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Background:  Patients often exhibit very severe or disabling forms of tremor that cannot be clearly characterized., Objective:  To present a series of 37 cases of tremor considered unclassifiable . Patients diagnosed with essential tremor according to criteria of the International Parkinson Disease and Movement Disorder Society (IPDMDS), who had been previously studied, were included as controls. All patients underwent a battery of tests between 2019 and 2022, which enabled us to compare them., Methods:  Relevant demographic and clinical information were collected. The following tools were applied: the Mini-Mental State Examination (MMSE); the Hospital Anxiety and Depression Scale (HADS); the Fahn-Tolosa-Marín Tremor Rating Scale (TRS); and the Quality of Life in Essential Tremor (QUEST). A simple brain magnetic resonance imaging (MRI) scan was performed for all patients. The categorical variables were compared using the Chi-squared test and the t -test with Fisher correction if appropriate, and the quantitative variables were compared through the two-tailed Student t -test. Values of p ≤ 0.01 were considered statistically significant., Results:  The cases presented higher scores on the anxiety and depression subscales of the HADS than the controls ( p ≤ 0.006 and 0.000 respectively). In all domains of the TRS, the cases scored significantly higher, as well as in the QUEST. History of enolism was higher among the controls, and history of orthostasis and rest tremor was higher among the cases ( p ≤ 0.000). Cerebellar atrophy was present in every patient in the case group, and in 24 subjects in the control group. Dystonia was observed in 7 subjects in the case group, and in none of the patients in the control group., Conclusion:  There are patients with unclassifiable and extremely disabling tremors who respond poorly to the pharmacological therapy options., Competing Interests: The author has no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Substantial evidence highlights the role of the cerebellum in the pathophysiology of tremor in essential tremor (ET), although its potential involvement in altered movement execution in this condition remains unclear. This study aims to explore potential correlations between the cerebellum and basal ganglia functional connectivity and voluntary movement execution abnormalities in ET, objectively assessed with kinematic techniques. A total of 20 patients diagnosed with ET and 18 healthy subjects were enrolled in this study. Tremor and repetitive finger tapping were recorded using an optoelectronic kinematic system. All participants underwent comprehensive 3T-MRI examinations, including 3D-T1 and blood-oxygen-level dependent (BOLD) sequences during resting state. Morphometric analysis was conducted on the 3D-T1 images, while a seed-based analysis was performed to investigate the resting-state functional connectivity (rsFC) of dorsal and ventral portions of the dentate nucleus and the external and internal segments of the globus pallidus. Finally, potential correlations between rsFC alterations in patients and clinical as well as kinematic scores were assessed. Finger tapping movements were slower in ET than in healthy subjects. Compared to healthy subjects, patients with ET exhibited altered FC of both dentate and globus pallidus with cerebellar, basal ganglia, and cortical areas. Interestingly, both dentate and pallidal FC exhibited positive correlations with movement velocity in patients, differently from that we observed in healthy subjects, indicating the higher the FC, the faster the finger tapping. The findings of this study indicate the possible role of both cerebellum and basal ganglia in the pathophysiology of altered voluntary movement execution in patients with ET., (© 2024. The Author(s).)

Essential tremor (ET) is the most common movement disorder globally and has negative impacts on quality of life. While medical treatments exist, approximately 50% of patients have tremor that is refractory to medication or experience intolerable medication side effects. Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an option for these patients and while incisionless, it is still invasive, although less so than other surgical treatments such as deep brain stimulation and radiofrequency thalamotomy. Despite MRgFUS being FDA-approved since 2016, there is still no current consensus on the best approaches for targeting, imaging, and outcome measurement. A 2-day workshop held by the Focused Ultrasound Foundation in September of 2023 convened experts and critical stakeholders in the field to share their knowledge and experiences. The goals of the workshop were to determine the optimal target location within the thalamus and compare best practices for localizing the target and tracking patient outcomes. This paper summarizes the current landscape, important questions, and discussions that will help direct future treatments to improve patient care and outcomes.

Objective: MR-guided focused ultrasound (MRgFUS) thalamotomy is an incisionless neurosurgical treatment for patients with medically refractory essential tremor and tremor-dominant Parkinson's disease. A low skull density ratio (SDR) < 0.40 is a known risk factor for treatment failure. The aim of this study was to identify useful sonication strategies for patients with a low SDR < 0.40 by modifying the standard sonication protocol using maximum high-energy sonication while minimizing the number of sonications., Methods: The authors retrospectively analyzed the effects of modified MRgFUS sonication on low-SDR tremor patients. All patients underwent head CT scans to calculate their SDR. The SDR threshold for MRgFUS thalamotomy was 0.35. The patients in the early series underwent the standard sonication protocol targeting the ventral intermediate nucleus contralateral to the treated hand side. The patients with a low SDR < 0.40 in the late series underwent a modified sonication protocol, in which the number of alignment sonications was minimized and high-energy treatment sonication (> 36,000 J) was used. The authors evaluated the lesion volume the following day and tremor improvement and adverse events 3 and 12 months after the procedure. The sonication patterns between low-SDR patients treated using different sonication protocols were examined using Fisher's exact test. ANOVA was used to examine the lesion volume and tremor improvement in high- and low-SDR patients treated using different sonication protocols., Results: Among 41 patients with an SDR < 0.40, 14 underwent standard sonication and 27 underwent modified sonication. Fewer alignment sonications and high-energy treatment sonications were used in the modified sonication group compared with the standard group (p < 0.001). The duration of modified sonication was significantly shorter than that of standard sonication (p < 0.001). The lesion volume and tremor improvement significantly differed among the high- and low-SDR groups with different sonication protocols (p < 0.001). Low-SDR patients treated using modified sonication protocols had comparable lesion volume and tremor improvement to the high-SDR group. The modified sonication protocol did not significantly increase adverse intraprocedural and postprocedural events., Conclusions: Minimizing alignment sonications and applying high-energy sonication in early treatment help to create an optimal lesion volume and control tremor in low-SDR patients.

MR-guided focused ultrasound (MRgFUS) has proven its efficacy and safety for the treatment of essential tremor (ET) and/or Parkinson's disease (PD). However, having a cardiac pacemaker has been considered an exclusion criterion for the use of MRgFUS. Only 2 patients with a cardiac pacemaker treated with MRgFUS have been previously reported, both treated using 1.5-T MRI. In this paper, the authors present their experience performing 3-T MRgFUS thalamotomy in 4 patients with an implanted cardiac pacemaker. Treatments were uneventful regarding complications or severe side effects. MRgFUS using 3-T MRI was found to be an efficient and safe treatment for ET and/or PD in patients with an MRI-compatible pacemaker.

Objective: Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging treatment for medication-refractory essential tremor (ET). The objective of this study was to evaluate long-term (up to 5 years) safety and efficacy of unilateral MRgFUS in the treatment of ET., Methods: The authors performed a systematic search through 4 databases to find relevant clinical studies. Binary outcomes were analyzed and reported as odds ratios and 95% confidence intervals, while continuous outcomes were analyzed and reported as standardized mean differences (SMDs) and 95% confidence intervals. Furthermore, a univariable meta-regression was performed to evaluate the association between various covariates and the outcomes including the mean difference in the Clinical Rating Scale for Tremor (CRST) score and hand tremor scores. Sensitivity analysis was performed to address any heterogeneity., Results: A total of 43 studies comprising 1818 patients with ET who underwent MRgFUS were identified. Of the 1539 patients with data on sex, 1095 (71.2%) were male. The mean follow-up duration ranged from 3 months to 8.4 years among the studies. The mean total CRST score significantly decreased at 3, 6, and 12 months post-MRgFUS (SMD -4.5, p = 0.0069; SMD -4.9, p = 0.0045; and SMD -2.95, p = 0.0039, respectively). The mean hand tremor scores significantly mitigated at 3, 6, 12, 24, and 36 months post-MRgFUS (SMD -3.99, p = 0.05; SMD -4.5, p = 0.05; SMD -1.99, p < 0.0001; SMD - 2.07, p = 0.0002; and SMD -2.1, p < 0.0001, respectively). Furthermore, the mean Quality of Life in Essential Tremor Questionnaire scores were improved at 3 months (SMD -2.8, p = 0.0025), 6 months (SMD -4.1, p = 0.04), 12 months (SMD -1.57, p = 0.0004), 2 years (SMD -1.64, p = 0.0003), and 3 years (SMD -1.14, p = 0.08). Our meta-regression findings showed that sex (p = 0.03), unlike age, handedness, symptom duration, and peak energy levels at 3 months, was associated with a significantly higher mean difference in tremor severity., Conclusions: This meta-analysis provides strong evidence supporting the efficacy and safety of unilateral MRgFUS for the treatment of ET in terms of tremor severity and quality of life with acceptable adverse events.

