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• Multi-pattern connection graph convolutional networks can effectively identify essential tremor with resting tremor and tremor-dominant Parkinson's disease. • Different connection modes may provide distinct discriminative information for diagnosis. • The occipital network and basal ganglion-temporal lobe networks appear to be tremor-related networks for rET and tPD, respectively. Essential tremor with resting tremor (rET) and tremor-dominant Parkinson's disease (tPD) share many similar clinical symptoms, leading to frequent misdiagnoses. Functional connectivity (FC) matrix analysis derived from resting-state functional MRI (Rs-fMRI) offers a promising approach for early diagnosis and for exploring FC network pathogenesis in rET and tPD. However, methods relying solely on a single connection pattern may overlook the complementary roles of different connectivity patterns, resulting in reduced diagnostic differentiation. Therefore, we propose a multi-pattern connection Graph Convolutional Network (MCGCN) method to integrate information from various connection modes, distinguishing between rET and healthy controls (HC), tPD and HC, and rET and tPD. We constructed FC matrices using three different connectivity modes for each subject and used these as inputs to the MCGCN model for disease classification. The classification performance of the model was evaluated for each connectivity mode. Subsequently, gradient-weighted class activation mapping (Grad-CAM) was used to identify the most discriminative brain regions. The important brain regions identified were primarily distributed within cerebellar-motor and non-motor cortical networks. Compared with single-pattern GCN, our proposed MCGCN model demonstrated superior classification accuracy, underscoring the advantages of integrating multiple connectivity modes. Specifically, the model achieved an average accuracy of 88.0% for distinguishing rET from HC, 88.8% for rET from tPD, and 89.6% for tPD from HC. Our findings indicate that combining graph convolutional networks with multi-connection patterns can not only effectively discriminate between tPD, rET, and HC but also enhance our understanding of the functional network mechanisms underlying rET and tPD. [ABSTRACT FROM AUTHOR]

[Display omitted] 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. [ABSTRACT FROM AUTHOR]

• Essential tremor is a neurological condition associated with movement disorder with more prevalence among adult group of population. But with the advancement in the area of functional neurosurgery such as stereotactic thalamotomy, the quality of life of such patients can be improved drastically. • We qualitatively analyzed 9 studies with a total of 274 patients of essential tremor patients. • Vim and Vom nucleus were the site of thalamotmy with ventral intermedius nucleus being the major one. • Ten different types of clinical tremor rating scales were used to assess pre operative and post operative and susbsequent follow ups of the tremor status of the patients. • Dysarthria and limb weakness was noted post operative complication in majority of the cases Good functional outcome was observed in patients of essential tremor who underwent unilateral thalamotomy compared to bilateral thalamotomy. Essential tremor is a neurological condition associated with movement disorder with more prevalence among adult group of population. The burden of essential tremor is peaking globally but with the advancement in the area of functional neurosurgery such as stereotactic thalamotomy, the quality of life of such patients can be improved drastically. This systemic review was conducted in accordance to the guidance of preferred Reporting items for Systematic Review and Meta-Analysis(PRISMA). Databases of "PubMed", "Embase", "Web of Science", "Cinhal Plus", and "Scopus" from inception till 2023 was undertaken. A combination of keywords, Medical Subject Headings (MeSH), and search terms such as Search strategy for PubMed search was as follows: "stereotactic thalamotomy" AND "essential tremor". This systematic review analyzed 9 studies with a total of 274 patients of essential tremor patients. Unilateral thalamotomy was carried out among 268 patients and bilateral thalamotomy in rest of the patients. Vim and Vom nucleus were the site of thalamotmy with ventral intermedius nucleus being the major one. Ten different types of clinical tremor rating scales were used to assess pre operative and post operative improvement in the tremor scales of the individual patients. Dysarthria and limb weakness was noted post operative complication in majority of the cases. Our study revealed that stereotactic thalamotomy provided good functional outcome in patients of essential tremor who underwent unilateral thalamotomy compared to bilateral thalamotomy. The positive outcome outweighs the complications in such functional surgery. [ABSTRACT FROM AUTHOR]

The primary aim of this study is to report long-term outcomes associated with deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) performed at our institution. We further aimed to elicit the factors associated with loss of efficacy and to discuss the need for exploring and establishing reliable rescue targets. To study long-term outcomes, we performed a retrospective chart review and extracted tremor scores of 43 patients who underwent VIM DBS lead implantation for essential tremor at our center. We further evaluated factors that could influence outcomes over time, including demographics, body mass index, duration of follow-up, degree of parenchymal atrophy indexed by the global cortical atrophy scale, and third ventricular width. In this cohort, tremor scores on the latest follow-up (median 52.7 months) were noted to be worse than initial postoperative scores in 56% of DBS leads. Furthermore, 14% of leads were associated with clinically significant loss of benefit. Factors including the length of time since the lead implantation, age at the time of surgery, sex, body mass index, preoperative atrophy, and third ventricular width were not predictive of long-term outcomes. Our study identified a substantial subgroup of VIM-DBS patient who experienced a gradual decline in treatment efficacy over time. We propose that this phenomenon can be attributed primarily to habituation and disease progression. Furthermore, we discuss the need to establish reliable and effective rescue targets for this subpopulation of patients, with ventral-oralis complex and dentate nucleus emerging as potential candidates. [ABSTRACT FROM AUTHOR]

Tremor is common with tacrolimus treatment and is linked with peak blood drug concentrations. We investigated the effect of switching from immediate-release tacrolimus (IR-TAC) to MeltDose prolonged-release tacrolimus (LCPT) on tremor in kidney transplant recipients experiencing tremor at therapeutic levels of IR-TAC. The Activities of Daily Living Subscale (ADL, range 0-48, lower = better) of the Essential Tremor Rating Scale was used to assess the effect of therapy change on speech, occupational impairment and social activities over a 12-month follow-up period. The study included 18 patients (mean age = 45.6 y, range 26-73; median (IQR) time from transplant = 1.1 y (0.6-1.5), with baseline IR-TAC trough concentrations (C 0) ranging from 4.2 to 9.4 ng/mL (mean C 0 = 6.7 ± 1.3 ng/mL). After the switch to LCPT, the mean ADL score improved from baseline 11.2 to 8.4 after 7 to 14 days (an 18% improvement, P <.001). This improvement was sustained after 3 months (ADL score = 5.0, 46% improvement vs baseline), 6 months (ADL score = 4.4, 48% improvement vs baseline), and 12 months (ADL score = 3.6, 63% improvement vs baseline); all P <.001. Despite a 40% reduction in LCPT daily doses (mean −1.9 mg/day compared to IR-TAC), the achieved C 0 was constant during the course of the 12-month observation (P =.755). The renal function remained stable after conversion (eGFR 12 months vs baseline = +1.1 mL/min/1.73 m2, 95% CI: −5.6 to +7.9). Conversion to LCPT may alleviate symptom burden and improve daily activities in kidney transplant recipients experiencing tremor within therapeutic IR-TAC concentrations. [ABSTRACT FROM AUTHOR]

Transcranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. /hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. The dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. VIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. MR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect. • Transcranial Ultrasound Stimulation induced more than 89 % reduction of essential tremor in 5 patients. • A sustained effect (more than 23min) was observed in 3 patients. • Stimulation was performed in the VIM and the DRT. • No significant thermal rise was measured by MR Thermometry during stimulation. [ABSTRACT FROM AUTHOR]

• CTX is a childhood-onset lipid storage disease usually diagnosed in adulthood. • Hand tremor was detected in 83.3% of patients as the first neurological sign. • Malar rash,a possibly new clinical finding in CTX,was detected in 75% of patients. • Malar rash and hand tremor showed complete recovery with CDCA treatment. Cerebrotendinous xanthomatosis (CTX, OMIM #213700) is a rare but treatable lipid storage disease resulting from mutations in the CYP27A1 gene. The study aims to evaluate patients diagnosed with CTX and reveal new information, especially about the signs of CTX and patients' response to the treatment. The study was conducted retrospectively in 12 definitively diagnosed CTX patients. The patients' clinical, laboratory, imaging, genetic findings, and chenodeoxycholic acid (CDCA) treatment results were analyzed. The median age at diagnosis for the patients was 16.5 years (minimum-maximum: 7–32). Juvenile cataracts, detected in more than 90% (11/12) of the patients, were the most common clinical finding. Malar rash, not previously reported in the literature for CTX, was present in 75% (9/12) of the patients. Hand tremors, the first neurological symptom, occurred in adolescence and were the initial symptom of the disease in five patients. Hand tremors were present in 83.3% (10/12) of the patients. Hand tremors (in 5 patients) and malar rash (in 2 patients) were clinical findings with full recovery due to the CDCA treatment. The study defines the malar rash finding, which has not been reported in the literature before, as a possible new clinical finding in CTX disease, attributed to its partial or full recovery with CDCA treatment. Additionally, as a novelty in the literature, our study highlights the full recovery of neurological findings, such as hand tremors, in CTX. Patients presenting with hand tremors and malar rash, especially in adolescence, should undergo CTX investigation for early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

