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Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies, whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disorder that, in some cases, is associated with cognitive impairment and tau accumulation. In this study, we explored tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify the tau seeding activity present in brain homogenates by detecting the conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Pathogenic tau assemblies exhibit seeding barriers, where a specific assembly structure cannot serve as a template for a native monomer if the amino acid sequences are incompatible. We recently leveraged this species barrier to define tauopathies systematically by substituting alanine (Ala) into the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. This Ala scan precisely classified the conformation of tau seeds from various tauopathies. In this study, we analyzed 18 ET patient brains with tau pathology, detecting robust tau seeding activity in 9 (50%) of the cases, predominantly localized to the temporal pole and temporal cortex. We further examined 8 of these ET cases using the Ala scan and found that the amino acid requirements for tau monomer incorporation into aggregates seeded from ET brain homogenates were identical to those of Alzheimer's disease (AD) and primary age-related tauopathy (PART), and distinct from other tauopathies, such as corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy (PSP). These findings indicate that in a pathologically confined subset of ET cases with significant tau pathology, tau assembly cores are identical to those seen in AD and PART. This could facilitate more precise diagnosis and targeted therapies for ET patients presenting with cognitive impairment., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Essential tremor (ET) is a syndrome characterized by both motor (tremor, gait, and balance dysfunction) and non-motor features like cognitive deficits, depression, sleep, mood, and anxiety disorders. The present study was conducted to characterize the clinical dysfunction and brain localization of gait and balance disturbances in ET patients., Methods: 174 ET patients and 150 matched healthy controls were evaluated. ET was diagnosed using the Consensus Statement on the Classification of Tremors, from the Task Force on Tremors of the Movement Disorder Society criteria. Participants were assessed by using a structured neuropsychological battery and validated gait scores. Diffusion tensor imaging (DTI) data comprising mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy were analyzed for all subjects., Results: The mean age of essential tremor cases was 45.1 ± 14.08 years. Male: female ratio in ET cases was 2.5:1. Cognitive impairment was observed in a quarter of ET patients. A significant difference was observed in Berg balance scale scores, tandem gait missteps, and tandem stance time between ET cases and controls (p-value < 0.0001). ET patients with higher tremor scores and head tremors were more aged and had poor gait and cognitive scores (p < 0.0001). In our study, we observed poor gait scores significantly correlated with an increase in mean, radial, and axial diffusivities as well as a decrease in fractional anisotropy over various white matter clusters in the brain. No such correlation was observed among the controls., Conclusion: The present study demonstrates a correlation between gait scores and DTI metrics suggesting a neuroanatomic basis for gait impairment in ET patients., 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 Elsevier Ltd. All rights reserved.)

Under stress, Purkinje cells (PCs) undergo a variety of reactive morphological changes. These can include swellings of neuronal processes. While axonal swellings, "torpedoes", have been well-studied, dendritic swellings (DS) have not been the centerpiece of study. Surprisingly little is known about their frequency or relationship to other morphological changes in degenerating PCs. Leveraging a large brain bank, we (1) examined the morphology of DS, (2) quantified DS, and (2) examined correlations between counts of DS versus 16 other PC morphological changes in a broad range of cerebellar degenerative disorders. There were 159 brains - 100 essential tremor (ET), 13 Friedreich's ataxia, and 46 spinocerebellar ataxia (SCA) (14 SCA1, 7 SCA2, 13 SCA3, 5 SCA6, 5 SCA7, and 2 SCA8). DS were a feature of PCs across all these disorders, with varying morphologies and changes elsewhere in the dendritic arbor. On Luxol fast blue/hematoxylin and eosin-stained sections, the median number of DS per PC ranged from 0.001 in ET to 0.025 in SCA8. Bielschowsky-stained sections yielded higher counts, from 0.003 in ET to 0.042 in SCA6. Torpedo counts exceeded DS counts by one order of magnitude. DS counts were more robustly correlated with torpedo counts than with counts for any of the other PC morphological changes. In summary, DS ranged in prevalence across cerebellar degenerative disorders, from 1/1,000 to 42/1,000 PCs. Across disorders of cerebellar degeneration, these swellings of the dendritic compartment were most robustly correlated with swellings of the axonal compartment, suggesting a similar type of cellular response to duress., Competing Interests: Declarations. Ethical Approval: All study subjects had signed informed consent forms approved by the respective university or institutional ethics boards. Consent to Participate: Informed consent was obtained from all individual participants included in the study. Consent: Written, signed, informed consent was obtained from all participants included in the study. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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/).)

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.

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.)

Objective: Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases., Methods: The current study utilized autoradiography with the SV2A radioligand [ 18 F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls., Results: Using [ 18 F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls., Conclusion: In this pilot study, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could expand on our sample size and focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Rest tremor is a movement disorder commonly found in diseases like Parkinson's disease (PD) and essential tremor (ET). Rest tremor typically shows slower progression in PD, but more severe progression in ET. However, the underlying white matter organization of rest tremor behind PD and ET remains unclear., Methods: This study included 57 ET patients (40 without rest tremor (ETWR), 17 with rest tremor (ETRT)), 68 PD patients (34 without rest tremor (PDWR), 34 with rest tremor (PDRT)), and 62 normal controls (NC). Fixel-based analysis was used to evaluate the structural changes of white matter in rest tremor in these different diseases., Results: The fiber-bundle cross-section (FC) of the right non-decussating dentato-rubro-thalamic tract and several fibers outside the dentato-rubro-thalamic pathway in ETWR were significantly higher than that in NC. The fiber density and cross-section of the left nigro-pallidal in PDWR is significantly lower than that in NC, while the FC of bilateral nigro-pallidal in PDRT is significantly lower than that in NC., Conclusion: ET patients with pure action tremor showed over-activation of fiber tracts. However, when superimposed with rest tremor, ET patients no longer exhibited over-activation of fiber tracts, but rather showed a trend of fiber tract damage. Except for the nigro-pallidal degeneration in all PD, PDRT will not experience further deterioration in fiber organization. These results provide important insights into the unique effects of rest tremor on brain fiber architecture in ET and PD., 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 Elsevier Ltd. All rights reserved.)

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.)