Background: Essential tremor (ET) and Parkinson's disease (PD) are the two most prevalent movement disorders, sharing several overlapping tremor clinical features. Although growing evidence pointed out that changes in similar brain network nodes are associated with these two diseases, the brain network topological properties are still not very clear., Objective: The combination of graph theory analysis with machine learning (ML) algorithms provides a promising way to reveal the topological pathogenesis in ET and tremor-dominant PD (tPD)., Methods: Topological metrics were extracted from Resting-state functional images of 86 ET patients, 86 tPD patients, and 86 age- and sex-matched healthy controls (HCs). Three steps were conducted to feature dimensionality reduction and four frequently used classifiers were adopted to discriminate ET, tPD, and HCs., Results: A support vector machine classifier achieved the best classification performance of four classifiers for discriminating ET, tPD, and HCs with 89.0% mean accuracy (mACC) and was used for binary classification. Particularly, the binary classification performances among ET vs. tPD, ET vs. HCs, and tPD vs. HCs were with 94.2% mACC, 86.0% mACC, and 86.3% mACC, respectively. The most power discriminative features were mainly located in the default, frontal-parietal, cingulo-opercular, sensorimotor, and cerebellum networks. Correlation analysis results showed that 2 topological features negatively and 1 positively correlated with clinical characteristics., Conclusions: These results demonstrated that combining topological metrics with ML algorithms could not only achieve high classification accuracy for discrimination ET, tPD, and HCs but also help to reveal the potential brain topological network pathogenesis in ET and tPD., (© 2024. Fondazione Società Italiana di Neurologia.)

Introduction: Essential tremor (ET) comprises motor and non-motor-related features, whereas the current neuro-pathogenetic basis is still insufficient to explain the etiologies of ET. Although cerebellum-associated circuits have been discovered, the large-scale cerebral network connectivity in ET remains unclear. This study aimed to characterize the ET in terms of functional connectivity as well as network. We hypothesized that the resting-state network (RSN) within cerebrum could be altered in patients with ET. Methods: Resting-state functional magnetic resonance imaging (fMRI) was used to evaluate the inter- and intra-network connectivity as well as the functional activity in ET and normal control. Correlation analysis was performed to explore the relationship between RSN metrics and tremor features. Results: Comparison of inter-network connectivity indicated a decreased connectivity between default mode network and ventral attention network in the ET group ( p < 0.05). Differences in functional activity (assessed by amplitude of low-frequency fluctuation, ALFF) were found in several brain regions participating in various RSNs ( p < 0.05). The ET group generally has higher degree centrality over normal control. Correlation analysis has revealed that tremor features are associated with inter-network connectivity (|r| = 0.135-0.506), ALFF (|r| = 0.313-0.766), and degree centrality (|r| = 0.523-0.710). Conclusion: Alterations in the cerebral network of ET were detected by using resting-state fMRI, demonstrating a potentially useful approach to explore the cerebral alterations in ET.

Background:  The magnetic resonance imaging-guided focused ultrasound (MRgFUS) has emerged as an innovative treatment for patients with medically refractory essential tremor (ET)., Objective:  This retrospective observational study aims to present the results of the first five patients with medically refractory ET who underwent MRgFUS treatment at this pioneering medical unit in Portugal., Methods:  We conducted a retrospective chart review for the first five patients who underwent unilateral MRgFUS thalamotomy of the ventral intermediate (Vim) nucleus to treat medically refractory ET at our medical unit., Results:  The mean patient age was 65.4 (26-84) years, and 60% were male. All patients had a family history of ET. The mean duration of disease was 17.4 years (range 10-24 years), and their dominant hand was the right. According to personal preference, the thalamotomy was performed on the left side in four patients, and on the right side in one. The MRgFUS thalamotomy led to significant improvements in both the clinical rating scale for tremor (CRST) score, by 62%, and the CRST composite score for the treated hand, by 73%. All patients experienced improvements in functionality and quality of life, by 52%. No severe adverse events were observed, and those that did occur during and following the procedure were mild and transient., Conclusion:  The initial results from Portugal's first MRgFUS medical unit indicate promising outcomes, with improvement in quality of life, as well as mild and temporary adverse events These findings contribute to the growing body of literature supporting the efficacy and safety of MRgFUS as a viable treatment option for patients with medication-resistant ET., Competing Interests: The authors have no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

Background: The basal ganglia-thalamocortical (BGTC) and cerebello-thalamocortical (CTC) networks are implicated in tremor genesis; however, exact contributions across disorders have not been studied. Objective: Evaluate the structural connectivity of BGTC and CTC in tremor-dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) with the aid of probabilistic tractography and graph theory analysis. Methods: Structural connectomes of the BGTC and CTC were generated by probabilistic tractography for TDPD ( n = 25), ETP (ET with rest tremor, n = 25), and healthy control (HC, n = 22). The Brain Connectivity Toolbox was used for computing standard topological graph measures of segregation, integration, and centrality. Tremor severity was ascertained using the Fahn-Tolosa-Marin tremor rating scale (FTMRS). Results: There was no difference in total FTMRS scores. Compared with HC, TDPD had a lower global efficiency and characteristic path length. Abnormality in segregation, integration, and centrality of bilateral putamen, globus pallidus externa (GPe), and GP interna (GPi), with reduction of centrality of right caudate and cerebellar lobule 8, was observed. ETP showed reduction in segregation and integration of right GPe and GPi, ventrolateral posterior nucleus, and centrality of right putamen, compared with HC. Differences between TDPD and ETP were a reduction of strength of the right putamen, and lower clustering coefficient, local efficiency, and strength of the left GPi in TDPD. Conclusions: Contrary to expectations, TDPD and ETP may not be significantly different with regard to tremor pathogenesis, with definite overlaps. There may be fundamental similarities in network disruption across different tremor disorders with the same tremor activation patterns, along with disease-specific changes.

Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a novel, minimally invasive ablative treatment for essential tremor (ET). The use of a four-tract probabilistic tractography technique, targeting the intersection between the dentato-rubro-thalamic tracts (both decussating and non-decussating), while evaluating the corticospinal tract and the medial lemniscus, may obtain immediate clinical results with reduced adverse events. Our aim is to present our experience with the four-tract technique for patients undergoing ET treatment with MRgFUS., Methods: Retrospective analysis of a prospective database of consecutive patients undergoing ET treatment in a single center from February 2022 to February 2023. Procedural parameters were collected, and tremor improvement was assessed with the Clinical Rating Scale for Tremor (CRST) at baseline and at 3 and 6 months. Adverse events were also reported., Results: Forty-three patients (median age, 72 years [interquartile range, 66-76]; 22 females) were evaluated. Tremor improved significatively in all CRST subsections at 3 months, including the CRST part A + B treated hand tremor (22 [19-27] vs 4 [2-7], p < 0.001) and CRST part C (16 [13-19] vs 3 [1-4], p < 0.001). Differences persisted significant at 6 months. Adverse events were few (4.1% of paresthesias and 12.5% of objective gait disturbance at follow-up) and recorded as mild. The median number of sonications was 7 [6-8] and mean operative time 68.7 ± 24.2 min., Conclusion: Our data show support for the feasibility and benefits of systematic targeting approach with four-tract probabilistic tractography for treating ET using MRgFUS., Clinical Relevance Statement: An approach with four-tract probabilistic tractography for treating essential tremor (ET) patients with magnetic resonance-guided focused ultrasound decreases interindividual variability with good clinical outcomes, low number of sonications, few adverse effects, and short procedure times., Key Points: • The optimal target for the treatment of essential tremor with MR-guided focused ultrasound remains unknown. • Four-tract probabilistic tractography is a feasible technique that reduces interindividual variability, with good clinical results, few side effects, and short operative time. • The four-tract tractography approach can be performed using different MRI scanners and post-processing software in comparison with the initial description of the technique., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Essential tremor (ET) and dystonic tremor (DT) are the two most common tremor disorders, and misdiagnoses are very common due to similar tremor symptoms. In this study, we explore the structural network mechanisms of ET and DT using brain grey matter (GM) morphological networks and combine those with machine learning models., Methods: 3D-T1 structural images of 75 ET patients, 71 DT patients, and 79 healthy controls (HCs) were acquired. We used voxel-based morphometry to obtain GM images and constructed GM morphological networks based on the Kullback-Leibler divergence-based similarity (KLS) method. We used the GM volumes, morphological relations, and global topological properties of GM-KLS morphological networks as input features. We employed three classifiers to perform the classification tasks. Moreover, we conducted correlation analysis between discriminative features and clinical characteristics., Results: 16 morphological relations features and 1 global topological metric were identified as the discriminative features, and mainly involved the cerebello-thalamo-cortical circuits and the basal ganglia area. The Random Forest (RF) classifier achieved the best classification performance in the three-classification task, achieving a mean accuracy (mACC) of 78.7%, and was subsequently used for binary classification tasks. Specifically, the RF classifier demonstrated strong classification performance in distinguishing ET vs. HCs, ET vs. DT, and DT vs. HCs, with mACCs of 83.0 %, 95.2 %, and 89.3 %, respectively. Correlation analysis demonstrated that four discriminative features were significantly associated with the clinical characteristics., Conclusion: This study offers new insights into the structural network mechanisms of ET and DT. It demonstrates the effectiveness of combining GM-KLS morphological networks with machine learning models in distinguishing between ET, DT, and HCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Tremor dominant Parkinson's disease (TDPD) and essential tremor plus (ETP) syndrome are commonly encountered tremor dominant neurological disorders. Although the basal ganglia thalamocortical (BGTC) and cerebello thalamocortical (CTC) networks are implicated in tremorogenesis, the extent of functional connectivity alterations across disorders is uncertain. This study aims to evaluate functional connectivity of the BGTC and CTC in TDPD and ETP. Resting state functional MRI was acquired for 25 patients with TDPD, ETP and 22 healthy controls (HC). Following pre-processing and denoising, seed-to-voxel based connectivity was carried out at FDR < 0.05 using ROIs belonging to the BGTC and CTC. Fahn-Tolosa-Marin tremor rating scale (FTMRS) was correlated with the average connectivity values at FDR < 0.05. Compared to HC, TDPD showed decreased connectivity between cerebellum and pre, post central gyrus. While, ETP showed decreased connectivity between pallidum and occipital cortex, precuneus, cuneus compared to HC. In comparison to ETP, TDPD showed increased connectivity between precentral gyrus, pallidum, SNc with the default mode network (DMN), and decreased connectivity between cerebellum with superior, middle frontal gyrus was observed. Tremor severity positively correlated with connectivity between SNc and DMN in TDPD, and negatively correlated with pallidal connectivity in ETP. Pattern of BGTC, CTC involvement is differential i.e., higher connectivity of the BGTC nodes in TDPD, and higher connectivity of cerebellar nodes in ETP. The interesting observation of pallidal involvement in ETP suggests the role of BGTC in the pathogenesis of ETP, and indicated similarities in concepts of tremor genesis in TDPD and ETP., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

