Disease Tremor Research Articles

Adaptive Deep Brain Stimulation for the Treatment of Parkinson Disease and Essential Tremor


 Horizon Scan reports provide brief summaries of information regarding new and emerging health technologies; Heath Technology Update articles typically focus on a single device or intervention.
 These technologies are identified through the CADTH Horizon Scanning Service as topics of potential interest to health care decision-makers in Canada.
 This Horizon Scan summarizes the available information regarding an emerging technology, Percept PC Deep Brain Stimulation (DBS) system with BrainSense technology, for the treatment of Parkinson disease and essential tremors.

Reduced Risk of Reoperations With Modern Deep Brain Stimulator Systems: Big Data Analysis From a United States Claims Database.

Objective: There have been significant improvements in the design and manufacturing of deep brain stimulation (DBS) systems, but no study has considered the impact of modern systems on complications. We sought to compare the relative occurrence of reoperations after de novo implantation of modern and traditional DBS systems in patients with Parkinson's disease (PD) or essential tremor (ET) in the United States.Design: Retrospective, contemporaneous cohort study.Setting: Multicenter data from the United States Centers for Medicare and Medicaid Services administrative claims database between 2016 and 2018.Participants: This population-based sample consisted of 5,998 patients implanted with a DBS system, of which 3,869 patients had a de novo implant and primary diagnosis of PD or ET. Follow-up of 3 months was available for 3,810 patients, 12 months for 3,561 patients, and 24 months for 1,812 patients.Intervention: Implantation of a modern directional (MD) or traditional omnidirectional (TO) DBS system.Primary and Secondary Outcome Measures: We hypothesized that MD systems would impact complication rates. Reoperation rate was the primary outcome. Associated diagnoses, patient characteristics, and implanting center details served as covariates. Kaplan–Meier analysis was performed to compare rates of event-free survival and regression models were used to determine covariate influences.Results: Patients implanted with modern systems were 36% less likely to require reoperation, largely due to differences in acute reoperations and intracranial lead reoperations. Risk reduction persisted while accounting for practice differences and implanting center experience. Risk reduction was more pronounced in patients with PD.Conclusions: In the first multicenter analysis of device-related complications including modern DBS systems, we found that modern systems are associated with lower reoperation rates. This risk profile should be carefully considered during device selection for patients undergoing DBS for PD or ET. Prospective studies are needed to further investigate underlying causes.

Implication of the LINGO2 gene in the predisposition to movement disorders

Previous reports on the pathogenesis of age-related movement disorders, such as Parkinson’s disease (PD) and essential tremor (ET), have demonstrated the potential implications of LINGO1 (leucine-rich repeat and immunoglobulin domain-containing protein) gene. Although LINGO2 has a high degree of homology with LINGO1, but it is less characterized and the role of LINGO2 in the development of PD/ET remains unreported. Hence, this meta-analysis was conducted to evaluate the role of LINGO2 in PD/ET pathogenesis. A total of 4 studies, which complied with the Hardy–Weinberg equilibrium, were included in the meta-analysis. Analysis of the pooled odds ratio and confidence interval of the studies were performed for five genetic models, namely: allelic, dominant, recessive, homozygous, and heterozygous. No significant association was observed between the LINGO2 polymorphism and PD/ET, although subgroup analysis through conventional meta-analysis indicated that the recessive models of rs7033345 and rs10812774 are significantly associated with predisposition to ET in the Asian population. However, trial sequential analyses for both polymorphisms were unlikely to reveal any robust effect. Hence, studies with larger samples on this association are needed in the future to corroborate our results.

Identifying and modulating distinct tremor states through peripheral nerve stimulation in Parkinsonian rest tremor

BackgroundResting tremor is one of the most common symptoms of Parkinson’s disease. Despite its high prevalence, resting tremor may not be as effectively treated with dopaminergic medication as other symptoms, and surgical treatments such as deep brain stimulation, which are effective in reducing tremor, have limited availability. Therefore, there is a clinical need for non-invasive interventions in order to provide tremor relief to a larger number of people with Parkinson’s disease. Here, we explore whether peripheral nerve stimulation can modulate resting tremor, and under what circumstances this might lead to tremor suppression.MethodsWe studied 10 people with Parkinson’s disease and rest tremor, to whom we delivered brief electrical pulses non-invasively to the median nerve of the most tremulous hand. Stimulation was phase-locked to limb acceleration in the axis with the biggest tremor-related excursion.ResultsWe demonstrated that rest tremor in the hand could change from one pattern of oscillation to another in space. Median nerve stimulation was able to significantly reduce (− 36%) and amplify (117%) tremor when delivered at a certain phase. When the peripheral manifestation of tremor spontaneously changed, stimulation timing-dependent change in tremor severity could also alter during phase-locked peripheral nerve stimulation.ConclusionsThese results highlight that phase-locked peripheral nerve stimulation has the potential to reduce tremor. However, there can be multiple independent tremor oscillation patterns even within the same limb. Parameters of peripheral stimulation such as stimulation phase may need to be adjusted continuously in order to sustain systematic suppression of tremor amplitude.