Essential tremor (ET) is one of the most common neurological diseases. New evidence suggest that ET is associated with cognitive disorders other than motor symptoms. We aimed to investigate executive dysfunctions, which are comorbid cognitive deficiencies that may accompany ET. The study was conducted as an observational, case-control study in the Neurology Department of Ankara City Hospital in a 3-month period. The "Fahn-Tolosa-Marin Tremor Evaluation Scale" was used to rate tremor severity. Both patients and control group were subjected to the Mini Mental Test, followed by the Stroop TBAG test (TBAG is composed of the first letters of "TUBİTAK Temel Bilimler Araştırma Grubu," which means Scientific and Technological Research Council of Turkey Basic Sciences Research Group), word fluency (category fluency), phonemic fluency (K), and abstract thinking (binary similarities, proverb interpretation) tests. Both the patient and the control group consisted of 20 women and 20 men, with age, gender, and educational background compatible. Mean age of the patient group was 34.80 ± 13.23 years, while it was 34.95 ± 10.21 years in control group. In the ET group, statistically significant impairment was detected in the Stroop Test section 5 duration and error + correction number, category fluency, binary similarity, and phonemic fluency tests compared to the control group. There was a correlation between the severity of tremor and especially Stroop, category fluency, and binary similarity tests such that, as the severity of tremor increased, these test scores deteriorated. In ET patients, an impairment, accompanying tremor, may be present in executive functions that are a part of frontal lobe functions even in younger patients. This finding may suggest that impairment in the cerebellum-thalamus-frontal lobe connection may play a role in ET pathology.

Background: Previous studies have demonstrated the importance of the locus coeruleus (LC) in sleep-wake regulation. Both essential tremor (ET) and Parkinson's disease (PD) share common sleep disorders, such as poor quality of sleep (QoS). LC pathology is a feature of both diseases. A question arises regarding the contribution of LC degeneration to the occurrence of poor QoS., Objective: To evaluate the association between LC impairment and sleep disorders in ET and PD patients., Methods: A total of 83 patients with ET, 124 with PD, and 83 healthy individuals were recruited and divided into ET/PD with/without poor QoS (Sle/NorET and Sle/NorPD) subgroups according to individual Pittsburgh Sleep Quality Index (PSQI) score. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and free-water imaging derived from diffusion MRI were performed. Subsequently, we evaluated the association between contrast-to-noise ratio of LC (CNRLC) and free-water value of LC (FWLC) with PSQI scores in ET and PD groups., Results: CNRLC was significantly lower in ET (p = 0.047) and PD (p = 0.018) than in healthy individuals, whereas no significant difference was found in FWLC among the groups. No significant differences were observed in CNR/FWLC between patients with/without sleep disorders after multiple comparison correction. No correlation was identified between CNR/FWLC and PSQI in ET and PD patients., Conclusions: LC degeneration was observed in both ET and PD patients, implicating its involvement in the pathophysiology of both diseases. Additionally, no significant association was observed between LC integrity and PSQI, suggesting that LC impairment might not directly relate to overall QoS.

Introduction: Sleep disturbances have been associated with essential tremor (ET). However, their pathophysiological underpinnings remain unknown. In this exploratory study, we examined the association between subjective sleep disturbances and the presence of Lewy pathology (LP) on postmortem brain examination in ET cases., Methods: Fifty-two ET cases enrolled in a prospective, longitudinal study were assessed over an average period of 42 months. Cases completed the Pittsburgh Sleep Quality Index (PSQI), which yields seven component scores (e.g., sleep quality, sleep latency). For each component score, we calculated the difference between the last score and the baseline score. Brains were harvested at death. Each had a complete neuropathological assessment, including extensive α-synuclein immunostaining. We examined the associations between baseline PSQI scores and the change in PSQI scores (last - first), and LP on postmortem brain examination., Results: ET cases had a mean baseline age of 87.1 ± 4.8 years. LP was observed in 12 (23.1%) of 52 cases; in 7 of these 12, LP was observed in the locus coeruleus (LC). Change in time needed to fall asleep (last - first sleep latency component score) was associated with presence of LP on postmortem brain examination - greater increase in sleep latency was associated with higher odds of LP (odds ratio = 2.98, p = 0.02). The greatest increase in sleep latency was observed in cases with LP in the LC (p = 0.04)., Conclusion: In ET cases, increases in sleep latency over time could be a marker of underlying LP, especially in the LC., (© 2024 S. Karger AG, Basel.)

Essential tremor (ET) is a common, progressive neurological disease characterized by an 8-12-Hz kinetic tremor. Despite its high prevalence, the patho-mechanisms of tremor in ET are not fully known. Through comprehensive studies in postmortem brains, we identified major morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs), suggesting that PC damage is central to ET pathogenesis. We previously performed a transcriptome analysis in ET cerebellar cortex, identifying candidate genes and several dysregulated pathways. To directly target PCs, we purified RNA from PCs isolated by laser capture microdissection and performed the first ever PC-specific RNA-sequencing analysis in ET versus controls. Frozen postmortem cerebellar cortex from 24 ETs and 16 controls underwent laser capture microdissection, obtaining ≥2000 PCs per sample. RNA transcriptome was analyzed via differential gene expression, principal component analysis (PCA), and gene set enrichment analyses (GSEA). We identified 36 differentially expressed genes, encompassing multiple cellular processes. Some ET (13/24) had greater dysregulation of these genes and segregated from most controls and remaining ETs in PCA. Characterization of genes/pathways enriched in this PCA and GSEA identified multiple pathway dysregulations in ET, including RNA processing/splicing, synapse organization/ion transport, and oxidative stress/inflammation. Furthermore, a different set of pathways characterized marked heterogeneity among ET patients. Our data indicate a range of possible mechanisms for the pathogenesis of ET. Significant heterogeneity among ET combined with dysregulation of multiple cellular processes supports the notion that ET is a family of disorders rather than one disease entity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants., Aim of the Study: to characterize the phenotype of an Italian family with ET and identify the genetic variant associated., Methods: Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure., Results: The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 ( KCNN2 ) (NM&#95;021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.

