Background: Intraoperative EEG provides a noninvasive window into cortical dynamics under anesthesia, but conventional spectral analysis cannot capture nonstationary modulation patterns linked to nociceptive processing. This study applied Holo- Hilbert spectral analysis (HHSA) to characterize cross-frequency modulation patterns in relation to the Surgical Pleth Index (SPI) during general anesthesia. Methods: Frontal EEG from 134 female patients undergoing gynecologic surgery was analyzed. Ten-minute segments were first examined to define canonical modulation structures, followed by one-minute epochs synchronized with SPI values to assess dynamic changes. HHSA decomposed each epoch into amplitude modulation patterns across carrier frequencies (1/64–64 Hz). Group comparisons between pain and no-pain epochs were performed using t-tests with Bonferroni correction. A linear mixedeffects model evaluated the effects of SPI, minimum alveolar concentration (MAC), heart rate (HR), and mean arterial pressure (NIBP-m) on alpha-band modulation (8–16-Hz carrier modulated by 3–8-Hz amplitude). Results: HHSA revealed two dominant cross-frequency interactions within the alpha-carrier band (8–16 Hz): one modulated by 3–6-Hz (high-delta to theta) and another by 1–2-Hz (low-delta) oscillations, indicating layered modulation under anesthesia. During nociceptive states (SPI > 60), modulation power increased in the alpha and high-delta bands, while theta and low-delta modulation weakened. Alpha-band modulation power rose with SPI and declined with MAC. Conclusions: HHSA revealed distinct cross-frequency modulation patterns reflecting the cortical balance between nociception and analgesia. Alpha-band modulation serves as a physiologically grounded EEG marker for individualized nociception monitoring under general anesthesia.
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