Tuned to Tremor: Increased Sensitivity of Cortico-Basal Ganglia Neurons to Tremor Frequency in the MPTP Nonhuman Primate Model of Parkinson's Disease.

Rest tremor is one of the most prominent clinical features of Parkinson's disease (PD). Here, we hypothesized that cortico-basal ganglia neurons tend to fire in a pattern that matches PD tremor frequency, suggesting a resonance phenomenon. We recorded spiking activity in the primary motor cortex (M1) and globus pallidus external segment of 2 female nonhuman primates, before and after parkinsonian state induction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The arm of nonhuman primates was passively rotated at seven different frequencies surrounding and overlapping PD tremor frequency. We found entrainment of the spiking activity to arm rotation and a significant sharpening of the tuning curves in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine state, with a peak response at frequencies that matched the frequency of PD tremor. These results reveal increased sensitivity of the cortico-basal ganglia network to tremor frequency and could indicate that this network acts not only as a tremor switch but is involved in setting its frequency.SIGNIFICANCE STATEMENT Tremor is a prominent clinical feature of Parkinson's disease; however, its underlying pathophysiology is still poorly understood. Using electrophysiological recordings of single cortico-basal ganglia neurons before and after the induction of a parkinsonian state, and in response to passive arm rotation, this study reports increased sensitivity to tremor frequency in Parkinson's disease. We found sharpening of the population tuning to the midrange of the tested frequencies (1-13.3 Hz) in the healthy state that further increased in the parkinsonian state. These results hint at the increased frequency-tuned sensitivity of cortico-basal ganglia neurons and suggest that they tend to resonate with the tremor.

Clinical and kinematic characterization of parkinsonian soft signs in essential tremor.

BACKGROUND: Subtle parkinsonian signs, i.e., rest tremor and bradykinesia, are considered soft signs for defining essential tremor (ET) plus. OBJECTIVES: Our study aimed to further characterize subtle parkinsonian signs in a relatively large sample of ET patients from a clinical and neurophysiological perspective. METHODS: We employed clinical scales and kinematic techniques to assess a sample of 82 ET patients. Eighty healthy controls matched for gender and age were also included. The primary focus of our study was to conduct a comparative analysis of ET patients (without any soft signs) and ET-plus patients with rest tremor and/or bradykinesia. Additionally, we investigated the asymmetry and side concordance of these soft signs. RESULTS: In ET-plus patients with parkinsonian soft signs (56.10% of the sample), rest tremor was clinically observed in 41.30% of cases, bradykinesia in 30.43%, and rest tremor plus bradykinesia in 28.26%. Patients with rest tremor had more severe and widespread action tremor than other patients. Furthermore, we observed a positive correlation between the amplitude of action and rest tremor. Most ET-plus patients had an asymmetry of rest tremor and bradykinesia. There was no side concordance between these soft signs, as confirmed through both clinical examination and kinematic evaluation. CONCLUSIONS: Rest tremor and bradykinesia are frequently observed in ET and are often asymmetric but not concordant. Our findings provide a better insight into the phenomenology of ET and suggest that the parkinsonian soft signs (rest tremor and bradykinesia) in ET-plus may originate from distinct pathophysiological mechanisms.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

Evaluation of rest tremor in different positions in Parkinson's disease and essential tremor plus.

