Materiały źródłowe

• #1 The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models – PMC Lock

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8698799/

  Essential tremor (ET) is a pathological tremor. […] The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future. […] The pathophysiology of ET, as well as the etiology of the disease, has not been fully understood to date. […] The results of surgical, neurophysiological, and postmortem studies in ET patients, as well as studies in animal models, indicate that brain structures such as the inferior olive nuclei (ION), cerebellum, red nucleus, thalamus, and cerebral cortex (the cerebello–thalamo–cortical network) are involved in the pathomechanism of this disease.

• #2 Essential tremor | Nature Reviews Disease PrimersClose bannerClose banner

  https://www.nature.com/articles/s41572-021-00314-w

  Essential tremor (ET) is one of the most common movement disorders, with a reported >60 million affected individuals worldwide. […] The definition and underlying pathophysiology of ET are contentious. […] Genetics account for most of the ET risk but environmental factors may also be involved. […] Structural changes in cerebellar Purkinje cells and neighbouring neuronal populations have been observed in post-mortem studies, and other studies have found GABAergic dysfunction and dysregulation of the cerebellar–thalamic–cortical circuitry. […] Further research in post-mortem studies, and animal and cell-based models may help identify new pathophysiological clues and therapeutic targets and, together with advances in omics and machine learning, may facilitate the development of precision medicine for patients with ET.

• #2 The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

  https://www.mdpi.com/2218-273X/11/12/1813

  Essential tremor (ET) is a pathological tremor. […] The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future. […] The pathophysiology of ET, as well as the etiology of the disease, has not been fully understood to date. […] The results of surgical, neurophysiological, and postmortem studies in ET patients, as well as studies in animal models, indicate that brain structures such as the inferior olive nuclei (ION), cerebellum, red nucleus, thalamus, and cerebral cortex (the cerebello–thalamo–cortical network) are involved in the pathomechanism of this disease.

• #3 Essential Tremor Types, Treatment | Froedtert & MCW

  https://www.froedtert.com/parkinsons-movement-disorders/tremors

  Essential tremor is a tremor not tied to any other condition. The cause of essential tremor is not known, but it likely has a genetic basis, and often times several generations of a family are affected. […] Deep brain stimulation (DBS) has been safely and effectively used to treat essential and other tremors for 20 years when other treatments have failed. The treatment involves a neurostimulator implant that delivers enough stimulation to disrupt the areas that cause your tremors and maintain normal brain activity.

• #3 The pathophysiology of essential tremor and Parkinson’s tremor

  https://repository.ubn.ru.nl/handle/2066/115731

  We review recent evidence about the pathophysiology of essential tremor and tremor in Parkinson’s disease. […] We believe that a network perspective is necessary to understand this common neurological symptom, and that knowledge of cerebral network dysfunction in tremor disorders will help to develop new therapies. […] Both essential tremor and Parkinson’s tremor are associated with increased activity in the cerebellothalamocortical circuit. […] However, different pathophysiological mechanisms lead to tremulous activity within this circuit. […] In essential tremor, GABAergic dysfunction of the cerebellar dentate nucleus and brain stem, possibly caused by neurodegeneration in these regions, may lead to tremulous activity within the cerebellothalamocortical circuit. […] In both disorders, network parameters such as the strength and directionality of interregional coupling are crucially altered. […] Exciting new research uses these network parameters to develop network-based therapies, such as closed-loop deep brain stimulation and transcranial magnetic or direct current stimulation.

