The Cerebellum

, Volume 13, Issue 5, pp 637–644 | Cite as

Physiologic Changes Associated with Cerebellar Dystonia

Review

Abstract

Dystonia is a neurologic disorder characterized by sustained involuntary muscle contractions. Lesions responsible for unilateral secondary dystonia are confined to the putamen, caudate, globus pallidus, and thalamus. Dysfunction of these structures is suspected to play a role in both primary and secondary dystonia. Recent evidence has suggested that the cerebellum may play a role in the pathophysiology of dystonia. The role of the cerebellum in ataxia, a disorder of motor incoordination is well established. How may the cerebellum contribute to two apparently very different movement disorders? This review will discuss the idea of whether in some cases, ataxia and dystonia lie in the same clinical spectrum and whether graded perturbations in cerebellar function may explain a similar causative role for the cerebellum in these two different motor disorders. The review also proposes a model for cerebellar dystonia based on the available animal models of this disorder.

Keywords

Cerebellum Dystonia Ataxia EMG DCN Cerebellar nuclei Purkinje neuron 

Notes

Acknowledgements

The author would like to thank the Dystonia Medical Research Foundation and the National Institutes of Health (K08NS072158 and R01NS085054) for their support.

Conflict of Interest

The author has no relevant conflicts of interest to declare.

