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Abstract BACKGROUND Several feasibility studies and a randomized, controlled, multicenter trial have demonstrated the safety and efficacy of unilateral transcranial magnetic resonance-guided focused ultrasound (FUS) lesioning of the ventral intermediate thalamic nucleus in treating essential tremor. OBJECTIVE To evaluate the safety and efficacy of FUS thalamotomy in a Japanese patient cohort through a prospective, multicenter, single-arm confirmatory trial. METHODS A total of 35 patients with disabling refractory essential tremor underwent unilateral FUS thalamotomy and were followed up for 12 post-treatment months. Safety was measured as the incidence and severity of treatment-related adverse events. Efficacy was measured as the tremor severity and quality of life improvements using the Clinical Rating Scale for Tremor and Questionnaire for Essential Tremor. RESULTS The mean skull density ratio (SDR) was 0.47. There was a significant decrease in the mean postural tremor score of the treated hand from baseline to 12 mo by 56.4% (95% CI: 46.7%-66.1%; P < .001), which was maintained at last follow-up. Quality of life improved by 46.3% (mean overall Questionnaire for Essential Tremor score of 17.4 [95% CI: 12.1-22.7]) and there were no severe adverse events. The most frequent adverse event was gait disturbance and all events resolved. CONCLUSION Unilateral FUS thalamotomy allowed significant and sustained tremor relief and improved the quality of life with an outstanding safety profile. The observed safety and efficacy of FUS thalamotomy were comparable to those reported in a previous multicenter study with a low SDR, and inclusion of the low SDR group did not affect effectiveness. Graphical Abstract Graphical Abstract

In this randomized, sham-controlled trial, MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor who had not had a response to medication. Adverse effects of the procedure included sensory deficits and gait disturbances. Essential tremor, the most common movement disorder, 1 is characterized by a distinctive postural and intention tremor typically affecting the hands more than the legs, trunk, head, or voice. 2 , 3 Essential tremor does not shorten life expectancy, but it can affect quality of life, functional activities, mood, and socialization. 4 – 6 Class I evidence exists for propranolol and primidone as first-line medications that reduce tremor by approximately 60% in 50% of patients. 7 – 11 If resistance to medications develops or side effects are unacceptable, neurosurgical intervention is considered, primarily targeting the nucleus ventralis intermedius of the thalamus, a component of tremor circuitry that . . .

Injection of botulinum toxin into each splenius capitis muscle at baseline and week 12 was more effective than placebo in reducing the severity of essential head tremor over 18 weeks. Effects waned at 24 weeks.

The 2018 Movement Disorder Society classification introduced essential tremor plus (ETP) as a category for patients with essential tremor (ET) accompanied by additional features of uncertain significance. While earlier studies have characterized clinical features of ETP, the factors that characterize the phenotypic expression of ETP remain unclear. We prospectively evaluated 70 consecutive patients with ET or ETP. Clinical and neurophysiological assessments included tremor severity (Clinical Rating Scale for Tremor, CRST), cognitive functions (Addenbrooke’s Cognitive Examination Revised, ACE-R), and accelerometric analysis. Statistical analyses examined between-group differences and factors influencing tremor characteristics. The prevalence of ETP (61%) exceeded that of ET. Among ETP patients, 77% exhibited two or more additional motor and/or cognitive features. Compared to ET patients, ETP patients demonstrated significantly higher tremor severity, lower tremor frequency, older age at assessment and onset, and poorer cognitive function, despite comparable disease duration. The accelerometric analysis revealed similar tremor patterns in both groups with quantitative differences in tremor amplitude and frequency. The propensity score matching and multiple regression analyses suggested that tremor severity and frequency are more influenced by age than by disease duration or diagnostic classification of ET/ETP. ACE-R score and the presence of resting tremor were also significant predictors of tremor severity. ETP represents a heterogeneous population with diverse neurological features, and age is likely a key determinant of severity and phenotypic expression. Comprehensive analysis is needed to identify other factors that may determine phenotype and treatment responsiveness.

Essential tremor is one of the most common tremor syndromes. According to the recent tremor classification, tremor as a symptom is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: axis 1—defining syndromes based on the clinical features such as historical features, tremor characteristics, associated signs, and laboratory tests; and axis 2—classifying the etiology (Bhatia et al., Mov Disord 33:75–87, 2018). The management of this condition has two major approaches. The first is to exclude treatable etiologies, as particularly during the onset of this condition the presentation of a variety of etiologies can be with monosymptomatic tremor. Once the few etiologies with causal treatments are excluded, all further treatment is symptomatic. Shared decision-making with enabling the patient to knowledgeably choose treatment options is needed to customize the management. Mild to moderate tremor severity can sometimes be controlled with occupational treatment, speech therapy of psychotherapy, or adaptation of coping strategy. First-line pharmacological treatments include symptomatic treatment with propranolol, primidone, and topiramate. Botulinum toxin is for selected cases. Invasive treatments for essential tremor should be considered for severe tremors. They are generally accepted as the most powerful interventions and provide not only improvement of tremor but also a significant improvement of life quality. The current standard is deep brain stimulation (DBS) of the thalamic and subthalamic region. Focused ultrasound thalamotomy is a new therapy attracting increasing interest. Radiofrequency lesioning is only rarely done if DBS or focused ultrasound is not possible. Radiosurgery is not well established. We present our treatment algorithm.

Introduction Essential tremor (ET) is the most common movement disorder among adults. Although ET has been recognized as a mono-symptomatic benign illness, reports of non-motor symptoms and non-tremor motor symptoms have increased its clinical heterogeneity. The neural correlates of ET are not clearly understood. The aim of this study was to understand the neurobiology of ET using resting state fMRI. Methods Resting state functional MR images of 30 patients with ET and 30 age- and gender-matched healthy controls were obtained. The functional connectivity of the two groups was compared using whole-brain seed-to-voxel-based analysis. Results The ET group had decreased connectivity of several cortical regions especially of the primary motor cortex and the primary somatosensory cortex with several right cerebellar lobules compared to the controls. The thalamus on both hemispheres had increased connectivity with multiple posterior cerebellar lobules and vermis. Connectivity of several right cerebellar seeds with the cortical and thalamic seeds had significant correlation with an overall score of Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) as well as the subscores for head tremor and limb tremor. Conclusion Seed-to-voxel resting state connectivity analysis revealed significant alterations in the cerebello-thalamo-cortical network in patients with ET. These alterations correlated with the overall FTM scores as well as the subscores for limb tremor and head tremor in patients with ET. These results further support the previous evidence of cerebellar pathology in ET.

The impact of Magnetic Resonance Imaging-guided Focused Ultrasound (MRgFUS) on vocal tremor is largely underexplored. We used artificial intelligence to investigate changes in vocal tremor in ET patients undergoing MRgFUS. Eighty-three controls and ET patients (mean age-SEM 70.0–1.0 years), including 39 patients without and 44 patients with clinically overt voice tremor, were assessed before and 24 h after MRgFUS targeting the ventral intermediate nucleus (Vim). Voice recordings were collected to calculate the receiver operating characteristic (ROC) curves, the likelihood ratios (LRs) for clinical-instrumental correlations, and the oscillatory activity peak by means of artificial intelligence algorithms. We found that before and after Vim-MRgFUS, artificial intelligence discriminated voices in ET and controls objectively with high accuracy. Also, we verified that Vim-MRgFUS improved voice tremor in ET. Moreover, the analysis showed positive correlations between LRs and clinical scores of voice tremor. Lastly, Vim-MRgFUS reduced the 4–6 Hz oscillatory activity peak in ET patients. Therefore, our observations pave the way for objective voice evaluations in ET patients following Vim-MRgFUS, for telemedicine purposes.

Background Essential tremor (ET) is a common movement disorder characterized by heterogeneous features, though the rate and pattern of worsening are variable. Longitudinal data combining clinical and objective motor measures remain limited, resulting in uncertainty regarding trajectories and predictors of progression in ET. Methods Twenty‐two patients from a previously established ET/ET‐plus cohort underwent a third clinical and kinematic evaluation almost seven years after baseline. Kinematic analysis assessed postural, kinetic, rest tremor, and finger‐tapping performance. Longitudinal changes were evaluated using non‐parametric statistics and linear mixed‐effects models adjusting for clinical covariates. Results Over time, tremor worsened overall. Kinematic measures indicated a selective increase in kinetic tremor severity, while rest and postural tremor amplitude remained stable. Clinically, tremor spread to a greater number of body regions. Soft neurological signs increased over time and were associated with greater tremor spread. Cognitive performance showed only a mild decline, partly related to age and affective symptoms. Higher baseline tremor severity was associated with greater worsening of kinetic tremor, and lower baseline cognitive scores with changes in postural tremor. Conclusions ET progression is heterogeneous and often non‐linear. Kinematic measures were particularly sensitive in capturing worsening of kinetic tremor, the most disabling clinical feature. The accumulation of soft neurological signs and their association with tremor spread support the notion of ET‐plus as a more advanced disease stage with broader cerebral involvement. Independent of disease progression, there were strong aging‐related effects. Future multimodal longitudinal studies may clarify how aging interacts with disease trajectories in essential tremor. Long‐term follow‐up (almost 7 years) of an ET/ET‐plus cohort (n = 22) shows heterogeneous and partly non‐linear progression, with a contribution of aging to disease burden. Tremor spreads anatomically over time, with selective worsening of kinetic tremor and increasing burden of soft neurological signs. Quantitative kinematic assessment complements clinical evaluation, enabling sensitive characterization of disease trajectories.

Peripheral nerve stimulation (PNS) demonstrates promise for some neurological conditions. However, its effectiveness for essential tremor (ET) requires further research. In this randomized, double-blind, sham-controlled trial, we investigated the safety and efficacy of a single, 40-minute PNS session in ET. Eighty-eight participants (age: 63.5 [52.5, 70.3], male: 57.95%) were assigned to active PNS stimulation ( n  = 45) or sham procedure ( n  = 43). Efficacy was assessed using accelerometer-measured tremor amplitude (m/s²), clinician-rated tremor severity using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), patients’ own experience with daily activities using the Bain and Findley Activities of Daily Living scale (BF-ADL), and their perceived improvement based on the Clinical Global Impression-Improvement scale (CGI-I). Assessments were conducted at baseline, immediately post-stimulation, and at multiple intervals up to 90 min (extending to 24 h for subjective outcomes). Temporal changes in outcomes over time were evaluated using the Generalized Estimating Equation (GEE). The effects of group, time, and their interaction (group*time) on the outcomes were subsequently assessed using GEE. GEE analyses revealed significant group*time interaction for tremor amplitude (B = − 51.61, 95%CI [− 94.60, − 8.62], p  = 0.019). However, no significant group*time interactions were observed for TETRAS, BF-ADL, and CGI-I. This study indicated the effect of PNS on reducing ET amplitude. ID: IRCT20161212031362N2.

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained shortly after the end of the stimulation and can be phenomenologically predicted. Finally, we use feature-based statistical-learning and neurophysiological-modelling to show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop, thus establishing its causal role. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may in the future represent a powerful neuromodulatory strategy to treat brain disorders. Aberrant synchronous oscillations have been associated with numerous brain disorders, including essential tremor. The authors show that synchronous cerebellar activity can casually affect essential tremor and that its underlying mechanism may be related to the temporal coherence of the tremulous movement.