Experimental Brain Research

, Volume 225, Issue 1, pp 47–53 | Cite as

Influence of (S)-ketamine on human motor cortex excitability

  • Oliver HöffkenEmail author
  • Ida S. Haussleiter
  • Andrea Westermann
  • Jörn Lötsch
  • Christoph Maier
  • Martin Tegenthoff
  • Peter Schwenkreis
Research Article


Previous studies demonstrated a reduction of motor cortical excitability through pharmacological NMDA receptor blockage. Interestingly, subanesthetic doses of racemic ketamine, a non-competitive NMDA receptor antagonist, had no effects on intracortical excitability evoked by transcranial magnetic stimulation. In this study, we aimed to substantiate these findings by using the more active enantiomer (S)-ketamine. (S)-ketamine has a threefold higher affinity for the NMDA receptor, but relatively little is known about its specific effects on human motor cortex excitability. Eleven healthy subjects (two female) participated in a randomized, double-blind, placebo-controlled cross-over study with four treatment conditions: either placebo or one of three subanesthetic doses of intravenous (S)-ketamine (serum target 10, 30 and 50 ng/ml, respectively). We assessed intracortical inhibition and facilitation using a paired-pulse TMS-paradigm. Resting motor threshold and cortical silent period were assessed as additional parameters. Solely at highest (S)-ketamine concentrations, intracortical inhibition was significantly reduced and intracortical facilitation strongly tended to be enhanced. In addition, we found a tendency to a prolonged silent period, while resting motor threshold was unaffected. We conclude that subanesthetic doses of (S)-ketamine show an enhancement on excitability in human motor cortex. Similar to findings using the racemic mixture of ketamine, the effect may be due to an increase in non-NMDA glutamatergic transmission which outweighs the NMDA receptor blockade.


(S)-ketamine TMS Motor cortex Excitability 



We thank Steven L. Shafer for providing STANPUMP. The first author acknowledges support from a DFG Grant. This study was supported by a grant from the Faculty of Medicine of the Ruhr-University Bochum (FoRUM AZ F417/2004). Sources of support: Equipment: STANPUMP is freely available from the author, Steven L. Shafer, M.D., Anesthesiology Service (112A), PAVAMC, 3801 Miranda Ave., Palo Alto, CA. 94304 at, accessed on July 3, 2012.

Conflict of interest

The authors O.H., I.H., J.L., A.W., and M.T. declare that there is no conflict of interest. C.M. received fees for consulting from Astellas Sanofi Aventis, Wyeth, Pfizer, Mundipharma, Eli Lilly. He received research funding from Pfizer, MSD, Mundipharma, Grünenthal, Astellas, Lilly. He is a member of the IMI “Europain” collaboration and industry members of this are as follows: AstraZeneca, Pfizer, Esteve, UCBPharma, Sanofi Aventis, Grünenthal, Eli Lilly, and Boehringer Ingelheim. P.S. received research funding from Bayer Health Care AG, Biogen Idec, Merck KGaA, and Teva Pharma GmbH.


  1. Adams HA, Werner C (1997) From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance? Anaesthesist 46:1026–1042PubMedCrossRefGoogle Scholar
  2. Badawy RA, Tarletti R, Mula M, Varrasi C, Cantello R (2011) The routine circular coil is reliable in paired-TMS studies. Clin Neurophysiol 122:784–788PubMedCrossRefGoogle Scholar
  3. Bouillon T, Bruhn J, Radu-Radulescu L, Andresen C, Cohane C, Shafer SL (2003) A model of the ventilatory depressant potency of remifentanil in the non-steady state. Anesthesiology 99:779–787PubMedCrossRefGoogle Scholar
  4. Bruhn J, Bouillon TW, Shafer SL (2000) Bispectral index (BIS) and burst suppression: revealing a part of the BIS algorithm. J Clin Monit Comput 16:593–596PubMedCrossRefGoogle Scholar
  5. Bustos G, Abarca J, Forray MI, Gysling K, Bradberry CW, Roth RH (1992) Regulation of excitatory amino acid release by N-methyl-D-aspartate receptors in rat striatum: in vivo microdialysis studies. Brain Res 585:105–115PubMedCrossRefGoogle Scholar
  6. Chizh BA (2007) Low dose ketamine: a therapeutic and research tool to explore N-methyl-D-aspartate (NMDA) receptor-mediated plasticity in pain pathways. J Psychopharmacol 21:259–271PubMedCrossRefGoogle Scholar
  7. Deakin JF, Lees J, McKie S, Hallak JE, Williams SR, Dursun SM (2008) Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry 65:154–164PubMedCrossRefGoogle Scholar
  8. Di Lazzaro V, Oliviero A, Profice P, Pennisi MA, Pilato F, Zito G, Dileone M, Nicoletti R, Pasqualetti P, Tonali PA (2003) Ketamine increases human motor cortex excitability to transcranial magnetic stimulation. J Physiol 547:485–496PubMedCrossRefGoogle Scholar
  9. Fleming MK, Sorinola IO, Newham DJ, Roberts-Lewis SF, Bergmann JH (2012) The effect of coil type and navigation on the reliability of transcranial magnetic stimulation. IEEE Trans Neural Syst Rehabil Eng 20:617–625PubMedCrossRefGoogle Scholar
  10. Gilbert DL, Ridel KR, Sallee FR, Zhang J, Lipps TD, Wassermann EM (2006) Comparison of the inhibitory and excitatory effects of ADHD medications methylphenidate and atomoxetine on motor cortex. Neuropsychopharmacology 31:442–449PubMedCrossRefGoogle Scholar
  11. Hallett M, Chen R, Ziemann U, Cohen LG (1999) Reorganization in motor cortex in amputees and in normal volunteers after ischemic limb deafferentation. Electroencephalogr Clin Neurophysiol Suppl 51:183–187PubMedGoogle Scholar
  12. Harrison NL, Simmonds MA (1985) Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex. Br J Pharmacol 84:381–391PubMedCrossRefGoogle Scholar
  13. Ihmsen H, Geisslinger G, Schuttler J (2001) Stereoselective pharmacokinetics of ketamine: R(−)−ketamine inhibits the elimination of S(+)-ketamine. Clin Pharmacol Ther 70:431–438PubMedCrossRefGoogle Scholar
  14. Ikoma K, Samii A, Mercuri B, Wassermann EM, Hallett M (1996) Abnormal cortical motor excitability in dystonia. Neurology 46:1371–1376PubMedCrossRefGoogle Scholar
  15. Irifune M, Shimizu T, Nomoto M, Fukuda T (1992) Ketamine-induced anesthesia involves the N-methyl-D-aspartate receptor-channel complex in mice. Brain Res 596:1–9PubMedCrossRefGoogle Scholar
  16. Kobayashi M, Pascual-Leone A (2003) Transcranial magnetic stimulation in neurology. Lancet Neurol 2:145–156PubMedCrossRefGoogle Scholar
  17. Kohrs R, Durieux ME (1998) Ketamine: teaching an old drug new tricks. Anesth Analg 87:1186–1193PubMedGoogle Scholar
  18. 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 471:501–519PubMedGoogle Scholar
  19. Liu J, Moghaddam B (1995) Regulation of glutamate efflux by excitatory amino acid receptors: evidence for tonic inhibitory and phasic excitatory regulation. J Pharmacol Exp Ther 274:1209–1215PubMedGoogle Scholar
  20. Lotsch J, Skarke C, Schmidt H, Rohrbacher M, Hofmann U, Schwab M, Geisslinger G (2006) Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin Pharmacol Ther 79:35–48PubMedCrossRefGoogle Scholar
  21. Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927PubMedGoogle Scholar
  22. Oertel BG, Felden L, Tran PV, Bradshaw MH, Angst MS, Schmidt H, Johnson S, Greer JJ, Geisslinger G, Varney MA, Lotsch J (2010) Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia. Clin Pharmacol Ther 87:204–211PubMedCrossRefGoogle Scholar
  23. Overall JE, Gorham DR (1962) Brief psychiatric rating scale. Psychol Rep 10:799–812CrossRefGoogle Scholar
  24. Roick H, von Giesen HJ, Benecke R (1993) On the origin of the postexcitatory inhibition seen after transcranial magnetic brain stimulation in awake human subjects. Exp Brain Res 94:489–498PubMedCrossRefGoogle Scholar
  25. Schuhfried G (2009) Daueraufmerksamkeit (DAUF) aus dem Wiener Testsystem (WTS). In: Schellig D, Drechsler R, Heinemann D, Sturm W (eds) Handbuch neuropsychologischer Testverfahren. Hogrefe, Aufmerksamkeit, Gedächtnis und exekutive Funktionen, pp 67–72Google Scholar
  26. Schwenkreis P, Witscher K, Janssen F, Addo A, Dertwinkel R, Zenz M, Malin JP, Tegenthoff M (1999) Influence of the N-methyl-D-aspartate antagonist memantine on human motor cortex excitability. Neurosci Lett 270:137–140PubMedCrossRefGoogle Scholar
  27. Shafer SL, Siegel LC, Cooke JE, Scott JC (1988) Testing computer-controlled infusion pumps by simulation. Anesthesiology 68:261–266PubMedCrossRefGoogle Scholar
  28. Shafer SL, Varvel JR, Aziz N, Scott JC (1990) Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology 73:1091–1102PubMedCrossRefGoogle Scholar
  29. Storustovu S, Sanchez C, Porzgen P, Brennum LT, Larsen AK, Pulis M, Ebert B (2004) R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter. Br J Pharmacol 142:172–180PubMedCrossRefGoogle Scholar
  30. van Berckel BN, Oranje B, van Ree JM, Verbaten MN, Kahn RS (1998) The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects. Psychopharmacology 137:271–281PubMedCrossRefGoogle Scholar
  31. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996a) The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 109:127–135PubMedCrossRefGoogle Scholar
  32. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996b) Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 40:367–378PubMedCrossRefGoogle Scholar
  33. Ziemann U, Rothwell JC, Ridding MC (1996c) Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 496(Pt 3):873–881PubMedGoogle Scholar
  34. Ziemann U, Chen R, Cohen LG, Hallett M (1998) Dextromethorphan decreases the excitability of the human motor cortex. Neurology 51:1320–1324PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Oliver Höffken
    • 1
    Email author
  • Ida S. Haussleiter
    • 2
  • Andrea Westermann
    • 3
  • Jörn Lötsch
    • 4
  • Christoph Maier
    • 3
  • Martin Tegenthoff
    • 1
  • Peter Schwenkreis
    • 1
  1. 1.Department of NeurologyRuhr-University BochumBochumGermany
  2. 2.Department of Psychiatry, LWL Institute of Mental Health, LWL University HospitalRuhr-University BochumBochumGermany
  3. 3.Department of Pain MedicineRuhr-University BochumBochumGermany
  4. 4.Institute of Clinical PharmacologyGoethe UniversityFrankfurt am MainGermany

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