Journal of Neurology

, Volume 258, Issue 7, pp 1268–1280 | Cite as

Effects of rTMS on Parkinson’s disease: a longitudinal fMRI study

  • Nadia González-García
  • Jorge L. Armony
  • Julian Soto
  • David Trejo
  • Marco A. Alegría
  • René Drucker-ColínEmail author
Original Communication


Parkinson’s disease is a movement disorder whose principal symptoms are tremor, rigidity, bradykinesia and postural instability. Initially, drugs like l-dopa or dopaminergic agonists are able to control these symptoms, but with the progress of the disease these drugs become less effective. Previous studies have reported that repetitive transcranial magnetic stimulation (rTMS) can improve these motor symptoms. The objective of this study was to investigate the neural mechanisms through which 25 Hz rTMS may improve motor symptoms in Parkinson’s disease. In a double-blind placebo-controlled study, we evaluated the effects of 25 Hz. rTMS in 10 Parkinson’s disease patients. Fifteen rTMS sessions were performed over the primary cortex on both hemispheres (one after the other) during a 12-week period. The patients were studied using functional magnetic resonance imaging during performance of a simple tapping and a complex tapping task, 1 week before the administration of the first rTMS session and just after the last session. rTMS improved bradykinesia, while functional magnetic resonance imaging showed different cortical patterns in prefrontal cortex when patients performed the complex tapping test. Furthermore, the improvement in bradykinesia is associated with caudate nucleus activity increases in simple tapping. Finally, we observed a relative change in functional connectivity between the prefrontal areas and the supplementary motor area after rTMS. These results show a potential beneficial effect of repetitive transcranial magnetic stimulation on bradykinesia in Parkinson’s disease which is substantiated by neural changes observed in functional magnetic resonance imaging.


Trancranial magnetic stimulation Parkinson’s disease fMRI Caudate nucleus Supplementary motor area 



We thank Diana Millan-Aldaco, Marcela Palomero-Rivero and Francisco Pérez-Eugenio for their technical support and advice. This work was supported by a grant from IMPULSA 02-UNAM. Nadia González-García had a CONACYT (México) fellowship and additional support from the PhD Program of Biomedical Sciences, UNAM.

