Optical cortico-cortical evoked potentials reveal structural and state-dependent cortical communication

Year: 2026

Authors: Resta F., Scaglione A., Conti E., Gerace E., Pavone F.S.

Autors Affiliation: European Lab Non Linear Spect LENS, Florence, Italy; Natl Res Council INO CNR, Natl Inst Opt, Sesto Fiorentino, Italy; Univ Florence, Dept Phys & Astron, Florence, Italy; Univ Florence, Dept Hlth Sci, Florence, Italy.

Abstract: Background: Cortico-cortical evoked potentials probe causal cortical communication in humans; however, establishing a preclinical methodological counterpart that combines cortex-wide coverage, high temporal resolution, minimal invasiveness, and awake-state recording remains challenging. Objective: To map causal cortical communication and determine how local excitability, anatomical connectivity, and brain state jointly shape signal propagation across the cortex. Methods: We used an all-optical platform that combines single-pulse transcranial optogenetic stimulation with widefield calcium imaging in awake mice, enabling stimulation and recording of cortex-wide responses from multiple motor, sensory, and association areas. We then related the spatiotemporal structure of these responses to local excitability, mesoscale functional organization, anatomical projection strength, and graded anesthesia. Results: Optical Cortico-Cortical Evoked Potentials uncovered a consistent two-stage pattern of cortical communication. An initial response propagated along the anatomical scaffold linking the stimulated site to its direct targets, indicating that structural connectivity constrains the earliest phase of signal transmission. This was followed by a later, more distributed phase that varied across stimulation sites and was more sensitive to brain state, consistent with recurrent network-level integration. Across regions, stronger local recruitment was associated with broader cortex-wide engagement, suggesting that local excitability helps govern the scale of effective connectivity. Conclusions: These findings establish oCCEPs as a scalable approach for causal mapping of cortical dynamics and support a two-stage principle of cortical communication: an early structurally constrained phase followed by later state-dependent integrative phase.

Journal/Review: BRAIN STIMULATION

Volume: 19 (6)      Pages from: 103224-1  to: 103224-15

More Information: The authors acknowledge financial support for the research, authorship, and/or publication of this article. This research was supported by the Italian National Recovery and Resilience Plan (NRRP), M4C2, funded by the European Union-NextGenerationEU Project IR0000011, CUP B51E22000150006, EBRAINS-Italy, and Project IR0000023, CUP B53C22001810006, SEE-LIFE.
KeyWords: Optogenetics; Widefield calcium imaging; CCEPs; Hierarchical clustering; Structural connectivity; Anesthesia; Mouse cortex; GECI; Network dynamics; Mesoscale imaging
DOI: 10.1016/j.brs.2026.103224