Optimal focused ultrasound lesion location in essential tremor

Abstract

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for medically refractory essential tremor. We investigate ablation sites and potential tracts associated with optimal tremor control and side effects based on the analysis of 351 cases from three international hospitals. Lesions were segmented on day 1 thin-cut T2 axial images, mapped to standard Montreal Neurological Institute space, and used to derive probabilistic maps and tracts associated with tremor improvement and side effects. Lesioning of a specific subregion within the ventral intermediate nucleus and the cerebellothalamic tract was associated with optimal tremor improvements. Some lesion locations and tracts were associated with differential side effects. Overlaps with the optimal tremor improvement sites accounted for variance in clinical improvements in out-of-sample cases. Efficacy of this location was further confirmed by test-retest cases that underwent two MRgFUS procedures. We identify and validate a target area for optimal tremor control and sites of avoidance associated with side effects.

Fig. 1.. Sweetspot results.

Area associated with optimal tremor control at 1-year post-MRgFUS thalamotomy. N-map of the top responders at 1 year (n = 62) defined as 100% improvement in FTM tremor score (subitems of part A, see Materials and Methods) and of the poorest responders at 1 year (n = 11) defined as <50% improvement in FTM tremor score (second row). The entire area covered by lesions (n = 200) is outlined by the dotted black lines. The sweetspot area of optimal tremor control (bottom row, FDR-corrected P < 0.05) was determined based on the 1-year post-MRgFUS thalamotomy FTM improvement, where the average improvement in our cohort was 86.0%. The Bonferroni-corrected area (P < 0.05) is outlined by the black solid lines. This same area is superimposed on the N-maps of the top and poorest responders to demonstrate their spatial relationships with the peak region of the sweetspot. The Vim (based on the DISTAL atlas) is defined by the white outline (61). Color bars in the first two rows represent number of patients, while color bar in the last row represents the z (signed rank) statistic.

Fig. 2.. Fiber filtering results.

All tracts within the DBS Tractography Atlas, v2 are shown in white (top and middle rows). Tracts associated with optimal tremor control (FDR corrected) at 1-year post-MRgFUS thalamotomy are shown in red (t value = 3.86 to 4.34), of which majority (70%) correspond to the cerebellothalamic tract (middle and bottom rows). A thresholded version of the N-map showing the site where lesions were mostly created is shown as the red volume.

Fig. 3.. Sourspots associated with side effects.

Areas associated with side effects at 1-day post-MRgFUS thalamotomy (except dysgeusia, which is shown at 3 months because the outcome was not collected at 1-day postprocedure). The N-map of all lesions is shown in the top row (n = 200). The sourspot of each side effect is shown in hot colors, and voxels negatively associated with the occurrence of the side effect are in cold colors. The FDR-corrected area (P < 0.05) is outlined in white for weakness, sensory deficits, and imbalance. The significant area at the uncorrected level (P < 0.05) is outlined in white for dysarthria and dysgeusia as they were not significant with FDR correction. The Vim (based on the DISTAL atlas) is defined by the brown outline in the axial and sagittal planes. The color bar in the first row represents number of patients, while color bars in the other rows represent the statistic value for the proportion test.

Fig. 4.. Tracts and sourspots associated with each type of side effect.

Tracts shown at an FDR-corrected significant level (P < 0.05) for weakness (dark green), sensory deficits (beige), and imbalance (yellow); shown at a significant level (P < 0.05) uncorrected for multiple comparisons for dysarthria (purple) and dysgeusia (green) in relation to the sweetspot (red) and each side effect’s respective sourspot. The Vim (based on the DISTAL atlas) is shown as a white wireframe. a = anterior; p = posterior; r = right; s = superior. (A) and (B) show views from lateral (sagittal view) and top (axial view), respectively. (C) shows sourspots and (D) fiber tracts of all types of side effects together (again including the optimal tremor response sweetspot in red).

Fig. 5.. Validation of sweetspot by out-of-sample cases.

Weighted average overlaps between the out-of-sample validation cases and the identified sweetspot were calculated (left) based on N = 102 independent cases from BWH and N = 49 cases that underwent MRgFUS thalamotomy at two hospitals in Toronto (middle). There were significant correlations between the weighted sweetspot lesion overlaps and tremor improvements at 3-month and 1-year time points in the independent BWH cases (R = 0.27, P = 0.012; R = 0.42, P = 7.9 × 10⁻⁴), as well as for the Toronto cohort (3 months: R = 0.29, P = 0.041, 1 year: R = 0.32, P = 0.033). Correlations between the weighted sweetspot lesion overlaps and tremor improvements across the entire test cohort (BWH and Toronto combined; n = 151) also led to significant findings for both percentage (R = 0.63, P = 2.0 × 10⁻⁴) and absolute tremor improvements (R = 0.48, P = 10⁻²; right).

Fig. 6.. Individual cases.

Postoperative day 1 T2-weighted MRIs with Wintermark zone 1 outlined in white and the Bonferroni-corrected sweetspot overlaid in red/yellow. Patients with (A) successful retreatment (green outline) and (B) unsuccessful retreatment (red outline). (C) Patients with 0% FTM tremor improvement at 1 year. (D) Comparison between the percent of overlaps between our sweetspot (recalculated without these six patients) and Wintermark zone 1 of lesions from treatments 1 and 2 color coded for patients who had sustained tremor control after second treatment (green) versus patients who did not (blue).

Fig. 7.. Comparison with published results.

Spatial relationships between our identified sweetspot and previously published optimal targets for MRgFUS thalamotomy in ET (top row) and spatial relationship of published DBS sweetspots. In the top row, our sweetspot after Bonferroni correction (green) and FDR correction (translucent green) and optimal FUS targets from Boutet et al. (23), retrieved from Lead-DBS software (blue), and Federau et al. (22) (yellow) are shown, and in the bottom row are published DBS sweetspots, with the traditional Guiot target (purple) and the Bonferroni-corrected sweetspot identified in the present study in views from the right (sagittal orientation, left) and from the back (coronal orientation, right) planes on a fast gray matter acquisition T1 inversion recovery brain scan in MNI space. The Vim (based on the DISTAL atlas) is shown in translucent white in all panels. Comparison includes studies (22), (23), (26), (57), and (–77).