Background/objectives: To evaluate the ability of swept-source optical coherence tomography (SS-OCT) implemented with angiography analysis (SS-OCTA) to detect neuro-retinal and vasculature changes in patients with Parkinson's disease (PD) and essential tremor (ET), and to distinguish between both pathologies., Subjects/methods: A total 42 PD and 26 ET patients and 146 controls underwent retinal evaluation using SS-OCT plus OCT-Angio™. The macular (m) and peripapillary (p) retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL), and macular vasculature were assessed. A Linear discriminant function (LDF) was calculated to evaluate the diagnostic ability of SS-OCTA in both PD and ET., Results: PD patients presented a reduction in mRNFL (p < 0.005), mGCL (all sectors, p < 0.05) and pRNFL (p < 0.005) vs healthy controls, and in mRNFL and pRNFL vs ET patients (p < 0.001). ET patients showed a significant reduction in mGCL vs controls (p < 0.001). No differences were observed in the macular vasculature between groups. Predictive diagnostic variables were significant only for PD and a LDF was obtained with an area under the ROC curve of 0.796., Conclusions: Neuro-retinal thinning is present in both diseases, being greater in PD. While SS-OCT could be useful in diagnosing ET and PD, the diagnostic potential for SS-OCTA based on an LDF applies only to PD, not ET., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: The pathophysiology of essential tremor (ET) is not fully understood, and studies suggest pathological changes mainly occur in the cerebellum and locus coeruleus (LC)., Methods: Fifty-three ET patients, including 30 patients with head tremor (h-ET), 23 patients without head tremor (nh-ET), 71 age and education matched healthy controls (HCs) were enrolled. All participants underwent Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and T1 scans on a 3-Tesla MR system. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNR LC ) and the score of The Essential Tremor Rating Assessment Scale (TETRAS) and cerebellum gray matter (GM) volume., Results: Significant difference of CNR LC was found between ET and HC groups. The CNR LC of ET groups is lower than the HC group (p = 0.031). Subgroup analysis showed that the CNR LC in nh-ET was significantly lower than HCs (p = 0.016). Compared to HCs, h-ETs showed marked atrophy in the cerebellum: the vermis IV-V and lobule VI (GRF corrected, p < 0.05). A significant negative correlation was found between CNR LC and the vermis lobule IV-V in h-ETs (r = - 0.651, p < 0.001). No significant correlation was found between CNR LC and TETRAS scores., Conclusion: The LC and the cerebellum might both involve in the pathophysiology of ET. LC evaluation using NM-MRI might be an effective tool for us to explore the pathophysiology of ET further., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Essential tremor (ET) is the most prevalent movement disorder with poorly understood etiology. Some neuroimaging studies report cerebellar involvement whereas others do not. This discrepancy may stem from underpowered studies, differences in statistical modeling or variation in magnetic resonance imaging (MRI) acquisition and processing. To resolve this, we investigated the cerebellar structural differences using a local advanced ET dataset augmented by matched controls from PPMI and ADNI. We tested the hypothesis of cerebellar involvement using three neuroimaging biomarkers: VBM, gray/white matter volumetry and lobular volumetry. Furthermore, we assessed the impacts of statistical models and segmentation pipelines on results. Results indicate that the detected cerebellar structural changes vary with methodology. Significant reduction of right cerebellar gray matter and increase of the left cerebellar white matter were the only two biomarkers consistently identified by multiple methods. Results also show substantial volumetric overestimation from SUIT-based segmentation-partially explaining previous literature discrepancies. This study suggests that current estimation of cerebellar involvement in ET may be overemphasized in MRI studies and highlights the importance of methods sensitivity analysis on results interpretation. ET datasets with large sample size and replication studies are required to improve our understanding of regional specificity of cerebellum involvement in ET. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 21 March 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.6084/m9.figshare.19697776 ., (© 2023. The Author(s).)

Background and Aims: This paper aimed to investigate the usefulness of applying machine learning on resting-state fMRI connectivity data to recognize the pattern of functional changes in essential tremor (ET), a disease characterized by slight brain abnormalities, often difficult to detect using univariate analysis., Methods: We trained a support vector machine with a radial kernel on the mean signals extracted by 14 brain networks obtained from resting-state fMRI scans of 18 ET and 19 healthy control (CTRL) subjects. Classification performance between pathological and control subjects was evaluated using a tenfold cross-validation. Recursive feature elimination was performed to rank the importance of the extracted features. Moreover, univariate analysis using Mann-Whitney U test was also performed., Results: The machine learning algorithm achieved an AUC of 0.75, with four networks (language, primary visual, cerebellum, and attention), which have an essential role in ET pathophysiology, being selected as the most important features for classification. By contrast, the univariate analysis was not able to find significant results among these two conditions., Conclusion: The machine learning approach identifies the changes in functional connectivity of ET patients, representing a promising instrument to discriminate specific pathological conditions and find novel functional biomarkers in resting-state fMRI studies., (© 2022. Fondazione Società Italiana di Neurologia.)

Essential tremor (ET) is one of the most common movement disorders. Over the last 10 years, magnetic resonance imaging (MRI) has shed light on the structural and functional abnormalities possibly involved in ET pathophysiology. In this systematic review, we aimed to identify the cortical and subcortical structures involved and the role that different brain areas play in the pathophysiology of motor and non-motor ET features. We found that structural (grey and white matter) cerebellar damage and connectivity alterations between the cerebellum and various cortical areas play a role in both motor and non-motor symptoms of ET. In particular, many studies found an association between MRI findings and non-motor symptoms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Essential Tremor Centralized Brain Repository is the largest repository of prospectively collected essential tremor (ET) brains (n = 231). Hence, we are uniquely poised to address several questions: What proportion of ET cases has Lewy pathology (LP)? What is the nature of that pathology and how does it relate to other comorbidities? Each brain had a complete neuropathological assessment, including α-synuclein immunostaining. We created a 10-category classification scheme to fully encapsulate the patterns of LP observed. Four metrics of cerebellar pathology were also quantified. Mean age at death = 89.0 ± 6.4 years. Fifty-eight (25.1%) had LP and 46 (19.9%) had early to late stages of Parkinson disease (PD). LP was very heterogeneous. Of 58 cases with LP, 14 (24.1%) clinically developed possible PD or PD after a latency of 5 or more years. There was a similar degree of cerebellar pathology in ET cases both with and without LP. In summary, 1 in 4 ET cases had LP-a proportion that seems higher than expected based on studies among control populations. Heterogeneous LP likely reflects clinical associations between ET and PD, and ET with Alzheimer disease-type neuropathology. These data further our understanding of ET and its relatedness to other degenerative diseases., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: To explore the cognitive functioning of ET patients without dementia and delineate its imaging counterpart., Methods: We enrolled 99 subjects (49 non-demented ET patients and 50 education-matched healthy controls) that underwent neuropsychological and MRI evaluation. In order to identify the cognitive parameters that better reflect the profile of ET patients, we used a double statistical approach: (i) direct comparison between groups and (ii) machine learning approach with feature selection. Then, to evaluate the correlation between cognitive performances and the degree of brain atrophy in the ET group, we included the results derived from the uni- and multivariate analysis in whole-brain voxel-based morphometry (VBM) model., Results: In ET patients, the univariate analysis showed differences in cognitive tests evaluating executive functions (FAB, MCST-CA), verbal memory-delayed recall (RAVLT-DR), and working memory (Digit Span B). The relative scores were significantly worse compared to controls, although within the normal range (subclinical dysfunctions). The machine learning approach also provided similar findings: tests exploring the executive functions, verbal memory, and language (RAVLT-DR, FAB, COWAT, RAVLT-IR, TOKEN) showed the highest importance rank in classification's task. Regardless of the explored test, the MRI analysis revealed a correlation (p < 0.005 uncorrected, whole brain) between test scores and widespread areas including cerebellum, inferior and middle frontal cortices, cingulate cortices, and temporal cortex., Conclusion: This study improves the knowledge on cognitive impairment in ET, as our findings demonstrate a heterogeneous pattern of cognitive dysfunction involving memory, executive function, and language domains in the ET group. This clinical profile relates with the deep involvement of the cerebellum and its connections with large-scale brain structures, suggesting that changes spreading in wide-ranging brain pathways may contribute to the physiopathology of cognitive dysfunction in ET., (© 2022. Fondazione Società Italiana di Neurologia.)