BACKGROUND: Rest tremor (RT) can be observed in several positions (seated, standing, lying down) but it is unknown whether the tremor features may vary across them. This study aimed to compare the RT electrophysiological features across different positions in tremor-dominant Parkinson's disease (PD) and essential tremor plus (ET with RT, rET). METHODS: We consecutively enrolled 90 tremor-dominant PD and 24 rET patients. The RT presence was evaluated in three positions: with the patient seated, the arm flexed at 90°, the forearm supported against gravity, and the hand hanging down from the chair armrest (hand-hanging position), in lying down supine and in standing position. RT electrophysiological features (amplitude, frequency, burst duration, pattern) were compared between the two patient groups and across the different positions. RESULTS: All PD and rET patients showed RT in hand-hanging position. Supine and standing RT were significantly more common in PD (67.8% and 75.6%, respectively) than in rET patients (37.5% and 45.8%, respectively). RT amplitude, frequency and pattern were significantly different between groups in hand-hanging position whereas only pattern was significantly different between PD and rET in both standing and supine positions. In each patient group, all RT electrophysiological features did not significantly vary across different recording positions (p > 0.05). DISCUSSION: In our study, PD and rET showed RT in hand-hanging, supine, and standing positions. RT pattern was the only electrophysiological feature significantly different between PD and rET patients in all these positions, enabling clinicians to perform the RT analysis for diagnostic purposes in different tremor positions.

Facial tremor in patients with Parkinson's disease: prevalence, determinants and impacts on disease progression.

BACKGROUND: Facial (lip and jaw) tremor (FT) is associated with Parkinson's disease (PD) but few studies have been conducted to explore its clinical profile. We performed this study to investigate the prevalence and clinical correlates of FT in PD, and further to evaluate its effect on disease progression. METHODS: A retrospective, cross-sectional (n = 2224) and longitudinal (n = 674) study was conducted. The presence of FT was based on a ≥ 1 score in the United PD Rating Scale (UPDRS) item 20A. Group comparisons were conducted, followed by a forward binary logistic regression analysis. Inverse probability of treatment weighting (IPTW) based on the propensity score and weighted or unweighted Cox regression models were used to explore the impact of FT on five clinical milestones including death, UPDRS III 11-point increase, Hoehn and Yahr (H&Y) stage reaching 3, dyskinesia development, and Montreal Cognitive Assessment 3-point decrease. RESULTS: FT was presented in 403 patients (18.1%), which showed increasing trends with disease duration and H&Y score. Age (P < 0.001), female (P < 0.001), disease duration (P = 0.001), speech (P = 0.011), rigidity (P = 0.026), rest tremor on limbs (P < 0.001), kinetic tremor on hands (P < 0.001), and axial symptoms (P = 0.013) were independent factors associated with FT. Both unweighted and weighted Cox regression models indicated that baseline FT and FT as the initial symptom were not associated with the five outcomes. CONCLUSIONS: Our study suggested that FT was not uncommon and provided a deeper insight into the characteristics of FT in PD. The predict value of FT on long-term progronis of PD may need future longer follwe-up study.

Discrimination between healthy and patients with Parkinson's disease from hand resting activity using inertial measurement unit.

BACKGROUND: Parkinson's disease (PD) is a neurological disease that affects the motor system. The associated motor symptoms are muscle rigidity or stiffness, bradykinesia, tremors, and gait disturbances. The correct diagnosis, especially in the initial stages, is fundamental to the life quality of the individual with PD. However, the methods used for diagnosis of PD are still based on subjective criteria. As a result, the objective of this study is the proposal of a method for the discrimination of individuals with PD (in the initial stages of the disease) from healthy groups, based on the inertial sensor recordings. METHODS: A total of 27 participants were selected, 15 individuals previously diagnosed with PD and 12 healthy individuals. The data collection was performed using inertial sensors (positioned on the back of the hand and on the back of the forearm). Different numbers of features were used to compare the values of sensitivity, specificity, precision, and accuracy of the classifiers. For group classification, 4 classifiers were used and compared, those being [Random Forest (RF), Support Vector Machine (SVM), K-Nearest Neighbor (KNN), and Naive Bayes (NB)]. RESULTS: When all individuals with PD were analyzed, the best performance for sensitivity and accuracy (0.875 and 0.800, respectively) was found in the SVM classifier, fed with 20% and 10% of the features, respectively, while the best performance for specificity and precision (0.933 and 0.917, respectively) was associated with the RF classifier fed with 20% of all the features. When only individuals with PD and score 1 on the Hoehn and Yahr scale (HY) were analyzed, the best performances for sensitivity, precision and accuracy (0.933, 0.778 and 0.848, respectively) were from the SVM classifier, fed with 40% of all features, and the best result for precision (0.800) was connected to the NB classifier, fed with 20% of all features. CONCLUSION: Through an analysis of all individuals in this study with PD, the best classifier for the detection of PD (sensitivity) was the SVM fed with 20% of the features and the best classifier for ruling out PD (specificity) was the RF classifier fed with 20% of the features. When analyzing individuals with PD and score HY = 1, the SVM classifier was superior across the sensitivity, precision, and accuracy, and the NB classifier was superior in the specificity. The obtained result indicates that objective methods can be applied to help in the evaluation of PD.

