Reviews

Animal Models of Tremor: Relevance to Human Tremor Disorders

Ming-Kai Pan1, Chun-Lun Ni2, Yeuh-Chi Wu2, Yong-Shi Li2 & Sheng-Han Kuo2*

1Department of Medical Research, National Taiwan University, Taipei, TW, 2Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

Abstract

Background: Tremor is the most common movement disorder; however, the pathophysiology of tremor remains elusive. While several neuropathological alterations in tremor disorders have been observed in post-mortem studies of human brains, a full understanding of the relationship between brain circuitry alterations and tremor requires testing in animal models. Additionally, tremor animal models are critical for our understanding of tremor pathophysiology, and/or to serve as a platform for therapy development.

Methods: A PubMed search was conducted in May 2018 to identify published papers for review.

Results: The methodology used in most studies on animal models of tremor lacks standardized measurement of tremor frequency and amplitude; instead, these studies are based on the visual inspection of phenotypes, which may fail to delineate tremor from other movement disorders such as ataxia. Of the animal models with extensive tremor characterization, harmaline-induced rodent tremor models provide an important framework showing that rhythmic and synchronous neuronal activities within the olivocerebellar circuit can drive action tremor. In addition, dopamine-depleted monkey and mouse models may develop rest tremor, highlighting the role of dopamine in rest tremor generation. Finally, other animal models of tremor have involvement of the cerebellar circuitry, leading to altered Purkinje cell physiology.

Discussion: Both the cerebellum and the basal ganglia are likely to play a role in tremor generation. While the cerebellar circuitry can generate rhythmic movements, the nigrostriatal system is likely to modulate the tremor circuit. Tremor disorders are heterogeneous in nature. Therefore, each animal model may represent a subset of tremor disorders, which collectively can advance our understanding of tremor.

Keywords: Essential tremor, Parkinson’s disease, dystonia, cerebellum, tremor, climbing fiber, Purkinje cells

Citation: Pan MK, Ni CL, Wu YC, Li YS, Kuo SH. Animal models of tremor: relevance to human tremor disorders. Tremor Other Hyperkinet Mov. 2018; 8. doi: 10.7916/D89S37MV

*To whom correspondence should be addressed. E-mail: sk3295@cumc.columbia.edu

Editor: Elan D. Louis, Yale University, USA,

Received: July 3, 2018 Accepted: August 10, 2018 Published: October 9, 2018

Copyright: © 2018 Pan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original authors and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.

Funding: Dr. Pan is supported by the Ministry of Science and Technology in Taiwan: MOST 104-2314-B-002-076-MY3 and 107-2321-B-002-020 (principal investigator). Dr. Kuo has received funding from the National Institutes of Health: NINDS #K08 NS083738 (principal investigator) and #R01 NS104423 (principle investigator), and the Louis V. Gerstner Jr. Scholar Award, Parkinson’s Foundation, and International Essential Tremor Foundation.

Financial Disclosures: None.

Conflicts of Interest: The authors report no conflict of interest.

Ethics Statement: This study was reviewed by the authors' institutional ethics committee and was considered exempted from further review.

Introduction

Tremor is the most common movement disorder phenomenology. Tremor disorders are classified based on the predominant tremor characteristics. Essential tremor (ET) is characterized by action tremor in the upper extremities, whereas Parkinson’s disease (PD) tremor classically presents as tremor at rest. Dystonic tremor (DT) is less rhythmic and is usually associated with sustained muscle twisting.1, 2 Other tremor disorders, including cerebellar outflow tremor, Holmes tremor, and orthostatic tremor, are relatively rare. Despite some clinical heterogeneity, one of the important aspects of tremor disorders is the overlapping clinical features. For example, severe ET patients can develop rest tremor, and severe PD patients can have action tremor.3 Many ET cases also have a dystonic component.4 While tremor disorders are likely to be heterogeneous groups of diseases with phenotypical overlaps, the brain circuitry preferentially involved in the generation of a specific type of tremor (action vs. rest vs. dystonic) is likely to share some commonalities with additional modulatory components. Therefore, studies of animal models with different types of tremor will likely lead to a comprehensive understanding of the mechanism of diverse yet overlapping clinical features of tremor.

Based on neuroimaging studies57 and pathological studies8, 9 in patients, the cerebellum is involved in tremor generation. In addition, magnetoencephalography and high-density electroencephalography have shown that brain areas interconnected with the cerebellum or further downstream regions, including the thalamus, motor and pre-motor cortex, and part of the brainstem, may affect tremor expression.6, 10 However, the mechanism by which structural alterations within the brain circuit generate tremor remains unclear. Similarly, the oscillatory neuronal activities are thought to be the physiological correlates for tremor.11, 12 Yet, it is unclear how the brain circuitry alterations generate these rhythmic neuronal activities to drive tremor. Thus, animal models are a useful tool to assess the relationship between structural brain alterations, altered neuronal physiology, and tremor. In addition, animal models of tremor may be a platform for therapy development. Note that tremor is a terminology for movement disorder that describes involuntary, rhythmic movements; therefore, tremor is a symptom, rather than a disease. Thus, animal models of tremor capture the symptoms of a disease, rather than reflect the biological processes underlying the disease.

The present paper will first review the validated tremor animal models with detailed clinical features (action tremor vs. rest tremor) and the pharmacological responses of tremor in these models using frequency-based measurement rather than merely visual observation. We will also briefly review other animal models of tremor with varied results. We will discuss how the pathophysiology learned from animal models of tremor can help us to understand the controversies of phenotypical overlaps of tremor disorders. Finally, we will attempt to apply the knowledge of tremor pathophysiology learned from animal models to explain some of the controversies in the tremor research field.

Methods

A PubMed search was conducted in May 2018 using the term “tremor” in combination with the following search terms: “animal models”, “mouse”, “rat”, “monkey”. In the initial screening, we identified 1,171 articles; of these, 64 and 1,039 articles that were not written in English and/or were irrelevant to the topic of this review, respectively, were disregarded. Therefore, we selected 68 of the remaining articles for this review. An additional five articles were included based on the references. Thus, a total of 73 articles were selected for this review (Table 1, Figure 1).

Table 1.

Search Strategy

Based on the search results, we will first discuss the most widely studied animal models for action tremor (harmaline-induced rodent models) and rest tremor (dopamine-depleted monkey models) with defined tremor frequency and characteristic measurement. We will next discuss the animal models of tremor with frequency measurement but no detailed action vs. rest tremor description. We will also review the current literature for animal models of tremor without objective tremor measurement; therefore, whether there is true tremor present in these animal models will require further investigation. We will also review the tremor pathophysiology in these animal models and how this knowledge should advance our understanding of human tremor disorders.

Results

Animal models of action tremor

The classical animal model of action tremor is the harmaline-induced model.13 A single dose of harmaline can induce action tremor by enhancing the coupling between the inferior olivary (IO) neurons.1417 The IO neurons have intrinsic subthreshold membrane potential oscillations at 1–10 Hz, and harmaline exposure can result in enhanced communications between IO neurons, which entrain the downstream Purkinje cells (PCs) to fire synchronously and rhythmically at around 10–16 Hz via axons of the IO neurons called climbing fibers (CFs).14, 15 Animals exposed to harmaline develop tremor at the same frequency.16, 17 During the tremor state, PCs fire rhythmic complex spikes, which originate from CF excitatory synaptic transmission onto PCs with a dramatic suppression of simple spikes.15, 18 Therefore, harmaline is thought to enhance the CF–PC synaptic transmission, which is intrinsically oscillatory, to drive tremor.