There is growing evidence that essential tremor (ET) patients are at high risk of cognitive impairment. Predictors of cognitive impairment have not been studied extensively. There is evidence from cross-sectional studies that sleep dysregulation is associated with cognitive dysfunction in ET, but longitudinal studies of the impact of sleep disruption on cognitive change have not been conducted. We investigated the extent to which sleep problems predict cognitive change in patients with ET. ET cases enrolled in a prospective, longitudinal study of cognitive performance. Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Cognitive abilities across five domains (memory, executive function, attention, language, and visuospatial ability), and a global cognitive score (mean of the domains) were extracted from an extensive neuropsychological assessment. Generalized estimated equations were used to examine the association between baseline sleep problems and cognitive changes over three follow-up assessments each spaced 18 months apart. The 188 non-demented ET cases had a mean age of 77.7 ± 9.5 years. Longer sleep latency was associated with longitudinal decline in executive function (p = 0.038), and marginally with longitudinal decline in global cognitive performance (p = 0.075). After excluding 29 cases with mild cognitive impairment, results were similar. Cognitively healthy people with ET who have longer sleep latency had greater declines in executive function during prospective follow-up. Early detection of, and possibly intervention for, abnormal sleep latency may protect against certain aspects of cognitive decline in ET patients. • Sleep dysfunction is one of the major non-motor symptoms of ET. • Cognitive deficits seem to also appear significantly in patients with ET. • Longer sleep latency is associated with decline in executive function. • Results were significant in cognitively healthy older adults. [ABSTRACT FROM AUTHOR]

• Among ET patients, overall tremor scores were associated with language function. • Elevated Fahn-Tolosa-Marin (FTM) scores correlated with increased severity in depression, language impairment, and visuospatial functioning. • Washington Heights Inwood Genetic Study of Essential Tremor (WHIGET) scores showed no association with any non-motor symptoms. Non-motor symptoms, including depression and cognitive impairment, are common in essential tremor (ET), but associations between these symptoms and tremor are poorly understood. A retrospective, single-institution, cohort study evaluated 140 patients with ET undergoing evaluation for deep brain stimulation (DBS) surgery. The Fahn-Tolosa-Marin (FTM) or Washington Heights-Inwood Genetic Study of ET (WHIGET) scale was used to grade tremor. Tremor scores were divided into quartiles. Patients underwent clinical neuropsychological evaluations that included a comprehensive cognitive test battery and Beck Depression Inventory-II (BDI-II). Subgroup analysis was performed with groups who met criteria for depression (BDI-II > 14) or overall cognitive impairment (<9th percentile on at least two dissimilar cognitive tests). Independent samples t-tests were used for continuous variables and chi square tests for categorical variables. Univariable and multivariable regressions were used to determine relationships between tremor and non-motor scores. Tremor quartile was correlated with language domain performance (p = 0.044) but not depression scores. FTM score was associated with BDI-II (β = 0.940, p = 0.010), language (β = −0.936, p = 0.012), and visuospatial domain (β = −0.836, p = 0.025) scores, such that worse tremor was associated with more depression and worse language and visuospatial function. WHIGET score was not associated with any neuropsychological scores on multivariable regression. FTM score was associated with language, visuospatial, and mood symptoms, suggesting a relationship between the severity of these symptom types. Different tremor scores capture different motor symptoms and relationships with nonmotor symptoms. [ABSTRACT FROM AUTHOR]

Cognitive disorder, parkinsonism, autonomic dysfunction (AuD) and rapid eye movement sleep behavior disorder (RBD) can occur prior to or simultaneously with Dementia with Lewy Body (DLB) onset. RBD is generally linked with progressive neurodegenerative traits. However, associations between RBD with DLB, RBD without DLB, and RBD duration effects on DLB symptoms remain unclear. To examine DLB symptom frequency and subtypes in RBD, and explore the effects of different RBD onset times on symptoms in de novo DLB patients. In this multicenter investigation, we consecutively recruited 271 de novo DLB patients. All had standardized clinical and comprehensive neuropsychological evaluations. Subgroup analyses, performed based on the duration of RBD confirmed by polysomnography before the DLB diagnosis, we compared the proportion of patients with cognitive impairment, parkinsonism, and AuD features between groups. Parkinsonism and AuD incidences were significantly elevated in DLB patients with RBD when compared with patients without RBD. Subgroup analyses indicated no significant differences in parkinsonism between DLB patients who developed RBD ≥10 years prior to the DLB diagnosis and DLB patients without RBD. The incidence of non-tremor-predominant parkinsonism and AuD was significantly higher in DLB patients whose RBD duration before the DLB diagnosis was <10 years when compared with DLB patients without RBD. We identified significant symptom and phenotypic variability between DLB patients with and without RBD. Also, different RBD duration effects before the DLB diagnosis had a significant impact on symptomatic phenotypes, suggesting the existence of a slowly progressive DLB neurodegenerative subtype. • DLB patients with RBD were more likely to develop parkinsonian traits and autonomic dysfuction. • Autonomic dysfunction was more common in DLB patients with RBD when compared with DLB patients without RBD. • Significant symptom and phenotype variability existed between DLB patients with and without RBD, and also different RBD durations had significant effects on symptomatic disease phenotypes. [ABSTRACT FROM AUTHOR]

To maximize clinical benefit and minimize stimulation-induced side effects, optimising deep brain stimulation (DBS) parameters is paramount. Recent literature suggests a potential benefit of short pulse width DBS (spDBS; ≤40 μs) over conventional pulse width DBS (cDBS; ≥60 μs) in movement disorders. To compare therapeutic window (TW), therapeutic and side effects and energy consumption of spDBS and cDBS in movement disorders. We systematically searched Medline, Embase, Cochrane Library and Web of Science. Appropriate paired analyses were performed. Nine Parkinson's disease (PD) (143 patients), 4 essential tremor (ET) (26 patients) and no dystonia studies were included in the meta-analysis. TW defined as therapeutic amplitude range was larger with spDBS vs. cDBS in PD (standardized mean difference (SMD) = -1.04, p < 0.001) and ET (SMD = −0.71, p < 0.001), but the TW in terms of charge per pulse (CPP) did not differ. In PD, no differences were found in therapeutic and side effects (MDS-UPDRS-III, speech and gait, dyskinesia, non-motor symptoms and quality of life). In ET, Fahn-Tolosa-Marin Tremor Rating Scale was lower with spDBS vs. cDBS (SMD = 0.36, p < 0.001). A qualitative analysis suggested fewer stimulation-induced side effects with spDBS. CPP was lower with spDBS vs. cDBS in PD (SMD = 0.79, p < 0.001) and ET (MD = 46.46 nC, p < 0.001), but real-world data on battery longevity are lacking. Although spDBS enlarges the TW as a wider amplitude range in both PD and ET, it does not alter TW defined by CPP. The therapeutic efficacy of spDBS is not different from cDBS in PD, but spDBS apparently induces more tremor reduction in ET. • Short pulse width DBS (spDBS) in movement disorders widens the amplitude-based therapeutic window. • SpDBS in movement disorders does not alter the therapeutic window defined by CPP. • In Parkinson's disease, spDBS seems non-inferior as to therapeutic and side effects. • In essential tremor (ET), spDBS appears superior as to therapeutic and side effects. • Future long-term studies on spDBS should address dystonia, battery longevity and ET habituation. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) has an increased estimated prevalence in patients with Parkinson's disease (PS). RLS frequently mimics symptoms intrinsic to PD, such as motor restlessness, contributing to making its diagnosis challenging in this population. We report the case of a patient with new-onset RLS following subthalamic deep-brain stimulation (DBS-STN). We assessed symptoms using suggested immobilization test (SIT) with both DBS-STN activated and switched off. A 59-year-old man with idiopathic PD developed disabling RLS following DBS-STN at age 58, with PD onset at 50 manifesting as left arm tremor. Despite improved motor symptoms during the month following surgery, the patient experienced left leg discomfort at rest, transiently alleviated by movements due to an irrepressible urge to move, and worsened at night. Symptoms had no temporal relationship with oral dopa-therapy and disappeared when DBS-STN was deactivated. A 1 h SIT assessed motor behavior with irrepressible urge to move, as well as sensory symptoms by visual analog scale. After 30 m DBS-STN was switched off followed by the appearance of tremor in the left arm while both motor and sensory symptoms of RLS disappeared in the left leg. The mechanisms of DBS-STN's impact on RLS remain controversial. We hypothesize the DBS-STN to induce in our patient a hyperdopaminergic tone. DBS-induced and DBS-ameliorated RLS represent interesting conditions to further understand the pathophysiology of RLS. Moreover, the present observation suggests that SIT can be a valuable tool to assess RLS in PD patients before and after DBS-STN in future prospective studies. • Deep brain stimulation may induce restless legs syndrome in Parkinson's patients. • Suggested immobilization test helps identify restless legs in Parkinson's patients. • Suggested immobilization test aids in distinguishing dyskinesia from restless legs. • A hyperdopaminergic tone may drive pathophysiology of restless legs syndrome. [ABSTRACT FROM AUTHOR]

