Basic Principles of rTMS in Motor Recovery After Stroke

  • Lukas J. Volz
  • Christian GrefkesEmail author


Repetitive transcranial magnetic stimulation (rTMS) can be used to promote recovery of motor function after stroke. We are only beginning to understand the neural underpinnings of stimulation after-effects on motor function. In this chapter, we summarize scientific evidence that motivates the rationale behind the two major rTMS approaches used in the rehabilitation of stroke patients. Finally, we present promising novel developments and future prospects that might help to pave the way to clinical applications of rTMS in stroke.


Transcranial Magnetic Stimulation Cortical Excitability Motor Recovery Intracortical Inhibition Chronic Stroke Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abbruzzese G, Morena M, Dall’Agata D, Abbruzzese M, Favale E (1991) Motor evoked potentials (MEPs) in lacunar syndromes. Electroencephalogr Clin Neurophysiol 81:202–208CrossRefPubMedGoogle Scholar
  2. Ackerley SJ, Stinear CM, Barber PA, Byblow WD (2010) Combining theta burst stimulation with training after subcortical stroke. Stroke 41:1568–1572CrossRefPubMedGoogle Scholar
  3. Ameli M, Grefkes C, Kemper F, Riegg FP, Rehme AK, Karbe H, Fink GR, Nowak DA (2009) Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann Neurol 66:298–309CrossRefPubMedGoogle Scholar
  4. Bachtiar V, Stagg CJ (2014) The role of inhibition in human motor cortical plasticity. Neuroscience 278:93–104CrossRefPubMedGoogle Scholar
  5. Bates KA, Rodger J (2014) Repetitive transcranial magnetic stimulation for stroke rehabilitation-potential therapy or misplaced hope? Restor Neurol Neurosci 33(4):557–569. doi: 10.3233/RNN-130359 CrossRefGoogle Scholar
  6. Biernaskie J, Szymanska A, Windle V, Corbett D (2005) Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur J Neurosci 21:989–999CrossRefPubMedGoogle Scholar
  7. Buma F, Kwakkel G, Ramsey N (2013) Understanding upper limb recovery after stroke. Restor Neurol Neurosci 31:707–722PubMedGoogle Scholar
  8. Cardenas-Morales L, Volz LJ, Michely J, Rehme AK, Pool EM, Nettekoven C, Eickhoff SB, Fink GR, Grefkes C (2014) Network connectivity and individual responses to brain stimulation in the human motor system. Cereb Cortex 24:1697–1707CrossRefPubMedGoogle Scholar
  9. Carrera E, Tononi G (2014) Diaschisis: past, present, future. Brain 137:2408–2422CrossRefPubMedGoogle Scholar
  10. Carter AR, Astafiev SV, Lang CE, Connor LT, Rengachary J, Strube MJ, Pope DL, Shulman GL, Corbetta M (2010) Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Ann Neurol 67:365–375PubMedCentralPubMedGoogle Scholar
  11. Catano A, Houa M, Caroyer JM, Ducarne H, Noel P (1996) Magnetic transcranial stimulation in acute stroke: early excitation threshold and functional prognosis. Electroencephalogr Clin Neurophysiol 101:233–239CrossRefPubMedGoogle Scholar
  12. Chang WH, Kim YH, Bang OY, Kim ST, Park YH, Lee PK (2010) Long-term effects of rTMS on motor recovery in patients after subacute stroke. J Rehabil Med 42:758–764CrossRefPubMedGoogle Scholar
  13. Cheng MY, Wang EH, Woodson WJ, Wang S, Sun G, Lee AG, Arac A, Fenno LE, Deisseroth K, Steinberg GK (2014) Optogenetic neuronal stimulation promotes functional recovery after stroke. Proc Natl Acad Sci U S A 111:12913–12918PubMedCentralCrossRefPubMedGoogle Scholar
  14. 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
  15. Cicinelli P, Traversa R, Bassi A, Scivoletto G, Rossini PM (1997) Interhemispheric differences of hand muscle representation in human motor cortex. Muscle Nerve 20:535–542CrossRefPubMedGoogle Scholar
  16. Cicinelli P, Pasqualetti P, Zaccagnini M, Traversa R, Oliveri M, Rossini PM (2003) Interhemispheric asymmetries of motor cortex excitability in the postacute stroke stage: a paired-pulse transcranial magnetic stimulation study. Stroke 34:2653–2658CrossRefPubMedGoogle Scholar
  17. Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST (2010) Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468:305–309PubMedCentralCrossRefPubMedGoogle Scholar
