Essential Tremor Patients Research Articles

In Vivo Insights: Near-Infrared Photon Sampling of Reflectance Spectra from Cranial and Extracranial Sites in Healthy Individuals and Patients with Essential Tremor

Near-infrared (NIR) spectroscopy is a powerful non-invasive technique for assessing the optical properties of human tissues, capturing spectral signatures that reflect their biochemical and structural characteristics. In this study, we investigated the use of NIR reflectance spectroscopy combined with chemometric analysis to distinguish between patients with Essential Tremor (ET) and healthy individuals. ET is a common movement disorder characterized by involuntary tremors, often making it difficult to clinically differentiate from other neurological conditions. We hypothesized that NIR spectroscopy could reveal unique optical fingerprints that differentiate ET patients from healthy controls, potentially providing an additional diagnostic tool for ET. We collected NIR reflectance spectra from both extracranial (biceps and triceps) and cranial (cerebral cortex and brainstem) sites in ET patients and healthy subjects. Using Partial Least Squares Discriminant Analysis (PLS-DA) and Partial Least Squares (PLS) regression models, we analyzed the optical properties of the tissues and identified significant wavelength peaks associated with spectral differences between the two groups. The chemometric analysis successfully classified subjects based on their spectral profiles, revealing distinct differences in optical properties between cranial and extracranial sites in ET patients compared to healthy controls. Our results suggest that NIR spectroscopy, combined with machine learning algorithms, offers a promising non-invasive method for the in vivo characterization and differentiation of tissues in ET patients.

Polysomnographic Findings into Sleep Disorders in Essential Tremor and Essential Tremor Plus: A Comparison with Healthy Controls.

To explore sleep patterns in individuals with Essential Tremor (ET) and Essential Tremor Plus (ET-Plus), compared to healthy controls, and assess differences between ET and ET-Plus, given the lack of established polysomnography (PSG) data on these groups and the potential for sleep disturbances to serve as clinical markers. We conducted a prospective cross-sectional study at NIMHANS, Bengaluru, from November 2021 to August 2023 on 45 patients (26 ET, 19 ET-Plus) and 45 controls. Tremor severity was assessed using TETRAS and FTMTRS, and sleep symptoms with ESS, PSQI, Mayo Sleep Questionnaire, RLS-Q, BQ, GAD-7 and PHQ-9. All cases and controls underwent overnight video PSG. Sleep scoring was manually done by a technically adequate sleep researcher and the first author following AASM (2022) guidelines with data analysed using R studio. ET patients exhibited younger onset age (30.8 ± 16.7 years) compared to ET-Plus patients (46.8 ± 11.1 years). ET-Plus had higher TETRAS and FTMRS scores (P < 0.001) than ET. Both ET and ET-Plus patients exhibited poorer sleep quality, excessive daytime sleepiness, REM sleep behavior disorder (RBD), and Restless Legs Syndrome (RLS) symptoms compared to controls. PSG findings supported these clinical observations, showing elevated Apnea-Hypopnea Index (AHI), reduced Total Sleep Time (TST), prolonged REM latency, decreased sleep efficiency, increased N1 stage duration, and reduced N2/N3 durations and percentages in patients versus controls. The study highlights significant sleep architecture abnormalities in both ET and ET-Plus patients as compared to healthy controls, with no differences between the ET groups.

Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer's disease and primary age-related tauopathy.

