MR-guided focused ultrasound thalamotomy modulates cerebello-thalamo-cortical tremor network in essential tremor patients

Abstract

Objectives: To advance the mechanistic understanding of changes occurring to brain connectivity after successful MR-guided Focused Ultrasound ventral intermediate nucleus (VIM) thalamotomy for essential tremor (ET).

Methods: This retrospective study included fifteen right-handed ET patients, who underwent successful unilateral VIM ablation and experienced improved hand tremor on their dominant hand. Resting-state fMRI scans were conducted both before and 1-year post-treatment for all participants. A seed-based whole brain resting-state functional connectivity (FC) analysis was performed, centering on tremor-related regions within the cerebello-thalamo-cortical (CTC) network, including the left and right ventral intermediate nucleus (VIM), primary motor cortex (M1H), and dentate nucleus (DN). The study examined both the changes in FC and their correlation with clinical outcomes evaluated using the Clinical Rating Scale for Tremor (CRST) at the 1-year post-treatment.

Results: ET patients demonstrated significant tremor improvement at the treated hand, which persisted throughout the 1-year study period. Compared with the baseline, FC of both left VIM and right VIM decreased in precentral gyrus and postcentral gyrus; FC of left M1 hand area increased in premotor cortex and supplemental motor area (SMA); and FC of left DN also increased in premotor cortex, SMA, M1, and anterior cingulate cortex (ACC). Association analysis between changes in left VIM functional connectivity and contralateral hand tremor scores revealed a significant negative correlation in the bilateral precentral gyrus, superior parietal lobule, precuneus, occipital cortex, and middle prefrontal cortex. Conversely, a significant positive correlation was observed in the frontal orbital cortex, right insular cortex, temporal pole, hippocampus, left lingual gyrus, right cerebellar lobules IV/V, left cerebellar lobule VI, and vermis IV/V.

Conclusion: Our findings of altered functional connectivity within the cerebello-thalamo-cortical network, encompassing regions involved in motor, sensory, attention, visual, and visuospatial functions, and its association with hand tremor improvement suggest that targeting functional connectivity abnormalities may be a potential approach for alleviating tremor symptoms in ET patients.

Keywords: MRgFUS thalamotomy; cerebello-thalamo-cortical network; essential tremor; resting-state fMRI; tremor network.

Figure 1

Representative VIM lesion overlapped on T1MPRAGE and T2w at pre-treatment, 24-h, and 1-year post the unilateral MRgFUS thalamotomy.

Figure 2

Improvement in hand tremor and functional disability following MRgFUS thalamotomy treatment. (A) Right-hand tremor score; (B) left-hand tremor score; and (C) functional disability score. The error bars represent the standard error of the mean (SEM). After thalamotomy treatment, the tremor was significantly reduced in the right hand (treated) and this reduction was maintained throughout the 12-month study period, while the tremor score in the left hand (untreated) showed no change. The functional disability for patients significantly improved following MRgFUS thalamotomy and this improvement was sustained throughout the 12-month study period. Asterisk (*) indicates a significant difference between baseline and post-treatment time points at 1, 3, 6, and 12 months.

Figure 3

The functional connectivity map of left VIM before the MRgFUS thalamotomy. The map shows widespread functional connectivity within the cerebello-thalamo-cortical tremor network and beyond. The right VIM exhibited a similar functional connectivity pattern (not shown). The significant level was defined as voxel-wise uncorrected p < 0.0001 and multiple comparison with cluster-wise corrected FDR p < 0.05. The color bar represents the T-value, with red-yellow colors indicating positive correlation. M1, primary motor cortex; S1, primary somatosensory cortex.

Figure 4

Significant clusters of functional connectivity (FC) differences between baseline and 1-year post-surgery with seeds of (A) Left VIM; (B) Right VIM; (C) Left M1H (Hand Area in Primary Motor Cortex); (D) Right M1H; (E) Left DN (Dentate Nucleus); and (F) Right DN. Pairwise t-tests were performed. Red-yellow colors show FC at 1-year post-surgery greater than baseline, and blue-purple; colors represent FC at 1-year post-surgery less than baseline. SMA, supramarginal gyrus; M1, Primary motor cortex; S1, somatosensory cortex; SPL, superior Parietal Lobe; mPFC, middle prefrontal cortex; sPFC, superior prefrontal cortex; SMG, supramarginal gyrus; AG, angular gyrus; ACC, anterior cingulate gyrus; ParaCC, paracingulate gyrus.

Figure 5

Significant associations between changes in right-hand tremor scores (pre-post) and left VIM FC changes (post-pre). (A) Clusters showing significant negative correlations; (B) representative scatter plot illustrating the strongest negative correlation in the cluster of bilateral PreCG, left PostCG, and left SPL [cluster coordinates: (−4, −30, 58), cluster size = 421 voxels, cluster p-FDR = 0.000004]; (C) clusters showing significant positive correlations; (D) representative scatter plot illustrating the strongest positive correlation in the cluster of the insular cortex and temporal pole [cluster coordinates: (46, 12, −16), cluster size = 359 voxels, cluster p-FDR = 0.000033]. PreCG, Precentral Gyrus; PostCG, Postcentral Gyrus; SPL, Superior Parietal Lobule.