Conflict of interest



  1. 1.
    Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, Cornu P, Pidoux B, Samson Y, Agid Y (1999) Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 340:1476–1480PubMedCrossRefGoogle Scholar
  2. 2.
    Bergman H, Feingold A, Nini A, Raz A, Slovin H, Abeles M, Vaadia E (1998) Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates. Trends Neurosci 21:32–38PubMedCrossRefGoogle Scholar
  3. 3.
    Bestmann S, Baudewig J, Siebner HR, Rothwell JC, Frahm J (2003) Subthreshold high-frequency TMS of human primary motor cortex modulates interconnected frontal motor areas as detected by interleaved fMRI-TMS. Neuroimage 20:1685–1696PubMedCrossRefGoogle Scholar
  4. 4.
    Bohning DE, Shastri A, McConnell KA, Nahas Z, Lorberbaum JP, Roberts DR, Teneback C, Vincent DJ, George MS (1999) A combined TMS/fMRI study of intensity-dependent TMS over motor cortex. Biol Psychiatry 45:385–394PubMedCrossRefGoogle Scholar
  5. 5.
    Bohning DE, Shastri A, Nahas Z, Lorberbaum JP, Andersen SW, Dannels WR, Haxthausen EU, Vincent DJ, George MS (1998) Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation. Invest Radiol 33:336–340PubMedCrossRefGoogle Scholar
  6. 6.
    Boraud T, Bezard E, Guehl D, Bioulac B, Gross C (1998) Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey. Brain Res 787:157–160PubMedCrossRefGoogle Scholar
  7. 7.
    Brown P (2003) Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson’s disease. Mov Disord 18:357–363PubMedCrossRefGoogle Scholar
  8. 8.
    Buhmann C, Glauche V, Sturenburg HJ, Oechsner M, Weiller C, Buchel C (2003) Pharmacologically modulated Fmri-cortical responsiveness to levodopa in drug-naive hemiparkinsonian patients. Brain 126:451–461PubMedCrossRefGoogle Scholar
  9. 9.
    Carrillo-Reid L, Tecuapetla F, Tapia D, Hernandez-Cruz A, Galarraga E, Drucker-Colin R, Bargas J (2008) Encoding network states by striatal cell assemblies. J Neurophysiol 99:1435–1450PubMedCrossRefGoogle Scholar
  10. 10.
    Catalan MJ, Ishii K, Honda M, Samii A, Hallett M (1999) A PET study of sequential finger movements of varying length in patients with Parkinson’s disease. Brain 122(Pt 3):483–495PubMedCrossRefGoogle Scholar
  11. 11.
    Dejean C, Hyland B, Arbuthnott G (2009) Cortical effects of subthalamic stimulation correlate with behavioral recovery from dopamine antagonist induced akinesia. Cereb Cortex 19:1055–1063PubMedCrossRefGoogle Scholar
  12. 12.
    DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285PubMedCrossRefGoogle Scholar
  13. 13.
    Dressler D, Voth E, Feldmann M, Benecke R (1990) Safety aspects of transcranial brain stimulation in man tested by single photon emission-computed tomography. Neurosci Lett 119:153–155PubMedCrossRefGoogle Scholar
  14. 14.
    Eckert T, Peschel T, Heinze HJ, Rotte M (2006) Increased pre-SMA activation in early PD patients during simple self-initiated hand movements. J Neurol 253:199–207PubMedCrossRefGoogle Scholar
  15. 15.
    Evans MK, Collins D, McDonald D (1994) Magnetic resonance scanning and epilepsy Plenum, New YorkGoogle Scholar
  16. 16.
    Fahn S, Elton R, Members of the UPDRS Development Committee. The Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M (eds) (1987) Recent Developments in Parkinson’s DiseaseGoogle Scholar
  17. 17.
    Filion M, Tremblay L (1991) Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 547:142–151PubMedGoogle Scholar
  18. 18.
    Forstmann BU, Anwander A, Schafer A, Neumann J, Brown S, Wagenmakers EJ, Bogacz R, Turner R (2010) Cortico-striatal connections predict control over speed and accuracy in perceptual decision making. Proc Natl Acad Sci USA 107:15916–15920PubMedCrossRefGoogle Scholar
  19. 19.
    Forstmann BU, Dutilh G, Brown S, Neumann J, von Cramon DY, Ridderinkhof KR, Wagenmakers EJ (2008) Striatum and pre-SMA facilitate decision-making under time pressure. Proc Natl Acad Sci USA 105:17538–17542PubMedCrossRefGoogle Scholar
  20. 20.
    Fox P, Ingham R, George MS, Mayberg H, Ingham J, Roby J, Martin C, Jerabek P (1997) Imaging human intra-cerebral connectivity by PET during TMS. Neuroreport 8:2787–2791PubMedCrossRefGoogle Scholar
  21. 21.
    Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ (1997) Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 6:218–229PubMedCrossRefGoogle Scholar
  22. 22.
    Fukudome T, Goto H, Izumoto H, Matsuo H, Shibuya N (2002) The effects of repetitive transcranial magnetic stimulation (rTMS) in the patients with Parkinson’s disease. Rinsho Shinkeigaku 42:35–37PubMedGoogle Scholar
  23. 23.
    Ghabra MB, Hallett M, Wassermann EM (1999) Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology 52:768–770PubMedGoogle Scholar
