Neuronal oscillations support cognitive processing. Modern views suggest that neuronal oscillations do not only reflect coordinated activity in spatially distributed networks, but also that there is interaction between the oscillations at different frequencies. For example, invasive recordings in animals and humans have found that the amplitude of fast oscillations (>40 Hz) occur non-uniformly within the phase of slower oscillations, forming the so-called cross-frequency coupling (CFC). However, the CFC patterns might be influenced by features in the signal that do not relate to underlying physiological interactions. For example, CFC estimates may be sensitive to spectral correlations due to non-sinusoidal properties of the alpha band wave morphology. To investigate this issue, we performed CFC analysis using experimental and synthetic data. The former consisted in a double-blind magnetoencephalography pharmacological study in which participants received either placebo, 0.5 or 1.5 mg of lorazepam (LZP; GABAergic enhancer) in different experimental sessions. By recording oscillatory brain activity with during rest and working memory (WM), we were able to demonstrate that posterior alpha (8–12 Hz) phase was coupled to beta-low gamma band (20–45 Hz) amplitude envelope during all sessions. Importantly, bicoherence values around the harmonics of the alpha frequency were similar both in magnitude and topographic distribution to the cross-frequency coherence (CFCoh) values observed in the alpha-phase to beta-low gamma coupling. In addition, despite the large CFCoh we found no significant cross-frequency directionality (CFD). Critically, simulations demonstrated that a sizable part of our empirical CFCoh between alpha and beta-low gamma coupling and the lack of CFD could be explained by two-three harmonics aligned in zero phase-lag produced by the physiologically characteristic alpha asymmetry in the amplitude of the peaks relative to the troughs. Furthermore, we showed that periodic signals whose waveform deviate from pure sine waves produce non-zero CFCoh with predictable CFD. Our results reveal the important role of the non-sinusoidal wave morphology on state of the art CFC metrics and we recommend caution with strong physiological interpretations of CFC and suggest basic data quality checks to enhance the mechanistic understanding of CFC.

GABAergic interneurons are strongly implicated in the generation of gamma and alpha oscillations in human occipital cortex where drug-induced power modulations predicted WM performance. Our findings bring us an important step closer to linking neuronal dynamics to behavior by embracing established animal models.

SummaryEEG reverse-correlation techniques have revealed that visual information processing entails a ∼10-Hz (alpha) occipital response that reverberates sensory inputs up to 1 s. However, the spatial distribution of these perceptual echoes remains unknown: are they synchronized across the brain, or do they propagate like a traveling wave? Here, in two experiments with varying stimulus locations, we demonstrate the systematic phase propagation of perceptual echoes. A single stimulation in the upper visual field produced an “echo traveling wave” propagating from posterior to frontal sensors. The simultaneous presentation of two independent stimuli in separate visual hemifields produced two superimposed traveling waves propagating in opposite directions. Strikingly, in each sensor, the phase of the two echoes differed, with a phase advance for the contralateral stimulus. Thus, alpha traveling waves sweep across the human brain, encoding stimulus position in the phase domain, in line with the 70-year-old “cortical scanning” hypothesis (Pitts and McCulloch, 1947).