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disease that, in some cases, is associated with cognitive impairment and tau accumulation. Consequently, we explored the tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify tau prion seeding activity present in brain homogenates based on conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Prions exhibit seeding barriers, whereby a specific assembly structure cannot serve as a template for a native monomer if the amino acids are not compatible. We recently exploited the tau prion species barrier to define tauopathies by systematically substituting alanine (Ala) in the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. The Ala scan precisely classified the conformation of tau seeds from diverse tauopathies. We next studied 18 ET patient brains with tau pathology. Only one case had concurrent high amyloid-β plaque pathology consistent with Alzheimer's disease (AD). We detected robust tau seeding activity in 9 (50%) of the patients. This predominantly localized to the temporal pole and temporal cortex. We examined 8 ET cases with the Ala scan and determined that the amino acid requirements for tau monomer incorporation into aggregates seeded from these ET brain homogenates were identical to those of AD and primary age-related tauopathy (PART), and completely distinct from other tauopathies such as corticobasal degeneration, chronic traumatic encephalopathy, and progressive supranuclear palsy. Based on these studies, tau assembly cores in a pathologically confined subset of ET cases with high tau pathology are identical to AD and PART. This could facilitate more precise diagnosis and therapy for ET patients with cognitive impairment.

The Direct Medical Cost of Essential Tremor.

To determine the direct medical cost of illness from essential tremor (ET) from a patient perspective. Secondary data from the Optum's de-identified Clinformatics® Data Mart Database (CDM) from 2018-2019 was used to assess medical resource utilization and costs. Propensity score matching was used to match patients age 40+ with to statistically similar controls. Generalized linear models were used to estimate average, adjusted total costs of care per year, by health care setting, and provider specialty. The final sample included 41,200 patients with at least one ET claim and 36,871 matched patients. Overall, ET patients ages 40+ had about $28,217 in direct medical costs per year, which was about $1,601 more than matched comparisons (p &lt; 0.001). This was driven by greater number of outpatient visits overall and with specialists. Extrapolating the estimates from our study and pairing them with published age-specific disease prevalence statistics for ET, we calculated an annual cost for direct medical care of ET patients ages 40+ to be about $9.4 billion. The estimated direct medical costs among adults age 40+ with an ET diagnosis aggregated to the population-level are non-trivial.

Impact of SARS-CoV-2 Infection on Essential Tremor: A Retrospective Clinical and Kinematic Analysis.

In the past few years, SARS-CoV-2 infection has substantially impacted public health. Alongside respiratory symptoms, some individuals have reported new neurological manifestations or a worsening of pre-existing neurological conditions. We previously documented two cases of essential tremor (ET) who experienced a deterioration in tremor following SARS-CoV-2 infection. However, the effects of SARS-CoV-2 on ET remain largely unexplored. This study aims to evaluate the impact of SARS-CoV-2 infection on a relatively broad sample of ET patients by retrospectively comparing their clinical and kinematic data collected before and after the exposure to SARS-CoV-2. We surveyed to evaluate the impact of SARS-CoV-2 infection on tremor features in ET. Subsequently, we retrospectively analysed clinical and kinematic data, including accelerometric recordings of postural and kinetic tremor. We included 36 ET patients (14 females with a mean age of 71.1 ± 10.6 years). Among the 25 patients who reported SARS-CoV-2 infection, 11 (44%) noted a subjective worsening of tremor. All patients reporting subjective tremor worsening also exhibited symptoms of long COVID, whereas the prevalence of these symptoms was lower (50%) in those without subjective exacerbation. The retrospective analysis of clinical data revealed a tremor deterioration in infected patients, which was not observed in non-infected patients. Finally, kinematic analysis revealed substantial stability of tremor features in both groups. The study highlighted a potential correlation between the SARS-CoV-2 infection and clinical worsening of ET. Long COVID contributes to a greater impact of tremor on the daily life of ET patients.

Quantitative Tractography-Based Evaluations in Essential Tremor Patients after MRgFUS Thalamotomy.

Magnetic resonance-guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug-refractory essential tremor (ET). The relationship between lesion characteristics, dentate-rubro-thalamic-tract (DRTT) involvement and clinical benefit remains unclear. To investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting. Forty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion-tensor 3 T-images and location and volume of the lesion were calculated. Probabilistic tractography identified both decussating (d-DRTT) and non-decussating (nd-DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd-DRTT. Despite the lesions predominantly intersecting the medial portion of the d-DRTT, with a significantly greater overlap in responder patients, we observed only a non-significant correlation between tremor improvement and increased d-DRTT-lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1-day MRI (r = 0.42, P < 0.01). Variability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method.

