TY - JOUR
T1 - Transcranial magnetic stimulation as biomarker of excitability in drug development
T2 - A randomized, double-blind, placebo-controlled, cross-over study
AU - Ruijs, Titia Q.
AU - Heuberger, Jules A.A.C.
AU - de Goede, Annika A.
AU - Ziagkos, Dimitrios
AU - Otto, Marije E.
AU - Doll, Robert J.
AU - van Putten, Michel J.A.M.
AU - Groeneveld, Geert Jan
N1 - Funding Information:
We thank Karen Broekhuizen who provided medical writing services on behalf of the Centre for Human Drug Research, Leiden, The Netherlands. This study was financially supported by Stichting Life Sciences Holland (LSH) - TKI, Health~Holland, under LSH Match number LSHM16055-SGF. The funding source had no involvement in the conduct of the research and preparation of the article.
Publisher Copyright:
© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2022/6
Y1 - 2022/6
N2 - Aims: The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof-of-mechanism in early-phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double-blind, placebo-controlled, 4-way cross-over study.Methods: In 16 healthy male subjects, single- and paired-pulse TMS-EMG–EEG measurements were performed predose and 1.5, 7 and 24 hours postdose. Treatment effects on motor-evoked potential, short and long intracortical inhibition and TMS-evoked potential amplitudes, were analysed using a mixed model ANCOVA and cluster-based permutation analysis.Results: We show that motor-evoked potential amplitudes decreased after administration of levetiracetam (estimated difference [ED] −378.4 μV; 95%CI: −644.3, −112.5 μV; P <.01), valproic acid (ED −268.8 μV; 95%CI: −532.9, −4.6 μV; P =.047) and lorazepam (ED −330.7 μV; 95%CI: −595.6, −65.8 μV; P =.02) when compared with placebo. Long intracortical inhibition was enhanced by levetiracetam (ED −60.3%; 95%CI: −87.1%, −33.5%; P <.001) and lorazepam (ED −68.2%; 95%CI: −94.7%, −41.7%; P <.001) at a 50-ms interstimulus interval. Levetiracetam increased TMS-evoked potential component N45 (P =.004) in a central cluster and decreased N100 (P <.001) in a contralateral cluster.Conclusion: This study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS-EMG–EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability.
AB - Aims: The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof-of-mechanism in early-phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double-blind, placebo-controlled, 4-way cross-over study.Methods: In 16 healthy male subjects, single- and paired-pulse TMS-EMG–EEG measurements were performed predose and 1.5, 7 and 24 hours postdose. Treatment effects on motor-evoked potential, short and long intracortical inhibition and TMS-evoked potential amplitudes, were analysed using a mixed model ANCOVA and cluster-based permutation analysis.Results: We show that motor-evoked potential amplitudes decreased after administration of levetiracetam (estimated difference [ED] −378.4 μV; 95%CI: −644.3, −112.5 μV; P <.01), valproic acid (ED −268.8 μV; 95%CI: −532.9, −4.6 μV; P =.047) and lorazepam (ED −330.7 μV; 95%CI: −595.6, −65.8 μV; P =.02) when compared with placebo. Long intracortical inhibition was enhanced by levetiracetam (ED −60.3%; 95%CI: −87.1%, −33.5%; P <.001) and lorazepam (ED −68.2%; 95%CI: −94.7%, −41.7%; P <.001) at a 50-ms interstimulus interval. Levetiracetam increased TMS-evoked potential component N45 (P =.004) in a central cluster and decreased N100 (P <.001) in a contralateral cluster.Conclusion: This study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS-EMG–EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability.
KW - Antiepileptic drugs
KW - Biomarkers
KW - Cortical excitability
KW - Levetiracetam
KW - Lorazepam
KW - TMS-EEG
KW - TMS-EMG
KW - Transcranial magnetic stimulation
KW - Valproic acid
UR - https://www.scopus.com/pages/publications/85124156301
U2 - 10.1111/bcp.15232
DO - 10.1111/bcp.15232
M3 - Article
C2 - 35028950
AN - SCOPUS:85124156301
SN - 0306-5251
VL - 88
SP - 2926
EP - 2937
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 6
ER -