Phase-dependent local brain states determine the impact of image-guided transcranial magnetic stimulation on motor...

Recent studies have synchronized transcranial magnetic stimulation (TMS) application with pre-defined brain oscillatory phases showing how brain response to perturbation depends on the brain state. However, none have investigated whether phase-dependent TMS can possibly modulate connectivity with homologous distant brain regions belonging to the same network. In the framework of network-targeted TMS, we investigated whether stimulation delivered at a specific phase of ongoing brain oscillations might favour stronger cortico-cortical (c-c) synchronization of distant network nodes connected to the stimulation target. Neuronavigated TMS pulses were delivered over the primary motor cortex (M1) during ongoing electroencephalography recording in 24 healthy individuals over two repeated sessions 1 month apart. Stimulation effects were analysed considering whether the TMS pulse was delivered at the time of a positive (peak) or negative (trough) phase of μ-frequency oscillation, which determines c-c synchrony within homologous areas of the sensorimotor network. Diffusion weighted imaging was used to study c-c connectivity within the sensorimotor network and identify contralateral regions connected with the stimulation spot. Depending on when during the μ-activity the TMS-pulse was applied (peak or trough), its impact on inter-hemispheric network synchrony varied significantly. Higher M1-M1 phase-lock synchronization after the TMS-pulse (0-200 ms) in the μ-frequency band was found for trough compared to peak stimulation trials in both study visits. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase the magnitude and reliability of the response to the external perturbation, with implications for interventions aimed at engaging more distributed functional brain networks. KEY POINTS: Synchronized transcranial magnetic stimulation (TMS) pulses with pre-defined brain oscillatory phases allow evaluation of the impact of brain states on TMS effects. TMS pulses over M1 at the negative peak of the μ-frequency band induce higher phase-lock synchronization with interconnected contralateral homologous regions. Cortico-cortical synchronization changes are linearly predicted by the fibre density and cross-section of the white matter tract that connects the two brain regions. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase the magnitude and reliability of within-network synchronization.