Frailty and outcomes after unilateral MRI-guided focused ultrasound thalamotomy for tremor.

Frailty is recognized as an important predictor of neurointerventional outcomes. MRI-guided focused ultrasound (MRgFUS) thalamotomy is a treatment option for patients with refractory essential tremor (ET) and tremor-dominant Parkinson's disease (TdPD). The aim of this study was to evaluate whether frailer MRgFUS thalamotomy patients had worse tremor outcomes or more complications. The authors performed a cohort analysis of patients treated with MRgFUS between 2020 and 2023. Inclusion criteria were unilateral MRgFUS thalamotomy for ET or TdPD with available follow-up data (minimum 3-month follow-up). Frailty was assessed using the 11-item modified frailty index (mFI-11), which includes 11 medical comorbidities. Tremor outcomes were assessed using the Clinical Rating Scale for Tremor Part B. Complications assessed included disturbances of sensation, speech and swallowing, balance and gait, and strength. In total, 169 eligible patients were identified, including 135 (79.9%) ET and 34 (20.1%) TdPD patients. Frailty did not result in significant differences in tremor outcomes in the combined (p = 0.833), ET (p = 0.902), or TdPD (p = 0.501) cohort, or in any adverse events at the last follow-up (all p > 0.05). The combined mean follow-up was 10.3 ± 5.8 months (range 3-24 months), with cohort-specific mean follow-ups of 10.8 ± 6.0 months for ET and 8.6 ± 4.6 months for TdPD. Between the ET and TdPD cohorts, no significant differences existed in age, sex, handedness, side treated, skull density ratio, number of sonications, peak and average temperatures, energy delivered, BMI, or American Society of Anesthesiologists classification. For medical comorbidities, only hypertension was significantly different (65.9% ET, 47.1% TdPD; p = 0.043). The ET patients were significantly frailer overall, with 20.7% ET and 35.3% TdPD patients considered robust (mFI-11 score of 0), 14.8% ET and 32.4% TdPD patients prefrail (mFI-11 score of 1), 25.9% ET and 8.8% TdPD patients frail (mFI-11 score of 2), and 38.5% ET and 23.5% TdPD patients severely frail (mFI-11 score ≥ 3) (p = 0.007). Increasing frailty is not associated with worse outcomes, suggesting that MRgFUS may be appropriate even for frailer patients. ET patients are frailer than TdPD patients selected for MRgFUS.

Is essential tremor a risk factor for carpal tunnel syndrome? A prospective study excluding the most common comorbid conditions

Aims: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper extremity, resulting from compression of the median nerve. Tremor, a rhythmic and involuntary movement of any part of the body, is the most common movement disorder, affecting millions of people worldwide. There is limited research on the coexistence of CTS and ET (essential tremor). Methods: This prospective study included patients aged 18-65 who presented to the neurology outpatient clinic and were diagnosed with ET. Participants supplied informed consent, a sociodemographic form, and the Fahn-Tolosa-Marin Clinical Tremor Rating Scale (FTM TRS). Patients were evaluated for the presence and severity of CTS with electromyography (EMG). The EMG data were categorized as normal, mild, moderate, and severe CTS. Results: In the study, the average age of the 50 ET patients was 56.0 (35.0-64.0) years. The gender distribution comprised 22 (44.0%) males and 28 (56.0%) females. The following tremor locations were reported: 41 (82.0%) in both upper extremities, 3 (6.0%) in the right upper extremity, 2 (4.0%) in the left upper extremity, 1 (2.0%) in both upper extremities, head tremor, and voice, and 3 (6.0%) in both upper extremities and head tremor. A high prevalence of CTS was detected in ET patients (46%). Additionally, a positive correlation was found between CTS in ET patients, long disease duration, and female gender. No significant relationship was found between FTM TRS Part A, Part B, Part C, total scores, and median sensory and motor nerve amplitude and velocity values in ETS patients. Conclusion: CTS is more common in patients with ET. This suggests that ET may be a risk factor for CTS, independent of other factors. Early diagnosis and treatment of CTS in patients with ET is important to improve their quality of life.

