How Thalamo-Cortical Loops Modulate Cortico-Cortical Evoked Potentials?

The thalamic origin of late components of cortico-cortical evoked potentials (CCEPs) was recently demonstrated, but the role of higher-order thalamic nuclei in modulating CCEP dynamics through cortico-thalamo-cortical loops remains unexplored. We analyzed stereoelectroencephalography recordings from five patients with refractory epilepsy who underwent cortical single-pulse electrical stimulation with simultaneous thalamic and cortical recording. Significant cortico-thalamic evoked potentials (CTEPs) and CCEPs were identified using t-tests. Effective connectivity was examined using nonlinear h2 correlation on averaged data and intertrial correlations to characterize bidirectional cortico-thalamic interactions at multiple timescales. Fifteen cortical stimulations evoked significant CTEPs localized in the pulvinar and CCEPs. H2 analysis revealed iterative recruitment of cortico-thalamic loops throughout the response, with alternating corticothalamic and thalamocortical connectivity. Intertrial correlation analysis demonstrated delayed thalamocortical connectivity, suggesting polysynaptic pathways. Cortico-thalamic loops contribute to CCEP dynamics through iterative recruitment at both short and long timescales, with thalamic involvement extending from early to late response components. These findings challenge the traditional view of CCEPs as purely reflecting direct cortico-cortical propagation and demonstrate that higher-order thalamic nuclei actively shape cortico-cortical connectivity patterns, with implications for interpreting CCEPs and understanding thalamic neuromodulation mechanisms in epilepsy.