Magnetic resonance-guided focused ultrasound for essential tremor:a prospective,single center,single-arm study

The safety and effectiveness of magnetic resonance-guided focused ultrasound thalamotomy has been broadly established and validated for the treatment of essential tremor.In 2018,the first magnetic resonance-guided focused ultrasound system in Chinese mainland was installed at the First Medical Center of the PLA General Hospital.This prospective,single center,open-label,single-arm study was part of a worldwide prospective multicenter clinical trial(ClinicalTrials.gov Identifier:NCT03253991)conducted to confirm the safety and efficacy of magnetic resonance-guided focused ultrasound for treating essential tremor in the local population.From 2019 to 2020,10 patients with medication refractory essential tremor were recruited into this open-label,single arm study.The treatment efficacy was determined using the Clinical Rating Scale for Tremor.Safety was evaluated according to the incidence and severity of adverse events.All of the subjects underwent a unilateral thalamotomy targeting the ventral intermediate nucleus.At the baseline assessment,the estimated marginal mean of the Clinical Rating Scale for Tremor total score was 58.3±3.6,and this improved after treatment to 23.1±6.4 at a 12-month follow-up assessment.A total of 50 adverse events were recorded,and 2 were defined as serious.The most common intraoperative adverse events were nausea and headache.The most frequent postoperative adverse events were paresthesia and equilibrium disorder.Most of the adverse events were mild and usually disappeared within a few days.Our findings suggest that magnetic resonance-guided focused ultrasound for the treatment of essential tremor is effective,with a good safety profile,for patients in Chinese mainland.

Essential tremor:A three-dimensional neurosphere in vitro model to assess the neurotoxicity of harmane

Objectives: To use a novel in vitro model of three-dimensional(3D) neurosphere cultures to assess neurotoxic or neuroprotective effects with harmane as a model compound.Methods: A reproducible model of 3D spheroids was developed from embryonic mouse cortical neurons,using molded agarose micro-wells;this method seems particularly practical as it is customizable and widely available and does not require specific cell treatments or assay components different from 2D cultures, allowing for the easy transposition of routine protocols. To assess the neurotoxic effects of harmane, a resazurin assay was performed to measure cell viability, and a highly sensitive fluorometric method, based on the oxidation of dichlorodihydrofluorescein, was applied to measure eventually induced reactive oxygen species(ROS) after exposure to harmane at increasing concentrations of 50 100,and 250 μm.Results: Hydrogel microwells facilitated the assembly of spheroids containing neurons and glial cells into a complex 3D structure and prevented the agglomeration of spheroids. Exposure to harmane induced cytotoxicity in 3D neural spheroids, which was correlated with harmane concentrations, with a 27%reduction in viability at 250 μm. Harmane that did not induce significant levels of oxidative stress was detected for all tested concentrations.Conclusion: This 3D neurosphere model mimics a neuronal microenvironment, allowing a fine study of neurodegenerative disorders and the effects of chemicals on the brain. This model opens novel opportunities, not only from a pathogenetic point of view but also from a therapeutic perspective.

Neural computational modeling reveals a major role of corticospinal gating of central oscillations in the generation of essential tremor

Essential tremor, also referred to as familial tremor, is an autosomal dominant genetic disease and the most common movement disorder. It typically involves a postural and motor tremor of the hands, head or other part of the body. Essential tremor is driven by a central oscillation signal in the brain. However, the corticospinal mechanisms involved in the generation of essential tremor are unclear. Therefore, in this study, we used a neural computational model that includes both monosynaptic and multisynaptic corticospinal pathways interacting with a propriospinal neuronal network. A virtual arm model is driven by the central oscillation signal to simulate tremor activity behavior. Cortical descending commands are classified as alpha or gamma through monosynaptic or multisynaptic corticospinal pathways, which converge respectively on alpha or gamma motoneurons in the spinal cord. Several scenarios are evaluated based on the central oscillation signal passing down to the spinal motoneurons via each descending pathway. The simulated behaviors are compared with clinical essential tremor characteristics to identify the corticospinal pathways responsible for transmitting the central oscillation signal. A propriospinal neuron with strong cortical inhibition performs a gating function in the generation of essential tremor. Our results indicate that the propriospinal neuronal network is essential for relaying the central oscillation signal and the production of essential tremor.

