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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2004 Jun;75(6):840–846. doi: 10.1136/jnnp.2003.016782

Altered cerebellar functional connectivity mediates potential adaptive plasticity in patients with multiple sclerosis

S Saini 1, N DeStefano 1, S Smith 1, L Guidi 1, M Amato 1, A Federico 1, P Matthews 1
PMCID: PMC1739042  PMID: 15145996

Abstract

Background: The cerebellum is of potential interest for understanding adaptive responses in motor control in patients with multiple sclerosis because of the high intrinsic synaptic plasticity of this brain region.

Objective: To assess the relative roles of interactions between the neocortex and the cerebellum using measures of functional connectivity.

Methods: A role for altered neocortical–cerebellar functional connectivity in adaptive responses to injury from multiple sclerosis was tested using 1.5 T functional magnetic resonance imaging (fMRI) during figure writing with the dominant right hand in patients with predominantly early relapsing-remitting multiple sclerosis.

Results: Patients (n = 14) showed a more bihemispheric pattern of activation in motor cortex than healthy controls (n = 11). Correlations between task related signal changes in neocortical and cerebellar regions of interest were used as a measure of functional connectivity. Healthy controls showed strong functional connectivity between the left motor cortex and the right cerebellar dentate nucleus. Significant connectivity between the left primary motor cortex and the right dentate was not found in patients. However, patients had significant connectivity between the left premotor neocortex and the ipsilateral (left) cerebellar cortex (crus I), which was not found in healthy controls.

Conclusions: Changes in apparent cerebellar–neocortical functional connectivity may mediate potentially adaptive changes in brain motor control in patients with multiple sclerosis. Similar changes in the cerebellum and premotor cortex have been reported in the healthy brain during motor learning, suggesting that common mechanisms may contribute to normal motor learning and motor recovery after injury from multiple sclerosis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adcock J. E., Wise R. G., Oxbury J. M., Oxbury S. M., Matthews P. M. Quantitative fMRI assessment of the differences in lateralization of language-related brain activation in patients with temporal lobe epilepsy. Neuroimage. 2003 Feb;18(2):423–438. doi: 10.1016/s1053-8119(02)00013-7. [DOI] [PubMed] [Google Scholar]
  2. Anderson B. J., Alcantara A. A., Greenough W. T. Motor-skill learning: changes in synaptic organization of the rat cerebellar cortex. Neurobiol Learn Mem. 1996 Sep;66(2):221–229. doi: 10.1006/nlme.1996.0062. [DOI] [PubMed] [Google Scholar]
  3. Bjartmar C., Wujek J. R., Trapp B. D. Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci. 2003 Feb 15;206(2):165–171. doi: 10.1016/s0022-510x(02)00069-2. [DOI] [PubMed] [Google Scholar]
  4. Brodal P., Bjaalie J. G. Salient anatomic features of the cortico-ponto-cerebellar pathway. Prog Brain Res. 1997;114:227–249. doi: 10.1016/s0079-6123(08)63367-1. [DOI] [PubMed] [Google Scholar]
  5. Brodal P. Principles of organization of the corticopontocerebellar projection to crus II in the cat with particular reference to the parietal cortical areas. Neuroscience. 1983 Nov;10(3):621–638. doi: 10.1016/0306-4522(83)90207-5. [DOI] [PubMed] [Google Scholar]
  6. Cohen M. S., DuBois R. M. Stability, repeatability, and the expression of signal magnitude in functional magnetic resonance imaging. J Magn Reson Imaging. 1999 Jul;10(1):33–40. doi: 10.1002/(sici)1522-2586(199907)10:1<33::aid-jmri5>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  7. Cramer S. C., Nelles G., Benson R. R., Kaplan J. D., Parker R. A., Kwong K. K., Kennedy D. N., Finklestein S. P., Rosen B. R. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke. 1997 Dec;28(12):2518–2527. doi: 10.1161/01.str.28.12.2518. [DOI] [PubMed] [Google Scholar]
  8. Di Piero V., Chollet F., Dolan R. J., Thomas D. J., Frackowiak R. The functional nature of cerebellar diaschisis. Stroke. 1990 Sep;21(9):1365–1369. doi: 10.1161/01.str.21.9.1365. [DOI] [PubMed] [Google Scholar]
  9. Dijkhuizen Rick M., Singhal Aneesh B., Mandeville Joseph B., Wu Ona, Halpern Elkan F., Finklestein Seth P., Rosen Bruce R., Lo Eng H. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study. J Neurosci. 2003 Jan 15;23(2):510–517. doi: 10.1523/JNEUROSCI.23-02-00510.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Doyon Julien, Song Allen W., Karni Avi, Lalonde Francois, Adams Michelle M., Ungerleider Leslie G. Experience-dependent changes in cerebellar contributions to motor sequence learning. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):1017–1022. doi: 10.1073/pnas.022615199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Horwitz B., Rumsey J. M., Donohue B. C. Functional connectivity of the angular gyrus in normal reading and dyslexia. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8939–8944. doi: 10.1073/pnas.95.15.8939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ito M. Synaptic plasticity in the cerebellar cortex and its role in motor learning. Can J Neurol Sci. 1993 May;20 (Suppl 3):S70–S74. [PubMed] [Google Scholar]
  13. Jenkinson M., Smith S. A global optimisation method for robust affine registration of brain images. Med Image Anal. 2001 Jun;5(2):143–156. doi: 10.1016/s1361-8415(01)00036-6. [DOI] [PubMed] [Google Scholar]
  14. Johansen-Berg Heidi, Rushworth Matthew F. S., Bogdanovic Marko D., Kischka Udo, Wimalaratna Sunil, Matthews Paul M. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A. 2002 Oct 10;99(22):14518–14523. doi: 10.1073/pnas.222536799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kim J. J., Thompson R. F. Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning. Trends Neurosci. 1997 Apr;20(4):177–181. doi: 10.1016/s0166-2236(96)10081-3. [DOI] [PubMed] [Google Scholar]
