Essential tremor pathology: neurodegeneration and reorganization of neuronal connections


Essential tremor (ET) is the most common tremor disorder globally and is characterized by kinetic tremor of the upper limbs, although other clinical features can also occur. Postmortem studies are a particularly important avenue for advancing our understanding of the pathogenesis of ET; however, until recently, the number of such studies has been limited. Several recent postmortem studies have made important contributions to our understanding of the pathological changes that take place in ET. These studies identified abnormalities in the cerebellum, which primarily affected Purkinje cells (PCs), basket cells and climbing fibres, in individuals with ET. We suggest that some of these pathological changes (for example, focal PC axonal swellings, swellings in and regression of the PC dendritic arbor and PC death) are likely to be primary and degenerative. By contrast, other changes, such as an increase in PC recurrent axonal collateral formation and hypertrophy of GABAergic basket cell axonal processes, could be compensatory responses to restore cerebellar GABAergic tone and cerebellar cortical inhibitory efficacy. Such compensatory responses are likely to be insufficient, enabling the disease to progress. Here, we review the results of recent postmortem studies of ET and attempt to place these findings into an anatomical–physiological disease model.

Key points

  • Several groups have identified pathological changes in the cerebellum of individuals with essential tremor (ET).

  • Cerebellar abnormalities in ET include changes to Purkinje cell (PC) axons and dendrites, displacement and loss of PCs, changes to basket cell axonal processes, abnormal distribution of climbing fibre connections to PCs and changes in GABA receptors in the dentate nucleus.

  • Some of the observed changes (for example, loss of PCs) could result in reduced GABAergic output from the cerebellum.

  • Some pathological changes in ET are likely to be primary and degenerative, whereas others could be regarded as compensatory responses aimed at restoring cerebellar GABAergic tone.

  • In the brains of individuals with ET, both PCs themselves and neighbouring GABAergic neurons (basket cells) might increase their connections with PCs, resulting in rewiring and reorganization of neuronal connections within the cerebellum.

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Fig. 1: The degenerative cascade in essential tremor: a provisional model.
Fig. 2: Putative ‘early’ pathological changes in essential tremor.
Fig. 3: Putative ‘middle’ pathological changes in ET.
Fig. 4: Putative ‘late’ pathological changes in ET.
Fig. 5: The ‘perfect storm’ of decreased cerebellar GABAergic output in essential tremor.


  1. 1.

    Louis, E. D. & Ferreira, J. J. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov. Disord. 25, 534–541 (2010).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Benito-Leon, J. & Louis, E. D. Clinical update: diagnosis and treatment of essential tremor. Lancet 369, 1152–1154 (2007).

    PubMed  Google Scholar 

  3. 3.

    Benito-Leon, J., Bermejo-Pareja, F., Morales, J. M., Vega, S. & Molina, J. A. Prevalence of essential tremor in three elderly populations of central Spain. Mov. Disord. 18, 389–394 (2003).

    PubMed  Google Scholar 

  4. 4.

    Louis, E. D. The primary type of tremor in essential tremor is kinetic rather than postural: cross-sectional observation of tremor phenomenology in 369 cases. Eur. J. Neurol. 20, 725–727 (2013).

    CAS  PubMed  Google Scholar 

  5. 5.

    Louis, E. D., Hernandez, N. & Michalec, M. Prevalence and correlates of rest tremor in essential tremor: cross-sectional survey of 831 patients across four distinct cohorts. Eur. J. Neurol. 22, 927–932 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Louis, E. D., Frucht, S. J. & Rios, E. Intention tremor in essential tremor: prevalence and association with disease duration. Mov. Disord. 24, 626–627 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Deuschl, G., Wenzelburger, R., Loffler, K., Raethjen, J. & Stolze, H. Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain 123, 1568–1580 (2000).

    PubMed  Google Scholar 

  8. 8.

    Louis, E. D., Gerbin, M. & Galecki, M. Essential tremor 10, 20, 30, 40: clinical snapshots of the disease by decade of duration. Eur. J. Neurol. 20, 949–954 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Stolze, H., Petersen, G., Raethjen, J., Wenzelburger, R. & Deuschl, G. The gait disorder of advanced essential tremor. Brain 124, 2278–2286 (2001).

    CAS  PubMed  Google Scholar 

  10. 10.

    Chandran, V. et al. Non-motor features in essential tremor. Acta Neurol. Scand. 125, 332–337 (2012).

    CAS  PubMed  Google Scholar 

  11. 11.

    Louis, E. D. Non-motor symptoms in essential tremor: a review of the current data and state of the field. Parkinsonism Relat. Disord. 22, S115–S118 (2016).

    PubMed  Google Scholar 

  12. 12.

    Putzke, J. D., Whaley, N. R., Baba, Y., Wszolek, Z. K. & Uitti, R. J. Essential tremor: predictors of disease progression in a clinical cohort. J. Neurol. Neurosurg. Psychiatry 77, 1235–1237 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Louis, E. D., Rios, E. & Henchcliffe, C. How are we doing with the treatment of essential tremor (ET)? Persistence of patients with ET on medication: data from 528 patients in three settings. Eur. J. Neurol. 17, 882–884 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Tio, M. & Tan, E. K. Genetics of essential tremor. Parkinsonism Relat. Disord. 22, S176–S178 (2016).

    PubMed  Google Scholar 

  15. 15.

    Louis, E. D. Environmental epidemiology of essential tremor. Neuroepidemiology 31, 139–149 (2008).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Dogu, O. et al. Elevated blood lead concentrations in essential tremor: a case-control study in Mersin, Turkey. Env. Health Perspect. 115, 1564–1568 (2007).

    CAS  Google Scholar 

  17. 17.