  24. 24.
    Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752PubMedCrossRefGoogle Scholar
  25. 25.
    Goldberg JA, Boraud T, Maraton S, Haber SN, Vaadia E, Bergman H (2002) Enhanced synchrony among primary motor cortex neurons in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine primate model of Parkinson’s disease. J Neurosci 22:4639–4653PubMedGoogle Scholar
  26. 26.
    Haslinger B, Erhard P, Kampfe N, Boecker H, Rummeny E, Schwaiger M, Conrad B, Ceballos-Baumann AO (2001) Event-related functional magnetic resonance imaging in Parkinson’s disease before and after levodopa. Brain 124:558–570PubMedCrossRefGoogle Scholar
  27. 27.
    Hershey T, Revilla FJ, Wernle AR, McGee-Minnich L, Antenor JV, Videen TO, Dowling JL, Mink JW, Perlmutter JS (2003) Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD. Neurology 61:816–821PubMedGoogle Scholar
  28. 28.
    Houeto JL, Mesnage V, Mallet L, Pillon B, Gargiulo M, du Moncel ST, Bonnet AM, Pidoux B, Dormont D, Cornu P, Agid Y (2002) Behavioural disorders, Parkinson’s disease and subthalamic stimulation. J Neurol Neurosurg Psychiatry 72:701–707PubMedCrossRefGoogle Scholar
  29. 29.
    Ivanoff J, Branning P, Marois R (2008) fMRI evidence for a dual process account of the speed-accuracy tradeoff in decision-making. PLoS One 3:e2635PubMedCrossRefGoogle Scholar
  30. 30.
    Jahanshahi M, Jones CR, Zijlmans J, Katzenschlager R, Lee L, Quinn N, Frith CD, Lees AJ (2010) Dopaminergic modulation of striato-frontal connectivity during motor timing in Parkinson’s disease. Brain 133:727–745PubMedCrossRefGoogle Scholar
  31. 31.
    Jenkins IH, Fernandez W, Playford ED, Lees AJ, Frackowiak RS, Passingham RE, Brooks DJ (1992) Impaired activation of the supplementary motor area in Parkinson’s disease is reversed when akinesia is treated with apomorphine. Ann Neurol 32:749–757PubMedCrossRefGoogle Scholar
  32. 32.
    Jenkins IH, Jahanshahi M, Jueptner M, Passingham RE, Brooks DJ (2000) Self-initiated versus externally triggered movements. II. The effect of movement predictability on regional cerebral blood flow. Brain 123(Pt 6):1216–1228PubMedCrossRefGoogle Scholar
  33. 33.
    Karimi M, Golchin N, Tabbal SD, Hershey T, Videen TO, Wu J, Usche JW, Revilla FJ, Hartlein JM, Wernle AR, Mink JW, Perlmutter JS (2008) Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease. Brain 131:2710–2719PubMedCrossRefGoogle Scholar
  34. 34.
    Khedr EM, Rothwell JC, Shawky OA, Ahmed MA, Hamdy A (2006) Effect of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson’s disease. Mov Disord 21:2201–2205PubMedCrossRefGoogle Scholar
  35. 35.
    Knutson B, Gibbs SE (2007) Linking nucleus accumbens dopamine and blood oxygenation. Psychopharmacology (Berl) 191:813–822CrossRefGoogle Scholar
  36. 36.
    Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL (1995) Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345:91–95PubMedCrossRefGoogle Scholar
  37. 37.
    Lomarev MP, Kanchana S, Bara-Jimenez W, Iyer M, Wassermann EM, Hallett M (2006) Placebo-controlled study of rTMS for the treatment of Parkinson’s disease. Mov Disord 21:325–331PubMedCrossRefGoogle Scholar
  38. 38.
    Magill PJ, Bolam JP, Bevan MD (2001) Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus-globus pallidus network. Neuroscience 106:313–330PubMedCrossRefGoogle Scholar
  39. 39.
    Mally J, Farkas R, Tothfalusi L, Stone TW (2004) Long-term follow-up study with repetitive transcranial magnetic stimulation (rTMS) in Parkinson’s disease. Brain Res Bull 64:259–263PubMedCrossRefGoogle Scholar
  40. 40.
    Mally J, Stone TW (2007) New advances in the rehabilitation of CNS diseases applying rTMS. Expert Rev Neurother 7:165–177PubMedCrossRefGoogle Scholar
  41. 41.
    Mally J, Stone TW (1999) Therapeutic and “dose-dependent” effect of repetitive microelectroshock induced by transcranial magnetic stimulation in Parkinson’s disease. J Neurosci Res 57:935–940PubMedCrossRefGoogle Scholar
  42. 42.
    Marsden JF, Limousin-Dowsey P, Ashby P, Pollak P, Brown P (2001) Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson’s disease. Brain 124:378–388PubMedCrossRefGoogle Scholar
  43. 43.
    Martilla UKRaRJ (1977) Disability and progression in Parkinson’s disease. Acta Neurol Scand 56:159–169CrossRefGoogle Scholar
  44. 44.
    Miller EK (1999) The prefrontal cortex: complex neural properties for complex behavior. Neuron 22:15–17PubMedCrossRefGoogle Scholar
  45. 45.
    Okabe S, Hanajima R, Ohnishi T, Nishikawa M, Imabayashi E, Takano H, Kawachi T, Matsuda H, Shiio Y, Iwata NK, Furubayashi T, Terao Y, Ugawa Y (2003) Functional connectivity revealed by single-photon emission computed tomography (SPECT) during repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. Clin Neurophysiol 114:450–457PubMedCrossRefGoogle Scholar
  46. 46.
    Olanow CW, Watts RL, Koller WC (2001) An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology 56:S1–S88PubMedGoogle Scholar
  47. 47.
    Pascual-Leone A, Valls-Sole J, Brasil-Neto JP, Cammarota A, Grafman J, Hallett M (1994) Akinesia in Parkinson’s disease. II. Effects of subthreshold repetitive transcranial motor cortex stimulation. Neurology 44:892–898PubMedGoogle Scholar
  48. 48.
    Paus T, Jech R, Thompson CJ, Comeau R, Peters T, Evans AC (1997) Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex. J Neurosci 17:3178–3184PubMedGoogle Scholar
  49. 49.
    Rolls ET, Thorpe SJ, Maddison SP (1983) Responses of striatal neurons in the behaving monkey. 1. Head of the caudate nucleus. Behav Brain Res 7:179–210PubMedCrossRefGoogle Scholar
  50. 50.
    Rowe J, Stephan KE, Friston K, Frackowiak R, Lees A, Passingham R (2002) Attention to action in Parkinson’s disease: impaired effective connectivity among frontal cortical regions. Brain 125:276–289PubMedCrossRefGoogle Scholar
  51. 51.
    Sabatini U, Boulanouar K, Fabre N, Martin F, Carel C, Colonnese C, Bozzao L, Berry I, Montastruc JL, Chollet F, Rascol O (2000) Cortical motor reorganization in akinetic patients with Parkinson’s disease: a functional MRI study. Brain 123(Pt 2):394–403PubMedCrossRefGoogle Scholar
  52. 52.
    Samuel M, Ceballos-Baumann AO, Blin J, Uema T, Boecker H, Passingham RE, Brooks DJ (1997) Evidence for lateral premotor and parietal overactivity in Parkinson’s disease during sequential and bimanual movements. A PET study. Brain 120(6):963–976Google Scholar
  53. 53.
    Schrag A, Ben-Shlomo Y, Brown R, Marsden CD, Quinn N (1998) Young-onset Parkinson’s disease revisited–clinical features, natural history, and mortality. Mov Disord 13:885–894PubMedCrossRefGoogle Scholar
  54. 54.
    Shimamoto H, Morimitsu H, Sugita S, Nakahara K, Shigemori M (1999) Therapeutic effect of repetitive transcranial magnetic stimulation in Parkinson’s disease. Rinsho Shinkeigaku 39:1264–1267PubMedGoogle Scholar
  55. 55.
    Siebner HR (2000) Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology 54:272; author reply 273Google Scholar
  56. 56.
    Siebner HR, Rossmeier C, Mentschel C, Peinemann A, Conrad B (2000) Short-term motor improvement after sub-threshold 5-Hz repetitive transcranial magnetic stimulation of the primary motor hand area in Parkinson’s disease. J Neurol Sci 178:91–94PubMedCrossRefGoogle Scholar
  57. 57.
    Siebner HR, Willoch F, Peller M, Auer C, Boecker H, Conrad B, Bartenstein P (1998) Imaging brain activation induced by long trains of repetitive transcranial magnetic stimulation. Neuroreport 9:943–948PubMedCrossRefGoogle Scholar
  58. 58.
    Speer AM, Kimbrell TA, DR J, Wassermann EM, Willis MW, Herscovitch P, Post RM (2000) Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry 48:1133–1141PubMedCrossRefGoogle Scholar
  59. 59.
    Strafella AP, Ko JH, Monchi O (2006) Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: the contribution of expectation. Neuroimage 31:1666–1672Google Scholar
  60. 60.
    Strafella AP, Paus T, Barrett J, Dagher A (2001) Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci 21:RC157PubMedGoogle Scholar
  61. 61.
    Strafella AP, Paus T, Fraraccio M, Dagher A (2003) Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126:2609–2615PubMedCrossRefGoogle Scholar
  62. 62.
    Tergau F, Wanschura V, Canelo M, Wischer S, Wassermann EM, Ziemann U, Paulus W (1999) Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation. Exp Brain Res 124:447–454PubMedCrossRefGoogle Scholar
  63. 63.
    Tournoux Ta (1988) Stereotactic coplanar atlas of the human brain. Stuttgart, GermanyGoogle Scholar
  64. 64.
    Worsley KJ, Marrett S, Neelin P, Evans AC (1996) Searching scale space for activation in PET images. Hum Brain Mapp 4:74–90PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Nadia González-García
    • 1
  • Jorge L. Armony
    • 2
  • Julian Soto
    • 3
  • David Trejo
    • 3
  • Marco A. Alegría
    • 4
  • René Drucker-Colín
    • 1
    Email author
  1. 1.Depto. de Neuropatología Molecular, Instituto de Fisiología CelularUniversidad Nacional Autónoma de MéxicoMexico, D.F.Mexico
  2. 2.Douglas Institute and Dept. of PsychiatryMcGill UniversityMontrealCanada
  3. 3.Hospital General de MéxicoMexicoMexico
  4. 4.Centro Neurológico ABC Santa FeMexico, D.F.Mexico

Personalised recommendations