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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.

Background and Objectives Transcranial sonography (TCS)‐detected substantia nigra hyperechogenicity (SN+) is a potential biomarker for Parkinson's disease (PD). While SN+ may indicate PD risk in essential tremor (ET), longitudinal undetermined tremor (UT) data are lacking; insufficient cross‐cohort validation hinders clinical translation. This study aimed to evaluate the predictive efficacy of SN+ for 8‐year PD risk and its subtype‐specific differences in ET/UT populations. Methods 180 patients with tremors who underwent TCS were enrolled and categorized based on the tremor type (ET/UT) and SN echogenicity grade (SN+/SN−). 127 patients (59 with ET, 68 with UT) completed a mean follow‐up period of 8.01 years (range: 7.41–8.67; median: 7.92), during which new‐onset PD was documented. Results In the ET cohort, 52.4% of SN+ individuals developed PD, compared to 7.9% in the SN− group. For UT, the PD incidence was 91.2% in SN+ individuals and 50.0% in SN− individuals. Multivariable‐adjusted Firth logistic regression revealed significant associations between SN+ and PD in the ET and UT groups. Moreover, Bayesian logistic regression confirmed SN+ was significantly associated with PD risk in both groups. The posterior probability of an odds ratio exceeding 5 for SN+ was greater than 80% in both cohorts. Subgroup interaction analysis demonstrated no evidence of effect modification by tremor subtype, indicating consistent SN+ effects across cohorts. Conclusions TCS‐detected SN+ is a predictor of PD progression over 8 years in both ET and UT cohorts. The consistent risk association across tremor subtypes in SN+ subgroups supports its clinical potential as a cross‐tremor subtype biomarker. Substantia Nigra Hyperechogenicity Predicts Parkinson's Disease Risk in Tremor Patients: Dual‐Cohort 8‐Year Evidence with Bayesian Validation.

Tremor occurs in various forms across diverse neurological disorders, including Parkinson’s disease and essential tremor. While clinically heterogeneous, converging evidence suggests a shared brain network may underlie tremor across conditions. Here, we empirically define such a network using four modalities: lesion locations, atrophy patterns, EMG-fMRI, and deep brain stimulation outcomes. We show that network connectivity robustly explains clinical outcomes in independent cohorts undergoing deep brain stimulation of the subthalamic nucleus for Parkinson’s disease and the ventral intermediate nucleus for essential tremor. Maps from each cohort accounted for outcomes in the respective other, supporting a disorder-independent tremor network. A multimodal agreement map revealed consistent substrates in the primary motor cortex and motor cerebellum. To validate the network, we test its predictive power in a third, independent cohort treated with pallidal stimulation for Parkinson’s disease. Our findings define a robust, cross-condition tremor network that may guide both invasive and noninvasive neuromodulation strategies. Goede et al. combined multiple modalities to define a common tremor network across disorders. This finding may help optimize deep brain stimulation and guide future noninvasive therapies.

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

Essential tremor (ET) is a common movement disorder affecting millions of people. Studies of ET patients and perturbations in animal models have provided a foundation for the neural networks involved in its pathophysiology. However, ET encompasses a wide variability of phenotypic expression, and this may be the consequence of dysfunction in distinct subcircuits in the brain. The cerebello-thalamo-cortical circuit is a common substrate for the multiple subtypes of action tremor. Within the cerebellum, three sets of cerebellar cortex-deep cerebellar nuclei connections are important for tremor. The lateral hemispheres and dentate nuclei may be involved in intention, postural and isometric tremor. The intermediate zone and interposed nuclei could be involved in intention tremor. The vermis and fastigial nuclei could be involved in head and proximal upper extremity tremor. Studying distinct cerebellar circuitry will provide important framework for understanding the clinical heterogeneity of ET.