  18. Delvaux V, Alagona G, Gerard P, De Pasqua V, Pennisi G, de Noordhout AM (2003) Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clin Neurophysiol 114:1217–1225CrossRefPubMedGoogle Scholar
  19. Di Pino G, Pellegrino G, Assenza G, Capone F, Ferreri F, Formica D, Ranieri F, Tombini M, Ziemann U, Rothwell JC, Di Lazzaro V (2014) Modulation of brain plasticity in stroke: a novel model for neurorehabilitation. Nat Rev Neurol 10:597–608CrossRefPubMedGoogle Scholar
  20. Duque J, Murase N, Celnik P, Hummel F, Harris-Love M, Mazzocchio R, Olivier E, Cohen LG (2007) Intermanual Differences in movement-related interhemispheric inhibition. J Cogn Neurosci 19:204–213CrossRefPubMedGoogle Scholar
  21. Eickhoff SB, Grefkes C (2011) Approaches for the integrated analysis of structure, function and connectivity of the human brain. Clin EEG Neurosci 42:107–121CrossRefPubMedGoogle Scholar
  22. Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD (1992) Interhemispheric inhibition of the human motor cortex. J Physiol 453:525–546PubMedCentralCrossRefPubMedGoogle Scholar
  23. Friston KJ, Harrison L, Penny W (2003) Dynamic causal modelling. Neuroimage 19:1273–1302CrossRefPubMedGoogle Scholar
  24. Funke K, Benali A (2011) Modulation of cortical inhibition by Modulation of cortical inhibition by rTMS – findings obtained from animal models. J Physiol 589:4423–4435PubMedCentralCrossRefPubMedGoogle Scholar
  25. Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, Waldvogel D, Wittenberg GF, Ishii K, Cohen LG, Hallett M (2006) Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke. Brain 129:791–808CrossRefPubMedGoogle Scholar
  26. Grefkes C, Fink GR (2012) Disruption of motor network connectivity post-stroke and its noninvasive neuromodulation. Curr Opin Neurol 25:670–675CrossRefPubMedGoogle Scholar
  27. Grefkes C, Ward NS (2014) Cortical reorganization after stroke: how much and how functional? Neuroscientist 20(1):56–70CrossRefPubMedGoogle Scholar
  28. Grefkes C, Nowak DA, Eickhoff SB, Dafotakis M, Kust J, Karbe H, Fink GR (2008) Cortical connectivity after subcortical stroke assessed with functional magnetic resonance imaging. Ann Neurol 63:236–246CrossRefPubMedGoogle Scholar
  29. Grefkes C, Nowak DA, Wang LE, Dafotakis M, Eickhoff SB, Fink GR (2010) Modulating cortical connectivity in stroke patients by rTMS assessed with fMRI and dynamic causal modeling. Neuroimage 50:233–242CrossRefPubMedGoogle Scholar
  30. Hallett M (2000) Transcranial magnetic stimulation and the human brain. Nature 406:147–150CrossRefPubMedGoogle Scholar
  31. Hamada M, Murase N, Hasan A, Balaratnam M, Rothwell JC (2013) The role of interneuron networks in driving human motor cortical plasticity. Cereb Cortex 23:1593–1605CrossRefPubMedGoogle Scholar
  32. Hendricks HT, Zwarts MJ, Plat EF, van Limbeek J (2002) Systematic review for the early prediction of motor and functional outcome after stroke by using motor-evoked potentials. Arch Phys Med Rehabil 83:1303–1308CrossRefPubMedGoogle Scholar
  33. Hermann DM, Chopp M (2012) Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol 11:369–380PubMedCentralCrossRefPubMedGoogle Scholar
  34. Hinder MR (2012) Interhemispheric connectivity between distinct motor regions as a window into bimanual coordination. J Neurophysiol 107:1791–1794CrossRefPubMedGoogle Scholar
  35. Hinder MR, Schmidt MW, Garry MI, Summers JJ (2010) Unilateral contractions modulate interhemispheric inhibition most strongly and most adaptively in the homologous muscle of the contralateral limb. Exp Brain Res 205:423–433CrossRefPubMedGoogle Scholar
  36. Hinder MR, Goss EL, Fujiyama H, Canty AJ, Garry MI, Rodger J, Summers JJ (2014) Inter- and Intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery. Brain Stimul 7:365–371CrossRefPubMedGoogle Scholar
  37. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45:201–206CrossRefPubMedGoogle Scholar
  38. Hummel F, Kirsammer R, Gerloff C (2003) Ipsilateral cortical activation during finger sequences of increasing complexity: representation of movement difficulty or memory load? Clin Neurophysiol 114:605–613CrossRefPubMedGoogle Scholar
  39. Khedr EM, Ahmed MA, Fathy N, Rothwell JC (2005) Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology 65:466–468CrossRefPubMedGoogle Scholar
  40. Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, Yoo WK, Hallett M (2006) Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke 37:1471–1476CrossRefPubMedGoogle Scholar
  41. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519PubMedCentralCrossRefPubMedGoogle Scholar
  42. Langhorne P, Bernhardt J, Kwakkel G (2011) Stroke rehabilitation. Lancet 377:1693–1702CrossRefPubMedGoogle Scholar
  43. Liepert J, Storch P, Fritsch A, Weiller C (2000) Motor cortex disinhibition in acute stroke. Clin Neurophysiol 111:671–676CrossRefPubMedGoogle Scholar
  44. Liuzzi G, Horniss V, Lechner P, Hoppe J, Heise K, Zimerman M, Gerloff C, Hummel FC (2014) Development of movement-related intracortical inhibition in acute to chronic subcortical stroke. Neurology 82:198–205CrossRefPubMedGoogle Scholar
  45. Lotze M, Markert J, Sauseng P, Hoppe J, Plewnia C, Gerloff C (2006) The role of multiple contralesional motor areas for complex hand movements after internal capsular lesion. J Neurosci 26:6096–6102CrossRefPubMedGoogle Scholar
  46. Malcolm MP, Triggs WJ, Light KE, Gonzalez Rothi LJ, Wu S, Reid K, Nadeau SE (2007) Repetitive transcranial magnetic stimulation as an adjunct to constraint-induced therapy: an exploratory randomized controlled trial. Am J Phys Med Rehabil 86:707–715PubMedCentralCrossRefPubMedGoogle Scholar
  47. Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A (2002) Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 113:936–943CrossRefPubMedGoogle Scholar
  48. Murase N, Duque J, Mazzocchio R, Cohen LG (2004) Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 55:400–409CrossRefPubMedGoogle Scholar
  49. Nettekoven C, Volz LJ, Kutscha M, Pool EM, Rehme AK, Eickhoff SB, Fink GR, Grefkes C (2014) Dose-dependent effects of theta burst rTMS on cortical excitability and resting-state connectivity of the human motor system. J Neurosci 34:6849–6859PubMedCentralCrossRefPubMedGoogle Scholar
  50. Nishimura Y, Onoe H, Morichika Y, Perfiliev S, Tsukada H, Isa T (2007) Time-dependent central compensatory mechanisms of finger dexterity after spinal cord injury. Science 318:1150–1155CrossRefPubMedGoogle Scholar
  51. Nowak DA, Grefkes C, Dafotakis M, Eickhoff S, Kust J, Karbe H, Fink GR (2008) Effects of low-frequency repetitive transcranial magnetic stimulation of the contralesional primary motor cortex on movement kinematics and neural activity in subcortical stroke. Arch Neurol 65:741–747CrossRefPubMedGoogle Scholar
  52. Nowak DA, Grefkes C, Ameli M, Fink GR (2009) Interhemispheric competition after stroke: brain stimulation to enhance recovery of function of the affected hand. Neurorehabil Neural Repair 23:641–656CrossRefPubMedGoogle Scholar
  53. Nudo RJ (2013) Recovery after brain injury: mechanisms and principles. Front Hum Neurosci 7:887PubMedCentralCrossRefPubMedGoogle Scholar
  54. Park CH, Chang WH, Ohn SH, Kim ST, Bang OY, Pascual-Leone A, Kim YH (2011) Longitudinal changes of resting-state functional connectivity during motor recovery after stroke. Stroke 42:1357–1362PubMedCentralCrossRefPubMedGoogle Scholar
  55. Redecker C, Wang W, Fritschy JM, Witte OW (2002) Widespread and long-lasting alterations in GABA(A)-receptor subtypes after focal cortical infarcts in rats: mediation by NMDA-dependent processes. J Cereb Blood Flow Metab 22:1463–1475CrossRefPubMedGoogle Scholar
  56. Rehme AK, Fink GR, von Cramon DY, Grefkes C (2011) The role of the contralesional motor cortex for motor recovery in the early days after stroke assessed with longitudinal FMRI. Cereb Cortex 21:756–768CrossRefPubMedGoogle Scholar
  57. Rehme AK, Volz LJ, Feis DL, Bomilcar-Focke I, Liebig T, Eickhoff SB, Fink GR, Grefkes C (2014) Identifying neuroimaging markers of motor disability in acute stroke by machine learning techniques. Cereb Cortex 25(9):3046–3056CrossRefPubMedGoogle Scholar
  58. Ridding MC, Ziemann U (2010) Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. J Physiol 588:2291–2304PubMedCentralCrossRefPubMedGoogle Scholar
  59. Silasi G, Murphy TH (2014) Stroke and the connectome: how connectivity guides therapeutic intervention. Neuron 83:1354–1368CrossRefPubMedGoogle Scholar
  60. Stephan KE, Penny WD, Moran RJ, den Ouden HE, Daunizeau J, Friston KJ (2010) Ten simple rules for dynamic causal modeling. Neuroimage 49:3099–3109PubMedCentralCrossRefPubMedGoogle Scholar
  61. Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD (2007) Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain 130:170–180CrossRefPubMedGoogle Scholar
  62. Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD (2012) The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 135:2527–2535CrossRefPubMedGoogle Scholar
  63. Sung WH, Wang CP, Chou CL, Chen YC, Chang YC, Tsai PY (2013) Efficacy of coupling inhibitory and facilitatory repetitive transcranial magnetic stimulation to enhance motor recovery in hemiplegic stroke patients. Stroke 44:1375–1382CrossRefPubMedGoogle Scholar
  64. Swayne OB, Rothwell JC, Ward NS, Greenwood RJ (2008) Stages of motor output reorganization after hemispheric stroke suggested by longitudinal studies of cortical physiology. Cereb Cortex 18:1909–1922PubMedCentralCrossRefPubMedGoogle Scholar
  65. Talelli P, Greenwood RJ, Rothwell JC (2007) Exploring Theta Burst Stimulation as an intervention to improve motor recovery in chronic stroke. Clin Neurophysiol 118:333–342CrossRefPubMedGoogle Scholar
  66. Traversa R, Cicinelli P, Bassi A, Rossini PM, Bernardi G (1997) Mapping of motor cortical reorganization after stroke. A brain stimulation study with focal magnetic pulses. Stroke 28:110–117CrossRefPubMedGoogle Scholar
  67. Traversa R, Cicinelli P, Pasqualetti P, Filippi M, Rossini PM (1998) Follow-up of interhemispheric differences of motor evoked potentials from the ‘affected’ and ‘unaffected’ hemispheres in human stroke. Brain Res 803:1–8CrossRefPubMedGoogle Scholar
  68. Valls-Sole J, Pascual-Leone A, Wassermann EM, Hallett M (1992) Human motor evoked responses to paired transcranial magnetic stimuli. Electroencephalogr Clin Neurophysiol 85:355–364CrossRefPubMedGoogle Scholar
  69. van Meer MP, van der Marel K, Wang K, Otte WM, El Bouazati S, Roeling TA, Viergever MA, Berkelbach van der Sprenkel JW, Dijkhuizen RM (2010) Recovery of sensorimotor function after experimental stroke correlates with restoration of resting-state interhemispheric functional connectivity. J Neurosci 30:3964–3972CrossRefPubMedGoogle Scholar
  70. Verstynen T, Diedrichsen J, Albert N, Aparicio P, Ivry RB (2005) Ipsilateral motor cortex activity during unimanual hand movements relates to task complexity. J Neurophysiol 93:1209–1222CrossRefPubMedGoogle Scholar
  71. Volz LJ, Benali A, Mix A, Neubacher U, Funke K (2013) Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat. Brain Stimul 6(4):598–606CrossRefPubMedGoogle Scholar
  72. Volz LJ, Sarfeld AS, Diekhoff S, Rehme AK, Pool EM, Eickhoff SB, Fink GR, Grefkes C (2015) Motor cortex excitability and connectivity in chronic stroke: a multimodal model of functional reorganization. Brain Struct Funct 220:1093–1107CrossRefPubMedGoogle Scholar
  73. von Monakow C (1914) Die Lokalisation im Grosshirn und der Abbau der Funktion durch kortikale Herde. Bergmann JF, WiesbadenGoogle Scholar
  74. Ward NS, Brown MM, Thompson AJ, Frackowiak RS (2003) Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 126:2476–2496PubMedCentralCrossRefPubMedGoogle Scholar
  75. 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
  76. Yoon KJ, Lee YT, Han TR (2011) Mechanism of functional recovery after repetitive transcranial magnetic stimulation (rTMS) in the subacute cerebral ischemic rat model: neural plasticity or anti-apoptosis? Exp Brain Res 214:549–556CrossRefPubMedGoogle Scholar
  77. Ziemann U (2011) Transcranial magnetic stimulation at the interface with other techniques: a powerful tool for studying the human cortex. Neuroscientist 17:368–381CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of NeurologyCologne University HospitalCologneGermany
  2. 2.Institute of Neurosciences and Medicine 3 – Cognitive NeuroscienceResearch Center JülichJülichGermany

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