Epicranial Direct Current Stimulation Suppresses Harmaline Tremor in Rats

IntroductionEssential tremor (ET) is the most common neurologic movement disorder worldwide. It is characterized by a postural tremor, mostly in the upper extremities, causing difficulties in daily activities that may lead to social exclusion. Some patients with ET do not respond well to or do not tolerate medication. Thus, deep brain stimulation can be offered. In a recent study, we proposed a novel neuromodulation technique called epicranial current stimulation (ECS) that works in a minimally invasive way by placing the electrodes subcutaneously under the skin and directly over the skull. In this study, we investigated the feasibility of using epicranial direct current stimulation (EDCS) to suppress tremor in a rat harmaline ET model.Materials and MethodsIn experiment 1, seven Sprague Dawley rats were implanted with ECS electrodes placed over the motor cortex (MC) and the cerebellum to investigate whether stimulating between them could suppress tremor. In experiments 2 and 3, eight rats were implanted with ECS electrodes placed over the MC, cerebellum, and the rostral skull to separate the effects on tremor caused by stimulating each target. During each experiment, the rats were injected with harmaline, which induced tremor that was quantified using an accelerometer. EDCS was then applied through the different electrode configurations to evaluate their tremor suppression effectiveness.ResultsResults from experiment 1 showed that MC_cathode-Cerebellar_anode suppressed tremor compared with stimulation-OFF but MC_anode-Cerebellar_cathode did not. Furthermore, experiments 2 and 3 showed that it was the cerebellar anodal electrode that was driving tremor suppression.ConclusionCerebellar EDCS suppressed harmaline tremor in rats in a polarity-dependent manner. EDCS could be a promising neuromodulation method for patients with ET.     

Imaging essential tremor

To investigate over time changes in striatal dopamine transporter (DAT), we performed two sequential N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl) tropane single photon computed tomography (SPECT) scans in 20 subjects with essential tremor (ET), in 13 with Parkinson disease (PD) and in 23 healthy controls (HC, one scan only). We also performed an [^99mTc]ethyl cysteinate dimer bicisate SPECT exam for regional brain network analysis in 9 ET, in a second group of 18 PD (9 with tremor, tPD and 9 akinetic‐rigid dominant, arPD) and in 8 HC. PD subjects had a reduced DAT binding in comparison to ET and HC with an annual decline rate of 7.3% in the contralateral putamen. There were no mean uptake differences between ET and HC at baseline and no uptake loss over time in ET. A discriminant analysis grouped 30% (first scan) and 5% (second scan) of ET as PD and a partition analysis showed overlap between ET and PD for caudate nucleus uptake. Spatial covariance analysis revealed that the expression of the PD‐related regional pattern separated both tPD and arPD from ET and HC. In conclusion, PD and ET do not share a common pattern of dopaminergic loss over time. However, mild impairment of dopamine transporter in the caudate nucleus may contribute to tremor onset in ET. © 2010 Movement Disorder Society     

A possible mechanism for the beneficial effect of ethanol in essential tremor

Background:  Essential tremor is one of the most common movement disorders in elderly people. The hypothesis of a disregulation of N -methyl- d -aspartate (NMDA) pathways has been suggested. It was shown experimentally that infusion of NMDA in cerebellar nuclei down-regulates glutamate release.
Methods:  We assessed the effects of intranuclear administration of harmaline on the NMDA-mediated regulation of glutamate in rats using reverse dialysis. We hypothesized that ethanol, which improves essential tremor in the clinic, antagonizes the effect of harmaline upon glutamatergic transmission. We tested the interaction of ethanol and harmaline upon glycerol (a marker of membrane turn-over), lactate, and pyruvate concentrations.
Results:  Harmaline increased the concentrations of glutamate and impaired the NMDA-mediated regulation of glutamate. Ethanol decreased the concentrations of glutamate during NMDA stimulation in case of pre-administration with harmaline. Concentrations of glycerol rose with harmaline. Glycerol levels markedly decreased during NMDA infusion when inhibitors of nitric oxide synthase, α-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonists or NMDA antagonists were administered. Harmaline increased lactate/pyruvate ratios during NMDA infusion but these ratios returned to normal values in presence of ethanol.
Discussion:  We provide a possible mechanism for the beneficial effect of ethanol on essential tremor. The concept of glutamatergic disregulation underlying essential tremor is highlighted. Consequences for our understanding of essential tremor are discussed.     

Subclinical tremor in normal controls with versus without a family history of essential tremor: data from the United States and Turkey

Background and purpose: Mild action tremor is very common in the population. One fundamental question is whether this tremor is related to the neurological disease essential tremor (ET), which occurs in a much smaller segment of the population? ET is often genetic, and variable phenotypic expression is well‐documented in the literature. We determined whether normal controls who report a family history of ET have greater action tremor than normal controls who do not report such a history. Methods: Controls, enrolled in two epidemiological studies (New York and Turkey), were examined in detail and action tremor was rated using a valid and reliable clinical rating scale, resulting in a total tremor score (range 0–36). Results: In New York, the total tremor score was higher in 44/406 (10.8%) controls who reported a family history of ET than in 362/406 controls with no such history (4.25 ± 2.51 vs. 3.78 ± 2.93, P = 0.02). Controls who reported a first‐degree relative with ET had the highest total tremor scores. In Turkey, the total tremor score was higher in 7/89 (7.9%) controls with a family history than in 82/89 controls with no family history (3.43 ± 4.54 vs. 1.13 ± 2.54, P = 0.048). All affected relatives in Turkey were first‐degree. Conclusions: These data suggest that some of the normal tremor exhibited by people in the population is likely to be subclinical, partially expressed ET and that the sphere of ET is wider than is apparent from a consideration of clinically diagnosed cases.     

Clinical features and nigrostriatal dysfunction in patients with combined postural and resting tremors

BackgroundThe characteristics of clinical features and nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors have been less clearly reported.MethodsThe present study examined 43 patients with a visible persistent bilateral postural tremor and a unilateral/bilateral resting tremor involving the hands and forearms. The patients had experienced tremors for more than 3 years, with no evidence of Parkinson's disease or other parkinsonian disorders. Visual and quantitative analyses of [¹⁸F] N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) PET in 36 patients were performed. Seventeen age-matched normal controls were also studied.ResultsOn visual analysis, 28 patients (78%) showed normal [¹⁸F] FP-CIT uptake and eight (22%) showed significantly reduced uptake, suggesting nigrostriatal dopaminergic neuronal degeneration. The reduced [¹⁸F] FP-CIT uptake was significantly associated with earlier age-at-onset of tremor and asymmetric presentation of resting tremor. On quantitative analysis, there were statistically significant differences in the [¹⁸F] FP-CIT uptake ratio in the posterior putamen between patients with reduced uptake (2.37 ± 1.83) and patients with normal uptake (6.39 ± 1.35) (P < 0.001). However, posterior putamen uptake levels in patients with normal [¹⁸F] FP-CIT uptake on visual analysis were similar to those in normal controls (7.22 ± 1.29) (P = 0.291).ConclusionThe nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors may be associated with earlier age-at-onset of tremor and asymmetric pattern of resting tremor, which might help to correctly diagnose patients with mixed tremors.     

GABAA receptor‐ and GABA transporter polymorphisms and risk for essential tremor

Background: Clinical features and animal models of essential tremor (ET) suggest gamma‐aminobutyric acid A receptor (GABA_AR) subunits and GABA transporters as putative candidate genes. Methods: A total of 503 ET cases and 818 controls were investigated for an association between polymorphisms in 15 GABA_AR and four GABA transporter genes and ET. Results: Nine nominally significant tagging SNPs (P values from 4.9 × 10⁻² to 5.2 × 10⁻⁴) were found in the hypothesis generation stage. Five SNPs were followed up in a second verification stage but failed to reach significance. (P values from 0.30 to 0.77). Discussion: In our samples, no evidence of association between GABA_AR and GABA transporter genes with ET was detected. Further studies are necessary to clarify the role of these genes in ET.     

Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model

Background

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. With drug treatment only partially efficient, new treatments are being developed.

Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications.

No preclinical method to evaluate potential new medications for essential tremor (ET) is available currently. Although harmaline tremor is a well known animal model of ET, it has not found utility as a preclinical drug screen and has not been validated with anti-ET medications. We measured harmaline tremor in rats (10 mg/kg s.c.) and mice (20 mg/kg s.c.) with a load sensor under the cage floor and performed spectral analysis on 20-minute epochs. The motion power over the tremor frequency bandwidth (8-12 Hz in rats; 10-16 Hz in mice) was divided by the motion power over the full motion frequency range (0-15 Hz in rats; 0-34 Hz in mice). The use of these measures greatly reduced data variability, permitting experiments with small sample sizes. Three drugs that suppress ET (propranolol, ethanol, and octanol) all significantly suppressed harmaline-induced tremor. We propose that, with this methodology, harmaline-induced tremor may be useful as a preclinical method to identify potential medications for ET.     

Low-dose acute vanillin is beneficial against harmaline-induced tremors in rats

Objective: To study the effect of pretreatment with low doses of vanillin, a flavoring agent used as a food additive, on harmaline-induced tremor in rats.