Visual function alterations in essential tremor: A case report

Our purpose is to report alterations in contrast sensitivity function(CSF)and in the magno,parvo and koniocellular visual pathways by means of a multichannel perimeter in case of an essential tremor(ET).A complete evaluation of the visual function was performed in a 69-year old patient,including the analysis of the chromatic discrimination by the Fansworth–Munsell 100 hue test,the measurement of the CSF by the CSV-1000E test,and the detection of potential alteration patterns in the magno,parvo and koniocellular visual pathways by means of a multichannel perimeter.Visual acuity and intraocular pressure(IOP)were within the ranges of normality in both eyes.No abnormalities were detected in the fundoscopic examination and in the optical coherence tomography(OCT)exam.The results of the color vision examination were also within the ranges of normality.A signi¯cant decrease in the achromatic CSFs for right eye(RE)and left eye(LE)was detected for all spatial frequencies.The statistical global values provided by the multichannel perimeter confirms that there were significant absolute sensitivity losses compared to the normal pattern in RE.In the LE,only a statistically significant decrease in sensitivity was detected for the blue-yellow(BY)channel.The pattern standard deviation(PSD)values obtained in our patient indicated that there were significant localized losses compared to the normality pattern in the achromatic channel of the RE and in the red-green(RG)channel of the LE.Some color vision alterations may be present in ET that cannot be detected with conventional color vision tests,such as the FM 100 Hue.

Predicting tremor improvement after MRgFUS thalamotomy in essential tremor from preoperative spontaneous brain activity:A machine learning approach

Magnetic resonance-guided focused ultrasound surgery(MRgFUS)thalamotomy is an emerging technique for medication-refractory essential tremor(ET),but with variable outcomes.This study used pattern regression analysis to identify brain signatures predictive of tremor improvements.Fifty-four ET patients(mean age=63.06 years,standard deviation(SD)=10.55 years,38 males)underwent unilateral MRg FUS thalamotomy and were scanned for resting-state functional magnetic resonance imaging(rsf MRI).Seventy-four healthy controls(mean age=58.09 years,SD=10.30 years,38 males)were recruited for comparison.Tremor responses at 12 months posttreatment were evaluated by the Clinical Rating Scale for Tremor.The fractional amplitude of low-frequency fluctuations(f ALFF)was calculated from rs-f MRI data.Two-sample t-test was used to generate a disease-specific mask,within which Multivariate Kernel Ridge Regression analyses were conducted.Predicted and actual clinical scores were compared using Pearson's correlation coefficient(r)and normalized mean squared error(Norm.MSE).Permutation test and leave-one-out strategy were applied for results validation.KRR identified f ALFF patterns that significantly predicted the hand tremor improvement(r=0.23,P=0.025;Norm.MSE=0.05,P=0.026)and the postural tremor improvement(r=0.28,P=0.025;Norm.MSE=0.06,P=0.023),but not action tremor improvement.Lobule VI of right cerebellum(Cerebelum_6_R),right superior occipital gyrus(Occipital_Sup_R)and lobule X of vermis(Vermis_10)contributed most for hand tremor prediction(normalized weights(NW):2.77%,2.40%,2.34%)while Vermis_10,left supplementary motor area(Supp_Motor_Area_L)and right hippocampus(Hippocampus_R)for postural tremor prediction(NW:2.69%,2.12%,2.05%).The low contributing NW of the individual brain regions suggested that the f ALFF pattern as a whole is an overall predicting feature.Preoperative f ALFF pattern predicts tremor benefits induced by MRg FUS thalamotomy.Clinical Trials.gov number:NCT04570046.

