EEG phase-amplitude coupling to stratify encephalopathy severity in the developing brain

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is difficult to classify within the narrow therapeutic window of hypothermia. Neurophysiological biomarkers are needed for timely differentiation of encephalopathy severity within the short therapeutic window for initiation of hypothermia therapy. Methods: A novel analysis of mean Phase Amplitude Coupling index, PAC_m, of amplitudes high frequencies (12–30 Hz) coupled with phases of low (1,2 Hz) frequencies was calculated from the 6 h EEG recorded during the first day of life. PAC_m values were compared to identify differences between mild versus higher-grade HIE, respectively, for each of the EEG electrodes. A receiver operating characteristic curve was generated to examine the performance of PAC_m. Results: 38 newborns with different HIE grades were enrolled in the first 6 h of life. Threshold PAC_m 0.001 at Fz, O1, O2, P3, and P4 had AUC >0.9 to differentiate HIE severity and predict the persistence of moderate to severe encephalopathy that requires treatment with hypothermia. Conclusion: PAC is a promising biomarker to identify mild from higher severity of HIE after birth.