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)... Show moreAims 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 mu V; 95%CI: -644.3, -112.5 mu V; P < .01), valproic acid (ED -268.8 mu V; 95%CI: -532.9, -4.6 mu V; P = .047) and lorazepam (ED -330.7 mu V; 95%CI: -595.6, -65.8 mu V; 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. Show less
Graph analysis was used to study the effects of accelerated intermittent theta burst stimulation (aiTBS) on the brain's network topology in medication-resistant depressed patients. Anatomical and... Show moreGraph analysis was used to study the effects of accelerated intermittent theta burst stimulation (aiTBS) on the brain's network topology in medication-resistant depressed patients. Anatomical and resting-state functional MRI (rs-fMRI) was recorded at baseline and after sham and verum stimulation. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS). Using various graph measures, the different effects of sham and verum aiTBS were calculated. It was also investigated whether changes in graph measures were correlated to clinical responses. Furthermore, by correlating baseline graph measures with the changes in HDRS in terms of percentage, the potential of graph measures as biomarker was studied. Although no differences were observed between the effects of verum and sham stimulation on whole-brain graph measures and changes in graph measures did not correlate with clinical response, the baseline values of clustering coefficient and global efficiency showed to be predictive of the clinical response to verum aiTBS. Nodal effects were found throughout the whole brain. The distribution of these effects could not be linked to the strength of the functional connectivity between the stimulation site and the node. This study showed that the effects of aiTBS on graph measures distribute beyond the actual stimulation site. However, additional research into the complex interactions between different areas in the brain is necessary to understand the effects of aiTBS in more detail. Show less
