Closed-loop deep brain stimulation for essential tremor based on thalamic local field potentials

Nonlinear interactions in the thalamocortical loop in essential tremor: A model-based frequency domain analysis

BackgroundThe vagus nerve (VN), the principal component of the parasympathetic branch of the autonomic nervous system (ANS), mediates bidirec communication between the central nervous system (CNS) and peripheral organs. Vagus nerve stimulation (VNS), delivered through invasive (iVNS) or non‐invasive (transcutaneous cervical [tcVNS] and transcutaneous auricular [taVNS]), exerts multimodal effects on multiple circuits and neurotransmitters, and is currently under investigation in movement disorders.ObjectivesThis systematic review evaluates the therapeutic potential of VNS in movement disorders (MDs), with a focus on Parkinson's disease (PD), parkinsonism, tremor and essential tremor (ET), cervical dystonia (CD), and Tourette's syndrome (TS).MethodsA systematic search of PubMed, Web of Science, and Scopus was conducted for studies published between 2020 and 2025, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 guidelines.ResultsThirty‐two studies met the inclusion criteria: 22 on PD or parkinsonism (14 clinical and 8 preclinical on PD, 1 clinical on multisystem atrophy), 6 on tremor and ET (4 clinical, 2 preclinical), 2 clinical studies on CD, and 1 clinical study on TS. Across conditions, VNS was reported to improve motor and non‐motor, enhance synaptic plasticity, modulate neurotransmitter activity relevant to MDs (GABA, norepinephrine, dopamine, and acetylcholine), and reduce neuroinflammation.ConclusionsCurrent evidence supports the multimodal effect of VNS in MDs, particularly in PD, where the most consistent benefits were observed. Non‐invasive taVNS represents a promising, safer alternative to iVNS. Larger randomized controlled trials with standardized protocols are needed to validate efficacy, optimize stimulation parameters, and determine long‐term clinical and biological impact. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate (VIM) nucleus stimulation for essential tremor activates the cortex at short latencies, and that this potential is related to the suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (seven brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event-related potential in the ipsilateral sensorimotor cortex, with peaks at discrete latencies beginning less than 1 ms after stimulus onset (mean latencies 0.9 ± 0.2, 5.6 ± 0.7, and 13.9 ± 1.4 ms, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (P < 0.0001, Levene's test), and R1 amplitude and frequency were both closely associated with tremor suppression (P < 0.0001, respectively). These findings demonstrate that effective VIM thalamic stimulation for essential tremor activates the cerebral cortex at approximately 1 ms after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that DBS may improve tremor by synchronizing the precise timing of discharges in nearby axons and, by extension, the distributed motor network to the stimulation frequency or one of its subharmonics.

