Dear Dr Leitao,

Thank you for submitting your manuscript entitled "Brain networks of emotions in sync: computational imaging of video-game playing" for consideration as a Research Article by PLOS Biology.

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Senior Editor

PLOS Biology

Dear Dr Leitao,

Thank you very much for submitting your manuscript "Brain networks of emotions in sync: computational imaging of video-game playing" for consideration as a Research Article at PLOS Biology. Your manuscript has been evaluated by the PLOS Biology editors, by an Academic Editor with relevant expertise, and by two independent reviewers. A third reviewer had also agreed to send comments, but is now significantly delayed. Thus, we have decided to move forward with only two sets of comments, not to delay the decision any longer. If belatedly the third reviewer submits the review, I'll forward it to you.

In light of the reviews (below), we will not be able to accept the current version of the manuscript, but we would welcome re-submission of a much-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 for further evaluation by the reviewers.

We expect to receive your revised manuscript within 2 months.

Please email us (plosbiology@plos.org) if you have any questions or concerns, or would like to request an extension. At this stage, your manuscript remains formally under active consideration at our journal; please notify us by email if you do not intend to submit a revision so that we may end consideration of the manuscript at PLOS Biology.

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You should also cite any additional relevant literature that has been published since the original submission and mention any additional citations in your response.

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https://blogs.plos.org/plos/2019/05/plos-journals-now-open-for-published-peer-review/

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

Sincerely,

Gabriel Gasque, Ph.D.,

Senior Editor

PLOS Biology

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

REVIEWS:

Reviewer #1: The authors examined the human brain activity evoked while playing games and found several distinctive functional domains in cortical and subcortical areas. The approach is unique and powerful and can assess interactive and self-relevant cognitive components in a controlled manner.

My concern is about their claim regarding synchronization. The authors argued about the existence of recurrent and dynamic synchronization across functional components (Fig. 1). However, given the slowness of fMRI signals, the results cannot provide strong evidence regarding the underlying interactive process. Instead, a more straightforward interpretation is that each brain region is involved in multiple distributed cognitive processes, as reported in recent literature (e.g., Shine et al., 2019; Nakai and Nishimoto, 2020) without assuming recurrent synchronization. The authors should elaborate on potential alternative interpretations and clarify what the current results can and cannot resolve.

Optionally, it would be great if the authors could provide a discussion on whether there is a sort of emotion present in a game-playing AI agent (e.g., Mnih et al., 2015; Vinyals et al., 2019), which has internal states that correspond to the variables discussed in this manuscript.

Shine JM, Breakspear M, Bell PT, et al. Human cognition involves the dynamic integration of neural activity and neuromodulatory systems. Nat Neurosci. 2019;22(2):289-296.

Nakai T, Nishimoto S. Quantitative models reveal the organization of diverse cognitive functions in the brain. Nat Commun. 2020;11(1):1142.

Mnih V, Kavukcuoglu K, Silver D, et al. Human-level control through deep reinforcement learning. Nature. 2015;518(7540):529-533.

Vinyals O, Babuschkin I, Czarnecki WM, et al. Grandmaster level in StarCraft II using multi-agent reinforcement learning. Nature. 2019;575(7782):350-354.

Reviewer #2: In this paper, Leitão and colleagues describe research that explores how appraisal, motivational, expressive, and physiological components contribute to the emergence of emotion. The research uses an interesting combination of a novel experimental paradigm, fMRI, and computational approaches to show the neural correlates of these components during emotional experiences, and how they interact. This manuscript has multiple strengths: it focuses on a timely and under-studied problem, it is clearly theoretically motivated, it includes multiple measures of emotion in addition to fMRI, and the statistical procedures appear appropriate. However, the significance of the results are somewhat difficult to appreciate as interpretation of findings relies on reverse inference and there are a few critical methodological and conceptual issues, as detailed below.

