State dependent motor cortex stimulation reveals distinct mechanisms for corticospinal excitability and cortical responses.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method that modulates brain activity by inducing electric fields in the brain. Real-time, state-dependent stimulation with TMS has shown that neural oscillation phase modulates corticospinal excitability. However, such motor-evoked potentials (MEPs) only indirectly reflect motor cortex activation and are unavailable at other brain regions of interest. The direct and secondary cortical effects of phase-dependent brain stimulation remain an open question. In this study, we recorded the cortical responses during single-pulse TMS using electroencephalography (EEG) concurrently with the MEP measurements in 20 healthy human volunteers (11 female). TMS was delivered at peak, rising, trough, and falling phases of mu (8-13 Hz) and beta (14-30 Hz) oscillations in the motor cortex. The cortical responses were quantified through TMS-evoked potential components N15, P50, and N100 as peak-to-peak amplitudes (P50-N15 and P50-N100). We further analyzed whether the pre-stimulus frequency band power was predictive of the cortical responses. We demonstrated that phase-specific targeting modulates cortical responses. The phase relationship between cortical responses was different for early and late responses. In addition, pre-TMS mu oscillatory power and phase significantly predicted both early and late cortical EEG responses in mu-specific targeting, indicating the independent causal effects of phase and power. However, only pre-TMS beta power significantly predicted the early and late TEP components during beta-specific targeting. Further analyses indicated distinct roles of mu and beta power on cortical responses. These findings provide insight to mechanistic understanding of neural oscillation states in cortical and corticospinal activation in humans.Significance Statement Understanding the effects of noninvasive neuromodulation on human brain provides valuable insights to its clinical utility. Brain state dependent stimulation helps us understand mechanisms leading to cortical responses and behavioral outcomes. Here we study the effects of the phase of ongoing oscillations in the motor cortex on cortical responses measured by electroencephalography. We also studied the relationship of phase preference between cortical responses and motor evoked potentials. Furthermore, we investigated the effects of the power of ongoing oscillations on cortical responses. These findings are important to understand the changes in biomarkers during state-dependent brain stimulation and their relationship to behavioral outcomes. At large, this helps the researchers to utilize state-dependent brain stimulation to enhance treatment efficacy.