Rest tremor in dystonia: epidemiology, differential diagnosis, and pathophysiology.

BACKGROUND: The most common type of tremor reported in dystonia patients is postural and kinetic. There is uncertainty regarding the prevalence of rest tremor in dystonia. OBJECTIVE: This review focuses on the clinical and neurophysiological features of rest tremor in dystonia, its differential diagnosis, and methods to distinguish it from other rest tremor syndromes. METHODS: A PubMed search was done, and the available literature identified. Bibliography of the available literature was reviewed for relevant references. RESULTS: Rest tremor in dystonia has been reported with a variable frequency of 1.81-12.05%. The most common body distribution is arm, and it tends to be asymmetric. Most of the affected patients have multifocal and segmental dystonia. Rest tremor is a late-onset phenomenon associated with severe and spreading dystonia. Clinically, it is difficult to distinguish rest tremor in dystonia from other rest tremor syndromes based on tremor characteristics; however, other neurological signs can provide clues to differentiate these syndromes. Surface electromyography and other neurophysiological tests can help differentiate the various rest tremor syndromes. CONCLUSION: Rest tremor in dystonia can be differentiated from other rest tremor syndromes based on neurophysiological techniques. There is some evidence to suggest that SWEDDs could be a form of dystonic tremor, but further studies are required to clarify this diagnostic dilemma. Data regarding the treatment of rest tremor in dystonia are virtually nonexistent, and there is an urgent need for prospective studies focusing its medical management and to know the surgical targets.

Revisiting the Clinical Phenomenology of "Cerebellar Tremor": Beyond the Intention Tremor.

Tremor is an involuntary, rhythmic, oscillatory movement of a body part. It is a central feature of a range of diseases resulting from pathological changes in the cerebellum. Interestingly, in modern times, the terms "cerebellar tremor" and "intention tremor" are often used synonymously and interchangeably. However, "cerebellar tremor" (i.e., tremors of cerebellar origin) do not always present exclusively as intention tremor. In this article, we comprehensively revisit the clinical phenomenology of tremors observed in various diseases that are based in the cerebellum. By this, we mean diseases for which the cerebellum and its various connections are often seen as playing a central and defining role. These include spinocerebellar ataxias, essential tremor, orthostatic tremor, dystonia, acute cerebellitis, cerebellar tumors, paraneoplastic cerebellar degeneration, and cerebellar strokes. The theme of this article is to highlight, through published data available in the current literature, that the clinical phenomenology of tremor of cerebellar origin is heterogeneous, and it extends beyond that of intention tremor to include postural tremors, kinetic tremor, rest tremor, and orthostatic tremor. This heterogeneity is consistent with the seminal work of Gordon Holmes, in which he described a variety of tremors aside from intention tremor in the setting of cerebellar lesions. In the end, it would seem that the notion that intention tremor is the sole signature of cerebellar lesions is an over-simplification and is not correct. Future studies are warranted to identify and further characterize the heterogeneity of tremors arising from the various cerebellar etiologies.

The influence of posture duration on hand tremor during tasks with attention-distraction in persons with Parkinson's disease.