Current FDA-approved transcranial MR-guided focused ultrasound (tcMRgFUS) transducers cause a curved dark band in 3 T brain images that runs through midbrain targets of ablative treatments for essential tremor and other applications, and signal is reduced by at least 25% elsewhere in the brain. This limits the set of scans that can be performed to guide and assess the effects of treatment. An electromagnetic simulation study was performed to elucidate the mechanisms causing the dark band. Based on the results, a pair of passive antennas in a "propeller-beanie" configuration were designed to manipulate the reflected waves to avoid signal cancellation within the brain. The antennas were optimized and validated with in-vivo experiments and hydrophone measurements. The simulation study revealed that the dark band is caused by RF waves reflected from the transducer's ground plane, which cancel with incoming waves from the scanner's body coil. The passive antennas shifted the dark band out of the brain and increased transmit efficiency in the center of brain 2.3 times while improving field homogeneity by 50%. They also increased receive sensitivity and SNR in anatomic and temperature imaging. They caused no detectable distortion in hydrophone-measured focal pressure profiles. The conductive ground planes and coupling media used in tcMRgFUS and other piezoelectric FUS transducers interact with a 3 T scanner's RF fields to reduce transmit efficiency and SNR. For tcMRgFUS scenario, "propeller beanie" passive reflecting antennas alleviated these effects. This could make a broader set of imaging sequences available to guide tcMRgFUS treatment. [ABSTRACT FROM AUTHOR]

Magnetic resonance-guided focused ultrasound (MRgFUS) has brought thalamotomy back to the frontline for essential tremor (ET). As functional organization of human brain strictly follows hierarchical principles which are frequently deficient in neurological diseases, whether additional damage from MRgFUS thalamotomy induces further disruptions of ET functional scaffolds are still controversial. This study was to examine the alteration features of brain functional frameworks following MRgFUS thalamotomy in patients with ET. We retrospectively obtained preoperative (ETpre) and postoperative 6-month (ET6m) data of 30 ET patients underwent MRgFUS thalamotomy from 2018 to 2020. Their archived functional MR images were used to functional gradient comparison. Both supervised pattern learning and stepwise linear regression were conducted to associate gradient features to tremor symptoms with additional neuropathophysiological analysis. MRgFUS thalamotomy relieved 78.19% of hand tremor symptoms and induced vast global framework alteration (ET6m vs. ETpre: Cohen d = − 0.80, P < 0.001). Multiple robust alterations were identified especially in posterior cingulate cortex ( ET 6 m ET6m vs. ET pre ETpre: Cohen d = 0.87, P = 0.048). Compared with matched health controls (HCs), its gradient distances to primary communities were significantly increased in ET pre ETpre patients with anomalous stepwise connectivity (P < 0.05 in ETpre vs. HCs), which were restored after MRgFUS thalamotomy. Both global and regional gradient features could be used for tremor symptom prediction and were linked to neuropathophysiological features of Parkinson disease and oxidative phosphorylation. MRgFUS thalamotomy not only suppress tremor symptoms but also rebalances atypical functional hierarchical architecture of ET patients. [ABSTRACT FROM AUTHOR]

• We reported a pair of siblings with OPDM2 exhibiting significant intrafamilial phenotypic heterogeneity. • The proband demonstrated rare features of neurogenic impairment, tremor and visual disturbance, which have been rarely reported in OPDM2, while the sister showed typical phenotype of OPDM. • The proband showed neurogenic impairment mimicking the phenotype of motor neuron disease (MND). • Ultra-long repeat expansions exceeding the upper limit could be non-pathogenic in OPDM2. Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease characterized by ocular, facial, bulbar and distal limb muscle weakness. Here, we presented a pair of siblings with OPDM2 displaying marked intrafamilial phenotypic heterogeneity. In addition to muscle weakness, the proband also demonstrated tremor and visual disturbance that have not been reported previously in OPDM2. Electrophysiological and pathological studies further suggested the presence of neurogenic impairment in the proband. Repeat-primed polymerase chain reaction (RP-PCR) and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR) confirmed the molecular diagnosis of OPDM2 in the siblings. Given the rarity of the case, the association between OPDM2 and tremor, visual disturbance, or neurogenic impairment remained to be explored. [ABSTRACT FROM AUTHOR]

[Display omitted] • We used quantified cortical thickness and subcortical volumes and performed regression to identify areas associated with ET or PD. • Smaller volumes in pallidum and thalamus were associated with greater odds of ET diagnosis. • Reduced thicknesses in anterior orbital gyrus, lateral orbital gyrus, and medial precentral gyrus were associated with ET. • Reduced volumes in caudate, amygdala, putamen, and basal forebrain were associated with PD. • Reduced thickness in pars orbitalis, supramarginal gyrus, and posterior cingulate were associated with PD. Essential tremor (ET) and Parkinson's disease (PD) are the most common tremor disorders and are common indications for deep brain stimulation (DBS). In some patients, PD and ET symptoms overlap and diagnosis can be challenging based on clinical criteria alone. The objective of this study was to identify structural brain differences between PD and ET DBS patients to help differentiate these disorders and improve our understanding of the different brain regions involved in these pathologic processes. We included ET and PD patients scheduled to undergo DBS surgery in this observational study. Patients underwent 3T brain MRI while under general anesthesia as part of their procedure. Cortical thicknesses and subcortical volumes were quantified from T1-weighted images using automated multi-atlas segmentation. We used logistic regression analysis to identify brain regions associated with diagnosis of ET or PD. 149 ET and 265 PD patients were included. Smaller volumes in the pallidum and thalamus and reduced thickness in the anterior orbital gyrus, lateral orbital gyrus, and medial precentral gyrus were associated with greater odds of ET diagnosis. Conversely, reduced volumes in the caudate, amygdala, putamen, and basal forebrain, and reduced thickness in the orbital part of the inferior frontal gyrus, supramarginal gyrus, and posterior cingulate were associated with greater odds of PD diagnosis. These findings identify structural brain differences between PD and ET patients. These results expand our understanding of the different brain regions involved in these disorders and suggest that structural MRI may help to differentiate patients with these two disorders. [ABSTRACT FROM AUTHOR]

Gamma knife (GK) thalamotomy has been used as a treatment option for essential tremor (ET). Numerous studies on GK use in ET treatment have reported more varied responses and complication rates. Data from 27 patients with ET who underwent GK thalamotomy were retrospectively analyzed. The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor, handwriting, and spiral drawing were evaluated. Postoperative adverse events and magnetic resonance imaging findings were also evaluated. The mean age at GK thalamotomy was 78.1 ± 4.2 years. The mean follow-up period was 32.5 ± 19.4 months. The preoperative postural tremor, handwriting, and spiral drawing scores were 3.4 ± 0.6, 3.3 ± 1.0, and 3.2 ± 0.8, respectively, all of which showed significant improvements to 1.5 ± 1.2 (55.9% improvement, P < 0.001), 1.4 ± 1.1 (57.6% improvement, P < 0.001), and 1.6 ± 1.3 (50% improvement, P < 0.001), respectively, at the available final follow-up evaluations. Three patients presented with no improvement in tremor. Six patients presented with adverse effects, including complete hemiparesis, foot weakness, dysarthria, dysphagia, lip numbness, and finger numbness, at the final follow-up period. Two patients presented with serious complications, including complete hemiparesis due to massive widespread edema and chronic encapsulated expanding hematoma. One patient died of aspiration pneumonia following severe dysphagia secondary to chronic encapsulated expanding hematoma. GK thalamotomy is an efficient procedure for treating ET. Careful treatment planning is necessary to reduce complication rates. The prediction of radiation complications will increase the safety and effectiveness of GK treatment. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is a disabling condition resulting from a dysfunction of cerebello-thalamo-cortical circuitry. Deep brain stimulation (DBS) or lesion of the ventral-intermediate thalamic nucleus (VIM) is an effective treatment for severe ET. Transcranial cerebellar brain stimulation has recently emerged as a non-invasive potential therapeutic option. Here, we aim to investigate the effects of high-frequency non-invasive cerebellar transcranial alternating current stimulation (tACS) in severe ET patients already operated for VIM-DBS. Eleven ET patients with VIM-DBS, and 10 ET patients without VIM-DBS and matched for tremor severity, were included in this double-blind proof-of-concept controlled study. All patients received unilateral cerebellar sham-tACS and active-tACS for 10 min. Tremor severity was blindly assessed at baseline, without VIM-DBS, during sham-tACS, during and at 0, 20, 40 min after active-tACS, using kinetic recordings during holding posture and action ('nose-to-target') task and videorecorded Fahn-Tolosa-Marin (FTM) clinical scales. In the VIM-DBS group, active-tACS significantly improved both postural and action tremor amplitude and clinical (FTM scales) severity, relative to baseline, whereas sham-tACS did not, with a predominant effect for the ipsilateral arm. Tremor amplitude and clinical severity were also not significantly different between ON VIM-DBS and active-tACS conditions. In the non-VIM-DBS group, we also observed significant improvements in ipsilateral action tremor amplitude, and clinical severity after cerebellar active-tACS, with a trend for improved postural tremor amplitude. In non-VIM-DBS group, sham- active-tACS also decreased clinical scores. These data support the safety and potential efficacy of high-frequency cerebellar-tACS to reduce ET amplitude and severity. [ABSTRACT FROM AUTHOR]

