Essential tremor is associated with disruption of functional connectivity in the ventral intermediate Nucleus--Motor Cortex--Cerebellum circuit

Abstract

The clinical benefits of targeting the ventral intermediate nucleus (VIM) for the treatment of tremors in essential tremor (ET) patients suggest that the VIM is a key hub in the network of tremor generation and propagation and that the VIM can be considered as a seed region to study the tremor network. However, little is known about the central tremor network in ET patients. Twenty-six ET patients and 26 matched healthy controls (HCs) were included in this study. After considering structural and head-motion factors and establishing the accuracy of our seed region, a VIM seed-based functional connectivity (FC) analysis of resting-state functional magnetic resonance imaging (RS-fMRI) data was performed to characterize the VIM FC network in ET patients. We found that ET patients and HCs shared a similar VIM FC network that was generally consistent with the VIM anatomical connectivity network inferred from normal nonhuman primates and healthy humans. Compared with HCs, ET patients displayed VIM-related FC changes, primarily within the VIM-motor cortex (MC)-cerebellum (CBLM) circuit, which included decreased FC in the CBLM and increased FC in the MC. Importantly, tremor severity correlated with these FC changes. These findings provide the first evidence that the pathological tremors observed in ET patients might be based on a physiologically pre-existing VIM - MC - CBLM network and that disruption of FC in this physiological network is associated with ET. Further, these findings demonstrate a potential approach for elucidating the neural network mechanisms underlying this disease.

Keywords: cerebellum; essential tremor; functional connectivity; functional magnetic resonance imaging; motor cortex; resting state; thalamus; ventral intermediate nucleus.

Figure 1

Location of the seed regions in the VIM and the other four ventral lateral thalamic nuclei and spatial specificity analysis. A: According to studies conducted by Papavassiliou et al. and Morel et al., we defined the VIM seed region (red color) and the other four ventral lateral thalamus nuclei seed regions (blue color) in standardized MNI space via anatomical imaging. B: Spatial specificity analysis to determine whether the VIM seed region displayed the strongest FC with the ipsilateral primary MC among these nuclei. VIM: ventral intermediate nucleus; partial FC: partial functional connectivity; ET: essential tremor; HCs: healthy controls. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Results of the one‐sample t‐test for left VIM seed region FC maps for the ET patient (upper) and HC groups (lower). The threshold was set at P < 0.05 with AlphaSim correction (cluster size ≥ 85 voxels, 1000 Monte Carlo simulations). The Ch2 image depicts the underlying structure. VIM: ventral intermediate nucleus; ET: essential tremor; HCs: healthy controls. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Difference in left VIM seed region FC between the ET patient and HC groups. The results were obtained using the two‐tailed two‐sample t test within a combined one‐sample t‐test mask (P < 0.01, AlphaSim corrected with a cluster size of ≥ 10 voxels, 1000 Monte Carlo simulations). Regions displaying increased FC in the ET patients compared with the HCs are indicated by warm colors, whereas those displaying decreased FC in the ET patients are indicated by cold colors. The Ch2 image shows the underlying structure. VIM: ventral intermediate nucleus; FC: functional connectivity; ET: essential tremor; HCs: healthy controls. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Imaging results‐behavior correlation analysis. The left panel shows the location of the ROIs, as determined by the two‐sample t‐test. The clusters displaying altered FC in essential tremor (ET) patients were identified as the ROIs. The middle panel shows the average FC values in each ROI for the ET patient and HC groups. The right panel shows the scatter plots of the mean FC value for each ET patient against the corresponding z score of the TRS parts A&B scores (P < 0.01, uncorrected). TRS parts A&B scores: the combined Fahn‐Tolosa‐Marin TRS parts A and B scores, zFC: Fisher's z‐transformation of FC. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]