    Louis, E. D. et al. Blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentration in essential tremor cases in Spain. Neurotoxicology 34, 264–268 (2013).

    CAS  PubMed  Google Scholar 

  18. 18.

    Louis, E. D. et al. Elevated brain harmane (1-methyl-9H-pyrido[3,4-b]indole) in essential tremor cases vs. controls. Neurotoxicology 38, 131–135 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Louis, E. D. et al. Risk of tremor and impairment from tremor in relatives of patients with essential tremor: a community-based family study. Ann. Neurol. 49, 761–769 (2001).

    CAS  PubMed  Google Scholar 

  20. 20.

    Tanner, C. M. et al. Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology 57, 1389–1391 (2001).

    CAS  PubMed  Google Scholar 

  21. 21.

    Lorenz, D. et al. High concordance for essential tremor in monozygotic twins of old age. Neurology 62, 208–211 (2004).

    CAS  PubMed  Google Scholar 

  22. 22.

    Clark, L. N. & Louis, E. D. Challenges in essential tremor genetics. Rev. Neurol. 171, 466–474 (2015).

    CAS  PubMed  Google Scholar 

  23. 23.

    Testa, C. M. Key issues in essential tremor genetics research: where are we now and how can we move forward? Tremor Other Hyperkinet. Mov. (2013).

    Article  Google Scholar 

  24. 24.

    Kuo, S. H. et al. Current opinions and consensus for studying tremor in animal models. Cerebellum 18, 1036–1063 (2019).

    PubMed  Google Scholar 

  25. 25.

    Tan, E. K. & Schapira, A. H. Hunting for genes in essential tremor. Eur. J. Neurol. 15, 889–890 (2008).

    CAS  PubMed  Google Scholar 

  26. 26.

    Hopfner, F. et al. Knowledge gaps and research recommendations for essential tremor. Parkinsonism Relat. Disord. 33, 27–35 (2016).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Louis, E. D. & Lenka, A. The olivary hypothesis of essential tremor: time to lay this model to rest? Tremor Other Hyperkinet. Mov. 7, 473 (2017).

    Google Scholar 

  28. 28.

    Llinas, R. & Volkind, R. A. The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp. Brain Res. 18, 69–87 (1973).

    CAS  PubMed  Google Scholar 

  29. 29.

    Llinas, R. & Yarom, Y. Oscillatory properties of guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study. J. Physiol. 376, 163–182 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    de Oliveira, R. B. et al. Pacemaker currents in mouse locus coeruleus neurons. Neuroscience 170, 166–177 (2010).

    PubMed  Google Scholar 

  31. 31.

    Burlhis, T. M. & Aghajanian, G. K. Pacemaker potentials of serotonergic dorsal raphe neurons: contribution of a low-threshold Ca2+ conductance. Synapse 1, 582–588 (1987).

    CAS  PubMed  Google Scholar 

  32. 32.

    Steriade, M. & Llinas, R. R. The functional states of the thalamus and the associated neuronal interplay. Physiol. Rev. 68, 649–742 (1988).

    CAS  PubMed  Google Scholar 

  33. 33.

    Raman, I. M., Gustafson, A. E. & Padgett, D. Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J. Neurosci. 20, 9004–9016 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Llinas, R. & Sugimori, M. Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J. Physiol. 305, 171–195 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Handforth, A. Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor. Tremor Other Hyperkinet. Mov. (2012).

    Article  Google Scholar 

  36. 36.

    Paterson, N. E., Malekiani, S. A., Foreman, M. M., Olivier, B. & Hanania, T. Pharmacological characterization of harmaline-induced tremor activity in mice. Eur. J. Pharmacol. 616, 73–80 (2009).

    CAS  PubMed  Google Scholar 

  37. 37.

    Louis, E. D., Huang, C. C., Dyke, J. P., Long, Z. & Dydak, U. Neuroimaging studies of essential tremor: how well do these studies support/refute the neurodegenerative hypothesis? Tremor Other Hyperkinet. Mov. 4, 235 (2014).

    Google Scholar 

  38. 38.

    Sharifi, S., Nederveen, A. J., Booij, J. & van Rootselaar, A. F. Neuroimaging essentials in essential tremor: a systematic review. Neuroimage Clin. 5, 217–231 (2014).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Louis, E. D. et al. Inferior olivary nucleus degeneration does not lessen tremor in essential tremor. Cerebellum Ataxias 5, 1 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Elkouzi, A., Kattah, J. C. & Elble, R. J. Hypertrophic olivary degeneration does not reduce essential tremor. Mov. Disord. Clin. Pract. 3, 209–211 (2016).

    PubMed  Google Scholar 

  41. 41.

    Louis, E. D. et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130, 3297–3307 (2007).

    PubMed  Google Scholar 

  42. 42.

    Lin, C. Y. et al. Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137, 3149–3159 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Erickson-Davis, C. R. et al. “Hairy baskets” associated with degenerative Purkinje cell changes in essential tremor. J. Neuropathol. Exp. Neurol. 69, 262–271 (2010).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Babij, R. et al. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 136, 3051–3061 (2013).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Louis, E. D. et al. Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain 137, 3142–3148 (2014).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Paris-Robidas, S. et al. Defective dentate nucleus GABA receptors in essential tremor. Brain 135, 105–116 (2012).

    PubMed  Google Scholar 

  47. 47.

    Luo, C., Rajput, A. H., Robinson, C. A. & Rajput, A. Gamma-aminobutyric acid (GABA)-B receptor 1 in cerebellar cortex of essential tremor. J. Clin. Neurosci. 19, 920–921 (2012).

    CAS  PubMed  Google Scholar 

  48. 48.

    Delay, C. et al. Increased LINGO1 in the cerebellum of essential tremor patients. Mov. Disord. 29, 1637–1647 (2014).