This work proposes a supervised machine learning method for target localization in deep brain stimulation (DBS). DBS is a recognized treatment for essential tremor. The effects of DBS significantly depend on the precise implantation of electrodes. Recent research on diffusion tensor imaging shows that the optimal target for essential tremor is related to the dentato-rubro-thalamic tract (DRTT), thus DRTT targeting has become a promising direction. The tractography-based targeting is more accurate than conventional ones, but still too complicated for clinical scenarios, where only structural magnetic resonance imaging (sMRI) data is available. In order to improve efficiency and utility, we consider target localization as a non-linear regression problem in a reduced-reference learning framework, and solve it with convolutional neural networks (CNNs). The proposed method is an efficient two-step framework, and consists of two image-based networks: one for classification and the other for localization. We model the basic workflow as an image retrieval process and define relevant performance metrics. Using DRTT as pseudo groundtruths, we show that individualized tractography-based optimal targets can be inferred from sMRI data with high accuracy. For two datasets of 280×220/272×227 (0.7/0.8 mm slice thickness) sMRI input, our model achieves an average posterior localization error of 2.3/1.2 mm, and a median of 1.7/1.02 mm. The proposed framework is a novel application of reduced-reference learning, and a first attempt to localize DRTT from sMRI. It significantly outperforms existing methods using 3D-CNN, anatomical and DRTT atlas, and may serve as a new baseline for general target localization problems.

Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is an effective treatment for essential tremor (ET). We studied 15 ​ET patients undergoing DBS to a major input/output tract of the Vim, the dentato-rubro-thalamic tract (DRTt), using resting state functional MRI (rsfMRI) to evaluate connectivity differences between DBS ON and OFF and elucidate significant regions most influential in impacting tremor control and/or concomitant gait ataxia. Anatomical/functional 1.5T MRIs were acquired and replicated for each DBS state. Tremor severity and gait ataxia severity were scored with DBS ON at optimal stimulation parameters and immediately upon DBS OFF. Whole brain analysis was performed using dual regression analysis followed by randomized permutation testing for multiple correction comparison. Regions of interest (ROI) analysis was also performed. All 15 patients had tremor improvement between DBS ON/OFF (p ​< ​0.001). Whole brain analysis revealed significant connectivity changes between states in the left pre-central gyrus and left supplemental motor area. Group analysis of ROIs revealed that, with threshold p ​< ​0.05, in DBS ON vs. OFF both tremor duration and tremor improvement were significantly correlated to changes in connectivity. A sub-group analysis of patients with greater ataxia had significantly decreased functional connectivity between multiple ROIs in the cortex and cerebellum when DBS was ON compared to OFF. Stimulation of the DRTt and concordant improvement of tremor resulted in connectivity changes seen in multiple regions outside the motor network; when combined with both structural and electrophysiologic connectivity, this may help to serve as a biomarker to improve DBS targeting and possibly predict outcome., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Albert Fenoy reports financial support was provided by National Institute of Neurological Disorders and Stroke. Stephen Kralik reports financial support was provided by National Institute of Neurological Disorders and Stroke. Zili Chu reports financial support was provided by National Institute of Neurological Disorders and Stroke. Albert Fenoy reports a relationship with Medtronic Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: High intensity focal ultrasound (HIFU) thalamotomy is a novel treatment for refractory tremor. This study aims to compare the reduction in tremor intensity and adverse effects of treatment between patients younger and older than 70 years of age., Patients and Methods: All the patients with refractory essential tremor treated with HIFU between March 2021 and March 2023 were included consecutively. Various demographic and clinical variables were analysed, including age and the items on the Clinical Rating Scale for Tremor (CRST). Cerebral vascular pathology was quantified using the Fazekas scale. Outcomes and adverse effects were compared between the patients aged 70 years or younger, and those older than 70 years., Results: Ninety patients were included, and 50 of them were over 70 years old. Prior to treatment, the CRST A + B score was 20.4 ± 5.7 among those under 70 years of age, and 23.3 ± 5.1 in those older (p = 0.013). At six months after treatment, the mean was 3.8 ± 5.1 and 4.8 ± 4.5, respectively (p = 0.314). We found no significant differences in the CRST C score (2.8 ± 4.1 and 3.5 ± 4.8, p = 0.442). There were also no significant differences between the patients with vascular pathology (Fazekas = 1) and those without (4.6 ± 7.3 and 4.3 ± 4, p = 0.832). There were no differences in the presence of adverse effects between the groups based on age and vascular pathology., Conclusions: Contrary to traditional opinion, older patients do not have a poorer response or a higher rate of adverse effects after HIFU treatment.

Background: Factors predicting clinical outcomes after MR-guided focused ultrasound (MRgFUS)-thalamotomy in patients with essential tremor (ET) are not well known., Objective: To examine the clinical outcomes and their relationship with patients' baseline demographic and clinical features and lesion characteristics at 6-month follow-up in ET patients., Methods: A total of 127 patients were prospectively evaluated at 1 (n = 122), 3 (n = 102), and 6 months (n = 78) after MRgFUS-thalamotomy. Magnetic resonance imaging (MRI) was obtained at 6 months (n = 60). Primary outcomes included: (1) change in the Clinical Rating Scale of Tremor (CRST)-A+B score in the treated hand and (2) frequency and severity of adverse events (AEs) at 6 months. Secondary outcomes included changes in all subitems of the CRST scale in the treated hand, CRST-C, axial tremor (face, head, voice, tongue), AEs, and correlation of primary outcomes at 6 months with lesion characteristics. Statistical analysis included linear mixed, standard, and logistic regression models., Results: Scores for CRST-A+B, CRST-A, CRST-B in the treated hand, CRST-C, and axial tremor were improved at each evaluation (P < 0.001). Five patients had severe AEs at 1 month that became mild throughout the follow-up. Mild AEs occurred in 71%, 45%, and 34% of patients at 1, 3, and 6 months, respectively. Lesion volume was associated with the reduction in the CRST-A (P = 0.003) and its overlapping with the ventralis intermedius nucleus (Vim) nucleus with the reduction in CRST-A+B (P = 0.02) and CRST-B (P = 0.008) at 6 months., Conclusions: MRgFUS-thalamotomy improves hand and axial tremor in ET patients. Transient and mild AEs are frequent. Lesion volume and location are associated with tremor reduction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Essential tremor (ET) affects numerous adults, impacting quality of life (QOL) and often defying pharmacological treatment. Surgical interventions like deep brain stimulation (DBS) and lesional approaches, including radiofrequency, gamma-knife radiosurgery, and magnetic resonance imaging (MRI)-guided focused ultrasound, offer solutions but are not devoid of limitations., Objectives: This retrospective, single-center, single-blinded pilot study aimed to assess the safety and efficacy of unilateral MRI-guided laser interstitial thermal therapy (MRIg-LITT) thalamotomy for medically intractable ET., Methods: Nine patients with ET, unresponsive to medications and unsuitable for DBS, underwent unilateral MRIg-LITT thalamotomy. We assessed tremor severity, QOL, cognitive function, and adverse events (AE) over a 12-month period., Results: Tremor severity significantly improved, with a reduction of 83.37% at 12 months post-procedure. QOL scores improved by 74.60% at 12 months. Reported AEs predominantly included transient dysarthria, proprioceptive disturbances, and gait balance issues, which largely resolved within a month. At 3 months, 2 patients (22%) exhibited contralateral hemiparesis requiring physiotherapy, with 1 patient (11%) exhibiting persistent hemiparesis at 12 months. No significant cognitive impairment was detected post-procedure., Conclusions: Unilateral MRIg-LITT thalamotomy yielded substantial and enduring tremor alleviation and enhanced QOL in patients with ET that is resistant to medication. The AE profile was acceptable. Our findings support the need for additional research with expanded patient cohorts and extended follow-up to corroborate these outcomes and to refine the role of MRIg-LITT as a targeted and minimally invasive approach for ET management. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Deep brain stimulation (DBS) is a therapy for Parkinson's disease (PD) and essential tremor (ET). The mechanism of action of DBS is still incompletely understood. Retrospective group analysis of intra-operative data recorded from ET patients implanted in the ventral intermediate nucleus of the thalamus (Vim) is rare. Intra-operative stimulation tests generate rich data and their use in group analysis has not yet been explored. Objective. To implement, evaluate, and apply a group analysis workflow to generate probabilistic stimulation maps (PSMs) using intra-operative stimulation data from ET patients implanted in Vim. Approach. A group-specific anatomical template was constructed based on the magnetic resonance imaging scans of 6 ET patients and 13 PD patients. Intra-operative test data (total: n = 1821) from the 6 ET patients was analyzed: patient-specific electric field simulations together with tremor assessments obtained by a wrist-based acceleration sensor were transferred to this template. Occurrence and weighted mean maps were generated. Voxels associated with symptomatic response were identified through a linear mixed model approach to form a PSM. Improvements predicted by the PSM were compared to those clinically assessed. Finally, the PSM clusters were compared to those obtained in a multicenter study using data from chronic stimulation effects in ET. Main results. Regions responsible for improvement identified on the PSM were in the posterior sub-thalamic area (PSA) and at the border between the Vim and ventro-oral nucleus of the thalamus (VO). The comparison with literature revealed a center-to-center distance of less than 5 mm and an overlap score (Dice) of 0.4 between the significant clusters. Our workflow and intra-operative test data from 6 ET-Vim patients identified effective stimulation areas in PSA and around Vim and VO, affirming existing medical literature. Significance. This study supports the potential of probabilistic analysis of intra-operative stimulation test data to reveal DBS's action mechanisms and to assist surgical planning., (Creative Commons Attribution license.)