Major issues:

1. Does the experimental manipulation have external validity? It seems like the types of negative emotions the CPM tries to explain (e.g., responding to a dangerous, life-threatening event) are quite different than playing a video game in the fMRI environment. To what degree are the self-report and brain measures valid indicators of "real life" emotions?

2. Interpretation of different brain systems largely relies on reverse inference, where the functional relevance of different brain regions is assumed rather than tested. Brain regions associated with increased coping potential were interpreted to reflect enhanced motor action control and planning during power. What are the relationships between brain activity associated with the pattern of brain activity observed with coping potential? Are they associated with measured differences in behavior in this way? The authors also note that brain regions are modulated by Goal Conduciveness are reminiscent of networks often reported for positive/rewarding and negative/aversive stimuli. How well does brain activity predict variation in self-reported valence (e.g., for trials similar to those used to assay subjective feelings post-scanning)? Linking component processes to better-established behaviors could better corroborate the findings.

3. Although some degree of neural synchronization takes place, it is not clear what drives this synchrony. Could it be explained by classic views of emotion where an appraisal of a particular event in the game triggers changes in autonomic physiology, expression, motivation, and feelings? Does the CPM make predictions about brain synchrony that differ from other theoretical views? How is recurrence needed to explain brain activity during the task? Do componential views offer insight here? In the absence of more direct comparisons between accounts, it is difficult to tell what we have learned from this interesting study.

Minor points.

1. The beginning of the introduction frames the paper around identifying essential neural circuits for emotion, but this is presumably not being tested with fMRI.

2. The use of liquid states machines is interesting, but could perhaps be described more extensively for readers unfamiliar with the approach

3. The discussion (and some of the introduction) suggests that most work on emotion does not focus on actual behavior. It is surprising that past work in this space is not cited or discussed, especially related work by Dean Mobbs using a similar manipulation with fMRI.

Dear Dr Leitao,

Thank you for submitting your revised Research Article entitled "Brain networks of emotions in sync: computational imaging of video-game playing" for publication in PLOS Biology. I have now obtained advice from the original reviewers and have discussed their comments with the Academic Editor.

In light of the reviews (below), we are pleased to offer you the opportunity to address the remaining points from the reviewer 1 in a revised version that we anticipate should not take you very long. We will then assess your revised manuscript and your response to the reviewers' comments and we may consult the reviewers again.

We expect to receive your revised manuscript within 1 month.

Please email us (plosbiology@plos.org) if you have any questions or concerns, or would like to request an extension. At this stage, your manuscript remains formally under active consideration at our journal; please notify us by email if you do not intend to submit a revision so that we may end consideration of the manuscript at PLOS Biology.

**IMPORTANT - SUBMITTING YOUR REVISION**

Your revisions should address the specific points made by each reviewer. Please submit the following files along with your revised manuscript:

1. A 'Response to Reviewers' file - this should detail your responses to the editorial requests, present a point-by-point response to all of the reviewers' comments, and indicate the changes made to the manuscript.

*NOTE: In your point by point response to the reviewers, please provide the full context of each review. Do not selectively quote paragraphs or sentences to reply to. The entire set of reviewer comments should be present in full and each specific point should be responded to individually.

You should also cite any additional relevant literature that has been published since the original submission and mention any additional citations in your response.

2. In addition to a clean copy of the manuscript, please also upload a 'track-changes' version of your manuscript that specifies the edits made. This should be uploaded as a "Related" file type.

*Resubmission Checklist*

When you are ready to resubmit your revised manuscript, please refer to this resubmission checklist: https://plos.io/Biology_Checklist

To submit a revised version of your manuscript, please go to https://www.editorialmanager.com/pbiology/ and log in as an Author. Click the link labelled 'Submissions Needing Revision' where you will find your submission record.