• #4 The Pathophysiology of Essential Tremor and Parkinson’s Tremor | Current Neurology and Neuroscience Reports

  https://link.springer.com/article/10.1007/s11910-013-0378-8

  We review recent evidence about the pathophysiology of essential tremor and tremor in Parkinson’s disease. […] Both essential tremor and Parkinson’s tremor are associated with increased activity in the cerebellothalamocortical circuit. […] In essential tremor, GABAergic dysfunction of the cerebellar dentate nucleus and brain stem, possibly caused by neurodegeneration in these regions, may lead to tremulous activity within the cerebellothalamocortical circuit. […] In both disorders, network parameters such as the strength and directionality of interregional coupling are crucially altered. […] This study provides convincing evidence for GABAergic dysfunction in the entire cerebellothalamocortical circuit of ET patients. […] This postmortem study shows reduced levels of GABA receptors in the dentate nucleus of ET patients, the extent of which is correlated with ET duration. […] Purkinje cell loss is a characteristic of essential tremor: towards a more mature understanding of pathogenesis.

• #5 The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models – PMC Lock

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8698799/

  The progressive nature of the disease and the close relationship with age (ET mainly affects the elderly) are the main arguments in favor of the neurodegenerative basis of ET. […] The fundamental question regarding the neurodegenerative nature of the disease is whether there are characteristic histopathological changes in the brain. […] The results of the research by Lin et al. seem to be interesting as they showed that the synaptic connections between the ION climbing fibers and the cerebellar cortex PCs of patients with ET differed from those observed in healthy controls. […] The mechanisms underlying ET and tremor in PD partially overlap. […] The hypothesis of the central oscillatory network could explain previously inconsistent data, e.g., why ET disappears after cerebellar stroke in some patients, while in others, the disease develops after an extensive cerebral hemispherectomy where large portions of the cerebellum are removed.

• #6 The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

  https://www.mdpi.com/2218-273X/11/12/1813

  The progressive nature of the disease and the close relationship with age (ET mainly affects the elderly) are the main arguments in favor of the neurodegenerative basis of ET. […] The fundamental question regarding the neurodegenerative nature of the disease is whether there are characteristic histopathological changes in the brain. […] The results of the research by Lin et al. seem to be interesting as they showed that the synaptic connections between the ION climbing fibers and the cerebellar cortex PCs of patients with ET differed from those observed in healthy controls. […] The hypothesis of the central oscillatory network could explain previously inconsistent data, e.g., why ET disappears after cerebellar stroke in some patients, while in others, the disease develops after an extensive cerebral hemispherectomy where large portions of the cerebellum are removed.

• #7 Essential tremor – Wikipedia

  https://en.wikipedia.org/wiki/Essential_tremor

  Essential tremor is one of the most prevalent and poorly-understood neurological disorders. Clinical, physiological and imaging studies point to involvement of the cerebellum and/or cerebellothalamocortical circuits. The traditional model for essential tremor, the olivary hypothesis, suggests that ET is caused by abnormal electrical activity in the inferior olivary nucleus. This activity makes neurons fire in a regular, synchronized way, which then disrupts signals to the cerebellum and leads to tremors. However, recent studies, especially those examining brain tissue, propose a new hypothesis that ET may be a neurodegenerative disease focused in the cerebellum, differing from the old theory. Changes in the cerebellum could also be mediated by alcoholic beverage consumption. Purkinje cells are especially susceptible to ethanol excitotoxicity. Impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor. Some cases have Lewy bodies in the locus ceruleus. ET cases that progress to Parkinson’s disease are less likely to have had cerebellar problems. Recent neuroimaging studies have suggested that the efficiency of the overall brain functional network in ET is disrupted.

• #8 Frontiers | The Essential Tremors: Evolving Concepts of a Family of Diseases

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.650601/full

  The past 10 years has seen a remarkable advance in our understanding of the disease traditionally referred to as “essential tremor” (ET). […] Studies of disease etiology have identified a number of candidate genes as well as explored several environmental determinants of disease. […] This emerging science has given rise to a new notion that the disease, in many cases, is one of cerebellar system degeneration. […] The decade has seen the beginnings and expansion of rigorous and controlled postmortem studies of ET brains, and these have identified and systematically cataloged the postmortem changes in the brains of patients with ET. This new science has given rise to a new notion that the disease, in many cases, is one of cerebellar system degeneration. […] While the majority of ET cases evidence a host of related degenerative features in the cerebellar cortex, a sizable minority of cases has Lewy body pathology, and an even smaller number has intranuclear inclusions. These data indicate that the postmortem findings, and hence the pathomechanisms, are not uniform across all ET cases.