The thalamus is central to brain functions ranging from primary sensory processing to higher-order cognition. Structural deficits in thalamic association nuclei such as the pulvinar and mediodorsal nuclei have previously been reported in schizophrenia. However, the specificity with regards to clinical presentation, and whether or not bipolar disorder (BD) is associated with similar alterations is unclear. We investigated thalamic nuclei volumes in 334 patients with schizophrenia spectrum disorders (SSD) (median age 29 years, 59 % male), 322 patients with BD (30 years, 40 % male), and 826 healthy controls (HC) (34 years, 54 % male). Volumes of 25 thalamic nuclei were extracted from T1-weighted magnetic resonance imaging using an automated Bayesian segmentation method and compared between groups. Furthermore, we explored associations with clinical characteristics across diagnostic groups, including psychotic and mood symptoms and medication use, as well as diagnostic subtype in BD. Significantly smaller volumes were found in the mediodorsal, pulvinar, and lateral and medial geniculate thalamic nuclei in SSD. Similarly, smaller volumes were found in BD in the same four regions, but mediodorsal nucleus volume alterations were limited to its lateral part and pulvinar alterations to its anterior region. Smaller volumes in BD compared to HC were seen only in BD type I, not BD type II. Across diagnoses, having more negative symptoms was associated with smaller pulvinar volumes. Structural alterations were found in both SSD and BD, mainly in the thalamic association nuclei. Structural deficits in the pulvinar may be of relevance for negative symptoms. [ABSTRACT FROM AUTHOR]

The AIFM1 gene encodes a mitochondrial protein that acts as a flavin adenine dinucleotide-dependent nicotinamide adenine dinucleotide oxidase and apoptosis regulator. Monoallelic pathogenic AIFM1 variants result in a spectrum of X-linked neurological disorders, including Cowchock syndrome. Common features in Cowchock syndrome include a slowly progressive movement disorder, cerebellar ataxia, progressive sensorineural hearing loss, and sensory neuropathy. We identified a novel maternally inherited hemizygous missense AIFM1 variant, c.1369C>T p.(His457Tyr), in two brothers with clinical features consistent with Cowchock syndrome using next-generation sequencing. Both individuals had a progressive complex movement disorder phenotype, including disabling tremor poorly responsive to medications. Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus ameliorated contralateral tremor and improved their quality of life; this suggests the beneficial role for DBS in treatment-resistant tremor within AIFM1 -related disorders. [ABSTRACT FROM AUTHOR]

Magnetic resonance-guided focused ultrasound (MRgFUS) lesioning of the ventralis intermedius nucleus (VIM) has shown promise in treating drug-refractory essential tremor (ET). It remains unknown whether focal VIM lesions by MRgFUS have broader restorative effects on information flow within the whole-brain network of ET patients. We applied an information-theoretical approach based on intrinsic ignition and the concept of transfer entropy (TE) to assess the spatiotemporal dynamics after VIM-MRgFUS. Eighteen ET patients (mean age 71.44 years) underwent repeated 3T resting-state functional magnetic resonance imaging combined with Clinical Rating Scale for Tremor (CRST) assessments one day before (T0) and one month (T1) and six months (T2) post-MRgFUS, respectively. We observed increased whole brain ignition-driven mean integration (IDMI) at T1 (p < 0.05), along with trend increases at T2. Further, constraining to motor network nodes, we identified significant increases in information-broadcasting (bilateral supplementary motor area (SMA) and left cerebellar lobule III) and information-receiving (right precentral gyrus) at T1. Remarkably, increased information-broadcasting in bilateral SMA was correlated with relative improvement of the CRST in the treated hand. In addition, causal TE-based effective connectivity (EC) at T1 showed an increase from right SMA to left cerebellar lobule crus II and from left cerebellar lobule III to right thalamus. In conclusion, results suggest a change in information transmission capacity in ET after MRgFUS and a shift towards a more integrated functional state with increased levels of global and directional information flow. • For the first time, functional consequences of a focal VIM-lesion, are described by advanced information theory-based measures. • Information broadcasting between hubs of the tremor network is improved post-MRgFUS, correlating with tremor improvement. • VIM-MRgFUS improves global information transfer, as evidenced by increased mean integration, suggesting restorative effects. [ABSTRACT FROM AUTHOR]

While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear. Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects. The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05). This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT. • Patient-specific pathway activation models of VIM-DBS were developed. • Activating the lateral cerebello-thalamic tract (CTT) related to tremor control. • Paresthesias occurred with medial lemniscus and posterior-medial CTT activation. • Stimulation of the anterior-medial CTT was associated with dysarthria. • These results provide guidance on how to optimize DBS for Essential Tremor. [ABSTRACT FROM AUTHOR]

Ethanol has been shown to suppress essential tremor (ET) in patients at low-to-moderate doses, but its mechanism(s) of action remain unknown. One of the ET hypotheses attributes the ET tremorgenesis to the over-activated firing of inferior olivary neurons, causing synchronic rhythmic firings of cerebellar Purkinje cells. Purkinje cells, however, also receive excitatory inputs from granule cells where the α6 subunit-containing GABAA receptors (α6GABAARs) are abundantly expressed. Since ethanol is a positive allosteric modulator (PAM) of α6GABAARs, such action may mediate its anti-tremor effect. Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of ethanol and α6GABAAR-selective pyrazoloquinolinone PAMs. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Ethanol significantly and dose-dependently attenuated action tremor at non-sedative doses (0.4-2.4 g/kg, i.p.). Propranolol and α6GABAAR-selective pyrazoloquinolinones also significantly suppressed tremor activity. Neither ethanol nor propranolol, but only pyrazoloquinolinones, restored burrowing activity in harmaline-treated mice. Importantly, intra-cerebellar micro-injection of furosemide (an α6GABAAR antagonist) had a trend of blocking the effect of pyrazoloquinolinone Compound 6 or ethanol on harmaline-induced tremor. In addition, the anti-tremor effects of Compound 6 and ethanol were synergistic. These results suggest that low doses of ethanol and α6GABAAR-selective PAMs can attenuate action tremor, at least partially by modulating cerebellar α6GABAARs. Thus, α6GABAARs are potential therapeutic targets for ET, and α6GABAAR-selective PAMs may be a potential mono- or add-on therapy. [ABSTRACT FROM AUTHOR]

Recent studies have reported that essential tremor (ET) presents with not only motor symptoms but also cognitive dysfunction. However, detailed pathological mechanisms remain unclear. Here, we evaluate the characteristics of cognitive changes in older patients. Eighty-five patients aged 65 years or older with ET but without dementia were evaluated for cognitive function using the Addenbrooke Cognitive Examination Revised (ACE-R). The patients were compared with healthy controls (HCs), and the characteristics of cognitive dysfunction were examined. Age at onset and correlations with tremor severity were also investigated. Moreover, we performed resting-state network (RSNs) analysis in a subset of these patients, and the functional connectivity (FC) within the networks was compared with age-matched controls. Compared to HCs, older patients with ET showed a clear reduction in the total (p = 0.001), attention (p = 0.005), verbal fluency (p = 0.001), and memory (p = 0.001) ACE-R scores. Older-onset patients showed significant cognitive dysfunction compared with younger-onset patients. Verbal fluency correlated with tremor severity in the multiple regression analysis (p < 0.001). RSNs showed an increase in FC in the frontal lobes within the language network in patients with ET compared to HCs (p < 0.05, FWE-corrected). Older patients with ET showed obvious cognitive dysfunction compared to HCs, indicating that cognitive dysfunction varies by age of onset and correlates with tremor severity. The results of the RSNs analysis suggest that the pathological mechanism of cognitive dysfunction in ET patients involves network changes similar to those in the early stages of Alzheimer's disease. • Elderly ET patients showed significant cognitive dysfunction compared to HCs. • The cognitive dysfunction in ET patients may vary with age of tremor onset. • Verbal fluency was a factor significantly associated with tremor severity. • ET patients demonstrated significant increases in FC in the language network. • ET may have changes similar to those of AD or more likely to complicate AD than HC. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is one of the most prevalent neurological diseases varying considerably in clinical manifestations and prognosis, which indicates the existence of subtypes. Identifying ET subtypes is crucial for explaining clinical heterogeneity. This study aimed to identify ET subtypes using unsupervised clustering analysis based on clinical manifestations and explore underlying brain topology within both functional and structural networks. We recruited 103 ET patients and 43 healthy control subjects. K-means clustering analysis was performed to identify ET subtypes based on age of onset, motor and non-motor symptoms. Functional MRI and diffusion tensor imaging data were used to construct functional and structural networks. Global attributes (clustering coefficient, characteristic path length, global efficiency, and local efficiency) and nodal attributes (nodal clustering coefficient, nodal efficiency, and nodal degree centrality) were calculated for topological analysis. We identified two subtypes: Subtype 1 (earlier age of onset – without nonmotor symptoms subtype) and Subtype 2 (later age of onset – with nonmotor symptoms subtype). Decreased clustering coefficient and global efficiency, increased characteristic path length were observed in Subtype 2 compared to NC, while only decreased global efficiency was observed in Subtype 1. More widespread brain regions with decreased nodal clustering coefficient were specifically observed in Subtype 2. We identified two ET subtypes based on comprehensive clinical information and revealed that Subtype 2 may be a more malignant subtype. Our study firstly unsupervisedly identifies the clinical heterogeneity of ET and provides neuroimaging evidence for better understanding the underlying disease biology. • Two clinical ET subtypes are defined using an unsupervised clustering method. • Subtype 2 demonstrates worse global and nodal functional topological organization. • Two subtypes demonstrate relatively preserved structural topological organization. [ABSTRACT FROM AUTHOR]