Both Parkinson disease (PD) and Essential tremor (ET) are movement disorders causing tremors in elderly individuals. Although PD and ET are different disease, they often present with similar initial symptoms, making their differentiation challenging with magnetic resonance imaging (MRI) techniques. This study aimed to identify structural brain differences among PD, ET, and health controls (HCs) using 7-Tesla (T) MRI. We assessed the whole-brain parcellation in gray matter volume, thickness, subcortical volume, and small regions of basal ganglia in PD (n = 18), ET (n = 15), and HCs (n = 18), who were matched for age and sex. Brain structure analysis was performed automatic segmentation through Freesurfer software. Small regions of basal ganglia were manually segmented by ITK-SNAP. Additionally, we examined the associations between clinical indicators (symptom duration, unified Parkinson diseases rating scale (UPDRS), and clinical rating scale for tremor (CRST)) and brain structure. PD showed a significant reduction in gray matter volume in the postcentral region compared to ET. ET showed a significant reduction in cerebellum volume compared to HCs. There was a negative correlation between CRST scores (B and C) and gray matter thickness in right superior frontal in ET. This study demonstrated potential of 7T MRI in differentiating brain structure differences among PD, ET, and HCs. Specific findings, such as parietal lobe atrophy in PD compared to ET and cerebellum atrophy in ET compared to HCs, the importance of advanced imaging techniques in accurately diagnosing and distinguishing between movement disorders that present with similar initial symptoms., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) for treatment of essential tremor (ET) traditionally targets the ventral intermediate (Vim) nucleus. Recent strategies include a secondary lesion to the posterior subthalamic area (PSA)., Objective: The aim was to compare lesion characteristics, tremor improvement, and adverse events (AE) between patients in whom satisfactory tremor suppression was achieved with lesioning of the Vim alone and patients who required additional lesioning of the PSA., Methods: Retrospective analysis of data collected from ET patients treated with MRgFUS at St Vincent's Hospital Sydney was performed. Clinical Rating Scale for Tremor (CRST), hand tremor score (HTS), and Quality of Life in Essential Tremor Questionnaire (QUEST) were collected pre- and posttreatment in addition to the prevalence of AEs. The lesion coordinates and overlap with the dentatorubrothalamic tract (DRTT) were evaluated using magnetic resonance imaging., Results: Twenty-one patients were treated in Vim only, and 14 were treated with dual Vim-PSA lesions. Clinical data were available for 29 of the 35 patients (19 single target and 10 dual target). At follow-up (mean: 18.80 months) HTS, CRST, and QUEST in single-target patients improved by 57.97% (P < 0.001), 36.71% (P < 0.001), and 58.26% (P < 0.001), whereas dual-target patients improved by 68.34% (P < 0.001), 35.37% (P < 0.003), and 46.97% (P < 0.005), respectively. The Vim lesion of dual-target patients was further anterior relative to the posterior commissure (PC) (7.84 mm), compared with single-target patients (6.92 mm), with less DRTT involvement (14.85% vs. 23.21%). Dual-target patients exhibited a greater proportion of patients with acute motor AEs (100% vs. 58%); however, motor AE prevalence was similar in both groups at long-term follow-up (33% vs. 38%)., Conclusion: Posterior placement of lesions targeting the Vim may confer greater tremor suppression. The addition of a PSA lesion, in patients with inadequate tremor control despite Vim lesioning, had a trend toward better long-term tremor suppression; however, this approach was associated with greater prevalence of gait disturbance in the short term., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The development of MR-guided focused ultrasound (MRgFUS) has provided a new therapeutic tool for neuropsychiatric disorders. In contrast to previously available neurosurgical techniques, MRgFUS allows precise impact on deep brain structures without the need for incision and yields an immediate effect. In its high-intensity modality (MRgHIFU), it produces accurate therapeutic thermoablation in previously selected brain targets. Importantly, the production of the lesion is progressive and highly controlled in real-time by both neuroimaging and clinical means. MRgHIFU ablation is already an accepted and widely used treatment for medically-refractory Parkinson's disease and essential tremor. Notably, other neurological disorders and diverse brain targets, including bilateral treatments, are currently under examination. Conversely, the low-intensity modality (MRgLIFU) shows promising prospects in neuromodulation and transient blood-brain barrier opening (BBBO). In the former circumstance, MRgLIFU could serve as a powerful clinical and research tool for non-invasively modulating brain activity and function. BBBO, on the other hand, emerges as a potentially impactful method to influence disease pathogenesis and progression by increasing brain target engagement of putative therapeutic agents. While promising, these applications remain experimental. As a recently developed technology, MRgFUS is not without challenges and questions to be addressed. Further developments and broader experience are necessary to enhance MRgFUS capabilities in both research and clinical practice, as well as to define device constraints. This clinical mini-review aims to provide an overview of the main evidence of MRgFUS application and to highlight unmet needs and future potentialities of the technique., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ENV was supported in 2021 by a fellowship from the Movement Disorders Group of the Spanish Neurology Society (Sociedad Española de Neurología) granted by Zambon and has received honoraria for lectures from Zambon and Palex. MARY has received speaker honoraria from Insightec and Palex and is supported by a grant from Fundación Nemesio Díez. MM has received lecture honoraria from Teva, Zambon, Palex, the Spanish Neurological Society and the International Parkinson and Movement Disorders Society. MM has received research grants from the Michael J. Fox Foundation and from Fundación Nemesio Díez. CGS has received speaker honoraria from Exeltis, Esteve, Società Italiana Parkinson e Disordini del Movimento and Fundación ACE, a grant from Asociación Madrileña de Neurología, funded by Bial and reimbursement of travel expenses to attend a scientific conference from Boston Scientific. RMF has received speaker honoraria and reimbursement from travel expenses to attend scientific conferences by Insightec and Palex., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Magnetic resonance-guided focused ultrasound (MRgFUS) is one of the newest surgical treatments for essential tremor (ET). During this procedure, a lesion is created within the thalamus to mitigate tremor. Targeting is done using a combination of stereotaxy, MR tractography, and sublesional heating, with tremor assessed during the procedure to gauge therapeutic effectiveness. Currently, tremor assessments are done qualitatively, but this approach requires the tremor change to be above a subjective threshold and provides no objective record of surgical tremor progression. Here, the authors present and demonstrate an MR-compatible accelerometer with custom MATLAB analysis code and graphical user interface to record, visualize, and quantify tremor in near real-time. Results can be exported and saved for future review. This method was used in 20 surgeries, with patients experiencing a 50.7% (95% CI -64.1% to -37.3%) improvement in the treated limb per the Clinical Rating Scale for Tremor. This method does not interrupt the surgery and is quantitative. As research on optimizing MRgFUS treatment for ET continues-for example, the refinement of targeting during sublesional sonications-such quantifying and recording of tremor changes will provide rapid and objective feedback.

Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for essential tremor (ET). However, its long-term outcomes and prognostic factors remain unclear. This study aimed to retrospectively investigate 38 patients with ET who underwent MRgFUS thalamotomy and were followed up for >2 years. The improvement in tremor was evaluated using the Clinical Rating Scale for Tremor (CRST). Adverse events were documented, and correlations with factors, such as skull density ratio (SDR), maximum mean temperature (T-max), and lesion size, were examined. Furthermore, the outcomes were compared between two groups, one that met the cutoff values, which was previously reported (preoperative CRST-B ≤ 25, T-max ≥ 52.5°C, anterior-posterior size of lesion ≥ 3.9 mm, superior-inferior [SI] size of lesion > 5.5 mm), and the other that did not. The improvement rate was 59.4% on average at the 2-year follow-up. Adverse events, such as numbness (15.8%), dysarthria (10.5%), and lower extremity weakness (2.6%), were observed even after 2 years, although these were mild. The factors correlated with tremor improvement were the T-max and SI size of the lesion (p < 0.05), whereas the SDR showed no significance. Patients who met the aforementioned cutoff values demonstrated a 69.8% improvement at the 2-year follow-up, whereas others showed a 43.6% improvement (p < 0.05). In conclusion, MRgFUS is effective even after 2 years. The higher the T-max and the larger the lesion size, the better the tremor control. Previously reported cutoff values clearly predict the 2-year prognosis, indicating the usefulness of MRgFUS.