Reasons for Hospitalizations and Emergency Department Visits Among Patients with Essential Tremor.

Prior studies suggest that patients with essential tremor (ET) have increased rates of healthcare utilization, but the reason for this increased use is unknown. The objective of this study was to evaluate the reasons for healthcare use among ET patients. This was a retrospective cross-sectional study of ET patients with an admission or emergency department (ED) visit at a tertiary health system from 2018-2023. Patients were matched on an encounter level with control patients based on propensity scores incorporating age, sex, race, and co-morbid conditions. The primary outcome was the odds of an encounter for each diagnostic category comparing ET patients with matched controls. Only inpatient admissions for neurologic diagnoses were more likely for ET compared to control patients (odds ratio (OR) 3.73, 95% confidence interval (CI) 2.54 - 5.49, p < 0.001). Once admissions related to the surgical treatment of tremor were excluded, admissions for neurologic diagnoses were equally likely among ET and control patients (OR 0.96, 95% CI 0.59 - 1.57, p = 0.88). Surgical treatment of tremor appears to be a key driver of healthcare use among ET patients. Future investigations should examine the pattern of healthcare use of ET patients before and after surgery. Prior studies have shown increased healthcare use among essential tremor (ET) patients. The objective of this study was to evaluate the reasons for healthcare use among ET patients compared to matched control patients. Surgical treatment of tremor was found to be a key driver of healthcare use among ET patients.

Neuronal tissue collection from intra-cranial instruments used in deep brain stimulation surgery for Parkinson’s disease with implications for study of alpha-synuclein

Alpha-synuclein (αSyn) forms pathologic aggregates in Parkinson’s disease (PD) and is implicated in mechanisms underlying neurodegeneration. While pathologic αSyn has been extensively studied, there is currently no method to evaluate αSyn within the brains of living patients. Patients with PD are often treated with deep brain stimulation (DBS) surgery in which surgical instruments are in direct contact with neuronal tissue; herein, we describe a method by which tissue is collected from DBS surgical instruments in PD and essential tremor (ET) patients and demonstrate that αSyn is detected. 24 patients undergoing DBS surgery for PD (17 patients) or ET (7 patients) were enrolled; from patient samples, 81.2 ± 44.8 µg of protein (n = 15), on average, was collected from surgical instruments. Light microscopy revealed axons, capillaries, and blood cells as the primary components of purified tissue (n = 3). ELISA assay further confirmed the presence of neuronal and glial tissue in DBS samples (n = 4). Further analysis was conducted using western blot, demonstrating that multiple αSyn antibodies are reactive in PD (n = 5) and ET (n = 3) samples; truncated αSyn (1–125 αSyn) was significantly increased in PD (n = 5) compared to ET (n = 3), in which αSyn misfolding is not expected (0.64 ± 0.25 vs. 0.25 ± 0.12, P = 0.046), thus showing that multiple forms of αSyn can be detected from living PD patients with this method.

A - 96 Cognitive Profiles of Patients with Essential Tremor and Parkinson’s Disease: a Comparative Study