A thorough history and physical examination may be insufficient for comprehensively studying patients with tremor. In such instances, neurophysiology serves as an adjunct to the physical examination. Our aim is to present compelling evidence supporting the utilization of neurophysiological studies in various tremor conditions. A panel of global experts, convened by the Study Group on Clinical Neurophysiology for Movement Disorders, examined the application and utility of neurophysiology across diverse movement disorders. This manuscript provides a detailed methodology for electrophysiological studies in tremors helping to differentiate them from myoclonus, comparing tremor in parkinson vs atypical parkinsonisms, describing dystonic tremor, describing the differences between Parkinson and essential tremor and the characteristics of functional tremor. Neurophysiological studies play a crucial role in characterizing tremor syndromes and aiding in their differentiation from other hyperkinetic movement disorders. • Neurophysiology helps differentiating tremor from myoclonus. • Neurophysiology helps differentiating tremor in Parkinson's disease from tremor in atypical Parkinsonian syndromes. • Neurophysiology helps differentiating dystonic tremor from Essential tremor. • Neurophysiology helps to identify patients with (comorbid) functional tremor. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a well-established treatment for motor circuit disorders such as Parkinson disease, dystonia, and essential tremor, particularly when pharmacological interventions are insufficient. 1-3 The increase in DBS-related publications and the growing number of patients receiving DBS highlight the acceptance and refinement of the procedure. 3,4 Despite its widespread use, comprehensive anatomical knowledge of deep brain nuclei remains critical for enhancing clinical efficacy. Accurate targeting of the complex three-dimensional anatomy of the target nuclei is crucial for maximizing therapeutic effects and minimizing adverse side effects. However, existing anatomical guides often lack depth perception. 5,6 We dissected specimens prepared using the Klingler method, 7 proceeding sequentially from lateral to medial, medial to lateral, and superior to inferior. We then generated a video guide for three-dimensional models of the DBS target nuclei at each stage using the photogrammetry method (Video 1). Our models were evaluated via augmented reality within a real-world context, and radiological models of these nuclei generated through segmentation were analyzed. Thus, our models and videos offer a novel method for visualizing the complex anatomy of deep brain nuclei, which could help enhance the precision of DBS procedures and may improve patient outcomes. This advanced understanding of spatial anatomical relationships may be beneficial for the continued development and success of DBS therapy. [ABSTRACT FROM AUTHOR]

• The orientation of diffusion gradients depends on MRI manufacturer. • Interpretation of diffusion color encoded (DCE) maps depends on brain orientation. • The ACPC system reliably reflects the anatomic physiologic brain orientation. • The most important angle mismatch between brain and gradients was the pitch. • ACPC reorientation of gradients improved the interpretation of DCE maps. The common structural interpretation of diffusion color-encoded (DCE) maps assumes that the brain is aligned with the gradients of the MRI machine. This is seldom achieved in the field, leading to incorrect red (R), green (G) and blue (B) DCE values for the expected orientation of fiber bundles. We studied the virtual reorientation of gradients according to the anterior commissure – posterior commissure (ACPC) system on the RGB derivatives. We measured mean ± standard deviation of average, standard deviation, skewness and kurtosis of RGB derivatives, before (rO) and after (acpcO) gradient reorientation, in one healthy-subject group with head routinely positioned (HS-routine), and in two patient groups, one with essential tremor (ET-Opti), and one with Parkinson's disease (PD-Opti), with head position optimized according to ACPC before acquisition. We studied the pitch, roll and yaw angles of reorientation, and we compared rO and acpcO conditions, and groups (ad hoc statistics). Pitch (maximum in the HS-routine group) was greater than roll and yaw. After reorientation of gradients, in the HS-routine group, DCE average increased, and Stddev, skewness and kurtosis decreased; R, G and B average increased, and R and B skewness and kurtosis decreased. By contrast, in the ET-Opti group and the PD-Opti group, R, G and B, average and Stddev increased, and skewness and kurtosis decreased. In both rO and acpcO conditions, in the ET-Opti and PD-Opti groups, average and standard deviation were higher, while skewness and kurtosis were lower. DCE map interpretability depends on brain orientation. Reorientation realigns gradients with the anatomic and physiologic position of the head and brain, as exemplified. [ABSTRACT FROM AUTHOR]

• The spectrum of gait, and balance disturbance in ET is not fully defined. • This is the first study that compared gait dysfunction with white matter DTI parameters in ET patients <65 years. • ET patients with higher total tremor score and head tremor had significantly poor gait scores and more cognitive impairment. • Poor gait scores significantly correlated with increase in diffusivities and decrease in FA over various WM clusters in brain. Essential tremor (ET) is a syndrome characterized by both motor (tremor, gait, and balance dysfunction) and non-motor features like cognitive deficits, depression, sleep, mood, and anxiety disorders. The present study was conducted to characterize the clinical dysfunction and brain localization of gait and balance disturbances in ET patients. 174 ET patients and 150 matched healthy controls were evaluated. ET was diagnosed using the Consensus Statement on the Classification of Tremors, from the Task Force on Tremors of the Movement Disorder Society criteria. Participants were assessed by using a structured neuropsychological battery and validated gait scores. Diffusion tensor imaging (DTI) data comprising mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy were analyzed for all subjects. The mean age of essential tremor cases was 45.1 ± 14.08 years. Male: female ratio in ET cases was 2.5:1. Cognitive impairment was observed in a quarter of ET patients. A significant difference was observed in Berg balance scale scores, tandem gait missteps, and tandem stance time between ET cases and controls (p-value < 0.0001). ET patients with higher tremor scores and head tremors were more aged and had poor gait and cognitive scores (p < 0.0001). In our study, we observed poor gait scores significantly correlated with an increase in mean, radial, and axial diffusivities as well as a decrease in fractional anisotropy over various white matter clusters in the brain. No such correlation was observed among the controls. The present study demonstrates a correlation between gait scores and DTI metrics suggesting a neuroanatomic basis for gait impairment in ET patients. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitor-related tremors occur in up to 50% of solid organ transplant recipients and are disabling in severe cases. We describe a bilateral lung transplant recipient with essential tremors that significantly worsened after tacrolimus initiation. She did not have improvement with the change to extended-release tacrolimus, the use of everolimus as a calcineurin inhibitor-sparing agent, or the addition of primidone, clonazepam, or propranolol. She underwent magnetic resonance–guided focused ultrasound thalamotomy with significant improvement in her tremor and activities of daily living. [ABSTRACT FROM AUTHOR]

• Cortico-muscular coherence and cortico-cortical out-strength were assessed on MEG-EMG signals in patients with essential tremor. • MRgFUS treatment of thalamic ViM nucleus resulted in immediate changes in cortico-muscular coherence. • A reorganization of the cortico-cortical communication occurred mainly long after MRgFUS treatment. Drug-resistant essential tremor (ET) can be treated by Magnetic-Resonance-guided Focused-Ultrasound (MRgFUS) targeted to thalamic ventralis-intermediate nucleus (ViM). We are presenting the results obtained in ET patients by evaluating the cortico-muscular coherence (CMC) and the out-strength among cortical areas. We recorded MEG-EMG signals in 16 patients with predominant tremor on the right upper limb. The examination was performed the day before MRgFUS (T0) treatment, 24 hours (T1), and 3-months (T2) after lesioning the left ViM. Normalized CMC (nCMC) and cortico-cortical out-strength among cortical areas were assessed during isometric extension of the right hand. According to the Essential Tremor Rating Assessment Scale, 13 of 16 patients were considered responders. At T1, in the beta-band, nCMC increased in the left hemisphere, namely in the areas directly involved in motor functions. At T2, the nCMC in non-motor areas decreased and the out-strength from other examined cortical areas toward the left motor-area decreased. In patients positively responding to MRgFUS, the CMC increased in the motor-area of the treated hemisphere immediately after the treatment, while the reorganization of CMC and cortico-cortical out-strength toward the cortical motor area occurred with a delay. The effective treatment with MRgFUS corresponds with a readjustment of the CMC and of the communication between cortical areas. [ABSTRACT FROM AUTHOR]