Harmaline-induced tremor is predominantly action tremor13 (Figure 2) that responds to propranolol, primidone, and alcohol.19 Therefore, harmaline-induced tremor has long been postulated to be an animal model of ET. Harmaline belongs to a group of naturally occurring compounds, called β-alkaloids. In ET patient blood and brain, increased harmaline-related β-alkaloids, such as harmane, have been observed,20, 21 suggesting that environmental factors may contribute to oscillatory activities in the olivocerebellar system in ET patients.

Under the conceptual framework of oscillatory neuronal activities in tremor, several modulatory agents that can influence the olivocerebellum have been tested in this harmaline-induced tremor model as pre-clinical studies for ET. For example, a gap junction blocker, carbenoxolone, has been shown to effectively suppress harmaline-induced tremor22 and T-type calcium channels that are important for PC complex spikes can also suppress harmaline-induced tremor.23 Currently, a phase II randomized placebo-controlled clinical trial for a T-type calcium channel blocker is underway for ET (clinicaltrials.gov: NCT03101241), partly based on the understanding of the cerebellar circuitry in harmaline-induced tremor.

While harmaline-induced tremor indicates the importance of the connections between the IO neurons and PCs (Figure 3), animal model studies suggest that other parts of the cerebellar system can also drive oscillatory neuronal activities. For example, the gamma-aminobutyric acid (GABA)-ergic deep cerebellar nuclei (DCN) send axons to IO neurons, which may control the coupling between IO neurons. Loss of this nucleo-olivary GABAergic control may result in enhanced electrotonic coupling between IO neurons, leading to synchronized PC complex spikes.24 Additionally, IO neurons also receive glutamatergic inputs, which may modulate the synchronization of PC firing.25 These regulatory components of the olivo-cerebellar system are likely to determine the frequency and the strength of neuronal synchrony, and potentially influence the presentation of tremor. In a post-mortem study of ET patients, there was no evidence of IO neuronal loss,26 which might have allowed the olivocerebellum system to generate rhythmic and synchronized neuronal activities, under the regulation of the above-mentioned nucleo-olivary control, to drive tremor. Whether ET patients exhibit alterations of these synaptic structures in IOs requires further investigation.

Harmaline has been shown to induce action tremor in a wide variety of animals, including mice,19, 22, 27 rats,19 cats,15 monkeys,28 and pigs,29 suggesting an evolutionarily conserved olivocerebellar circuit for tremor generation. However, different species may have different frequencies in harmaline-induced tremor (mice, 10–16 Hz; rats, 8–12 Hz; pigs, 8–12 Hz).19 Note that ET patients have tremor at 4–12 Hz.11 Interestingly, the chronic responses to harmaline also differ among species. Repeated exposures to harmaline will induce “tolerance” in rats and pigs, where the tremor decreases with repeat exposure. This phenomenon presents an exception in mouse models, which tend to develop robust tremor even with repeated harmaline injections.29, 30 Neuropathological assessment between rats and mice with repeated harmaline exposures showed that rats have extensive PC loss,31 which may be due to excitotoxicity from overstimulation of CF synaptic transmission onto PCs,31 whereas PCs in mice are relatively preserved.30 These results might indicate that preserved PCs may be required for the continuous harmaline-induced tremor, which is thought to generate from CF-driven synaptic activities. In ET patients, moderate PC loss has also been identified.8, 32 Whether the PC loss in ET is due to the longstanding, abnormal excitatory synaptic transmission or is a primary PC degenerative process requires further investigation.

While harmaline-induced action tremor models present similarities to ET, this model remains controversial. First, agents that can worsen ET, such as valproate and lithium, tend to suppress harmaline-induced action tremor;33 however, these tremor-suppressing effects might be due to the non-specific reduction of motor activities because harmaline induces predominantly action tremor. Further studies are required. Second, harmaline is a toxin model and, as such, tremor amplitude may be dose-dependent and further influenced by the timing of tremor assessment. Third, the rapid tolerance of harmaline in animals such as rats and pigs present difficulty for large-scale drug screening. However, the aforementioned animal models still have significant value for the validation of specific agents.

Nonetheless, harmaline-induced action tremor models indicate that the olivocerebellum is capable of generating action tremor and neuronal rhythmicity and synchrony might underlie the pathophysiology of tremor. Along these lines, the structural alterations that can lead to neuronal synchrony and/or rhythmicity within the olivocerebellar circuitry may contribute to tremor. For example, abnormal CF–PC synaptic connections have been identified in post-mortem studies of ET cerebellum. Specifically, CFs form synaptic connections with the distal, spiny branchlets of PC dendrites, which should have been the parallel fiber territory.9,3437 This CF–PC synaptic pathology distinguishes ET from other cerebellar degenerative disorders.35 Furthermore, this CF–PC synaptic pathology may occur across different subtypes of ET, regardless of age of tremor onset and family history of tremor.9 The extension of CF synapses onto the parallel fiber synaptic territory on PCs is likely to increase the influence of IO activities on PCs, which might enhance the synchrony and rhythmicity in the cerebellar circuitry.38, 39 The other source of neuronal synchrony within the cerebellar circuitry may occur at the level of downstream of PC dendritic synapses. For example, PC axonal collaterals and sprouting have been found in post-mortem studies of ET cerebellum,40 possibly in response to partial PC loss. It is possible that this PC axonal sprouting process could set up rhythmicity and synchrony within the cerebellar circuitry. Note that post-mortem studies of human pathology need to be interpreted with caution. In particular, observations in human studies cannot establish whether the structural changes are the consequences of longstanding neuronal activities associated with tremor or the primary causes for tremor. Detailed tremor measurements and physiology studies in animal models with the above-mentioned pathological alterations will likely provide further mechanistic insight.41 In addition, changes in ion channels and/or receptors have not been extensively studied post-mortem in human brains affected by tremor, which might shed light on the pathomechanism of tremor.

In summary, different levels of neuronal synchrony within the cerebellar system are believed to set up the pathophysiological substrate for tremor generation, which may partly explain the clinical heterogeneity of ET.4

Animal models of rest tremor

Rest tremor is one of the cardinal features of PD. While dopamine neuronal loss in the nigrostriatal system is the pathological hallmark of PD,42 dopamine depletion in animals leads to bradykinesia, with rest tremor not consistently reported in such models.43, 44 The most commonly used toxin to deplete dopamine terminals in mice is 6-hydroxydopamine (6-OHDA) injection into the striatum; this procedure can infrequently induce rest tremor.44 Even in mice models with 6-OHDA-induced rest tremor, tremor is usually not a prominent feature. It is currently unknown why some mice develop rest tremor while others don’t. Detailed mechanistic studies are required.