Since the initial description of Essential Tremor (ET), the entity of ET with rest tremor has proven to be a controversial concept. Some authors argued it could be a late manifestation of ET, others suggested it could be a variant of ET, yet others suggested it could represent a transitional state between ET and Parkinson's disease. The novel tremor classification has proposed the construct of ET-plus to differentiate patients with rest tremor from pure ET. However, there is no clarity of what ET-plus rest tremor represents. With the aim of shedding light on this controversial entity, we have, therefore, systematically reviewed all clinical, electrophysiological, imaging and anatomopathological studies indexed in the Medline database published both before and after the new tremor classification and involving patients with ET-plus rest tremor. Forty-four studies involving 4028 patients were included in this review and analyzed in detail by means of descriptive statistics. The results of the current review suggest that ET-plus rest tremor is a heterogenous group of conditions: thus, rest tremor might represent a late feature of ET, might reflect a different disorder with higher age at onset and lower dependance on genetic susceptibility than ET, might suggest the development of Parkinson's disease or might indicate a misdiagnosis of ET. The reviewed lines of evidence refuse recent claims arguing against the construct of ET-plus, which should be viewed as a syndrome with different possible underpinnings, and highlights methodological issues to be solved in future research., (© 2022. The Author(s).)

Background and Aims: Recent years have witnessed the switch from considering essential tremor (ET) a monosymptomatic disorder to consider it as part of a spectrum, including other neurological signs, such as mild cognitive impairment and dementia, thus defining it as "ET plus." There are few data on cognitive impairment in ET patients. The aim of this review is to analyze the clinical characteristics of ET patients developing cognitive impairment, their neuropsychological profile, the underpinning mechanisms, and the possible biomarkers., Methods: The authors performed a narrative review on cognitive decline in essential tremor, including articles written in English since the year 2000., Discussion: The most recent pathogenetic theories of cognitive impairment in ET rely on the cerebellar dysfunction, being part of the Cerebellar Cognitive Affective Syndrome spectrum. Cognitive impairment in ET patients could be assessed through many tests that demonstrate the involvement of different domains, such as attention, executive functions, and language. There are some clinical characteristics of ET that may indicate a greater risk of developing cognitive impairment, namely, cerebellar symptoms, falls, age at onset, and family history. However, there are no established clinical, neurophysiological, neuropathological, and fluid biomarkers of cognitive impairment in ET., Conclusions: Increasing data are showing in ET the presence of cerebellar symptoms and cognitive impairment. Further studies are needed to better understand cognition in ET patients, and to define the boundary between ET and ET plus, since deeper phenotyping might have important clinical and therapeutic implications., (© 2022. Fondazione Società Italiana di Neurologia.)

