Dear Dr. Valizadeh,

Thank you very much for submitting your manuscript "Transmission delays and frequency detuning can regulate information flow between brain regions" for consideration at PLOS Computational Biology.

Let me apologize for the delay with which this decision is reaching you. These are difficult times, and a series of unfortunate coincidences made your paper end in the long tail of the distributions of editorial turnout times.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

Some of the concerns are major, and also point to a limited novelty and significance of the biological insight.

At this stage we prefer to give you the opportunity to revise it, but even if the technical issues are addressed, should the concerns about novelty and significance remain, we will propose conditional acceptance in PLOS One.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The review is uploaded as an attachment

Reviewer #2: The authors analyze the impact of transmission delays and frequency detuning for the information flow between brain regions. For this they use 2 populations of Hodgkin Huxley neurons and analyze the coherence, mutual information and the phase response curves. The manuscript is well written and seems technically sound and the results are sound and interesting, but a link to the literature on the impact of time-delays in oscillatory brain network models and neuronal fields is missing.

Below are my specific comments:

- Neural field dynamics with local and global connectivity and time delay has been studied for more than 10 years, see e.g. Jirsa PTRSA 2009.

- The impact of time-delays for the large scale brain dynamics has also been extensively studied, both analytically and computationally. Authors should make an effort to discuss their results also in the light of the findings about the impact of time-delays and the frequency missmatch on the synchronization of Kuramoto oscillators in brain networks (Petkoski et al PLOS CB 2018), which also hold for other oscillators (Petkoski et al. PTRSA 2019). Similarly, implicit time delays in KM (with phase shifts) were studied by Moon et al Plos CB 2015.

- how is the oscillation frequency in Fig 1 defined? Is it a simple ensemble average of frequencies of the firing for all the neurons, or is it the frequency of the locking? For phase oscillators these two can be different in asymmetric networks (as it is the case here with the E/I imbalance), see e.g. Petkoski et al PRE 2013.

- would the results be different if there are no time delays within the populations? This approach is for example common when using brain network model, e.g. Sanz Leon Neoroimage 2015.

- Can the authors elaborate on the advantage of using populations of neurons instead of neuronal masses such as Wong Wang or Jansen Ritt models? Do they expect at least the PRC and coherence results to be fully confirmed if neuronal masses are used?

- the way delta is defined in Eq. 6, requires all the oscillators to be synchronized. Isn’t this too strict condition, and wouldn’t it be more general if the time-delays are explicit in the coupling function, so that the phase shift as defined by the authors still holds, but only for the locked neurons? Similarly, for the simulation of the Kuramoto oscillators, are the the time-delays explicit in the interactions, or there are phase-shifts instead, implying the model to be valid only if all the neurons are synchronized?

- can it be stated more clearly what is the impact of the assymetry in the coupling, as it was done for example in the above mentioned similar works by Moon et al Plos CB 2015 &Petkoski et al Plos CB 2018?

- line 395 typo, “In” instead of “If”.

Taken together, I cannot recommend publication of the manuscript in the current form.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: No: There is any extra data. But I think it is not necessary.

Reviewer #2: None

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Reviewer #1: No

Reviewer #2: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

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Attachments

Attachment

Submitted filename: PCOMPBIOL-D-20-01170_review.pdf

Dear Dr. Valizadeh,

We are pleased to inform you that your manuscript 'Transmission delays and frequency detuning can regulate information flow between brain regions' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Review is uploaded as an attachment

Reviewer #2: The authors have addressed most of the issues I have raised and I recommend the article to be published in the current form.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: None

Reviewer #2: None

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PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Attachments

Attachment

Submitted filename: revissions.pdf