The early work for rest tremor comes from studies in monkeys: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated vervet (African green) monkeys develop robust rest tremor while MPTP-treated rhesus (Macaca mulatta) monkeys have only very infrequent rest tremor.43 The rest tremor in vervet monkeys is approximately 5–7 Hz, measured using an accelerometer, with corresponding synchronous firing of pallidal neurons. This tremor is very similar to that in PD patients.43 Detailed neuropathological studies comparing these two types of MPTP-treated monkeys found that vervet monkeys have more affected dopamine neurons in the retrorubral area, whereas rhesus monkeys have more profound dopamine neuronal loss in the substantia nigra pars compacta.4547 The retrorubral dopamine system has preferential projection to the pallidum, suggesting that pallidal dopamine might play a role in rest tremor generation,48 which is consistent with recent findings in human functional magnetic resonance imaging (fMRI) studies.7, 49 However, there are few studies focusing on the anatomy and functions of the pallidal dopamine pathway, and its role in tremor generation remains largely unknown. Further comparisons of the neuropathology and physiology between animal models will lead to a better understanding of the mechanism of rest tremor.

Recent advancement of knowledge of rest tremor comes from human neuroimaging studies7, 49 which demonstrate that the interaction between the basal ganglia and the cerebellum is important for rest tremor generation. Specifically, the “dimmer-switch” model proposes that the basal ganglia initiate tremor whereas the cerebellum modulates tremor amplitude and rhythmicity50 (Figure 3). The involvement of the cerebellum system is further supported by the effectiveness of deep-brain stimulations in the region of the thalamus that receives cerebellar output both in 6-OHDA-treated mice with rest tremor44 and in PD patients.51 Another evidence of the cerebellar involvement in rest tremor is that PD patients have hyper-metabolism in the cerebellum based on the positron emission tomography (PET).52 Whether this hypermetabolism in the cerebellum has a structural basis or merely reflects functional neuronal activities remains to be studied. Intriguingly, a study recently found abnormal CF–PC synaptic organization and other PC pathology in post-mortem brain studies of PD cases with rest tremor,35 which may suggest that structural changes in the cerebellum contribute to rest tremor. The detailed mechanism of how the interaction between the basal ganglia and the cerebellum generates rest tremor requires further studies in animal models to test the causal relationship between structural alterations in the brain circuitry and tremor.

Other tremor animal models with quantitative tremor measurement

Recently, several quantitative studies of novel animal models have been performed. However, it is unclear whether these animals have predominantly action tremor or rest tremor. Therefore, we have included these animal models and the related pathophysiology in this section.

A recent discovery of tremor of Waddles (wdl) mice, which have spontaneous mutations in the Car8 gene,53 has greatly advanced our understanding of tremor in animal models. CAR8 protein is predominantly expressed in PCs and the loss-of-function mutation of Car8 in wdl mice results in tremor of 5–15 Hz. wdl mice have altered frequency and regularity of simple spike and complex spikes of PCs, which likely underlie the physiology of tremor. Another interesting feature of wdl mice is the disturbance of the microzonal organization of the cerebellum. The cerebellar circuitry has been organized in the microzones, for which there are specific sets of CF–PC–DCN connections that govern motor control.54 The afferent inputs to the cerebellum, mossy fibers, also follow such microzonal rules. The microzones of the cerebellum could be traced by a set of PC markers, such as zebrin II or excitatory amino acid transporter type 4 (EAAT4).55, 56 The disturbance of microzonal organization within the cerebellum may cause improper neuronal signaling, leading to tremor. It remains to be studied in detail how this altered PC firing in the context of microzonal organization can lead to tremor in wdl mice. Further post-mortem studies in microzonal organization of tremor disorders using the human brain will test the relevance of such findings in patients. Nonetheless, mutations of Car8 have been found in patients with tremor and ataxia,57, 58 which further contribute to the translational aspect of this mouse model and human disorders.

One of the main hypotheses of tremor generation is PC loss,8, 32 which may potentially be modeled by the recent identification of the Shaker rat. This natural mutant rat develops low-frequency tremor of around 5 Hz; the predominant pathology of this rat is PC loss, particularly in the anterior lobe of the cerebellum.59 Interestingly, the tremor is present at the stage of mild to moderate PC loss whereas the Shaker rats eventually develop frank ataxia with severe PC loss, indicating that tremor might arise in the intermediate stage of PC degeneration.60 However, if partial PC loss is sufficient to cause tremor, one would expect to observe tremor in the early stage of hereditary ataxias with PC degeneration such as spinocerebellar ataxias (SCAs). However, tremor only occurs in a minor subset of SCA patients.61 Within the common types of SCAs, SCA2 often has tremor when compared with SCA1 and SCA6.61 Therefore, further comparisons of varied subtypes of SCAs with PC degeneration might provide further insight into the pathophysiology of tremor.

Another hypothesis for tremor states that GABA deficiency within the cerebellar circuitry leads to enhanced pacemaking neuronal activities.62 This hypothesis originated from the observation of a subset of ET patients who responded to GABAergic medications, such as primidone and alcohol.63, 64 Relevant to this clinical observation, a moderate decrease in GABA receptors has been identified post-mortem in the ET dentate nucleus.65 Along these lines, knockout mice with GABAA receptor α1 subunit deficiency have been found to develop tremor that is responsive to propranolol and primidone.66 However, the detailed physiological alterations in dentate neurons and PCs in the freely moving GABAA receptor α1 subunit knockout mice still need to be determined, and whether this mouse model has predominant rest or action tremor requires further investigation. The aforementioned mouse model has some unique characteristics that are distinct from those of ET patients. First, diazepam, a medication than may lessen tremor in ET patients,63 can dramatically enhance tremor in this mouse model. The GABAA receptor α1 subunit knockout mice have a 15–19 Hz tremor,66 which is at a significantly higher frequency than that in ET patients.11 Third, a recent neuroimaging finding showed that ET patients do not have obvious GABA deficiency in the dentate nucleus,67 which questions the relevance of this mouse model to ET in humans. Another possibility is that GABA deficiency in ET patients occurs outside the dentate nucleus, such as in the thalamic nucleus68 or IO neurons,24 which might cause oscillatory neuronal activities and tremor. Alcohol responsiveness remains a phenomenon of interest in studies of ET. While this mouse model does not possess the GABAA receptor α1 subunit, mouse tremor can be suppressed by alcohol, indicating that an alternative factor, such as different subtypes of GABA receptors, might be responsible for this tremor-suppression effect. Future studies on the neuronal population-specific GABAA receptor α1 subunit knockout will advance our understanding of the role of GABAergic synaptic transmission in tremor.

Animal models of tremor with less defined tremor measurement

In our extensive literature search, we found that animal models of tremor could be divided into two broad categories: chemical- or lesion-induced (Table 2), or based on genetic mutations (Table 3). However, tremor is usually not the primary interest of these published animal models, and tremor frequency and amplitudes are less defined than in the above-mentioned animal models. In addition, for those with objective tremor measurement, confirmatory studies are needed to better delineate these tremor phenotypes. Moreover, ataxia and tremor are two symptoms related to cerebellar dysfunction. Ataxia is associated with motion irregularity, whereas tremor is movement with defined frequency and rhythm. Therefore, detailed measurement of frequency and variability of motions in animal models should enhance understanding of the brain circuitry for ataxia and tremor.

