Experimental Brain Research

, Volume 187, Issue 1, pp 25–31

Impairment of movement-associated brain deactivation in multiple sclerosis: further evidence for a functional pathology of interhemispheric neuronal inhibition

  • S. C. Manson
  • C. Wegner
  • M. Filippi
  • F. Barkhof
  • C. Beckmann
  • O. Ciccarelli
  • N. De Stefano
  • Christian Enzinger
  • F. Fazekas
  • F. Agosta
  • A. Gass
  • J. Hirsch
  • H. Johansen-Berg
  • L. Kappos
  • T. Korteweg
  • C. Polman
  • L. Mancini
  • F. Manfredonia
  • S. Marino
  • D. H. Miller
  • X. Montalban
  • J. Palace
  • M. Rocca
  • S. Ropele
  • A. Rovira
  • S. Smith
  • A. Thompson
  • J. Thornton
  • T. Yousry
  • J. A. Frank
  • P. M. Matthews
Research Article

Abstract

Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.

Keywords

fMRI Multiple sclerosis Movement Inhibitory neurotransmission 

Abbreviations

EDSS

Extended Disability Status Score

EPI

Echoplanar image

fMRI

Functional MRI

MNI

Montreal Neurological Institute

PMd

Dorsal premotor cortex

ROI

Region of interest

References

  1. Allison JD, Meador KJ, Loring DW, Figueroa RE, Wright JC (2000) Functional MRI cerebral activation and deactivation during finger movement. Neurology 54:135–142PubMedGoogle Scholar
  2. Amunts K, Janke L, Mohlberg H, Steinmetz H, Zilles K (2000) Interhemispheric asymmetry of the human motor cortex related to handedness and gender. Neuropsychologia 38:304–312PubMedCrossRefGoogle Scholar
  3. Au Duong MV, Audoin B, Boulanouar K, Ibarrola D, Malikova I, Confort-Gouny S et al (2005) Altered functional connectivity related to white matter changes inside the working memory network at the very early stage of MS. J Cereb Blood Flow Metab 25:1245–1253PubMedCrossRefGoogle Scholar
  4. Audoin B, Ibarrola D, Ranjeva JP, Confort-Gouny S, Malikova I, Ali-Cherif A et al (2003) Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of MS. Hum Brain Mapp 20:51–58PubMedCrossRefGoogle Scholar
  5. Beckmann CF, DeLuca M, Devlin JT, Smith SM (2005) Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci 360:1001–1013PubMedCrossRefGoogle Scholar
  6. Bell EC, Willson MC, Wilan AH, Dave S, Silverstone PH (2006) Males and females differ in brain activation during cognitive tasks. Neuroimage 30:529–538PubMedCrossRefGoogle Scholar
  7. Cader S, Cifelli A, Abu-Omar Y, Palace J, Matthews PM (2006) Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis. Brain 129:527–537PubMedCrossRefGoogle Scholar
  8. Cader S, Johansen-Berg H, Wylezinska M, Palace J, Behrens TE, Smith S, Matthews PM (2007) Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis. Neuroimage 36(1):19–27PubMedCrossRefGoogle Scholar
  9. De Luca M, Beckmann CF, De Stefano N, Matthews PM, Smith SM (2006) fMRI resting state networks define distinct modes of long-distance interactions in the human brain. Neuroimage 15(29):1359–1367Google Scholar
  10. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T et al (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489PubMedCrossRefGoogle Scholar
  11. Filippi M, Rocca MA, Falini A, Caputo D, Ghezzi A, Colombo B et al (2002) Correlations between structural CNS damage and functional MRI changes in primary progressive MS. Neuroimage 15:537–546PubMedCrossRefGoogle Scholar
  12. Filippi M, Rocca MA, Mezzapesa DM, Falini A, Colombo B, Scotti G et al (2004a) A functional MRI study of cortical activations associated with object manipulation in patients with MS. Neuroimage 21:1147–1154PubMedCrossRefGoogle Scholar
  13. Filippi M, Rocca MA, Mezzapesa DM, Ghezzi A, Falini A, Martinelli V et al (2004b) Simple and complex movement-associated functional MRI changes in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Hum Brain Mapp 21:108–117PubMedCrossRefGoogle Scholar
  14. Filippi M, Rocca MA (2005) MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system. J Neurol 252(Suppl 5):v16–v24PubMedCrossRefGoogle Scholar
  15. Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC (1995) Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 33:636–647PubMedCrossRefGoogle Scholar
  16. Greicius MD, Srivastava G, Reiss AL, Menon V (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA 101:4637–4642PubMedCrossRefGoogle Scholar
  17. Jenkinson M, Smith S (2001) A global optimisation method for robust affine registration of brain images. Med Image Anal 5:143–156PubMedCrossRefGoogle Scholar
  18. Jenkinson M, Bannister P, Brady M, Smith S (2002) Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17:825–841PubMedCrossRefGoogle Scholar
  19. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452PubMedGoogle Scholar
  20. Lee MA, Smith S, Palace J, Narayanan S, Silver N, Minicucci L, Filippi M, Miller DH, Arnold DL, Matthews PM (1999) Spatial mapping of T2 and gadolinium-enhancing T1 lesion volumes in multiple sclerosis: evidence for distinct mechanisms of lesion genesis? Brain 122(Pt 7):1261–1270PubMedCrossRefGoogle Scholar
  21. Lee M, Reddy H, Johansen-Berg H, Pendlebury S, Jenkinson M, Smith S et al (2000) The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann Neurol 47:606–613Google Scholar
  22. Lenzi D, Conte A, Mainero C, Fasca V, Fubelli F, Totaro P, Caramia F, Inghilleri M, Pozzilli C, Pantano P (2007) Effects of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: a functional and anatomical study. Hum Brain Mapp 28:636–644PubMedCrossRefGoogle Scholar
  23. Leocani L, Colombo B, Magnani G, Martinelli-Boneschi F, Cursi M, Rossi P et al (2001) Fatigue in multiple sclerosis is associated with abnormal cortical activation to voluntary movement—EEG evidence. Neuroimage 13:1186–1192PubMedCrossRefGoogle Scholar
  24. MacKiernan KA, Kaufman JN, Kucera-Thompson J, Binder JR (2003) A parametric manipulation of factors affecting task-induced deactivation in functional neuroimaging. J Cogn Neurosci 15:294–408CrossRefGoogle Scholar
  25. Manson SC, Palace J, Frank JA, Matthews PM (2006) Loss of interhemispheric inhibition in patients with multiple sclerosis is related to corpus callosum atrophy. Exp Brain Res 174:728–733PubMedCrossRefGoogle Scholar
  26. Mason MF, Norton MI, Van Horn JD, Wegner DM, Grafton ST, Macrae CN (2007) Wandering minds: the default network and stimulus-independent thought. Science 315(5810):393–395PubMedCrossRefGoogle Scholar
  27. Morgan K, Sammer G, Courtney SM, Wolters T, Melchior H, Blecker CR, Oschmann P, Kaps M, Vaitl D (2007) Distinct mechanisms of altered brain activation in patients with multiple sclerosis. Neuroimage 37:937–946CrossRefGoogle Scholar
  28. Pantano P, Iannetti GD, Caramia F, Mainero C, Di Legge S, Bozzao L et al (2002a) Cortical motor reorganization after a single clinical attack of multiple sclerosis. Brain 125:1607–1615PubMedCrossRefGoogle Scholar
  29. Pantano P, Mainero C, Iannetti GD, Caramia F, Di Legge S, Piattella MC et al (2002b) Contribution of corticospinal tract damage to cortical motor reorganization after a single clinical attack of multiple sclerosis. Neuroimage 17:1837–1843PubMedCrossRefGoogle Scholar
  30. Pantano P, Mainero C, Lenzi D, Caramia F, Iannetti GD, Piattella MC et al (2005) A longitudinal fMRI study on motor activity in patients with multiple sclerosis. Brain 128:2146–2153PubMedCrossRefGoogle Scholar
  31. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231PubMedCrossRefGoogle Scholar
  32. Raichle ME (1998) The neural correlates of consciousness: an analysis of cognitive skill learning. Philos Trans R Soc Lond B Biol Sci 353:1889–1901PubMedCrossRefGoogle Scholar
  33. Reddy H, Narayanan S, Arnoutelis R, Jenkinson M, Antel J, Matthews PM et al (2000a) Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 123(Pt 11):2314–2320PubMedCrossRefGoogle Scholar
  34. Reddy H, Narayanan S, Matthews PM, Hoge RD, Pike GB, Duquette P et al (2000b) Relating axonal injury to functional recovery in MS. Neurology 54:236–239PubMedGoogle Scholar
  35. Reddy H, Narayanan S, Woolrich M, Mitsumori T, Lapierre Y, Arnold DL et al (2002) Functional brain reorganization for hand movement in patients with multiple sclerosis: defining distinct effects of injury and disability. Brain 125:2646–2657PubMedCrossRefGoogle Scholar
  36. Rocca MA, Falini A, Colombo B, Scotti G, Comi G, Filippi M (2002a) Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage. Ann Neurol 51:330–339PubMedCrossRefGoogle Scholar
  37. Rocca MA, Matthews PM, Caputo D, Ghezzi A, Falini A, Scotti G et al (2002b) Evidence for widespread movement-associated functional MRI changes in patients with PPMS. Neurology 58:866–872PubMedGoogle Scholar
  38. Rocca MA, Gavazzi C, Mezzapesa DM, Falini A, Colombo B, Mascalchi M et al (2003a) A functional magnetic resonance imaging study of patients with secondary progressive multiple sclerosis. Neuroimage 19:1770–1777PubMedCrossRefGoogle Scholar
  39. Rocca MA, Mezzapesa DM, Falini A, Ghezzi A, Martinelli V, Scotti G et al (2003b) Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis. Neuroimage 18:847–855PubMedCrossRefGoogle Scholar
  40. Rocca MA, Gallo A, Colombo B, Falini A, Scotti G, Comi G et al (2004) Pyramidal tract lesions and movement-associated cortical recruitment in patients with MS. Neuroimage 23:141–147Google Scholar
  41. Rocca MA, Colombo B, Falini A, Ghezzi A, Martinelli V, Scotti G et al (2005) Cortical adaptation in patients with MS: a cross-sectional functional MRI study of disease phenotypes. Lancet Neurol 4:618–626PubMedCrossRefGoogle Scholar
  42. Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P (2005) Altered resting state networks in mild cognitive impairment and mild Alzheimer’s disease: an fMRI study. Hum Brain Mapp 26:231–239PubMedCrossRefGoogle Scholar
  43. Shmuel A, Augath M, Oeltermann A, Logothetis NK (2006) Negative functional MRI response correlates with decreases in neuronal activity in monkey visual area V1. Nat Neurosci 9(4):569–577PubMedCrossRefGoogle Scholar
  44. Stefanovic B, Warnking JM, Pike GB (2004) Hemodynamic and metabolic responses to neuronal inhibition. Neuroimage 22:771–778PubMedCrossRefGoogle Scholar
  45. Woolrich MW, Behrens TE, Beckmann CF, Jenkinson M, Smith SM (2004) Multilevel linear modelling for FMRI group analysis using Bayesian inference. Neuroimage 21:1732–1747PubMedCrossRefGoogle Scholar
  46. Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A et al (1997) Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 120(Pt 1):141–157PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • S. C. Manson
    • 1
    • 2
  • C. Wegner
    • 1
  • M. Filippi
    • 3
  • F. Barkhof
    • 4
  • C. Beckmann
    • 1
  • O. Ciccarelli
    • 5
  • N. De Stefano
    • 6
  • Christian Enzinger
    • 7
  • F. Fazekas
    • 7
  • F. Agosta
    • 3
  • A. Gass
    • 8
  • J. Hirsch
    • 8
  • H. Johansen-Berg
    • 1
  • L. Kappos
    • 8
  • T. Korteweg
    • 4
  • C. Polman
    • 4
  • L. Mancini
    • 5
    • 9
  • F. Manfredonia
    • 5
  • S. Marino
    • 6
  • D. H. Miller
    • 5
  • X. Montalban
    • 10
  • J. Palace
    • 1
  • M. Rocca
    • 3
  • S. Ropele
    • 7
  • A. Rovira
    • 10
  • S. Smith
    • 1
  • A. Thompson
    • 5
  • J. Thornton
    • 5
  • T. Yousry
    • 5
  • J. A. Frank
    • 2
  • P. M. Matthews
    • 1
    • 11
    • 12
  1. 1.Centre for Functional Magnetic Resonance Imaging of the BrainUniversity of OxfordOxfordUK
  2. 2.Experimental RadiologyNational Institutes of HealthBethesdaUSA
  3. 3.Neuroimaging Research Unit, Department of NeurologyScientific Institute and UniversityMilanItaly
  4. 4.Department of RadiologyVU University Medical CentreAmsterdamThe Netherlands
  5. 5.NMR Research Unit, Institute of NeurologyUniversity College LondonLondonUK
  6. 6.Department of Neurological and Behavioural SciencesUniversity of SienaSienaItaly
  7. 7.Department of NeurologyMedical University GrazGrazAustria
  8. 8.Department of NeurologyUniversity HospitalBaselSwitzerland
  9. 9.Department of Neuroradiology, National Hospital for Neurology and NeurosurgeryUCLH NHS Foundation TrustLondonUK
  10. 10.Department of Radiology, Magnetic Resonance UnitHospital Vall d’HebronBarcelonaSpain
  11. 11.Department of Clinical NeurosciencesImperial CollegeLondonUK
  12. 12.Clinical Imaging Centre, Clinical Pharmacology and Discovery MedicineGlaxoSmithKline, Hammersmith Hospital LondonUK

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