BACKGROUND: Tremor is one of the hallmarks and most bothersome symptoms in Parkinson's disease (PD). The classical PD tremor is present at rest, but postural tremor also occurs. PD tremor can be continuous or intermittently present and can have a re-emergent nature. The tremor intensity is affected by attention and stress level. Observations of PD tremor have indicated increased tremor intensity with time during 30-s tremor assessments. This phenomenon has not previously been studied systematically. Thus, in order to contribute to our understanding of the mechanisms associated with PD tremor, our aim was to investigate the influence of time during a posture holding and a resting task on hand tremor characteristics in persons with PD compared to healthy peers. METHOD: Fifty persons with PD and at least one tremoring hand (tremor intensity exceeding mean + 2SD of a healthy reference group (REF), N = 40) were included from a clinical trial population. Hand accelerations in a rest and postural condition were measured in 30-s assessments while the participants performed a self-paced simple subtraction task with eyes closed to standardize attention without inducing stress. Tremor intensity, maximal power, frequency of maximal power and tremor onset time was calculated for three consecutive 10-s time intervals. RESULTS: Tremor intensity and maximal power increased significantly during the 30-s recording in the PD-group in both conditions (1st-3rd time-interval, tremor intensity: rest + 65% p < 0.0001, postural + 55% p < 0.0001; maximal power: rest + 93% p < 0.0001, postural + 82% p < 0.001). No effect of time was found on frequency of maximal power in the PD-group or on any effect measure in the REF-group. CONCLUSION: Tremor intensity and maximal power increased with time in the PD-group during 30-s tasks, while no change with time was found in the REF-group. In contrast, frequency of maximal power remained unchanged, which may suggest that the same neural circuits were responsible for the tremor generation throughout the tasks. The increase in tremor intensity and maximal power could not solely be explained by re-emergence of tremor. This suggests an increasing or gradually more synchronized cortico-spinal drive throughout the tasks. However, this requires further studies to determine.

The effect of 8 weeks of treatment with transcranial pulsed electromagnetic fields on hand tremor and inter-hand coherence in persons with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) tremor comprises asymmetric rest and postural tremor with unilateral onset. Tremor intensity can be amplified by stress and reduced by attention, and the medical treatment is complex. Mirror movements and unintentional synchronization of bimanual movements, possibly caused by insufficient inhibition of inter-hemispheric crosstalk, have been reported in PD, indicating a lag of lateralization. Potential neuroprotective effects of pulsed electromagnetic fields (PEMF) have been reported in-vitro and in rodents, as have influences of PEMF on human tremor. The aim was to investigate the effect of 8 weeks daily transcranial PEMF treatment (T-PEMF) of persons with PD on rest and postural hand tremor characteristics and on inter-hand coherence. METHODS: Hand accelerations of 50 PD participants with uni- or bilateral tremor participating in a clinical trial were analysed. A rest and postural tremor task performed during serial subtraction was assessed before and after 8 weeks of T-PEMF (30 min/day, 50 Hz, ±50 V, 3 ms squared pulses) or placebo treatment (sham stimulation 30 min/day). Forty matched healthy persons (no treatment) were included as reference. Intensity and inter-hand coherence related measures were extracted. RESULTS: The T-PEMF treatment decreased the inter-hand coherence in the PD group with unilateral postural tremor. The PD group with unilateral postural tremor was less clinically affected by the disease than the PD group with bilateral postural tremor. However, no differences between T-PEMF and placebo treatment on either intensity related or coherence related measures were found when all persons with PD were included in the analyses. The peak power decreased and the tremor intensity tended to decrease in both treatment groups. CONCLUSIONS: Eight weeks of T-PEMF treatment decreased inter-hand coherence in the PD group with unilateral postural tremor, while no effects of T-PEMF treatment were found for the entire PD group. The unilateral postural tremor group was less clinically affected than the bilateral postural tremor group, suggesting that early treatment initiation may be beneficial. In theory, a reduced inter-hand coherence could result from a neuronal treatment response increasing inter-hemispheric inhibition. However, this requires further studies to determine. Studies of even longer treatment periods would be of interest. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02125032. Registered 29 April 2014, https://clinicaltrials.gov/ct2/show/NCT02125032?term=NCT02125032&rank=1.