    CAS  PubMed  Google Scholar 

  49. 49.

    Shill, H. A. et al. Pathologic findings in prospectively ascertained essential tremor subjects. Neurology 70, 1452–1455 (2008).

    CAS  PubMed  Google Scholar 

  50. 50.

    Symanski, C. et al. Essential tremor is not associated with cerebellar Purkinje cell loss. Mov. Disord. 29, 496–500 (2014).

    PubMed  Google Scholar 

  51. 51.

    Rajput, A., Robinson, C. A. & Rajput, A. H. Essential tremor course and disability: a clinicopathologic study of 20 cases. Neurology 62, 932–936 (2004).

    PubMed  Google Scholar 

  52. 52.

    Beliveau, E. et al. Accumulation of amyloid-beta in the cerebellar cortex of essential tremor patients. Neurobiol. Dis. 82, 397–408 (2015).

    CAS  PubMed  Google Scholar 

  53. 53.

    Louis, E. D., Babij, R., Cortes, E., Vonsattel, J. P. & Faust, P. L. The inferior olivary nucleus: a postmortem study of essential tremor cases versus controls. Mov. Disord. 28, 779–786 (2013).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Deuschl, G. & Elble, R. Essential tremor — neurodegenerative or nondegenerative disease towards a working definition of ET. Mov. Disord. 24, 2033–2041 (2009).

    PubMed  Google Scholar 

  55. 55.

    Grimaldi, G. & Manto, M. Is essential tremor a Purkinjopathy? The role of the cerebellar cortex in its pathogenesis. Mov. Disord. 281, 1759–1761 (2013).

    Google Scholar 

  56. 56.

    Louis, E. D. Essential tremor: a common disorder of Purkinje neurons? Neuroscientist 22, 108–118 (2016).

    PubMed  Google Scholar 

  57. 57.

    Benito-Leon, J. Essential tremor: a neurodegenerative disease? Tremor Other Hyperkinet. Mov. 4, 252 (2014).

    Google Scholar 

  58. 58.

    Samson, M. & Claassen, D. O. Neurodegeneration and the cerebellum. Neurodegener. Dis. 17, 155–165 (2017).

    PubMed  Google Scholar 

  59. 59.

    Bonuccelli, U. Essential tremor is a neurodegenerative disease. J. Neural Transm. 119, 1383–1387 (2012).

    PubMed  Google Scholar 

  60. 60.

    Tak, A. Z. A., Sengul, Y. & Karadag, A. S. Evaluation of thickness of retinal nerve fiber layer, ganglion cell layer, and choroidal thickness in essential tremor: can eyes be a clue for neurodegeneration? Acta Neurol. Belg. 118, 235–241 (2018).

    PubMed  Google Scholar 

  61. 61.

    Drachman, D. A. The amyloid hypothesis, time to move on: amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimers Dement. 10, 372–380 (2014).

    PubMed  Google Scholar 

  62. 62.

    Golde, T. E., Borchelt, D. R., Giasson, B. I. & Lewis, J. Thinking laterally about neurodegenerative proteinopathies. J. Clin. Invest. 123, 1847–1855 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Hirsch, E. C., Jenner, P. & Przedborski, S. Pathogenesis of Parkinson’s disease. Mov. Disord. 28, 24–30 (2013).

    CAS  PubMed  Google Scholar 

  64. 64.

    Louis, E. D. From neurons to neuron neighborhoods: the rewiring of the cerebellar cortex in essential tremor. Cerebellum 13, 501–512 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Louis, E. D. Essential tremor and the cerebellum. Handb. Clin. Neurol. 155, 245–258 (2018).

    PubMed  Google Scholar 

  66. 66.

    Martuscello, R. T. et al. Gene expression analysis of the cerebellum in essential tremor. Neurosci. Lett. 7, 134540 (2019).

    Google Scholar 

  67. 67.

    Yaginuma, M. et al. Paraneoplastic cerebellar ataxia with mild cerebello-olivary degeneration and an anti-neuronal antibody: a clinicopathological study. Neuropathol. Appl. Neurobiol. 26, 568–571 (2000).

    CAS  PubMed  Google Scholar 

  68. 68.

    Petito, C. K., Hart, M. N., Porro, R. S. & Earle, K. M. Ultrastructural studies of olivopontocerebellar atrophy. J. Neuropathol. Exp. Neurol. 32, 503–522 (1973).

    CAS  PubMed  Google Scholar 

  69. 69.

    Matsumoto, R., Nakano, I., Arai, N., Suda, M. & Oda, M. Progressive supranuclear palsy with asymmetric lesions in the thalamus and cerebellum, with special reference to the unilateral predominance of many torpedoes. Acta Neuropathol. 92, 640–644 (1996).

    CAS  PubMed  Google Scholar 

  70. 70.

    Louis, E. D., Kuo, S. H., Vonsattel, J. P. & Faust, P. L. Torpedo formation and Purkinje cell loss: modeling their relationship in cerebellar disease. Cerebellum 13, 433–439 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Baurle, J. & Grusser-Cornehls, U. Axonal torpedoes in cerebellar Purkinje cells of two normal mouse strains during aging. Acta Neuropathol. 88, 237–245 (1994).

    CAS  PubMed  Google Scholar 

  72. 72.

    Louis, E. D., Yi, H., Erickson-Davis, C., Vonsattel, J. P. & Faust, P. L. Structural study of Purkinje cell axonal torpedoes in essential tremor. Neurosci. Lett. 450, 287–291 (2009).

    CAS  PubMed  Google Scholar 

  73. 73.

    Brownlees, J. et al. Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. Hum. Mol. Genet. 11, 2837–2844 (2002).