• #9 Essential tremor pathology: neurodegeneration and reorganization of neuronal connections | Nature Reviews NeurologyClose bannerClose banner

  https://www.nature.com/articles/s41582-019-0302-1

  Essential tremor (ET) is the most common tremor disorder globally and is characterized by kinetic tremor of the upper limbs, although other clinical features can also occur. […] Several recent postmortem studies have made important contributions to our understanding of the pathological changes that take place in ET. […] These studies identified abnormalities in the cerebellum, which primarily affected Purkinje cells (PCs), basket cells and climbing fibres, in individuals with ET. […] We suggest that some of these pathological changes (for example, focal PC axonal swellings, swellings in and regression of the PC dendritic arbor and PC death) are likely to be primary and degenerative. […] By contrast, other changes, such as an increase in PC recurrent axonal collateral formation and hypertrophy of GABAergic basket cell axonal processes, could be compensatory responses to restore cerebellar GABAergic tone and cerebellar cortical inhibitory efficacy.

• #10 Essential Tremor: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/1150290-overview

  In patients with essential tremor, [18 F]fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scan studies identified increased glucose consumption in the medulla. In addition, [15 O]H2 O PET scan studies demonstrated an increase in medullary regional cerebral blood flow in subjects with essential tremor (only after the administration of ethanol), and bilateral overactivity of cerebellar circuitry. […] Fundamental debate exists as to whether essential tremor is a neurodegenerative disease. Data suggesting that it is neurodegenerative includes postmortem findings of pathologic abnormalities in the brainstem and cerebellum, including Lewy bodies in the locus ceruleus, loss of Purkinje cells, and abnormalities of the dentate nucleus; reduction in cerebellar cortical N-acetylaspartate/total creatine (NAA/tCR); white matter changes on diffusion tensor imaging; and clinical studies demonstrating an association with cognitive and gait changes.

• #11 Essential tremor pathology: neurodegeneration and reorganization of neuronal connections | Nature Reviews NeurologyClose bannerClose banner

  https://www.nature.com/articles/s41582-019-0302-1

  Such compensatory responses are likely to be insufficient, enabling the disease to progress. […] Several groups have identified pathological changes in the cerebellum of individuals with essential tremor (ET). […] Cerebellar abnormalities in ET include changes to Purkinje cell (PC) axons and dendrites, displacement and loss of PCs, changes to basket cell axonal processes, abnormal distribution of climbing fibre connections to PCs and changes in GABA receptors in the dentate nucleus. […] Some of the observed changes (for example, loss of PCs) could result in reduced GABAergic output from the cerebellum. […] Some pathological changes in ET are likely to be primary and degenerative, whereas others could be regarded as compensatory responses aimed at restoring cerebellar GABAergic tone. […] In the brains of individuals with ET, both PCs themselves and neighbouring GABAergic neurons (basket cells) might increase their connections with PCs, resulting in rewiring and reorganization of neuronal connections within the cerebellum.

• #12 The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models – PMC Lock

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8698799/

  Another important hypothesis postulates that disturbances in cerebellar GABAergic transmissions are at the root of ET. […] The stimulation of dopamine D3/D2 receptors using the preferential D3 receptor agonist pramipexole has been shown to attenuate harmaline-induced tremor in rats, as well as reducing tremor in a small group of patients with ET. […] The results of studies with non-selective adenosine receptor antagonists, such as theophylline and caffeine, provide conflicting data. […] The only problem with these types of compounds is that they could cause several side effects which are related to the presence of A1 receptors in the periphery.