Introduction: and objective: Tremor is a disabling symptom of PD that usually responds poorly to available standard pharmacological agents. This study aimed to assess the effect of Zonisamide 25 mg on tremor in tremor-dominant PD patients as compared to placebo.Methods: This was a randomized, placebo-controlled, double-blind study. Parkinson's disease patients were allocated either to the intervention group (standard treatment along with Zonisamide 25 mg add-on) or the placebo group (standard treatment along with placebo). Baseline Unified Parkinson's Disease Rating Scale (UPDRS) and Tremor Research Group Essential Tremor Rating Scale (TETRAS) scores, as well as accelerometric tremor analysis were done and follow-up assessments of the same were done after 12 weeks of intervention. Percentage change from baseline in the UPDRS tremor score was the primary outcome whereas percentage change from baseline of total UPDRS score, UPDRS rigidity and bradykinesia scores, TETRAS score, and accelerometric tremor analysis values were the secondary outcomes.Results: There was no significant difference in the percentage change from baseline UPDRS tremor scores between the two groups (placebo: 8.33 [-19.89-23.86] vs drug: 26.14 [-35.58 to -16.07], p-value: 0.164, CI: 0.157-0.171). Best-case analysis for missing values showed a significant improvement in the drug group, compared to the placebo group (p-value: < 0.001, CI: <0.001 - <0.001).Conclusion: Zonisamide at a dose of 25 mg per day did not improve tremor in tremor-dominant PD patients, however, a positive trend was seen as compared to Placebo in the UPDRS tremor score. Larger studies are required to confirm this finding. [ABSTRACT FROM AUTHOR]

Background: Orthostatic tremor is a rare and debilitating movement disorder. Its first-line treatment is pharmacological. For pharmaco-refractory patients, surgical treatment options such as deep brain stimulation (DBS) and spinal cord stimulation (SCS) have been investigated recently.Objectives: We conducted a systematic review of all published outcome and safety data on DBS and SCS for orthostatic tremor patients.Methods: We searched Pubmed and Embase for studies describing orthostatic tremor patients treated with DBS or SCS. We collected all available outcome and safety data and our primary endpoint was the change in unsupported stance duration 1 year postoperatively (±6 months).Results: We included 15 studies, reporting on 32 orthostatic tremor patients who underwent DBS, 4 patients SCS and 2 both. The ventral intermediate nucleus and the zona incerta were targeted in 25/34 and 9/34 DBS cases, respectively. The median stance time at 1 year follow-up was 240 s compared to 30 s pre-operatively (p < 0.001). Stimulation-induced side effects occurred in the majority of patients, but were often transient. Bilateral stimulation appeared more effective than unilateral and stimulation settings were comparable to thalamic DBS for essential tremor. There were insufficient data available to draw meaningful conclusions on the long-term effects of DBS. Due to insufficient data, no conclusions could be drawn on the effects of SCS on orthostatic tremor.Conclusion: DBS may be effective to increase stance time in orthostatic tremor patients in the first year, but further research is necessary to evaluate the long-term effects and the role of spinal cord stimulation. [ABSTRACT FROM AUTHOR]

Introduction: Essential tremor (ET) is one of the most common neurological disorders, affecting an estimated 2.2% of the entire US population. Despite its high prevalence and associated morbidity and mortality, there are no published data on the medical costs associated with ET care.Methods: This is a retrospective secondary data analysis using the 5% Medicare claims data from 2016 to study age-eligible Medicare beneficiaries diagnosed with ET (diagnostic code G250) relative to a propensity score-matched group of comparison beneficiaries without ET (27,081 in each arm). Comparisons were matched within age strata and on the full set of Charlson comorbidity indicators, race, and sex. We examined encounter-level costs (amounts paid) and total annual costs of care (in constant $2021 dollars) adjusting for age, sex, race/ethnicity, provider specialty, setting, and the most common comorbidities, using a generalized linear model.Results: The final sample included 54,162 total beneficiaries, with an average age of 75, 65% female and 94% Non-Hispanic White. On average, Medicare beneficiaries with at least one outpatient or physician office visit with an ET diagnosis have $1068 (95% CI: $981, $1154) in additional direct medical care expenditures per year relative to statistically similar comparison beneficiaries of the same age. Across the population, we predicted aggregated additional spending attributable to ET among Medicare beneficiaries between $1.5 billion and $5.4 billion per year.Conclusion: The estimated direct medical costs among Medicare beneficiaries with an ET diagnosis aggregated to the population-level are non-trivial. These data begin to fill a gap in knowledge. [ABSTRACT FROM AUTHOR]

Introduction: People with essential tremor commonly experience psychological difficulties that are not addressed. The effect of stigma, i.e., negative judgement by others because of a perceived difference in this case shaky movement, is a heretofore unstudied element. This project was undertaken to develop and field test a new measure for stigma associated with essential tremor.Methods: Under guidance from a patient panel and an expert panel of neurologists and psychologists, the essential tremor stigma construct was delineated, and survey items were written to quantify three dimensions of interest: cumulative experience of stigma; related psychological distress; and resulting behavioral dysfunction. After pilot testing and revision, the essential tremor stigma measure underwent field testing by 198 essential tremor patients at two academic neurology clinics.Results: The experience, distress and dysfunction scales were shown to have good internal consistency and test-retest reliability. Retained items demonstrated acceptable correlations and response properties. The validity of the distress scale was supported by concurrence with an existing stigma scale for neurologic disease, while a patient's openness to psychologic referral was predicted by higher scores on the dysfunction scale.Conclusion: This new measure is introduced to study the phenomenon of stigma associated with essential tremor. It may prove useful in assessing potential treatments for the psychological distress and maladaptive behavior that result from this stigma. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a treatment for medically refractory essential tremor (ET), but there is a paucity of literature examining the effects of DBS on voice in patients with ET pre-DBS and post-DBS. This study aimed to report a comprehensive evaluation of voice in patients with ET pre-DBS and 6-months post-DBS. Case series. Five patients receiving DBS for ET underwent voice evaluations pre-DBS and 6-months post-DBS. One patient had concurrent ET of the vocal tract (ETVT). The evaluation included patient-reported, perceptual, acoustic, and phonatory aerodynamic analyses of voice. Voice Handicap Index-10, Grade, Roughness, Breathiness, Asthenia, Strain Scale, perturbation measures, cepstral spectral index of dysphonia, cepstral peak prominence, and mean phonatory airflow measures were also among the data collected. Patients with ET presented with minimal changes in perceptual, acoustic, and phonatory aerodynamic parameters. Perceived vocal roughness significantly increased 6-months post-DBS (P = 0.047). The patient with ETVT presented with clinically significant improvement in almost all collected voice parameters 6-months post-DBS. This is the first study to provide data encompassing auditory perceptual voice analysis, voice-specific patient-reported quality of life measures, acoustic, and phonatory aerodynamic outcomes in patients pre-DBS and 6-months post-DBS for ET. The results of our preliminary study have implications for the use of a comprehensive voice assessment to identify and measure change in voice outcomes in patients with ET and ETVT pre- and postsurgery. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is one of the most common movement disorders in adults, and its early assessment and diagnosis are crucial for disease management in movement disorders. Nowadays, the severity of tremors can only be diagnosed and evaluated by laboratory tests. However, there are certain subjective factors in traditional assessment methods by the naked eye of a neurologist, which often leads to some biases. This study proposes a novel multi-modal signals-based automated quantitative assessment system for tremor severity. Specifically, we develop a two-stage framework that performs posture pattern recognition on the raw data, then extracts kinematic parameters to build an individualized model for each task. Besides, we established a strict clinical paradigm, including 121 ET patients, finely evaluated by a committee of neurologists to build a high-quality database. The models' performances showed that most of the kinematic parameters designed in this study could effectively map the severity of the tremor. The F1 score for classification of the posture task based on deep learning networks was 99.02%, and the quantification of symptom scores based on machine learning models ranged from 94.77 to 99.00%. These results demonstrate the effectiveness of the proposed framework can automatically provide objective and accurate scores for ET symptom assessment. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the accuracy of the SureTune3 postoperative imaging software in determining the location of a deep brain stimulation (DBS) electrode based on clinical outcomes and the adverse effects (AEs) observed. Twenty-six consecutive patients with Parkinson disease (n = 17), essential tremor (n = 8), and dystonia (n = 1) who underwent bilateral DBS surgery (52 electrodes) were included in this study. Presurgical assessments were performed in all patients prior to surgery and at 3 and 6 months after surgery, using quality-of-life and clinical scales in each case. The SureTune3 software was used to evaluate the anatomical positioning of the DBS electrodes. Following DBS surgery, motor and quality-of-life improvement was observed in all patients. Different AEs were detected in 12 patients, in 10 of whom (83.3%) SureTune3 related the symptoms to the positioning of an electrode. A clinical association was observed with SureTune3 for 48 of 52 (92.3%) electrodes, whereas no association was found between the AEs or clinical outcomes and the SureTune3 reconstructions for 4 of 52 electrodes (7.7%) from 4 different patients. In 2 patients, the contact chosen was modified based on the SureTune3 data, and in 2 cases, the software helped determine that second electrode replacement surgery was necessary. The anatomical position of electrodes analyzed with SureTune3 software was strongly correlated with both the AEs and clinical outcomes. Thus, SureTune3 may be useful in clinical practice, and it could help improve stimulation parameters and influence decisions to undertake electrode replacement surgery. [ABSTRACT FROM AUTHOR]

