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. 2003 Nov;74(11):1509–1515. doi: 10.1136/jnnp.74.11.1509

Childhood onset generalised dystonia can be modelled by increased gain in the indirect basal ganglia pathway

T Sanger 1
PMCID: PMC1738212  PMID: 14617707

Abstract

Clinical experience suggests an important role of the indirect basal ganglia pathway in the genesis of childhood onset generalised dystonia, but it has been difficult to reconcile the increased muscle activity in dystonia with the current model of basal ganglia function in which the indirect pathway is considered primarily inhibitory. The aim of this study was to present a modification of the direct–indirect pathway model, in which the indirect pathway is inverting rather than purely inhibitory, so that while high signals are inhibited, low signals are amplified. As the basal ganglia may be a feedback loop that modifies cortical activity, instability from excessive gain in this feedback loop could explain features of dystonia. A detailed mathematical model is provided, together with simulations of cortical cell population spiking behaviour when connected through a basal ganglia loop. The simulations show that increased gain in the indirect pathway relative to the direct pathway can lead to unstable uncontrolled synchronous oscillations in cortex and basal ganglia. This behaviour could result in dystonia. The model provides a consistent explanation for the association of dystonia with parkinsonism and disorders characterised by dopamine depletion, the ability to treat some dystonias with dopamine, the ability of neuroleptic drug treatment to cause an acute dystonic reaction treatable with anticholinergic drugs, and the ability of pallidotomy or deep brain stimulation of the internal pallidum to alleviate symptoms of generalised dystonia.

