Inter-regional delays fluctuate in the human cerebral cortex

Reviewer #1 (Public Review):

Summary:
Moon et al analyse ECoG data obtained during speech listening and focus on the relationship of two aspects: 1) delays between voltage signals at individual electrodes to other electrodes in the vicinity and 2) the power of those signals in a range of spectral bands. They find that high power in frequencies below 30 Hz is correlated with longer delays. They further look for this pattern of results in an oscillator model.

Strengths:
The manuscript examines whether a finding made in cats in the late 90s generalises to intracranial recordings from humans. Specifically, the amplitude of low-frequency oscillations should be related to the delay of cross-correlation between areas. The authors find evidence for such a relationship and show this in individual participants. After inspecting this phenomenon from many different angles, they also added an oscillator model and claimed that they found a similar pattern there. As such, the manuscript reports an extensive body of work carried out on high-quality data.

Weaknesses:
The manuscript's readability and flow could be optimised: terms are used that aren't explained, and the structure seems somewhat convoluted. Showing single-subject results is laudable, however, the authors could consider adding group results that integrate across participants, and perhaps relaying single-participant plots to the supplemental material. The manuscript would benefit if analyses were motivated more clearly. Sometimes, I am unsure why a given analysis was carried out, why it was carried out in a specific way, and what question it was intended to answer.

Reviewer #2 (Public Review):

Summary:
In the paper "Inter-regional Delays Fluctuate in the Human Cerebral Cortex," the authors aim to investigate how global changes in the power of brain oscillations affect the latency and strength of cortico-cortical couplings. They measured changes in brain oscillations and inter-regional couplings using human intracranial recordings. Additionally, the authors employed oscillator models to elucidate their empirical findings.

Strengths:
The authors tested their hypotheses using human intracranial data, which provides a direct measurement of brain activity with high spatial and temporal resolution. This offers a unique insight into the interplay between oscillatory power and inter-regional coupling in the human brain.

Weaknesses:
The authors had access to only a subset of brain regions. Although this limitation is common in many intracranial studies, their discussion of global changes in brain oscillations is impacted by the lack of whole-brain coverage, and thus the global nature of these oscillations should be interpreted with caution.

The description of the analysis procedure is not always clear.

Summary of main concerns:
My primary concerns relate to possible circularity in the analysis and the incomplete reporting of statistical results. For instance, correlation values are often provided without associated p-values, making it difficult to assess their significance. Furthermore, in some sections of the text, it is unclear whether specific results are supported by any statistical tests.

Crucial information is buried in the supplemental materials (e.g., the figure showing results for broad-band high-frequency power). Some details about the specific paradigm are missing in the methods section, making it challenging to determine if additional controls are necessary in the analyses. I encourage the authors to clarify certain aspects of the analysis and results to ensure their conclusions are substantiated by the data. Should the results be robust, I believe the study will be significant for researchers interested in brain oscillations and beyond.

Reviewer #3 (Public Review):

Summary:
This is my assessment of the manuscript entitled "Inter-regional delays fluctuate in the human cerebral cortex" submitted by Moon et al. to eleventh article deals with an interesting question, namely: how do different areas in the brain synchronize with each other. As the title indicates, the article shows that interregional activity can be more or less out of sync, and that the degree of synchronicity depends on the global power of low and high-frequency oscillations.

Overall, I found the paper interesting, although, as written, it is sometimes not clear why studying these inter-regional delays is important. For a broader audience, it is necessary to better emphasize the relevance of inter-regional delays, and what we learn from studies like this beyond the mechanistic aspect of how waves spread in the human brain. Also, it is important to explain why the task (listening to audio) was chosen, and what this task offers in comparison to, for example, studying spontaneous activity. I understand that intra-cranial data from humans is precious and difficult to obtain, so I am not asking for more data, just for a clear honest explanation of why this task was chosen.

Beyond these minor formatting issues, I have two main concerns on the data analysis and interpretation. In a nutshell, they deal with:

- Cross-correlating alpha power with inter-electrode lags computed from raw signals where alpha itself is included. IMO this could lead to obvious high correlation values simply because low-frequency signals spread passively (with some delays) across electrodes. High-frequency signals spread less and are thus less correlated in neighboring electrodes.

- Possible influence of the referencing scheme on the data. I could not find any information about where reference and ground electrodes were located but I fear that epochs of zero-lag coherence could be simply due to common referencing. Non-zero lag synchrony could be explained by generators becoming more or less active close to the recording electrodes. This is probably the most parsimonious explanation of the activity observed and explaining it does not require any coupled oscillators.

Strengths:
The paper relies on a strong dataset from intracranial recordings in humans. Conceptually the paper has strong value as it seeks to explore global and local activity dynamics within the human brain.

Weaknesses:
There are a number of methodological issues that need to be clarified, which could potentially influence the results obtained and their interpretation (i.e. corr-correlating alpha with itself, the influence of the referencing scheme on inter-electrode lags).