Cortical markers of PAS-induced long-term potentiation and depression in the motor system: A TMS-EEG Registered Report

Paired associative stimulation (PAS), a neuromodulation protocol combining transcranial magnetic stimulation (TMS) pulses to the primary motor cortex (M1) with electrical median nerve stimulation, promotes synaptic plasticity (long-term potentiation - LTP, long-term depression - LTD) in the human motor system following Hebbian associative plasticity induction. To date, PAS effects have been mainly investigated at the corticospinal level. In the present Registered Report, we leveraged TMS and electroencephalography (TMS-EEG) co-registration to track the cortical dynamics related to M1-PAS, aiming to better characterize the neurophysiological substrates, grounding the effectiveness of such protocol. In two within-subject sessions, 30 healthy participants underwent the standard M1-PAS protocols inducing LTP (PASLTP) and LTD (PASLTD) while measuring motor-evoked potentials (MEPs) and TMS-evoked potentials (TEPs) from M1 stimulation before, immediately after, and 30 minutes after the end of the PAS, applied both at supra- (i.e., 110%) and sub- (i.e., 90%) resting motor threshold intensities. Besides replicating MEPs enhancement and inhibition after PASLTP and PASLTD, our results showed that the P30 and N100 M1-TEPs components were significantly modulated immediately following PASLTP and PASLTD administration. These effects were detectable only in suprathreshold conditions, suggesting that M1 subthreshold stimulation could not be optimal for tracking cortical effects of PAS. Furthermore, exploratory analyses showed that P60 amplitude at baseline successfully predicted the magnitude of P30 modulations after PASLTP administration. Our findings provide compelling evidence regarding the specificity of early TEP components in reflecting changes in M1 reactivity that underpin PAS effects and associative plasticity induction within the motor system. From a broader perspective, our study fosters evidence about using TMS-EEG biomarkers to track complex plastic changes induced in the human brain, exploiting neuromodulatory non-invasive brain stimulation protocols based on associative mechanisms, like PAS.