Deep Brain Stimulation for Arm Tremor: A Randomized Trial Comparing Two Targets

Abstract

Objective: Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM) effectively suppresses arm tremor. Uncontrolled studies suggest the posterior subthalamic area (PSA) may be superior. We compared the intra-individual efficacy of VIM- versus PSA-DBS on tremor suppression and arm function.

Methods: We performed a randomized, double-blind, crossover trial at Oslo University Hospital in patients (18-80 years) with isolated or combined action tremor affecting at least one arm. Four-contact DBS leads were implanted (bi- or unilaterally) with a trajectory to cover the VIM (upper two contacts) and PSA (lower two contacts). Patients were randomized (1:1 ratio) post-surgery to: Group 1, VIM-stimulation months 0-3 (period 1), then PSA-stimulation months 4-6 (period 2); Group 2, PSA-stimulation first, then VIM-stimulation. Primary endpoint was the difference in improvement from baseline to the end of the VIM- versus PSA-period in the sum of the dominant arm tremor scores of the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS), items 5/6 + 10-14.

Results: Forty-five patients were randomized to Group 1 (n = 23) or 2 (n = 22). In the primary endpoint per-protocol analysis (mixed model, n = 40), mean difference in the sum FTMTRS score improvement for the dominant arm was -2.65 points (95% CI -4.33 to -0.97; p = 0.002). The difference in favour of PSA stimulation was highly significant in period 2, but not period 1.

Interpretation: Our randomized trial demonstrated that PSA stimulation provided superior tremor suppression compared with VIM stimulation. A period effect reducing tremor for up to three months in both groups was most likely attributed to a post-surgery stun effect. ANN NEUROL 2022;91:585-601.

FIGURE 1

Trial profile.

FIGURE 2

Primary endpoint by sequence and period. Left panel shows the mean of individual patient score changes from baseline in the sum of the dominant arm FTMTRS items (5/6 + 10–14), for Group 1/Sequence 1 (stimulation first in the VIM, then PSA; red‐filled circles) and Group 2/Sequence 2 (stimulation first in the PSA, then VIM; blue‐filled squares). Bars represent standard error of the mean. Right panel shows score changes in each individual patient. In four patients of each group in whom tremor improvement favoured PSA the most (difference > 6 points), diagnoses were cerebellar tremor (n = 5), essential tremor (n = 2) and segmental dystonic tremor (n = 1). (Non‐parametric tests comparing these four patients with the remaining patients of their respective group showed no significant differences in active contact coordinates for the VIM‐ or PSA‐period (left hemisphere), stimulation current applied, age at surgery, disease duration or gender). PSA, posterior subthalamic area; VIM, ventral intermediate nucleus; FTMTRS, Fahn‐Tolosa‐Marin Tremor Rating Scale.

FIGURE 3

Lead location of individual patients, and an example of an ‘ideal’ trajectory. Left hemisphere is shown anatomically, but all leads are shown, with those in the right hemisphere projected onto the left hemisphere. Upper panels: coronal plane, lower panels: sagittal plane. Panels A and C show lead locations. Panels B and D show an example of a study patient (male 54 years, diagnosis essential tremor) with an “ideal” left trajectory, with coordinates of the active contact used in the VIM‐period: X = 12.61 mm (lateral to the ICL‐line (48.5% of the ICL‐length), Y = −5.36 mm (posterior) to MCP (;29.4% anterior to PC), Z = 0.80 mm above the AC‐PC plane, and in the PSA‐period: X = 11.55, Y = −7.25, Z = −2.57 (ICL‐length 26.0 mm). His tremor improved very well with both targets, but 2 points better in the PSA versus VIM. AC, anterior commissure; ICL, intercommissural line; MCP, mid‐commissural point; PC, posterior commissure; PSA, posterior subthalamic area; RN, red nucleus; SN, substantia nigra; STN, subthalamic nucleus; VIM, ventral intermediate nucleus.

FIGURE 4

Active contact location of individual patients in each randomized period and at one‐year follow‐up. Left hemisphere is shown anatomically, but all contacts are shown, with those in the right hemisphere projected onto the left hemisphere. Upper panels: coronal plane, lower panels: sagittal plane. Panels A and C show the location of each patient's active contact used in the VIM treatment period (red dots) and PSA period (light blue dots); panels B and D show the active contact used at the one‐year follow‐up (pink dots). The mean (standard deviation) AC‐PC‐based coordinates for the active contacts were in the left/right hemispheres for the VIM period: X (mm lateral to the ICL‐line) = 13.29(1.45)/−13.10 (1.32), Y (mm anterior–posterior relative to MCP) = −4.74(1.83)/−4.85 (1.51), Z (mm superior/inferior to the ICL‐plane) = −0.25(1.67)/−0.24(1.44); for the PSA period: X = 12.25(1.37)/−11.90(1.13), Y = −6.58(1.52)/−6.88(1.20), Z = −3.02 (1.40)/−3.04(1.32). Coordinates in the MNI‐space were in the left/right hemispheres for the VIM‐period: X = 12.47 (1.21)/12.65 (1.11), Y = −15.28 (2.28)/−16.43(1.84), Z = −3.22 (1.71)/−3.15 (1.84); for the PSA‐period: X = −12.05 (1.20)/11.95 (0.93), Y = −17.64 (1.74)/−18.54 (1.35), Z = −5.61 (1.61)/−5.94 (1.53). AC, anterior commissure; MCP, mid‐commissural point; MNI, Montreal Neurological Institute; PC, posterior commissure; PSA, posterior subthalamic area; VIM, ventral intermediate nucleus.