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Selected References

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  1. Albin R. L., Young A. B., Penney J. B. The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989 Oct;12(10):366–375. doi: 10.1016/0166-2236(89)90074-x. [DOI] [PubMed] [Google Scholar]
  2. Alexander G. E., Crutcher M. D., DeLong M. R. Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. Prog Brain Res. 1990;85:119–146. [PubMed] [Google Scholar]
  3. Alexander G. E., Crutcher M. D. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 1990 Jul;13(7):266–271. doi: 10.1016/0166-2236(90)90107-l. [DOI] [PubMed] [Google Scholar]
  4. Bejjani B. P., Damier P., Arnulf I., Papadopoulos S., Bonnet A. M., Vidailhet M., Agid Y., Pidoux B., Cornu P., Dormont D. Deep brain stimulation in Parkinson's disease: opposite effects of stimulation in the pallidum. Mov Disord. 1998 Nov;13(6):969–970. doi: 10.1002/mds.870130618. [DOI] [PubMed] [Google Scholar]
  5. Berardelli A., Rothwell J. C., Hallett M., Thompson P. D., Manfredi M., Marsden C. D. The pathophysiology of primary dystonia. Brain. 1998 Jul;121(Pt 7):1195–1212. doi: 10.1093/brain/121.7.1195. [DOI] [PubMed] [Google Scholar]
  6. Bonelli Raphael M., Niederwieser Gerald, Diez Josef, Gruber Andreas, Költringer Peter. Pramipexole ameliorates neurologic and psychiatric symptoms in a Westphal variant of Huntington's disease. Clin Neuropharmacol. 2002 Jan-Feb;25(1):58–60. doi: 10.1097/00002826-200201000-00011. [DOI] [PubMed] [Google Scholar]
  7. Bressman S. B. Dystonia. Curr Opin Neurol. 1998 Aug;11(4):363–372. doi: 10.1097/00019052-199808000-00013. [DOI] [PubMed] [Google Scholar]
  8. Brown J., Bullock D., Grossberg S. How the basal ganglia use parallel excitatory and inhibitory learning pathways to selectively respond to unexpected rewarding cues. J Neurosci. 1999 Dec 1;19(23):10502–10511. doi: 10.1523/JNEUROSCI.19-23-10502.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Byl N. N., Merzenich M. M., Jenkins W. M. A primate genesis model of focal dystonia and repetitive strain injury: I. Learning-induced dedifferentiation of the representation of the hand in the primary somatosensory cortex in adult monkeys. Neurology. 1996 Aug;47(2):508–520. doi: 10.1212/wnl.47.2.508. [DOI] [PubMed] [Google Scholar]
  10. Casey D. E. Dopamine D1 (SCH 23390) and D2 (haloperidol) antagonists in drug-naive monkeys. Psychopharmacology (Berl) 1992;107(1):18–22. doi: 10.1007/BF02244960. [DOI] [PubMed] [Google Scholar]
  11. DeLong M. R. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 1990 Jul;13(7):281–285. doi: 10.1016/0166-2236(90)90110-v. [DOI] [PubMed] [Google Scholar]
  12. Fahn S., Bressman S. B., Marsden C. D. Classification of dystonia. Adv Neurol. 1998;78:1–10. [PubMed] [Google Scholar]
  13. Gerfen C. R., Engber T. M., Mahan L. C., Susel Z., Chase T. N., Monsma F. J., Jr, Sibley D. R. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science. 1990 Dec 7;250(4986):1429–1432. doi: 10.1126/science.2147780. [DOI] [PubMed] [Google Scholar]
  14. Gerfen C. R. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. Annu Rev Neurosci. 1992;15:285–320. doi: 10.1146/annurev.ne.15.030192.001441. [DOI] [PubMed] [Google Scholar]
  15. Hallett M. Is dystonia a sensory disorder? Ann Neurol. 1995 Aug;38(2):139–140. doi: 10.1002/ana.410380203. [DOI] [PubMed] [Google Scholar]
  16. Hallett M. Physiology of basal ganglia disorders: an overview. Can J Neurol Sci. 1993 Aug;20(3):177–183. doi: 10.1017/s0317167100047909. [DOI] [PubMed] [Google Scholar]
  17. Hallett M. The neurophysiology of dystonia. Arch Neurol. 1998 May;55(5):601–603. doi: 10.1001/archneur.55.5.601. [DOI] [PubMed] [Google Scholar]
  18. Harwood G., Hierons R., Fletcher N. A., Marsden C. D. Lessons from a remarkable family with dopa-responsive dystonia. J Neurol Neurosurg Psychiatry. 1994 Apr;57(4):460–463. doi: 10.1136/jnnp.57.4.460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hikosaka O. Basal ganglia--possible role in motor coordination and learning. Curr Opin Neurobiol. 1991 Dec;1(4):638–643. doi: 10.1016/s0959-4388(05)80042-x. [DOI] [PubMed] [Google Scholar]
  20. Kistrup K., Gerlach J. Selective D1 and D2 receptor manipulation in Cebus monkeys: relevance for dystonia and dyskinesia in humans. Pharmacol Toxicol. 1987 Sep;61(3):157–161. doi: 10.1111/j.1600-0773.1987.tb01795.x. [DOI] [PubMed] [Google Scholar]
  21. Lenz F. A., Suarez J. I., Metman L. V., Reich S. G., Karp B. I., Hallett M., Rowland L. H., Dougherty P. M. Pallidal activity during dystonia: somatosensory reorganisation and changes with severity. J Neurol Neurosurg Psychiatry. 1998 Nov;65(5):767–770. doi: 10.1136/jnnp.65.5.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Low P. A., Allsop J. L., Halmagyi G. M. Huntington's chorea: the rigid form (Westphal variant) treated with levodopa. Med J Aust. 1974 Mar 16;1(11):393–394. doi: 10.5694/j.1326-5377.1974.tb47770.x. [DOI] [PubMed] [Google Scholar]
  23. Marsden C. D., Rothwell J. C. The physiology of idiopathic dystonia. Can J Neurol Sci. 1987 Aug;14(3 Suppl):521–527. doi: 10.1017/s031716710003804x. [DOI] [PubMed] [Google Scholar]
  24. Mink J. W. The basal ganglia: focused selection and inhibition of competing motor programs. Prog Neurobiol. 1996 Nov;50(4):381–425. doi: 10.1016/s0301-0082(96)00042-1. [DOI] [PubMed] [Google Scholar]
  25. Naumann M., Pirker W., Reiners K., Lange K. W., Becker G., Brücke T. Imaging the pre- and postsynaptic side of striatal dopaminergic synapses in idiopathic cervical dystonia: a SPECT study using [123I] epidepride and [123I] beta-CIT. Mov Disord. 1998 Mar;13(2):319–323. doi: 10.1002/mds.870130219. [DOI] [PubMed] [Google Scholar]
  26. Nishiyama N., Yukishita S., Hagiwara H., Kakimoto S., Nomura Y., Segawa M. Gene mutation in hereditary progressive dystonia with marked diurnal fluctuation (HPD), strictly defined dopa-responsive dystonia. Brain Dev. 2000 Sep;22 (Suppl 1):S102–S106. doi: 10.1016/s0387-7604(00)00152-2. [DOI] [PubMed] [Google Scholar]
  27. Olanow C. W., Brin M. F., Obeso J. A. The role of deep brain stimulation as a surgical treatment for Parkinson's disease. Neurology. 2000;55(12 Suppl 6):S60–S66. [PubMed] [Google Scholar]
  28. Parent A., Hazrati L. N. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Brain Res Rev. 1995 Jan;20(1):91–127. doi: 10.1016/0165-0173(94)00007-c. [DOI] [PubMed] [Google Scholar]
  29. Parent A., Hazrati L. N. Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain Res Rev. 1995 Jan;20(1):128–154. doi: 10.1016/0165-0173(94)00008-d. [DOI] [PubMed] [Google Scholar]
  30. Peacock L., Lublin H., Gerlach J. The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment. Eur J Pharmacol. 1990 Sep 4;186(1):49–59. doi: 10.1016/0014-2999(90)94059-7. [DOI] [PubMed] [Google Scholar]
  31. Perlmutter J. S., Tempel L. W., Black K. J., Parkinson D., Todd R. D. MPTP induces dystonia and parkinsonism. Clues to the pathophysiology of dystonia. Neurology. 1997 Nov;49(5):1432–1438. doi: 10.1212/wnl.49.5.1432. [DOI] [PubMed] [Google Scholar]
  32. Playford E. D., Fletcher N. A., Sawle G. V., Marsden C. D., Brooks D. J. Striatal [18F]dopa uptake in familial idiopathic dystonia. Brain. 1993 Oct;116(Pt 5):1191–1199. doi: 10.1093/brain/116.5.1191. [DOI] [PubMed] [Google Scholar]
  33. Sanger T. D., Merzenich M. M. Computational model of the role of sensory disorganization in focal task-specific dystonia. J Neurophysiol. 2000 Nov;84(5):2458–2464. doi: 10.1152/jn.2000.84.5.2458. [DOI] [PubMed] [Google Scholar]
  34. Sanger T. D. Probability density estimation for the interpretation of neural population codes. J Neurophysiol. 1996 Oct;76(4):2790–2793. doi: 10.1152/jn.1996.76.4.2790. [DOI] [PubMed] [Google Scholar]
  35. Sanger T. D., Tarsy D., Pascual-Leone A. Abnormalities of spatial and temporal sensory discrimination in writer's cramp. Mov Disord. 2001 Jan;16(1):94–99. doi: 10.1002/1531-8257(200101)16:1<94::aid-mds1020>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  36. Sanger Terence D., Pascual-Leone Alvaro, Tarsy Daniel, Schlaug Gottfried. Nonlinear sensory cortex response to simultaneous tactile stimuli in writer's cramp. Mov Disord. 2002 Jan;17(1):105–111. doi: 10.1002/mds.1237. [DOI] [PubMed] [Google Scholar]
  37. Segawa M., Hosaka A., Miyagawa F., Nomura Y., Imai H. Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol. 1976;14:215–233. [PubMed] [Google Scholar]
  38. Segawa M., Nishiyama N., Nomura Y. DOPA-responsive dystonic parkinsonism--pathophysiologic considerations. Adv Neurol. 1999;80:389–400. [PubMed] [Google Scholar]
  39. Stern E. A., Kincaid A. E., Wilson C. J. Spontaneous subthreshold membrane potential fluctuations and action potential variability of rat corticostriatal and striatal neurons in vivo. J Neurophysiol. 1997 Apr;77(4):1697–1715. doi: 10.1152/jn.1997.77.4.1697. [DOI] [PubMed] [Google Scholar]
  40. Todd R. D., Carl J., Harmon S., O'Malley K. L., Perlmutter J. S. Dynamic changes in striatal dopamine D2 and D3 receptor protein and mRNA in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) denervation in baboons. J Neurosci. 1996 Dec 1;16(23):7776–7782. doi: 10.1523/JNEUROSCI.16-23-07776.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vitek J. L., Chockkan V., Zhang J. Y., Kaneoke Y., Evatt M., DeLong M. R., Triche S., Mewes K., Hashimoto T., Bakay R. A. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol. 1999 Jul;46(1):22–35. doi: 10.1002/1531-8249(199907)46:1<22::aid-ana6>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  42. Vitek J. L., Giroux M. Physiology of hypokinetic and hyperkinetic movement disorders: model for dyskinesia. Ann Neurol. 2000 Apr;47(4 Suppl 1):S131–S140. [PubMed] [Google Scholar]
  43. Wichmann T., DeLong M. R. Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg Clin N Am. 1998 Apr;9(2):223–236. [PubMed] [Google Scholar]
  44. Wilson C. J., Groves P. M. Spontaneous firing patterns of identified spiny neurons in the rat neostriatum. Brain Res. 1981 Sep 7;220(1):67–80. doi: 10.1016/0006-8993(81)90211-0. [DOI] [PubMed] [Google Scholar]
  45. Wilson C. J., Kawaguchi Y. The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons. J Neurosci. 1996 Apr 1;16(7):2397–2410. doi: 10.1523/JNEUROSCI.16-07-02397.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wilson C. J. The generation of natural firing patterns in neostriatal neurons. Prog Brain Res. 1993;99:277–297. doi: 10.1016/s0079-6123(08)61352-7. [DOI] [PubMed] [Google Scholar]

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