Gene Expression Analysis of Laser-Captured Purkinje Cells in the Essential Tremor Cerebellum.

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.

Challenging functional connectivity data: machine learning application on essential tremor recognition.

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.

The Contribution of Neuroimaging to the Understanding of Essential Tremor Pathophysiology: a Systematic Review.

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.

Essential tremor plus rest tremor: current concepts and controversies.

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.

Cognitive functioning in essential tremor without dementia: a clinical and imaging study.

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.

Essential tremor and cognitive impairment: who, how, and why.

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.

Anatomical texture patterns identify cerebellar distinctions between essential tremor and Parkinson's disease.

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.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

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.

Essential Tremor versus "ET-plus": A Detailed Postmortem Study of Cerebellar Pathology.

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.

Aberrant global and local efficiency of the executive subnetwork in essential tremor.

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.

Clinical characteristics of patients with essential tremor or essential tremor plus.

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.

Connectivity profile of thalamic deep brain stimulation to effectively treat essential tremor.

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.

Demoralization in essential tremor: prevalence, clinical correlates, and dissociation from tremor severity.

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.

Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach.

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.

Gait worsening and the microlesion effect following deep brain stimulation for essential tremor.

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.

Clinical correlates of abnormal subcortical volumes in Essential Tremor.

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.

Abnormal hippocampal subfields are associated with cognitive impairment in Essential Tremor.

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.

Neuroimaging and neuropathological findings in essential tremor.

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.

Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor.

Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemniscus, pyramidal, and dentato-rubro-thalamic). The area of optimal tremor response at 3 months after the procedure was identified at the posterior portion of the ventral intermediate nucleus. Lesions extending beyond the posterior region of the ventral intermediate nucleus and lateral to the lateral thalamic border were associated with increased risk of acute adverse sensory and motor effects, respectively. Acute adverse effects on gait and dysmetria occurred with lesions inferolateral to the thalamus. Lesions inferolateral to the thalamus or medial to the ventral intermediate nucleus were also associated with acute adverse speech effects. Diffusion-weighted imaging revealed that lesions associated with adverse sensory and gait/dysmetria effects compromised the medial lemniscus and dentato-rubro-thalamic tracts, respectively. Lesions associated with adverse motor and speech effects encroached on the pyramidal tract. Lesions larger than 170 mm3 were associated with an increased risk of acute adverse effects. Tremor improvement and acute adverse effects of MRgFUS for essential tremor are highly dependent on the location and size of lesions. These novel findings could refine current MRgFUS treatment planning and targeting, thereby improving clinical outcomes in patients.

Cerebello-cortical network fingerprints differ between essential, Parkinson's and mimicked tremors.

Cerebello-thalamo-cortical loops play a major role in the emergence of pathological tremors and voluntary rhythmic movements. It is unclear whether these loops differ anatomically or functionally in different types of tremor. We compared age- and sex-matched groups of patients with Parkinson's disease or essential tremor and healthy controls (n = 34 per group). High-density 256-channel EEG and multi-channel EMG from extensor and flexor muscles of both wrists were recorded simultaneously while extending the hands against gravity with the forearms supported. Tremor was thereby recorded from patients, and voluntarily mimicked tremor was recorded from healthy controls. Tomographic maps of EEG-EMG coherence were constructed using a beamformer algorithm coherent source analysis. The direction and strength of information flow between different coherent sources were estimated using time-resolved partial-directed coherence analyses. Tremor severity and motor performance measures were correlated with connection strengths between coherent sources. The topography of oscillatory coherent sources in the cerebellum differed significantly among the three groups, but the cortical sources in the primary sensorimotor region and premotor cortex were not significantly different. The cerebellar and cortical source combinations matched well with known cerebello-thalamo-cortical connections derived from functional MRI resting state analyses according to the Buckner-atlas. The cerebellar sources for Parkinson's tremor and essential tremor mapped primarily to primary sensorimotor cortex, but the cerebellar source for mimicked tremor mapped primarily to premotor cortex. Time-resolved partial-directed coherence analyses revealed activity flow mainly from cerebellum to sensorimotor cortex in Parkinson's tremor and essential tremor and mainly from cerebral cortex to cerebellum in mimicked tremor. EMG oscillation flowed mainly to the cerebellum in mimicked tremor, but oscillation flowed mainly from the cerebellum to EMG in Parkinson's and essential tremor. The topography of cerebellar involvement differed among Parkinson's, essential and mimicked tremors, suggesting different cerebellar mechanisms in tremorogenesis. Indistinguishable areas of sensorimotor cortex and premotor cerebral cortex were involved in all three tremors. Information flow analyses suggest that sensory feedback and cortical efferent copy input to cerebellum are needed to produce mimicked tremor, but tremor in Parkinson's disease and essential tremor do not depend on these mechanisms. Despite the subtle differences in cerebellar source topography, we found no evidence that the cerebellum is the source of oscillation in essential tremor or that the cortico-bulbo-cerebello-thalamocortical loop plays different tremorogenic roles in Parkinson's and essential tremor. Additional studies are needed to decipher the seemingly subtle differences in cerebellocortical function in Parkinson's and essential tremors.