Tremor and hand-arm vibration syndrome (HAVS) in road maintenance workers.

OBJECTIVES: The aim of this study was to evaluate postural and rest tremor among workers using vibrating hand tools, taking into account the possible effects of toxicants such as alcohol and tobacco. A further aim was to study workers diagnosed with hand-arm vibration syndrome (HAVS) at the time of examination. METHODS: This study comprises 103 road maintenance workers, 55 exposed to vibrating hand tools (age 41.0 years; range 21-62) and 48 referents (age 38.5 years; range 19-64). They were examined with the CATSYS Tremor Pen®. Exposure to vibrating tools and serum biomarkers of alcohol and tobacco consumption were measured. RESULTS: Cumulative exposure to vibrating tools was associated with increased postural (p < 0.01) and rest tremor (p < 0.05) and with a higher Center Frequency of postural tremor (p < 0.01) among smokers and users of smokeless tobacco. Rest tremor Center Frequency was higher than postural tremor frequency (p < 0.001). CONCLUSIONS: The main findings indicate an association between cumulative exposure to hand-held vibrating tools, tremor parameters and consumption of tobacco products. The hand position is important when testing for tremor. Rest tremor had a higher Center Frequency. Postural tremor was more strongly associated with exposure than rest tremor. The finding of increased tremor among the HAVS subjects indicated that tremor might be a part of the clinical picture of a HAVS diagnosis. As with all cross-sectional studies, inferences should be made with caution when drawing conclusions about associations between exposure and possible effects. Future research using longitudinal design is required to validate the findings of the present study.

Rest tremor in idiopathic adult-onset dystonia.

BACKGROUND: Tremor in dystonia has been described as a postural or kinetic abnormality. In recent series, however, patients with idiopathic adult-onset dystonia also displayed rest tremor. METHODS: The frequency and distribution of rest tremor were studied in a cohort of 173 consecutive Italian patients affected by various forms of idiopathic adult-onset dystonia attending our movement disorder clinic over 8 months. RESULTS: Examination revealed tremor in 59/173 patients (34%): 12 patients had head tremor, 34 patients had arm tremor, whilst 13 patients presented tremor in both sites. Head tremor was postural in all patients, whereas arm tremor was postural/kinetic in 28 patients, only at rest in one and both postural/kinetic and at rest in 18 patients. Patients with tremor were more likely to have segmental/multifocal dystonia. Patients who had rest tremor (either alone or associated with action tremor) had a higher age at dystonia onset and a greater frequency of dystonic arm involvement than patients with action tremor alone or without tremor. CONCLUSIONS: Both action and rest tremor are part of the tremor spectrum of adult-onset dystonia and are more frequently encountered in segmental/multifocal dystonia. The higher age at dystonia onset and the greater frequency of arm dystonia in patients with rest tremor may have pathophysiological implications and may account, at least in part, for the previous lack of identification of rest tremor as one possible type of tremor present in dystonia.

Prevalence and correlates of rest tremor in essential tremor: cross-sectional survey of 831 patients across four distinct cohorts.