• We measured power in the tremor band (4–8 Hz) in the 15 major superficial upper-limb muscles of persons with Essential Tremor. • Tremor-band power varied between patients, but on average, the anterior deltoid and wrist extensor ulnaris muscles exhibited the most power. • The distribution was similar for postural and kinetic tremor, different limb positions, repetitions, and patient characteristics. Peripheral tremor suppression has the potential to reduce tremor, but we do not currently know where best to intervene. The purpose of this study was to characterize the distribution of tremorogenic activity among upper-limb muscles. Surface electromyography was recorded from the 15 major superficial muscles of the upper limb while 25 patients with Essential Tremor performed postural and kinetic tasks. We defined tremorogenic activity as power in the tremor band (4–8 Hz) and determined the distribution of this power among muscles. The distribution varied considerably between patients (mean r = 0.58), but on average, the greatest power was found in the anterior deltoid and extensor carpi ulnaris muscles. Other muscles with high power included the extensor carpi radialis, pectoralis major, lateral deltoid, and brachialis muscles. This distribution was similar (mean r ≥ 0.88) for postural and kinetic tremor, various limb configurations, repetitions, and patient characteristics (sex, tremor severity, age of onset, and duration). We identified a rough pattern in which muscles opposing gravity appeared to have the highest tremor-band power; we hypothesize that the distribution of tremorogenic muscle activity depends in part on the distribution of voluntary activity required by the task. Understanding which muscles exhibit the most tremorogenic activity is one of the steps in the pursuit of optimizing peripheral tremor suppression. [ABSTRACT FROM AUTHOR]

Background: The construct of Essential Tremor plus (ET-plus) refers to patients who also have rest tremor and/or mild neurologic signs of unknown significance. It is unclear whether soft signs represent confounding factors or are useful in suspecting an alternative condition.Methods: Using a Bayesian approach to ET-plus patients recruited in The ITAlian tremor Network (TITAN), we analyzed the probability that these patients do not have ET.Results: The data of 274 ET-plus patients were extracted from the TITAN database. The majority of patients (240/274; 87.5%) had a single soft sign. The post-test probability of not having ET was different according to the specific soft sign: namely, 0.64 (rest tremor); 0.46 (questionable dystonia); 0.85 (questionable bradykinesia); 0.19 (soft gait impairment); and 0.09 (questionable cognitive issues). In patients with multiple soft signs, the post-test probability of not having ET was higher than 50% for 7 out of 11 combinations, accounting for 44.1% of subjects. Overall, the post-test probability of not having ET was higher than 50% in up to 71.5% of ET-plus patients.Discussion: We have here shown that: 1) the soft signs differently contribute in modulating the probability that a patient does not have ET; and 2) the effect of multiple soft signs are not always addictive. Future studies are needed to collect prevalence figures of soft signs in different neurological disorders as well as in the elderly and to calculate their value in predicting the development of an alternative tremor syndrome. [ABSTRACT FROM AUTHOR]

MRI-guided focused ultrasound (MRgFUS) thalamotomy is a novel, effective, and non-invasive treatment for essential tremor (ET). However, the network mediating MRgFUS in treating ET is not precisely known. This study aimed to identify the disease-specific network associated with the therapeutic effects of MRgFUS thalamotomy on ET and investigate its regional characteristics and genetic signatures to gain insights into the neurobiological mechanism of ET and MRgFUS thalamotomy. Twenty-four ET patients treated with MRgFUS thalamotomy underwent resting-state functional MRI at baseline and postoperative 6 months to measure the fractional amplitude of low-frequency fluctuation (fALFF). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject fALFF data to identify the ET-related network. Genetic functional enrichment analysis was conducted to study the genetic signatures of this ET-related network using brain-wide gene expression data. OrT/CVA analysis revealed a significant ET-related network for which subject expression showed consistent increases after surgery. The treatment-induced increases in subject expression were significantly correlated with concurrent tremor improvement. This network was characterized by increased activity in the sensorimotor cortex and decreased activity in the posterior cingulate cortex. It was correlated with an expression map of a weighted combination genes enriched for mitochondria relevant ontology terms. This study demonstrates that the therapeutic effects of MRgFUS thalamotomy on ET are associated with modulating a distinct ET-related network which may be driven by mitochondria relevant neurobiological mechanism. Quantification of treatment-induced modulation on the ET-related network can provide an objective marker for evaluating the efficacy of MRgFUS thalamotomy. [ABSTRACT FROM AUTHOR]

Background: Essential tremor (ET) is characterized by action tremor, although rest tremor may also occur. Despite this, rest tremor has not been studied extensively. A dearth of studies compare the relationship of rest tremor to other types of tremors in ET.Methods: Two-hundred-and-thirteen ET cases underwent detailed neurological examination, including evaluations of rest, simple kinetic, postural, and intention tremors. A movement disorders neurologist assessed the prevalence of each type of tremor. Each instance of tremor was classified as either symmetrical (present and equally severe on both sides of the body) or asymmetrical (only present on or more severe on one side of the body). Asymmetrical rest tremor that co-occurred with other types of asymmetrical tremors in a given case was further classified as either concordant (i.e., asymmetry on the same side of the body) or discordant (i.e., asymmetry on opposite sides of the body). Chi-square analyses examined the prevalence of concordant versus discordant pairings.Results: Sixty-two cases (29.2%) had rest tremor while seated. Fifteen (7.4%) had rest tremor while standing. Among asymmetric tremor pairings, concordant pairings occurred 2-2.7 times more frequently than discordant pairings - for pairings involving rest tremor while seated, 73.2% were concordant and 26.8% discordant (p < 0.001); for pairings involving rest tremor while standing, 66.7% were concordant and 33.3% were discordant (p = 0.25).Conclusions: Rest tremor often lateralized with other tremor types. These data add to our knowledge of the phenotypic manifestations of ET. [ABSTRACT FROM AUTHOR]

Group analysis of patients with deep brain stimulation (DBS) has the potential to help understand and optimize the treatment of patients with movement disorders. Probabilistic stimulation maps (PSM) are commonly used to analyze the correlation between tissue stimulation and symptomatic effect but are applied with different methodological variations. To compute a group-specific MRI template and PSMs for investigating the impact of PSM model parameters. Improvement and occurrence of dizziness in 68 essential tremor patients implanted in caudal zona incerta were analyzed. The input data includes the best parameters for each electrode contact (screening), and the clinically used settings. Patient-specific electric field simulations (n = 488) were computed for all DBS settings. The electric fields were transformed to a group-specific MRI template for analysis and visualization. The different comparisons were based on PSMs representing occurrence (N-map), mean improvement (M-map), weighted mean improvement (wM-map), and voxel-wise t-statistics (p-map). These maps were used to investigate the impact from input data (clinical/screening settings), clustering methods, sampling resolution, and weighting function. Screening or clinical settings showed the largest impacts on the PSMs. The average differences of wM-maps were 12.4 and 18.2% points for the left and right sides respectively. Extracting clusters based on wM-map or p-map showed notable variation in volumes, while positioning was similar. The impact on the PSMs was small from weighting functions, except for a clear shift in the positioning of the wM-map clusters. The distribution of the input data and the clustering method are most important to consider when creating PSMs for studying the relationship between anatomy and DBS outcome. [Display omitted] • A high-resolution patient-specific template of the deep brain anatomy was created. • Probabilistic stimulation maps (PSM) were developed for improvement and side effect. • Distribution of input data is an important factor when creating PSMs. • Response clusters are highly dependent on the analysis method. • Weighting functions and high resolution has less importance in resulting PSMs. [ABSTRACT FROM AUTHOR]