Methods: Sprague Dawley rats (110 ± 5 g) were divided into groups of six animals each. Vanillin (6.25 mg, 12.5 mg, and 25 mg/kg) was administered by gavage to different groups of rats, 30 minutes before the induction of tremor. Harmaline (10 mg/kg, i.p.) was used for the induction of tremor. The latency of onset, duration, tremor intensity, tremor index, and spontaneous locomotor activity were recorded. A separate batch of animals was used for the determination of serotonin (5HT) and 5 hydroxyindole acetic acid (5HIAA) levels in the brain.

Results: Harmaline treatment resulted in characteristic tremor that lasted for more than 2 hours and decreased the locomotor activity of rats. Pre-treatment with vanillin significantly reduced the duration, intensity, and tremor index of harmaline-treated animals. Vanillin treatment also significantly attenuated harmaline-induced decrease in the locomotor activity. An increase in 5HT levels and the changes in 5HIAA/5HT ratio observed in harmaline treated rats were significantly corrected in vanillin pretreated animals.

Discussion: Vanillin in low doses reduces harmaline-induced tremor in rats, probably through its modulating effect on serotonin levels in the brain. These findings suggest a beneficial effect of vanillin in essential tremor.     

Clinical characteristics of essential tremor in Taiwan: an exploratory‐comparative study

Background: There are few large‐scale clinical analyses of essential tremor (ET) in Asia. We studied the detailed clinical profile with emphasizing the age of onset, tremor location, specific tremor patterns, and rate of progression (ROP) to delineate the characteristics of Taiwanese ET patients and found the difference between the Taiwanese and the Caucasians ET patients. Methods: All ET patients fulfilled the Movement Disorders Society diagnosis criteria were investigated with a standardized assessment protocol, which including clinical evaluation, uniform severity scoring, self‐reported questionnaires, accelerometry, surface electromyography, and videotaped tremor examination. Results: Of 219 patients recruited from July 2008 to October 2009, 153 completed the study protocol. Their mean age was 58.9 years and 47% were women, and 33.3% had family history (FH). There was bimodal distribution in age of tremor onset in patients without but not in those with FH. Head tremor (HT) was present in 48 of 153 (31%) patients. Patients with HT showed slower tremor frequency and less ROP than those without HT. Sixty‐seven (44%) patients presented with intention tremor (IT). Male gender and voice tremor were predictive factors of IT occurrence. Conclusions: Comparing with the Caucasians, Taiwanese ET patients have different patterns of onset‐age distribution and lack of female predominance in ET with HT. However, patients with IT and without HT also progressed more rapid as found in the Caucasian.     

What is the functional significance of nondominant arm tremor in essential tremor?

Tremor in the dominant arm is often the focus of clinical attention in essential tremor (ET) yet many daily activities require both arms. The functional relevance of nondominant arm tremor has rarely been studied. In 181 right‐handed patients with ET, action tremor in each arm was rated using a clinical rating scale. Tremor disability was self‐reported and a performance‐based test of function was administered. Independently of tremor on the right, greater tremor severity on the left was associated with greater self‐reported disability (P = 0.02) and greater performance‐based dysfunction (P < 0.001). In 5.0% of patients, tremor was largely restricted to the nondominant arm. Nondominant arm tremor, independent of dominant arm tremor, had a significant functional correlate, contributing to both greater perceived and greater observable functional difficulty. In 5% of patients, tremor in the nondominant arm was the likely motivator for seeking care, which is another indication of its functional significance. © 2010 Movement Disorder Society.     

Essential tremor is not associated with cerebellar Purkinje cell loss

There has been controversy as to whether there is an underlying neurodegenerative process of the cerebellum in essential tremor (ET). The aim of this study was to examine whether ET is associated with Purkinje cell (PC) loss. Prospectively categorized ET and control subjects who were longitudinally examined in the Arizona Study for Aging and Neurodegenerative Disorders and came to autopsy between 1998 and 2013 underwent standardized neuropathological assessment of the brain. PC linear density of the cerebellar hemisphere was calculated in a blinded manner. There were 56 ET cases and 62 age‐matched controls free of dementia and other neurodegenerative disorders included in the study. Mean PC linear density was 3.80 ± 0.81 cells per mm for tremor cases and 3.82 ± 0.91 cells per mm for controls (Δ 0.02; 95% confidence interval [CI]: ?0.30‐0.34). PC counts were not associated with tremor duration (r = 0.06; 95% CI: ?0.21‐0.32). These data demonstrate that ET is not associated with cerebellar PC loss. © 2014 International Parkinson and Movement Disorder Society     