Essential tremor-Parkinson's disease syndrome: clinical characteristics and subtypes using cluster analysis

Background: Essential tremor (ET) and Parkinson’s disease (PD) are common movement disorders. ET-PD syndrome is characterized by the occurrence of PD in patients with a previous history of ET, which may be an independent phenotype distinct from PD. This study aims to identify clinical characteristics and subtypes in ET-PD. Methods: A total of 93 newly diagnosed ET-PD patients and 93 newly diagnosed PD patients matched for age, sex, education, and disease duration of PD were selected using propensity score matching analysis. The K-means cluster analysis was performed for 11 variables derived from the ET-PD group, and cluster profiles were established through statistical analysis of demographic and clinical variables. Results: The ET-PD group consisted of a high number of patients with a family history of ET exhibiting evident tremor with milder hypokinesia and postural instability symptoms, as compared to the PD group. Through the cluster analysis, two clusters of ET-PD patients were identified. The ET-PD cluster 1 ( n = 34) had a shorter ET duration before PD onset, lower number of patients with a family history of ET, higher unified PD rating scale instability scores, higher non-motor symptoms scores (non-motor symptoms scale D1 scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and PD sleep scale-2 scores), and higher Chinese version of the PD questionnaire-39 scores relative to the ET-PD cluster 2 ( n = 59). Conclusion: ET-PD patients had significantly different characteristics for motor symptoms as compared to PD patients, and may be distinctly divided into two clinical subtypes, namely, the ET-PD complex type and the ET-PD simple type.

Supplementation with high-GABA-producing Lactobacillus plantarum L5 ameliorates essential tremor triggered by decreased gut bacteria-derived GABA

Background Theγ-aminobutyric acid(GABA)hypothesis posits a role of GABA deficiency in the central nervous system in the pathogenesis and progression of essential tremor(ET).However,the specific causative factor for GABA deficiency is not clear.The gut microbiota in mammals has recently been considered as a significant source of GABA.Furthermore,the GABA-based signals originating from the intestine can be transmitted to the brain through the“enteric nervous system-vagus nerve-brain”axis.However,the plausible contribution of gut microbiota to ET seems inspiring but remains obscure.Methods Fecal samples from patients with ET and healthy controls were examined by metagenomic sequencing to compare the composition of gut microbiota and the expression of genes involved in GABA biosynthesis.The impact of gut microbiota on ET was explored through transplantation of fecal microbiota from patients with ET into the murine ET model.Lactic acid bacteria producing high amounts of GABA were identified through whole-genome sequencing and ultra-performance liquid chromatography-tandem mass spectrometry.Subsequently,mice were treated with the high-GABA-producing strain Lactobacillus plantarum L5.Tremor severity,behavioral tests,pro-inflammatory cytokines,GABA concentration,and gut microbiota composition were examined in these mice.Results The gut microbiota of patients with ET demonstrated an impaired GABA-producing capacity and a reduced fecal GABA concentration.Transplantation of the gut microbiota from patients with ET induced an extension of tremor duration and impaired mobility in the murine model of ET.L5 exhibited an augmented GABA-producing capacity,with the De Man-Rogosa-Sharpe culture broth containing 262 mg/l of GABA.In addition,administration of L5 significantly decreased the tremor severity and enhanced the movement capability and grasping ability of ET mice.In vivo mechanistic experiments indicated that L5 reshaped the gut microbial composition,supplemented the mucosa-associated microbiota with GABA-producing capacity,increased the GABA concentrations in the cerebellum,and diminished inflammation in the central nervous system.Conclusions These findings highlight that deficiency of GABA-producing gut microbes plays an essential role in the pathogenesis of ET and that L5 is a promising candidate for treating ET.

Neuronal firing in the ventrolateral thalamus of patients with Parkinson＇s disease differs from that with essential tremor

Background Although thalamotomy could dramatically improve both parkinsonian resting tremor and essential tremor （ET）, the mechanisms are obviously different. This study aimed to investigate the neuronal activities in the ventrolateral thalamus of Parkinson＇s disease （PD） and ET. Methods Thirty-six patients （PD： 20, ET： 16） were studied. Microelectrode recordings in the ventral oral posterior （Vop）and the ventral intermediate nucleus （Vim） of thalamus was performed on these patients who underwent thalamotomy.Electromyography （EMG） was recorded simultaneously on the contralateral limbs to surgery. Single unit analysis and the interspike intervals （ISIs） were measured for each neuronal type. ISI histogram and auto-correlograms were constructed to estimate the pattern of neuronal firing. Mann-Whitney test and Kruskal-Wallis （K-W） test were used to compare the mean spontaneous firing rate （MSFR） of neurons of PD and ET patients. Results Three hundred and twenty-three neurons were obtained from 20 PD trajectories, including 151 （46.7%） tremor related neuronal activity, 74 neurons （22.9%） with tonic firing, and 98 （30.4%） neurons with irregular discharge. One hundred and eighty-seven neurons were identified from 16 ET trajectories including 46 （24.6%） tremor-related neuronal activity, 77 （41.2%） neurons with tonic firing, and 64 neurons （34.2%） with irregular discharge. The analysis of MSFR of neurons with tonic firing was 26.7 （3.4-68.3） Hz （n=74） and that of neurons with irregular discharge （n=98） was 13.9 （3.0-58.1） Hz in PD; whereas MSFR of neurons with tonic firing （n=77） was 48.8 （19.0-135.5） Hz and that of neurons with irregular discharge （n=64） was 26.3 （8.7-84.7） Hz in ET. There were significant differences in the MSFR of two types of neuron for PD and ET （K-W test, both P〈0.05）. Significant differences in the MSFR of neuron were also obtained from Vop and Vim of PD and ET （16.3 Hz vs. 34.8 Hz, 28.0 Hz vs. 49.9 Hz） （K-W test, both P 〈0.05）, respectively. Conclusion In consistent with recent findings, the decreased MSFR of neurons observed in the Vop is likely to be involved in PD whereas the increased MSFR of neurons seen in the Vim may be a cause of ET.

Essential tremor： treatment with deep brain stimulation of the ventral intermediate nucleus of the thalamus

Essential tremor （ET） is one of the most common neurological degenerative disorders. Increased evidences indicated that ET is a hereditary of disease. Furthermore, this age-related, progressive disorder is thought to be associated with neuronal loss.1 It has been reported that the sensitivity and specificity of family history given by ET patients are 43.3% and 94.4%,

Deep brain stimulation of the subthalamic nucleus for essential tremor

Essential tremor （ET）, characterized by a postural and/or kinetic tremor and primarily manifested in theupper extremities, head, and other parts of the body, is one of the most common neurological disorders.1 The traditional target for the neurosurgical treatment of ET, the ventral intermedius nucleus （Vim） of the thalamus, has confirmed that chronic deep brain stimulation （DBS1 is an effective, standard, and primary procedure for ET. However, the loss of tremor suppression due to tolerance of chronic Vim stimulation, accompanied by other adverse effects, such as paresthesias, dysarthria, dysequilibrium, hyperhidrosis, and localized pain, has necessitated changes in the stimulation target in some patients.

DNA methylome study of human cerebellar tissues identified genes and pathways possibly involved in essential tremor

Background:Essential tremor(ET)is a neurological syndrome of unknown origin with poorly understood etiology and pathogenesis.It is suggested that the cerebellum and its tracts may be involved in the pathophysiology of ET.DNA methylome interrogation of cerebellar tissue may help shine some light on the understanding of the mechanism of the development of ET.Our study used postmortem human cerebellum tissue samples collected from 12 ET patients and 11 matched non-ET controls for DNA methylome study to identify differentially methylated genes in ET.Results:Using Nugen’s Ovation reduced representation bisulfite sequencing(RRBS),we identified 753 genes encompassing 938 CpG sites with significant differences in DNA methylation between the ET and the control group.Identified genes were further analyzed with Ingenuity Pathway Analysis(IPA)by which we identified certain significant pathways,upstream regulators,diseases and functions,and networks associated with ET.Conclusions:Our study provides evidence that there are significant differences in DNA methylation patterns between the ET and control samples,suggesting that the methylation alteration of certain genes in the cerebellum may be associated with ET pathogenesis.The identified genes allude to the GABAergic hypothesis which supports the notation that ET is a neurodegenerative disease,particularly involving the cerebellum.

4D printing of soft orthoses for tremor suppression

Tremor is an involuntary and oscillatory movement disorder that makes daily activities difficult for affected patients. Hand tremor-suppression orthoses are noninvasive, wearable devices designed to mitigate tremors. Various studies have shown that these devices are effective, economical, and safe;however, they have drawbacks such as large weight, awkward shape, and rigid parts. This study investigates different types of tremor-suppression orthoses and discusses their efficiency, mechanism,benefits, and disadvantages. First, various orthoses(with passive, semi-active, and active mechanisms) are described in detail.Next, we look at how additive manufacturing(AM) has progressed recently in making sensors and actuators for application in tremor orthoses. Then, the materials used in AM are further analyzed. It is found that traditional manufacturing problems can be solved with the help of AM techniques, like making orthoses that are affordable, lighter, and more customizable. Another concept being discussed is using smart materials and AM methods, such as four-dimensional(4D) printing, to make orthoses that are more comfortable and efficient.

Molecular imaging of movement disorders

Positron emission tomography measures the activity of radioactively labeled compounds which distribute and accumulate in central nervous system regions in proportion to their metabolic rate or blood flow. Specific circuits such as the dopaminergic nigrostriatal projection can be studied with ligands that bind to the pre-synaptic dopamine transporter or post-synaptic dopamine receptors (D1 and D2). Single photon emission computerized tomography (SPECT) measures the activity of similar tracers labeled with heavy radioactive species such as technetium and iodine. In essential tremor, there is cerebellar hypermetabolism and abnormal GABAergic function in premotor cortices, dentate nuclei and ventral thalami, without significant abnormalities in dopaminergic transmission. In Huntington’s disease, there is hypometabolism in the striatum, frontal and temporal cortices. Disease progression is accompanied by reduction in striatal D1 and D2 binding that correlates with trinucleotide repeat length, disease duration and severity. In dystonia, there is hypermetabolism in the basal ganglia, supplementary motor areas and cerebellum at rest. Thalamic and cerebellar hypermetabolism is seen during dystonic movements, which can be modulated by globus pallidus deep brain stimulation (DBS). Additionally, GABA-A receptor activity is reduced in motor, premotor and somatosensory cortices. In Tourette’s syndrome, there is hypermetabolism in premotor and sensorimotor cortices, as well as hypometabolism in the striatum, thalamus and limbic regions at rest. During tics, multiple areas related to cognitive, sensory and motor functions become hypermetabolic. Also, there is abnormal serotoninergic transmission in prefrontal cortices and bilateral thalami, as well as hyperactivity in the striatal dopaminergic system which can be modulated with thalamic DBS. In Parkinson’s disease (PD), there is asymmetric progressive decline in striatal dopaminergic tracer accumulation, which follows a caudal-to-rostral direction. Uptake declines prior to symptom presentation and progresses from contralateral to the most symptomatic side to bilateral, correlating with symptom severity. In progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), striatal activity is symmetrically and diffusely decreased. The caudal-to-rostral pattern is lost in PSP, but could be present in MSA. In corticobasal degeneration (CBD), there is asymmetric, diffuse reduction of striatal activity, contralateral to the most symptomatic side. Additionally, there is hypometabolism in contralateral parieto-occipital and frontal cortices in PD; bilateral putamen and cerebellum in MSA; caudate, thalamus, midbrain, mesial frontal and prefrontal cortices in PSP; and contralateral cortices in CBD. Finally, cardiac sympathetic SPECT signal is decreased in PD. The capacity of molecular imaging to provide in vivo time courses of gene expression, protein synthesis, receptor and transporter binding, could facilitate the development and evaluation of novel medical, surgical and genetic therapies in movement disorders.

Magnetic resonance imaging-guided focused ultrasound thalamotomy launch with remote telemedicine international proctorship

Background: COVID-19 limitations have hindered the implementation of new technologies by preventing proctors from coming to the site.We share our first experience of magnetic resonance imaging(MRI)-guided focused ultrasound(MRgFUS)treatment with an international remote online proctorship,and develop and evaluate the methodology of remote MRgFUS proctorship.Methods: This single-center,nonrandomized controlled prospective study included 94 patients:27 with essential tremor(ET)and 67 with tremor-dominant Parkinson's disease(PD).The coming of proctors was impossible,so we arranged for the remote participation of proctors from the United Kingdom,Spain,and Israel.A total of 38 patients(40.4%)received telemedicine-proctored treatment(proctor group)and 56 received their treatment independently(solo group).We used the Clinical Rating Scale for Tremor(CRST)for ET patients and the Unified Parkinson's Disease Rating Scale(UPDRS)Part III for PD patients.Results: In patients with ET,success rates were 81.8%(proctor group)and 100%(solo group)(p=0.22).CRST reduction on the treated side was 71.43%[65.83%;80.56%](proctor group)versus 60.87%[53.99;79.58](solo group)(p=0.19).None of the patients showed worsening of tremors within 1 year.In patients with PD,the success rates were 92.6%(proctor group)and 100%(solo group)(p=0.08).The UPDRS Part III improvement was 30.1%(proctor group)versus 39.9%(solo group)(p=0.003).The 1-year recurrence rate was 40%(proctor group)and 17.5%(solo group)(p=0.04).No complications were observed at 6 months.Conclusions: We developed a feasible and safe methodology for telemedicine remote online-proctored MRgFUS treatment.No significant difference was observed between the solo and developed remote proctor protocols in terms of complication rate,effect,and long-term results;however,UPDRS Part III improvement was better in the PD solo group.This study demonstrated that the MRgFUS international proctorship can be performed successfully remotely.

Rest tremor revisited:Parkinson’s disease and other disorders

Tremor is the most common movement disorder characterized by a rhythmical,involuntary oscillatory movement of a body part.Since distinct diseases can cause similar tremor manifestations and vice-versa,it is challenging tomake an accurate diagnosis.This applies particularly for tremor at rest.This entity was only rarely studied in the past,although a multitude of clinical studies on prevalence and clinical features of tremor in Parkinson’s disease(PD),essential tremor and dystonia,have been carried out.Monosymptomatic rest tremor has been further separated from tremor-dominated PD.Rest tremor is also found in dystonic tremor,essential tremor with a rest component,Holmes tremor and a few even rarer conditions.Dopamine transporter imaging and several electrophysiological methods provide additional clues for tremor differential diagnosis.New evidence from neuroimaging and electrophysiological studies has broadened our knowledge on the pathophysiology of Parkinsonian and non-Parkinsonian tremor.Large cohort studies are warranted in future to explore the nature course and biological basis of tremor in common tremor related disorders.

Implication of the LINGO2 gene in the predisposition to movement disorders

Previous reports on the pathogenesis of age-related movement disorders,such as Parkinson’s disease(PD)and essential tremor(ET),have demonstrated the potential implications of LINGO1(leucine-rich repeat and immunoglobulin domain-containing protein)gene.Although LINGO2 has a high degree of homology with LINGO1,but it is less characterized and the role of LINGO2 in the development of PD/ET remains unreported.Hence,this metaanalysis was conducted to evaluate the role of LINGO2 in PD/ET pathogenesis.A total of 4 studies,which complied with the Hardy-Weinberg equilibrium,were included in the meta-analysis.Analysis of the pooled odds ratio and confidence interval of the studies were performed for five genetic models,namely:allelic,dominant,recessive,homozygous,and heterozygous.No significant association was observed between the LINGO2 polymorphism and PD/ET,although subgroup analysis through conventional metaanalysis indicated that the recessive models of rs7033345 and rs10812774 are significantly associated with predisposition to ET in the Asian population.However,trial sequential analyses for both polymorphisms were unlikely to reveal any robust effect.Hence,studies with larger samples on this association are needed in the future to corroborate our results.