  16. Kleim Jeffrey A., Freeman John H., Jr, Bruneau Rochelle, Nolan Brian C., Cooper Natalie R., Zook Alison, Walters Drew. Synapse formation is associated with memory storage in the cerebellum. Proc Natl Acad Sci U S A. 2002 Sep 16;99(20):13228–13231. doi: 10.1073/pnas.202483399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Koski L., Paus T. Functional connectivity of the anterior cingulate cortex within the human frontal lobe: a brain-mapping meta-analysis. Exp Brain Res. 2000 Jul;133(1):55–65. doi: 10.1007/s002210000400. [DOI] [PubMed] [Google Scholar]
  18. Krupa D. J., Thompson J. K., Thompson R. F. Localization of a memory trace in the mammalian brain. Science. 1993 May 14;260(5110):989–991. doi: 10.1126/science.8493536. [DOI] [PubMed] [Google Scholar]
  19. Lafleur Martin F., Jackson Philip L., Malouin Francine, Richards Carol L., Evans Alan C., Doyon Julien. Motor learning produces parallel dynamic functional changes during the execution and imagination of sequential foot movements. Neuroimage. 2002 May;16(1):142–157. doi: 10.1006/nimg.2001.1048. [DOI] [PubMed] [Google Scholar]
  20. Lee M., Reddy H., Johansen-Berg H., Pendlebury S., Jenkinson M., Smith S., Palace J., Matthews P. M. The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann Neurol. 2000 May;47(5):606–613. [PubMed] [Google Scholar]
  21. Marshall R. S., Perera G. M., Lazar R. M., Krakauer J. W., Constantine R. C., DeLaPaz R. L. Evolution of cortical activation during recovery from corticospinal tract infarction. Stroke. 2000 Mar;31(3):656–661. doi: 10.1161/01.str.31.3.656. [DOI] [PubMed] [Google Scholar]
  22. Matthews P. M., De Stefano N., Narayanan S., Francis G. S., Wolinsky J. S., Antel J. P., Arnold D. L. Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Semin Neurol. 1998;18(3):327–336. doi: 10.1055/s-2008-1040884. [DOI] [PubMed] [Google Scholar]
  23. Medana I. M., Esiri M. M. Axonal damage: a key predictor of outcome in human CNS diseases. Brain. 2003 Mar;126(Pt 3):515–530. doi: 10.1093/brain/awg061. [DOI] [PubMed] [Google Scholar]
  24. Meyer B. U., Röricht S., Machetanz J. Reduction of corticospinal excitability by magnetic stimulation over the cerebellum in patients with large defects of one cerebellar hemisphere. Electroencephalogr Clin Neurophysiol. 1994 Oct;93(5):372–379. doi: 10.1016/0168-5597(94)90125-2. [DOI] [PubMed] [Google Scholar]
  25. Narayanan S., Fu L., Pioro E., De Stefano N., Collins D. L., Francis G. S., Antel J. P., Matthews P. M., Arnold D. L. Imaging of axonal damage in multiple sclerosis: spatial distribution of magnetic resonance imaging lesions. Ann Neurol. 1997 Mar;41(3):385–391. doi: 10.1002/ana.410410314. [DOI] [PubMed] [Google Scholar]
  26. Pantano Patrizia, Iannetti Gian Domenico, Caramia Francesca, Mainero Caterina, Di Legge Silvia, Bozzao Luigi, Pozzilli Carlo, Lenzi Gian Luigi. Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain. 2002 Jul;125(Pt 7):1607–1615. doi: 10.1093/brain/awf164. [DOI] [PubMed] [Google Scholar]
  27. Pantano Patrizia, Mainero Caterina, Iannetti Gian Domenico, Caramia Francesca, Di Legge Silvia, Piattella Maria Cristina, Pozzilli Carlo, Bozzao Luigi, Lenzi Gian Luigi. Contribution of corticospinal tract damage to cortical motor reorganization after a single clinical attack of multiple sclerosis. Neuroimage. 2002 Dec;17(4):1837–1843. doi: 10.1006/nimg.2002.1313. [DOI] [PubMed] [Google Scholar]
  28. Pariente J., Loubinoux I., Carel C., Albucher J. F., Leger A., Manelfe C., Rascol O., Chollet F. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol. 2001 Dec;50(6):718–729. doi: 10.1002/ana.1257. [DOI] [PubMed] [Google Scholar]
  29. Reddy H., Lassonde M., Bemasconi N., Bemasconi A., Matthews P. M., Andermann F., Amold D. L. An fMRI study of the lateralization of motor cortex activation in acallosal patients. Neuroreport. 2000 Aug 3;11(11):2409–2413. doi: 10.1097/00001756-200008030-00014. [DOI] [PubMed] [Google Scholar]
  30. Reddy H., Matthews P. M., Lassonde M. Functional MRI cerebral activation and deactivation during finger movement. Neurology. 2000 Oct 24;55(8):1244–1244. doi: 10.1212/wnl.55.8.1244. [DOI] [PubMed] [Google Scholar]
  31. Reddy H., Narayanan S., Arnoutelis R., Jenkinson M., Antel J., Matthews P. M., Arnold D. L. Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain. 2000 Nov;123(Pt 11):2314–2320. doi: 10.1093/brain/123.11.2314. [DOI] [PubMed] [Google Scholar]
  32. Reddy H., Narayanan S., Matthews P. M., Hoge R. D., Pike G. B., Duquette P., Antel J., Arnold D. L. Relating axonal injury to functional recovery in MS. Neurology. 2000 Jan 11;54(1):236–239. doi: 10.1212/wnl.54.1.236. [DOI] [PubMed] [Google Scholar]
  33. Riahi F., Zijdenbos A., Narayanan S., Arnold D., Francis G., Antel J., Evans A. C. Improved correlation between scores on the expanded disability status scale and cerebral lesion load in relapsing-remitting multiple sclerosis. Results of the application of new imaging methods. Brain. 1998 Jul;121(Pt 7):1305–1312. doi: 10.1093/brain/121.7.1305. [DOI] [PubMed] [Google Scholar]
  34. Rocca M. A., Matthews P. M., Caputo D., Ghezzi A., Falini A., Scotti G., Comi G., Filippi M. Evidence for widespread movement-associated functional MRI changes in patients with PPMS. Neurology. 2002 Mar 26;58(6):866–872. doi: 10.1212/wnl.58.6.866. [DOI] [PubMed] [Google Scholar]
  35. Rocca Maria A., Falini Andrea, Colombo Bruno, Scotti Giuseppe, Comi Giancarlo, Filippi Massimo. Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage. Ann Neurol. 2002 Mar;51(3):330–339. doi: 10.1002/ana.10120. [DOI] [PubMed] [Google Scholar]
  36. Rouiller E. M., Liang F., Babalian A., Moret V., Wiesendanger M. Cerebellothalamocortical and pallidothalamocortical projections to the primary and supplementary motor cortical areas: a multiple tracing study in macaque monkeys. J Comp Neurol. 1994 Jul 8;345(2):185–213. doi: 10.1002/cne.903450204. [DOI] [PubMed] [Google Scholar]
  37. Schmahmann J. D. An emerging concept. The cerebellar contribution to higher function. Arch Neurol. 1991 Nov;48(11):1178–1187. doi: 10.1001/archneur.1991.00530230086029. [DOI] [PubMed] [Google Scholar]
  38. Seitz R. J., Höflich P., Binkofski F., Tellmann L., Herzog H., Freund H. J. Role of the premotor cortex in recovery from middle cerebral artery infarction. Arch Neurol. 1998 Aug;55(8):1081–1088. doi: 10.1001/archneur.55.8.1081. [DOI] [PubMed] [Google Scholar]
  39. Small S. L., Hlustik P., Noll D. C., Genovese C., Solodkin A. Cerebellar hemispheric activation ipsilateral to the paretic hand correlates with functional recovery after stroke. Brain. 2002 Jul;125(Pt 7):1544–1557. doi: 10.1093/brain/awf148. [DOI] [PubMed] [Google Scholar]
  40. Smith Stephen M., Zhang Yongyue, Jenkinson Mark, Chen Jacqueline, Matthews P. M., Federico Antonio, De Stefano Nicola. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage. 2002 Sep;17(1):479–489. doi: 10.1006/nimg.2002.1040. [DOI] [PubMed] [Google Scholar]
  41. Ungerleider Leslie G., Doyon Julien, Karni Avi. Imaging brain plasticity during motor skill learning. Neurobiol Learn Mem. 2002 Nov;78(3):553–564. doi: 10.1006/nlme.2002.4091. [DOI] [PubMed] [Google Scholar]
  42. Voogd J., Glickstein M. The anatomy of the cerebellum. Trends Neurosci. 1998 Sep;21(9):370–375. doi: 10.1016/s0166-2236(98)01318-6. [DOI] [PubMed] [Google Scholar]
  43. Weiller C., Ramsay S. C., Wise R. J., Friston K. J., Frackowiak R. S. Individual patterns of functional reorganization in the human cerebral cortex after capsular infarction. Ann Neurol. 1993 Feb;33(2):181–189. doi: 10.1002/ana.410330208. [DOI] [PubMed] [Google Scholar]
  44. Woolrich M. W., Ripley B. D., Brady M., Smith S. M. Temporal autocorrelation in univariate linear modeling of FMRI data. Neuroimage. 2001 Dec;14(6):1370–1386. doi: 10.1006/nimg.2001.0931. [DOI] [PubMed] [Google Scholar]

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