Abstract
The syndrome of oculopalatal tremor (OPT) featuring the olivo-cerebellar hypersychrony leads to disabling pendular nystagmus and palatal myoclonus. This rare disorder provides valuable information about the motor physiology and offers insights into the mechanistic underpinning of common movement disorders. This focused review summarizes the last decade of OPT research from our laboratory and addresses three critical questions: 1) How the disease of inferior olive affects the physiology of motor learning? We discovered that our brain’s ability to compensate for the impaired motor command and implement errors to correct future movements could be affected if the cerebellum is occupied in receiving and transmitting the meaningless signal. A complete failure of OPT patients to adapt to change in rapid eye movements (saccades) provided proof of this principle. 2) Whether maladaptive olivo-cerebellar circuit offers insight into the mechanistic underpinning of the common movement disorder, dystonia, characterized by abnormal twisting and turning of the body part. We discovered that the subgroup of patients who had OPT also had dystonia affecting the neck, trunk, limbs, and face. We also found that the subjects who had tremor predominant neck dystonia (without OPT) also had impaired motor learning on a long and short timescale, just like those with OPT. Altogether, our studies focused on dystonia suggested the evidence for the maladaptive olive-cerebellar system. 3) We discovered that the OPT subjects had difficulty in perceiving the direction of their linear forward motion, i.e., heading, suggesting that olivo-cerebellar hypersynchrony also affects perception.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andreescu, C. E., Milojkovic, B. A., Haasdijk, E. D., Kramer, P., De Jong, F. H., Krust, A., et al. (2007). Estradiol improves cerebellar memory formation by activating estrogen receptor beta. The Journal of Neuroscience, 27(40), 10832–10839. https://doi.org/10.1523/JNEUROSCI.2588-07.2007.
Argyelan, M., Carbon, M., Niethammer, M., Ulug, A. M., Voss, H. U., Bressman, S. B., Dhawan, V., & Eidelberg, D. (2009). Cerebellothalamocortical connectivity regulates penetrance in dystonia. The Journal of Neuroscience, 29(31), 9740–9747. https://doi.org/10.1523/JNEUROSCI.2300-09.2009.
Barash, S., Melikyan, A., Sivakov, A., Zhang, M., Glickstein, M., & Thier, P. (1999). Saccadic dysmetria and adaptation after lesions of the cerebellar cortex. The Journal of Neuroscience, 19(24), 10931–10939.
Bertolini, G., Ramat, S., Bockisch, C. J., Marti, S., Straumann, D., & Palla, A. (2012). Is vestibular self-motion perception controlled by the velocity storage? Insights from patients with chronic degeneration of the vestibulo-cerebellum. PLoS One, 7(6), e36763. https://doi.org/10.1371/journal.pone.0036763.
Beylergil, S. B., Gupta, P., & Shaikh, A. G. (2020). Does inferior-olive Hypersynchrony affect vestibular heading perception? Cerebellum. https://doi.org/10.1007/s12311-020-01103-z.
Calderon, D. P., Fremont, R., Kraenzlin, F., & Khodakhah, K. (2011). The neural substrates of rapid-onset dystonia-parkinsonism. Nature Neuroscience, 14(3), 357–365. https://doi.org/10.1038/nn.2753.
Catz, N., Dicke, P. W., & Thier, P. (2008). Cerebellar-dependent motor learning is based on pruning a Purkinje cell population response. Proceedings of the National Academy of Sciences of the United States of America, 105(20), 7309–7314. https://doi.org/10.1073/pnas.0706032105.
Chen-Harris, H., Joiner, W. M., Ethier, V., Zee, D. S., & Shadmehr, R. (2008). Adaptive control of saccades via internal feedback. The Journal of Neuroscience, 28(11), 2804–2813. https://doi.org/10.1523/JNEUROSCI.5300-07.2008.
Coesmans, M., Weber, J. T., De Zeeuw, C. I., & Hansel, C. (2004). Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron, 44(4), 691–700. https://doi.org/10.1016/j.neuron.2004.10.031.
Delmaire, C., Vidailhet, M., Elbaz, A., Bourdain, F., Bleton, J. P., Sangla, S., Meunier, S., Terrier, A., & Lehericy, S. (2007). Structural abnormalities in the cerebellum and sensorimotor circuit in writer's cramp. Neurology, 69(4), 376–380. https://doi.org/10.1212/01.wnl.0000266591.49624.1a.
Eccles, J. C. (1977). An instruction-selection theory of learning in the cerebellar cortex. Brain Research, 127(2), 327–352. https://doi.org/10.1016/0006-8993(77)90550-9.
Ethier, V., Zee, D. S., & Shadmehr, R. (2008). Changes in control of saccades during gain adaptation. The Journal of Neuroscience, 28(51), 13929–13937. https://doi.org/10.1523/JNEUROSCI.3470-08.2008.
Fan, X., Hughes, K. E., Jinnah, H. A., & Hess, E. J. (2012). Selective and sustained alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation in cerebellum induces dystonia in mice. The Journal of Pharmacology and Experimental Therapeutics, 340(3), 733–741. https://doi.org/10.1124/jpet.111.190082.
Filip, P., Lungu, O. V., & Bares, M. (2013). Dystonia and the cerebellum: A new field of interest in movement disorders? Clinical Neurophysiology, 124(7), 1269–1276. https://doi.org/10.1016/j.clinph.2013.01.003.
Fujita, M. (2016). A theory of cerebellar cortex and adaptive motor control based on two types of universal function approximation capability. Neural Networks, 75, 173–196. https://doi.org/10.1016/j.neunet.2015.12.012.
Goto, N., & Kaneko, M. (1981). Olivary enlargement: Chronological and morphometric analyses. Acta Neuropathologica, 54(4), 275–282. https://doi.org/10.1007/bf00697000.
Goyal, M., Versnick, E., Tuite, P., Cyr, J. S., Kucharczyk, W., Montanera, W., Willinsky, R., & Mikulis, D. (2000). Hypertrophic olivary degeneration: Metaanalysis of the temporal evolution of MR findings. AJNR. American Journal of Neuroradiology, 21(6), 1073–1077.
Hutchinson, M., Nakamura, T., Moeller, J. R., Antonini, A., Belakhlef, A., Dhawan, V., & Eidelberg, D. (2000). The metabolic topography of essential blepharospasm: A focal dystonia with general implications. Neurology, 55(5), 673–677.
Ito, M. (2013). Error detection and representation in the olivo-cerebellar system. Front Neural Circuits, 7, 1. https://doi.org/10.3389/fncir.2013.00001.
LeDoux, M. S., & Lorden, J. F. (1998). Abnormal cerebellar output in the genetically dystonic rat. Advances in Neurology, 78, 63–78.
LeDoux, M. S., Lorden, J. F., & Ervin, J. M. (1993). Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat. Experimental Neurology, 120(2), 302–310. https://doi.org/10.1006/exnr.1993.1064.
LeDoux, M. S., Lorden, J. F., & Meinzen-Derr, J. (1995). Selective elimination of cerebellar output in the genetically dystonic rat. Brain Research, 697(1–2), 91–103.
Leznik, E., Makarenko, V., & Llinas, R. (2002). Electrotonically mediated oscillatory patterns in neuronal ensembles: An in vitro voltage-dependent dye-imaging study in the inferior olive. Journal of Neuroscience, 22(7), 2804–2815.
Llinas, R. R., Leznik, E., & Urbano, F. J. (2002). Temporal binding via cortical coincidence detection of specific and nonspecific thalamocortical inputs: A voltage-dependent dye-imaging study in mouse brain slices. Proceedings of the National Academy of Sciences of the United States of America, 99(1), 449–454. https://doi.org/10.1073/pnas.012604899.
Mahajan, A., Gupta, P., Jacobs, J., Marsili, L., Sturchio, A., Jinnah, H. A., et al. (2020). Impaired saccade adaptation in tremor-dominant cervical dystonia-evidence for maladaptive cerebellum. Cerebellum. https://doi.org/10.1007/s12311-020-01104-y.
Marr, D. (1969). A theory of cerebellar cortex. The Journal of Physiology, 202(2), 437–470. https://doi.org/10.1113/jphysiol.1969.sp008820.
Neychev, V. K., Gross, R. E., Lehericy, S., Hess, E. J., & Jinnah, H. A. (2011). The functional neuroanatomy of dystonia. Neurobiology of Disease, 42(2), 185–201. https://doi.org/10.1016/j.nbd.2011.01.026.
Odergren, T., Stone-Elander, S., & Ingvar, M. (1998). Cerebral and cerebellar activation in correlation to the action-induced dystonia in writer's cramp. Movement Disorders, 13(3), 497–508. https://doi.org/10.1002/mds.870130321.
Pizoli, C. E., Jinnah, H. A., Billingsley, M. L., & Hess, E. J. (2002). Abnormal cerebellar signaling induces dystonia in mice. The Journal of Neuroscience, 22(17), 7825–7833.
Prudente, C. N., Pardo, C. A., Xiao, J., Hanfelt, J., Hess, E. J., Ledoux, M. S., et al. (2013). Neuropathology of cervical dystonia. Experimental Neurology, 241, 95–104. https://doi.org/10.1016/j.expneurol.2012.11.019.
Raike, R. S., Pizoli, C. E., Weisz, C., van den Maagdenberg, A. M., Jinnah, H. A., & Hess, E. J. (2012). Limited regional cerebellar dysfunction induces focal dystonia in mice. Neurobiology of Disease, 49C, 200–210. https://doi.org/10.1016/j.nbd.2012.07.019.
Sadnicka, A., Hoffland, B. S., Bhatia, K. P., van de Warrenburg, B. P., & Edwards, M. J. (2012). The cerebellum in dystonia - help or hindrance? Clinical Neurophysiology, 123(1), 65–70. https://doi.org/10.1016/j.clinph.2011.04.027.
Schnier, F., & Lappe, M. (2011). Differences in intersaccadic adaptation transfer between inward and outward adaptation. Journal of Neurophysiology, 106(3), 1399–1410. https://doi.org/10.1152/jn.00236.2011.
Schonewille, M., Belmeguenai, A., Koekkoek, S. K., Houtman, S. H., Boele, H. J., van Beugen, B. J., Gao, Z., Badura, A., Ohtsuki, G., Amerika, W. E., Hosy, E., Hoebeek, F. E., Elgersma, Y., Hansel, C., & de Zeeuw, C. I. (2010). Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron, 67(4), 618–628. https://doi.org/10.1016/j.neuron.2010.07.009.
Schonewille, M., Gao, Z., Boele, H. J., Veloz, M. F., Amerika, W. E., Simek, A. A., et al. (2011). Reevaluating the role of LTD in cerebellar motor learning. Neuron, 70(1), 43–50. https://doi.org/10.1016/j.neuron.2011.02.044.
Shaikh, A. G. (2014). Motion perception without Nystagmus--a novel manifestation of cerebellar stroke. Journal of Stroke and Cerebrovascular Diseases, 23(5), 1148–1156. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.10.005.
Shaikh, A. G., Hong, S., Liao, K., Tian, J., Solomon, D., Zee, D. S., Leigh, R. J., & Optican, L. M. (2010). Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity. Brain, 133(Pt 3), 923–940. https://doi.org/10.1093/brain/awp323.
Shaikh, A. G., Thurtell, M. J., Optican, L. M., & Leigh, R. J. (2011). Pharmacological tests of hypotheses for acquired pendular nystagmus. Annals of the New York Academy of Sciences, 1233, 320–326. https://doi.org/10.1111/j.1749-6632.2011.06118.x.
Shaikh, A. G., Palla, A., Marti, S., Olasagasti, I., Optican, L. M., Zee, D. S., & Straumann, D. (2013a). Role of cerebellum in motion perception and vestibulo-ocular reflex-similarities and disparities. Cerebellum, 12(1), 97–107. https://doi.org/10.1007/s12311-012-0401-7.
Shaikh, A. G., Wong, A. L., Zee, D. S., & Jinnah, H. A. (2013b). Keeping your head on target. The Journal of Neuroscience, 33(27), 11281–11295. https://doi.org/10.1523/JNEUROSCI.3415-12.2013.
Shaikh, A. G., Ghasia, F. F., DeLong, M. R., Jinnah, H. A., Freeman, A., & Factor, S. A. (2015a). Ocular palatal tremor plus dystonia - new syndromic association. Movement Disorders Clinical Practice, 2(3), 267–270. https://doi.org/10.1002/mdc3.12193.
Shaikh, A. G., Zee, D. S., & Jinnah, H. A. (2015b). Oscillatory head movements in cervical dystonia: Dystonia, tremor, or both? Movement Disorders, 30(6), 834–842. https://doi.org/10.1002/mds.26231.
Shaikh, A. G., Zee, D. S., Crawford, J. D., & Jinnah, H. A. (2016). Cervical dystonia: a neural integrator disorder. Brain, 139(Pt 10), 2590–2599. https://doi.org/10.1093/brain/aww141.
Shaikh, A. G., Wong, A. L., Optican, L. M., & Zee, D. S. (2017). Impaired motor learning in a disorder of the inferior olive: Is the cerebellum confused? Cerebellum, 16(1), 158–167. https://doi.org/10.1007/s12311-016-0785-x.
Straube, A., & Deubel, H. (1995). Rapid gain adaptation affects the dynamics of saccadic eye movements in humans. Vision Research, 35(23–24), 3451–3458. https://doi.org/10.1016/0042-6989(95)00076-Q.
Tarnutzer, A. A., Palla, A., Marti, S., Schuknecht, B., & Straumann, D. (2012). Hypertrophy of the inferior olivary nucleus impacts perception of gravity. Frontiers in Neurology, 3, 79.
Thobois, S., Ballanger, B., Xie-Brustolin, J., Damier, P., Durif, F., Azulay, J. P., Derost, P., Witjas, T., Raoul, S., le Bars, D., & Broussolle, E. (2008). Globus pallidus stimulation reduces frontal hyperactivity in tardive dystonia. Journal of Cerebral Blood Flow and Metabolism, 28(6), 1127–1138. https://doi.org/10.1038/sj.jcbfm.9600610.
Tian, J., Ethier, V., Shadmehr, R., Fujita, M., & Zee, D. S. (2009). Some perspectives on saccade adaptation. Annals of the New York Academy of Sciences, 1164, 166–172. https://doi.org/10.1111/j.1749-6632.2009.03853.x.
Tyrrell, T., & Willshaw, D. (1992). Cerebellar cortex: Its simulation and the relevance of Marr's theory. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 336(1277), 239–257. https://doi.org/10.1098/rstb.1992.0059.
Xiao, J., & Ledoux, M. S. (2005). Caytaxin deficiency causes generalized dystonia in rats. Brain Research. Molecular Brain Research, 141(2), 181–192. https://doi.org/10.1016/j.molbrainres.2005.09.009.
Xu-Wilson, M., Chen-Harris, H., Zee, D. S., & Shadmehr, R. (2009). Cerebellar contributions to adaptive control of saccades in humans. The Journal of Neuroscience, 29(41), 12930–12939. https://doi.org/10.1523/JNEUROSCI.3115-09.2009.
Yamazaki, T., & Lennon, W. (2019). Revisiting a theory of cerebellar cortex. Neuroscience Research, 148, 1–8. https://doi.org/10.1016/j.neures.2019.03.001.
Zoons, E., & Tijssen, M. A. (2013). Pathologic changes in the brain in cervical dystonia pre- and post-mortem - a commentary with a special focus on the cerebellum. Experimental Neurology, 247, 130–133. https://doi.org/10.1016/j.expneurol.2013.04.005.
Funding
This work was supported by American Academy of Neurology Career Award (Shaikh), American Parkinson’s Disease Association George C Cotzias Memorial Fellowship (Shaikh), Dystonia Medical Research Foundation Research Grant (Shaikh), Dystonia Medical Research Foundation Clinical Fellowship (Mahajan), Fight for Sight grant (Ghasia), and Blind Children’s Association grant (Ghasia), and philanthropic funds to the Department of Neurology at University Hospitals (The Allan Woll Fund). Dr.Shaikh has Penni and Stephen Weinberg Research Chair in Brain Health.
Author information
Authors and Affiliations
Contributions
ME, SB, PG, AM, FG: collected data, analyzed data, conceptualized paper, edited the paper.
AS: analyzed data, conceptualized analysis/interpretation/paper, wrote paper, edited paper.
Corresponding author
Ethics declarations
Conflicts of interest/competing interest
The authors have no conflicts of competing interests.
Conflict of interest
The authors declare no conflict of interest.
Ethics approval, consent to participate
The institutional review board at respective institutes (Johns Hopkins, University of Cincinnati, The Cleveland Clinic, and Louis Stokes Cleveland VA Medical Center approved the study protocol and consent material for subjects published in corresponding papers and reviewed here. The subjects signed an informed consent form before participation.
Additional information
Action Editor: Jonathan David Victor
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article belongs to the Topical Collection: Vision and Action
Guest Editors: Aasef Shaikh and Jeffrey Shall
Rights and permissions
About this article
Cite this article
Elkasaby, M., Beylergil, S.B., Gupta, P. et al. Lessons learned from the syndrome of oculopalatal tremor. J Comput Neurosci 49, 309–318 (2021). https://doi.org/10.1007/s10827-020-00757-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10827-020-00757-2