Subcortical reorganization in amyotrophic lateral sclerosis

  • C. Konrad
  • A. Jansen
  • H. Henningsen
  • J. Sommer
  • P.   A. Turski
  • B. R. Brooks
  • S. Knecht
Research Article


The cerebral cortex reorganizes in response to central or peripheral lesions. Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a—albeit finally ineffective—mechanism to compensate for the ongoing loss of motor neurons in ALS.


Amyotrophic lateral sclerosis Basal ganglia Cerebellum Magnetic resonance imaging Neuronal plasticity 



This work was supported by the NRW-Nachwuchsgruppe Kn2000 of the Nordrhein-Westfalen Ministry of Education and Research (Fö.1KS9604/0), the Interdisciplinary Center of Clinical Research Münster (IZKF Projects FG2, Kne3/074/04, FG4), the Innovative Medizinische Forschung Münster (KN520301), the Deutsche Forschungsgemeinschaft (Kn 285/6-1 and 6-3), the Amyotrophic Lateral Sclerosis Association, and the Muscular Dystrophy Association—ALS Division.


  1. Alexander GE, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266–271CrossRefPubMedGoogle Scholar
  2. 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
  3. Blakemore SJ, Frith CD, Wolpert DM (2001) The cerebellum is involved in predicting the sensory consequences of action. Neuroreport 12:1879–1884CrossRefPubMedGoogle Scholar
  4. Brooks BR (1994) El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 124(Suppl):96–107CrossRefPubMedGoogle Scholar
  5. Brooks BR, Bushara K, Khan A, Hershberger J, Wheat JO, Belden D, Henningsen H (2000) Functional magnetic resonance imaging (fMRI) clinical studies in ALS–paradigms, problems and promises. Amyotroph Lateral Scler Other Motor Neuron Disord 1(Suppl 2):S23–32CrossRefPubMedGoogle Scholar
  6. Bruehlmeier M, Dietz V, Leenders KL, Roelcke U, Missimer J, Curt A (1998) How does the human brain deal with a spinal cord injury? Eur J Neurosci 10:3918–3922CrossRefPubMedGoogle Scholar
  7. Byrnes ML, Thickbroom GW, Phillips BA, Mastaglia FL (2001) Long-term changes in motor cortical organisation after recovery from subcortical stroke. Brain Res 889(1–2):278–287CrossRefPubMedGoogle Scholar
  8. Cao Y, D’Olhaberriague L, Vikingstad EM, Levine SR, Welch KM (1998) Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis. Stroke 29:112–122PubMedGoogle Scholar
  9. Carpentier AC, Constable RT, Schlosser MJ, de Lotbiniere A, Piepmeier JM, Spencer DD, Awad IA (2001) Patterns of functional magnetic resonance imaging activation in association with structural lesions in the rolandic region: a classification system. J Neurosurg 94:946–954PubMedCrossRefGoogle Scholar
  10. Chapman LJ, Chapman JP (1987) The measurement of handedness. Brain Cogn 6:175–183CrossRefPubMedGoogle Scholar
  11. Chollet F, DiPiero V, Wise RJ, Brooks DJ, Dolan RJ, Frackowiak RS (1991) The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 29:63–71CrossRefPubMedGoogle Scholar
  12. Dettmers C, Connelly A, Stephan KM, Turner R, Friston KJ, Frackowiak RS, Gadian DG (1996) Quantitative comparison of functional magnetic resonance imaging with positron emission tomography using a force-related paradigm. Neuroimage 4:201–209CrossRefPubMedGoogle Scholar
  13. Doyon J, Benali H (2005) Reorganization and plasticity in the adult brain during learning of motor skills. Curr Opin Neurobiol 15:161–167CrossRefPubMedGoogle Scholar
  14. Doyon J, Penhune V, Ungerleider LG (2003) Distinct contribution of the cortico-striatal and cortico-cerebellar systems to motor skill learning. Neuropsychologia 41:252–262CrossRefPubMedGoogle Scholar
  15. Flament D, Ellermann JM, Kim SG, Ugurbil K, Ebner TJ (1996) Functional magnetic resonance imaging of cerebellar activation during the learning of a visuomotor dissociation task. Hum Brain Mapp 4:210–226CrossRefGoogle Scholar
  16. Friston KJ, Holmes AP, Price CJ, Buchel C, Worsley KJ (1999a) Multisubject fMRI studies and conjunction analyses. Neuroimage 10:385–396CrossRefGoogle Scholar
  17. Friston KJ, Holmes AP, Worsley KJ (1999b) How many subjects constitute a study? Neuroimage 10:1–5CrossRefGoogle Scholar
  18. Gandevia SC, McCloskey DI (1977) Sensations of heaviness. Brain 100:345–354PubMedCrossRefGoogle Scholar
  19. Graybiel AM (2000) The basal ganglia. Curr Biol 10:R509–R511CrossRefPubMedGoogle Scholar