• #13 The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

  https://www.mdpi.com/2218-273X/11/12/1813

  Another important hypothesis postulates that disturbances in cerebellar GABAergic transmissions are at the root of ET. […] There are several arguments for the idea that ET is associated with the abnormal function of the GABA inhibitory neurotransmitter system. […] The neuroimaging studies using positron emission tomography (PET) with [11C]flumazenil, a ligand that specifically binds to the benzodiazepine site on the GABA-A receptor, yielded contrasting results. […] The adenosine A1 receptors seem to be especially interesting as a potential therapeutic target for tremor treatment, since they are present in all brain structures important for harmaline tremor. […] All these findings suggest that adenosine A1 receptors might be a potential therapeutic target for the treatment of ET.

• #14 Essential Tremor: What We Can Learn from Current Pharmacotherapy | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.318

  To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. […] Potentiating GABA receptors in the CNS and inhibiting beta-adrenergic systems most consistently improve tremor. Inhibiting glutaminergic systems, carbonic anhydrase, SV2A receptors, and alpha-2 delta subunits less consistently improve tremor, whereas Na channel inhibition does not affect tremor.

• #14 Essential Tremor: What We Can Learn from Current Pharmacotherapy | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.318

  This review will summarize the mechanisms of action of medications that may affect tremor in order to improve our understanding of potential neurotransmitter/receptor pathology and provide a substrate for future rational drug development. […] Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. […] Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A.

• #14 Essential Tremor: What We Can Learn from Current Pharmacotherapy | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.318

  The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. […] The pathophysiology of essential tremor (ET) is only partially understood. There is some understanding of culpable macro-circuitry, mostly based on functional positron emission tomography (PET)/single-photon emission computed tomography studies, functional magnetic resonance imaging, tractography, transcranial stimulation, and other electrophysiological techniques. However, there is very little understanding at the cellular level. Post-mortem pathology of ET is inconsistent: variably being normal, demonstrating Lewy body pathology, or cerebellar Purkinje cell degeneration. […] Our current understanding regarding germane neurotransmitter system pathology in ET is largely inferred from the clinical response of medicines that were serendipitously found to affect tremor.

• #15 Frontiers | Imaging the Pathophysiology of Essential Tremor—A Systematic Review

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.680254/full

  Background: The pathophysiology underlying essential tremor (ET) still is poorly understood. Recent research suggests a pivotal role of the cerebellum in tremor genesis, and an ongoing controversy remains as to whether ET constitutes a neurodegenerative disorder. […] In addition, there is mounting evidence that alterations in the integrity of the inhibitory gamma-aminobutyric acid (GABA) neurotransmitter system is a contributory factor in ET pathophysiology. […] There is robust evidence indicating that the cerebellum plays a key role within a multiple oscillator tremor network which underlies tremor genesis. However, whether cerebellar dysfunction relies on a neurodegenerative process remains unclear. […] The clinical, demographical, and genetic heterogeneity of ET translates into neuroimaging and likely explains the various inconsistencies reported.

• #16 Tremors | MedLink Neurology

  https://www.medlink.com/articles/tremors

  In this article, the author reviews new studies related to the pathogenesis of essential tremor, including Purkinje cell pathology as well as LINGO1 and SLC1A2 genes. Clinical diagnosis of tremor disorders and treatment strategies for essential tremor are described in detail. […] The underlying source of essential tremor has been debated as being peripheral or central. The current wisdom suggests that the cause is central and the suggested oscillator involves the cerebellum and its pathways, especially the inferior olive and cerebellar outflow tracts. […] The GABA hypothesis in essential tremor implies that tremor is due to hyperactivity of cerebellothalamic circuits due to reduced GABAergic function. […] The rs9652490 variant of the LINGO1 gene has been associated with both essential tremor and Parkinson disease. […] Increase in Purkinje cell loss with axonal torpedo pathology as well as Bergmann gliosis have been reported in essential tremor.

