Cross-frequency coupling patterns during oddball processing in disorders of consciousness: a delta-gamma predominance

Phase-amplitude coupling (PAC) between low- and high-frequency oscillations provides a candidate mechanism for integrating information across cortical networks. While PAC alterations have been reported in disorders of consciousness (DOC), the frequency specificity and task dependence of these changes remain poorly characterized.

To systematically examine cross-frequency coupling patterns during auditory oddball processing in DOC patients and explore whether specific frequency combinations or frequency shifts are associated with different levels of consciousness.

Sixty-two participants [20 healthy controls (HC), 21 minimally conscious state (MCS), 21 unresponsive wakefulness syndrome (UWS)] underwent EEG recording during an auditory oddball paradigm. PAC was quantified using the Kullback-Leibler modulation index across comprehensive frequency ranges (phase: 1-31 Hz; amplitude: 8-77 Hz) without strong a priori band assumptions. Group comparisons relied on non-parametric permutation testing and bootstrap confidence intervals.

Delta-gamma coupling (1-4 Hz phase) dominated across all groups, with delta-gamma PAC consistently and significantly exceeding theta-gamma, alpha-gamma and beta-gamma coupling (all p < 0.001). A descriptive trend towards a downshift in the peak coupled amplitude frequency was observed along the consciousness continuum, with median values in the gamma range for HC (39.5 Hz) and MCS patients (35.0 Hz) and in the high-beta range for UWS patients (23.0 Hz), but this trend did not reach statistical significance (Kruskal-Wallis, p = 0.329). Conversely, between-group differences in delta-gamma coupling strength were not significant (p = 0.218), in the context of marked inter-individual heterogeneity (CV = 0.67 in HC, 0.73 in MCS) that was paradoxically lowest in the UWS group (CV = 0.50).

Auditory oddball processing preferentially engages delta-gamma, rather than theta-gamma, coupling in both healthy individuals and DOC patients, supporting the view that PAC signatures are task- and paradigm-specific rather than universal markers of consciousness. Within this framework, a non-significant tendency towards frequency slowing and a reduction in PAC variability in UWS emerge as preliminary, hypothesis-generating features that warrant further investigation in larger, longitudinal and multi-paradigm cohorts.