BACKGROUND AND PURPOSE: Essential tremor (ET) is amongst the most commonly encountered neurological disorders. Its hallmark feature is kinetic tremor. However, other tremors may also occur in ET patients, creating considerable diagnostic confusion amongst treating physicians. Hence, characterizing the prevalence and clinical accompaniments of these other tremors is of value. Surprisingly, there are few data on the prevalence of rest tremor in ET patients, and even fewer data on the clinical correlates of such tremor. METHODS: Eight hundred and thirty-one patients in four distinct settings (population, genetics study, study of environmental epidemiology, brain bank) underwent a detailed videotaped neurological examination that was reviewed by a senior movement disorders neurologist. Rest tremor was evaluated in several positions (seated, standing, lying down). RESULTS: The prevalence of rest tremor whilst seated or standing was lowest in the population-based setting (1.9%), highest in the brain bank study (46.4%) and intermediate in the remaining two settings (9.6% and 14.7%, respectively). Rest tremor was restricted to the arms and was not observed in the legs. Rest tremor was associated with older age, longer disease duration (in some studies), greater tremor severity and, to some extent, the presence of cranial tremors. CONCLUSIONS: Rest tremor can be a common clinical feature of ET. Its prevalence is highly dependent on the setting in which patients are evaluated, ranging from as low as 1% to nearly 50%. Rest tremor seems to emerge as a clinical feature with advancing disease. The anatomical substrates for this type of tremor remain unknown at present.

Action tremor in Parkinson's disease: frequency and relationship to motor and non-motor signs.

BACKGROUND AND PURPOSE: Action tremor may occur in patients with Parkinson's disease and cause misdiagnosis with other movement disorders such as essential tremor and dystonia. Data on the frequency of action tremor in Parkinson's disease and on the relationships with other motor and non-motor signs are limited. METHODS: A cross-sectional study of 237 patients with Parkinson's disease staging 1-2 on the Hoehn-Yahr scale was conducted. Data on action tremor and other motor and non-motor signs were collected using the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale. RESULTS: Action tremor was found in 46% of patients and was associated with both severity of rest tremor (adjusted odds ratio 3.0, P < 0.001) and severity of rigidity (adjusted odds ratio 1.5, P = 0.004). No association was found between action tremor and severity of bradykinesia (adjusted odds ratio 0.97, P = 0.4) or axial symptoms (adjusted odds ratio 0.9, P = 0.3). Moreover, patients who had action tremor reported a significant lower mean number of non-motor symptoms than those who had not (2.1 ± 1.3 vs. 2.4 ± 1.3; P = 0.04). CONCLUSIONS: Action tremor is a relatively frequent motor sign in patients with Parkinson's disease staging 1-2 on the Hoehn-Yahr scale. Action tremor correlates with rest tremor and rigidity and may be associated with a lower burden of non-motor symptoms. These findings suggest a contribution of non-dopaminergic mechanisms to action tremor pathophysiology.

Differential influences of rest tremor on brain fiber architecture in essential tremor and Parkinson's disease.

BACKGROUND: Rest tremor is a movement disorder commonly found in diseases like Parkinson's disease (PD) and essential tremor (ET). Rest tremor typically shows slower progression in PD, but more severe progression in ET. However, the underlying white matter organization of rest tremor behind PD and ET remains unclear. METHODS: This study included 57 ET patients (40 without rest tremor (ETWR), 17 with rest tremor (ETRT)), 68 PD patients (34 without rest tremor (PDWR), 34 with rest tremor (PDRT)), and 62 normal controls (NC). Fixel-based analysis was used to evaluate the structural changes of white matter in rest tremor in these different diseases. RESULTS: The fiber-bundle cross-section (FC) of the right non-decussating dentato-rubro-thalamic tract and several fibers outside the dentato-rubro-thalamic pathway in ETWR were significantly higher than that in NC. The fiber density and cross-section of the left nigro-pallidal in PDWR is significantly lower than that in NC, while the FC of bilateral nigro-pallidal in PDRT is significantly lower than that in NC. CONCLUSION: ET patients with pure action tremor showed over-activation of fiber tracts. However, when superimposed with rest tremor, ET patients no longer exhibited over-activation of fiber tracts, but rather showed a trend of fiber tract damage. Except for the nigro-pallidal degeneration in all PD, PDRT will not experience further deterioration in fiber organization. These results provide important insights into the unique effects of rest tremor on brain fiber architecture in ET and PD.

