Experimental Brain Research

, Volume 173, Issue 4, pp 603–611 | Cite as

Lorazepam-induced effects on silent period and corticomotor excitability

  • V. K. Kimiskidis
  • S. Papagiannopoulos
  • D. A. Kazis
  • K.  Sotirakoglou
  • G.  Vasiliadis
  • F. Zara
  • A. Kazis
  • K. R. Mills
Research Article


TMS studies on the CNS effects of benzodiazepines have provided contradictory results. The objective of this study is to describe the effects of lorazepam on silent period (SP) and corticomotor excitability. Twelve healthy male subjects (median age 35 years) were studied at baseline, following i.v. lorazepam administration and after reversal of the benzodiazepine effects with i.v. flumazenil. Lorazepam was given at a low-dose in one subject (0.0225 mg/kg bolus + 2 μg/kg/h infusion) and at a high-dose (0.045 mg/kg bolus + 2.6 μg/kg/h infusion) in the rest. Threshold (Thr) was measured at 1% steps. SPs were investigated with two complementary methods. First, SPs were elicited using a wide range of stimulus intensities (SIs) (from 5 to 100% maximum SI at 5% increments). At each SI, four SPs were obtained and the average value of SP duration was used to construct a stimulus/response (S/R) curve of SI versus SP .The resulting S/R curves were then fitted to a Boltzman function, the best-fit values of which were statistically compared for each experimental condition (i.e., baseline vs. lorazepam vs. flumazenil). Second, a large number of SPs (n=100) was elicited during each of the three experimental conditions using blocks of four stimuli with an intensity alternating between MT and 200% MT. This method was employed so as to reveal the dynamic, time-varying effects of lorazepam and flumazenil on SP duration at two stimulus intensity (SI) levels. MEP recruitment curves were constructed at rest and during activation and fitted to a Boltzman function the best-fit values of which were statistically compared for each experimental condition. Lorazepam at a low dose did not affect Thr, SP, or the active MEP recruitment curves. The high dose also had no effect on Thr and the active MEPs whereas the resting MEP recruitment curves were depressed post-lorazepam at the higher range of stimulus intensities. With regard to SP, the Max value of the S/R curve decreased from 251±4.6 ms at baseline to 215.2±3.1 ms post-lorazepam (P<0.01). V50 also decreased significantly (from 47.92±0.9% to 43.73±0.81%, P<0.01) whereas there was no significant change regarding slope and SP Thr. The statistical analysis of the SP S/R curves as well as the study of SPs at two SI levels revealed that lorazepam reduced SP duration when high intensity stimuli were used (>60%). In contrast, at low SIs a small increase in SP duration was noted post-drug. Enhancement of GABAergic inhibition by lorazepam results in a reduction of SP duration when high SIs is used. At the lower range of SIs, a small but statistically significant increase in SP duration is observed. The kinetic behavior of this phenomenon as well as the possible underlying mechanisms are discussed.


Lorazepam Transcranial magnetic stimulation Silent period 


  1. Assumpcao JA, Bernardi N, Brown J, Stone TW (1979) Selective antagonism by benzodiazepines of neuronal responses to excitatory amino acids in the cerebral cortex. Br J Pharmacol 67:563–568PubMedGoogle Scholar
  2. Boroojerdi B (2002) Pharmacologic influences on TMS effects. J Clin Neurophysiol 19(4):255–271CrossRefPubMedGoogle Scholar
  3. Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG (2001) Mechanisms influencing stimulus-response properties of the human corticospinal system. Clin Neurophysiol 112:931–937CrossRefPubMedGoogle Scholar
  4. Carlen PL, Guverich N, Polc P (1983) Low-dose benzodiazepine neuronal inhibition:enhanced Ca 2+-mediated K+-conductance. Brain Res 271:358–364CrossRefPubMedGoogle Scholar
  5. Crunelli V, Haby M, Jassik-Gerschenfeld D, Leresche N, Pirchio M (1988) Cl− and K+- dependent inhibitory post-synaptic potentials evoked by interneurons of the rat lateral geniculate nucleus. J Physiol 399:153–176PubMedGoogle Scholar
  6. Di Lazzaro V, Oliviero A, Meglio M, Cioni B, Tamburrini G, Tonali P, Rothwell JC (2000) Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex. Clin Neurophysiol 111:794–799CrossRefPubMedGoogle Scholar
  7. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone P, Insola A, Tonali PA, Rothwell JC (2004) The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115:255–266CrossRefPubMedGoogle Scholar
  8. Di Lazzaro V, Oliviero A, Saturno E, Dileone M, Pilato F, Nardone R, Ranieri F, Musumeci G, Fiorilla T, Tonali P (2005) Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans. J Physiol 564:661–668CrossRefPubMedGoogle Scholar
  9. Fingelkurts AA, Fingelkurts AA, Kivisaari R, Pekkonen E, Ilmoniemi RJ, Kahkonen S (2004) The interplay of lorazepam-induced brain oscillations: microstructural electromagnetic study. Clin Neurophysiol 115:674–690CrossRefPubMedGoogle Scholar
  10. Greenblatt DJ, Sethy VH (1990) Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam and oxazepam. Psychopharmacology 102:373–378CrossRefPubMedGoogle Scholar
  11. Greenblatt DJ, Moltke LL, Ehrenberg BL, Harmatz JS, Corbett KE, Wallace DW, Shader RI (2000) Kinetics and dynamics of lorazepam during and after continuous intravenous infusion. Crit Care Med 28:2750–2757CrossRefPubMedGoogle Scholar
  12. Huguenard JR, Prince DA (1994) Clonazepam suppresses GABAB-mediated inhibition in thalamic relay neurons through effects in nucleus reticularis. J Neurophysiol 71:2576–2581PubMedGoogle Scholar
  13. Inghilleri M, Berardelli A, Marchetti P, Manfredi M (1996) Effects of diazepam, baclofen and thiopental on the silent period evoked by transcranial magnetic stimulation in humans. Exp Brain Res 109:467–472CrossRefPubMedGoogle Scholar
  14. Kimiskidis VK, Papagiannopoulos S, Sotirakoglou K, Kazis DA, Kazis A, Mills KR (2005) Silent period to transcranial magnetic stimulation: construction and properties of stimulus-response curves in healthy volunteers. Exp Brain Res 163:21–31CrossRefPubMedGoogle Scholar
  15. Lopantsev V, Schwartzkroin PA (1999) GABAA-Dependent chloride influx modulates GABAB-mediated IPSPs in hippocampal pyramidal cells. J Neurophysiol 82:1218–1223PubMedGoogle Scholar
  16. Macdonald RL, Barker JL (1978) Benzodiazepines specifically modulate GABAmediated postsynaptic inhibition in cultured mammalian neurons. Nature 271:563–564CrossRefPubMedGoogle Scholar
  17. Malcangio M, Bowery NG (1996) GABA and its receptors in the spinal cord. TiPS 17:457–462PubMedGoogle Scholar
  18. Mathis J, de Quervain D, Hess CW (1998) Dependence of the transcranially induced silent period on the ‘instruction set’ and the individual reaction time. Electroencephalogr Clin Neurophysiol 109:426–435CrossRefPubMedGoogle Scholar
  19. McLean MJ, Macdonald RL (1988) Benzodiazepines, but not beta carbolines, limit high frequency firing of action potentials of spinal cord neurons in cell culture. J Pharmacol Exp Ther 244:789–795PubMedGoogle Scholar
  20. Mills KR (1999) Measurement of the silent period. In: Mills KR (ed) Magnetic stimulation of the human nervous system. Oxford University, Oxford, pp 177Google Scholar
  21. Mills KR, Nithi KA (1997) Corticomotor threshold to magnetic stimulation: normal values and repeatability. Muscle Nerve 20:570–576CrossRefPubMedGoogle Scholar
  22. Mills KR, Boniface SJ, Schubert M (1992) Magnetic brain stimulation with a double coil: the importance of coil orientation. Electroencephalogr Clin Neurophysiol 85:17–21CrossRefPubMedGoogle Scholar
  23. Mody I, De Koninck Y, Otis TS, Soltesz I (1994) Bridging the cleft at GABA synapses in the brain. Trends Neurosci 17:517–525CrossRefPubMedGoogle Scholar
  24. Motulsky H, Christopoulos A (2003) Fitting models to biological data using linear and non-linear regression. A practical guide to curve fitting. GraphPad Inc, San Diego CA, 134–48
  25. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H (1997) Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol 498:817–823PubMedGoogle Scholar
  26. Palmieri MG, Iani C, Scalise A, Desiato MT, Loberti M, Telera S, Caramia MD (1999) The effect of benzodiazepines and flumazenil on motor cortical excitability in the human brain. Brain Res 815:192–199CrossRefPubMedGoogle Scholar
  27. Rogers CJ, Twyman RE, Macdonald RL (1994) Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal cord neurons in culture. J Physiol 475:69–82PubMedGoogle Scholar
  28. Schaerer MT, Buhr A, Baur R, Sigel E (1998) Amino acid residue 200 on the α1 subunit of GABA-a receptors affects the interaction with selected benzodiazepine binding site ligands. Eur J Pharmacol 354:283–287CrossRefPubMedGoogle Scholar
  29. Schonle PW, Isenberg C, Crozier TA, Dressler D, Machetanz J, Conrad B (1989) Changes of transcranially evoked motor responses in man by midazolam, a short acting benzodiazepine. Neurosci Lett 101:321–324CrossRefPubMedGoogle Scholar
  30. Schreckenberger M, Lange-Asschenfeld C, LochmannM, Mann K, Siessmeier T, Buchholz HG, Bartenstein P, Grunder G (2004) The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans. Neuroimage 22:637–644CrossRefPubMedGoogle Scholar
  31. Stanford IM, Wheal HV, Chad JE (1995) Bicuculline enhances the late GABAB receptor-mediated paired-pulse inhibition observed in rat hippocampal slices. Eur J Pharmacol 277:229–234CrossRefPubMedGoogle Scholar
  32. Study RE, Barker JL (1981) Diazepam and (–)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyric acid responses in cultured central neurons. Proc Natl Acad Sci USA 78:7180–7184PubMedCrossRefGoogle Scholar
  33. Thomson AM, Destexhe A (1999) Dual intracellular recordings and computational models of slow inhibitory postsynaptic potentials in rat neocortical and hippocampal slices. Neuroscience 92:1193–1215CrossRefPubMedGoogle Scholar
  34. Weinbroum A, Halpern P, Geller E (1991) The use of flumazenil in the management of acute drug poisoning–a review. Intensive Care Med 17(Suppl 1):S32–S38CrossRefPubMedGoogle Scholar
  35. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J (1999) Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol 517:591–597CrossRefPubMedGoogle Scholar
  36. Yung HY, Sohn YH, Mason A, Considine E, Hallett M (2004) Flumazenil does not affect intracortical motor excitability in humans: a transcranial magnetic stimulation study. Clin Neurophysiol 115:325–329CrossRefPubMedGoogle Scholar
  37. Ziemann U (2005) Evaluation of epilepsy and anticonvulsants. In: Hallett M, Chokroverty S (eds) Magnetic stimulation in clinical neurophysiology. Elsevier, Philadelphia, pp 253–265Google Scholar
  38. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W (1996) The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 109:127–135CrossRefPubMedGoogle Scholar
  39. Ziemann U, Tergau F, Wischer S, Hildebrandt J, Paulus W (1998) Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A paired transcranial magnetic stimulation study. Electroencephalogr Clin Neurophysiol 109:321–330CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • V. K. Kimiskidis
    • 1
  • S. Papagiannopoulos
    • 1
  • D. A. Kazis
    • 1
  • K.  Sotirakoglou
    • 2
  • G.  Vasiliadis
    • 1
  • F. Zara
    • 1
  • A. Kazis
    • 1
  • K. R. Mills
    • 3
  1. 1.Department of Neurology III, “G.Papanikolaou” HospitalAristotle University of ThessalonikiThessalonikiGreece
  2. 2.Laboratory of Mathematics & StatisticsAgricultural University of AthensAthensGreece
  3. 3.Academic Unit of Clinical Neurophysiology, Guy’s, King’s and St Thomas School of MedicineKing’s College HospitalLondonUK

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