    CAS  PubMed  Google Scholar 

  74. 74.

    Beaulieu, J. M., Nguyen, M. D. & Julien, J. P. Late onset of motor neurons in mice overexpressing wild-type peripherin. J. Cell Biol. 147, 531–544 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Cleveland, D. W. & Rothstein, J. D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2, 806–819 (2001).

    CAS  PubMed  Google Scholar 

  76. 76.

    Liem, R. K. & Leung, C. L. Neuronal intermediate filament overexpression and neurodegeneration in transgenic mice. Exp. Neurol. 184, 3–8 (2003).

    CAS  PubMed  Google Scholar 

  77. 77.

    Robertson, J., Kriz, J., Nguyen, M. D. & Julien, J. P. Pathways to motor neuron degeneration in transgenic mouse models. Biochimie 84, 1151–1160 (2002).

    CAS  PubMed  Google Scholar 

  78. 78.

    Louis, E. D. et al. Torpedoes in Parkinson’s disease, Alzheimer’s disease, essential tremor, and control brains. Mov. Disord. 24, 1600–1605 (2009).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Louis, E. D., Kuo, S. H., Tate, W. J., Kelly, G. C. & Faust, P. L. Cerebellar pathology in childhood-onset vs. adult-onset essential tremor. Neurosci. Lett. 659, 69–74 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Louis, E. D. et al. Torpedoes in the cerebellar vermis in essential tremor cases vs. controls. Cerebellum 10, 812–819 (2011).

    PubMed  Google Scholar 

  81. 81.

    Louis, E. D. et al. Neurofilament protein levels: quantitative analysis in essential tremor cerebellar cortex. Neurosci. Lett. 518, 49–54 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Mann, D. M., Stamp, J. E., Yates, P. O. & Bannister, C. M. The fine structure of the axonal torpedo in Purkinje cells of the human cerebellum. Neurol. Res. 1, 369–378 (1980).

    CAS  PubMed  Google Scholar 

  83. 83.

    Kato, T. & Hirano, A. A Golgi study of the proximal portion of the human Purkinje cell axon. Acta Neuropathol. 68, 191–195 (1985).

    CAS  PubMed  Google Scholar 

  84. 84.

    Choe, M. et al. Purkinje cell loss in essential tremor: random sampling quantification and nearest neighbor analysis. Mov. Disord. 31, 393–401 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. 85.

    Axelrad, J. E. et al. Reduced Purkinje cell number in essential tremor: a postmortem study. Arch. Neurol. 65, 101–107 (2008).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Yu, M. et al. Increased number of Purkinje cell dendritic swellings in essential tremor. Eur. J. Neurol. 19, 625–630 (2012).

    CAS  PubMed  Google Scholar 

  87. 87.

    Louis, E. D. et al. Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach. Acta Neuropathol. 138, 859–876 (2019).

    PubMed  Google Scholar 

  88. 88.

    Nakano, I. & Hirano, A. Atrophic cell processes of large motor neurons in the anterior horn in amyotrophic lateral sclerosis: observation with silver impregnation method. J. Neuropathol. Exp. Neurol. 46, 40–49 (1987).

    CAS  PubMed  Google Scholar 

  89. 89.

    Mavroudis, I. A. et al. Dendritic and spinal pathology of the Purkinje cells from the human cerebellar vermis in Alzheimer’s disease. Psychiatr. Danub. 25, 221–226 (2013).

    PubMed  Google Scholar 

  90. 90.

    Ferrer, I., Fabregues, I., Pineda, M., Gracia, I. & Ribalta, T. A Golgi study of cerebellar atrophy in human chronic alcoholism. Neuropathol. Appl. Neurobiol. 10, 245–253 (1984).

    CAS  PubMed  Google Scholar 

  91. 91.

    Dusart, I. & Sotelo, C. Lack of Purkinje cell loss in adult rat cerebellum following protracted axotomy: degenerative changes and regenerative attempts of the severed axons. J. Comp. Neurol. 347, 211–232 (1994).

    CAS  PubMed  Google Scholar 

  92. 92.

    Rossi, F., Jankovski, A. & Sotelo, C. Differential regenerative response of Purkinje cell and inferior olivary axons confronted with embryonic grafts: environmental cues versus intrinsic neuronal determinants. J. Comp. Neurol. 359, 663–677 (1995).

    CAS  PubMed  Google Scholar 

  93. 93.

    Rossi, F., Gianola, S. & Corvetti, L. The strange case of Purkinje axon regeneration and plasticity. Cerebellum 5, 174–182 (2006).

    PubMed  Google Scholar 

  94. 94.

    Chan-Palay, V. The recurrent collaterals of Purkinje cell axons: a correlated study of the rat’s cerebellar cortex with electron microscopy and the Golgi method. Z. Anat. Entwicklungsgesch 134, 200–234 (1971).

    CAS  PubMed  Google Scholar 

  95. 95.

    Dusart, I., Morel, M. P., Wehrle, R. & Sotelo, C. Late axonal sprouting of injured Purkinje cells and its temporal correlation with permissive changes in the glial scar. J. Comp. Neurol. 408, 399–418 (1999).

    CAS  PubMed  Google Scholar 

  96. 96.

    Carulli, D., Buffo, A. & Strata, P. Reparative mechanisms in the cerebellar cortex. Prog. Neurobiol. 72, 373–398 (2004).

    CAS  PubMed  Google Scholar 

  97. 97.

    Rajput, A. H., Robinson, C. A., Rajput, M. L., Robinson, S. L. & Rajput, A. Essential tremor is not dependent upon cerebellar Purkinje cell loss. Parkinsonism Relat. Disord. 18, 626–628 (2012).