There have been no previous reports of chronic encapsulated expanding hematoma after Gamma Knife thalamotomy. The present case underwent Gamma Knife thalamotomy for essential tremor at the age of 78 years. Three- and 12-month posttreatment magnetic resonance imaging (MRI) showed small T2 high-intensity lesions on the target and along with the internal capsule. Hemiparesis developed 17 months after the treatment. Twenty months post treatment, T2-MRI showed a hypointense mass across the target and internal capsule. Gradual expansion of the mass was confirmed on MRI at 26-38 months. A 54-month posttreatment MRI showed marked expansion of the mass with multiple cysts surrounded by a T2-hypointense rim. Gadolinium-enhanced T1-MRI showed partial enhancement of the mass. MRI findings suggested a radiation-induced cavernoma. Hemiparesis, dysesthesia, and pain on the right side of the body persisted even after steroid therapy for several months. Long-term careful observation is necessary after Gamma Knife thalamotomy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Essential tremor (ET) is among the most prevalent movement disorders, and by some accounts, the most common form of cerebellar degeneration. Over the past 15 years, we have carefully documented a large number of postmortem changes within the cerebellum; these cerebellar changes differ significantly between ET and controls. A recent Consensus Classification of tremor proposed that ET patients with other neurological signs aside from action tremor (e.g., parkinsonism, ataxia, cognitive changes, dystonia) should be segregated off as "ET-plus". This diagnostic concept has raised considerable controversy and its validity is not yet established. Indeed, "ET-plus" has not been distinguished from ET based on differences in genetics, pathology or prognosis. Here we determine whether ET cases differ from "ET-plus" cases in underlying pathological changes in the postmortem brain. We examined postmortem brains from 50 ET cases (24 ET and 26 ET-plus), using a set of 14 quantitative metrics of cerebellar pathology determined by histologic and immunohistochemical methods. These metrics reflect changes across the Purkinje cell (PC) body (PC counts, empty baskets, heterotopias), PC dendrites (swellings), PC axon (torpedoes and associated axonal changes), basket cell axonal hypertrophy and climbing fiber-PC dendrite synaptic changes. ET and ET-plus were similar with respect to 13 of 14 cerebellar pathologic metrics (p > 0.05). Only one metric, the linear density of thickened PC axon profiles, differed between these groups (ET = 0.529 ± 0.397, ET-plus = 0.777 ± 0.477, p = 0.013), although after correcting for multiple comparisons, there were no differences. If ET-plus were indeed a different entity, then the underlying pathological basis should be distinct from that of ET. This study demonstrated there were no pathological differences in cerebellar cortex between ET versus ET-plus cases. These data do not support the notion that ET and ET-plus represent distinct clinical-pathological entities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The ventral intermediate nucleus of the thalamus (VIM) is an important relay station receiving cerebellar and pallidal fiber tracts. Data on structural visualization of the VIM however is limited and uncertainty prevails to what extent lesional approaches to treat tremor affect the VIM itself or passing tracts. The aim of the study was to analyze the localization of individual lesions with respect to the VIM and the cerebello-thalamic tract (CTT)., Methods: We employed ultrahigh resolution (7 Tesla) MRI to delineate the VIM and performed 3 T-DTI-imaging pre- and post-interventional in seven ET patients undergoing transcranial magnetic resonance guided focused ultrasound (tcMRgFUS). Tremor improvement was measured using a modified subscore of the Clinical Rating Scale for Tremor., Results: All subjects showed substantial tremor improvement (88.5%, range 80.7%-94,8%) after tcMRgFUS. We found only a minor overlap of the lesions with the VIM (4%, range 1%-7%) but a larger overlap with the CTT (43%, range 23%-60%) in all subjects., Conclusions: Lesions within the CTT rather than the VIM seem to drive the tremorlytic response and clinical improvement in tcMRgFUS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Essential Tremor (ET) is increasingly recognized as a complex disorder with additional clinical signs other than tremor. It is still unknown whether a unique pathophysiologic or neurodegenerative process underlies progression and prognosis of the disease. The aim of the study was to identify ET phenotypes through a clinical-instrumental data-driven approach and to characterize possible patterns of neurodegeneration., Methods: ET patients were categorized using spatio-temporal and kinematic variables related to mobility and dynamic stability processed by motion transducers. Differences between the identified groups in clinical-demographic variables, neuropsychological performances and retinal parameters by Optical Coherence Tomography (OCT) segmentation analysis were tested., Results: Twenty-five ET patients were studied. Based on clustering of kinematic and spatio-temporal gait parameters, two independent groups were identified: cluster "A" (N = 15) and cluster "B" (N = 10). Compared to group A, group B had overall worse performance in mobility, especially on turning tasks. Identified clusters did not differ in terms of age, age at onset and disease duration. Patients in group B had more head tremor and more severe action tremor in the upper limbs as compared to group A, demonstrating also worse performances on cognitive assessments. Based on OCT analysis, group B presented a reduced thickness of the retinal inner layer as compared to group A, suggesting underlying neurodegenerative processes., Conclusions: The presence of gait and mobility impairment, associated with midline tremor, cognitive decline and retinal degeneration suggests a subtype of ET associated with neurodegeneration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Voxel-based morphometry is an established technique to study focal structural brain differences in neurologic disease. More recently, texture-based analysis methods have enabled a pattern-based assessment of group differences, at the patch level rather than at the voxel level, allowing a more sensitive localization of structural differences between patient populations. In this study, we propose a texture-based approach to identify structural differences between the cerebellum of patients with Parkinson's disease (n = 280) and essential tremor (n = 109). We analyzed anatomical differences of the cerebellum among patients using two features: T1-weighted MRI intensity, and a texture-based similarity feature. Our results show anatomical differences between groups that are localized to the inferior part of the cerebellar cortex. Both the T1-weighted intensity and texture showed differences in lobules VIII and IX, vermis VIII and IX, and middle peduncle, but the texture analysis revealed additional differences in the dentate nucleus, lobules VI and VII, vermis VI and VII. This comparison emphasizes how T1-weighted intensity and texture-based methods can provide a complementary anatomical structure analysis. While texture-based similarity shows high sensitivity for gray matter differences, T1-weighted intensity shows sensitivity for the detection of white matter differences., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: To develop a fast and accurate convolutional neural network based method for segmentation of thalamic nuclei., Methods: A cascaded multi-planar scheme with a modified residual U-Net architecture was used to segment thalamic nuclei on conventional and white-matter-nulled (WMn) magnetization prepared rapid gradient echo (MPRAGE) data. A single network was optimized to work with images from healthy controls and patients with multiple sclerosis (MS) and essential tremor (ET), acquired at both 3 T and 7 T field strengths. WMn-MPRAGE images were manually delineated by a trained neuroradiologist using the Morel histological atlas as a guide to generate reference ground truth labels. Dice similarity coefficient and volume similarity index (VSI) were used to evaluate performance. Clinical utility was demonstrated by applying this method to study the effect of MS on thalamic nuclei atrophy., Results: Segmentation of each thalamus into twelve nuclei was achieved in under a minute. For 7 T WMn-MPRAGE, the proposed method outperforms current state-of-the-art on patients with ET with statistically significant improvements in Dice for five nuclei (increase in the range of 0.05-0.18) and VSI for four nuclei (increase in the range of 0.05-0.19), while performing comparably for healthy and MS subjects. Dice and VSI achieved using 7 T WMn-MPRAGE data are comparable to those using 3 T WMn-MPRAGE data. For conventional MPRAGE, the proposed method shows a statistically significant Dice improvement in the range of 0.14-0.63 over FreeSurfer for all nuclei and disease types. Effect of noise on network performance shows robustness to images with SNR as low as half the baseline SNR. Atrophy of four thalamic nuclei and whole thalamus was observed for MS patients compared to healthy control subjects, after controlling for the effect of parallel imaging, intracranial volume, gender, and age (p < 0.004)., Conclusion: The proposed segmentation method is fast, accurate, performs well across disease types and field strengths, and shows great potential for improving our understanding of thalamic nuclei involvement in neurological diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618., (© 2020 American Neurological Association.)

This study is to investigate the presence of brain gray matter abnormalities in young onset essential tremor (ET) patients with arm tremor. Thirty ET patients together with 30 healthy volunteers were taken as candidates. Magnetic resonance imaging (MRI) was performed and voxel-based morphometry was used to compare gray matter density between the patients and volunteers. Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) rating scale was applied to assess tremor severity in the patients. Eventually Twenty-Seven ET patients and Twenty-Seven volunteers were enrolled in the study. Voxel-based morphometry showed significant expansion of the bilateral cerebellum, occipital fusiform cortices, right inferior temporal gyrus, and precentral lobes (P < 0.05, TFCE corrected). Decrease in gray matter was detected only in the left parietal lobe. Region of interest analysis showed volume enlargement in thalamus, midbrain, and precuneus (P < 0.05, TFCE corrected). Importantly, significant negative correlation was found between the lateralized index of cerebellum and the tremor score which might implicate that the altered rightward lateralization in the cerebellum is possibly a response of the tremor effects in ET patients. Cerebellar gray matter expansion in young onset ET patients with arm tremor might be the result of compensation towards decline of cerebellar function., 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 © 2020 Elsevier Ltd. All rights reserved.)