ROLE OF TREMOR SYNDROME IN DIFFERENTIAL DIAGNOSTICS OF DISEASES

The aim of the study was to examine the clinical features of the tremor syndrome. 72 patients with Parkinson's disease and 26 patients with essential tremor were examined. Disease diagnosis is based on the 2017 Movement Disorder Society (MDS) criteria. Along with standard neurological examination and neuroimaging, clinical features of tremor were studied in patients. It was found that in 35% of cases with Parkinson's disease and essential tremor, the syndrome manifests itself in a combined form. Thus, the patients showed a combination of resting tremor, postural tremor and kinetic tremor. This creates certain difficulties. Therefore, in the presence of a combined manifestation of tremor, the determination of his leading type, its dynamic observation and the detection of other neurological syndromes accompanying tremor can help in the diagnosis of the disease.

Therapeutic application of rTMS in neurodegenerative and movement disorders: A review

Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that makes use of the magnetic field generated when an electric current passes through a magnetic coil placed over the scalp. It can be applied as a single stimulus at a time, in pairs of stimuli, or repetitively in trains of stimuli (repetitive TMS, rTMS). RTMS can induce changes in brain activity, whose after-effects reflect the processes of long-term potentiation and long-term depression, as certain protocols, namely those using low frequencies (≤1 Hz) seem to suppress cortical excitability, while those using high frequencies (>1 Hz) seem to enhance it. It is a technique with very few and mostly mild side-effects, whose effects can persist for long time periods, and as such, it has been studied as a potential treatment option in a multitude of neurodegenerative diseases, including those affecting movement. Although rTMS has received approval as a treatment strategy of only a few aspects in movement disorders in the latest guidelines, its further use seems to also be promising in their context. In this review, we gathered the available literature on the therapeutic application of rTMS in movement disorders, namely Parkinson’s disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Dystonia, Tic disorders and Essential Tremor.

The Role of the Cerebellum in Tremor - Evidence from Neuroimaging.

Background:Neuroimaging research has played a key role in identifying which cerebral changes are associated with tremor. Here we will focus on the cerebellum, which may drive tremor oscillations, process tremor-related afferents, modulate activity in remote brain regions, or a combination.Methods:On the 6th of October 2021, we conducted a PubMed search to select articles providing neuroimaging evidence for cerebellar involvement in essential tremor (ET), Parkinson’s disease (PD) tremor, and dystonic tremor (DT).Results:In ET, tremor-related activity is found in motor areas of the bilateral cerebellum, and altered functional connectivity within and outside the cerebellum correlates with tremor severity. Furthermore, ET is associated with cerebellar atrophy, but also with compensatory structural changes outside the cerebellum (e.g. supplementary motor area). In PD, tremor-related cerebellar activity and increased cerebello-thalamic coupling has been found. Emerging evidence suggests that the cerebellum plays a key role in dopamine-resistant rest tremor and in postural tremor. Cerebellar structural alterations have been identified in PD, but only some relate to tremor. DT is associated with more widespread cerebral networks than other tremor types.Discussion:In ET, the cerebellum likely acts as an oscillator, potentially due to loss of inhibitory mechanisms. In contrast, in PD the cerebellum may be a modulator, which contributes to tremor oscillations by influencing the thalamo-cortical system. The precise role of the cerebellum in DT remains unclear. We recommend that future research measures tremor-related activity directly by combining electrophysiology with neuroimaging, while brain stimulation techniques may be used to establish causality.Highlights:This review of neuroimaging studies has provided convincing evidence that the cerebellum plays a key role in the pathophysiology of ET, PD tremor, and dystonic tremor syndromes. This contribution may consist of driving tremor oscillations, processing tremor-related afferents, modulating activity in remote brain regions, or all the above.

Enhanced Parkinson\u2019s Disease Tremor Severity Classification by Combining Signal Processing with Resampling Techniques

Tremor is an indicative symptom of Parkinson’s disease (PD). Healthcare professionals have clinically evaluated the tremor as part of the Unified Parkinson’s disease rating scale (UPDRS) which is inaccurate, subjective and unreliable. In this study, a novel approach to enhance the tremor severity classification is proposed. The proposed approach is a combination of signal processing and resampling techniques; over-sampling, under-sampling and a hybrid combination. Resampling techniques are integrated with well-known classifiers, such as artificial neural network based on multi-layer perceptron (ANN-MLP) and random forest (RF). Advanced metrics are calculated to evaluate the proposed approaches such as area under the curve (AUC), geometric mean (Gmean) and index of balanced accuracy (IBA). The results show that over-sampling techniques performed better than other resampling techniques, also hybrid techniques performed better than under-sampling techniques. The proposed approach improved tremor severity classification significantly and show that the best approach to classify tremor severity is the combination of ANN-MLP with Borderline SMOTE which has obtained 93.81% overall accuracy, 96% Gmean, 91% IBA and 99% AUC. Besides, it is found that different resampling techniques performed differently with different classifiers.

Disparities surrounding DBS surgery for Parkinson’s disease and essential tremor in Hawaii

Disparities surrounding DBS surgery for Parkinson’s disease and essential tremor in Hawaii

Development and validation of an instrument for measuring parkinsonian motor impairment: TRAPS-D.

Parkinson's disease is incurable, idiopathic, degenerative, and progressive, and affects about 1% of the elderly population. Multidisciplinary clinical treatment is the best and most adopted therapeutic option, while surgical treatment is used in less than 15% of those affected. In practice, there is a lack of reliable and validated scales for measuring motor impairment, and monitoring and screening for surgical indications. To develop and validate an instrument for measuring parkinsonian motor impairment in candidates for neurosurgical treatment. The development and validation methods followed published guidelines. The first part was the choice of domains that would make up the construct: cardinal signs of disease (tremor, rigidity (stiffness), posture/balance/gait, hypokinesia/akinesia, and speech), along with pain and dyskinesia. A multi-professional working group prepared an initial pilot instrument. Ten renowned specialists evaluated, judged, and suggested modifications to the instrument. The second phase was the evaluation of the content of each domain and the respective ability to classify commitment intensity. The third phase was the correction of the main flaws detected and new submission to the board. The instrument was applied to 41 candidates for neurosurgical treatment in two situations: with and without medication RESULTS: The final form received 100% agreement from the judges. Its average time for application was 8min. It was very responsive (p = 0.001, Wilcoxon) in different situations (On-Off). TRASP-D is a valid instrument for measuring motor impairment in patients with Parkinson's disease who are candidates for neurosurgical treatment. It allows measurement in multiple domains with reliability and sensitivity.

First experience in the United States with true remote programming in deep brain stimulation therapy for movement disorders

DBS in Parkinson's disease and Essential tremor requires multiple in-person programming sessions burdening patients and caregivers. The recent FDA approved NeuroSphere™ Virtual Clinic enables clinicians for the first time to remotely connect into patient IPGs to perform system checks and actively adjust stimulation parameters. This is the first report describing clinical workflow and experience with the platform.

A New Approach to the Differential Diagnosis of Patients with Parkinson’s Disease and Essential Tremor

A New Approach to the Differential Diagnosis of Patients with Parkinson’s Disease and Essential Tremor

Connection between olfactory dysfunction and severity of tremor

Neurological disorders it's a problem for a number of people worldwide. Parkinson's disease (PD) and essential tremor (ET) are among them. Tremor is the common symptom both for PD (rest tremor) and ET (postural-kinetic tremor). Olfactory dysfunction is stipulated to be the first manifest of PD preceding the movement disorders. It happens due to the neurodegenerative process starting in olfactory bulbs. Currently available data on the olfactory function in ET are insufficient and some of them are contradictory.

Plasma acyl-carnitines, bilirubin, tyramine and tetrahydro-21-deoxycortisol in Parkinson's disease and essential tremor. A case control biomarker study

Background and purposeGiven the overlapping clinical manifestations and pathology, the differentiation between essential tremor (ET) and Parkinson's disease (PD) is difficult. Our aims were to examine the plasma metabolomics profiling and their association with motor and non-motor symptoms (NMS) in patients with PD, and to determine differences between de novo PD compared to moderate-advanced PD vs. controls and patients with ET. MethodsPlasma samples were collected from 137 subjects including 35 age matched controls, 29 NOVO-PD, 35 PD and 38 ET patients. PD severity, motor and NMS including cognitive function were assessed using the UPDRS, NMS and PD cognitive rating scales, respectively. Metabolomics analysis was performed by UPLC-ESI-QToF-MS followed by unsupervised multivariate statistics. The area under the curve of the biomarkers according to distribution of their concentrations and the diagnosis of PD (NOVO-PD, advanced PD) vs ET and healthy controls was used as a measurement of diagnostic ability. ResultsSeveral acyl-carnitines, bilirubin, tyramine and tetrahydro-21-deoxycortisol (THS) presented good predictive accuracy (AUC higher than 0.8) for differentiating de novo PD and advanced PD from controls and ET, suggesting an alteration in the lipid oxidation pathway. In multivariate regression analysis, metabolite levels were not significantly associated with motor and NMS severity in PD. ConclusionsDiverse acyl-carnitines, bilirubin, tyramine and some adrenal gland derived metabolites are suggested as potential biomarkers able to distinguish between PD from controls and ET.