Over the last three decades, measuring and modulating cerebellar activity and its connectivity with other brain regions has become an emerging research topic in clinical neuroscience. The most important connection is the cerebellothalamocortical pathway, which can be functionally interrogated using a paired‐pulse transcranial magnetic stimulation paradigm. Cerebellar brain inhibition reflects the magnitude of suppression of motor cortex excitability after stimulating the contralateral cerebellar hemisphere and therefore represents a neurophysiological marker of the integrity of the efferent cerebellar tract. Observations that cerebellar noninvasive stimulation techniques enhanced performance of certain motor and cognitive tasks in healthy individuals have inspired attempts to modulate cerebellar activity and connectivity in patients with cerebellar diseases in order to achieve clinical benefit. We here comprehensively explore the therapeutic potential of these techniques in two movement disorders characterized by prominent cerebellar involvement, namely the degenerative ataxias and essential tremor. The article aims to illustrate the (patho)physiological insights obtained from these studies and how these translate into clinical practice, where possible by addressing the association with cerebellar brain inhibition. Finally, possible explanations for some discordant interstudy findings, shortcomings in our current understanding, and recommendations for future research will be provided. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Essential Tremor (ET) is a common movement disorder that can be disabling. Initial treatment is in the form of medical therapies. Patients with medically refractory ET seek surgical intervention which include radiofrequency thalamotomy, deep brain stimulation, and radiosurgical thalamotomy. Radiosurgical thalamotomy is a minimally invasive surgical option which is especially valuable for elderly and high surgical risk patients. The purpose of this study was to retrospectively analyze the outcomes of stereotactic radiosurgery for patients suffering from medically refractory essential tremor. During a 19-year period (1996-2015), 73 patients underwent gamma knife thalamotomy for intractable essential tremor. A median central dose of 140 Gy (range, 130-150) was delivered to the nucleus ventralis intermedius through a single 4-mm isocenter. We used the Fahn-Tolosa-Marin clinical tremor rating scale to score tremor, handwriting, drawing, and ability to drink fluids. The median time to last follow-up was 28 months (range, 6-152). After gamma knife thalamotomy, 93.2% improved in tremor. Forty-four patients (60.3%) experienced tremor arrest or barely perceptible tremor. Eighteen patients (24.7%) noted tremor arrest and complete restoration of motor function. Tremor improvement was sustained at last follow-up in 96% of patients who experience tremor relief. Mean tremor score improved from 3.19 before to 1.27 after gamma knife thalamotomy (P < 0.0001). Mean handwriting score improved from 2.97 to 1.25 (P < 0.0001). Mean drawing score improved from 3.16 to 1.26 (P < 0.0001). Mean drinking score improved from 3.14 to 1.56 (P < 0.0001). Imaging follow-up showed three types of lesions: enhancing lesion, streaking along internal capsule on fluid-attenuated inversion recovery, and significant reactive changes. Three patients (4%) experienced temporary adverse radiation effects. Radiosurgery is a safe and valuable treatment option for medically refractory essential tremor, especially for the elderly or those with high surgical risk for DBS or radiofrequency thalamotomy. © 2017 International Parkinson and Movement Disorder Society.

For patients with essential tremor (ET) who have significant disability and in whom drug treatments no longer work, deep brain stimulation of the

Electrical stimulation of the thalamus dramatically reduces essential tremor (ET). It has been hypothesized that the cerebellum and inferior olive are involved in the generation of ET, and thalamic stimulation is presumed to dampen ET through interactions with cerebellar output to the thalamus. Evidence suggests that abnormal timing of agonist and antagonist muscle responses contribute to cerebellar tremor (CbT); however, this relationship has not been investigated for ET. The mechanisms of the tremor and improvement are unknown. To measure the effect of ventral intermediate thalamic stimulation in controlling the ET response to sudden stretch of an agonist muscle and to determine whether, in ET, the timing relationships between the initial agonist and antagonist electromyography (EMG) responses show abnormalities similar to those seen in CbT. The authors studied ET subjects (with implanted thalamic stimulators turned off and on) and normal controls as they responded to mechanical torque pulses given at the wrist joint. The wrist joint angle, wrist agonist, and antagonist EMG were recorded. Like CbT, patients with ET showed delayed onsets of antagonist EMG and excessive rebound. Thalamic stimulation reduced the tremor but did not alter the antagonist delay or the rebound. In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist-antagonist timing.

SAGE-324/BIIB124 is an investigational positive allosteric modulator of GABAA receptors. KINETIC (NCT04305275), a double-blind, randomized, placebo-controlled, phase 2 study, evaluated SAGE-324/BIIB124 in individuals with essential tremor (ET). Individuals aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 or placebo once daily for 28 days. The primary endpoint was change from baseline in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 (upper-limb tremor) at day 29 with SAGE-324/BIIB124 versus placebo. Between May 2020 and February 2021, 69 U.S. participants were randomly assigned to receive SAGE-324/BIIB124 (n = 34) or placebo (n = 35). There was a significant reduction from baseline in TETRAS-PS Item 4 at day 29 with SAGE-324/BIIB124 versus placebo (least squares mean [standard error]: -2.31 [0.401] vs. -1.24 [0.349], P = 0.0491). The most common treatment-emergent adverse events included somnolence, dizziness, fatigue, and balance disorder. These results support further development of SAGE-324/BIIB124 for potential ET treatment. © 2024 Sage Therapeutics, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

