Effects of the selective α5-GABAAR antagonist S44819 on excitability in the human brain: A TMS–EMG and TMS–EEG phase I study

Journal of Neuroscience

Volumn 36, Issue 49, 2016, Pages 12312-12320

  Darmani, Ghazaleh ^a   Zipser, Carl M ^a   Böhmer, Gabriele M ^b   Deschet, Karine ^c   Müller Dahlhaus, Florian ^a   Belardinelli, Paolo ^a   Schwab, Matthias ^b,d,e   Ziemann, Ulf ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

^b UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

^c IRIS Institut de Recherches Internationales Servier   (France)

^d UNIVERSITY OF TÜBINGEN   (Germany)

^e DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

Author keywords

Excitability; Human cortex; Motor evoked potential; TMS EEG; Tonic inhibition; 5 GABAAR

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR ALPHA5; 4 AMINOBUTYRIC ACID A RECEPTOR BLOCKING AGENT; COTININE; PLACEBO; 4 AMINOBUTYRIC ACID A RECEPTOR; GABRA5 PROTEIN, HUMAN;

ADULT; AMPLITUDE MODULATION; ARTICLE; CONTROLLED STUDY; CROSSOVER PROCEDURE; DOUBLE BLIND PROCEDURE; DRUG EFFECT; DRUG EFFICACY; DRUG SCREENING; ELECTROENCEPHALOGRAPHY; ELECTROMYOGRAPHY; HUMAN; HUMAN EXPERIMENT; MALE; MOTOR EVOKED POTENTIAL; NERVE EXCITABILITY; NORMAL HUMAN; PHARMACOKINETIC PARAMETERS; PHASE 1 CLINICAL TRIAL; PRIMARY MOTOR CORTEX; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; STIMULUS RESPONSE; TRANSCRANIAL MAGNETIC STIMULATION; BRAIN; CLINICAL TRIAL; DRUG EFFECTS; PROCEDURES; YOUNG ADULT;

ADULT; BRAIN; CROSS-OVER STUDIES; DOUBLE-BLIND METHOD; ELECTROENCEPHALOGRAPHY; ELECTROMYOGRAPHY; EVOKED POTENTIALS, MOTOR; GABA-A RECEPTOR ANTAGONISTS; HEALTHY VOLUNTEERS; HUMANS; MALE; RECEPTORS, GABA-A; TRANSCRANIAL MAGNETIC STIMULATION; YOUNG ADULT;

EID: 85006059520     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.1689-16.2016     Document Type: Article

References (53)

1. Bonato C, Miniussi C, Rossini PM (2006) Transcranial magnetic stimulation and cortical evoked potentials: a TMS/EEG co-registration study. Clin Neurophysiol 117:1699-1707.
2. Boroojerdi B, Battaglia F, Muellbacher W, Cohen LG (2001) Mechanisms influencing stimulus-response properties of the human corticospinal system. Clin Neurophysiol 112:931-937.
3. Brünig I, Scotti E, Sidler C, Fritschy JM (2002) Intact sorting, targeting, and clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J Comp Neurol 443:43-55.
4. Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA (2004) Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A 101:3662-3667.
5. Carmichael ST (2012) Brain excitability in stroke: the yin and yang of stroke progression. Arch Neurol 69:161-167.
6. Casarotto S, Romero Lauro LJ, Bellina V, Casali AG, Rosanova M, Pigorini A, Defendi S, Mariotti M, Massimini M (2010) EEG responses to TMS are sensitive to changes in the perturbation parameters and repeatable over time. PLoS One 5:e10281.
7. Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST (2010) Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468:305-309.
8. Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Blüthmann H, Möhler H, Rudolph U (2002) Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors. Proc Natl Acad SciU S A 99:8980-8985.
9. Di Lazzaro V, Ziemann U (2013) The contribution of transcranial magnetic stimulation in the functional evaluation of microcircuits in human motor cortex. Front Neural Circuits 7:18.
10. 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 111:794-799.
11. 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 564:661-668.
12. Di Lazzaro V, Pilato F, Dileone M, Ranieri F, Ricci V, Profice P, Bria P, Tonali PA, Ziemann U (2006) GABAA receptor subtype specific enhancement of inhibition in human motor cortex. J Physiol 575:721-726.
13. Di Lazzaro V, Pilato F, Dileone M, Profice P, Ranieri F, Ricci V, Bria P, Tonali PA, Ziemann U (2007) Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study. Clin Neurophysiol 118:2207-2214.
14. Di Lazzaro V, Ziemann U, Lemon RN (2008) State of the art: physiology of transcranial motor cortex stimulation. Brain Stimul 1:345-362.
15. Farrant M, Nusser Z (2005) Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 6:215-229.
16. Ferreri F, Pasqualetti P, Mättä S, Ponzo D, Ferrarelli F, Tononi G, Mervaala E, Miniussi C, Rossini PM (2011) Human brain connectivity during single and paired pulse transcranial magnetic stimulation. Neuroimage 54:90-102.
17. Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, Kaelin-Lang A, Mima T, Rossi S, Thickbroom GW, Rossini PM, Ziemann U, Valls-Solé J, Siebner HR (2012) A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 123: 858-882.
18. Ilic TV, Meintzschel F, Cleff 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.
19. Institut de Recherches Internationales Servier (2014) S44819. Investigator’s brochure.
20. Jung 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 115:325-329.
21. Keel JC, Smith MJ, Wassermann EM (2001) A safety screening questionnaire for transcranial magnetic stimulation [letter]. Clin Neurophysiol 112:720.
22. Komssi S, Kähkönen S, Ilmoniemi RJ (2004) The effect of stimulus intensity on brain responses evoked by transcranial magnetic stimulation. Hum Brain Mapp 21:154-164.
23. Lioumis P, Kicic D, Savolainen P, Mäkelä JP, Kähkönen S (2009) Reproducibility of TMS-Evoked EEG responses. Hum Brain Mapp 30:1387-1396.
24. Litvak V, Komssi S, Scherg M, Hoechstetter K, Classen J, Zaaroor M, Pratt H, Kahkonen S (2007) Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex. Neuroimage 37:56-70.
25. Maris E, Oostenveld R (2007) Nonparametric statistical testing of EEG-and MEG-data. J Neurosci Methods 164:177-190.
26. Martin LJ, Zurek AA, MacDonald JF, Roder JC, Jackson MF, Orser BA (2010) Alpha5GABAA receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory. J Neurosci 30:5269-5282.
27. Massimini M, Ferrarelli F, Huber R, Esser SK, Singh H, Tononi G (2005) Breakdown of cortical effective connectivity during sleep. Science 309: 2228-2232.
28. Maubach K (2003) GABA(A) receptor subtype selective cognition enhancers. Curr Drug Targets CNS Neurol Disord 2:233-239.
29. Mitchell SJ, Silver RA (2003) Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron 38:433-445.
30. Möhler H (2006) GABA(A) receptor diversity and pharmacology. Cell Tissue Res 326:505-516.
31. Möhler H, Fritschy JM, Rudolph U (2002) A new benzodiazepine pharmacology. J Pharmacol Exp Ther 300:2-8.
32. Müller-Dahlhaus JF, Liu Y, Ziemann U (2008) Inhibitory circuits and the nature of their interactions in the human motor cortex: a pharmacological TMS study. J Physiol 586:495-514.
33. Nitsche MA, Paulus W (2000) Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 527:633-639.
34. Nitsche MA, Paulus W (2001) Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57: 1899-1901.
35. Nitsche MA, Seeber A, Frommann K, Klein CC, Rochford C, Nitsche MS, Fricke K, Liebetanz D, Lang N, Antal A, Paulus W, Tergau F (2005) Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J Physiol 568:291-303.
36. Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97-113.
37. Pálvölgyi A, Etherington LA, Mihalik B, Ling I, Pallagi K, Kertész S, Gunn BG, Brown AR, Livesey MR, Belelli D, Barkóczy J, Varga P, Spedding M, Gacsályi I, Lambert JJ, Antoni FA (2016) Selective targeting of extrasynaptic α5-GABAA receptors by S44819 (Egis-13529), a novel competitive GABAA receptor inhibitor compound. Soc Neurosci Abstr 124.16.
38. Peurala SH, Müller-Dahlhaus JF, Arai N, Ziemann U (2008) Interference of short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF). Clin Neurophysiol 119:2291-2297.
39. Premoli I, Rivolta D, Espenhahn S, Castellanos N, Belardinelli P, Ziemann U, Müller-Dahlhaus F (2014a) Characterization of GABAB-receptor mediated neurotransmission in the human cortex by paired-pulse TMS-EEG. Neuroimage 103:152-162.
40. Premoli I, Castellanos N, Rivolta D, Belardinelli P, Bajo R, Zipser C, Espenhahn S, Heidegger T, Müller-Dahlhaus F, Ziemann U (2014b) TMS-EEG signatures of GABAergic neurotransmission in the human cortex. J Neurosci 34:5603-5612.
41. Quirk K, Blurton P, Fletcher S, Leeson P, Tang F, Mellilo D, Ragan CI, McKernan RM (1996) [3H]L-655,708, a novel ligand selective for the benzodiazepine site of GABAA receptors which contain the alpha 5 subunit. Neuropharmacology 35:1331-1335.
42. Ridding MC, Taylor JL, Rothwell JC (1995) The effect of voluntary contraction on cortico-cortical inhibition in human motor cortex. J Physiol 487: 541-548.
43. Rogasch NC, Fitzgerald PB (2013) Assessing cortical network properties using TMS-EEG. Hum Brain Mapp 34:1652-1669.
44. Rogasch NC, Thomson RH, Daskalakis ZJ, Fitzgerald PB (2013) Shortlatency artifacts associated with concurrent TMS-EEG. Brain Stimul 6:868-876.
45. Rogasch NC, Thomson RH, Farzan F, Fitzgibbon BM, Bailey NW, Hernandez-Pavon JC, Daskalakis ZJ, Fitzgerald PB (2014) Removing artefacts from TMS-EEG recordings using independent component analysis: importance for assessing prefrontal and motor cortex network properties. Neuroimage 101:425-439.
46. Sanger TD, Garg RR, Chen R (2001) Interactions between two different inhibitory systems in the human motor cortex. J Physiol 530:307-317.
47. Schmidt S, Bruehl C, Frahm C, Redecker C, Witte OW (2012) Age dependence of excitatory-inhibitory balance following stroke. Neurobiol Aging 33:1356-1363.
48. Teo JT, Terranova C, Swayne O, Greenwood RJ, Rothwell JC (2009) Differing effects of intracortical circuits on plasticity. Exp Brain Res 193:555-563.
49. Thut G, Veniero D, Romei V, Miniussi C, Schyns P, Gross J (2011) Rhythmic TMS causes local entrainment of natural oscillatory signatures. Curr Biol 21:1176-1185.
50. 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 517:591-597.
51. Ziemann U, Lönnecker S, Steinhoff BJ, Paulus W (1996a) The effect of lorazepam on the motor cortical excitability in man. Exp Brain Res 109: 127-135.
52. Ziemann U, Lönnecker S, Steinhoff BJ, Paulus W (1996b) Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 40:367-378.
53. Ziemann U, Reis J, Schwenkreis P, Rosanova M, Strafella A, Badawy R, Müller-Dahlhaus F (2015) TMS and drugs revisited 2014. Clin Neurophysiol 126:1847-1868.