Gradual enhancement of corticomotor excitability during cortico-cortical paired associative stimulation

Cortico-cortical paired associative stimulation (ccPAS) is an effective transcranial magnetic stimulation (TMS) method for inducing associative plasticity between interconnected brain areas in humans. Prior ccPAS studies have focused on protocol's aftereffects. Here, we investigated physiological changes induced "online" during ccPAS administration. We tested 109 participants receiving ccPAS over left ventral premotor cortex (PMv) and primary motor cortex (M1) using a standard procedure (90 paired-pulses with 8-ms interstimulus interval, repeated at 0.1 Hz frequency). On each paired-pulse, we recorded a motor-evoked potential (MEP) to continuously trace the emergence of corticomotor changes. Participant receiving forward-ccPAS (on each pair, a first TMS pulse was administered over PMv, second over M1, i.e., PMv-to-M1) showed a gradual and linear increase in MEP size that did not reach a plateau at the end of the protocol and was greater in participants with low motor threshold. Participants receiving reverse-ccPAS (i.e., M1-to-PMv) showed a trend toward inhibition. Our study highlights the facilitatory and inhibitory modulations that occur during ccPAS administration and suggest that online MEP monitoring could provide insights into the malleability of the motor system and protocol's effectiveness. Our findings open interesting prospects about ccPAS potential optimization in experimental and clinical settings.