Dear Prof. Mendes,

Thank you very much for submitting your manuscript "Active probing to highlight approaching transitions to ictal states in coupled neural mass models" for consideration at PLOS Computational Biology.

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.

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,

Peter Neal Taylor

Associate Editor

PLOS Computational Biology

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

***********************

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: The article discusses the important issue of predicting epileptic discharges using the existing computational neural mass model. A feature of this work is the analysis of signals received from the model. The task of predicting discharges is solved by modeling external stimuli by changing the parameters of the model.

The disadvantages of the work include:

0. In the "abstract" section, authors should better identify the methods that were used in this particular work.

1. Using the term lag-1 autocorrelation without clarification at the initial mention.

2. Not all known mesoscale EEG models are listed on line 124 (for example https://doi.org/10.1371/journal.pone.0114316, https://doi.org/10.1007/BF00202790, https://doi.org/10.1371/journal.pone.0239125).

3. On line 229, it is not entirely clear what is "a moving average filter of size 20".

4. Line 253. Please clarify what does "5 au" mean.

5. In my opinion, the "Conclusions" section should be written in a little more detail.

It should be emphasized that new was obtained by analyzing the signals of the existing Wendling model.

In general, the work is done and described at a good level, the results are presented clearly and in sufficient detail.

Reviewer #2: The Ms describes application of neural mass model to study stimulation-based assessment of system closeness to seizure. The stimulation-based biomarkers of approaching transitions are based on a critical slowing down signal measures and are shown be able to identify proximity of the ictal state. The study is original and offers useful, conceptual insight into the problem of seizure prediction using active paradigms. The authors are familiar with the literature relevant to the problem and describe their work in this context. In general it is very good work that deserves a publication. I have only minor comments to improve the Ms .

Minor points:

1. The authors use 2 model settings – with unilateral and bilateral stimulation. The unilateral stimulation is delivered only to the side with the ‘normal’ set of parameters. It seems counterintuitive. The most direct test would be to selectively stimulate the population with ‘pathological’ set of parameters to see if the probing stimulus can identify the on-going process of ictogenesis. Such test is not performed. Please explain your rationale of probing ‘normal’ network rather than ‘epileptic’ one in the unilateral setting.

2. Figure 4, top row, shows that Variance, Lag-1 AC and to some extend Kurtosis measured in Population 1 are sensitive to B parameter change (I-B setting). In the text it is described that feature changes indicating change of B were not found except AC(1). Please clarify.

3. The meaning of black dots in Spearman rank correlations in all figures is not explained.

4. Figures 4, 5, 7, 8 are not referred in the text.

5. Model settings are named Ia, Ib etc (ln. 205-212). They are referred to as I-A, I-B later in the text. Please unify.

6. Figure 2 is a bit confusing, partly because of panel annotations a.1, a.2, b.1 etc. I suggest to mark the panels with headings e.g. ‘Population 1’, ‘Population 2’, ‘Active’, ‘Passive’ etc. It will help to quickly get information from the figure without going through the (complex) legend. Also the role of enlarged signals is not clear. What is the reader supposed to learn from them? I suggest to simplify the figure by removing them or at least making them smaller.

7. Setting III-A is mentioned in ln. 378. It is not described in the Model setting section.

**********

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: Yes

Reviewer #2: Yes

**********

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

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.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions, please see http://journals.plos.org/compbiol/s/submission-guidelines#loc-materials-and-methods

Dear Prof. Mendes,

We are pleased to inform you that your manuscript 'Active probing to highlight approaching transitions to ictal states in coupled neural mass models' 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,

Peter Neal Taylor

Associate Editor

PLOS Computational Biology

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

***********************************************************

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: All the points that I raised were adequately addressed.

Reviewer #2: None

**********

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: Yes

Reviewer #2: Yes

**********

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