Abstract Objective Essential tremor (ET) is traditionally thought of as a pure motor condition1 defined by isolated action tremor. However, research suggests cognitive decline is more prevalent in ET than originally proposed2. Movement Disorder Society guidelines recommend patients with ET and cognitive decline be classified “ET-Plus3”. ET-related cognitive decline may occur through breakdown of prefrontal integrity via frontocerebellar networks. This is similar to frontosubcortical dysfunction in PD, which may result in similar cognitive changes. The present study compared cognitive profiles of patients with ET to PD and healthy controls (HC). Method Data was obtained through Baylor College of Medicine’s Neuropsychology Repository. 51 ET patients were compared to 190 PD patients and 189 age-matched HC. Group differences were assessed with one-way ANOVAs and post-hoc t-tests. Results ET performed worse than HC on multiple cognitive measures including executive functioning, processing speed, and memory. Largest effects were observed on Trailmaking B (p &amp;lt; 0.001, d = 0.93) and Stroop Word Reading (p &amp;lt; 0.001, d = 1.15). ET performed similarly to PD across most measures, although PD performed worse on Logical Memory I &amp; II (p &amp;lt; 0.001, d = 0.57), and Clock Drawing (p = 0.001, d = 0.49). Rates of mild cognitive impairment were similar in ET (45%) and PD (44%). Conclusion(s) Findings suggest cognitive deficits in ET occur in a similar pattern and at a similar rate as in PD. The findings are consistent with research exploring the phenotypic heterogeneity of ET and provide evidence against the prevailing belief that ET is monosymptomatic.

Postmortem Fatty Acid Abnormalities in the Cerebellum of Patients with Essential Tremor.

Fatty acids play many critical roles in brain function but have not been investigated in essential tremor (ET), a frequent movement disorder suspected to involve cerebellar dysfunction. Here, we report a postmortem comparative analysis of fatty acid profiles by gas chromatography in the cerebellar cortex from ET patients (n = 15), Parkinson's disease (PD) patients (n = 15) and Controls (n = 17). Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)/ phosphatidylserine (PS) were separated by thin-layer chromatography and analyzed separately. First, the total amounts of fatty acids retrieved from the cerebellar cortex were lower in ET patients compared with PD patients, including monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). The diagnosis of ET was associated with lower cerebellar levels of saturated fatty acids (SFA) and PUFA (DHA and ARA) in the PE fraction specifically, but with a higher relative content of dihomo-γ-linolenic acid (DGLA; 20:3 ω-6) in the PC fraction. In contrast, a diagnosis of PD was associated with higher absolute concentrations of SFA, MUFA and ω-6 PUFA in the PI + PS fractions. However, relative PI + PS contents of ω-6 PUFA were lower in both PD and ET patients. Finally, linear regression analyses showed that the ω-3:ω-6 PUFA ratio was positively associated with age of death, but inversely associated with insoluble α-synuclein. Although it remains unclear how these FA changes in the cerebellum are implicated in ET or PD pathophysiology, they may be related to an ongoing neurodegenerative process or to dietary intake differences. The present findings provide a window of opportunity for lipid-based therapeutic nutritional intervention.

Exploring White Matter Microstructure with Symptom Severity and Outcomes Following Deep Brain Stimulation in Tremor Syndromes.

Essential tremor (ET) and dystonic tremor (DT) are movement disorders that cause debilitating symptoms, significantly impacting daily activities and quality of life. A poor understanding of their pathophysiology, as well as the mediators of clinical outcomes following deep brain stimulation (DBS), highlights the need for biomarkers to accurately characterise and optimally treat patients. We assessed the white matter microstructure of pathways implicated in the pathophysiology and therapeutic intervention in a retrospective cohort of patients with DT (n = 17) and ET (n = 19). We aimed to identity associations between white matter microstructure, upper limb tremor severity, and tremor improvement following DBS. A fixel-based analysis pipeline was implemented to investigate white matter microstructural metrics in the whole brain, cerebello-thalamic pathways and tracts connected to stimulation volumes following DBS. Associations with preoperative and postoperative severity were analysed within each disorder group and across combined disorder groups. DBS led to significant improvements in both groups. No group differences in stimulation positions were identified. When white matter microstructural data was aligned according to the maximally affected upper limb, increased fiber density, and combined fiber density & cross-section of fixels in the left cerebellum were associated with greater tremor severity across DT and ET patients. White matter microstructure did not show associations with postoperative changes in cerebello-thalamic pathways, or tracts connected to stimulation volumes. Diffusion changes of the cerebellum are associated with the severity of upper limb tremor and appear to overlap in essential or dystonic tremor disorders.