Background: The International Parkinson and Movement Disorder Society introduced the category of essential tremor (ET)-plus in its new ET classification scheme, but how the clinical correlates of ET-plus differ from those of "pure" ET is unclear. By comparing the clinical characteristics of ET and ET-plus patients, we expect to better understand the impact and invoked questions of the new classification on clinical practice., Methods: We reviewed the medical records of 280 ET syndrome patients in an ongoing cross-sectional study in a Chinese population and reclassified them according to the new criteria. Clinico-demographic characteristics were compared between ET and ET-plus patients. Risk factors of diagnosis of ET-plus were explored using logistic regression., Results: A total of 121 patients (50.8%) were reclassified as having ET and 117 as having ET-plus. ET-plus group was significantly older at tremor onset, less educated, and more likely to have cranial tremor, depression symptom, anxiety symptom, and probable REM sleep behavior disorder. ET-plus group also showed more severe upper limb tremor and cognition impairment. Regression analysis identified four independent risk factors associated with ET-plus: late tremor onset (OR 3.04, 95%CI 1.60-5.79), less educated (OR 0.91, 95%CI 0.85-0.97), severe upper limb tremor (OR 2.46, 95%CI 1.30-4.62), and presence of cranial tremor (OR 2.30, 95%CI 1.20-4.41)., Conclusions: The new classification scheme emphasized that ET syndrome is heterogeneous. ET-plus cannot be seen as a subtype or a diagnosis of ET syndrome, but rather as a placeholder, representing an area of current scientific uncertainty., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Essential tremor (ET) is one of the most common neurological diseases, with a central feature of an 8-12 Hz kinetic tremor. While previous postmortem studies have identified a cluster of morphological changes in the ET cerebellum centered in/around the Purkinje cell (PC) population, including a loss of PCs in some studies, the underlying molecular mechanisms for these changes are not clear. As genomic studies of ET patients have yet to identify major genetic contributors and animal models that fully recapitulate the human disease do not yet exist, the study of human tissue is currently the most applicable method to gain a mechanistic insight into ET disease pathogenesis. To begin exploration of an underlying molecular source of ET disease pathogenesis, we have performed the first transcriptomic analysis by direct sequencing of RNA from frozen cerebellar cortex tissue in 33 ET patients compared to 21 normal controls. Principal component analysis showed a heterogenous distribution of the expression data in ET patients that only partially overlapped with control patients. Differential expression analysis identified 231 differentially expressed gene transcripts ('top gene hits'), a subset of which has defined expression profiles in the cerebellum across neuronal and glial cell types but a largely unknown relationship to cerebellar function and/or ET pathogenesis. Gene set enrichment analysis (GSEA) identified dysregulated pathways of interest and stratified dysregulation among ET cases. By GSEA and mining curated databases, we compiled major categories of dysregulated processes and clustered string networks of known interacting proteins. Here we demonstrate that these 'top gene hits' contribute to regulation of four main biological processes, which are 1) axon guidance, 2) microtubule motor activity, 3) endoplasmic reticulum (ER) to Golgi transport and 4) calcium signaling/synaptic transmission. The results of our transcriptomic analysis suggest there is a range of different processes involved among ET cases, and draws attention to a particular set of genes and regulatory pathways that provide an initial platform to further explore the underlying biology of ET., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study aims to use probabilistic tractography to ascertain the global (GE) and local efficiency (LE) of the executive subnetwork in essential tremor (ET). Significantly lower GE of the whole executive subnetwork and lower LE of the left rostral middle frontal gyrus, frontal pole, inferior frontal gyrus, bilateral anterior cingulate cortex, and medial orbitofrontal cortex. These results imply ineffective and inadequate communication of the executive subnetwork, and may be causally associated with the executive dysfunction observed in ET.

Introduction: There is growing evidence that a proportion of patients with Essential Tremor (ET) may develop a memory impairment over time. However, no studies have evaluated whether hippocampal damage really occur in ET. This study investigated the macro and micro-structural integrity of the hippocampus in ET subjects using a multimodal MRI approach., Methods: Neuropsychological and MRI data were acquired from 110 participants (60 patients with ET and 50 age-, sex-, and education-matched healthy controls [HC]). Whole-brain T1-weighted and Diffusion Tensor Imaging (DTI) were performed to assess macro-and microstructural alterations. MRI parameters (volume; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi were obtained. In order to evaluate the relationship between MRI alterations and neurocognitive impairment, hippocampal parameters were also correlated with cognitive test scores., Results: Compared to controls, ET patients showed a subclinical memory impairment with significantly lower memory scores, but within the normal ranges. Despite the subclinical damage, however, ET patients showed a significant increase in MD values in the bilateral hippocampi in comparison with HC. A significant correlation was also found between MD and memory scores in ET., Conclusion: This study improves the knowledge on memory impairment in ET, as our results demonstrate for the first time the hippocampal microstructural damage related to subclinical memory impairment in ET patients. Further studies are needed before these findings can be considered predictive of a distinct ET subtype or suggestive of a co-occurent dementia., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose. None of the authors have received financial support or funding for the research covered in this article., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: Essential tremor (ET) is associated with psychological difficulties, including anxiety and depression. Demoralization (feelings of helplessness, hopelessness, inability to cope), another manifestation of psychological distress, has yet to be investigated in ET. Our objectives are to (1) estimate the prevalence of demoralization in ET, (2) assess its clinical correlates, and (3) determine whether demoralization correlates with tremor severity., Methods: We administered the Kissane Demoralization Scale (KDS-II) and several psychosocial evaluations (ie, scales assessing subjective incompetence, resilience, and depression [eg, Geriatric Depression Scale]) to 60 ET subjects. Tremor was assessed with a disability score and total tremor score. KDS-II >8 indicated demoralization., Results: Among 60 ET subjects (mean age = 70.2 ± 6.8 years), the prevalence of demoralization was 13.3%, 95% confidence interval = 6.9-24.2%. Although there was overlap between demoralization and depression (10% of the sample meeting criteria for both), 54% of depressed subjects were not demoralized, and 25% of demoralized subjects were not depressed. Demoralization correlated with psychological factors, but demoralized subjects did not have significantly higher total tremor scores, tremor disability scores, or years with tremor., Conclusions: Demoralization has a prevalence of 13.3% in ET, similar to that in other chronic or terminal illnesses (eg, cancer 13-18%, Parkinson's disease 18.1%, coronary heart disease 20%). Demoralization was not a function of increased tremor severity, suggesting that it is a separable construct, which could dictate how a patient copes with his/her disease. These data further our understanding of the psychological and psychosocial correlates of ET.