HIGH-PERFORMANCE MODELING, IDENTIFICATION AND ANALYSIS OF HETEROGENEOUS ABNORMAL NEUROLOGICAL MOVEMENT’S PARAMETERS BASED ON COGNITIVE NEURO FEEDBACK-INFLUENCES

The technique is based on a hybrid model of the neuro-system (Brain cortex nodes and tremor-object), which describes on the basis of wave signal propagation the state and behavior of tremor-objects T, namely the segmental de-scription of 3D elements of trajectories of anormal neurological movements of the studied tremor-objects (limb of the hand) taking into account the matrix of cogni-tive influences of groups of cortex neuro-nodes. The rapid analytical solution of the model as a vector function that describes the 3D elements of the trajectories at each movements segment are constructed using the hybrid integral Fourier’s transformations and hybrid spectral function. The main element of the solution is the adaptive infuences matrix that determines the state parameters of the action of certain groups of brain neuro- cortex. Models and methods of multivariable identification are being developed to investigate their neuro-feedback, which suggest high-speed parallel computations on multicore computers. This model-ing technology consider as a scientific basis for designing inelidgence information systems of the quality medical diagnostic i of critical neurological diseases.Key words: Computer simulation, Software system, High-performance compu-ting, Tremor diseases, Modeling of objects and processes, Multi-parameter iden-tification.

Task-Oriented Intelligent Solution to Measure Parkinson’s Disease Tremor Severity

Tremor is a common symptom of Parkinson's disease (PD). Currently, tremor is evaluated clinically based on MDS-UPDRS Rating Scale, which is inaccurate, subjective, and unreliable. Precise assessment of tremor severity is the key to effective treatment to alleviate the symptom. Therefore, several objective methods have been proposed for measuring and quantifying PD tremor from data collected while patients performing scripted and unscripted tasks. However, up to now, the literature appears to focus on suggesting tremor severity classification methods without discrimination tasks effect on classification and tremor severity measurement. In this study, a novel approach to identify a recommended system is used to measure tremor severity, including the influence of tasks performed during data collection on classification performance. The recommended system comprises recommended tasks, classifier, classifier hyperparameters, and resampling technique. The proposed approach is based on the above-average rule of five advanced metrics results of four subdatasets, six resampling techniques, six classifiers besides signal processing, and features extraction techniques. The results of this study indicate that tasks that do not involve direct wrist movements are better than tasks that involve direct wrist movements for tremor severity measurements. Furthermore, resampling techniques improve classification performance significantly. The findings of this study suggest that a recommended system consists of support vector machine (SVM) classifier combined with BorderlineSMOTE oversampling technique and data collection while performing set of recommended tasks, which are sitting, stairs up and down, walking straight, walking while counting, and standing.

Dopamine Transporter Scan: Determining the Diagnostic Performance of Hermes Brain Registration and Analysis Software Suite with Parkinson Disease and Essential Tremor Disease Patients

Parkinson Disease is the most baffling and complex of all neurological disorders because its causes barely remain a mystery. The hallmark of Parkinson Disease (PD) is the loss of brain cells that transport dopamine in the basal ganglia of the brain. The study devised a robust semi-quantitative brain analysis technique to accurately differentiate patients with PD from patients with Essential Tremor (ET). The mode of data collection was retrospective since the brain scans, consisting PD and ET patients, were previously carried out using a Toshiba SPECT scanner. The sample size was made up of 15 brain scans of ET and PD patients. Five Hermes BRASS techniques were used to determine the specific bindings and binding ratios in the putamen and caudate regions of the brain while the mean binding ratios were calculated using MS Excel. Hermes BRASS techniques numbers; 2, 3 and 4 (Table 8) misdiagnosed one patient out of the 15 patients. However, notable was the fact that diagnostic technique number 3 had no instance of coincidence diagnosis. The graphical and numerical outcomes obtained with Hermes BRASS and MS Excel showed that a population of PD patients was separable from a population of ET disease patients. T-test confirmed that value of the derived t-statistics (0.19) was less than value of the t-statistics (2.18). Hence the alternate hypothesis was accepted since the difference between the two populations was significant. The quest to identify a robust Hermes diagnostic technique that differentiates patients with PD from patients with ET was successfully realized where the Hermes New BRASS had remarkable improvement over the Hermes Old BRASS. Most essentially the incidence of misdiagnosis, in the differentiation of patients with PD from patients with ET, was minimized to one patient out of the 15 patients. This translated to patients deriving maximum benefit from the pool of medical drugs available for the treatment of PD and ET patients.