Radiomics based on diffusion tensor imaging and 3D T1-weighted MRI for essential tremor diagnosis.

Due to the absence of biomarkers, the misdiagnosis of essential tremor (ET) with other tremor diseases and enhanced physiologic tremor is very common in practice. Combined radiomics based on diffusion tensor imaging (DTI) and three-dimensional T1-weighted imaging (3D-T1) with machine learning (ML) give a most promising way to identify essential tremor (ET) at the individual level and further reveal the potential imaging biomarkers. Radiomics features were extracted from 3D-T1 and DTI in 103 ET patients and 103 age-and sex-matched healthy controls (HCs). After data dimensionality reduction and feature selection, five classifiers, including the support vector machine (SVM), random forest (RF), logistic regression (LR), extreme gradient boosting (XGBoost) and multi-layer perceptron (MLP), were adopted to discriminate ET from HCs. The mean values of the area under the curve (mAUC) and accuracy were used to assess the model's performance. Furthermore, a correlation analysis was conducted between the most discriminative features and clinical tremor characteristics. All classifiers achieved good classification performance (with mAUC at 0.987, 0.984, 0.984, 0.988 and 0.981 in the test set, respectively). The most powerful discriminative features mainly located in the cerebella-thalamo-cortical (CTC) and visual pathway. Furthermore, correlation analysis revealed that some radiomics features were significantly related to the clinical tremor characteristics in ET patients. These results demonstrated that combining radiomics with ML algorithms could not only achieve high classification accuracy for identifying ET but also help us to reveal the potential brain microstructure pathogenesis in ET patients.

Automated Sleep Detection in Movement Disorders Using Deep Brain Stimulation and Machine Learning.

Automated sleep detection in movement disorders may allow monitoring sleep, potentially guiding adaptive deep brain stimulation (DBS). The aims were to compare wake-versus-sleep status (WSS) local field potentials (LFP) in a home environment and develop biomarkers of WSS in Parkinson's disease (PD), essential tremor (ET), and Tourette's syndrome (TS) patients. Five PD, 2 ET, and 1 TS patient were implanted with Medtronic Percept (3 STN [subthalamic nucleus], 3 GPi [globus pallidus interna], and 2 ventral intermediate nucleus). Over five to seven nights, β-band (12.5-30 Hz) and/or α-band (7-12 Hz) LFP power spectral densities were recorded. Wearable actigraphs tracked sleep. From sleep to wake, PD LFP β-power increased in STN and decreased in GPi, and α-power increased in both. Machine learning classifiers were trained. For PD, the highest WSS accuracy was 93% (F1 = 0.93), 86% across all patients (F1 = 0.86). The maximum accuracy was 86% for ET and 89% for TS. Chronic intracranial narrowband recordings can accurately identify sleep in various movement disorders and targets in this proof-of-concept study. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effects on Gait and Balance of VIM Gamma Knife Radiosurgery in Essential Tremor

Introduction: Essential tremor (ET) is the most common movement disorder, characterized by an action tremor in the upper limbs. Neurosurgical techniques targeting the thalamic ventrointermediate nucleus (VIM) including thermocoagulation demonstrated a potential risk for gait and posture worsening. This study evaluates the potential effect of VIM Gamma Knife radiosurgery (GKR) in ET on gait and posture performances. Methods: We conducted a prospective study to quantitatively assess gait and balance in severe ET patients before and 1 year after unilateral GKR. Seventy-three patients were included in this series. Results: First, we confirmed the unilateral GKR efficacy in severe ET patients: global tremor score and impairments in activities of daily living improved, respectively, by 67% and 71.7%. The global gait and posture analysis found no significant differences before and 1 year after GKR. Three patients (4.1%) developed mild to moderate gait and posture impairment with proprioceptive ataxia. All of these AEs were induced by a hyper-response to radiosurgery. Conclusions: Gait and posture performances were not statistically significant at the population. Nevertheless, gait and posture worsened in 4% of patients after GKR, all in the setting of hyper-response. This study shows that GKR may be a safe neurosurgical alternative to improve ADL in a population of patients with TE.

