Background: Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of alpha 6 beta 38 extra -synaptic GABA A receptors, that in vitro respond to non -intoxicating alcohol levels. We previously found that lowdose alcohol reduces harmaline tremor in wild -type mice, but not in littermates lacking 8 or alpha 6 subunits. Here we addressed whether low -dose alcohol requires the beta 3 subunit for tremor suppression. Methods: We tested whether low -dose alcohol suppresses tremor in cre-negative mice with intact beta 3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the alpha 6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power. Results: Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicletreated controls in floxed beta 3 cre- mice, but had no effect on tremor in floxed beta 3 cre+ littermates that have beta 3 knocked out. This was not due to potential interference of alpha 6 expression by the insertion of the cre gene into the alpha 6 gene since non-floxed beta 3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol. Discussion: As alpha 6 beta 38 GABA A receptors are sensitive to low -dose alcohol, and cerebellar granule cells express beta 3 and are the predominant brain site for alpha 6 and 8 expression together, our overall findings suggest alcohol acts to suppress tremor by modulating alpha 6 beta 38 GABA A receptors on these cells. Novel drugs that target this receptor may potentially be effective and well -tolerated for essential tremor. Highlights We previously found with the harmaline essential tremor model that GABA A receptors containing alpha 6 and 8 subunits mediate tremor suppression by alcohol. We now show that beta 3 subunits in alpha 6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating alpha 6 beta 38 extra -synaptic GABA A receptors.

Background: A long-standing question is why essential tremor often responds to non-intoxicating amounts of alcohol. Blood flow imaging and high-density electroencephalography have indicated that alcohol acts on tremor within the cerebellum. As extra-synaptic d-subunit-containing GABA A receptors are sensitive to low alcohol levels, we wondered whether these receptors mediate alcohol's anti-tremor effect and, moreover, whether the d-associated GABA A receptor a6 subunit, found abundantly in the cerebellum, is required. Methods: We tested the hypotheses that low-dose alcohol will suppress harmaline-induced tremor in wild-type mice, but not in littermates lacking GABA A receptor d subunits, nor in littermates lacking a6 subunits. As the neurosteroid ganaxolone also activates extra-synaptic GABA A receptors, we similarly assessed this compound. The harmaline mouse model of essential tremor was utilized to generate tremor, measured as a percentage of motion power in the tremor bandwidth (9-16 Hz) divided by background motion power at 0.25-32 Hz. Results: Ethanol, 0.500 and 0.575 g/kg, and ganaxolone, 7 and 10 mg/kg, doses that do not impair performance in a sensitive psychomotor task, reduced harmaline tremor compared to vehicle-treated controls in wild-type mice but failed to suppress tremor in littermates lacking the d or the a6 GABA A receptor subunit. Discussion: As cerebellar granule cells are the predominant brain site intensely expressing GABA A receptors containing both a6 and d subunits, these findings suggest that this is where alcohol acts to suppress tremor. It is anticipated that medications designed specifically to target a6 beta d-containing GABA A receptors may be effective and well-tolerated for treating essential tremor. Highlights: How does alcohol temporarily ameliorate essential tremor? This study with a mouse model found that two specific kinds of GABA receptor subunits were needed for alcohol to work. As receptors with both these subunits are found mainly in cerebellum, this work suggests this is where alcohol acts to suppress tremor.

Background: Prior work using GABAA receptor subunit knockouts and the harmaline model has indicated that low-dose alcohol, gaboxadol, and ganaxolone suppress tremor via α6βδ GABAA receptors. This suggests that drugs specifically enhancing the action of α6βδ or α6βγ2 GABAA receptors, both predominantly expressed on cerebellar granule cells, would be effective against tremor. We thus examined three drugs described by in vitro studies as selective α6βδ (ketamine) or α6βγ2 (Compound 6, flumazenil) receptor modulators. Methods: In the first step of evaluation, the maximal dose was sought at which 6/6 mice pass straight wire testing, a sensitive test for psychomotor impairment. Only non-impairing doses were used to evaluate for anti-tremor efficacy in the harmaline model, which was assessed in wildtype and α6 subunit knockout littermates. Results: Ketamine, in maximally tolerated doses of 2.0 and 3.5 mg/kg had minimal effect on harmaline tremor in both genotypes. Compound 6, at well-tolerated doses of 1–10 mg/kg, effectively suppressed tremor in both genotypes. Flumazenil suppressed tremor in wildtype mice at doses (0.015–0.05 mg/kg) far lower than those causing straight wire impairment, and did not suppress tremor in α6 knockout mice. Discussion: Modulators of α6βδ and α6βγ2 GABAA receptors warrant attention for novel therapies as they are anticipated to be effective and well-tolerated. Ketamine likely failed to attain α6βδ-active levels. Compound 6 is an attractive candidate, but further study is needed to clarify its mechanism of action. The flumazenil results provide proof of principle that targeting α6βγ2 receptors represents a worthy strategy for developing essential tremor therapies. Highlights We tested for harmaline tremor suppression drugs previously described as in vitro α6βδ or α6βγ2 GABAA receptor-selective modulators. Well-tolerated flumazenil doses suppressed tremor in α6-wildtype but not α6-knockout mice. Compound 6 and ketamine failed to display this profile, likely from off-target effects. Selective α6 modulators hold promise as tremor therapy.