Lesion of the Cerebellar Noradrenergic Innervation Enhances the Harmaline-Induced Tremor in Rats

Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway has been suggested to be crucial for the harmaline-induced tremor. The cerebellum receives two catecholaminergic pathways: the dopaminergic pathway arising from the ventral tegmental area/substantia nigra pars compacta, and the noradrenergic one from the locus coeruleus. The aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervations to the harmaline-induced tremor in rats. Rats were injected bilaterally into the cerebellar vermis with 6-hydroxydopamine (6-OHDA; 8 μg/0.5 μl) either alone or this treatment was preceded (30 min earlier) by desipramine (15 mg/kg ip). Harmaline was administered to animals in doses of 7.5 or 15 mg/kg ip. Tremor of forelimbs was measured as a number of episodes during a 90-min observation. Rats were killed by decapitation 30 or 120 min after harmaline treatment. The levels of dopamine, noradrenaline, serotonin, and their metabolites were measured by HPLC in the cerebellum, substantia nigra, caudate–putamen, and frontal cortex. 6-OHDA injected alone enhanced the harmaline-induced tremor. Furthermore, it decreased the noradrenaline level by ca. 40–80% in the cerebellum and increased the levels of serotonin and 5-HIAA in the caudate–putamen and frontal cortex in untreated and/or harmaline-treated animals. When 6-OHDA treatment was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum while inducing its compensatory activation in others. The latter lesion did not markedly influence the tremor induced by harmaline. The present study indicates that noradrenergic innervation of the cerebellum interacts with cerebral serotonergic systems and plays an inhibitory role in the harmaline-induced tremor.     

Action‐induced clonus mimicking tremor

Action tremor has been described in cerebellar, task‐specific, dystonic, or Holmes tremor. We report 2 patients who developed unilateral kinetic or isometric action tremor of the upper extremity, following cervical spondylotic myelopathy and capsular ischemic stroke. Slight motor weakness and spasticity with exaggerated tendon jerks and passive stretch‐induced clonus were present on the same limb. The central motor pathways lesions might have been responsible for a hyperexcitability of the stretch‐reflex arc and an enhancement of the coactivation of skeletal muscles through a loss of the descending or segmental control of the spinal reflexes. The unusual topography of the symptoms, their occurrence during motion, and the similar frequency of the passive clonus and the action tremor, led us to hypothesize that both patients had prolonged action‐induced clonus, mimicking action tremor. Lesions of the central motor pathways lesions might be responsible for action tremor under certain conditions © 2007 Movement Disorder Society     

LINGO1 polymorphisms are associated with essential tremor in Europeans

Essential tremor (ET) is one of the most common movement disorders. Former association studies focussing on candidate genes in ET found a number of risk variants but most of them were not replicated. Recently, a genome‐wide association study revealed two intronic sequence variants in the LINGO1 gene associated with ET. Here, we have confirmed association between sequence variants in the LINGO1 gene and the ET phenotype in independent German and French ET samples. The odds ratios for the identified intronic markers rs8030859 (P = 1.0×10^?4), rs9652490 (P = 9.1×10^?4), and rs11856808 (P = 3.6×10^?2) were 1.72 (CI 1.31‐2.26), 1.61 (CI 1.21‐2.14), and 1.30 (CI 1.02‐1.66), respectively, in our German sample. LINGO1 is an interesting candidate gene because it plays a key role in central nervous system biology, is selectively expressed in the nervous system, and is an inhibitor of oligodendrocyte differentiation and neuronal myelination. Our study gives further evidence that LINGO1 acts as a susceptibility gene for ET. © 2010 Movement Disorder Society     

Dual task interference in psychogenic tremor.

Psychogenic tremor (PT) is visually indistinguishable from voluntarily mimicked tremor. Healthy volunteers have difficulties with carrying out simultaneously two tasks due to the phenomenon known as dual task interference. Therefore, performing voluntary rhythmic movements would be a burden for carrying out fast ballistic movements with the contralateral hand. We hypothesized that, similarly to healthy volunteers performing rhythmic movements, patients with PT should show the effects of dual task interference, and this may distinguish them from patients with other types of tremor. We studied 6 patients with PT, 9 with Parkinson's disease (PD) and predominantly unilateral tremor, 11 with essential tremor (ET), and 10 normal volunteers (NV) mimicking tremor. They were requested to perform a unilateral simple reaction time task (SRT) to a visual imperative signal in two different conditions: at rest (rSRT) and during contralateral hand tremor (tSRT). Reaction time was significantly longer in tSRT than in rSRT in PT and in NV groups (P < 0.01 for both groups). However, no significant differences were observed between rSRT and tSRT in PD and ET. The delay of unilateral tSRT with respect to rSRT suggests an effect of tremorlike oscillatory movements on reaction time that is consistent with the concept of dual-task interference in NV or PT patients but not in PD or ET. These observations may be useful in the evaluation of psychogenic movement disorders.     

Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor

To evaluate the posterior subthalamic area (PSA) as a target for deep brain stimulation (DBS) in the treatment of essential tremor (ET). The ventral intermediate nucleus of the thalamus is the traditional target for DBS in the treatment of ET. Recent studies have presented beneficial effects of DBS in the PSA in the treatment of tremor. Twenty‐one patients with ET were included in this study. All patients were evaluated before and 1 year after surgery, on and off stimulation, using the essential tremor rating scale (ETRS). A marked microlesional effect was noticed in 83%, in some cases obviating the need for electrical stimulation for many months. The total ETRS was reduced from 46.2 at baseline to 18.7 (60%). Item 5/6 (tremor of the upper extremity) was improved from 6.2 to 0.3 (95%), and items 11 to 14 (hand function) from 9.7 to 1.3 (87%) concerning the contralateral hand. Activities of daily living were improved by 66%. No severe complication occurred. Eight patients presented a postoperative mild dysphasia that regressed within days to weeks. DBS in the PSA resulted in a marked reduction of tremor. © 2010 Movement Disorder Society     

特发性震颤的临床和电生理学特点

目的 探讨特发性震颤(EI)的临床和电生理学特点.方法 回顾性分析并比较33例ET患者(ET组)和30例生理性震颤患者(对照组)的震颤类型、程度、幅度和负重对其的影响,以总结ET的临床和电生理学特点.结果 ET组患者动作性震颤(KT)的震颤程度明显高于对照组,震颤幅度明显大于对照组(均P＜0.01);而姿势性震颤(PT...     

Essential tremor: an overdiagnosed condition?

The diagnosis of essential tremor (ET) and its differentiation from other types of tremor is often difficult. In 1994 Bain et al. defined a classical phenotype by studying 20 patients with pure essential tremor and similarly affected family members in at least three generations. We assessed how many of the patients diagnosed by different neurologists at our institution as having ET conformed to this defined phenotype. We randomly selected 50 patients who were diagnosed with ET by any neurologist at the National Hospital for Neurology and Neurosurgery since the publication of the Bain et al. report, and determined the number of patients who had clinical features compatible with the phenotype that it had defined. Only 25 (50%) of these patients had ET so defined. Ten patients clearly had alternative diagnoses: four had clear additional dystonia, two neuropathic tremor, two had unilateral leg tremor, one drud-induced tremor, and one sudden onset after head trauma. The remaining 15 patients also had atypical features including myoclonus (one), onset in a body part other than the arms (six), sudden onset (two), rest tremor (seven), onset after the age of 65 years (four), a family member with an isolated head tremor (one), or reduced armswing (two). The diagnosis of ET is overused even among experienced neurologists, and other types of tremor should be considered in atypical patients before making this diagnosis. Received: 30 November 1999 / Received in revised form: 12 May 2000 / Accepted: 21 June 2000     

Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study

Both postural and kinetic tremors may occur in essential tremor (ET), however the relative contribution of each is not clear. ET has been variably defined with respect to kinetic and postural tremors. To examine the relative severity of postural and kinetic tremors in ET, 50 ET cases from a clinic and 55 from a community underwent a videotaped tremor examination. Kinetic and postural tremors were rated using a validated clinical rating scale (score range, 0-3). Thirty-one cases also underwent accelerometry to precisely quantify tremor amplitude. In clinic cases, the mean postural tremor rating was 1.25 (S.D., 0.89). The mean kinetic tremor rating was 52% higher (1.90; S.D., 0.57; P < 0.001). The community cases had similar characteristics. Sixty percent of the 105 cases had postural tremor ratings scoring 0 or 1 (no tremor or low amplitude, intermittent tremor). In clinic cases, the mean amplitude of postural tremor during tremor analysis was 0.51 mm (S.D., 0.66 mm), and the mean amplitude of kinetic tremor was 2.91 mm (S.D., 2.11 mm; P < 0.01). Similar values were obtained for community cases. These quantitative data suggest that kinetic tremor is more severe than postural tremor in ET. The majority of cases had mild or absent postural tremor. Despite this, ET is defined only as a postural tremor in many studies. Our data argue for a more consistent inclusion of kinetic tremor in diagnostic criteria for ET.