In chemically induced animal models of tremor6981 (Table 2), we found that agents working on the cholinergic axis are able to induce tremor. For example, agents that promote the cholinergic nervous system, such as oxotremorine,70 arecoline,70 nicotine,75 pilocarpine,72 and physostigmine,74 can produce tremor in rodents. Interestingly, promoting muscarinic (oxotremorine), nicotinic (arecoline, pilocarpine, and nicotine), or both (physostigmine) types of cholinergic receptor systems can produce tremor, but whether the tremor characteristics differ in these animal models requires further investigation. One of the clinical implications is that rest tremor in PD can be treated with anticholinergics;82 therefore, rest tremor may be associated with a hypercholinergic state. Further investigation is needed.

In lesion-induced animal models of tremor, we found that cerebellar lesions could produce tremor81 and/or change the frequency of physiological tremor80 in monkeys, highlighting the contribution of the cerebellum to tremor (Table 2).

Finally, there is a list of animal models of tremor with different genetic mutations83103 (Table 3). Most of the tremor measurements in these animal models are based on observation only and require objective assessment to delineate rest and action tremor, which are the defining features for human tremor disorders. Many of these genetic tremor animal models have a dysfunctional cerebellar circuit (Table 3). The genetic models provide an invaluable resource for stable tremor phenotypes. Additionally, tremor in some of the models is regulated developmentally and throughout adulthood, which can be further studied to understand the role of aging in the underlying neuropathology and physiology.

The relevant knowledge learned from animal models in the context of controversies in the tremor field

Animal models of tremor allow researchers to perform detailed physiological studies and brain circuitry dissections using optogenetic tools or electric stimulations. Therefore, animal models can be considered as tools to understand tremor disorders. In the present paper we posit a question: “How do animal models of tremor help us to move towards a better understanding of the current controversies in the tremor field?” To answer this question, we will discuss two major controversies in the tremor field: 1) the relationship between tremor and dystonia, 2) the relationship between ET and PD.

Many ET patients have co-existing dystonic features.4 It remains unclear whether dystonia and tremor are generated from the same or different sources in ET patients with dystonic features. Therefore, we reviewed the literature in animal models, and aimed to find a similarity between tremor and dystonia. Interestingly, both tremor and dystonia could originate from the dysfunctional cerebellum. From a harmaline-induced tremor model, PC rhythmic firing could drive real-time rhythmic motor activities (i.e., tremor).15 In mouse models with viral-mediated DYT1 or DYT12 knockdown in the cerebellum, dystonia may be induced, with a corresponding increased burst firing of PCs.104106 These studies suggest that real-time abnormalities of PC firing might lead to involuntary movements, which has also been demonstrated by artificially driving PC activities using optogenetics.107 Therefore, abnormal PC firing may be a common neurophysiological underpinning for tremor and a subset of dystonia. Abnormal PC firing could be at times rhythmic and at times high-frequency, burst firing depending on the different stages of the disease process, and these abnormal PC firing patterns may be temporally and spatially segregated within the cerebellar cortex. This can lead to overlapping tremor and dystonia symptoms in different body regions and/or hand positions. Within this framework, the dystonic feature in a subset of ET patients might originate in the cerebellar region. Future studies of different animal models of tremor and dystonia should help to settle this controversy.

The overlapping of symptoms between ET and PD remains controversial. According to epidemiological studies, ET patients have a fivefold increased risk for PD, and these PD patients are often the tremor-predominant type.108, 109 Severe ET patients will have rest tremor,108 whereas PD patients often have postural and/or action tremor.110 It is possible that overlap between ET and PD occurs at the brain circuitry level. As mentioned above, the structural changes in the ET cerebellum may generate oscillatory neuronal activities to drive tremor. In PD, dopamine deficiency may cause infrequent tremor, but the structural changes in the cerebellum can amplify this tremor. This dopamine deficiency associated with rest tremor might be at the level of the globes pallid us internal or the ventrolateral thalamus based on human fMRI studies.7, 111 A recent study found abnormal CF–PC synaptic connections in the cerebellum of both ET and PD patients,35 possibly demonstrating common brain circuitry abnormalities in these two disorders (Figure 3). This concept is further supported by evidence of the ability of harmaline to intensify rest tremor in monkeys.28 Future studies in animal models should aim to simulate structural changes in the cerebellar circuits and the dopamine system in ET and PD, respectively, such studies should help decode this pathomechanism.

Conclusions

The use of animal models in tremor research is an emerging field. As we begin to comprehensively understand tremor disorders based on genetic, neuroimaging, and neuropathological studies in humans, modeling these genetic and pathological alterations in animal models will greatly advance our understanding of how tremor is generated. Established animal models are likely to provide an important platform to screen therapies for tremor disorders.

References

1. Elias WJ, Shah BB. Tremor. JAMA 2014;311:948–954. doi: 10.1001/jama.2014.1397

2. Elble R, Deuschl G. Milestones in tremor research. Mov Disord 2011;26:1096–1105. doi: 10.1002/mds.23579

3. Thenganatt MA, Louis ED. Distinguishing essential tremor from Parkinson’s disease: bedside tests and laboratory evaluations. Exp Rev Neurother 2012;12:687–696. doi: 10.1586/ern.12.49

4. Bhatia KP, Bain P, Bajaj N, Elble RJ, Hallett M, Louis ED. Consensus statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord 2018;33:75–87. doi: 10.1002/mds.27121

5. Cerasa A, Quattrone A. Linking essential tremor to the cerebellum-neuroimaging evidence. Cerebellum 2016;15:263–275. doi: 10.1007/s12311-015-0739-8

6. Schnitzler A, Münks C, Butz M, Timmermann L, Gross J. Synchronized brain network associated with essential tremor as revealed by magnetoencephalography. Mov Disord 2009;24:1629–1635. doi: 10.1002/mds.22633

7. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 2011;69:269–281. doi: 10.1002/ana.22361

8. Louis EDE, Faust PLP, Vonsattel J-PGJ, Honig LSL, Rajput AA, Robinson CAC. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297–3307. doi: 10.1093/brain/awm266

9. Lee D, Gan SR, Faust PL, Louis ED, Kuo SH. Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes. Parkinsonism Relar Disord 2018;51:24–29. doi: 10.1016/j.parkreldis.2018.02.032

10. Muthuraman M, Deuschl G, Anwar AR, Mideksa KG, von Helmolt F, Schneider SA. Essential and aging-related tremor: differences of central control. Mov Disord 2015;30:1673–1680. doi: 10.1002/mds.26410

11. Haubenberger D, Hallett M. Essential tremor. New Engl J Med 2018;378:1802–1810. doi: 10.1056/NEJMcp1707928

12. Filip P, Lungu OV, Manto MU, Bares M. Linking essential tremor to the cerebellum: physiological evidence. Cerebellum 2016;15:774–780. doi: 10.1007/s12311-015-0740-2