We consider the question whether the inferior olive (IO) is required for essential tremor (ET). Much evidence shows that the olivocerebellar system is the main system capable of generating the widespread synchronous oscillatory Purkinje cell (PC) complex spike (CS) activity across the cerebellar cortex that would be capable of generating the type of bursting cerebellar output from the deep cerebellar nuclei (DCN) that could underlie tremor. Normally, synchronous CS activity primarily reflects the effective electrical coupling of IO neurons by gap junctions, and traditionally, ET research has focused on the hypothesis of increased coupling of IO neurons as the cause of hypersynchronous CS activity underlying tremor. However, recent pathology studies of brains from humans with ET and evidence from mutant mice, particularly the hotfoot17 mouse, that largely replicate the pathology of ET, suggest that the abnormal innervation of multiple Purkinje cells (PCs) by climbing fibers (Cfs) is related to tremor. In addition, ET brains show partial PC loss and axon terminal sprouting by surviving PCs. This may provide another mechanism for tremor. It is proposed that in ET, these three mechanisms may promote tremor. They all involve hypersynchronous DCN activity and an intact IO, but the level at which excessive synchronization occurs may be at the IO level (from abnormal afferent activity to this nucleus), the PC level (via aberrant Cfs), or the DCN level (via terminal PC collateral innervation).

Available essential tremor (ET) therapies have limitations.

Thursday, April 30April 14, 2020Free AccessEfficacy and Safety of CX-8998 in T-CALM, a Randomized, Double-Blind, Placebo-Controlled, Phase 2a Trial in Participants With Essential Tremor: Subgroup Analysis by Baseline Tremor Severity (1842)Hyder A. Jinnah, Spyros Papapetropoulos, Margaret Lee, Stacey Boyer, Evan Newbold, Rajesh Pahwa, Kelly E. Lyons, … Show All … , Rodger Elble, William Ondo, Theresa Zesiewicz, Peter Hedera, Adrian Handforth, Jenna Elder, and Mark Versavel Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1842 Letters to the Editor

We review advances in understanding Purkinje cell (PC) complex spike (CS) physiology that suggest increased CS synchrony underlies syndromic essential tremor (ET). We searched PubMed for papers describing factors that affect CS synchrony or cerebellar circuits potentially related to tremor. Inferior olivary (IO) neurons are electrically coupled, with the degree of coupling controlled by excitatory and GABAergic inputs. Clusters of coupled IO neurons synchronize CSs within parasagittal bands via climbing fibers (Cfs). When motor cortex is stimulated in rats at varying frequencies, whisker movement occurs at ~10 Hz, correlated with synchronous CSs, indicating that the IO/CS oscillatory rhythm gates movement frequency. Intra-IO injection of the GABAA receptor antagonist picrotoxin increases CS synchrony, increases whisker movement amplitude, and induces tremor. Harmaline and 5-HT2a receptor activation also increase IO coupling and CS synchrony and induce tremor. The hotfoot17 mouse displays features found in ET brains, including cerebellar GluRδ2 deficiency and abnormal PC Cf innervation, with IO- and PC-dependent cerebellar oscillations and tremor likely due to enhanced CS synchrony. Heightened coupling within the IO oscillator leads, through its dynamic control of CS synchrony, to increased movement amplitude and, when sufficiently intense, action tremor. Increased CS synchrony secondary to aberrant Cf innervation of multiple PCs likely also underlies hotfoot17 tremor. Deep cerebellar nucleus (DCN) hypersynchrony may occur secondary to increased CS synchrony but might also occur from PC axonal terminal sprouting during partial PC loss. Through these combined mechanisms, increased CS/DCN synchrony may plausibly underlie syndromic ET.

