Time-dependent enhancement of corticospinal excitability during cortico-cortical paired associative stimulation of the hV6A-M1 network in the human brain

Cortico-cortical paired associative stimulation (ccPAS) is a powerful transcranial magnetic stimulation (TMS) protocol thought to rely on Hebbian plasticity and known to strengthen effective connectivity, mainly within frontal lobe networks. Here, we expand on previous work by exploring the effects of ccPAS on the pathway linking the medial posterior parietal area hV6A with the primary motor cortex (M1), whose plasticity mechanisms remain largely unexplored. To assess the effective connectivity of the hV6A-M1 network, we measured motor-evoked potentials (MEPs) in 30 right-handed volunteers at rest during dual-site, paired-pulse TMS. Consistent with previous findings, we found that MEPs were inhibited when the conditioning stimulus over hV6A preceded the test stimulus over M1 by 12 ms, highlighting inhibitory hV6A-M1 causal interactions. We then manipulated the hV6A-M1 circuit via ccPAS using different inter-stimulus intervals (ISI) never tested before. Our results revealed a time-dependent modulation. Specifically, only when the conditioning stimulus preceded the test one by 12 ms did we find a gradual increase of MEP amplitude during ccPAS, and excitatory aftereffects. In contrast, when ccPAS was applied with an ISI of 4 ms or 500 ms, no corticospinal excitability changes were observed, suggesting that temporal specificity is a critical factor in modulating the hV6A-M1 network. These results suggest that ccPAS can induce time-dependent Hebbian plasticity in the dorsomedial parieto-frontal network at rest, offering novel insights into the network's plasticity and temporal dynamics.