13. Cheng MM, Tang G, Kuo SH. Harmaline-induced tremor in mice: videotape documentation and open questions about the model. Tremor Other Hyperkinet Mov 2013;3. doi: 10.7916/D8H993W3

14. Llinas R, Baker R, Sotelo C. Electrotonic coupling between neurons in cat inferior olive. J Neurophysiol 1974;37:560–571. doi: 10.1152/jn.1974.37.3.560

15. Llinas R, Volkind RA. The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res 1973;18:69–87. doi: 10.1007/BF00236557

16. Llinas R, Yarom Y. Electrophysiology of mammalian inferior olivary neurons in vitro. different types of voltage-dependent ionic conductances. J Physiol 1981;315:549–567. doi: 10.1113/jphysiol.1981.sp013763

17. Llinás RR. The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties. Front Neural Circuits 2013;7:96. doi: 10.3389/fncir.2013.00096

18. White JJ, Lin T, Brown AM, Arancillo M, Lackey EP, Stay TL. An optimized surgical approach for obtaining stable extracellular single-unit recordings from the cerebellum of head-fixed behaving mice. J Neurosci Methods 2016;262:21–31. doi: 10.1016/j.jneumeth.2016.01.010

19. Martin FC, Thu Le A, Handforth A. Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications. Mov Disord 2005;20:298–305. doi: 10.1002/mds.20331

20. Louis ED, Zheng W, Jurewicz EC, Watner D, Chen J, Factor-Litvak P. Elevation of blood beta-carboline alkaloids in essential tremor. Neurology 2002;59:1940–1944. doi: 10.1212/01.WNL.0000038385.60538.19

21. Louis ED, Factor-Litvak P, Liu X, Vonsattel J-PG, Galecki M, Jiang W. Elevated brain harmane (1-methyl-9H-pyrido[3,4-b]indole) in essential tremor cases vs. controls. Neurotoxicology 2013;38C:131–135. doi: 10.1016/j.neuro.2013.07.002

22. Martin FC, Handforth A. Carbenoxolone and mefloquine suppress tremor in the harmaline mouse model of essential tremor. Mov Disord 2006;21:1641–1649. doi: 10.1002/mds.20940

23. Handforth A, Homanics GE, Covey DF, Krishnan K, Lee JY, Sakimura K. T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor. Neuropharmacol 2010;59:380–387. doi: 10.1016/j.neuropharm.2010.05.012

24. Lang EJ, Sugihara I, Llinas R. GABAergic modulation of complex spike activity by the cerebellar nucleoolivary pathway in rat. J Neurophysiol 1996;76:255–275. doi: 10.1152/jn.1996.76.1.255

25. Lang EJ. Organization of olivocerebellar activity in the absence of excitatory glutamatergic input. J Neurosci 2001;21:1663–1675. doi: 10.1523/JNEUROSCI.21-05-01663.2001

26. Louis ED, Babij R, Cortes E, Vonsattel JPG, Faust PL. The inferior olivary nucleus: a postmortem study of essential tremor cases versus controls. Mov Disord 2013;28:779–786. doi: 10.1002/mds.25400

27. Long MA, Deans MR, Paul DL, Connors BW. Rhythmicity without synchrony in the electrically uncoupled inferior olive. J Neurosci 2002;22:10898–10905. doi: 10.1523/JNEUROSCI.22-24-10898.2002

28. Battista AF, Nakatani S, Goldstein M, Anagnoste B. Effect of harmaline in monkeys with central nervous system lesions. Exp Neurol 1970;28:513–524. doi: 10.1016/0014-4886(70)90189-5

29. Lee J, Kim I, Lee J, Knight E, Cheng L, Kang SI. Development of harmaline-induced tremor in a swine model. Tremor Other Hyperkinet Mov 2018;8. doi: 10.7916/D8J68TV7

30. Miwa H, Kubo T, Suzuki A, Kihira T, Kondo T. A species-specific difference in the effects of harmaline on the rodent olivocerebellar system. Brain Res 2006;1068:94–101. doi: 10.1016/j.brainres.2005.11.036

31. O’Hearn E, Molliver ME. Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Neuroscience 1993;55:303–310. doi: 10.1016/0306-4522(93)90500-F

32. Choe M, Cortes E, Vonsattel JP, Kuo SH, Faust PL, Louis ED. Purkinje cell loss in essential tremor: Random sampling quantification and nearest neighbor analysis. Mov Disord 2016;31:393–401. doi: 10.1002/mds.26490

33. Paterson NE, Malekiani SA, Foreman MM, Olivier B, Hanania T. Pharmacological characterization of harmaline-induced tremor activity in mice. Eur J Pharmacol 2009;616:73–80. doi: 10.1016/j.ejphar.2009.05.031

34. Kuo SH, Lin CY, Wang J, Liou JY, Pan MK, Louis RJ. Deep brain stimulation and climbing fiber synaptic pathology in essential tremor. Ann Neurol 2016;80:461–465. doi: 10.1002/ana.24728

35. Kuo SH, Lin CY, Wang J, Sims PA, Pan MK, Liou JY. Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases. Acta Neuropathol 2017;133:121–138. doi: 10.1007/s00401-016-1626-1

36. Lin C-Y, Louis ED, Faust PL, Koeppen AH, Vonsattel J-PG, Kuo S-H. Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 2014;137:3149–3159. doi: 10.1093/brain/awu281

37. Louis RJ, Lin C-Y, Faust PL, Koeppen AH, Kuo S-H. Climbing fiber synaptic changes correlate with clinical features in essential tremor. 2015;84:2284–2286. doi: 10.1212/WNL.0000000000001636

38. Yoshida T, Katoh A, Ohtsuki G, Mishina M, Hirano T. Oscillating Purkinje neuron activity causing involuntary eye movement in a mutant mouse deficient in the glutamate receptor delta2 subunit. J Neurosci 2004;24:2440–2448. doi: 10.1523/JNEUROSCI.0783-03.2004

39. Kitazawa S, Wolpert DM. Rhythmicity, randomness and synchrony in climbing fiber signals. Trends Neurosci 2005;28:611–619. doi: 10.1016/j.tins.2005.09.004

40. Babij R, Lee M, Cortes E, Vonsattel JPG, Faust PL, Louis ED. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 2013;136:3051–3061. doi: 10.1093/brain/awt238

41. Handforth A. Linking Essential tremor to the cerebellum-animal model evidence. Cerebellum 2016, 15:285–298. doi: 10.1007/s12311-015-0750-0

42. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003;39:889–909. doi: 10.1016/S0896-6273(03)00568-3

43. Bergman H, Raz A, Feingold A, Nini A, Nelken I, Hansel D. Physiology of MPTP tremor. Mov Disord 1998;13(Suppl. 3):29–34. doi: 10.1002/mds.870131305

44. Bekar L, Libionka W, Tian GF, Xu Q, Torres A, Wang X. Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor. Nat Med 2008;14:75–80. doi: 10.1038/nm1693

45. Deutch AY, Elsworth JD, Goldstein M, Fuxe K, Redmond DE, Jr., Sladek JR. Preferential vulnerability of A8 dopamine neurons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurosci Lett 1986;68:51–56. doi: 10.1016/0304-3940(86)90228-4

