Skip to main content
SpringerLink
Log in

Motor intracortical inhibition in PD: L-DOPA modulation of high-frequency rTMS effects

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

Dopaminergic drugs and deep brain stimulation restore cortical inhibition in Parkinson disease (PD) patients. High-frequency rTMS was also found to increase cortical inhibition in PD but its therapeutic effect is still controversial. Here we hypothesize that, if dopaminergic drugs reverse to normal cortical excitability in M1, the effect of high-frequency (hf)-rTMS in PD patients could depend on whether they are in a medicated or unmedicated state. The present study aims to explore the lasting effects of sub-threshold hf rTMS trains over M1 on cortical inhibition in patients with “on” and without “off” L-DOPA treatment. Fourteen PD patients were examined twice while “on” and “off” medication. In both conditions, a paired-pulse paradigm was used to evaluate short intracortical inhibition (SICI) and long intracortical inhibition (LICI) that were evaluated before and after hf rTMS trains applied on the motor cortex. The results were compared with those obtained from normal controls. In baseline condition, SICI and LICI were significantly reduced in “off” compared to “on” patients and controls. hf-rTMS over the motor cortex significantly increased SICI and LICI in “off” medication PD patients. Magnetic stimulation proved to be ineffective when the same patients were in “on” state. The results showed that hf-rTMS affected intracortical inhibition (ICI) only in unmedicated patients. By restoring cortical inhibitory circuits dopaminergic drugs, normalize the excitability changes in M1 subsequent to motor rTMS. Whether patients are in a medicated or an unmedicated state would therefore appear to be critical for rTMS effects in PD patients. If a positive correlation exists between increased cortical inhibition and clinical improvement, hf-rTMS during the “off” state could be regarded as a potential add-on treatment to reduce the need of L-dopa and thus delay the adverse effects of its chronic use.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Aydin-Abidin S, Moliadze V, Eysel UT, Funke K (2006) Effects of repetitive TMS on visually evoked potentials and EEG in the anaesthetized cat: dependence on stimulus frequency and train duration. J Physiol 574:443–455

    Article  PubMed  CAS  Google Scholar 

  • Bares M, Kanovsky P, Klajblova H, Rektor I (2003) Intracortical inhibition and facilitation are impaired in patients with early Parkinson’s disease: a paired TMS study. Eur J Neurol 10:385–389

    Article  PubMed  CAS  Google Scholar 

  • Berardelli A, Rona S, Inghilleri M, Manfredi M (1996) Cortical inhibition in Parkinson’s disease. A study with paired magnetic stimulation. Brain 119:71–77

    Article  PubMed  Google Scholar 

  • Berardelli A, Inghilleri M, Gilio F, et al (1999) Effects of repetitive cortical stimulation on the silent period evoked by magnetic stimulation. Exp Brain Res 125:82–86

    Article  PubMed  CAS  Google Scholar 

  • Buhmann C, Gorsler A, Baumer T, et al (2004) Abnormal excitability of premotor-motor connections in de novo Parkinson’s disease. Brain 127:2732–2746

    Article  PubMed  CAS  Google Scholar 

  • Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis MS, Mutani R (1991) Parkinson’s disease rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology 41:1449–1456

    PubMed  CAS  Google Scholar 

  • Cantello R, Tarletti R, Civardi C (2002) Transcranial magnetic stimulation and Parkinson’s disease. Brain Res Brain Res Rev 38:309–327

    Article  PubMed  Google Scholar 

  • Cepeda C, Radisalvljevic Z, Peacock W, Levine MS (1992) Differential modulation by dopamine of responses evoked by excitatory amino acids in human cortex. Synapse 11:330–341

    Article  PubMed  CAS  Google Scholar 

  • Chen R, Garg RR, Lozano AM, Lang AE (2001) Effects of internal globus pallidus stimulation on motor cortex excitability. Neurology 56:716–723

    PubMed  CAS  Google Scholar 

  • Cunic D, Roshan L, Khan FI, Lozano AM, Lang AE, Chen R (2002) Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson’s disease. Neurology 58:1665–1672