Essential tremor (ET) is the most common tremor disorder globally and is characterized by kinetic tremor of the upper limbs, although other clinical features can also occur. Postmortem studies are a particularly important avenue for advancing our understanding of the pathogenesis of ET; however, until recently, the number of such studies has been limited. Several recent postmortem studies have made important contributions to our understanding of the pathological changes that take place in ET. These studies identified abnormalities in the cerebellum, which primarily affected Purkinje cells (PCs), basket cells and climbing fibres, in individuals with ET. We suggest that some of these pathological changes (for example, focal PC axonal swellings, swellings in and regression of the PC dendritic arbor and PC death) are likely to be primary and degenerative. By contrast, other changes, such as an increase in PC recurrent axonal collateral formation and hypertrophy of GABAergic basket cell axonal processes, could be compensatory responses to restore cerebellar GABAergic tone and cerebellar cortical inhibitory efficacy. Such compensatory responses are likely to be insufficient, enabling the disease to progress. Here, we review the results of recent postmortem studies of ET and attempt to place these findings into an anatomical-physiological disease model.

Several morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson's disease (PD), dystonia]. Using a postmortem series of 156 brains [50 ET, 23 SCA (6 SCA3; 17 SCA 1, 2 or 6), 15 MSA, 29 PD, 14 dystonia, 25 controls], we generated data on 37 quantitative morphologic metrics, which were grouped into 8 broad categories: (1) PC loss, (2) heterotopic PCs, (3) PC dendritic changes, (4) PC axonal changes (torpedoes), (5) PC axonal changes (other than torpedoes), (6) PC axonal changes (torpedo-associated), (7) basket cell axonal hypertrophy, (8) climbing fiber-PC synaptic changes. Our analyses used z scored raw data for each metric across all diagnoses (5772 total data items). Principal component analysis revealed that diagnostic groups were not uniform with respect to cerebellar pathology. Dystonia and PD each differed from controls in only 2/37 metrics, whereas ET differed in 21, SCA3 in 8, MSA in 19, and SCA1/2/6 in 26 metrics. Comparing ET with primary disorders of cerebellar degeneration (i.e., SCAs), we observed a spectrum of changes reflecting differences of degree, being generally mild in ET and SCA3 and more severe in SCA1/2/6. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. Thus, the degree of cerebellar degeneration in ET aligns it with a milder end in the spectrum of cerebellar degenerative disorders, and a somewhat distinctive signature of degenerative changes marks each of these disorders.

Essential tremor is the most prevalent movement disorder and is often refractory to medical treatment. Deep brain stimulation offers a therapeutic approach that can efficiently control tremor symptoms. Several deep brain stimulation targets (ventral intermediate nucleus, zona incerta, posterior subthalamic area) have been discussed for tremor treatment. Effective deep brain stimulation therapy for tremor critically involves optimal targeting to modulate the tremor network. This could potentially become more robust and precise by using state-of-the-art brain connectivity measurements. In the current study, we used two normative brain connectomes (structural and functional) to show the pattern of effective deep brain stimulation electrode connectivity in 36 patients with essential tremor. Our structural and functional connectivity models were significantly predictive of postoperative tremor improvement in out-of-sample data (P < 0.001 for both structural and functional leave-one-out cross-validation). Additionally, we segregated the somatotopic brain network based on head and hand tremor scores. These resulted in segregations that mapped onto the well-known somatotopic maps of both motor cortex and cerebellum. Crucially, this shows that slightly distinct networks need to be modulated to ameliorate head versus hand tremor and that those networks could be identified based on somatotopic zones in motor cortex and cerebellum. Finally, we propose a multi-modal connectomic deep brain stimulation sweet spot that may serve as a reference to enhance clinical care, in the future. This spot resided in the posterior subthalamic area, encroaching on the inferior borders of ventral intermediate nucleus and sensory thalamus. Our results underscore the importance of integrating brain connectivity in optimizing deep brain stimulation targeting for essential tremor., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Voxel-based morphometry (VBM) has been used to study human brain gray matter (GM) alterations in essential tremor (ET) for over one decade. However, the literature revealed heterogeneous findings., Methods: We therefore conducted a coordinate-based meta-analysis to synthesize the VBM studies to examine which brain regions show the most reliable GM alterations in patients with ET relative to healthy controls., Results: A total of 16 original VBM studies, comprising 387 patients with ET and 355 healthy controls, were included in this meta-analysis. This quantitative meta-analysis revealed no evidence of robust and reliable alterations in regional brain GM structures in ET. Meta-regression analyses indicate that many moderators (e.g., MR field strength, statistical methodology, age, onset age, gender, illness severity, illness duration, and family history) account for some of the heterogeneity in GM across studies., Conclusions: High heterogeneity in GM alterations across studies may reflect true heterogeneity in ET regarding the clinic, etiology, and pathology, as well as possibly the VBM methodological variations. Currently, this heterogeneity limits the use of VBM as a reliable tool to distinguish ET from healthy controls. In order to improve reproducibility of VBM results in ET, future research may benefit from increasing the sample size, comprehensively subtyping ET phenotypes, and using well-designed and standardized imaging acquisition and analytical protocols. Furthermore, data sharing should be considered as a high priority.

Objective: To investigate the effects of unilateral thalamic deep brain stimulation (DBS) on walking in persons with medication-refractory essential tremor (ET)., Methods: We performed laboratory-based gait analyses on 24 persons with medication-refractory ET before and after unilateral thalamic DBS implantation. Normal and tandem walking parameters were analysed across sessions (PRE-DBS/DBS OFF/DBS ON) by repeated measures analyses of variance. Pearson's correlations assessed whether changes in walking after DBS were global (ie, related across gait parameters). Baseline characteristics, lead locations and stimulation parameters were analysed as possible contributors to gait effects., Results: DBS minimally affected gait at the cohort level. However, 25% of participants experienced clinically meaningful gait worsening. Walking speed decreased by >30% in two participants and by >10% in four others. Decreased walking speed correlated with increased gait variability, indicating global gait worsening in affected participants. The worsening persisted even after the stimulation was turned off. Participants with worse baseline tandem walking performance may be more likely to experience post-DBS gait worsening; the percentage of tandem missteps at baseline was nearly three times higher and tandem walking speeds were approximately 30% slower in participants who experienced gait worsening. However, these differences in tandem walking in persons with gait worsening as compared with those without worsening were not statistically significant. Lead locations and stimulation parameters were similar in participants with and without gait worsening., Conclusion: Global gait worsening occurred in 25% of participants with unilateral DBS for medication-refractory ET. The effect was present on and off stimulation, likely indicating a microlesion effect., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Essential tremor is a chronic neurological syndrome of heterogenous clinical phenotypes and multiple etiologies. Numerous studies have been done in order to investigate the pathological, neuroimaging, physiological, and clinical features of essential tremor; however, a clear pathophysiological mechanism has not been identified. One of the brain structures has been extensively investigated at the macroscopic and the microscopic level in the cerebellum. In the present study, we aim to discuss the main neuroimaging and neuropathological changes of the cerebellum in essential tremor., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transcranial focused ultrasound is a non-invasive therapeutic modality that can be used to treat essential tremor. Beams of energy are focused into a small spot in the thalamus, resulting in tissue heating and ablation. Here, we report on a rapid 3D numeric simulation framework that can be used to predict focal spot characteristics prior to the application of ultrasound. By comparing with magnetic resonance proton resonance frequency shift thermometry (MR thermometry) data acquired during treatments of essential tremor, we verified that our simulation framework can be used to predict focal spot position, and with patient-specific calibration, predict focal spot temperature rise. Preliminary data suggests that lateral smearing of the focal spot can be simulated. The framework may also be relevant for other therapeutic ultrasound applications such as blood brain barrier opening and neuromodulation.

Multi-domain cognitive impairment (CI) has been frequently described in patients with essential tremor (ET). However, the exact neuroanatomical basis for this impairment is uncertain. This study aims to ascertain the role of the hippocampal formation in cognitive impairment in ET. Forty patients with ET and 40 age, gender and education matched healthy controls (HC) were enrolled. Cognition was assessed using a structured neuropsychological battery and patients were categorized as ET with CI (ETCI) and ET without CI (ETNCI). Automatic segmentation of hippocampal subfields was performed using FreeSurfer 6.0. The obtained volumes were correlated with scores of neuropsychological tests. Significant atrophy of the left subiculum, CA4, granule-cell layer of dentate gyrus, right molecular layer, and hypertrophy of bilateral parasubiculum, right hippocampus-amygdala-transition-area, bilateral hippocampal tail (HT) and widening of right hippocampal fissure was observed in ET. Trends toward atrophy of right subiculum, and widening of left HF was also observed. Comparison of HC and ETCI revealed atrophy of right subiculum, hypertrophy of bilateral parasubiculum, HT, and widening of left HF. ETCI showed a trend toward widening of right HF. ETNCI had isolated left parasubicular hypertrophy and in comparison, to ETNCI the ETCI subgroup had atrophy of bilateral fimbria. Significant correlations were observed between the volumes of HT, HF, fimbria and scores of tests for executive function, working and verbal memory. Patients with ET have significant volumetric abnormalities of several hippocampal subfields and these abnormalities may be important contributors for some forms of cognitive impairment observed in ET.

Essential tremor (ET) is considered to be a neurodegenerative disorder and it is plausible that the observed motor and non-motor symptoms may be attributable to functional alterations secondary to abnormalities of subcortical nuclei. This study aims to compare the volumes of subcortical nuclei in patients with ET to ascertain neuroimaging correlates of motor and non-motor features of ET. Forty patients of ET and 40 age- and gender-matched healthy controls (HC) were enrolled in this study. Tremor severity was quantified with the Fahn-Tolosa-Marin tremor rating scale. Patients of ET with and without a rest tremor were also compared. Structural imaging was performed on a 3T scanner, and volumes of subcortical structures were obtained using Freesurfer. There was no difference in total brain volume between ET and HC. However, compared to HC, significantly lower volumes of bilateral thalamus, hippocampus, and ventral diencephalon were observed in patients with ET. A significantly higher volume was observed in the right caudate nucleus, pallidum, amygdala, and bilateral putamen, and nucleus accumbens. No difference was observed between patients of ET with and without a rest tremor. Patients with ET have significant alterations in volumes of subcortical nuclei, which are not limited to the motor domain and include structures involved in cognitive and behavioral functions. These results add to the growing concept of a neurodegenerative pathophysiology of ET with abnormalities extending beyond the cerebellum.

Essential tremor (ET) is a common movement disorder characterized by postural or kinetic tremor. We aimed to evaluate median nerve enlargement in patients with ET using ultrasonography (USG). Thirty-eight hands from 19 patients with ET and 24 hands from 13 controls underwent nerve conduction studies (NCS) and USG at the wrist. Tremor severity was measured using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). The median nerve cross sectional area (mCSA) in USG and NCS parameters were compared using ANCOVA. We evaluated the correlation between mCSA and NCS parameters or FTM-TRS scores using linear regression analysis. mCSA was significantly larger (p<0.001) and NCS parameters were different in two groups. Also, mCSA was negatively correlated with part B and C scores of FTM-TRS (p<0.001 and p = 0.039, respectively). In conclusion, median nerve enlargement with the changes of NCS parameters was observed and correlated with the severity of tremor in patients with ET., Competing Interests: The authors have declared that no competing interests exist.

The underlying biology of essential tremor (ET) is poorly understood. Purkinje cell (PC) loss has been observed in some studies, although this finding remains somewhat controversial. Basket cells are interneurons whose axonal collaterals form a plexus around PC soma. When there is PC loss, this basket plexus appears empty. We used dual immunohistochemical staining for calbindin D28k and glutamic acid decarboxylase to quantify "empty baskets" as an indirect and alternative method of detecting PC loss. Microscopic analyses on 127 brains included ET and a spectrum of motor neurodegenerative diseases (50 ET, 27 spinocerebellar ataxias [SCAs], 25 Parkinson disease, 25 controls). The median percentage of empty baskets in ET patients was 1.5 times higher than controls (48.8% vs 33.5%, p < 0.001) but lower in ET than in SCA1 (59.7%, p = 0.011), SCA2 (77.5%, p = 0.003), and SCA6 (87.0%, p < 0.001). PC loss is not a feature of SCA3, and the median percentage of empty baskets (30.1%) was similar to controls (p = 0.303). These data provide support for PC loss in ET and are consistent with the notion that ET could represent a mild form of cerebellar degeneration with an intermediate degree of PC loss.