Real-Time Brain-State-Coupled Corticocortical Paired Associative Stimulation of Cognitive Networks

Brain networks coordinate distributed neuronal assemblies to support cognition. Spike-timing-dependent plasticity (STDP) and neuronal oscillations are key substractes for state-gated learning rules that shape network coupling and cognitive operations; nonetheless, how STDP mechanisms interact with neuronal oscillations is largely unexplored in humans. Corticocortical paired associative stimulation (ccPAS) provides a noninvasive system-level model of associative timing rules by pairing dual-site transcranial magnetic stimulation (TMS) across axonally connected regions with an interstimulus interval matched to pathway conduction. Here we (1) synthesize ccPAS applications and barriers to brain-state-coupled implementation in cognitive networks; (2) provide an actionable roadmap for real-time state estimation, targeting, and dual-site parameter selection; and (3) demonstrate a novel implementation of theta phase-locked frontoparietal (FP) ccPAS with concurrent EEG in adult human participants. We tested whether ccPAS delivered at the positive phase of ongoing theta (POS) induces distinct changes in evoked EEG activity and FP connectivity compared with phase-uncoupled ccPAS (RAND) and phase-locked single-site prefrontal (PREF) controls. At the evoked level, POS produced a frontocentral polarity reversal of the canonical N45 component and a right parietotemporal negativity relative to both controls. At the network level, POS induced frequency-specific reconfigurations in postintervention connectivity beyond either control ingredient alone. Together, these changes in evoked activity and rapid network reconfiguration provide the first empirical evidence consistent with phase-gated STDP in humans-whereby oscillatory phase gates cortical excitability and modulates STDP efficacy-emerging as short-term network-level expression. Future work will assess long-term plasticity by tracking connectivity at later time points and testing for concomitant behavioral effects.