    PubMed  CAS  Google Scholar 

  • Daskalakis ZJ, Moller B, Christensen BK, Fitzgerald PB, Gunraj C, Chen R (2006) The effects of repetitive transcranial magnetic stimulation on cortical inhibition in healthy human subjects. Exp Brain Res 174:403–412

    Article  PubMed  Google Scholar 

  • Dauper J, Peschel T, Schrader C, et al (2002) Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability. Neurology 59:700–706

    PubMed  CAS  Google Scholar 

  • de Groot M, Hermann W, Steffen J, Wagner A, Grahmann F (2001) Contralateral and ipsilateral repetitive transcranial magnetic stimulation in Parkinson patients. Nervenarzt 72:932–938

    Article  PubMed  Google Scholar 

  • Fierro B, Brighina F, Vitello G, et al (2005) Modulatory effects of low- and high-frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation. J Physiol 1, 565:659–665

    Article  CAS  Google Scholar 

  • Fitzgerald PB, Fountain S, Daskalakis ZJ (2006) A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin Neurophysiol 117:2584–2596

    Article  PubMed  Google Scholar 

  • Fregni F, Simon DK, Wu A, Pascual-Leone A (2005) Non-invasive brain stimulation for Parkinson’s disease: a systematic review and meta-analysis of the literature. J Neurol Neurosurg Psychiatry 76:1614–1623

    Article  PubMed  CAS  Google Scholar 

  • Gangitano M, Valero-Cabre A, Tormos JM, Mottaghy FM, Romero JR, Pascual-Leone A (2002) Modulation of input-output curves by low and high frequency repetitive transcranial magnetic stimulation of the motor cortex. Clin Neurophysiol 113:1249–1257

    Article  PubMed  Google Scholar 

  • Ghabra MB, Hallett M, Wassermann EM (1999) Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology 52:768–770

    PubMed  CAS  Google Scholar 

  • Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752

    Article  PubMed  CAS  Google Scholar 

  • Gil Z, Amitai Y (1996) Properties of convergent thalamocortical and intracortical synaptic potentials in single neurons of neocortex. J Neurosci 16:6567–6578

    PubMed  CAS  Google Scholar 

  • Gilio F, Curra A, Inghilleri M, Lorenzano C, Manfredi M, Berardelli A (2002) Repetitive magnetic stimulation of cortical motor areas in Parkinson’s disease: implications for the pathophysiology of cortical function. Mov Disord 17:467–473

    Article  PubMed  CAS  Google Scholar 

  • Ili’c TV, Meintzschel F, CleV U, Ruge D, Kessler KR, Ziemann U (2002) Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity. J Physiol 545:153–167

    Article  CAS  Google Scholar 

  • Karreman M, Moghaddam B (1996) The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem 66:589–598

    Article  PubMed  CAS  Google Scholar 

  • Keck ME, Welt T, Muller MB, et al (2002) Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology 43:101–109

    Article  PubMed  CAS  Google Scholar 

  • Khedr EM, Farweez HM, Islam H (2003) Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson’s disease patients. Eur J Neurol 10:567–572

    Article  PubMed  CAS  Google Scholar 

  • Khedr EM, Rothwell JC, Ahmed MA, Shawky OA, Farouk M (2007) Modulation of motor cortical excitability following rapid-rate transcranial magnetic stimulation. Cin Neurophysiol 118:140–145

    Article  Google Scholar 

  • Kujirai T, Caramia MD, Rothwell JC, et al (1993) Corticocortical inhibition in human motor cortex. J Physiol 471:501–519

    PubMed  CAS  Google Scholar 

  • Lefaucheur JP, Drouot X, Von Raison F, Menard-Lefaucheur I, Cesaro P, Nguyen JP (2004) Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson’s disease. Clin Neurophysiol 115:2530–2541

    Article  PubMed  Google Scholar 

  • Maeda F, Gangitano M, Thall M, Pascual-Leone A (2002) Inter- and intra-individual variability of paired-pulse curves with transcranial magnetic stimulation (TMS). Clin Neurophysiol 113:376–382

    Article  PubMed  Google Scholar 

  • Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A (2000) Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res 133:425–430

    Article  PubMed  CAS  Google Scholar 

  • Marchese R, Trompetto C, Buccolieri A, Abbruzzese G (2000) Abnormalities of motor cortical excitability are not correlated with clinical features in atypical parkinsonism. Mov Disord 15:1210–1214

    Article  PubMed  CAS  Google Scholar 

  • Mir P, Matsunaga K, Gilio F, Quinn NP, Siebner HR, Rothwell JC (2005) Dopaminergic drugs restore facilitatory premotor-motor interactions in Parkinson disease. Neurology 64:1906–1912

    Article  PubMed  CAS  Google Scholar 

  • Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H, Takano H, Nakatoh S (1995) Intracortical facilitation and inhibition after paired magnetic stimulation in humans under anesthesia. Neurosci Lett 199:155–157

    Article  PubMed  CAS  Google Scholar 

  • Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H (1997) Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol 498:817–823

    PubMed  CAS  Google Scholar 

  • Okabe S, Ugawa Y, Kanazawa I (2003) Effectiveness of rTMS on Parkinson’s disease study group. 0.2-Hz repetitive transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinson’s disease. Mov Disord 18:382–388

    Article  PubMed  Google Scholar 

  • 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 44:892–898

    PubMed  CAS  Google Scholar 

  • Peinemann A, Lehner C, Mentschel C, Munchau A, Conrad B, Siebner HR (2000) Subthreshold 5-Hz repetitive transcranial magnetic stimulation of the human primary motor cortex reduces intracortical paired-pulse inhibition. Neurosci Lett 296:21–24

    Article  PubMed  CAS  Google Scholar 

  • Peinemann A, Reimer B, Loer C, Quartarone A, Munchau A, Conrad B, Siebner HR (2004) Long-lasting increase in corticospinal excitability after 1,800 pulses of subthreshold 5 Hz repetitive TMS to the primary motor cortex. Clin Neurophysiol 115:1519–1526

    Article  PubMed  Google Scholar 

  • Pierantozzi M, Palmieri MG, Marciani MG, Bernardi G, Giacomini P, Stanzione P (2001) Effect of apomorphine on cortical inhibition in Parkinson’s disease patients: a transcranial magnetic stimulation study. Exp Brain Res 141:52–62

    Article  PubMed  CAS  Google Scholar 

  • Pierantozzi M, Palmieri MG, Mazzone P, et al (2002) Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson’s disease paralleling apomorphine effects: a paired magnetic stimulation study. Clin Neurophysiol 113:108–113

    Article  PubMed  CAS  Google Scholar 

  • Priori A, Berardelli A, Inghilleri M, Accornero N, Manfredi M (1994) Motor cortical inhibition and the dopaminergic system. Pharmacological changes in the silent period after transcranial brain stimulation in normal subjects, patients with Parkinson’s disease and drug-induced parkinsonism. Brain 117:317–323

    Article  PubMed  Google Scholar 

  • Ridding MC, Inzelberg R, Rothwell JC (1995) Changes in excitability of motor cortical circuitry in patients with Parkinson’s disease. Ann Neurol 37:181–188

    Article  PubMed  CAS  Google Scholar 

  • Romeo S, Gilio F, Pedace F, et al (2000) Changes in the cortical silent period after repetitive magnetic stimulation of cortical motor areas. Exp Brain Res 135:504–510

    Article  PubMed  CAS  Google Scholar 

  • Salako SE (2006) The declaration of Helsinki 2000: ethical principles and the dignity of difference. Med Law 25:341–354

    PubMed  CAS  Google Scholar 

  • Sanger TD, Garg RR, Chen R (2001) Interactions between two different inhibitory systems in the human motor cortex. J Physiol 530:307–317

    Article  PubMed  CAS  Google Scholar 

  • Shimamoto H, Takasaki K, Shigemori M, Imaizumi T, Ayabe M, Shoji H (2001) Therapeutic effect and mechanism of repetitive transcranial magnetic stimulation in Parkinson’s disease. J Neurol 248(Suppl 3):III48–III52

    PubMed  Google Scholar 

  • Siebner HR, Mentschel C, Auer C, Lehner C, Conrad B (2000a) Repetitive transcranial magnetic stimulation causes a short-term increase in the duration of the cortical silent period in patients with Parkinson’s disease. Neurosci Lett 284:147–150

    Article  PubMed  CAS  Google Scholar 

  • Siebner HR, Rossmeier C, Mentschel C, Peinemann A, Conrad B (2000b) 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 178:91–94

    Article  PubMed  CAS  Google Scholar 

  • Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J (2002) Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol 543:699–708

    Article  PubMed  CAS  Google Scholar 

  • 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(15):RC 157

    Google Scholar 

  • Strafella AP, Paus T, Fraraccio M, Dagher A (2003) Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain 126:2609–2615

    Article  PubMed  Google Scholar 

  • Strafella AP, Valzania F, Nassetti SA, et al (2000) Effects of chronic levodopa and pergolide treatment on cortical excitability in patients with Parkinson’s disease: a transcranial magnetic stimulation study. Clin Neurophysiol 111:1198–1202

    Article  PubMed  CAS  Google Scholar 

  • Tergau F, Wassermann EM, Paulus W, Ziemann U (1999) Lack of clinical improvement in patients with Parkinson’s disease after low and high frequency repetitive transcranial magnetic stimulation. Electroencephalogr Clin Neurophysiol Suppl 51:281–288

    PubMed  CAS  Google Scholar 

  • Tsuji S, Akamatsu N (2003) Does transcranial magnetic stimulation improve the motor symptoms of Parkinson disease? J Neurol 250(Suppl 3):III47–III50

    PubMed  Google Scholar 

  • Valls-Sole J, Pascual-Leone A, Wassermann EM, Hallett M (1992) Human motor evoked responses to paired transcranial magnetic stimuli. Electroencephalogr Clin Neurophysiol 85:355–364

    Article  PubMed  CAS  Google Scholar 

  • Valzania F, Strafella AP, Quatrale R, et al (1997) Motor evoked responses to paired cortical magnetic stimulation in Parkinson’s disease. Electroencephalogr Clin Neurophysiol 105:37–43

    Article  PubMed  CAS  Google Scholar 

  • Wassermann EM (1998) Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the international workshop on the safety of repetitive transcranial magnetic stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol 108:1–16

    Article  PubMed  CAS  Google Scholar 

  • Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J (1999) Differential effects on motor cortical inhibition induced by blockade of GABA uptake in humans. J Physiol 517:591–597

    Article  PubMed  CAS  Google Scholar 

  • Wu T, Sommer M, Tergau F, Paulus W (2000) Lasting influence of repetitive transcranial magnetic stimulation on intracortical excitability in human subjects. Neurosci Lett 287:37–40

    Article  PubMed  CAS  Google Scholar 

  • Ziemann U, Tergau F, Bruns D, Baudewig J, Paulus W (1997) Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs. Electroencephalogr Clin Neurophysiol 105:430–437

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Neurosciences, University of Palermo, Via G. La Loggia, 1, 90129, Palermo, Italy

    Brigida Fierro, Filippo Brighina, Marco D’Amelio, Ornella Daniele, Innocenzo Lupo, Paolo Ragonese, Antonio Palermo & Giovanni Savettieri

Authors
  1. Brigida Fierro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Filippo Brighina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco D’Amelio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ornella Daniele
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Innocenzo Lupo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paolo Ragonese
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Antonio Palermo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giovanni Savettieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Filippo Brighina.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fierro, B., Brighina, F., D’Amelio, M. et al. Motor intracortical inhibition in PD: L-DOPA modulation of high-frequency rTMS effects. Exp Brain Res 184, 521–528 (2008). https://doi.org/10.1007/s00221-007-1121-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-007-1121-y

Keywords

Search

Navigation