In 2016, the International Parkinson and Movement Disorder Society (MDS) Task Force for Genetic Nomenclature in Movement Disorders laid out a new proposal for naming genetically determined movement disorders. This proposal sought to address the difficulties arising from the practical usage of numbered loci (eg, DYT1, DYT2, DYT3, etc.) as names for disorders. The proposal incited commentary highlighting concerns of subjectivity, neglecting relevant non-movement features, and predicting the need for constant change as knowledge. An evaluation of the use of the nomenclature in the recent peer-reviewed literature revealed variable implementation across movement phenotypes. The nomenclature has strengths and weaknesses, which are discussed in this article. A consideration of opportunities for improvement is warranted, and weighing the options will be the task of the MDS Nomenclature in Genetic Movement Disorders Study Group. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A special issue on childhood-onset movement disorders.

Infection-related movement disorders (IRMD) represent an important group of secondary movement disorders whose prevalence, patterns, treatment and outcomes remain poorly understood. To survey members of the International Parkinson and Movement Disorder Society regarding prevailing practices in IRMD. A cross-sectional online survey was conducted. Of 95 responses received, 75 (78.9%) were from the Asia-Oceania (AO) region and were further analyzed. The highest number of responses was from India (67/75, 89.3%). The most frequent phenotypes included ataxia (64, 85.3%), chorea (49, 65.3%), myoclonus (55, 73.3%) and parkinsonism (43, 57.3%). Tuberculosis-related (61, 81.3%), subacute sclerosing panencephalitis (50, 66.7%), and dengue-related movement disorders (49, 65.3%) were most frequent. Variable outcomes were observed by 46 (61.3%) respondents and 66 (88%) indicated that up to 50% of patients experienced persistence of IRMD. This survey provides critical insights into prevailing practices in the field of IRMD from the AO region.

The genetic architecture of essential tremor (ET) remains incompletely understood. A key challenge is translating genome-wide association study (GWAS) loci into specific effector genes to elucidate disease mechanisms and develop targeted therapies. To implement a multistage computational framework to prioritize high-confidence candidate genes for ET and to assess these predictions against publicly available, patient-derived transcriptomic data. We employed a convergent evidence strategy to prioritize genes, integrating cross-tissue (UTMOST) and tissue-specific (FUSION) transcriptome-wide association studies (TWAS) with gene-based association tests (MAGMA). Prioritized genes were subjected to causal inference analyses (summary-data-based Mendelian randomization [SMR] and colocalization), co-expression network analysis (GeneMANIA), and pharmacogenomic analysis (DGIdb). We leveraged spatial transcriptomics to characterize gene expression patterns across cortical layers and cell types. Finally, we validated computational predictions using two independent post-mortem brain datasets from ET patients and controls. Our prioritization pipeline identified 12 high-confidence candidate genes. Co-expression network analysis revealed 83.3% of candidates exhibit functional relationships, forming three modules centered on RNA processing (NRBP1), metabolic regulation (SLC5A6), and nucleotide synthesis (CAD). Pharmacogenomic analysis demonstrated 66.7% of candidates possess therapeutic target potential. Spatial transcriptomics revealed preferential expression in cortical Layer 5 pyramidal neurons. However, validation in post-mortem cerebellar tissue showed no significant differential expression. Our study provides a robust pipeline for ET gene prioritization and puts forward a novel cortical hypothesis for the disease. The discordance between strong computational predictions and their lack of validation in available patient tissue highlights a critical gap in the field. © 2025 International Parkinson and Movement Disorder Society.

The most common indication for movement disorder surgery is Parkinson's disease (PD), and the incidence of PD increases with age. The analysis reported here was undertaken with the primary goal of examining whether there is a relationship between peri-operative complications and age. The Nationwide Inpatient Sample (Agency for Healthcare Research and Quality, Rockville, MD, USA) was queried for 10 years beginning in 1999 for patients undergoing deep brain stimulator insertion, pallidotomy, and thalamotomy for treatment of PD, essential tremor, and dystonia. Inpatient complications, including death, stroke (both ischemic and hemorrhagic), and other overall complications were examined. The relative risks associated with advanced age; primary diagnosis; treatment modality; the diagnoses of hypertension, diabetes, and nicotinism; and the cumulative number of comorbidities were examined. There were 5464 patients who met inclusion criteria, including 4145 patients treated for PD and 4961 patients treated with deep brain stimulation (DBS). Overall in-hospital mortality was 0.26%, with 0.15% related to surgical factors. There was a correlation between in-hospital mortality, increasing age, and number of medical comorbidities. After multivariate regression no factor remained predictive of mortality. Having more than 1 medical comorbidity or PD increased the risk of in-hospital complications. Patients with PD were more likely to suffer hemorrhage or stroke. Hypertension, diabetes, nicotinism, and modality of treatment were not associated with increased mortality, hemorrhage or stroke risk, or in-hospital mortality in univariate or multivariate analysis. Both age and medical comorbidity are correlated with in-hospital complications, but age appears to serve as a surrogate for comorbidity. Surgery for PD appears to carry an increased risk of hemorrhage or stroke and in-hospital complications.

ABSTRACTIntroductionThe aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD.MethodsOdor identification with the 16‐item Sniffin' Sticks test (SS‐16) was assessed in a total of 646 PD patients and 606 controls from three European centers (A, B, and C), as well as 75 patients with atypical parkinsonism or essential tremor and in a prospective cohort of 24 patients with idiopathic rapid eye movement sleep behavior disorder (center A). Reduced odor sets most discriminative for PD were determined in a discovery cohort derived from a random split of PD patients and controls from center A using L1‐regularized logistic regression. Diagnostic accuracy was assessed in the rest of the patients/controls as validation cohorts.ResultsOlfactory performance was lower in PD patients compared with controls and non‐PD patients in all cohorts (each P < 0.001). Both the full SS‐16 and a subscore of the top eight discriminating odors (SS‐8) were associated with an excellent discrimination of PD from controls (areas under the curve ≥0.90; sensitivities ≥83.3%; specificities ≥82.0%) and from non‐PD patients (areas under the curve ≥0.91; sensitivities ≥84.1%; specificities ≥84.0%) in all cohorts. This remained unchanged when patients with >3 years of disease duration were excluded from analysis. All 8 incident PD cases among patients with idiopathic rapid eye movement sleep behavior disorder were predicted with the SS‐16 and the SS‐8 (sensitivity, 100%; positive predictive value, 61.5%).ConclusionsOdor identification testing provides excellent diagnostic accuracy in the distinction of PD patients from controls and diagnostic mimics. A reduced set of eight odors could be used as a quick tool in the workup of patients presenting with parkinsonism and for PD risk indication. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Essential tremor involves the cerebellum, yet quantitative analysis of dentate nucleus neurons has not been conducted. To quantitatively compare neuronal density or neuronal number in the dentate nucleus of essential tremor versus age-matched controls. Using a 7-μm thick Luxol fast blue hematoxylin and eosin-stained paraffin section, dentate nucleus neuronal density (neurons/mm2 ) was determined in 25 essential tremor cases and 25 controls. We also applied a stereological approach in a subset of four essential tremor cases and four controls to estimate total dentate nucleus neuronal number. Dentate nucleus neuronal density did not differ between essential tremor cases and controls (P = 0.44). Total dentate nucleus neuronal number correlated with neuronal density (P = 0.007) and did not differ between essential tremor cases and controls (P = 0.95). Neuronal loss, observed in the Purkinje cell population in essential tremor, did not seem to similarly involve the dentate nucleus in essential tremor. © 2020 International Parkinson and Movement Disorder Society.