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has been implemented as a therapeutic alternative for the treatment of drug-refractory essential tremor (ET). However, its impact on the brain structural network is still unclear., Purpose: To investigate both global and local alterations of the white matter (WM) connectivity network in ET after MRgFUS thalamotomy., Study Type: Retrospective., Subjects: Twenty-seven ET patients (61 ± 11 years, 19 males) with MRgFUS thalamotomy and 28 healthy controls (HC) (61 ± 11 years, 20 males) were recruited for comparison., Field Strength/sequence: A 3 T/single shell diffusion tensor imaging by using spin-echo-based echo-planar imaging, three-dimensional T1 weighted imaging by using gradient-echo-based sequence., Assessment: Patients were undergoing MRgFUS thalamotomy and their clinical data were collected from pre-operation to 6-month post-operation. Network topological metrics, including rich-club organization, small-world, and efficiency properties were calculated. Correlation between the topological metrics and tremor scores in ET groups was also calculated to assess the role of neural remodeling in the brain., Statistical Tests: Two-sample independent t-tests, chi-squared test, ANOVA, Bonferroni test, and Spearman's correlation. Statistical significance was set at P < 0.05., Results: For ET patients, the strength of rich-club connection and clustering coefficient significantly increased vs. characteristic path length decreased at 6-month post-operation compared with pre-operation. The distribution pattern of rich-club regions was different in ET groups. Specifically, the order of the rich-club regions was changed according to the network degree value after MRgFUS thalamotomy. Moreover, the altered nodal efficiency in the right temporal pole of the superior temporal gyrus (R = 0.434-0.596) and right putamen (R = 0.413-0.436) was positively correlated with different tremor improvement., Data Conclusion: These findings might improve understanding of treatment-induced modulation from a network perspective and may work as an objective marker in the assessment of ET tremor control with MRgFUS thalamotomy., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 4., (© 2023 International Society for Magnetic Resonance in Medicine.)

Objective: The aim of this study was to compare outcomes of direct targeting in deep brain stimulation (DBS) for essential tremor using 7T MRI versus 3T MRI. The authors hypothesized that 7T MRI direct targeting would be noninferior to 3T MRI in early tremor outcomes., Methods: A retrospective study was conducted on patients undergoing unilateral thalamic DBS for essential tremor between 2021 and 2023. Two matched cohorts were assessed, one using 7T MRI and the other using 3T MRI for surgical planning. The primary endpoint was the percentage improvement in the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) scores. Additionally, the authors assessed optimized programming settings and variance in electrode position on postoperative imaging. Demographic and clinical data were compared using the nonparametric Mann-Whitney U-test. The squared Euclidean distance of each contact from the group mean centroid was calculated and averaged across the entire cohort to provide the variance (i.e., the mean squared distance) of electrode contact position., Results: A total of 34 patients were analyzed, with 17 in each cohort. There were no significant differences in demographic information or mean surgical dates between the groups. There were no differences in intraoperative target repositioning or adverse events. The 7T group had a significantly greater TRS improvement than the 3T group (64.9% ± 11.4% vs 50.9% ± 16.4%, p = 0.004). Patients in the 7T cohort also had a lower mean stimulation current compared with those in the 3T cohort (2.0 ± 0.8 mA vs 2.7 ± 0.9 mA, p = 0.01). Image evaluation revealed that although the mean electrode position was comparable between 7T and 3T, the 7T electrode positioning was more clustered, indicating a lower variance in the final electrode location. The mean Euclidean distance between the individual electrode tips and the group centroid was significantly less at 7T than at 3T (1.82 ± 0.68 mm vs 2.75 ± 0.81 mm, p = 0.001)., Conclusions: Despite concerns for increased artifacts and distortions at 7T, the authors show that these effects can be mitigated with an appropriate workflow, leading to improved surgical outcomes with direct targeting using 7T MRI. Their results suggest similar accuracy but greater precision in targeting with 7T MRI compared with 3T MRI, resulting in lower stimulation currents and improved tremor reduction. Future studies are needed to assess outcomes related to 7T MRI in targeting other subcortical structures.

Objective: The objective was to investigate the effectiveness and safety of MR-guided focused ultrasound (MRgFUS) treatment in patients with essential tremor, particularly those with low skull density ratio (SDR) and including those with very low SDR, and to identify the factors influencing treatment effectiveness and to provide insights into therapeutic approaches for patients with lower SDR., Methods: Real-world data from 101 patients who underwent MRgFUS between July 2019 and March 2022 at a single institution were analyzed. Tremor severity was assessed using the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (CRST). The patients were categorized into quartile groups based on their mean SDR, and the characteristics, treatment effectiveness, treatment parameters, and adverse events were evaluated among these subgroups., Results: Patients were classified into 4 quartiles based on the mean SDR: quartile 1 (Q1) (SDR 0.26-0.37), Q2 (SDR 0.38-0.42), Q3 (SDR 0.43-0.49), and Q4 (SDR 0.50-0.75). MRgFUS significantly improved total CRST and tremor score across all SDR subgroups. Additionally, there were no significant differences in the improvement rates among the 4 subgroups. Analysis of the treatment parameters revealed that lower mean SDR was associated with lower target maximum temperature and smaller coagulation volume after focused ultrasound (FUS). Regarding adverse events, headache and nausea during FUS and facial and head edema on the day after surgery were more frequent in the Q1 subgroup (very low-SDR group). In contrast, numbness was more common in the Q4 subgroup. However, all these adverse events had resolved by the 3-month follow-up except numbness., Conclusions: This study suggested that MRgFUS is effective and safe for patients with medication-resistant essential tremor, including those with very low mean SDR. However, the very low-SDR group had insufficient temperature elevation at the target site compared with the high-SDR group, suggesting the need for a different strategy. Notably, with careful adjustments and considerations, positive outcomes can still be achieved in patients with very low SDR. Therefore, very low SDR should not be considered an absolute exclusion criterion because it is expected to increase the number of patients who benefit from MRgFUS.

Patients with drug-resistant essential tremor (ET) may undergo Gamma Knife stereotactic radiosurgical thalamotomy (SRS-T), where the ventro-intermediate nucleus of the thalamus (Vim) is lesioned by focused beams of gamma radiations to induce clinical improvement. Here, we studied SRS-T impacts on left Vim dynamic functional connectivity (dFC, n = 23 ET patients scanned before and 1 year after intervention), and on surface-based morphometric brain features (n = 34 patients, including those from dFC analysis). In matched healthy controls (HCs), three dFC states were extracted from resting-state functional MRI data. In ET patients, state 1 spatial stability increased upon SRS-T (F 1,22  = 19.13, p = 0.004). More frequent expression of state 3 over state 1 before SRS-T correlated with greater clinical recovery in a way that depended on the MR signature volume (t 6  = 4.6, p = 0.004). Lower pre-intervention spatial variability in state 3 expression also did (t 6  = - 4.24, p = 0.005) and interacted with the presence of familial ET so that these patients improved less (t 6  = 4.14, p = 0.006). ET morphometric profiles showed significantly lower similarity to HCs in 13 regions upon SRS-T (z ≤ - 3.66, p ≤ 0.022), and a joint analysis revealed that before thalamotomy, morphometric similarity and states 2/3 mean spatial similarity to HCs were anticorrelated, a relationship that disappeared upon SRS-T (z ≥ 4.39, p < 0.001). Our results show that left Vim functional dynamics directly relates to upper limb tremor lowering upon intervention, while morphometry instead has a supporting role in reshaping such dynamics., (© 2024. The Author(s).)

Introduction: Deep brain stimulation (DBS) is a routine neurosurgical procedure utilized to treat various movement disorders including Parkinson's disease (PD), essential tremor (ET), and dystonia. Treatment efficacy is dependent on stereotactic accuracy of lead placement into the deep brain target of interest. However, brain shift attributed to pneumocephalus can introduce unpredictable inaccuracies during DBS lead placement. This study aimed to determine whether intracranial air is associated with brain shift in patients undergoing staged DBS surgery., Methods: We retrospectively evaluated 46 patients who underwent staged DBS surgery for PD, ET, and dystonia. Due to the staged nature of DBS surgery at our institution, the first electrode placement is used as a concrete fiducial marker for movement in the target location. Postoperative computed tomography (CT) images after the first electrode implantation, as well as preoperative, and postoperative CT images after the second electrode implantation were collected. Images were analyzed in stereotactic targeting software (BrainLab); intracranial air was manually segmented, and electrode shift was measured in the x, y, and z plane, as well as a Euclidian distance on each set of merged CT scans. A Pearson correlation analysis was used to determine the relationship between intracranial air and brain shift, and student's t test was used to compare means between patients with and without radiographic evidence of intracranial air., Results: Thirty-six patients had pneumocephalus after the first electrode implantation, while 35 had pneumocephalus after the second electrode implantation. Accumulation of intracranial air following the first electrode implantation (4.49 ± 6.05 cm3) was significantly correlated with brain shift along the y axis (0.04 ± 0.35 mm; r (34) = 0.36; p = 0.03), as well as the Euclidean distance of deviation (0.57 ± 0.33 mm; r (34) = 0.33; p = 0.05) indicating statistically significant shift on the ipsilateral side. However, there was no significant correlation between intracranial air and brain shift following the second electrode implantation, suggesting contralateral shift is minimal. Furthermore, there was no significant difference in brain shift between patients with and without radiographic evidence of intracranial air following both electrode implantation surgeries., Conclusion: Despite observing volumes as high as 22.0 cm3 in patients with radiographic evidence of pneumocephalus, there was no significant difference in brain shift when compared to patients without pneumocephalus. Furthermore, the mean magnitude of brain shift was &lt;1.0 mm regardless of whether pneumocephalus was presenting, suggesting that intracranial air accumulation may not produce clinical significant brain shift in our patients., (© 2024 S. Karger AG, Basel.)