BACKGROUND:Perampanel is a noncompetitive antagonist of alpha-amino-3-hydroxy-5-methylisoxazole propionic acid glutamate receptors suggested to modulate tremor.OBJECTIVES:To assess the efficacy and tolerability of perampanel for essential tremor.METHODS:This was a double-blind, placebo-controlled, randomized, cross-over trial involving 26 patients titrated to 8 mg/day or a lower maximally tolerated dose as monotherapy or adjunct to antitremor medication. Tremor was assessed at the beginning and end of each 14-week treatment arm. The primary endpoint was change in the videotaped performance subscale of The Essential Tremor Rating Assessment Scale, scored by a blinded rater. Secondary endpoints included change in The Essential Tremor Rating Assessment Scale Activity of Daily Living and Quality of Life in Essential Tremor and Subject Global Impression of Change subscales.RESULTS:Data are available for 15 and 11 participants who completed placebo and perampanel arms, respectively. Perampanel was superior to placebo on the primary endpoint (P = 0.028), Activity of Daily Living (P = 0.009), and Subject Global Impression of Change (P = 0.016), but not Quality of Life (p = 0.48). Video scores were rated >50% improved in 3/11 on perampanel and 0/15 on placebo. Adverse events were more likely on perampanel (especially at >4 mg/day) than on placebo, leading to withdrawal (36% vs. 10%) and dose reduction (41% vs. 15%). Adverse events more common with perampanel included imbalance/falls (50% vs. 10%), dizziness (36% vs. 10%), and irritability (27% vs. 5%).CONCLUSIONS:These findings suggest that perampanel exerts efficacy for some persons with essential tremor, but this population appears prone to adverse events.

Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied. To overcome these obstacles, animal models can provide an important means to look into human tremor disorders. In this manuscript, we will discuss the use of different species of animals (mice, rats, fruit flies, pigs, and monkeys) to model human tremor disorders. Several ways to manipulate the brain circuitry and physiology in these animal models (pharmacology, genetics, and lesioning) will also be discussed. Finally, we will discuss how these animal models can help us to gain knowledge of the pathophysiology of human tremor disorders, which could serve as a platform towards developing novel therapies for tremor.

Background: Metabolic imaging has revealed excessive cerebellar activity in essential tremor patients. Golgi cells control cerebellar activity by releasing gamma-aminobutyric acid (GABA) onto synaptic and extrasynaptic receptors on cerebellar granule cells. We postulated that the extrasynaptic GABAA receptor-specific agonist THIP (gaboxadol; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) would suppress tremor in the harmaline model of essential tremor and, since cerebellar extrasynaptic receptors contain α6 and δsubunits, would fail to do so in mice lacking either subunit. Methods: Digitally measured motion power, expressed as 10–16 Hz power (the tremor bandwidth) divided by background 8–32 Hz motion power, was accessed during pre-harmaline baseline, pre-THIP harmaline exposure, and after THIP administration (0, 2, or 3 mg/kg). These low doses were chosen as they did not impair performance on the straight wire test, a sensitive test for psychomotor impairment. Littermate δ wild-type and knockout (Gabrd+/+, Gabrd–/–) and littermate α6 wild-type and knockout (Gabra6+/+, Gabra6–/–) mice were tested. Results: Gabrd+/+ mice displayed tremor reduction at 3 mg/kg THIP but not 2 mg/kg, and Gabra6+/+ mice showed tremor reduction at 2 and 3 mg/kg. Their respective subunit knockout littermates displayed no tremor reduction compared with vehicle controls at either dose. Discussion: The loss of anti-tremor efficacy with deletion of either δ or α6 GABAA receptor subunits indicates that extrasynaptic receptors containing both subunits, most likely located on cerebellar granule cells where they are highly expressed, mediate tremor suppression by THIP. A medication designed to activate only these receptors may display a favorable profile for treating essential tremor.

Background: Increased depression, hearing loss, dementia, alcoholism, and mortality in essential tremor patients remain unexplained. We investigated whether conditions associated with tremor are linked to chronic stress. Methods: The FY2013 Veterans Affairs database was queried for 38 selected dual diagnosis combinations in 5,854,223 veterans aged 21–95 years. Results: Post-traumatic stress disorder, anxiety, and depression were the most common psychiatric diagnoses in tremor patients, with the odds ratio exceeding 2 in all 15-year cohorts. Depending on age, patients with essential tremor were more likely than those without to have obsessive–compulsive disorder, bipolar illness, schizophrenia, use tobacco and abuse alcohol, have hypertension, obesity, hyperlipidemia, diabetes, vitamin D deficiency, coronary and cerebrovascular diseases, congestive heart failure, stroke, asthma, hypothyroidism, irritable bowel syndrome, renal insufficiency, alcoholic liver disease, hearing loss, glaucoma, macular degeneration, migraine, epilepsy, idiopathic polyneuropathy, history of head trauma, and 'Alzheimer's dementia. In contrast, lung and colorectal cancer, amyotrophic lateral sclerosis, psychostimulant abuse, and rheumatoid arthritis were not more common. Discussion: Post-traumatic stress disorder, anxiety, and depression, strongly associated with essential tremor, are known risk factors for poor health habits, tobacco use and alcohol abuse; collectively these are risk factors for vascular disease, with further negative health consequences for multiple organ systems. As essential tremor is associated with all these conditions, we propose that chronic stress is not only responsible for the conditions associated with tremor but in some cases itself directly and indirectly induces essential tremor, so that tremor and poor health share a common cause.