  20. Hammer RP Jr, Tomiyasu U, Scheibel AB (1979) Degeneration of the human Betz cell due to amyotrophic lateral sclerosis. Exp Neurol 63:336–346CrossRefPubMedGoogle Scholar
  21. Henningsen H, Knecht S, Deppe M, Bremer J, Mock B, Konrad C, Kolan M, Wheat J, Edgar T, Sorenson JA, Turski P, Brooks BR (1998) Common recruitment pattern of associative motor areas in patients with degeneration of cortical pyramidal cells, as measured by fMRI. Neuroimage 7:S1001Google Scholar
  22. Hudson AJ, Kiernan JA, Munoz DG, Pringle CE, Brown WF, Ebers GC (1993) Clinicopathological features of primary lateral sclerosis are different from amyotrophic lateral sclerosis. Brain Res Bull 30:359–364CrossRefPubMedGoogle Scholar
  23. Jenkins IH, Brooks DJ, Nixon PD, Frackowiak RS, Passingham RE (1994) Motor sequence learning: a study with positron emission tomography. J Neurosci 14:3775–3790PubMedGoogle Scholar
  24. Jueptner M, Frith CD, Brooks DJ, Frackowiak RS, Passingham RE (1997a) Anatomy of motor learning. II. Subcortical structures and learning by trial and error. J Neurophysiol 77:1325–1337Google Scholar
  25. Jueptner M, Stephan KM, Frith CD, Brooks DJ, Frackowiak RS, Passingham RE (1997b) Anatomy of motor learning. I. Frontal cortex and attention to action. J Neurophysiol 77:1313–1324Google Scholar
  26. Kew JJ, Leigh PN, Playford ED, Passingham RE, Goldstein LH, Frackowiak RS, Brooks DJ (1993) Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study. Brain 116:655–680PubMedCrossRefGoogle Scholar
  27. Kew JJ, Brooks DJ, Passingham RE, Rothwell JC, Frackowiak RS, Leigh PN (1994) Cortical function in progressive lower motor neuron disorders and amyotrophic lateral sclerosis: a comparative PET study. Neurology 44:1101–1110PubMedGoogle Scholar
  28. Kiernan JA, Hudson AJ (1991) Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis. Brain 114:843–853PubMedCrossRefGoogle Scholar
  29. Kilgard MP, Merzenich MM (1998) Cortical map reorganization enabled by nucleus basalis activity. Science 279:1714–1718CrossRefPubMedGoogle Scholar
  30. Konrad C, Henningsen H, Bremer J, Mock B, Deppe M, Buchinger C, Turski P, Knecht S, Brooks BR (2002) Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Exp Brain Res 143:51–56CrossRefPubMedGoogle Scholar
  31. Konrad C, Henningsen H, Jansen A, Knecht S (2005) Comparing brain activation across groups with different motor abilities. J Neurol: DOI: 10.1007/s00415-005-0973-yGoogle Scholar
  32. Krings T, Topper R, Willmes K, Reinges MH, Gilsbach JM, Thron A (2002) Activation in primary and secondary motor areas in patients with CNS neoplasms and weakness. Neurology 58:381–390PubMedGoogle Scholar
  33. Lawyer T, Netsky MG (1953) Amyotrophic lateral sclerosis. A clinicoanatomical study of fifty-three cases. AMA Arch Neurol Psychiatry 69:171–192PubMedGoogle Scholar
  34. Liepert J, Hamzei F, Weiller C (2000) Motor cortex disinhibition of the unaffected hemisphere after acute stroke. Muscle Nerve 23:1761–1763CrossRefPubMedGoogle Scholar
  35. Liepert J, Dettmers C, Terborg C, Weiller C (2001) Inhibition of ipsilateral motor cortex during phasic generation of low force. Clin Neurophysiol 112:114–121CrossRefPubMedGoogle Scholar
  36. Liepert J, Hamzei F, Weiller C (2004) Lesion-induced and training-induced brain reorganization. Restor Neurol Neurosci 22:269–277PubMedGoogle Scholar
  37. Middleton FA, Strick PL (1997) New concepts about the organization of basal ganglia output. Adv Neurol 74:57–68PubMedGoogle Scholar
  38. Middleton FA, Strick PL (2000) Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev 31:236–250CrossRefPubMedGoogle Scholar
  39. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113CrossRefPubMedGoogle Scholar
  40. Pascual-Leone A, Peris M, Tormos JM, Pascual AP, Catala MD (1996) Reorganization of human cortical motor output maps following traumatic forearm amputation. Neuroreport 7:2068–2070PubMedCrossRefGoogle Scholar
  41. Perkel DJ, Farries MA (2000) Complementary ‘bottom-up’ and ‘top-down’ approaches to basal ganglia function. Curr Opin Neurobiol 10:725–731CrossRefPubMedGoogle Scholar
  42. Pioro EP, Antel JP, Cashman NR, Arnold DL (1994) Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology 44:1933–1938PubMedGoogle Scholar
  43. Price CJ, Friston KJ (1999) Scanning patients with tasks they can perform. Hum Brain Mapp 8:102–108CrossRefPubMedGoogle Scholar
  44. Roricht S, Machetanz J, Irlbacher K, Niehaus L, Biemer E, Meyer BU (2001) Reorganization of human motor cortex after hand replantation. Ann Neurol 50:240–249CrossRefPubMedGoogle Scholar
  45. Sanes JN, Donoghue JP (2000) Plasticity and primary motor cortex. Annu Rev Neurosci 23:393–415CrossRefPubMedGoogle Scholar
  46. Schoenfeld MA, Tempelmann C, Gaul C, Kuhnel GR, Duzel E, Hopf JM, Feistner H, Zierz S, Heinze HJ, Vielhaber S (2005) Functional motor compensation in amyotrophic lateral sclerosis. J Neurol 252(8):944–952CrossRefPubMedGoogle Scholar
  47. Scholz VH, Flaherty AW, Kraft E, Keltner JR, Kwong KK, Chen YI, Rosen BR, Jenkins BG (2000) Laterality, somatotopy and reproducibility of the basal ganglia and motor cortex during motor tasks. Brain Res 879:204–215CrossRefPubMedGoogle Scholar
  48. Small SL, Hlustik P, Noll DC, Genovese C, Solodkin A (2002) Cerebellar hemispheric activation ipsilateral to the paretic hand correlates with functional recovery after stroke. Brain 125:1544–1557CrossRefPubMedGoogle Scholar
  49. Thach WT, Goodkin HP, Keating JG (1992) The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 15:11–1978–1911.1988CrossRefGoogle Scholar
  50. Toni I, Krams M, Turner R, Passingham RE (1998) The time course of changes during motor sequence learning: a whole-brain fMRI study. Neuroimage 8:50–61CrossRefPubMedGoogle Scholar
  51. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15:273–289CrossRefPubMedGoogle Scholar
  52. van Mier H, Tempel LW, Perlmutter JS, Raichle ME, Petersen SE (1998) Changes in brain activity during motor learning measured with PET: effects of hand of performance and practice. J Neurophysiol 80:2177–2199PubMedGoogle Scholar
  53. Wall JT, Xu J, Wang X (2002) Human brain plasticity: an emerging view of the multiple substrates and mechanisms that cause cortical changes and related sensory dysfunctions after injuries of sensory inputs from the body. Brain Res Brain Res Rev 39:181–215CrossRefPubMedGoogle Scholar
  54. Ward NS (2004) Functional reorganization of the cerebral motor system after stroke. Curr Opin Neurol 17:725–730CrossRefPubMedGoogle Scholar
  55. Ward NS, Brown MM, Thompson AJ, Frackowiak RS (2003a) Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 126:2476–2496CrossRefGoogle Scholar
  56. Ward NS, Brown MM, Thompson AJ, Frackowiak RS (2003b) Neural correlates of outcome after stroke: a cross-sectional fMRI study. Brain 126:1430–1448CrossRefGoogle Scholar
  57. Weder B, Seitz RJ (1994) Deficient cerebral activation pattern in stroke recovery. Neuroreport 5:457–460PubMedCrossRefGoogle Scholar
  58. Weiller C (1998) Imaging recovery from stroke. Exp Brain Res 123:13–17CrossRefPubMedGoogle Scholar
  59. Weiller C, Chollet F, Friston KJ, Wise RJ, Frackowiak RS (1992) Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann Neurol 31:463–472CrossRefPubMedGoogle Scholar
  60. Weiller C, Ramsay SC, Wise RJ, Friston KJ, Frackowiak RS (1993) Individual patterns of functional reorganization in the human cerebral cortex after capsular infarction. Ann Neurol 33:181–189CrossRefPubMedGoogle Scholar
  61. Wexler BE, Fulbright RK, Lacadie CM, Skudlarski P, Kelz MB, Constable RT, Gore JC (1997) An fMRI study of the human cortical motor system response to increasing functional demands. Magn Reson Imaging 15:385–396CrossRefPubMedGoogle Scholar
  62. Wiesendanger M, Rouiller EM, Kazennikov O, Perrig S (1996) Is the supplementary motor area a bilaterally organized system? In: Luders HO (ed) Supplementary sensorimotor area. Lippincott-Raven, Philadelphia, pp 85–94Google Scholar
  63. Wunderlich G, Knorr U, Herzog H, Kiwit JC, Freund HJ, Seitz RJ (1998) Precentral glioma location determines the displacement of cortical hand representation. Neurosurgery 42:18–26CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • C. Konrad
    • 1
  • A. Jansen
    • 2
  • H. Henningsen
    • 3
  • J. Sommer
    • 2
  • P.   A. Turski
    • 4
  • B. R. Brooks
    • 5
  • S. Knecht
    • 2
  1. 1.Department of Psychiatry and Psychotherapy, IZKFUniversity of MuensterMuensterGermany
  2. 2.Department of Neurology, IZKFUniversity of MuensterMuensterGermany
  3. 3.Department of NeurologyKlinikum LueneburgLueneburgGermany
  4. 4.Department of RadiologyUniversity of Wisconsin-MadisonMadisonUSA
  5. 5.Department of NeurologyUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations