AbstractPhase synchronization of neuronal oscillations in specific frequency bands coordinates anatomically distributed neuronal processing and communication. Typically, oscillations and synchronization take place concurrently in many distinct frequencies, which serve separate computational roles in cognitive functions. While within-frequency phase synchronization has been studied extensively, less is known about the mechanisms that govern neuronal processing distributed across frequencies and brain regions. Such integration of processing between frequencies could be achieved via cross-frequency coupling (CFC), either by phase-amplitude coupling (PAC) or by n:m-cross-frequency phase synchrony (CFS). So far, studies have mostly focused on local CFC in individual brain regions, whereas the presence and functional organization of CFC between brain areas have remained largely unknown. We posit that inter-areal CFC may be essential for large-scale coordination of neuronal activity and investigate here whether genuine CFC networks are present in human resting-state brain activity.To assess the functional organization of CFC networks, we identified brain-wide CFC networks at meso-scale resolution from stereo-electroencephalography (SEEG) and at macro-scale resolution from source-reconstructed magnetoencephalography (MEG) data. We developed a novel graph-theoretical method to distinguish genuine CFC from spurious CFC that may arise from non-sinusoidal signals ubiquitous in neuronal activity. We show that genuine inter-areal CFC is present in human resting-state activity in both MEG and SEEG data. Both CFS and PAC networks coupled theta and alpha oscillations with higher frequencies in large-scale networks connecting anterior and posterior brain regions. CFS and PAC networks had distinct spectral patterns and opposing distribution of low- and high frequency network hubs, implying that they constitute distinct CFC mechanisms. The strength of CFS networks was also predictive of cognitive performance in a separate neuropsychological assessment. In conclusion, these results provide evidence for inter-areal CFS and PAC being two distinct mechanisms for coupling oscillations across frequencies in large-scale brain networks.

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