In this review, we hope to stimulate interest in animal models as opportunities to understand tremor mechanisms within the cerebellar system. We begin by considering the harmaline model of essential tremor (ET), which has ET-like anatomy and pharmacology. Harmaline induces the inferior olive (IO) to burst fire rhythmically, recruiting rhythmic activity in Purkinje cells (PCs) and deep cerebellar nuclei (DCN). This model has fostered the IO hypothesis of ET, which postulates that factors that promote excess IO, and hence PC complex spike synchrony, also promote tremor. In contrast, the PC hypothesis postulates that partial PC cell loss underlies tremor of ET. We describe models in which chronic partial PC loss is associated with tremor, such as the Weaver mouse, and others with PC loss that do not show tremor, such as the Purkinje cell degeneration mouse. We postulate that partial PC loss with tremor is associated with terminal axonal sprouting. We then discuss tremor that occurs with large lesions of the cerebellum in primates. This tremor has variable frequency and is an ataxic tremor not related to ET. Another tremor type that is not likely related to ET is tremor in mice with mutations that cause prolonged synaptic GABA action. This tremor is probably due to mistiming within cerebellar circuitry. In the final section, we catalog tremor models involving neurotransmitter and ion channel perturbations. Some appear to be related to the IO hypothesis of ET, while in others tremor may be ataxic or due to mistiming. In summary, we offer a tentative framework for classifying animal action tremor, such that various models may be considered potentially relevant to ET, subscribing to IO or PC hypotheses, or not likely relevant, as with mistiming or ataxic tremor. Considerable further research is needed to elucidate the mechanisms of tremor in animal models.

Essential tremor affects the hands during actions and can be disabling. Although common, no medications for it have emerged from basic research. Animal tremor models offer an approach to identify targets for drug development. In one model, the drug harmaline induces whole-body tremor in a rodent that lasts at least 1.5 h. In another model, the α1 subunit of the γ-aminobutyric acid type A (GABAA) receptor is knocked out, leading to tremor that is best seen when the mouse is picked up by the tail. Each model has limitations and does not perfectly predict drug efficacy for essential tremor. Nonetheless, they offer a useful starting point to test hypotheses on what may suppress tremor. In this chapter, we describe the models and review progress to date. The models suggest that drugs that block neuronal gap junctions or T-type calcium channels, or activate certain GABA receptors, might be useful for tremor.

Objective: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy. Methods: This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries. Results: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001). Conclusion: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population. Classification of evidence: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.

Background Harmaline and harmine are tremorigenic β-carbolines that, on administration to experimental animals, induce an acute postural and kinetic tremor of axial and truncal musculature. This drug-induced action tremor has been proposed as a model of essential tremor. Here we review what is known about harmaline tremor. Methods Using the terms harmaline and harmine on PubMed, we searched for papers describing the effects of these β-carbolines on mammalian tissue, animals, or humans. Results Investigations over four decades have shown that harmaline induces rhythmic burst-firing activity in the medial and dorsal accessory inferior olivary nuclei that is transmitted via climbing fibers to Purkinje cells and to the deep cerebellar nuclei, then to brainstem and spinal cord motoneurons. The critical structures required for tremor expression are the inferior olive, climbing fibers, and the deep cerebellar nuclei; Purkinje cells are not required. Enhanced synaptic norepinephrine or blockade of ionic glutamate receptors suppresses tremor, whereas enhanced synaptic serotonin exacerbates tremor. Benzodiazepines and muscimol suppress tremor. Alcohol suppresses harmaline tremor but exacerbates harmaline-associated neural damage. Recent investigations on the mechanism of harmaline tremor have focused on the T-type calcium channel. Discussion Like essential tremor, harmaline tremor involves the cerebellum, and classic medications for essential tremor have been found to suppress harmaline tremor, leading to utilization of the harmaline model for preclinical testing of antitremor drugs. Limitations are that the model is acute, unlike essential tremor, and only approximately half of the drugs reported to suppress harmaline tremor are subsequently found to suppress tremor in clinical trials.

To revise and update the 2005 American Academy of Neurology practice parameters for treating essential tremor (ET), the Quality Standards Subcommittee examined the ET literature from 2004 to April 2010. A computer-based search identified 589 articles, of which 252 were scrutinized fully by two or more committee members. The committee concluded that the following recommendations from 2005 should remain unchanged:

Recent work exploring the use of high-molecular weight alcohols to treat essential tremor (ET) has identified octanoic acid as a potential novel tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET.