermedius (Vim) nucleus of the thalamus, a region that relays proprioceptive information for movement sensation (kinaesthesia). Gait disturbances have been observed with bilateral Vim DBS, but the long-term effects on proprioceptive processing are unknown. We aimed to determine whether Vim DBS surgical implantation or stimulation leads to proprioceptive deficits in the upper limb. We assessed two groups of tremor subjects on measures of proprioception (kinaesthesia, position sense) and motor function using a robotic exoskeleton. In the first group (Surgery), we tested patients before and after implantation of Vim DBS, but before DBS was turned on to determine if proprioceptive deficits were inherent to tremor or caused by DBS implantation. In the second group (Stim), we tested subjects with chronically implanted Vim DBS ON and OFF stimulation. Compared to controls, there were no proprioceptive deficits before or after DBS implantation in the Surgery group. Surprisingly, those that received chronic long-term stimulation (LT-stim, 3-10 years) displayed significant proprioceptive deficits ON and OFF stimulation not present in subjects with chronic short-term stimulation (ST-stim, 0.5-2 years). LT-stim had significantly larger variability and reduced workspace area during the position sense assessment. During the kinesthetic assessment, LT-stim made significantly larger directional errors and consistently underestimated the speed of the robot, despite generating normal movement speeds during motor assessment. Chronic long-term Vim DBS may potentially disrupt proprioceptive processing, possibly inducing irreversible plasticity in the Vim nucleus and/or its network connections. Our findings in the upper limb may help explain some of the gait disturbances seen by others following Vim DBS.

Keywords: deep brain stimulation (DBS); kinesthesia; position sense; proprioception; sensorimotor; tremor.

Figure 1

Experimental tasks (top panels) with corresponding exemplar control data (bottom panels). (A) Visually guided reaching: Motor control was measured by quantifying reaching behavior in a standard center-out reaching task. An exemplar control (bottom panel) depicts intact reaching behavior with straight, accurate reaches to each of the four targets along with consistent hand speed performance taken from a single target. (B) Position matching: The robot moved the subjects' arm (top panel, right arm in example) to one of nine locations in the workspace. Subjects then mirror-matched the location of the robot movement (top panel, left arm) to where they had sensed their arm had been moved. The exemplar control (bottom panel), demonstrates that the subject (open symbols) could accurately match the locations of the robot movement (black closed symbols). The dotted gray line shows the outline of the subject's data from the outer 8 points mirrored directly onto the robot workspace for visualization purposes. (C) Kinaesthetic matching: The robot moved the subjects' arm (top panel, right arm in example) to one of three locations in the workspace. As soon as the subject felt the robot move their arm, they were to mirror-match the speed, direction and length of the robot-generated movement (top panel). The exemplar control (bottom panel), demonstrates that for a single direction of the task, the subject (open symbols, gray lines) was able to consistently and accurately match the direction and length of the robot-generated movement (closed symbols, black line). The dotted gray line shows subject performance mirrored directly onto the robot movement for visualization purposes.

Figure 2

Exemplar reaching data for a subject with tremor before and after Vim DBS implantation. (A) Pre-surgery (left panel), and post-surgery reaching behavior (right panel). (B) Performance on three measures of reaching behavior for posture speed (left panel), a measure of resting hand speed before movement initiation; initial direction error (middle panel), a measure of directional error in the beginning phase of movement to the target; corrective path length (right panel), a measure of corrective distance covered to stabilize at the target after the initial phase of movement. Average control performance (n = 6) is displayed as a solid dark gray line with a gray box representing control subject variability (Standard Deviation). Average patient subject data is plotted as a solid black line, and individual subject data is plotted as dotted lines for Pre- and Post-Surgery (n = 6). We observed that posture speed and corrective path length improved post-surgery.

Figure 3

Exemplar position matching for a subject before and after left Vim DBS implantation. (A) Pre-surgery position matching behavior (top panel), and post-surgery position matching behavior (bottom panel). (B) Performance on two measures of position matching for pre-surgery (n = 4) and post-surgery subjects (n = 2): end point variability (left panel), a measure of subject ability to consistently match location of robot movement; workspace contraction/expansion (right panel), a measure of subject ability to conserve the shape of the workspace generated by the robot movements. Control data is indicated by the black line (mean) and gray box (SD). Average patient data is indicated by filled circles and solid line, individual patient data is indicated by open circles and dotted lines. We observed no significant differences in position matching behavior pre- or post-surgery.

Figure 4

Exemplar data for the kinaesthetic matching task for a subject before and after left Vim DBS implantation. (A) Pre-surgery kinaesthetic matching behavior (top panel), and post-surgery kinaesthetic matching behavior (bottom panel). (B) Performance on two measures of the kinaesthetic matching task show no impairment in sense of movement direction (initial direction error, left panel) or ability to match the speed of the robot-generated movement (peak speed ratio, right panel). Average control performance (n = 6) is displayed as a solid dark gray line with a gray box representing control subject variability (Standard Deviation). Average patient subject data is presented as a solid black line, with individual subjects as dotted lines. Overall, we observed intact kinaesthetic behavior both pre- (n = 6) and post-surgery (n = 6).

Figure 5

Exemplar reaching data for subjects OFF and ON Vim DBS. (A) Reaching behavior for a single subject from the short-term stim group OFF (top panel) and ON stimulation (bottom panel). (B) Reaching behavior for a single subject from the long-term stim group OFF (top panel) and ON stimulation (bottom panel). (C) Performance on three measures of reaching behavior: posture speed (left panel), a measure of resting hand speed before movement initiation; initial direction error (middle panel), a measure of directional error in the beginning phase of movement to the target; corrective path length (right panel), a measure of corrective distance covered to stabilize at the target after the initial phase of movement. Average control performance (n = 11) is displayed as a solid dark gray line with a gray box representing control subject variability (Standard Deviation). Average patient subject data is presented as thicker solid lines (ST, blue; LT, red), with individual subject data as thinner dotted lines. Subjects in both ST (n = 6) and LT (n = 5) groups show improvement in posture speed with stimulators ON.

Figure 6

Exemplar position matching for a short-term stim subject with a left Vim DBS implant (A) and a long-term stim subject with a right Vim DBS implant (B), OFF (top panels) and ON stimulation (bottom panels). (C) Performance on two measures of position matching: end point variability (top panel), a measure of ability to consistently match location of the robot movement; workspace contraction/expansion (bottom panel), a measure of subject ability to conserve the shape of the workspace generated by the robot movements. Average control performance (n = 11) is displayed as a solid dark gray line with a gray box representing control subject variability (Standard Deviation). Average patient subject performance is displayed as a thick line, with thinner dotted lines representing individual subjects. Subjects in the LT-stim (red, n = 5) group displayed increased variability and a tendency to contract the workspace compared to controls and the ST-stim group (blue, n = 6).

Figure 7

Exemplar data for the kinaesthetic matching task in a ST-stim subject with left Vim DBS (A) and a LT-stim subject with right Vim DBS (B), OFF (top panels) and ON stimulation (bottom panels). (C) Performance on two measures of the kinaesthetic matching task show that all subjects in the LT-stim group (n = 5) make large directional error (K-IDE, left panel), and have difficulty modulating their hand speed to match the speed of the robotic movement, with a tendency to move more slowly (PSR, right panel) compared to controls (n = 11) and ST-stim subjects (n = 6). Average control performance (n = 11) is displayed as a solid dark gray line with a gray box representing subject variability (Standard Deviation). Average patient subject data is displayed as a thicker line, with thinner dotted lines representing individual subjects.