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.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

Rhythmicity is an important feature of tremor that is widely viewed as having diagnostic significance. We hypothesized that rhythmicity might be a generic function of tremor severity, reflecting greater oscillatory entrainment of motor pathways. Postural hand tremor and forearm electromyograms were recorded from 49 controls, 78 Parkinson patients, and 133 essential tremor patients. Rhythmicity was quantified in terms of approximate entropy and three measures of cycle-to-cycle frequency variability: tremor stability index, cycle-to-cycle variability, and power spectral bandwidth. Physiological tremor was less rhythmic than Parkinson tremor and essential tremor, but the two pathological tremors did not differ significantly. Hand tremor amplitude and forearm electromyogram-hand tremor coherence were moderate statistical predictors of rhythmicity in both pathological tremors. Adding a 1-kg weight to the hand had little effect on the rhythmicity metrics, except for a moderate reduction in the approximate entropy of physiological tremor. We conclude that these four rhythmicity metrics are not helpful in distinguishing postural tremors in Parkinson disease and essential tremor. The moderate correlations of rhythmicity with tremor amplitude and electromyogram coherence suggest that rhythmicity of pathological tremors is largely a generic reflection of oscillatory neuronal entrainment. Comparisons of tremor rhythmicity in pathological conditions must control for tremor amplitude and electromyogram coherence.

The aim of this study was to assess the effects of novel stimulation algorithms of deep brain stimulation (short pulse and directional stimulation) in the ventrointermediate thalamus and posterior subthalamic area (VIM/PSA-DBS) on tremor in Parkinson’s disease (PD) and to compare the effects with those in essential tremor (ET). We recruited six PD patients (70.8 ± 10.4 years) and seven ET patients (64.4 ± 9.9 years) with implanted VIM/PSA-DBS in a stable treatment condition (> 3 months postoperatively). Tremor severity and ataxia were assessed in four different stimulation conditions in a randomized order: DBS switched off (STIM OFF), omnidirectional stimulation with 60 µs (oDBS60), omnidirectional stimulation with 30 µs (oDBS30), directional stimulation at the best segment with 60 µs (dDBS60). In both patient groups, all three DBS stimulation modes reduced the total tremor score compared to STIM OFF, whereas stimulation-induced ataxia was reduced by oDBS30 and partially by dDBS60 compared to oDBS60. Tremor reduction was more pronounced in PD than in ET due to a limited DBS effect on intention and action-specific drawing tremor in ET. In PD and ET tremor, short pulse or directional VIM/PSA-DBS is an effective and well tolerated therapeutic option. Trial registration: The study was registered in the DRKS (ID DRKS00025329, 18.05.2021, German Clinical Trials Register, DRKS—Deutsches Register Klinischer Studien).

Background Distinguishing between essential tremor (ET) and tremor‐dominant Parkinson's disease (PD‐TD) can be challenging due to overlapping motor symptoms. This study aims to investigate the differences in nonmotor symptoms (NMS) between ET and PD‐TD patients to provide additional evidence for differentiating these two conditions. Methods This retrospective study included 1656 participants, comprising 558 PD‐TD patients, 584 ET patients, and 514 controls. ET patients were assessed using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), while PD‐TD patients were evaluated based on the Unified Parkinson's Disease Rating Scale (UPDRS). All participants were assessed for NMS using the Nonmotor Symptoms Scale (NMSS). Results The composite NMSS score for the PD‐TD group was significantly higher than that for the ET group and the control group (23.44 ± 20.20 vs. 12.60 ± 14.89 vs. 9.37 ± 12.44, p < 0.001). Compared to ET patients, PD‐TD patients had an increased risk of all NMS, especially in hyposmia (OR = 7.70, 95% CI: 5.11–11.62). The NMSS score, urinary symptoms, and hyposmia may play a role in differentiating ET from PD‐TD. The area under the curve (AUC) is 0.766 (95% CI: 0.739–0.793), with a sensitivity of 80.8% and specificity of 58.6%. When family history is included in the analysis, the AUC increases to 0.819 (95% CI: 0.795–0.843), with sensitivity improving to 82.4% and specificity to 68.2%. Conclusions The study reveals significant differences in NMS between ET and PD‐TD. Compared to patients with ET, those with PD‐TD exhibit more frequent and severe NMS. NMS and family history are helpful in differentiating between ET and PD‐TD. This study highlights significantly higher nonmotor symptoms (NMS) in tremor‐dominant Parkinson's disease (PD‐TD) compared to essential tremor (ET), particularly hyposmia (OR = 7.70, 95% CI: 5.11–11.62). NMSS scores, urinary symptoms, and hyposmia may help distinguish PD‐TD from ET. The area under the curve (AUC) is 0.766 (95% CI: 0.739–0.793), with 80.8% sensitivity and 58.6% specificity. Including family history improves the AUC to 0.819 (95% CI: 0.795–0.843), with sensitivity at 82.4% and specificity at 68.2%.