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 MRgFUS thalamotomy and were scanned for resting-state functional magnetic resonance imaging (rs-fMRI). 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 (fALFF) was calculated from rs-fMRI 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 fALFF 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 fALFF pattern as a whole is an overall predicting feature. Preoperative fALFF pattern predicts tremor benefits induced by MRgFUS thalamotomy. ClinicalTrials.gov number: NCT04570046.

Probabilistic Refinement of Focused Ultrasound Thalamotomy Targeting for Parkinson's Disease Tremor.

There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD). Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET. We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients. The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute < 0.05), with peak TDPD improvement (87%) at x = -13.5; y = -15.0; z = 1.5, ~3.5 mm anterior and 3 mm dorsal to the ET target. Discriminative connectivity projections were to the motor and premotor regions in TDPD, and to the motor and somatosensory regions in ET. The disorder-specific voxel-wise efficacy map could be used to estimate outcome in TDPD patients with high accuracy (R = 0.8; R2 = 0.64; P < 0.0001). The model was validated using the independent cohort of nine TDPD patients (R = 0.73; R2 = 0.53; P = 0.025-voxel analysis). We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Resting-State Network Analysis Reveals Altered Functional Brain Connectivity in Essential Tremor.

Introduction: Essential tremor (ET) comprises motor and non-motor-related features, whereas the current neuro-pathogenetic basis is still insufficient to explain the etiologies of ET. Although cerebellum-associated circuits have been discovered, the large-scale cerebral network connectivity in ET remains unclear. This study aimed to characterize the ET in terms of functional connectivity as well as network. We hypothesized that the resting-state network (RSN) within cerebrum could be altered in patients with ET. Methods: Resting-state functional magnetic resonance imaging (fMRI) was used to evaluate the inter- and intra-network connectivity as well as the functional activity in ET and normal control. Correlation analysis was performed to explore the relationship between RSN metrics and tremor features. Results: Comparison of inter-network connectivity indicated a decreased connectivity between default mode network and ventral attention network in the ET group (p < 0.05). Differences in functional activity (assessed by amplitude of low-frequency fluctuation, ALFF) were found in several brain regions participating in various RSNs (p < 0.05). The ET group generally has higher degree centrality over normal control. Correlation analysis has revealed that tremor features are associated with inter-network connectivity (|r| = 0.135-0.506), ALFF (|r| = 0.313-0.766), and degree centrality (|r| = 0.523-0.710). Conclusion: Alterations in the cerebral network of ET were detected by using resting-state fMRI, demonstrating a potentially useful approach to explore the cerebral alterations in ET.

Estimating Disability in Patients with Essential Tremor: Comparison of Tremor Rating Scale, Spiral Drawing, and Accelerometric Tremor Power.

Although performance rating scales, spiral drawing, water pouring, and accelerometry are commonly used to assess tremor severity, the extent to which their results correlate with impairment in activities of daily living (ADL) remains unclear. The aim was to identify the most effective predictors of ADL in essential tremor (ET). Forty ET patients were examined using The Essential Tremor Rating Assessment Scale (TETRAS), spiral drawing, volume of water spilled, and accelerometric tremor power. Root-mean-square error, R2, and F-test were calculated for models predicting TETRAS ADL subscore. TETRAS Performance Subscale explained the variability in TETRAS ADL with an R2 value of 0.686. Models incorporating spiral rating and accelerometric tremor power (R2 = 0.731) and water spillage volume (R2 = 0.756) were not statistically superior. TETRAS performance subscore predicted nearly 70% ADL impairment in ET patients. Incorporating the spiral rating, accelerometric tremor power, and water pouring test did not enhance ADL estimation.