Transcranial Magnetic Stimulation in Tremor Syndromes: Pathophysiologic Insights and Therapeutic Role

Transcranial magnetic stimulation (TMS) is a painless, non-invasive, and established brain stimulation technique to investigate human brain function. Over the last three decades, TMS has shed insight into the pathophysiology of many neurological disorders. Tremor is an involuntary, rhythmic oscillatory movement disorder commonly related to pathological oscillations propagated via the cerebello-thalamo-cortical pathway. Although tremor is the most common movement disorder and recent imaging studies have enhanced our understanding of the critical pathogenic networks, the underlying pathophysiology of different tremor syndromes is complex and still not fully understood. TMS has been used as a tool to further our understanding of tremor pathophysiology. In addition, repetitive TMS (rTMS) that can modulate brain functions through plasticity effects has been targeted to the tremor network to gain potential therapeutic benefits. However, evidence is available for only a few studies that included small patient samples with limited clinical follow-up. This review aims to discuss the role of TMS in advancing the pathophysiological understanding as well as emerging applications of rTMS for treating individual tremor syndromes. The review will focus on essential tremor, Parkinson's disease tremor, dystonic tremor syndrome, orthostatic tremor, and functional tremor.

Dissecting the role of interprotomer cooperativity in the activation of oligomeric high-temperature requirement A2 protein

The human high-temperature requirement A2 (HtrA2) mitochondrial protease is critical for cellular proteostasis, with mutations in this enzyme closely associated with the onset of neurodegenerative disorders. HtrA2 forms a homotrimeric structure, with each subunit composed of protease and PDZ (PSD-95, DLG, ZO-1) domains. Although we had previously shown that successive ligand binding occurs with increasing affinity, and it has been suggested that allostery plays a role in regulating catalysis, the molecular details of how this occurs have not been established. Here, we use cysteine-based chemistry to generate subunits in different conformational states along with a protomer mixing strategy, biochemical assays, and methyl-transverse relaxation optimized spectroscopy-based NMR studies to understand the role of interprotomer allostery in regulating HtrA2 function. We show that substrate binding to a PDZ domain of one protomer increases millisecond-to-microsecond timescale dynamics in neighboring subunits that prime them for binding substrate molecules. Only when all three PDZ-binding sites are substrate bound can the enzyme transition into an active conformation that involves significant structural rearrangements of the protease domains. Our results thus explain why when one (or more) of the protomers is fixed in a ligand-binding-incompetent conformation or contains the inactivating S276C mutation that is causative for a neurodegenerative phenotype in mouse models of Parkinson's disease, transition to an active state cannot be formed. In this manner, wild-type HtrA2 is only active when substrate concentrations are high and therefore toxic and unregulated proteolysis of nonsubstrate proteins can be suppressed.

Optimal closed-loop deep brain stimulation using multiple independently controlled contacts.

Deep brain stimulation (DBS) is a well-established treatment option for a variety of neurological disorders, including Parkinson’s disease and essential tremor. The symptoms of these disorders are known to be associated with pathological synchronous neural activity in the basal ganglia and thalamus. It is hypothesised that DBS acts to desynchronise this activity, leading to an overall reduction in symptoms. Electrodes with multiple independently controllable contacts are a recent development in DBS technology which have the potential to target one or more pathological regions with greater precision, reducing side effects and potentially increasing both the efficacy and efficiency of the treatment. The increased complexity of these systems, however, motivates the need to understand the effects of DBS when applied to multiple regions or neural populations within the brain. On the basis of a theoretical model, our paper addresses the question of how to best apply DBS to multiple neural populations to maximally desynchronise brain activity. Central to this are analytical expressions, which we derive, that predict how the symptom severity should change when stimulation is applied. Using these expressions, we construct a closed-loop DBS strategy describing how stimulation should be delivered to individual contacts using the phases and amplitudes of feedback signals. We simulate our method and compare it against two others found in the literature: coordinated reset and phase-locked stimulation. We also investigate the conditions for which our strategy is expected to yield the most benefit.