Essential tremor (ET) is a progressive disorder characterized by altered network connectivity between the cerebellum, thalamus, and cortical regions. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) of the ventral intermediate nucleus (VIM) is an effective, minimally invasive treatment for ET. The impact of MRgFUS interventions on regional Gray Matter Volume (GMV) are as yet not well understood. Forty-six patients with medication-resistant ET underwent unilateral VIM-MRgFUS. Voxel-based morphometry was applied to investigate GMV changes over a time span of 6 months in the whole brain and the thalamus in particular to investigate local and distant effects. Clinically, contralateral tremor significantly decreased by 68 % at 6 months following MRgFUS. In addition to local GMV decreases in thalamic nuclei (VIM, ventral lateral posterior, centromedian thalamus and pulvinar), VBM revealed remote GMV decreases in the ipsilesional insula and the anterior cingulate cortex as well as the contralesional middle occipital gyrus. Increased GMV was found in the right superior and middle temporal gyrus, as well as in the left inferior temporal gyrus. There was no significant correlation between regional GMV declines and tremor improvement. However, temporal volume increases were associated with improved motor-related functional abilities and quality of life outcomes. Our findings implicate distributed structural changes following unilateral VIM-MRgFUS. Structural losses could reflect Wallerian degeneration of VIM output neurons or plasticity due to decreased sensory input following tremor improvement. • MRgFUS targeting the VIM causes local GMV changes in thalamic nuclei exceeding the VIM. • MRgFUS causes distributed morphometric increases and decreases in cortical areas. • Findings may be driven by Wallerian degeneration or altered functional input. [ABSTRACT FROM AUTHOR]

Assessing the severity of kinetic tremor is important in clinical and research settings. Archimedes spirals are often used to assess tremor severity. Rating tremor from spirals has been based solely on visual information. However, one can often "hear" tremor. We evaluated the type of information that could be gained from hearing tremors and assessed its validity using visualized tremor as a gold standard. 52 essential tremor cases (94 spirals), 11 Parkinson's disease patients and 11 controls (20 spirals each) were enrolled. During videotaping, cases drew Archimedes spirals in a standardized manner. Three experienced movement disorders neurologists first listened to videotaped spiral drawing (no visual) and assigned a tremor severity rating using Washington Heights Inwood Genetic Study of Essential Tremor (WHIGET) ratings (0, 0.5, 1, 1.5, 2, 3). Later, the neurologist rated the physical (i.e., visual) spiral and assigned a WHIGET tremor rating. The Spearman's correlation coefficient (visual vs. auditory rating) was 0.721 (p < 0.001) and the weighted kappa statistic was 0.674, a level of agreement that is considered good. Auditory information provides in-time synchronous corroboration of what the rater is seeing. That is, it informs the visual data and provides construct validity. The results of this study have ramifications for observational and experimental therapeutic studies, which commonly rely on videotaped tremor examinations. Additional corroborative information is available if the sound is left on. Regardless of the decision to present sound to the rater or not, clear instructions and a standardized practice within the study are imperative. • Archimedes spirals are often used to assess tremor severity. • Ratings are usually based on visual information, but one can often "hear" tremor. • A neurologist assigned tremor severity ratings based on auditory data. • Agreement between auditory and visual ratings was very high. • Auditory assessment of tremor has been underappreciated. [ABSTRACT FROM AUTHOR]

There is growing body of evidence that some patients with essential tremor (ET) have an increased risk for developing Parkinson's disease (PD) and, therefore, as noted in our paper, ET may be considered a prodromal feature of PD. Although a genetic causal link between ET and PD has not been established, future development of diagnostic and progression biomarkers may provide insight into the relationship between these common movement disorders. [ABSTRACT FROM AUTHOR]

Primidone and propranolol are primary treatments for essential tremor, however the exact mechanisms underlying their efficacy are not fully elucidated. Understanding how these medications alleviate tremor may guide the development of additional pharmacologic treatments. Our prospective observational study employed transcranial magnetic stimulation (TMS) to explore mechanisms of primidone and propranolol effects in essential tremor. Eyeblink classical conditioning (EBCC) was tested as a potential predictor of treatment response. Patients with essential tremor underwent two evaluations: prior to commencing primidone or propranolol and following a minimum of three months of treatment. Tremor severity was assessed using accelerometry and clinically. TMS was employed to study changes in corticospinal excitability - resting and active motor thresholds, resting and active input/output curves and intracortical excitability - cortical silent period (CSP), short interval intracortical inhibition intensity curve (SICI), long interval intracortical inhibition (LICI), intracortical facilitation (ICF), and short afferent inhibition (SAI). EBCC, a marker of cerebellar function, was studied at baseline. Of the 54 enrolled patients (28 primidone, 26 propranolol), 35 completed both visits. Primidone effect on decreasing hand tremor was associated with decreased corticospinal excitability, prolongation of CSP, increased LICI, increased SAI and decreased SICI. Propranolol effect on hand tremor was associated with decreased corticospinal excitability and increased SAI. Better EBCC at baseline predicted better response to primidone. Primidone exerts its therapeutic effects by blocking voltage-gated sodium channels and by modulating GABA-A and GABA-B intracortical circuits. Propranolol's central effects are likely mediated via noradrenergic modulation of GABA outflow. • Primidone and propranolol treatments for essential tremor studied with TMS. • Primidone reduces tremor by modulating GABA-A and GABA-B intracortical circuits. • Propranolol's tremor reduction linked to decreased corticospinal excitability and increased SAI. • Better baseline EBCC predicts improved response to primidone treatment. • Study advances understanding of how primidone and propranolol alleviate tremor. [ABSTRACT FROM AUTHOR]

• Essential tremor (ET) and Parkinson's disease (PD) share overlapping clinical and pathophysiological features. • A subset of ET patients may eventually progress to PD. • ET may represent a prodromal feature of PD, similar to RBD and hyposmia. [ABSTRACT FROM AUTHOR]

The differential diagnosis of early Parkinson's disease (PD) by a single biomarker is still challenging due to its symptomatic overlap with other neurological diseases. Increasing evidences support the use of saliva biomarkers of neurodegeneration, including microRNAs and α-synuclein (α-syn) seeding activity, to diagnose patients with idiopathic PD and multiple system atrophy (MSA). Our previous study confirmed the salivary microRNA-29a-3p (miRNA-29a-3p) and α-syn seeding activity could differentiate PD and MSA from healthy control subjects (HCs) and patients with essential tremor (ET). We set up α-syn real-time quaking induced conversion seed amplification assay (α-syn RT-QuIC SAA) in 203 participants from the Peking University First Hospital with PD (n = 101), MSA (n = 32), ET (n = 17) and healthy control subjects (HCs, n = 53). We also determined miRNA-29a-3p in saliva by real time quantitative PCR (RT-qPCR) and, in 155 participants (36HCs, 80PD, 22MSA, 17ET). Sensitivity of RT-QuIC seed amplification assay (SAA) for PD was 70.30 %, for MSA was 56.25 % and specificity for healthy controls was 92.45 %. The expression level of saliva miRNA-29a-3p was significantly decreased in patients with PD (p < 0.001) and MSA (p < 0.0001), and allowed differentiation with HCs (PD vs. HCs, AUC 0.69; MSA vs. HCs, AUC 0.95). Sensitivity of salivary miRNA-29a-3p for PD and MSA were 70.00 % and 95.45 %, respectively, and specificity for PD and MSA were 77.23 % and 80.56 %, respectively. By combining the salivary α-syn RT-QuIC SAA with miRNA-29a-3p, sensitivity for PD vs. HCs increasing to 75.00 %, while sensitivity for MSA vs. HCs increasing to 90.00 %. Specificity was 91.67 % for PD and 88.89 % for MSA after combining assessment of salivary α-syn RT-QuIC SAA. Salivary α-syn RT-QuIC SAA yielded 100.00 % sensitivity and 79.21 % specificity for PD vs. ET, and 100.00 % sensitivity and 65.63 % specificity for MSA vs. ET. Salivary miRNA-29a-3p provied 88.24 % sensitivity and 48.75 % specificity for PD vs. ET and 86.36 % sensitivity and 88.24 % specificity for MSA vs. ET. The combined assessment of saliva markers provided a better diagnostic value for ET vs. synucleinopathies (ET vs. PD: 88.24 % sensitivity and 81.25 % specificity; ET vs. MSA: 94.12 % sensitivity and 90.00 % specificity) than RT-QuIC SAA alone, or miRNA-29a-3p alone. The combination of lag phase and miRNA-29a-3p could add higher specificity (85.71 %) which increased approximately 40 percent (specificity: miRNA-29a-3p 47.50 %, lag phase 48.98 %) for discriminating PD from MSA. However, the sensitivity of combining these two methods was 61.11 %, which was lower than lag phase alone (89.66 %) or miRNA-29a-3p alone (95.45 %). This study confirmed that saliva, a non-invasive biofluid in synucleinopathies possessed potential diagnostic power between PD, MSA, ET and normal controls. We show the combined value of saliva miRNA-29a-3p and saliva α-syn RT-QuIC SAA in the diagnosis and differential diagnosis of Parkinsonism. • Combining salivary α-syn seeding activity and miRNA-29a-3p improved sensitivity to differentiate PD from HCs. • Combining salivary α-syn seeding activity and miRNA-29a-3p improved sensitivity to differentiate MSA from HCs. • Combining salivary miRNA-29a-3p level and α-syn RT-QuIC lag phase improved specificity to discriminate PD fromMSA. [ABSTRACT FROM AUTHOR]