References

  1. 1.
    Fahn S. The varied clinical expressions of dystonia. Neurol Clin. 1984;2(3):541–54.PubMedGoogle Scholar
  2. 2.
    Berardelli A et al. The pathophysiology of primary dystonia. Brain. 1998;121(Pt 7):1195–212.PubMedCrossRefGoogle Scholar
  3. 3.
    Marsden CD et al. The anatomical basis of symptomatic hemidystonia. Brain. 1985;108(Pt 2):463–83.PubMedCrossRefGoogle Scholar
  4. 4.
    den Dunnen WF. Neuropathological diagnostic considerations in hyperkinetic movement disorders. Front Neurol. 2013;4:7.Google Scholar
  5. 5.
    Furukawa Y et al. Striatal dopamine in early-onset primary torsion dystonia with the DYT1 mutation. Neurology. 2000;54(5):1193–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Walker RH et al. TorsinA immunoreactivity in brains of patients with DYT1 and non-DYT1 dystonia. Neurology. 2002;58(1):120–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Rostasy K et al. TorsinA protein and neuropathology in early onset generalized dystonia with GAG deletion. Neurobiol Dis. 2003;12(1):11–24.PubMedCrossRefGoogle Scholar
  8. 8.
    McNaught KS et al. Brainstem pathology in DYT1 primary torsion dystonia. Ann Neurol. 2004;56(4):540–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Vitek JL et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol. 1999;46(1):22–35.PubMedCrossRefGoogle Scholar
  10. 10.
    Delmaire C et al. Structural abnormalities in the cerebellum and sensorimotor circuit in writer's cramp. Neurology. 2007;69(4):376–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Le Ber I et al. Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia. Neurology. 2006;67(10):1769–73.PubMedCrossRefGoogle Scholar
  12. 12.
    Kuoppamaki M et al. Slowly progressive cerebellar ataxia and cervical dystonia: clinical presentation of a new form of spinocerebellar ataxia? Mov Disord. 2003;18(2):200–6.PubMedCrossRefGoogle Scholar
  13. 13.
    van de Warrenburg BP et al. The syndrome of (predominantly cervical) dystonia and cerebellar ataxia: new cases indicate a distinct but heterogeneous entity. J Neurol Neurosurg Psychiatry. 2007;78(7):774–5.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    LeDoux MS, Brady KA. Secondary cervical dystonia associated with structural lesions of the central nervous system. Mov Disord. 2003;18(1):60–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum. 2005;4(1):2–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Eidelberg D et al. Functional brain networks in DYT1 dystonia. Ann Neurol. 1998;44(3):303–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Sadnicka A et al. The cerebellum in dystonia—help or hindrance? Clin Neurophysiol. 2012;123(1):65–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Niethammer M et al. Hereditary dystonia as a neurodevelopmental circuit disorder: evidence from neuroimaging. Neurobiol Dis. 2011;42(2):202–9.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Argyelan M et al. Cerebellothalamocortical connectivity regulates penetrance in dystonia. J Neurosci. 2009;29(31):9740–7.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Campbell DB, Hess EJ. L-type calcium channels contribute to the tottering mouse dystonic episodes. Mol Pharmacol. 1999;55(1):23–31.PubMedGoogle Scholar
  21. 21.
    Sprunger LK et al. Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3. Hum Mol Genet. 1999;8(3):471–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Lorden JF et al. Neuropharmacological correlates of the motor syndrome of the genetically dystonic (dt) rat. Adv Neurol. 1988;50:277–97.PubMedGoogle Scholar
  23. 23.
    Pizoli CE et al. Abnormal cerebellar signaling induces dystonia in mice. J Neurosci. 2002;22(17):7825–33.PubMedGoogle Scholar
  24. 24.
    LeDoux MS, Lorden JF, Ervin JM. Cerebellectomy eliminates the motor syndrome of the genetically dystonic rat. Exp Neurol. 1993;120(2):302–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Raman IM, Gustafson AE, Padgett D. Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J Neurosci. 2000;20(24):9004–16.PubMedGoogle Scholar
  26. 26.
    Raman IM, Bean BP. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J Neurosci. 1997;17(12):4517–26.PubMedGoogle Scholar
  27. 27.
    Ito M et al. Inhibitory control of intracerebellar nuclei by the purkinje cell axons. Exp Brain Res. 1970;10(1):64–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Mittmann W, Koch U, Hausser M. Feed-forward inhibition shapes the spike output of cerebellar Purkinje cells. J Physiol. 2005;563(Pt 2):369–78.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Dizon MJ, Khodakhah K. The role of interneurons in shaping Purkinje cell responses in the cerebellar cortex. J Neurosci. 2011;31(29):10463–73.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Thach WT. Discharge of Purkinje and cerebellar nuclear neurons during rapidly alternating arm movements in the monkey. J Neurophysiol. 1968;31(5):785–97.PubMedGoogle Scholar
  31. 31.
    Frysinger RC et al. Cerebellar cortical activity during antagonist cocontraction and reciprocal inhibition of forearm muscles. J Neurophysiol. 1984;51(1):32–49.PubMedGoogle Scholar
  32. 32.
    Smith AM, Bourbonnais D. Neuronal activity in cerebellar cortex related to control of prehensile force. J Neurophysiol. 1981;45(2):286–303.PubMedGoogle Scholar
  33. 33.
    Espinoza E, Smith AM. Purkinje cell simple spike activity during grasping and lifting objects of different textures and weights. J Neurophysiol. 1990;64(3):698–714.PubMedGoogle Scholar
  34. 34.
    Wetts R, Kalaska JF, Smith AM. Cerebellar nuclear cell activity during antagonist cocontraction and reciprocal inhibition of forearm muscles. J Neurophysiol. 1985;54(2):231–44.PubMedGoogle Scholar
  35. 35.
    Medina JF, Lisberger SG. Variation, signal, and noise in cerebellar sensory-motor processing for smooth-pursuit eye movements. J Neurosci. 2007;27(25):6832–42.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Shidara M et al. Inverse-dynamics model eye movement control by Purkinje cells in the cerebellum. Nature. 1993;365(6441):50–2.PubMedCrossRefGoogle Scholar
