Phase-Amplitude Coupling in Theta and Beta Bands: A Potential Electrophysiological Marker for Obstructive Sleep Apnea

Abstract

Background: Phase-amplitude coupling (PAC) between the phase of low-frequency signals and the amplitude of high-frequency activities plays many physiological roles and is involved in the pathological processed of various neurological disorders. However, how low-frequency and high-frequency neural oscillations or information synchronization activities change under chronic central hypoxia in OSA patients and whether these changes are closely associated with OSA remains largely unexplored. This study arm to elucidate the long-term consequences of OSA-related oxygen deprivation on central nervous system function.

Methods: : We screened 521 patients who were clinically suspected of having OSA at our neurology and sleep centers. Through polysomnography (PSG) and other clinical examinations, 103 patients were ultimately included in the study and classified into mild, moderate, and severe OSA groups based on the severity of hypoxia determined by PSG. We utilized the phase-amplitude coupling (PAC) method to analyze the modulation index (MI) trends between different frequency bands during NREM (N1/N2/N3), REM, and wakefulness stages in OSA patients with varying severity levels. We also examined the correlation between the MI index and OSA hypoxia indices.

Results: Apart from reduced N2 sleep duration and increased microarousal index, the sleep architecture remained largely unchanged among OSA patients with varying severity levels. Compared to the mild OSA group, patients with moderate and severe OSA exhibited higher MI values of PAC in the low-frequency theta phase and high-frequency beta amplitude in the frontal and occipital regions during N1 sleep and wakefulness. No significant differences in the MI of phase-amplitude coupling were observed during N2/3 and REM sleep. Moreover, the MI of phase-amplitude coupling in theta and beta bands positively correlated with hypoxia-related indices, including the apnea-hypopnea index (AHI) and oxygenation desaturation index (ODI), and the percentage of oxygen saturation below 90% (SaO2<90%).

Conclusion: OSA patients demonstrated increased MI values of theta phase and beta amplitude in the frontal and occipital regions during N1 sleep and wakefulness. This suggests that cortical coupling is prevalent and exhibits sleep-stage-specific patterns in OSA. Theta-beta PAC during N1 and wakefulness was positively correlated with hypoxia-related indices, suggesting a potential relationship between these neural oscillations and OSA severity. The present study provides new insights into the relationship between neural oscillations and respiratory hypoxia in OSA patients.

Keywords: EEG; MI; PAC; modulation index; obstructive sleep apnea; phase-amplitude coupling; polysomnography.

Figure 1

Flow chart of patient screening and grouping, clinical data collection, sleep EEG processing and data analysis.

Figure 2

Comodulograms of signals with PAC-MI values in the frontal cortex in OSA patients during the NREM sleep. The modulation index (MI) of amplitudes in the high-frequency range (7–45 Hz) and the phases of signals in the low-frequency range (1–29 Hz) of F3/F4 channels across the mild OSA, moderate OSA, and severe OSA groups during NREM stages N1 (A), N2 (B), and N3 (C). The PAC-MI of the low-frequency (5–7 Hz) and high-frequency (25–29 Hz) was significantly increase in the N1 stage.

Figure 3

Comodulograms of signals with PAC-MI values in the occipital cortex in OSA patients during the NREM. The modulation index (MI) of amplitudes in the high-frequency range (7–45 Hz) and the phases of signals in the low-frequency range (1–29 Hz) of O1/O2 channels across the mild OSA, moderate OSA, and severe OSA groups during NREM stages N1 (A), N2 (B), and N3 (C). The PAC-MI of the low-frequency (5–7 Hz) and high-frequency (25–29 Hz) was also significantly increase in the N1 stage.

Figure 4

Comodulograms of signals with PAC-MI values in the frontal and occipital cortex in OSA patients during the REM sleep and wakefulness. The modulation index (MI) of high-frequency amplitudes (7–45 Hz) and low-frequency phases (1–29 Hz) for the F3/F4 and O1/O2 channels across the mild OSA, moderate OSA, and severe OSA groups showed no statistically significant differences during REM sleep (A); however, it increased significantly during wakefulness (B).

Figure 5

Histogram of the theta-beta PAC-MI in the whole sleep stages in OSA patients. (A and B) Comprise with mild OSA and moderate OSA group, the theta-beta PAC-MI of F3/F4 channel in the severe OSA group was significantly increase in NRME N1 and wakefulness. (C) The theta-beta PAC-MI of O1 channel in the whole sleep states had no statistically significant differences in the three OSA groups. (D) In O2 channel, the theta-beta PAC-MI in the severe OSA group was significantly increase only in the wakefulness period. Star symbols represent statistical significance levels: * represents p < 0.05, no stars represent p > 0.05.

Figure 6

Matrix of Pearson’s correlation coefficients among demographics, PAC-MI, OSA symptom severity. BMI showed a positive correlation with the N1 sleep and wakefulness of F4/O2 channel. The AHI exhibited a positive correlation with MI value during N1 sleep and wakefulness of F4/O2 channel. ODI was positively correlated with MI during N1 sleep in the F3 channel, while SaO2<90% was positively correlated with MI values during wake period in the O2 channel. A color-coded correlation scale is presented on the right of the plot. Based upon the scale, blue ones stand for lower correlations and red ellipses stand for higher correlations, ns illustrate insignificant correlations of a given variable with itself. Star symbols represent statistical significance levels: *** represents p < 0.001, ** represents p < 0.01, * represents p < 0.05, no stars represent p > 0.05. MAI: microarousal index.