Evaluation and Management of Tremor.

Tremor is a commonly encountered condition in the primary care setting and can manifest at rest, with action, or both. Common causes include Parkinson disease, essential tremor, and drug-induced tremor. In this article, the authors discuss how to examine a patient with tremor and which features of the history and examination can help clue the provider in to the appropriate diagnosis. They also review treatments for varying types of tremor and when referral to a neurologist may be necessary.

Multimodal imaging and electrophysiological study in the differential diagnosis of rest tremor.

Introduction: Distinguishing tremor-dominant Parkinson's disease (tPD) from essential tremor with rest tremor (rET) can be challenging and often requires dopamine imaging. This study aimed to differentiate between these two diseases through a machine learning (ML) approach based on rest tremor (RT) electrophysiological features and structural MRI data. Methods: We enrolled 72 patients including 40 tPD patients and 32 rET patients, and 45 control subjects (HC). RT electrophysiological features (frequency, amplitude, and phase) were calculated using surface electromyography (sEMG). Several MRI morphometric variables (cortical thickness, surface area, cortical/subcortical volumes, roughness, and mean curvature) were extracted using Freesurfer. ML models based on a tree-based classification algorithm termed XGBoost using MRI and/or electrophysiological data were tested in distinguishing tPD from rET patients. Results: Both structural MRI and sEMG data showed acceptable performance in distinguishing the two patient groups. Models based on electrophysiological data performed slightly better than those based on MRI data only (mean AUC: 0.92 and 0.87, respectively; p = 0.0071). The top-performing model used a combination of sEMG features (amplitude and phase) and MRI data (cortical volumes, surface area, and mean curvature), reaching AUC: 0.97 ± 0.03 and outperforming models using separately either MRI (p = 0.0001) or EMG data (p = 0.0231). In the best model, the most important feature was the RT phase. Conclusion: Machine learning models combining electrophysiological and MRI data showed great potential in distinguishing between tPD and rET patients and may serve as biomarkers to support clinicians in the differential diagnosis of rest tremor syndromes in the absence of expensive and invasive diagnostic procedures such as dopamine imaging.

Combined cortical thickness and blink reflex recovery cycle to differentiate essential tremor with and without resting tremor.

Objective: To investigate the performance of structural MRI cortical and subcortical morphometric data combined with blink-reflex recovery cycle (BRrc) values using machine learning (ML) models in distinguishing between essential tremor (ET) with resting tremor (rET) and classic ET. Methods: We enrolled 47 ET, 43 rET patients and 45 healthy controls (HC). All participants underwent brain 3 T-MRI and BRrc examination at different interstimulus intervals (ISIs, 100-300 msec). MRI data (cortical thickness, volumes, surface area, roughness, mean curvature and subcortical volumes) were extracted using Freesurfer on T1-weighted images. We employed two decision tree-based ML classification algorithms (eXtreme Gradient Boosting [XGBoost] and Random Forest) combining MRI data and BRrc values to differentiate between rET and ET patients. Results: ML models based exclusively on MRI features reached acceptable performance (AUC: 0.85-0.86) in differentiating rET from ET patients and from HC. Similar performances were obtained by ML models based on BRrc data (AUC: 0.81-0.82 in rET vs. ET and AUC: 0.88-0.89 in rET vs. HC). ML models combining imaging data (cortical thickness, surface, roughness, and mean curvature) together with BRrc values showed the highest classification performance in distinguishing between rET and ET patients, reaching AUC of 0.94 ± 0.05. The improvement in classification performances when BRrc data were added to imaging features was confirmed by both ML algorithms. Conclusion: This study highlights the usefulness of adding a simple electrophysiological assessment such as BRrc to MRI cortical morphometric features for accurately distinguishing rET from ET patients, paving the way for a better classification of these ET syndromes.