Pharmacological evidence for propagation dynamics of TMS-evoked potentials in the human brain.

BACKGROUND: Transcranial magnetic stimulation-evoked potentials (TEPs) propagate from the stimulation site to distributed brain networks, with early propagation thought to occur predominantly through feedforward processes and later propagation through recurrent processes. We employed pharmacological manipulation to probe mechanisms that underlie feedforward and recurrent signal propagation in the human brain. METHODS: We manipulated TEP propagation using GABAAergic drugs in placebo-controlled randomized crossover experiments in healthy participants. Experiment 1 tested zolpidem and alprazolam, while Experiment 2 tested diazepam. Experiment 3 compared active and sham TMS-EEG to verify the specificity of diazepam effects on TEPs. RESULTS: Alprazolam decreased β-band phase coupling within large-scale neural networks in the early feedforward stage. During the late recurrent stage, it reduced significant current density (SCD), significant current scattering (SCS) and the perturbational complexity index (PCI-lz). In contrast, zolpidem increased early-stage SCD and TMS-induced event-related spectral perturbations, but did not affect β-band phase coupling, SCS, or PCI-lz. Structural equation modeling revealed that the early-stage changes in β-band phase coupling predicted directly or indirectly the late-stage changes in SCD, SCS, PCI-lz and saccadic peak velocity, a marker of GABAAergic sedation. Diazepam replicated the alprazolam effects. The active vs. sham TMS-EEG comparison showed that the reductions in late-stage SCD and SCS induced by diazepam reflected specific modulation of TEPs. CONCLUSIONS: Findings provide a novel framework of how local neural dynamics shape signal propagation to large-scale networks and identify early-stage β-band phase coupling as a key mechanism. Consequently, considering propagation dynamics is important when interpreting PCI alterations in brain disorders.