Introduction: Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is an effective treatment for drug-resistant tremor. The most frequent side effects are ataxia, gait disturbance, paresthesias, dysgeusia, and hemiparesis. Here, we report the first case of thalamic hand dystonia rapidly occurring after MRgFUS thalamotomy of the ventral intermediate nucleus (V.im)., Case Presentation: MRgFUS thalamotomy was performed in a 60-year-old left-handed patient for his disabling medically refractory essential tremor. The intervention resulted in a marked reduction of his action tremor. However, the patient developed an unvoluntary abnormal posture in his left hand a few days after the procedure with difficulty holding a cigarette between his fingers. Brain MRI revealed the expected MRgFUS lesion within the right V.im as well as an extension of the lesion anteriorly to the V.im in the ventro-oralis nucleus. Tractography showed that the lesion disrupted the dentato-rubro-thalamic tract as expected with a lesion suppressing tremor. However, the lesion also was interrupted fibers connecting to the superior frontal and pre-central cortices (primary motor cortex, premotor cortex, and supplementary area). We hypothesized that the interventional MRgFUS thalamotomy was slightly off target, which induced a dysfunction within the cortico-striato-thalamo-cortical network and the cerebello-thalamo-cortical pathway reaching a sufficient threshold of basal ganglia/cerebellum circuitry interference to induce dystonia., Conclusion: This rare side effect emphasizes the risk of imbalance within the dystonia network (i.e., basal ganglia-cerebello-thalamo-cortical circuit) secondary to V.im thalamotomy., (© 2024 S. Karger AG, Basel.)

Background: Thalamic deep brain stimulation (DBS) is an efficacious treatment for drug-resistant essential tremor (ET) and the dentato-rubro-thalamic tract (DRT) constitutes an important target structure. However, up to 40% of patients habituate and lose treatment efficacy over time, frequently accompanied by a stimulation-induced cerebellar syndrome. The phenomenon termed delayed therapy escape (DTE) is insufficiently understood. Our previous work showed that DTE clinically is pronounced on the non-dominant side and suggested that differential involvement of crossed versus uncrossed DRT (DRTx/DRTu) might play a role in DTE development., Methods: We retrospectively enrolled right-handed patients under bilateral thalamic DBS >12 months for ET from a cross-sectional study. They were characterized with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) and Scale for the Assessment and Rating of Ataxia (SARA) scores at different timepoints. Normative fiber tractographic evaluations of crossed and uncrossed cerebellothalamic pathways and volume of activated tissue (VAT) studies together with [ 18 F]Fluorodeoxyglucose positron emission tomography were applied., Results: A total of 29 patients met the inclusion criteria. Favoring DRTu over DRTx in the non-dominant VAT was associated with DTE (R 2  = 0.4463, p < 0.01) and ataxia (R 2  = 0.2319, p < 0.01). Moreover, increasing VAT size on the right (non-dominant) side was associated at trend level with more asymmetric glucose metabolism shifting towards the right (dominant) dentate nucleus., Conclusion: Our results suggest that a disbalanced recruitment of DRTu in the non-dominant VAT induces detrimental stimulation effects on the dominant cerebellar outflow (together with contralateral stimulation) leading to DTE and thus hampering the overall treatment efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Magnetic resonance-guided focused ultrasound (MRgFUS) is an effective treatment option for essential tremor (ET) and tremor dominant Parkinson's disease (TDPD), which is often performed with sedation or in the presence of an anesthesiologist in an effort to minimize adverse events and maximize patient comfort. This study explores the safety, feasibility, and tolerability of performing MRgFUS without an anesthesiologist., Methods: This is a single academic center, retrospective review of 180 ET and TDPD patients who underwent MRgFUS treatment without anesthesiologist support. Patient demographics, intra-procedural treatment parameters, peri-procedural adverse events, and 3-month Clinical Rating Scale for Tremor Part B (CRST-B) scores were compared to MRgFUS studies that utilized varying degrees of anesthesia., Results: There were no anesthesia related adverse events or unsuccessful treatments. There were no early treatment terminations due to patient discomfort, regardless of skull density ratio. 94.6% of patients would repeat the procedure again. The most common side effects during treatment were facial/tongue paresthesia (26.3%), followed by nausea (22.3%), dysarthria (8.6%), and scalp pain (8.0%). No anxiolytic, pain, or antihypertensive medications were administered. The most common early adverse event after MRgFUS procedure was gait imbalance (58.3%). There was a significant reduction of 83.1% (83.4% ET and 80.5% TDPD) of the mean CRST-B scores of the treated hand when comparing 3-month and baseline scores (1.8 vs. 10.9, n = 109, p &lt; 0.0001)., Conclusion: MRgFUS without intra-procedural anesthesiologist support is a safe, feasible, and well-tolerated option, without an increase in peri-procedural adverse events., (© 2024 S. Karger AG, Basel.)

Background: MR-guided focused ultrasound (MRgFUS) thalamotomy is a novel and effective treatment for medication-refractory tremor in essential tremor (ET), but how the brain responds to this deliberate lesion is not clear., Objective: The current study aimed to evaluate the immediate and longitudinal alterations of functional networks after MRgFUS thalamotomy., Methods: We retrospectively obtained preoperative and postoperative 30-day, 90-day, and 180-day data of 31 ET patients subjected with MRgFUS thalamotomy from 2018 to 2020. Their archived resting-state functional MRI data were used for functional network comparison as well as graph-theory metrics analysis. Both partial least squares (PLS) regression and linear regression were conducted to associate functional features to tremor symptoms., Results: MRgFUS thalamotomy dramatically abolished tremors, while global functional network only sustained immediate fluctuation within one week after the surgery. Network-based statistics have identified a long-term enhanced corticostriatal subnetwork by comparison between 180-day and preoperative data (P = 0.019). Within this subnetwork, network degree, global efficiency and transitivity were significantly recovered in ET patients right after MRgFUS thalamotomy compared to the pre-operative timepoint (P < 0.05), as well as hemisphere lateralization (P < 0.001). The PLS main component significantly accounted for 33.68 % and 34.16 % of the total variances of hand tremor score and clinical rating scale for tremor (CRST)-total score (P = 0.037 and 0.027). Network transitivity of this subnetwork could serve as a reliable biomarker for hand tremor score control prediction at 180-day after the surgery (β = 2.94, P = 0.03)., Conclusion: MRgFUS thalamotomy promoted corticostriatal connectivity activation correlated with tremor improvement in ET patient after MRgFUS thalamotomy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal., Objectives: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET., Methods: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response., Results: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events., Conclusions: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Essential tremor (ET) can be debilitating. Treatments for ET include beta-blockers and surgical interventions. Low-intensity focused ultrasound (LIFU) may offer an office-based non-invasive alternative., Objective: This pilot open label clinical trial explores safety, feasibility, and potential efficacy of LIFU in treatment of ET., Methods: We report outcomes from the first 10 participants in this IRB-approved trial of LIFU for treatment of ET. The ventral intermediate nucleus of the thalamus (Vim) was targeted using structural and functional MRI. Participants underwent eight 10-min sessions of LIFU targeting the contralateral (Vim) to the most affected hand. Safety was closely monitored; Global Rating of Change (GRC) and The Essential Tremor Rating Scale (TETRAS) scores were collected., Results: No adverse effects were reported. Eight participants reported a GRC ≥2. TETRAS performance subscale demonstrated clinically significant improvement in all participants., Conclusion: Preliminary findings support LIFU's safety and feasibility. The potential efficacy encourages additional sham-controlled studies., Competing Interests: Declaration of competing interest This study did not receive any external funding. Authors CMD, JRS, JMH, KDM, JKG, SAB, KRH, KCE, TK, and SEJ have no conflicts of interest to disclose. Author AB is the founder and CEO of Brainsonix Corp., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Deep brain stimulation (DBS) studies have shown that stimulation of the motor segment of the thalamus based on probabilistic tractography is predictive of improvement in essential tremor (ET). However, probabilistic methods are computationally demanding, requiring the need for alternative tractography methods for use in the clinical setting. The purpose of this study was to compare probabilistic vs deterministic tractography methods for connectivity-based targeting in patients with ET., Methods: Probabilistic and deterministic tractography methods were retrospectively applied to diffusion-weighted data sets in 36 patients with refractory ET. The thalamus and precentral gyrus were selected as regions of interest and fiber tracking was performed between these regions to produce connectivity-based thalamic segmentations, per prior methods. The resultant deterministic target maps were compared with those of thresholded probabilistic maps. The center of gravity (CG) of each connectivity map was determined and the differences in spatial distribution between the tractography methods were characterized. Furthermore, the intersection between the connectivity maps and CGs with the therapeutic volume of tissue activated (VTA) was calculated. A mixed linear model was then used to assess clinical improvement in tremor with volume of overlap., Results: Both tractography methods delineated the region of the thalamus with connectivity to the precentral gyrus to be within the posterolateral aspect of the thalamus. The average CG of deterministic maps was more medial-posterior in both the left (3.7 ± 1.3 mm 3 ) and the right (3.5 ± 2.2 mm 3 ) hemispheres when compared to 30 %-thresholded probabilistic maps. Mixed linear model showed that the volume of overlap between CGs of deterministic and probabilistic targeting maps and therapeutic VTAs were significant predictors of clinical improvement., Conclusions: Deterministic tractography can reconstruct DBS thalamic target maps in approximately 5 min comparable to those produced by probabilistic methods that require > 12 h to generate. Despite differences in CG between the methods, both deterministic-based and probabilistic targeting were predictive of clinical improvement in ET., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Pouratian and Dr. Bari report grants and personal fees from Brainlab., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The olivo-cerebellar circuit is thought to play a crucial role in the pathophysiology of essential tremor (ET). Whether olivo-cerebellar circuit dysfunction is also present at rest, in the absence of clinical tremor and linked voluntary movement, remains unclear. Assessing this network in detail with fMRI is challenging, considering the brainstem is close to major arteries and pulsatile cerebrospinal fluid-filled spaces obscuring signals of interest. Here, we used methods tailored to the analysis of infratentorial structures. We hypothesize that the olivo-cerebellar circuit shows altered intra-network connectivity at rest and decreased functional coupling with other parts of the motor network in ET. In 17 ET patients and 19 healthy controls, we investigated using resting state fMRI intracerebellar functional and effective connectivity on a dedicated cerebellar atlas. With independent component analysis, we investigated data-driven cerebellar motor network activations during rest. Finally, whole-brain connectivity of cerebellar motor structures was investigated using identified components. In ET, olivo-cerebellar pathways show decreased functional connectivity compared with healthy controls. Effective connectivity analysis showed an increased inhibitory influence of the dentate nucleus towards the inferior olive. Cerebellar independent component analyses showed motor resting state networks are less strongly connected to the cerebral cortex compared to controls. Our results indicate the olivo-cerebellar circuit to be affected at rest. Also, the cerebellum is "disconnected" from the rest of the motor network. Aberrant activity, generated within the olivo-cerebellar circuit could, during action, spread towards other parts of the motor circuit and potentially underlie the characteristic tremor of this patient group., (© 2022. The Author(s).)

