Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Rebalances Atypical Functional Hierarchy in Patients with Essential Tremor
Research Report: Reshaping Functional Hierarchies in Medication-Refractory Essential Tremor Through MRgFUS Therapy
Essential tremor (ET), a prevalent movement disorder, is characterized by involuntary limb tremors, particularly noticeable during specific tasks. While traditional pharmacological treatments and deep brain stimulation (DBS) have shown efficacy in symptom management, therapeutic options remain limited for medication-refractory ET patients. This study investigates the impact of Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy on the functional frameworks and hierarchical organization of the brain, exploring its mechanisms and value in ET treatment.
Background and Objectives
The pathophysiology of ET remains elusive, with functional connectivity abnormalities as a key feature. Brain organization typically adheres to strict hierarchical principles, and this structure is frequently disrupted in neurological diseases. Advances in MRgFUS technology enable precise thalamotomy without craniotomy, anesthesia, or ionizing radiation, significantly reducing tremors and earning FDA approval for ET treatment. However, as MRgFUS results in irreversible thalamic damage, concerns arise regarding its potential to further disrupt brain functional hierarchies.
This study aims to evaluate changes in brain functional frameworks post-MRgFUS thalamotomy using functional gradient analysis, examining its influence on hierarchical organization and associated neuropathophysiological mechanisms.
Study Design and Methods
Data Sources and Patient Information
A retrospective analysis was conducted on 30 medication-refractory ET patients who underwent MRgFUS thalamotomy at the Chinese PLA General Hospital between 2018 and 2020. Pre- and postoperative six-month functional MRI (fMRI) data were analyzed. Patients had a mean age of 62 years and a mean disease duration of 18 years; 70% had a family history of ET. Data from 30 matched healthy controls and an additional healthy dataset were included for gradient alignment.
Experimental Process
Imaging Data Collection and Preprocessing
Resting-state fMRI data were acquired using a 3T scanner. Preprocessing steps included format conversion, temporal correction, spatial normalization, and noise reduction. Functional connectivity networks were constructed, and principal gradient components were extracted using dimensionality reduction techniques.Functional Gradient Analysis
Gradients reflected gradual changes in functional connectivity, with the first two components representing the VIS-DMN and SM-DMN axes of connectivity.Linking Gradients to Tremor Symptoms
Supervised learning models (e.g., Support Vector Regression) and stepwise linear regression were employed to associate gradient features with tremor symptoms, such as CRST scores.Neuropathophysiological Mechanisms
The Allen Human Brain Atlas (AHBA) and gene expression data were utilized to explore biological mechanisms underlying gradient framework alterations.
Key Findings
1. Tremor Alleviation and Gradient Framework Remodeling
MRgFUS significantly alleviated tremor symptoms, reducing CRST total scores from 56.70 to 22.93 post-treatment, with a tremor improvement rate of 78.19%. Postoperative changes in brain functional gradients were notable, with a significant reduction in global variance explained by Gradient-2 (from 23% to 19%, $p<0.001$).
2. Local Gradient Feature Changes
Post-treatment restoration of Gradient-2 features was observed, particularly in the Posterior Cingulate Cortex (PCC) region. This restoration was linked to improved balance between the DMN, SM, and VIS networks.
3. Predictive Value of Gradient Features
Gradient features predicted tremor symptoms, with CRST-B scores showing significant correlations ($r=0.45$, $p=0.006$). Preoperative DMN gradient features were strong predictors of postoperative improvement rates.
4. Neuropathophysiological Mechanisms
Gene enrichment analysis revealed that gradient alterations were associated with pathways related to Parkinson’s disease and oxidative phosphorylation, suggesting potential mechanistic links between ET and these biological processes.
Discussion and Implications
Functional Remodeling and Mechanisms
The significant perturbation of global gradient frameworks post-MRgFUS highlights the dual role of thalamotomy: disrupting brain integrity while driving functional adaptations. Recovery of DMN-related gradients (e.g., PCC) suggests a rebalancing of neurodynamic hierarchies, particularly in the SM-DMN-VIS axis. These findings support the hypothesis that DMN dysfunction underpins tremor pathology and its resolution contributes to symptom improvement.
Subcortical Changes
Alterations in cerebellum and thalamus gradients were observed, though not statistically significant after multiple comparisons. This may result from the scale sensitivity of gradient tools, imaging limitations of 3T MRI, or the subtle functional changes induced by MRgFUS.
Biological Insights
The association of gradient changes with Parkinson’s disease and mitochondrial dysfunction reinforces the shared neuropathological underpinnings between ET and Parkinson’s. This supports a dynamic remodeling process post-MRgFUS and highlights potential therapeutic targets.
Limitations and Future Directions
The study’s limitations include a small sample size, short follow-up duration, and technical constraints in capturing subcortical changes. Future research should involve larger cohorts, longitudinal designs, and advanced imaging modalities (e.g., 7T MRI). Validating predictive biomarkers with independent datasets will enhance their clinical utility.
This study underscores MRgFUS’s potential not only to relieve tremor symptoms but also to remodel dysfunctional brain hierarchies, offering valuable insights into ET’s neurodynamic basis. These findings advance our understanding of MRgFUS as a therapeutic modality and its broader implications for movement disorders.