Phase-specific stimulation reveals consistent sinusoidal modulation of human corticospinal excitability along the oscillatory beta cycle

The responsiveness of neuronal populations to incoming information fluctuates. Retrospective analyses of randomly applied stimuli reveal a neural input-output relationship along the intrinsic oscillatory cycle. Prospectively harnessing this biological mechanism would necessitate frequency- and phase-specificity, intra- and inter-individual consistency, and instantaneous access to the oscillatory cycle. We used a novel real-time approach to electroencephalography-triggered transcranial magnetic stimulation to precisely target 8 equidistant phases of the oscillatory cycle in the human motor cortex of male and female healthy participants. The phase-dependency of corticospinal excitability was investigated in ten different intrinsic frequencies (4, 8, 12, 16, 20, 24, 28, 32, 36, and 40Hz) and indexed by motor-evoked potentials (MEP) in the corresponding forearm muscle. On both the individual and group level, we detected a consistent sinusoidal MEP modulation along the oscillatory cycle at 24Hz ({chi}22 =9.2, p=.01), but not at any other target frequency (all {chi}22 .08). Moreover, cross-validations showed also at 24Hz the highest consistency of the optimal phase between prospective (real-time) and retrospective (out-of-sample) testing (r=.605, p<.001), and across experimental sessions on three different days (r[≥].45). The optimal corticospinal signal transmission was at the transition from the trough to the rising flank of the oscillatory 24Hz cycle. Integrating real-time measurement and brain stimulation revealed that the sinusoidal input-output relationship of corticospinal signal transmission is frequency- and phase specific, and consistent within and across individuals and sessions. In future, this approach allows to selectively and repetitively target windows of increased responsiveness, and to thereby investigate potential cumulative effects on plasticity induction.