• #17

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/tremors/

  Four basic mechanisms are linked to the production of tremor. It is likely that combinations of these mechanisms produce tremor in different diseases. Mechanical oscillations of the limb can occur at a particular joint; this mechanism applies in cases of physiologic tremor. Reflex oscillation is elicited by afferent muscle spindle pathways and is responsible for stronger tremors by synchronization. This mechanism is a possible cause of tremor in hyperthyroidism or other toxic states. Central oscillators are groups of cells in the central nervous system present in the thalamus, basal ganglia, and inferior olive. These cells have the capacity to fire repetitively and produce tremor. Parkinsonian tremor might originate in the basal ganglia, and essential tremor might originate within the inferior olive and thalamus. Abnormal functioning of the cerebellum can produce tremor. Positron emission tomography studies have shown cerebellar activation in almost all forms of tremor. […] Essential tremor is the most common form of all movement disorders. Classic essential tremor is predominantly a postural- or action-type tremor, and usually the patient has a positive family history of tremor.

• #18 Mechanism Behind Ulixacaltamide to Treat Essential Tremor: Marcio Souza

  https://www.neurologylive.com/view/mechanism-behind-ulixacaltamide-treat-essential-tremor-marcio-souza

  At the meeting, NeurologyLive sat down with Marcio Souza, MD, president and chief executive officer at Praxis Precision Medicine, to discuss the mechanism of action of ulixacaltamide. In the conversation, he noted that the drug targets specific T-type calcium channels that are overreactive in the brain networks regulating movement, particularly in the cerebro-thalamo-cortical circuitry linked to tremor. […] Ulixacaltamide, which has shown promise in previous phase 1/2 studies, has a selective action on these channels, avoiding effects on other calcium channels elsewhere in the body. Furthermore, Souza spoke on the specialized drug delivery system of ulixacaltamide, which ensures sustained coverage throughout the day without causing tolerability issues.

• #19 Hypothetical membrane mechanisms in essential tremor | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-6-68

  Essential tremor (ET) is the most common movement disorder and its pathophysiology is unknown. We hypothesize that increased membrane excitability in motor circuits has a key role in the pathogenesis of ET. […] Specifically, we propose that neural circuits controlling ballistic movements are inherently unstable due to their underlying reciprocal innervation. Such instability is enhanced by increased neural membrane excitability and the circuit begins to oscillate. These oscillations manifest as tremor. […] Therefore we hypothesize that increased membrane excitability in pre-motor neurons has a key role in pathogenesis of ET. […] The model simulated oscillations resembling ET when Ih was increased (with or without an increase in IT). […] In summary, simulations support our hypothesis that an increase in premotor neural excitability, caused by increasing Ih and IT, results in oscillations of a reciprocally innervated neural circuit. These oscillations resemble ET. The frequency of tremor is determined by both IT and Ih.

• #20 Decreased EAAT2 protein expression in the essential tremor cerebellar cortex | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-014-0157-z

  Genetic polymorphisms in SLC1A2 have been linked with essential tremor. SLC1A2 encodes excitatory amino acid transporter type 2 (EAAT2), which clears glutamate from the synaptic cleft. One postulated mechanism for essential tremor is the over-excitation of glutamatergic olivo-cerebellar climbing fibers, leading to excitotoxic death of Purkinje cells. Therefore, the expression level of glutamate transporters could be important in essential tremor pathogenesis. Our main finding, a significant reduction in cerebellar cortical EAAT2 protein levels in essential tremor, suggests that Purkinje cells in essential tremor might be more vulnerable to excitotoxic damage than those of controls. […] Clinical and neuroimaging evidence has pointed to the importance of the cerebellum in the pathogenesis of ET. One hypothesized mechanism for ET is that it is a disorder of over-excitation of glutamatergic olivo-cerebellar climbing fibers, which results in excitotoxic damage to PCs. Alterations in EAAT levels in the cerebellar cortex could result in a breakdown in normal extracellular glutamate homeostasis, enhancing vulnerability to excitotoxic damage.

• #21 Decreased EAAT2 protein expression in the essential tremor cerebellar cortex | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-014-0157-z

  In summary, EAAT2 levels were significantly decreased in the ET cerebellar cortex, in contrast to similar levels of EAAT1 levels between ET cases and controls. ET brains might be more vulnerable to excitotoxic damage than those of controls. Further study of the relationship between astrocytes and PC injury might be central to understanding ET pathogenesis.

• #22 Frontiers | Imaging the Pathophysiology of Essential Tremor—A Systematic Review

  https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.680254/full

  The dopaminergic axis appears to be largely preserved in ET. […] With the exception of one study, there is no evidence for pathological nigral iron accumulation as typically observed in PD. However, only one study did not apply an ROI-based approach limited to the substantia nigra, and this study did observe a significant increase of iron accumulation in the bilateral globus pallidus internus. […] Finally, MRS and radiotracer studies lend some support to the hypothesis that dysfunction of the GABAergic system is involved in ET pathophysiology.

• #23 Essential Tremor: A Common Disorder With Limited Treatments

  https://www.uspharmacist.com/article/essential-tremor-a-common-disorder-with-limited-treatments

  The precise etiology and pathophysiology of ET are unknown. Many studies indicate a hereditary linkage. Approximately 50% to 60% of ET patients have a first-degree relative with ET. ET, often referred to as familiar tremor, is believed to be inherited via an autosomal-dominant gene. Although the exact gene has yet to be discovered, some studies have found loci of specific interest. One theory holds that early-onset ET is more commonly tied to the hereditary form of ET, as opposed to nongenetic ET. Based on clinical observation, it is believed that the cerebellum or the cerebellothalamocortical pathway is the center of origin or site of involvement. However, disagreement exists as to whether ET is a specific disease or a manifestation of symptoms of various causes. […] In recent years, the term benign has become outdated, since studies have found nonmotor symptoms with progression of ET. These symptoms include cognitive changes, depression, social phobias, anxiety, and hearing and smelling defects. Additionally, some patients have impaired gait, which supports the belief that ET originates in the cerebellum.

• #24 Essential Tremor – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK499986/

  Some reports suggest that the neuropathology of essential tremor is localized in the brainstem (locus coeruleus) and cerebellum, but the presence of cerebellar pathology is controversial. However, it is believed that essential tremor is a risk factor for the development of Parkinson disease. In addition, there has also been an association between essential tremors and dystonic movements. […] The etiology of essential tremor is mostly unexplained. About half of the cases of essential tremor appear to result from a genetic mutation; although, a specific gene has not been identified. This form is referred to as familial tremor and is an autosomal dominant disorder. The variability in age of onset, the presence of sporadic cases, and incomplete concordance of essential tremor among monozygotic twins suggest that environmental factors play a role.

• #25 Overactive Brain Waves Trigger Essential Tremor | Columbia University Irving Medical Center

  https://www.cuimc.columbia.edu/news/overactive-brain-waves-trigger-essential-tremor

  The source of essential tremor, a movement disorder that causes involuntary trembling of the hands, arms, and head, has been enigmatic, impeding the development of effective treatments for a condition that affects 4% of people over 40. […] Now a new study from the Vagelos College of Physicians and Surgeons at Columbia University Irving Medical Center and NewYork-Presbyterian suggests the tremors are caused by overactive brain waves at the base of the brain, raising the possibility of treating the disorder with neuromodulation to calm the oscillations. […] This study pins down how those structural changes affect brain activity to drive tremor. […] A new study suggests that patients with essential tremor have unusual brain waves in the cerebellum that cause the tremors (the same brain waves in mice produce tremor).

• #26 Overactive Brain Waves Trigger Essential Tremor | Columbia University Irving Medical Center

  https://www.cuimc.columbia.edu/news/overactive-brain-waves-trigger-essential-tremor

  Among 20 essential tremor patients examined with cerebellar EEG, most had strong oscillations (between 4 and 12 Hz) in the cerebellum that were not found in any of the 20 control subjects. […] The researchers first discovered the cerebellar oscillations in mice that had developed tremors closely resembling those seen in essential tremor patients. […] These results established a causal relationship between the brain oscillations and tremor. […] In previous studies of postmortem brain tissue from essential tremor patients, the Columbia team discovered that patients with essential tremor had an abnormally high number of synapses, or connections, between two types of nerve cells in the brain’s cerebellum—climbing fibers and Purkinje cells. […] In the current study, again using postmortem brain tissue, the researchers found that the formation of these synapses appears to be influenced by a protein called glutamate receptor delta 2 (GluR2).

• #27 Overactive Brain Waves Trigger Essential Tremor | Columbia University Irving Medical Center

  https://www.cuimc.columbia.edu/news/overactive-brain-waves-trigger-essential-tremor

  When the team reduced expression of GluR2 in mice, the animals developed tremors similar to those seen in humans. […] Restoring GluR2 function suppressed the tremors, proving that the protein plays a key role in essential tremor. […] The study opens several new possibilities for treatment of essential tremor, Kuo says. […] Using cerebellar EEG as a guide, we may be able to use neuromodulation techniques such as tDCS or TMS (transcranial direct-current stimulation or transcranial magnetic stimulation) to reduce tremor, or even drugs to reduce transmission between the climbing fibers and Purkinje cells. […] Kuo is also working to develop medications that increase GluR2 expression in the brain, which may reduce tremor.

• #28 GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis — Olink®

  https://olink.com/publication/gwas-meta-analysis-reveals-key-risk-loci-in-essential-tremor-pathogenesis

  Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. […] Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. […] CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. […] Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling.

• #29 GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis — Olink®

  https://olink.com/publication/gwas-meta-analysis-reveals-key-risk-loci-in-essential-tremor-pathogenesis

  Genetic correlation analyses reveals a positive association between ET and Parkinsons disease, depression, and anxiety-related phenotypes. […] This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

• #30 Finding the mechanism of Essential tremor – Taipeh Vertretung in der Bundesrepublik Deutschland 駐德國台北代表處

  https://roc-taiwan.org/de_de/post/8150.html

  What is essential tremor? Why it is important? […] While ET is such a common disorder, the mechanism of ET remains largely unknown. […] We found a mechanism of ET and developed a new technique (cerebellar electroencephalography, or cerebellar EEG) and a related clinical biomarker (abnormal cerebellar oscillations) for ET. […] The overgrowth of cerebellar fibers is associated with the loss of a cerebellar protein called GluRδ2, whose function is to stabilize the synapses between the fibers and the neurons and therefore control the fiber growth. […] We found that the loss of GluRδ2 protein leads to the overgrowth of cerebellar climbing fibers, whose activities cause too much synchronization and oscillations of cerebellar neurons and therefore generate tremor. […] In summary, we found a pathophysiology of ET, with mutually referenced mouse and human evidence spanning molecular (GluRδ2 deficiency), structural (cerebellar fiber overgrowth), physiological (excessive cerebellar oscillations) and behavioral (action tremor) levels. […] More importantly, the discovery of an ET mechanism and the corresponding clinical biomarker by novel cerebellar EEG technology could significantly benefit clinical diagnosis and guide the new drug development in future works.

• #31 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200116/Essential-tremor-caused-by-overactive-brain-waves.aspx

  Now a new study from Columbia University Irving Medical Center and NewYork-Presbyterian suggests the tremors are caused by overactive brain waves at the base of the brain, raising the possibility of treating the disorder with neuromodulation to calm the oscillations. […] This study pins down how those structural changes affect brain activity to drive tremor. […] Among 20 essential tremor patients examined with cerebellar EEG, most had strong oscillations (between 4 and 12 Hz) in the cerebellum that were not found in any of the 20 control subjects. Patients with more severe tremors had stronger oscillations. […] „These results established a causal relationship between the brain oscillations and tremor, which cannot be directly tested in patients,” says Kuo. […] In previous studies of postmortem brain tissue from essential tremor patients, the Columbia team discovered that patients with essential tremor had an abnormally high number of synapses, or connections, between two types of nerve cells in the brain’s cerebellum–climbing fibers and Purkinje cells.

• #32 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20200116/Essential-tremor-caused-by-overactive-brain-waves.aspx

  „When this protein is underexpressed, any excess synapses that form between climbing fibers and Purkinje cells are not eliminated, resulting in too many neuronal connections,” says Kuo. […] Restoring GluR2 function suppressed the tremors, proving that the protein plays a key role in essential tremor. […] The study opens several new possibilities for treatment of essential tremor, Kuo says: Using cerebellar EEG as a guide, we may be able to use neuromodulation techniques such as tDCS or TMS (transcranial direct-current stimulation or transcranial magnetic stimulation) to reduce tremor, or even drugs to reduce transmission between the climbing fibers and Purkinje cells.

• #33 Essential Tremor Medication: Beta-Blockers, Nonselective, Anticonvulsants, Other

  https://emedicine.medscape.com/article/1150290-medication

  The mechanism of action in the reduction of essential tremor is not known. The action is hypothesized to be mediated primarily by peripheral beta2 adrenoreceptors, but some evidence indicates that beta1-receptor antagonists such as metoprolol also have some efficacy. Peripheral beta2 adrenoreceptors are located in the extrafusal muscle fibers and on the intrafusal fibers of the muscle spindles. […] Primidone is believed to have an independent mechanism for its effect on tremor. […] Topiramate’s mechanism of action is unknown, but the blockage of voltage-dependent sodium channels and the augmentation of GABA are thought to play a role. […] Some agents in this class have demonstrated tremor-suppressing effects. Their mechanism of action is unknown, but it presumably involves the CNS.

• #34

  https://www.beaumont.org/conditions/essential-tremor

  The cause of essential tremor is unknown, but for most people who have it, the condition seems to run in their family. […] Although the cause isn’t known, one theory is that the cerebellum and certain other parts of the brain are not communicating correctly in people with essential tremor disorder. The cerebellum is a part of the brain that controls muscle coordination. […] Propanolol blocks the stimulating action of neurotransmitters to calm your trembling. Primidone is a common antiseizure medication that also controls the actions of neurotransmitters.

• #35 Essential Tremor | University of Michigan Health

  https://www.uofmhealth.org/conditions-treatments/brain-neurological-conditions/essential-tremor

  Essential tremor, also known as familial tremor, is the most common movement disorder, affecting an estimated 5 percent of people worldwide. […] Deep brain stimulation is the most commonly-performed surgery for essential tremor and is highly effective. […] Deep brain stimulation involves placing an electrode in a structure of the brain called the thalamus. When electrical stimulation is delivered to the brain, the tremor improves. Its like a pacemaker for the brain, instead of the heart. Deep brain stimulation has several advantages over ablation (where cells in the brain are destroyed), including reversibility.

• #36 Essential Tremor – Symptoms, Diagnosis, TreatmentGroup 9Group 9Group 49

  https://www.barrowneuro.org/condition/essential-tremor/

  Essential tremor may be inherited, but this mechanism only accounts for about half of cases. The cause in other cases is unknown. However, the thalamus, a structure deep within the brain, is thought to be involved. […] In deep brain stimulation, a surgically implanted device called a neurostimulator delivers small electrical pulses to the thalamus to interrupt signals that may be causing your tremors. […] Focused ultrasound thalamotomy is another option for the treatment of essential tremor. It is a minimally invasive procedure that uses sound waves to deactivate a small part of the thalamus, which is the part of the brain where essential tremor arises.

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