  37. 37.
    Holdefer RN, Miller LE. Dynamic correspondence between Purkinje cell discharge and forelimb muscle activity during reaching. Brain Res. 2009;1295:67–75.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Thach WT. Correlation of neural discharge with pattern and force of muscular activity, joint position, and direction of intended next movement in motor cortex and cerebellum. J Neurophysiol. 1978;41(3):654–76.PubMedGoogle Scholar
  39. 39.
    Ebner TJ, Hewitt AL, Popa LS. What features of limb movements are encoded in the discharge of cerebellar neurons? Cerebellum. 2011;10(4):683–93.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Rispal-Padel L, Cicirata F, Pons C. Cerebellar nuclear topography of simple and synergistic movements in the alert baboon (Papio papio). Exp Brain Res. 1982;47(3):365–80.PubMedCrossRefGoogle Scholar
  41. 41.
    Heiney SA et al. Precise control of movement kinematics by optogenetic inhibition of Purkinje cell activity. J Neurosci. 2014;34(6):2321–30.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Witter L et al. Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation. Front Neural Circ. 2013;7:133.Google Scholar
  43. 43.
    Hoshi E et al. The cerebellum communicates with the basal ganglia. Nat Neurosci. 2005;8(11):1491–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Calderon DP et al. The neural substrates of rapid-onset dystonia-Parkinsonism. Nat Neurosci. 2011;14(3):357–65.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Hore J, Wild B, Diener HC. Cerebellar dysmetria at the elbow, wrist, and fingers. J Neurophysiol. 1991;65(3):563–71.PubMedGoogle Scholar
  46. 46.
    Hallett M, Shahani BT, Young RR. EMG analysis of patients with cerebellar deficits. J Neurol Neurosurg Psychiatry. 1975;38(12):1163–9.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Hallett M et al. Physiological analysis of simple rapid movements in patients with cerebellar deficits. J Neurol Neurosurg Psychiatry. 1991;54(2):124–33.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Bastian AJ, Zackowski KM, Thach WT. Cerebellar ataxia: torque deficiency or torque mismatch between joints? J Neurophysiol. 2000;83(5):3019–30.PubMedGoogle Scholar
  49. 49.
    Flament D, Hore J. Movement and electromyographic disorders associated with cerebellar dysmetria. J Neurophysiol. 1986;55(6):1221–33.PubMedGoogle Scholar
  50. 50.
    Breakefield XO et al. The pathophysiological basis of dystonias. Nat Rev Neurosci. 2008;9(3):222–34.PubMedCrossRefGoogle Scholar
  51. 51.
    Hallett M. Pathophysiology of dystonia. J Neural Transm Suppl. 2006;70:485–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Lehericy S et al. The anatomical basis of dystonia: current view using neuroimaging. Mov Disord. 2013;28(7):944–57.PubMedCrossRefGoogle Scholar
  53. 53.
    Guehl D et al. Primate models of dystonia. Prog Neurobiol. 2009;87(2):118–31.PubMedCrossRefGoogle Scholar
  54. 54.
    van der Kamp W et al. Rapid elbow movements in patients with torsion dystonia. J Neurol Neurosurg Psychiatry. 1989;52(9):1043–9.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Berardelli A et al. Single-joint rapid arm movements in normal subjects and in patients with motor disorders. Brain. 1996;119(Pt 2):661–74.PubMedCrossRefGoogle Scholar
  56. 56.
    Ozelius LJ et al. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet. 1997;17(1):40–8.PubMedCrossRefGoogle Scholar
  57. 57.
    MacKinnon CD et al. Corticospinal excitability accompanying ballistic wrist movements in primary dystonia. Mov Disord. 2004;19(3):273–84.PubMedCrossRefGoogle Scholar
  58. 58.
    Carrea RM, Mettler FA. Physiologic consequences following extensive removals of the cerebellar cortex and deep cerebellar nuclei and effect of secondary cerebral ablations in the primate. J Comp Neurol. 1947;87(3):169–288.PubMedCrossRefGoogle Scholar
  59. 59.
    Dow RS, Moruzzi G. The physiology and pathology of the cerebellum. Minneapolis: University of Minnesota Press; 1958. 675 p.Google Scholar
  60. 60.
    Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94.PubMedCrossRefGoogle Scholar
  61. 61.
    Walter JT et al. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006;9(3):389–97.PubMedCrossRefGoogle Scholar
  62. 62.
    Shakkottai VG et al. Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Invest. 2004;113(4):582–90.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Shakkottai VG et al. Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci. 2011;31(36):13002–14.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Kasumu AW et al. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. Chem Biol. 2012;19(10):1340–53.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Person AL, Raman IM. Synchrony and neural coding in cerebellar circuits. Front Neural Circ. 2012;6:97.Google Scholar
  66. 66.
    Gauck V, Jaeger D. The control of rate and timing of spikes in the deep cerebellar nuclei by inhibition. J Neurosci. 2000;20(8):3006–16.PubMedGoogle Scholar
  67. 67.
    De Zeeuw CI et al. Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci. 2011;12(6):327–44.PubMedCrossRefGoogle Scholar
  68. 68.
    Person AL, Raman IM. Purkinje neuron synchrony elicits time-locked spiking in the cerebellar nuclei. Nature. 2012;481(7382):502–5.CrossRefGoogle Scholar
  69. 69.
    LeDoux MS, Hurst DC, Lorden JF. Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat. Neuroscience. 1998;86(2):533–45.PubMedCrossRefGoogle Scholar
  70. 70.
    Luna-Cancalon K et al. Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcay mice. Neurobiol Dis. 2014;67C:140–8.CrossRefGoogle Scholar
  71. 71.
    McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol. 2001;63:815–46.PubMedCrossRefGoogle Scholar
  72. 72.
    Chen G et al. Low-frequency oscillations in the cerebellar cortex of the tottering mouse. J Neurophysiol. 2009;101(1):234–45.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of MichiganAnn ArborUSA

Personalised recommendations