Aims: The purpose of this study was to clarify the dentato-rubro-thalamic (DRT) pathway in action tremor in comparison to normal controls (NC) and disease controls (i.e., rest tremor) by using multi-modality magnetic resonance imaging (MRI)., Methods: This study included 40 essential tremor (ET) patients, 57 Parkinson's disease (PD) patients (29 with rest tremor, 28 without rest tremor), and 41 NC. We used multi-modality MRI to comprehensively assess major nuclei and fiber tracts of the DRT pathway, which included decussating DRT tract (d-DRTT) and non-decussating DRT tract (nd-DRTT), and compared the differences in DRT pathway components between action and rest tremor., Results: Bilateral dentate nucleus (DN) in the ET group had excessive iron deposition compared with the NC group. Compared with the NC group, significantly decreased mean diffusivity and radial diffusivity were observed in the left nd-DRTT in the ET group, which were negatively correlated with tremor severity. No significant difference in each component of the DRT pathway was observed between the PD subgroup or the PD and NC., Conclusion: Aberrant changes in the DRT pathway may be specific to action tremor and were indicating that action tremor may be related to pathological overactivation of the DRT pathway., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: Thalamic deep brain stimulation (DBS) is the primary surgical therapy for essential tremor (ET). Thalamic DBS traditionally uses an atlas-based targeting approach, which, although nominally accurate, may obscure individual anatomic differences from population norms. The objective of this study was to compare this traditional atlas-based approach with a novel quantitative modeling methodology grounded in individual tissue microstructure (N-of-1 approach)., Materials and Methods: The N-of-1 approach uses individual patient diffusion tensor imaging (DTI) data to perform thalamic segmentation and volume of tissue activation (VTA) modeling. For each patient, the thalamus was individually segmented into 13 nuclei using DTI-based k-means clustering. DBS-induced VTAs associated with tremor suppression and side effects were then computed for each patient with finite-element electric-field models incorporating DTI microstructural data. Results from N-of-1 and traditional atlas-based modeling were compared for a large cohort of patients with ET treated with thalamic DBS., Results: The size and shape of individual N-of-1 thalamic nuclei and VTAs varied considerably across patients (N = 22). For both methods, tremor-improving therapeutic VTAs showed similar overlap with motor thalamic nuclei and greater motor than sensory nucleus overlap. For VTAs producing undesirable sustained paresthesia, 94% of VTAs overlapped with N-of-1 sensory thalamus estimates, whereas 74% of atlas-based segmentations overlapped. For VTAs producing dysarthria/motor contraction, the N-of-1 approach predicted greater spread beyond the thalamus into the internal capsule and adjacent structures than the atlas-based method., Conclusions: Thalamic segmentation and VTA modeling based on individual tissue microstructure explain therapeutic stimulation equally well and side effects better than a traditional atlas-based method in DBS for ET. The N-of-1 approach may be useful in DBS targeting and programming, particularly when patient neuroanatomy deviates from population norms., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Loss of MRI hyperintense signal in nigrosome-1 (assessed with susceptibility-weighted imaging) is a biomarker for Parkinson's disease (PD). Current clinical practice involves subjectively rating the appearance of nigrosome-1 which is challenging. The study aimed to test and compare a simple method for quantifying nigrosome-1 with the current subjective rating method., Methods: Two experienced neuroradiologists measured area of hyperintense signal in nigrosome-1 (quantitative method) and rated nigrosome-1 appearance (as normal, attenuated, or absent; subjective method) in 42 patients encompassing the full spectrum of nigrosome-1 integrity (21 patients aged 55.5 ± 20.9 years with Essential tremor (ET) and a subset of 21 patients aged 69.6 ± 8.6 years with PD). Neuroradiologists were blinded to each other's measurements, clinical notes, and patient group., Results: Both methods yielded a significant difference between the groups (PD vs ET; p < 0.001). Pooled (across sides) area of nigrosome-1 hyperintense signal was significantly smaller in the PD group (median = 2.1 mm 2 , range = 0-15.8 mm 2 ) than ET group (median = 8.3 mm 2 , range = 0-15.7 mm 2 ; p < 0.001). Inter-rater reliability was high to very high for both methods (subjective: weighted kappa = 0.640, p < 0.001; quantitative: W = 0.733, p = 0.004). Our primary hypothesis that area of nigrosome-1 hyperintense signal exhibits higher inter-rater reliability than subjective rating of nigrosome-1 appearance was not supported., Conclusion: The simple quantitative method, used with subjectively rated nigrosome-1 appearance, may improve confidence in longitudinal clinical reporting, when nigrosome-1 is attenuated. However, further work on the incremental diagnostic value of planimetry and bias, repeatability and reproducibility are needed before it can be recommended in clinical practice., Competing Interests: Declaration of Competing Interest The work was supported by the University of South Australia and Flinders Foundation (Health Seed Grant). MC holds an Australian Government Research Training Program (RTP) Scholarship. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Deep brain stimulation (DBS) relies on precise targeting of key structures such as the subthalamic nucleus (STN) for Parkinson's disease (PD) and the ventro-intermedius nucleus of the thalamus (Vim) for essential tremor (ET). Segmentation software, such as GuideXT© and Suretune©, are commercially available for atlas-based identification of deep brain structures. However, no study has compared the concordance of the segmentation results between the two software., Methods: We retrospectively compared the concordance of segmentation of GuideXT© and Suretune© software by comparing the position of the segmented key structures with clinically predicted targets obtained using the newly developed RebrAIn© software as a reference., Results: We targeted the STN in 44 MRI from PD patients (88 hemispheres) and the Vim in 31 MRI from ET patients (62 hemispheres) who were elected for DBS. In 22 STN targeting (25%), the target positioning was not correlating between GuideXT© and Suretune©. Regarding the Vim, targets were located in the segmented Vim in 37%, the posterior subthalamic area (PSA) in 60%, and the STN in 3% of the cases using GuideXT©; the proportions were 34%, 60%, and 6%, respectively, using Suretune©. The mean distance from the centre of the RebrAIn© targeting to the segmented Vim by Suretune© was closer (0.64 mm) than with GuideXT© (0.96 mm; p = 0.0004)., Conclusion: While there is some level of concordance in the segmentation results of key structures for DBS treatment among software models, differences persist. Therefore, such software should still be considered as tools and should not replace clinician experience in DBS planning., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Radiofrequency thalamotomy (RF-T) is an established treatment for refractory tremor. It is unclear whether connectivity-guided targeting strategies could further augment outcomes. The aim of this study was to evaluate the efficacy and safety of MRI connectivity-guided RF-T in severe tremor., Methods: Twenty-one consecutive patients with severe tremor (14 with essential tremor [ET], 7 with Parkinson's disease [PD]) underwent unilateral RF-T at a single institution between 2017 and 2020. Connectivity-derived thalamic segmentation was used to guide targeting. Changes in the Fahn-Tolosa-Marin Rating Scale (FTMRS) were recorded in treated and nontreated hands as well as procedure-related side effects., Results: Twenty-three thalamotomies were performed (with 2 patients receiving a repeated intervention). The mean postoperative assessment time point was 14.1 months. Treated-hand tremor scores improved by 63.8%, whereas nontreated-hand scores deteriorated by 10.1% (p < 0.01). Total FTMRS scores were significantly better at follow-up compared with baseline (mean 34.7 vs 51.7, p = 0.016). Baseline treated-hand tremor severity (rho = 0.786, p < 0.01) and total FTMRS score (rho = 0.64, p < 0.01) best correlated with tremor improvement. The most reported side effect was mild gait ataxia (n = 11 patients)., Conclusions: RF-T guided by connectivity-derived segmentation is a safe and effective option for severe tremor in both PD and ET.

