Dear Dr. Hosoya,

Thank you very much for submitting your manuscript "Interspike intervals within retinal spike bursts combinatorially encode multiple stimulus features" 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.

The paper presents potentially interesting results. However, two of the reviewers raised major concerns, which need to be addressed through appropriate additional research work and text revisions.

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).

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Sincerely,

Stefano Panzeri

Guest Editor

PLOS Computational Biology

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

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The paper presents potentially interesting results. However, two of the reviewers raised major concerns, which need to be addressed through appropriate additional research work and text revisions.

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: In their manuscript "Interspike intervals within retinal spike bursts combinatorially encode multiple stimulus features" the authors analyze the relation between intraburst ISIs of 2-spike or 3-spike bursts and stimulus features on data recorded from salamander retinal ganglion cells. The authors identify stimulus features encoded by the different ISIs.

The analysis is timely and very naturally extends previous studies which showed that the number of spikes within a burst, the burst onset and duration of a burst carry stimulus information. The manuscript is very well written and the figures are clear and informative.

Major point:

There is a conceptual issue with the mutual information analysis. A couple of times (lines 98, 116, 152), the authors mention the "information about the stimulus". Intuitively, I would expect that stimulus here is referring to the light intensity profile. But from Materials and Methods, it becomes clear that the authors are referring to information about "event" identity. The authors define "events" as reproducible bursts. Essentially, an event is not an external stimulus variable but itself a neural response property which happens to be linked to the external stimulus onset. However, even for constant stimuli, RGCs can elicit complex patterns for hundreds of milliseconds similar to the patterns shown in Fig 1. Thus, there seems to be a conflation of the firing dynamics of the RGCs and the light intensity profile in the mutual information analysis. Therefore, it seems the authors show that they can distinguish between different time points relative to a stimulus onset but not necessarily between different stimuli i.e. between different intensity profiles or between different intensities within a profile. In my opinion, this is not "information about the stimulus". This concerns the mutual information analysis only. The authors also evaluate relations of intraburst ISIs to amplitudes and temporal phases of oscillatory components which I find convincing.

Minor points:

The authors analyzed 2-spike and 3-spike bursts only and state that bursts with 4 or more spikes were too rare to conduct a similar analysis (line 314 and Fig 1D, though the illustrated green reproducible burst in Fig 1A then appears to be unusual). I was wondering, could anything be said when pooling together all bursts with more than 3 spikes? Do the first two intraburst ISIs hint at the same characteristics as for the 3-spike bursts? An answer to this question would shed light on the general validity of the amplitude and phase encoding.

Line 480: typo: insert "in" before "the open"

Reviewer #2: This is a very interesting study supporting the multiplexed encoding of stimulus information in a combinatorial burst code. The authors analysed data from retinal ganglion cells of salamander larvae when stimulated with oscillatory light stimuli and natural scenes. The main result is that intra-burst ISIs encode faster features of the stimuli in comparison with spike number alone. Moreover, the study shows that ISIs can combinatorially encode different features of the stimulus. The analyses are done with great attention to detail and there is an overall excellent quality of presentation.

Reviewer #3: review is uploaded as an attachment.

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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: The authors stated that they will provide data and code on acceptance.

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Fleur Zeldenrust

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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Reproducibility:

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Attachments

Attachment

Submitted filename: review_plos_2020.pdf

Attachment

Submitted filename: PCOMPBIOL-D-20-00205_reviewer_commented.pdf

Dear Dr. Hosoya,

Thank you very much for submitting your manuscript "Interspike intervals within retinal spike bursts combinatorially encode multiple stimulus features" 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. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript (only minor text edits) according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. 

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

[1] A letter containing a detailed list of your responses to all 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.

Thank you again for your submission to our journal. 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,

Stefano Panzeri

Guest Editor

PLOS Computational Biology

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

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

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: The authors revised their manuscript extensively and satisfactorily addressed all of my concerns. In particular, they clarified the relation between ISI burst patterns and stimuli as opposed to event identity by revising their estimator. Their results are still qualitatively similar, supporting the robustness of their findings. They also performed a more extensive analysis of the contributions of different ISIs, yielding interesting results.

Reviewer #3: See pdf

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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: Yes

Reviewer #3: 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 #3: Yes: Fleur Zeldenrust

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 see http://journals.plos.org/ploscompbiol/s/submission-guidelines#loc-materials-and-methods

Attachments

Attachment

Submitted filename: review_plos_2020_2.pdf

Dear Dr. Hosoya,

We are pleased to inform you that your manuscript 'Interspike intervals within retinal spike bursts combinatorially encode multiple stimulus features' 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,

Stefano Panzeri

Guest Editor

PLOS Computational Biology

Daniele Marinazzo

Deputy Editor

PLOS Computational Biology

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