Protocol for Modulating Anesthesia Delta Oscillations Using Closed Loop Auditory Stimulation

Clara Pic Roca^1,2Hanieh Bazregarzadeh¹Louis Morisson^1,3,4Antonio Martin¹Olivier Verdonck^3,4Steve Gibbs^1,2Jean-Marc LINA^1,5Julie Carrier^1,6Philippe Richebé^4,7Catherine Duclos^1,2,8*

• ¹Centre d'etudes avancees en medecine du sommeil, Montreal, Canada
• ²Universite de Montreal Departement de Neurosciences, Montreal, Canada
• ³Hopital Maisonneuve-Rosemont, Montreal, Canada
• ⁴Université de Montréal, Department of Anesthesiology and Pain Medicine, Montréal, Canada
• ⁵Ecole de Technologie Supérieure, Department of Electrical Engineer, Montréal, Canada
• ⁶Université de Montréal , Departement of Psychology, Montréal, Canada
• ⁷Polyclinique Bordeaux Nord Aquitaine, Department of Anesthesia and Intensive Care, Bordeaux, France
• ⁸Université de Montréal, Departement of Anesthesiology and Pain Medicine, Montréal, Canada

Delta waves (0.1–4 Hz) are a hallmark of unconsciousness in both sleep and general anesthesia (GA). Closed-loop auditory stimulation (CLAS) delivers brief sounds phase-locked to ongoing slow oscillations and can modulate slow-wave activity (SWA) during sleep, but its efficacy and translational relevance under propofol anesthesia, particularly in the presence of nociceptive input, remain unknown. We describe a prospective, within-subject protocol in 30 neurologically healthy adults undergoing elective surgery under propofol GA. Intraoperative high-density electroencephalography (hd-EEG; 128 channels) is recorded while a real-time CLAS algorithm detects δ-waves at the Fz electrode, and triggers pink-noise bursts in three conditions: in-phase (peak-locked), anti-phase (trough-locked), and sham. An extended in-phase block is then combined with a standardized tetanic nociceptive stimulus (100 Hz, 70 mA, 30 s) to test robustness under an arousal challenge. Depth of hypnosis is monitored with the Bispectral Index (BIS), and nociceptive/autonomic reactivity with the Nociception Level (NOL) index. Primary outcomes quantify δ-wave morphology and SWA (amplitude, slopes, duration/frequency, transition frequency, density, power spectral density), along with topography, source estimation, and propagation. Secondary outcomes include depth of anesthesia (BIS), nociceptive balance (NOL), functional connectivity (weighted and directed phase-lag indices), graph-theoretical organization (global efficiency, clustering, modularity, small-worldness), and EEG microstates (duration, coverage, transitions). We hypothesize that in-phase CLAS will increase amplitude, slope, duration, and density of δ-waves, and decrease frequency and transition frequency relative to sham, whereas anti-phase CLAS will cause a disruption of parameters relative to sham. Under nociception, in-phase CLAS is expected to partially preserve δ-wave integrity, with effects attenuated relative to non-nociceptive conditions. We anticipate BIS values to remain within the surgical range but trend lower during in-phase CLAS, alongside reduced nociceptive/autonomic responses. At the network level, we expect CLAS-induced δ-wave reinforcement to be associated with more locally coherent δ-band activity and reduced frontoparietal integration, consistent with deeper unconsciousness. If confirmed, these findings would position CLAS as a candidate neuromodulation strategy to reinforce anesthetic δ-wave dynamics and help stabilize anesthesia without necessarily increasing pharmacological dose, while also providing a systems-level test of the role of slow oscillations in sustaining unconsciousness.