    CAS  PubMed  Google Scholar 

  98. 98.

    Louis, E. D., Ford, B., Pullman, S. & Baron, K. How normal is ‘normal’? Mild tremor in a multiethnic cohort of normal subjects. Arch. Neurol. 55, 222–227 (1998).

    CAS  PubMed  Google Scholar 

  99. 99.

    Elble, R. J. Tremor in ostensibly normal elderly people. Mov. Disord. 13, 457–464 (1998).

    CAS  PubMed  Google Scholar 

  100. 100.

    Marshall, J. The effect of ageing upon physiological tremor. J. Neurol. Neurosurg. Psychiatry 24, 14–17 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Louis, E. D., Ferrer, M., Eliasen, E. H., Gaini, S. & Petersen, M. S. Tremor in normal adults: a population-based study of 1158 adults in the Faroe Islands. J. Neurol. Sci. 400, 169–174 (2019).

    PubMed  Google Scholar 

  102. 102.

    Stoodley, C. J. & Schmahmann, J. D. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage 44, 489–501 (2009).

    PubMed  Google Scholar 

  103. 103.

    Stoodley, C. J. & Schmahmann, J. D. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex 46, 831–844 (2010).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Bodranghien, F. et al. Consensus paper: revisiting the symptoms and signs of cerebellar syndrome. Cerebellum 15, 369–391 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Winkelman, M. D. & Hines, J. D. Cerebellar degeneration caused by high-dose cytosine arabinoside: a clinicopathological study. Ann. Neurol. 14, 520–527 (1983).

    CAS  PubMed  Google Scholar 

  106. 106.

    Salinsky, M. C., Levine, R. L., Aubuchon, J. P. & Schutta, H. S. Acute cerebellar dysfunction with high-dose ARA-C therapy. Cancer 51, 426–429 (1983).

    CAS  PubMed  Google Scholar 

  107. 107.

    Louis, E. D., Faust, P. L. & Vonsattel, J. P. Purkinje cell loss is a characteristic of essential tremor: towards a more mature understanding of pathogenesis. Parkinsonism Relat. Disord. 18, 1003–1004 (2012).

    PubMed  Google Scholar 

  108. 108.

    Louis, E. D., Faust, P. L. & Vonsattel, J. P. Purkinje cell loss is a characteristic of essential tremor. Parkinsonism Relat. Disord. 17, 406–409 (2011).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Cohen, C. Statistical Power Analysis for The Behavioral Sciences 2nd edn (Lawrence Erlbaum, 1988).

  110. 110.

    Lee, P. et al. A quantitative study of empty baskets in essential tremor and other motor neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 78, 113–122 (2019).

    CAS  PubMed  Google Scholar 

  111. 111.

    Louis, E. D. et al. Cerebellar pathology in familial vs. sporadic essential tremor. Cerebellum 75, 663–672 (2017).

    Google Scholar 

  112. 112.

    Stefansson, H. et al. Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat. Genet. 41, 277–279 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Tan, E. K. et al. LINGO1 variant increases risk of familial essential tremor. Neurology 73, 1161–1162 (2009).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Kuo, S. H. et al. Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta Neuropathol. 125, 879–889 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Arellano, J. I., Munoz, A., Ballesteros-Yanez, I., Sola, R. G. & DeFelipe, J. Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain 127, 45–64 (2004).

    CAS  PubMed  Google Scholar 

  116. 116.

    Kuo, S. H. et al. Increased number of heterotopic Purkinje cells in essential tremor. J. Neurol. Neurosurg. Psychiatry 82, 1038–1040 (2011).

    PubMed  Google Scholar 

  117. 117.

    Nakamura, R., Kurita, K., Kawanami, T. & Kato, T. An immunohistochemical study of Purkinje cells in a case of hereditary cerebellar cortical atrophy. Acta Neuropathol. 97, 196–200 (1999).

    CAS  PubMed  Google Scholar 

  118. 118.

    Gomez, C. M. et al. Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann. Neurol. 42, 933–950 (1997).

    CAS  PubMed  Google Scholar 

  119. 119.

    Yamada, M., Sato, T., Tsuji, S. & Takahashi, H. CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol. 115, 71–86 (2008).

    CAS  PubMed  Google Scholar 

  120. 120.

    Louis, E. D. et al. Heterotopic Purkinje cells: a comparative postmortem study of essential tremor and spinocerebellar ataxias 1, 2, 3, and 6. Cerebellum 17, 104–110 (2018).

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Shahbazian, M. D., Orr, H. T. & Zoghbi, H. Y. Reduction of Purkinje cell pathology in SCA1 transgenic mice by p53 deletion. Neurobiol. Dis. 8, 974–981 (2001).

    CAS  PubMed  Google Scholar 

  122. 122.

    Mangaru, Z. et al. Neuronal migration defect of the developing cerebellar vermis in substrains of C57BL/6 mice: cytoarchitecture and prevalence of molecular layer heterotopia. Dev. Neurosci. 35, 28–39 (2013).

    CAS  PubMed  Google Scholar 

  123. 123.

    Yang, Q. et al. Morphological Purkinje cell changes in spinocerebellar ataxia type 6. Acta Neuropathol. 100, 371–376 (2000).

    CAS  PubMed  Google Scholar 

  124. 124.

    Watanabe, M. Molecular mechanisms governing competitive synaptic wiring in cerebellar Purkinje cells. Tohoku J. Exp. Med. 214, 175–190 (2008).

    CAS  PubMed  Google Scholar 

  125. 125.

    Lee, D., Gan, S. R., Faust, P. L., Louis, E. D. & Kuo, S. H. Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes. Parkinsonism Relat. Disord. 51, 24–29 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Koeppen, A. H., Ramirez, R. L., Bjork, S. T., Bauer, P. & Feustel, P. J. The reciprocal cerebellar circuitry in human hereditary ataxia. Cerebellum 12, 493–503 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Louis, E. D. et al. Neuropathologic findings in essential tremor. Neurology 66, 1756–1759 (2006).

    CAS  PubMed  Google Scholar 

  128. 128.

    Lee, M. et al. Decreased EAAT2 protein expression in the essential tremor cerebellar cortex. Acta Neuropathol. Commun. 2, 157 (2014).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Kanai, Y. & Hediger, M. A. The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur. J. Pharmacol. 479, 237–247 (2003).

    CAS  PubMed  Google Scholar 

  130. 130.

    Louis, E. D. et al. Essential tremor associated with pathologic changes in the cerebellum. Arch. Neurol. 63, 1189–1193 (2006).

    PubMed  Google Scholar 

  131. 131.

    Louis, E. D. Linking essential tremor to the cerebellum: neuropathological evidence. Cerebellum 15, 235–242 (2016).

    PubMed  Google Scholar 

  132. 132.

    Louis, E. D. Re-thinking the biology of essential tremor: from models to morphology. Parkinsonism Relat. Disord. 20, S88–S93 (2014).

    PubMed  Google Scholar 

  133. 133.

    Rossi, F., Jankovski, A. & Sotelo, C. Target neuron controls the integrity of afferent axon phenotype: a study on the Purkinje cell-climbing fiber system in cerebellar mutant mice. J. Neurosci. 15, 2040–2056 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Louis, E. D., Lee, M., Cortes, E., Vonsattel, J. P. & Faust, P. L. Matching asymmetry of tremor with asymmetry of postmortem cerebellar hemispheric changes in essential tremor. Cerebellum 13, 462–470 (2014).

    PubMed  Google Scholar 

  135. 135.

    Bares, M. et al. Consensus paper: decoding the contributions of the cerebellum as a time machine. From neurons to clinical applications. Cerebellum 18, 266–286 (2019).

    PubMed  Google Scholar 

  136. 136.

    Palkovits, M., Mezey, E., Hamori, J. & Szentagothai, J. Quantitative histological analysis of the cerebellar nuclei in the cat. I. Numerical data on cells and on synapses. Exp. Brain Res. 28, 189–209 (1977).

    CAS  PubMed  Google Scholar 

  137. 137.

    Caddy, K. W. & Biscoe, T. J. Structural and quantitative studies on the normal C3H and Lurcher mutant mouse. Philos. Trans. R. Soc. Lond. B Biol. Sci. 287, 167–201 (1979).

    CAS  PubMed  Google Scholar 

  138. 138.

    Heckroth, J. A. Quantitative morphological analysis of the cerebellar nuclei in normal and lurcher mutant mice. I. Morphology and cell number. J. Comp. Neurol. 343, 173–182 (1994).

    CAS  PubMed  Google Scholar 

  139. 139.

    Person, A. L. & Raman, I. M. Synchrony and neural coding in cerebellar circuits. Front. Neural Circuits 6, 97 (2012).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    de Solages, C. et al. High-frequency organization and synchrony of activity in the Purkinje cell layer of the cerebellum. Neuron 58, 775–788 (2008).

    PubMed  Google Scholar 

  141. 141.

    Witter, L., Rudolph, S., Pressler, R. T., Lahlaf, S. I. & Regehr, W. G. Purkinje cell collaterals enable output signals from the cerebellar cortex to feed back to Purkinje cells and interneurons. Neuron 91, 312–319 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Mullen, R. J., Eicher, E. M. & Sidman, R. L. Purkinje cell degeneration, a new neurological mutation in the mouse. Proc. Natl Acad. Sci. USA 73, 208–212 (1976).

    CAS  PubMed  Google Scholar 

  143. 143.

    Levin, S. I. et al. Impaired motor function in mice with cell-specific knockout of sodium channel Scn8a (NaV1.6) in cerebellar Purkinje neurons and granule cells. J. Neurophysiol. 96, 785–793 (2006).

    CAS  PubMed  Google Scholar 

  144. 144.

    Louis, E. D., Agnew, A., Gillman, A., Gerbin, M. & Viner, A. S. Estimating annual rate of decline: prospective, longitudinal data on arm tremor severity in two groups of essential tremor cases. J. Neurol. Neurosurg. Psychiatry 82, 761–765 (2011).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Gonzalez-Burgos, G. & Lewis, D. A. GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia. Schizophr. Bull. 34, 944–961 (2008).

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Lang, E. J., Sugihara, I. & Llinas, R. Olivocerebellar modulation of motor cortex ability to generate vibrissal movements in rat. J. Physiol. 571, 101–120 (2006).

    CAS  PubMed  Google Scholar 

  147. 147.

    Schnitzler, A., Munks, C., Butz, M., Timmermann, L. & Gross, J. Synchronized brain network associated with essential tremor as revealed by magnetoencephalography. Mov. Disord. 24, 1629–1635 (2009).

    PubMed  Google Scholar 

  148. 148.

    Muthuraman, M. et al. Essential and aging-related tremor: differences of central control. Mov. Disord. 30, 1673–1680 (2015).

    PubMed  Google Scholar 

  149. 149.

    Muthuraman, M. et al. Cerebello-cortical network fingerprints differ between essential, Parkinson’s and mimicked tremors. Brain 141, 1770–1781 (2018).

    PubMed  Google Scholar 

  150. 150.

    Brown, A. M. et al. Molecular layer interneurons shape the spike activity of cerebellar Purkinje cells. Sci. Rep. 9, 1742 (2019).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Han, K. S. et al. Ephaptic coupling promotes synchronous firing of cerebellar Purkinje cells. Neuron 100, 564–578 e3 (2018).

    CAS  PubMed  Google Scholar 

  152. 152.

    Handforth, A. Linking essential tremor to the cerebellum-animal model evidence. Cerebellum 15, 285–298 (2016).

    PubMed  Google Scholar 

  153. 153.

    Louis, E. D. The evolving definition of essential tremor: what are we dealing with? Parkinsonism Relat. Disord. 46, S87–S91 (2018).

    PubMed  Google Scholar 

  154. 154.

    Louis, E. D., Ford, B. & Barnes, L. F. Clinical subtypes of essential tremor. Arch. Neurol. 57, 1194–1198 (2000).

    CAS  PubMed  Google Scholar 

  155. 155.

    Hoskovcova, M. et al. Disorders of balance and gait in essential tremor are associated with midline tremor and age. Cerebellum 12, 27–34 (2012).

    Google Scholar 

  156. 156.

    Louis, E. D., Rios, E. & Rao, A. K. Tandem gait performance in essential tremor: clinical correlates and association with midline tremors. Mov. Disord. 25, 1633–1638 (2010).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Louis, E. D. et al. Older onset essential tremor: more rapid progression and more degenerative pathology. Mov. Disord. 24, 1606–1612 (2009).

    PubMed  PubMed Central  Google Scholar 

  158. 158.

    Lenka, A., Bhalsing, K. S., Jhunjhunwala, K. R., Chandran, V. & Pal, P. K. Are patients with limb and head tremor a clinically distinct subtype of essential tremor? Can. J. Neurol. Sci. 42, 181–186 (2015).

    PubMed  Google Scholar 

  159. 159.

    Ondo, W. G., Sutton, L., Dat Vuong, K., Lai, D. & Jankovic, J. Hearing impairment in essential tremor. Neurology 61, 1093–1097 (2003).

    CAS  PubMed  Google Scholar 

  160. 160.

    Gerbin, M., Viner, A. S. & Louis, E. D. Sleep in essential tremor: a comparison with normal controls and Parkinson’s disease patients. Parkinsonism Relat. Disord. 18, 279–284 (2012).

    PubMed  Google Scholar 

  161. 161.

    Benito-Leon, J., Louis, E. D. & Bermejo-Pareja, F. Population-based case-control study of cognitive function in essential tremor. Neurology 66, 69–74 (2006).

    PubMed  Google Scholar 

  162. 162.

    Bhatia, K. P. et al. Consensus Statement on the classification of tremors. From the task force on tremor of the International Parkinson and Movement Disorder Society. Mov. Disord. 33, 75–87 (2018).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Elble, R. J. The essential tremor syndromes. Curr. Opin. Neurol. 29, 507–512 (2016).

    PubMed  Google Scholar 

  164. 164.

    Louis, E. D. Essential tremors: a family of neurodegenerative disorders? Arch. Neurol. 66, 1202–1208 (2009).

    PubMed  PubMed Central  Google Scholar 

  165. 165.

    Louis, E. D. ‘Essential tremor’ or ‘the essential tremors’: is this one disease or a family of diseases? Neuroepidemiology 42, 81–89 (2014).

    PubMed  Google Scholar 

  166. 166.

    Louis, E. D. Essential tremor: “plus” or “minus”. Perhaps now is the time to adopt the term “the essential tremors”. Parkinsonism Relat. Disord. 56, 111–112 (2018).

    PubMed  Google Scholar 

  167. 167.

    Prasad, S. & Pal, P. K. Reclassifying essential tremor: implications for the future of past research. Mov. Disord. 24, 437 (2019).

    Google Scholar 

  168. 168.

    Albanese, A. Classifying tremor: language matters. Mov. Disord. 33, 3–4 (2018).

    PubMed  Google Scholar 

  169. 169.

    Fasano, A., Lang, A. E. & Espay, A. J. What is "essential" about essential tremor? A diagnostic placeholder. Mov. Disord. 33, 58–61 (2018).

    PubMed  Google Scholar 

  170. 170.

    Louis, E. D. et al. Essential tremor-plus — a controversial new concept. Lancet Neurol. (2019).

    Article  PubMed  Google Scholar 

  171. 171.

    Kuo, S. H. et al. Cerebellar pathology in early onset and late onset essential tremor. Cerebellum 16, 473–482 (2016).

    Google Scholar 

  172. 172.

    Vilarino-Guell, C. et al. LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease. Neurogenetics 11, 401–408 (2010).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    Thier, S. et al. LINGO1 polymorphisms are associated with essential tremor in Europeans. Mov. Disord. 25, 717–723 (2010).

    PubMed  Google Scholar 

  174. 174.

    Vilarino-Guell, C. et al. LINGO1 rs9652490 is associated with essential tremor and Parkinson disease. Parkinsonism Relat Disord 16, 109–111 (2010).

    PubMed  Google Scholar 

  175. 175.

    Clark, L. N. et al. Replication of the LINGO1 gene association with essential tremor in a North American population. Eur. J. Hum. Genet. 18, 838–843 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Wu, Y. W. et al. Analysis of Lingo1 variant in sporadic and familial essential tremor among Asians. Acta Neurol. Scand. 124, 264–268 (2011).

    CAS  PubMed  Google Scholar 

  177. 177.

    Lorenzo-Betancor, O. et al. Lack of association of LINGO1 rs9652490 and rs11856808 SNPs with familial essential tremor. Eur. J. Neurol. 18, 1085–1089 (2011).

    CAS  PubMed  Google Scholar 

  178. 178.

    Bourassa, C. V. et al. LINGO1 variants in the French-Canadian population. PLOS ONE 6, e16254 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Radovica, I., Inashkina, I., Smeltere, L., Vitols, E. & Jankevics, E. Screening of 10 SNPs of LINGO1 gene in patients with essential tremor in the Latvian population. Parkinsonism Relat. Disord. 18, 93–95 (2012).

    PubMed  Google Scholar 

  180. 180.

    Jimenez-Jimenez, F. J. et al. LINGO1 and risk for essential tremor: results of a meta-analysis of rs9652490 and rs11856808. J. Neurol. Sci. 317, 52–57 (2012).

    CAS  PubMed  Google Scholar 

  181. 181.

    Zuo, X. et al. Screening for two SNPs of LINGO1 gene in patients with essential tremor or sporadic Parkinson’s disease in Chinese population. Neurosci. Lett. 481, 69–72 (2010).

    CAS  PubMed  Google Scholar 

  182. 182.

    Bormann, P., Roth, L. W., Andel, D., Ackermann, M. & Reinhard, E. zfNLRR, a novel leucine-rich repeat protein is preferentially expressed during regeneration in zebrafish. Mol. Cell Neurosci. 13, 167–179 (1999).

    CAS  PubMed  Google Scholar 

  183. 183.

    Brose, K. & Tessier-Lavigne, M. Slit proteins: key regulators of axon guidance, axonal branching, and cell migration. Curr. Opin. Neurobiol. 10, 95–102 (2000).

    CAS  PubMed  Google Scholar 

  184. 184.

    Nguyen-Ba-Charvet, K. T. & Chedotal, A. Role of Slit proteins in the vertebrate brain. J. Physiol. Paris. 96, 91–98 (2002).

    CAS  PubMed  Google Scholar 

  185. 185.

    Thier, S. et al. Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor. Neurology 79, 243–248 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Tan, E. K. et al. SLC1A2 variant associated with essential tremor but not Parkinson disease in Chinese subjects. Neurology 80, 1618–1619 (2013).

    PubMed  Google Scholar 

  187. 187.

    Garcia-Martin, E. et al. No association of the SLC1A2 rs3794087 allele with risk for essential tremor in the Spanish population. Pharmacogenet. Genomics 23, 587–590 (2013).

    CAS  PubMed  Google Scholar 

  188. 188.

    Ross, J. P. et al. SLC1A2 rs3794087 does not associate with essential tremor. Neurobiol. Aging 35, 935.e9-10 (2014).

    PubMed  Google Scholar 

  189. 189.

    Muller, S. H. et al. Genome-wide association study in essential tremor identifies three new loci. Brain 139, 3163–3169 (2016).

    PubMed  PubMed Central  Google Scholar 

  190. 190.

    Merner, N. D. et al. Exome sequencing identifies FUS mutations as a cause of essential tremor. Am. J. Hum. Genet. 91, 313–319 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Hor, H. et al. Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. Hum. Mol. Genet. 24, 5677–5686 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Sanchez, E. et al. SORT1 mutation resulting in sortilin deficiency and p75(NTR) upregulation in a family with essential tremor. ASN Neuro 7, 1759091415598290 (2015).

    PubMed  PubMed Central  Google Scholar 

  193. 193.

    Bergareche, A. et al. SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy. Hum. Mol. Genet. 24, 7111–7120 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Liu, X. et al. Identification of candidate genes for familial early-onset essential tremor. Eur. J. Hum. Genet. 24, 1009–1015 (2016).

    CAS  PubMed  Google Scholar 

  195. 195.

    Odgerel, Z. et al. Whole genome sequencing and rare variant analysis in essential tremor families. PLOS ONE 14, e0220512 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

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The work of E.D.L. and P.L.F. is supported by the NIH National Institute of Neurological Disorders and Stroke (grant number R01 NS088257).

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In January 2019, the authors searched PubMed using the keyword “essential tremor” in combination with “biology” (101 results), “mechanisms” (247 results), “pathophysiology” (187 results), “post-mortem” (61 results), “cerebellum” (326 results), “Purkinje” (92 results), “inferior olive” (33 results), “thalamus” (513 results), “motor loop” (5 results) or “degeneration” (118 results). During the initial screening of the abstracts and full texts, publications that were not relevant to this Review, duplicates, and those that were published in languages other than English were removed. The references from these articles as well as full-text articles and abstracts from the authors’ personal collections were also thoroughly searched for additional articles.

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Both authors contributed equally to discussion of the content of the article, writing, and reviewing and/or editing of the manuscript before submission. E.D.L. also researched data for the article.

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Correspondence to Elan D. Louis.

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Kinetic tremor

A tremor that occurs during voluntary movement.

Bielschowsky stain

A silver stain that is useful for staining neuronal filamentous structures, including axons, neurofibrillary tangles and amyloid plaques.

Golgi–Kopsch method

A silver staining technique that is useful to visualize nerve processes belonging to individual neurons.

Arciform axons

Purkinje cell axons that gradually curve back towards the Purkinje cell layer.

Enhanced physiological tremor

A generally low-amplitude, upper-limb action tremor that is observed in the large majority of healthy individuals and can be exacerbated by stress or drugs.

Pinceau structure

Resembling a pincer.

Complex spike

A Purkinje cell action potential generated from a single excitatory climbing fibre, originating in the inferior olive, through hundreds of synapses across the proximal Purkinje cell dendritic tree. Complex spikes occur at low frequency with a characteristic burst of small spikelets and produce a prolonged depolarization.

Vibrissal movements

Movement of the facial whiskers of rodents.

Ephaptic coupling

Electrical conduction that involves adjacent nerve fibres, distinct from direct neuron to neuron communication through synapses.

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Louis, E.D., Faust, P.L. Essential tremor pathology: neurodegeneration and reorganization of neuronal connections. Nat Rev Neurol 16, 69–83 (2020).

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