46. German DC, Dubach M, Askari S, Speciale SG, Bowden DM. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian syndrome in Macaca fascicularis: which midbrain dopaminergic neurons are lost?Neuroscience 1988;24:161–174. doi: 10.1016/0306-4522(88)90320-X

47. Oiwa Y, Eberling JL, Nagy D, Pivirotto P, Emborg ME, Bankiewicz KS. Overlesioned hemiparkinsonian non-human primate model: correlation between clinical, neurochemical and histochemical changes. Front Biosci 2003;8:a155–166. doi: 10.2741/1104

48. Rivlin-Etzion M, Elias S, Heimer G, Bergman H. Computational physiology of the basal ganglia in Parkinson's disease. Prog Brain Res 2010;183:259–273. doi: 10.1016/S0079-6123(10)83013-4

49. Dirkx MF, den Ouden H, Aarts E, Timmer M, Bloem BR, Toni I. The cerebral network of Parkinson's tremor: an effective connectivity fMRI study. J Neurosci 2016;36:5362–5372. doi: 10.1523/JNEUROSCI.3634-15.2016

50. Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain 2012;135:3206–3226. doi: 10.1093/brain/aws023

51. Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie RM. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. New Engl J Med 2000;342:461–468. doi: 10.1056/NEJM200002173420703

52. Meyer PT, Frings L, Rucker G, Hellwig S. (18)F-FDG PET in Parkinsonism: differential diagnosis and evaluation of cognitive impairment. J Nuclear Med 2017;58:1888–1898. doi: 10.2967/jnumed.116.186403

53. White JJ, Arancillo M, King A, Lin T, Miterko LN, Gebre SA. Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration. Neurobiol Disease 2016;86:86–98. doi: 10.1016/j.nbd.2015.11.008

54. Apps R, Hawkes R. Cerebellar cortical organization: a one-map hypothesis. Nat Rev Neurosci 2009;10:670–681. doi: 10.1038/nrn2698

55. Beckinghausen J, Sillitoe RV. Insights into cerebellar development and connectivity. Neurosci Lett 2018. doi: 10.1016/j.neulet.2018.05.013

56. Apps R, Hawkes R, Aoki S, Bengtsson F, Brown AM, Chen G. Cerebellar modules and their role as operational cerebellar processing units. Cerebellum 2018;17:654–682. doi: 10.1007/s12311-018-0959-9

57. Turkmen S, Guo G, Garshasbi M, Hoffmann K, Alshalah AJ, Mischung C. CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet 2009;5:e1000487. doi: 10.1371/journal.pgen.1000487

58. Kaya N, Aldhalaan H, Al-Younes B, Colak D, Shuaib T, Al-Mohaileb F. Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII. Am J Med Genet B, Neuropsychiatric Genet 2011;156b:826–834. doi: 10.1002/ajmg.b.31227

59. Clark BR, LaRegina M, Tolbert DL. X-linked transmission of the shaker mutation in rats with hereditary Purkinje cell degeneration and ataxia. Brain Res 2000;858:264–273. doi: 10.1016/S0006-8993(99)02415-4

60. Anderson C, Pulst SM. Deep cerebellar stimulation to treat degenerative cerebellar ataxias. Am Acad Neurol 2018; Abstract S18:005.

61. Gan SR, Wang J, Figueroa KP, Pulst SM, Tomishon D, Lee D. Postural tremor and ataxia progression in spinocerebellar ataxias. Tremor Other Hyperkinet Mov 2017;7. doi: 10.7916/D8GM8KRH

62. Schaefer SM, Vives Rodriguez A, Louis ED. Brain circuits and neurochemical systems in essential tremor: insights into current and future pharmacotherapeutic approaches. Exp Rev Neurother 2018;18:101–110. doi: 10.1080/14737175.2018.1413353

63. Zesiewicz TA, Kuo SH. Essential tremor. BMJ Clin Evid 2015. doi: 10.1212/WNL.0000000000004372

64. Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234–238. doi: 10.1212/WNL.41.2_Part_1.234

65. Paris-Robidas S, Brochu E, Sintes M, Emond V, Bousquet M, Vandal M. Defective dentate nucleus GABA receptors in essential tremor. Brain 2012;135:105–116. doi: 10.1093/brain/awr301

66. Kralic JE, Criswell HE, Osterman JL, O’Buckley TK, Wilkie ME, Matthews DB. Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice. The J Clin Invest 2005;115:774–779. doi: 10.1172/JCI200523625

67. Louis ED, Hernandez N, Dyke JP, Ma RE, Dydak U. In vivo dentate nucleus gamma-aminobutyric acid concentration in essential tremor vs. controls. Cerebellum 2018;17:165–172. doi: 10.1007/s12311-017-0891-4

68. Boecker H, Weindl A, Brooks DJ, Ceballos-Baumann AO, Liedtke C, Miederer M. GABAergic dysfunction in essential tremor: an 11C-flumazenil PET study. J Nuclear Med 2010;51:1030–1035. doi: 10.2967/jnumed.109.074120

69. Podurgiel SJ, Spencer T, Kovner R, Baqi Y, Muller CE, Correa M. Induction of oral tremor in mice by the acetylcholinesterase inhibitor galantamine: reversal with adenosine A2A antagonism. Pharmacol Biochem Behav 2016;140:62–67. doi: 10.1016/j.pbb.2015.10.008

70. Nannan G, Runmei Y, Fusheng L, Shoulan Z, Guangqing L. Effects of AIT-082, a purine derivative, on tremor induced by arecoline or oxotremorine in mice. Pharmacol 2007;80:21–26. doi: 10.1159/000102601

71. Itoh M. The role of brain acetylcholine in phenol-induced tremor in mice. Arch Oral Biol 1995;40:365–372. doi: 10.1016/0003-9969(94)00191-D

72. Salamone JD, Collins-Praino LE, Pardo M, Podurgiel SJ, Baqi Y, Muller CE. Conditional neural knockout of the adenosine A(2A) receptor and pharmacological A(2A) antagonism reduce pilocarpine-induced tremulous jaw movements: studies with a mouse model of parkinsonian tremor. Eur Neuropsychopharmacol 2013;23:972–977. doi: 10.1016/j.euroneuro.2012.08.004

73. Chen PH, Tilson HA, Marbury GD, Karoum F, Hong JS. Effect of chlordecone (Kepone) on the rat brain concentration of 3-methoxy-4-hydroxyphenylglycol: evidence for a possible involvement of the norepinephrine system in chlordecone-induced tremor. Toxicol Appl Pharmacol 1985;77:158–164. doi: 10.1016/0041-008X(85)90276-5

74. Gothoni P. Ethanol withdrawal tremor does not interact with physostigmine-induced tremor in rat. Pharmacol Biochem Behav 1985;23:339–344. doi: 10.1016/0091-3057(85)90003-6

75. Mansner R, Mattila MJ. Nicotine induced tremor and antidiuresis and brain nicotine levels in the rat. Med Biol 1975;53:169–176.