Please make sure to read the following important policies and guidelines while preparing your revision:

*Published Peer Review*

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. Please see here for more details:

https://blogs.plos.org/plos/2019/05/plos-journals-now-open-for-published-peer-review/

*PLOS Data Policy*

Please note that as a condition of publication PLOS' data policy (http://journals.plos.org/plosbiology/s/data-availability) requires that you make available all data used to draw the conclusions arrived at in your manuscript. If you have not already done so, you must include any data used in your manuscript either in appropriate repositories, within the body of the manuscript, or as supporting information (N.B. this includes any numerical values that were used to generate graphs, histograms etc.). For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5

*Blot and Gel Data Policy*

We require the original, uncropped and minimally adjusted images supporting all blot and gel results reported in an article's figures or Supporting Information files. We will require these files before a manuscript can be accepted so please prepare them now, if you have not already uploaded them. Please carefully read our guidelines for how to prepare and upload this data: https://journals.plos.org/plosbiology/s/figures#loc-blot-and-gel-reporting-requirements

*Protocols deposition*

To enhance the reproducibility of your results, we recommend that if applicable you deposit your 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: https://journals.plos.org/plosbiology/s/submission-guidelines#loc-materials-and-methods

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

Sincerely,

Gabriel Gasque, Ph.D.,

Senior Editor

PLOS Biology

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

REVIEWS:

Reviewer #1: The authors provided some more details and discussions that support their original arguments regarding recurrent or feedback components. In particular, the additional Table S10 and the related discussion seem to be critical.

That being said, I am still not fully convinced, partly because they did not provide interpretable details of their methodology. The following information and control analysis will provide more concrete support:

(I) They should provide more methodological details on (A) feedback vs. (B) non-feedback models in Table S10. They could modify Figures 6/S2 to illustrate A and B. It is unclear what "lambda" indicates, as they do not show it in any equation, diagram, etc. It is also unclear what "rough cross-validation" means.

(II) Please provide the following negative and positive control simulation analyses:

(1) Prepare mock fMRI/behavior model signals with or without feedback components.

(2) Add correlated noise to (1).

(3) Apply temporal low-pass filtering to (2).

(4) Run the analysis pipeline (Figure S2?) to (3).

(5) Test analyses in Table S10.

If the simulation analyses above can detect the presence and absence of feedback components, that should be convincing evidence that their pipeline works to examine the difference, even using challenging fMRI data.

Reviewer #2: The authors have done an excellent job of addressing all points raised during review. This work is exceptional for its combination of theory, unique experimental design, and computational approaches. I hope it inspires similar research in this area.

Dear Dr Leitao,

Thank you for submitting your revised Research Article entitled "Brain networks of emotions in sync: computational imaging of video-game playing" for publication in PLOS Biology. I have now discussed your revision with the Academic Editor, and I'm delighted to let you know that we're now editorially satisfied with your manuscript.

However, we would like you to consider changing the name of the article to convey the central biological message of your findings. We suggest the following title, but would be happy to discuss alternatives:

"Computational imaging of video-game playing shows dynamic synchronization of cortical and sub-cortical networks of emotions"

In addition, before we can formally accept your paper and consider it "in press", we also need to ensure that your article conforms to our guidelines. A member of our team will be in touch shortly with a set of requests. As we can't proceed until these requirements are met, your swift response will help prevent delays to publication. Please also make sure to address the data and other policy-related requests noted at the end of this email.

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Please do not hesitate to contact me should you have any questions.

Sincerely,

Gabriel Gasque, Ph.D.,

Senior Editor,

ggasque@plos.org,

PLOS Biology

------------------------------------------------------------------------

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-- Please indicate within your manuscript if your protocol approved by the Research Ethics Committee of the Geneva University Hospital adhered to the Declaration of Helsinki or any other specific national or international ethical guidelines.

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Dear Dr Leitão,

On behalf of my colleagues and the Academic Editor, Kevin S LaBar, I am pleased to inform you that we will be delighted to publish your Research Article in PLOS Biology.

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Gabriel Gasque,

Senior Editor

PLOS Biology