Essential tremor (ET) is a common disease in the elderly population. Severe, medication-refractory ET may require surgical intervention via ablation or deep brain stimulation (DBS). Thalamic Vim (Ventral intermediate nucleus), targeted indirectly using atlas-based coordinates, is the classical target in these procedures. We present a case of an ET patient with a non-MR-compatible cardiac orphaned leads who was a candidate for DBS surgery. Due to the lead constraints of MR use, we used a head computed tomography (CT) with contrast media as the reference exam to define the AC, PC, and midline, and to register and indirectly target the Vim. For target validation, we used intraoperative electrophysiological recordings and intraoperative CT. We implanted bilateral directional leads at the target location. We used the-essential-tremor-rating-assessment-scale (TETRAS) pre and postoperatively to clinically evaluate tremor. Intraoperative micro-electrode recordings (MERs) showed individual tremor cells and a robust increase in normalized root mean square (NRMS) indicating entry to the Vim. Postoperative visualization using lead-DBS along with dramatic clinical improvements show that we were able to accurately target the Vim. Our results show that CT-only registration and planning for thalamic Vim DBS is feasible, and that MERs and intraoperative CT are useful adjuncts for Vim target validation., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Magnetic resonance-guided focused ultrasound (MRgFUS) has brought thalamotomy back to the frontline for essential tremor (ET). As functional organization of human brain strictly follows hierarchical principles which are frequently deficient in neurological diseases, whether additional damage from MRgFUS thalamotomy induces further disruptions of ET functional scaffolds are still controversial. This study was to examine the alteration features of brain functional frameworks following MRgFUS thalamotomy in patients with ET. We retrospectively obtained preoperative (ET pre ) and postoperative 6-month (ET 6m ) data of 30 ET patients underwent MRgFUS thalamotomy from 2018 to 2020. Their archived functional MR images were used to functional gradient comparison. Both supervised pattern learning and stepwise linear regression were conducted to associate gradient features to tremor symptoms with additional neuropathophysiological analysis. MRgFUS thalamotomy relieved 78.19% of hand tremor symptoms and induced vast global framework alteration (ET 6m vs. ET pre : Cohen d = - 0.80, P < 0.001). Multiple robust alterations were identified especially in posterior cingulate cortex ([Formula: see text] ET 6m vs. [Formula: see text] ET pre : Cohen d = 0.87, P = 0.048). Compared with matched health controls (HCs), its gradient distances to primary communities were significantly increased in [Formula: see text] ET pre patients with anomalous stepwise connectivity (P < 0.05 in ET pre vs. HCs), which were restored after MRgFUS thalamotomy. Both global and regional gradient features could be used for tremor symptom prediction and were linked to neuropathophysiological features of Parkinson disease and oxidative phosphorylation. MRgFUS thalamotomy not only suppress tremor symptoms but also rebalances atypical functional hierarchical architecture of ET patients., (© 2023. The American Society for Experimental Neurotherapeutics, Inc.)

Background: Essential tremor (ET) and Parkinson's disease (PD) are the most common tremor disorders and are common indications for deep brain stimulation (DBS). In some patients, PD and ET symptoms overlap and diagnosis can be challenging based on clinical criteria alone. The objective of this study was to identify structural brain differences between PD and ET DBS patients to help differentiate these disorders and improve our understanding of the different brain regions involved in these pathologic processes., Methods: We included ET and PD patients scheduled to undergo DBS surgery in this observational study. Patients underwent 3T brain MRI while under general anesthesia as part of their procedure. Cortical thicknesses and subcortical volumes were quantified from T1-weighted images using automated multi-atlas segmentation. We used logistic regression analysis to identify brain regions associated with diagnosis of ET or PD., Results: 149 ET and 265 PD patients were included. Smaller volumes in the pallidum and thalamus and reduced thickness in the anterior orbital gyrus, lateral orbital gyrus, and medial precentral gyrus were associated with greater odds of ET diagnosis. Conversely, reduced volumes in the caudate, amygdala, putamen, and basal forebrain, and reduced thickness in the orbital part of the inferior frontal gyrus, supramarginal gyrus, and posterior cingulate were associated with greater odds of PD diagnosis., Conclusions: These findings identify structural brain differences between PD and ET patients. These results expand our understanding of the different brain regions involved in these disorders and suggest that structural MRI may help to differentiate patients with these two disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Essential tremor (ET) is a common slowly-progressive neurologic disorder. It is predominantly characterized by kinetic tremors involving bilateral upper limbs. Although ET shares motor similarities with Parkinson disease (PD), there is no known relationship between ET and PD., Methods: We studied white matter differences between 17 ET and 68 PD patients using standard diffusion tensor imaging and fixel-based analysis (FBA). Diffusion magnetic resonance imaging data were acquired from two scanners (General Electric (GE) and Philips) with different numbers of diffusion directions. Fractional anisotropy maps were generated by the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL), and FBA was performed using MRtrix3 to obtain fiber density, fiber bundle, and fiber density bundle cross-section., Results: Compared with PD, significantly lower values of fiber density, fiber bundle, and fiber density bundle cross-section were found in the corpus callosum and left tapetum of the ET group. Additionally, significantly lower functional anisotropy values were found in the ET compared to the PD group, principally in the corpus callosum, corona radiata, and cingulum. In conclusion, differences in white matter integrity between ET and PD were observed by both FBA-based metrics and diffusion tensor imaging., Conclusions: Advanced diffusion-based metrics may provide a better understanding of the white matter microstructural characteristics in disparate motor-associated diseases with different underlying phenotypes, such as ET and PD., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Functional ultrasound (fUS), an emerging hemodynamic-based functional neuroimaging technique, is especially suited to probe brain activity and primarily used in animal models. Increasing use of pharmacological models for essential tremor extends new research to the utilization of fUS imaging in such models. Harmaline-induced tremor is an easily provoked model for the development of new therapies for essential tremor (ET). Furthermore, harmaline-induced tremor can be suppressed by the same classic medications used for essential tremor, which leads to the utilization of this model for preclinical testing. However, changes in local cerebral activities under the effect of tremorgenic doses of harmaline have not been completely investigated. In this study, we explored the feasibility of fUS imaging for visualization of cerebral activation and deactivation associated with harmaline-induced tremor and tremor-suppressing effects of propranolol. The spatial resolution of fUS using a high frame rate imaging enabled us to visualize time-locked and site-specific changes in cerebral blood flow associated with harmaline-evoked tremor. Intraperitoneal administration of harmaline generated significant neural activity changes in the primary motor cortex and ventrolateral thalamus (VL Thal) regions during tremor and then gradually returned to baseline level as tremor subsided with time. To the best of our knowledge, this is the first functional ultrasound study to show the neurovascular activation of harmaline-induced tremor and the therapeutic suppression in a rat model. Thus, fUS can be considered a noninvasive imaging method for studying neuronal activities involved in the ET model and its treatment.

Introduction: There is some debate on the relationship between essential tremor with rest tremor (rET) and the classic ET syndrome, and only few MRI studies compared ET and rET patients. This study aimed to explore structural cortical differences between ET and rET, to improve the knowledge of these tremor syndromes., Methods: Thirty-three ET patients, 30 rET patients and 45 control subjects (HC) were enrolled. Several MR morphometric variables (thickness, surface area, volume, roughness, mean curvature) of brain cortical regions were extracted using Freesurfer on T1-weighted images and compared among groups. The performance of a machine learning approach (XGBoost) using the extracted morphometric features was tested in discriminating between ET and rET patients., Results: rET patients showed increased roughness and mean curvature in some fronto-temporal areas compared with HC and ET, and these metrics significantly correlated with cognitive scores. Cortical volume in the left pars opercularis was also lower in rET than in ET patients. No differences were found between ET and HC. XGBoost discriminated between rET and ET with mean AUC of 0.86 ± 0.11 in cross-validation analysis, using a model based on cortical volume. Cortical volume in the left pars opercularis was the most informative feature for classification between the two ET groups., Conclusion: Our study demonstrated higher cortical involvement in fronto-temporal areas in rET than in ET patients, which may be linked to the cognitive status. A machine learning approach based on MR volumetric data demonstrated that these two ET subtypes can be distinguished using structural cortical features., (© 2023. The Author(s).)