76. Growdon JH. Postural changes, tremor, and myoclonus in the rat immediately following injections of p-chloromaphetamine. Neurology 1977;27:1074–1077. doi: 10.1212/WNL.27.11.1074

77. Hudson PM, Chen PH, Tilson HA, Hong JS. Effects of p,p'-DDT on the rat brain concentrations of biogenic amine and amino acid neurotransmitters and their association with p,p'-DDT-induced tremor and hyperthermia. J Neurochem 1985;45:1349–1355. doi: 10.1111/j.1471-4159.1985.tb07199.x

78. Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM. A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model. Pharmacol Biochem Behav 2008;90:540–544. doi: 10.1016/j.pbb.2008.04.010

79. Gao DM, Benazzouz A, Piallat B, Bressand K, Ilinsky IA, Kultas-Ilinsky K. High-frequency stimulation of the subthalamic nucleus suppresses experimental resting tremor in the monkey. Neuroscience 1999;88:201–212. doi: 10.1016/S0306-4522(98)00235-8

80. Elble RJ, Schieber MH, Thach WT, Jr. Activity of muscle spindles, motor cortex and cerebellar nuclei during action tremor. Brain Res 1984;323:330–334. doi: 10.1016/0006-8993(84)90308-1

81. Gemba H, Sasaki K, Yoneda Y, Hashimoto S, Mizuno N. Tremor in the monkey with a cerebellar lesion. Exp Neurol 1980;69:173–182. doi: 10.1016/0014-4886(80)90152-1

82. Koller WC. Pharmacologic treatment of parkinsonian tremor. Arch Neurol 1986;43:126–127. doi: 10.1001/archneur.1986.00520020020009

83. Conti V, Aghaie A, Cilli M, Martin N, Caridi G, Musante L. crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1). Int J Mol Mede 2006;18:593–600. doi: 10.3892/ijmm.18.4.593

84. Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem 2015;135:958–974. doi: 10.1111/jnc.13292

85. Hunanyan AS, Fainberg NA, Linabarger M, Arehart E, Leonard AS, Adil SM. Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization. Epilepsia 2015;56:82–93. doi: 10.1111/epi.12878

86. Gomez-Grau M, Albaiges J, Casas J, Auladell C, Dierssen M, Vilageliu L. New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease. Sci Rep 2017;7:41931. doi: 10.1038/srep41931

87. Jones JM, Dionne L, Dell’Orco J, Parent R, Krueger JN, Cheng X. Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder. Neurobiol Dis 2016;89:36–45. doi: 10.1016/j.nbd.2016.01.018

88. Killoy KM, Harlan BA, Pehar M, Helke KL, Johnson JA, Vargas MR. Decreased glutathione levels cause overt motor neuron degeneration in hSOD1(WT) over-expressing mice. Exp Neurol 2018;302:129–135. doi: 10.1016/j.expneurol.2018.01.004

89. Garcia PL, Hossain MI, Andrabi SA, Falany CN. Generation and characterization of SULT4A1 mutant mouse models. Drug Metab Dispos 2018;46:41–45. doi: 10.1124/dmd.117.077560

90. White JJ, Sillitoe RV. Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat Comm 2017;8:14912. doi: 10.1038/ncomms14912

91. Traka M, Millen KJ, Collins D, Elbaz B, Kidd GJ, Gomez CM. WDR81 is necessary for Purkinje and photoreceptor cell survival. J Neurosci 2013;33:6834–6844. doi: 10.1523/JNEUROSCI.2394-12.2013

92. Perkins EM, Clarkson YL, Sabatier N, Longhurst DM, Millward CP, Jack J. Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 2010;30:4857–4867. doi: 10.1523/JNEUROSCI.6065-09.2010

93. Mironova YA, Lin JP, Kalinski A, Huffman L, Lenk GM, Havton LA. Protective role of the lipid phosphatase Fig4 in the adult nervous system. Hum Mol Genet 2018;27:2443–2453. doi: 10.1093/hmg/ddy145

94. Khalili K, Del Valle L, Muralidharan V, Gault WJ, Darbinian N, Otte J. Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Mol Cell Biol 2003;23:6857–6875. doi: 10.1128/MCB.23.19.6857-6875.2003

95. Sarna JR, Hawkes R. Patterned Purkinje cell loss in the ataxic sticky mouse. Eur J Neurosci 2011;34:79–86. doi: 10.1111/j.1460-9568.2011.07725.x

96. Jacquelin C, Strazielle C, Lalonde R. Neurologic function during developmental and adult stages in Dab1(scm) (scrambler) mutant mice. Behav Brain Res 2012;226:265–273. doi: 10.1016/j.bbr.2011.09.020

97. Duchala CS, Shick HE, Garcia J, Deweese DM, Sun X, Stewart VJ. The toppler mouse: a novel mutant exhibiting loss of Purkinje cells. J Comp Neurol 2004;476:113–129. doi: 10.1002/cne.20206

98. Boillee S, Peschanski M, Junier MP. The wobbler mouse: a neurodegeneration jigsaw puzzle. Mol Neurobiol 2003;28:65–106. doi: 10.1385/MN:28:1:65

99. Grusser-Cornehls U, Grusser C, Baurle J. Vermectomy enhances parvalbumin expression and improves motor performance in weaver mutant mice: an animal model for cerebellar ataxia. Neuroscience 1999;91:315–326. doi: 10.1016/S0306-4522(98)00618-6

100. Tanaka M, Soma K, Izawa T, Yamate J, Franklin RJ, Kuramoto T. Abnormal myelinogenesis in the central nervous system of the VF mutant rat with recoverable tremor. Brain Res 2012;1488:104–112. doi: 10.1016/j.brainres.2012.09.037

101. Kuramoto T, Nomoto T, Fujiwara A, Mizutani M, Sugimura T, Ushijima T. Insertional mutation of the Attractin gene in the black tremor hamster. Mamm Genome 2002;13:36–40. doi: 10.1007/s00335-001-2116-9

102. Nishitani A, Tanaka M, Shimizu S, Kunisawa N, Yokoe M, Yoshida Y. Involvement of aspartoacylase in tremor expression in rats. Exp Anim 2016;65:293–301. doi: 10.1538/expanim.16-0007

103. Ohno Y, Shimizu S, Tatara A, Imaoku T, Ishii T, Sasa M. Hcn1 is a tremorgenic genetic component in a rat model of essential tremor. PloS one 2015;10:e0123529. doi: 10.1371/journal.pone.0123529

104. Fremont R, Calderon DP, Maleki S, Khodakhah K. Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. J Neurosci 2014;34:11723–11732. doi: 10.1523/JNEUROSCI.1409-14.2014

105. Fremont R, Tewari A, Khodakhah K. Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia-Parkinsonism. Neurobiol Dis 2015;82:200–212. doi: 10.1016/j.nbd.2015.06.004

106. Fremont R, Tewari A, Angueyra C, Khodakhah K. A role for cerebellum in the hereditary dystonia DYT1. eLife 2017;6. doi: 10.7554/eLife.22775.001

107. Lee KH, Mathews PJ, Reeves AM, Choe KY, Jami SA, Serrano RE. Circuit mechanisms underlying motor memory formation in the cerebellum. Neuron 2015;86:529–540. doi: 10.1016/j.neuron.2015.03.010

108. Thenganatt MA, Jankovic J. The relationship between essential tremor and Parkinson's disease. Parkinsonism Relat Disord 2016;22(Suppl. 1):S162–165. doi: 10.1016/j.parkreldis.2015.09.032

109. Shahed J, Jankovic J. Exploring the relationship between essential tremor and Parkinson’s disease. Parkinsonism Relat Disord 2007;13:67–76. doi: 10.1016/j.parkreldis.2006.05.033

110. Dirkx MF, Zach H, Bloem BR, Hallett M, Helmich RC. The nature of postural tremor in Parkinson disease. Neurology 2018;90(13):e1095–e1103. doi: 10.1212/WNL.0000000000005215

111. Dirkx MF, den Ouden HE, Aarts E, Timmer MH, Bloem BR, Toni I. Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus. Brain 2017;140:721–734. doi: 10.1212/WNL.0000000000005215

Table 1. Search Strategy

Key Words and Combination Number of Publications
Tremor AND Animal models Total Included Excluded
Tremor AND mouse 194 12 182 (not in English, 9; not relevant, 173)
Tremor AND rat 413 37 376 (not in English, 15; not relevant, 361)
Tremor AND monkey 470 15 455 (not in English, 31; not relevant, 424)
Total number of articles included for review 94 4 90 (not in English, 9; not relevant, 81)
Total number of articles included from the references of the including articles 68
Final number of articles included for review 5
73

Table 2. Chemical- or Lesion-induced Animal Models of Tremor

Chemical/Lesion Tremor Type and Frequency (Hz) Tremor Measurement Reference

Abbreviations: EMG, Electromyography; DCN, Deep Cerebellar Nucleus.

Mouse Harmaline-induced 10–16 Hz body tremor Force plate-based measurement 19
6-OHDA-induced 4–5 Hz body tremor Electromyography or force plate-based measurement 44
Galantamine-induced Oral tremor (3–7.5 Hz frequency range, with a peak frequency of approximately 6 Hz) Observation 69
Oxotremorine-induced and arecoline-induced Tremor Multiple electrical physiological signals real-time analyzer 70
Phenol-induced Tremor Observation 71
Pilocarpine-induced Oral tremor Observation 72
Rat Harmaline-induced 8–12 Hz body tremor Force plate-based measurement 19
Chlordecone-induced Tremor Force plate setting 73
Ethanol withdrawal physostigmine-induced, arecoline-induced Tremor(6–7 Hz)tremor (11–13 Hz) tremor (peak of 13 Hz) Objective measure, not detailed in method 74
Nicotine-induced Tremor Observation 75
p-Chloroamphetamine-induced Tremor Observation 76
p,p'-DDT-induced Tremor Observation 77
Tacrine-induced Oral tremor Observation 78
Monkey MPTP-induced 5–7 Hz limb tremor Accelerometer 43
Electrical coagulation of the brainstem area including the substantia nigra and the red nucleus Resting tremor (stable frequency of 4.46 ± 0.59 Hz) An accelerometer connected to a computer system 79
Repeated electrode penetration of the dentate and interpositus nuclei Change the physiological tremor frequency from 11–13 Hz to 5–7 Hz EMG 80
Partial cerebellectomy (including unilateral DCN) Tremor EMG 81

Table 3. Genetic Animal Models of Tremor

Gene/Lesion Tremor Type (Hz) Tremor Measure Ataxia/Others Cerebellar Pathology/Physiology Reference
Mouse Car8 mutation Tremor (4–14 Hz) Tremor monitor (San Diego instruments) Ataxia Microzonal organization defects, abnormal Purkinje cell firing 53
crv4 mutation Intention tremor Observation Ataxia 83
Cp/Heph mutation Tremor Observation Ataxia 84
D801N mutation Tremor Observation Abnormal motor coordination 85
GABAA α1 subunit knockout Tremor (15–19 Hz) Tremor measured by suspending the tail and attached to the stereo speaker Absent spontaneous GABAergic inhibitory postsynaptic potentials 66
NPC1 mutation Tremor Observation Motor impairment, hyperactivity, impaired learning and memory 86
SCN8A mutation Tremor Observation Ataxia and dystonia Impaired repetitive firing of Purkinje cells in cerebellar slices 87
SOD1 mutation Tremor Observation Loss of extension reflex in hind-limbs, decreased grip strength and paralysis 88
SULT4A1 mutation Tremor Observation Ataxia and absence seizures 89
Vglut2 deletion in the climbing fiber synapses Tremor (4–14 Hz) Tremor monitor (San Diego instruments) Dystonia Abnormal Purkinje cell simple spike firing (Silencing climbing fiber synaptic transmission) 90
Wdr81 mutation Tremor Observation Abnormal gait Purkinje cell degeneration 91
β-III spectrin knockout Tremor Observation Motor incoordination and a wide hindlimb gait Purkinje cell loss and cerebellar atrophy 92
Fig4 knockout Intention tremor Observation hypomyelination of the cerebellum and spongiform degeneration in the deep cerebellar nuclei 93
Pura knockout Action tremor Observation Waddling gait Reduced number of Purkinje cells and granule cells 94
Sticky mouse (Aars mutation) Tremor Observation Ataxia Purkinje cell degeneration 95
Scrambler mouse Body tremor Observation Abnormal gait 96
Toppler mouse Action tremor Observation Ataxia Purkinje cell loss 97
Wobbler mouse Head tremor Observation Unsteady gait and muscle atrophy 98
Weaver mouse Tremor Observation Ataxia and hypertonia 99
Rat VF mutation Generalized tremor (especially the caudal body) that peaks between 4–8 weeks and gradually subsides Observation Abnormal myelin-associated vacuoles in the white matter of cerebellum 100
Shaker mutation Tremor (4–5 Hz) Force plate-based measurement Ataxia Purkinje cell degeneration 60
TRM/Kyo mutation Whole body tremor, responsive to propranolol Observation 102
Hamster bt mutation Tremor Observation Defective myelination in the central nervous system 101

Figure 1. Search Strategy. Flow diagram for the literature search results.

Figure 2. Characteristics of Harmaline-Induced Tremor in Mice. (A) A representative time-frequency plot of harmaline-induced mouse tremor, which shows that harmaline can induce action tremor at the peak frequency around 13–15 Hz. The tremor was induced by a single intraperitoneal injection of harmaline hydrochloride (Sigma) at 5 mg/kg into a WT C57BL/6J mouse, and the mouse tremor was measured using Convuls-1 sensing platform (Columbus Instruments), co-registered with a video-based motion detection (NeuroMotive, BlackRock microsystem) to separate action vs. rest tremor. (B) The quantification of movement intensity at different frequency, showing that tremor occurs at action but minimal at rest in harmaline-induced tremor mouse model.

Figure 3. Brain Circuitry for Tremor. Schematics for the brain circuitry involved in the tremor of animal models. The brain circuitry alterations in each animal model of tremor are highlighted. CF, Climbing Fiber; DCN, Deep Cerebellar Nucleus; IO, Inferior Olive; PC, Purkinje Cell; VL, Ventrolateral Nucleus of the Thalamus.