Dear Dr Eippert,

Thank you for submitting your manuscript entitled "Closing the gap between brain and body: non-invasive multi-channel electrophysiology enables human spinal cord imaging with single-trial precision" for consideration as a Research Article by PLOS Biology. Please accept my apologies for the delay in getting back to you as we consulted with an academic editor about your submission.

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Richard

Richard Hodge, PhD

Senior Editor, PLOS Biology

rhodge@plos.org

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Dear Dr Eippert,

Thank you for your patience while your manuscript "Closing the gap between brain and body: non-invasive multi-channel electrophysiology enables human spinal cord imaging with single-trial precision" was peer-reviewed at PLOS Biology as a Methods and Resources Article. Please accept my sincere apologies for the delays that you have experienced during the peer review process. Your manuscript has now been evaluated by the PLOS Biology editors, an Academic Editor with relevant expertise, and by two independent reviewers.

In light of the reviews, which you will find at the end of this email, we would like to invite you to revise the work to thoroughly address the reviewers' reports.

As you will see, the reviewers are generally very positive about the approach and think it is well-designed and an important contribution. However, Reviewer #1 asks that additional reporting details are provided and notes that the limitations around the user selection of the time period should be discussed. In addition, Reviewer #2 asks that additional proof-of-concept studies are provided to fully demonstrate the utility of the approach. After discussions with the Academic Editor, we also ask that you please provide a comparison with other recent papers based on fMRI recordings in the discussion section.

Given the extent of revision needed, we cannot make a decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is likely to be sent for further evaluation by all or a subset of the reviewers.

We expect to receive your revised manuscript within 3 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 withdraw it.

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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,

Richard

Richard Hodge, PhD

Senior Editor, PLOS Biology

rhodge@plos.org

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

REVIEWS:

Reviewer #1: This is an important paper which outlines electrophysiological recordings along the complete neuro-axis from peripheral nerve , through brainstem and to primary sensor cortex.

It highlights the quality of work that can be done with standard and affordable electrophysiological measures.

This represents a huge amount of recording time and number of subjects in a well designed paradigm.

I do have one major concern, that is hopefully a misunderstanding, and that concerns the CCA analysis.

Firstly, as the authors point out, there is the user selection of the time-period and then a choice of the significant CCA component. This adds to some loss of objectivity. This should be noted in the limitations section. As the time-window was user specified, please make it clear how SNR was calculated (i.e. if you choose the peak to optimize, and then measure SNR at that peak is there some circularity).

Please make it clear how CCA was used in the Interaction ration section. For example, it would seem that amplitudes can only be compared if the same linear (CCA) mixture is used for all comparisons (rather than a different CCA mixture for each component).

Secondly, could the authors please be more explicit with the notation on page 22.

Please give the dimensions of X and Y and the wx, wy in terms of rows and columns.

Also please specify Y in terms of X . As far as I understand Y is a repetition of a specific latency range of mean(X) over Ntrials.

Then also please specify (explicitly in equation) how the canonical component of interest is created

My confusion is that normally one would have more (at least 4 times) trials (rows) than features (columns).

My understanding is that, by definition, one would expect a very high and significant canonical correlations otherwise.

Again, hopefully adding more information (like effective degrees of freedom and as many other details of the CCA as possible etc) should remove these concerns.

One way to show this is less of a worry empirically could be to replace the raw data X with the resting state data (as used elegantly to demonstrate the late component in figure 3G). Ideally this would not show a significant component.

Minor.

Figure 1. Please put number of subjects that went into grand average into figure caption.

Reviewer #2: The paper shows the optimization of a methodology to record spinal cord activities in a non invasive way. The demonstration of the efficacy of the approach is well-designed and the results quite convincing. However, I found a bit limited the overall investigation of the real usability of this approach. I would suggest the authors to add some experiments with more "ecological" touch or proprioceptive stimuli of hand and foot...what is the overall ability to discriminate these sensations? it is able to provide results which are anatomically plausible etc. This kind of analysis would make more convincing the overall translational possibility of this approach.

Dear Dr Eippert,

Thank you for your patience while we considered your revised manuscript "Closing the gap between brain and body: non-invasive multi-channel electrophysiology enables human spinal cord imaging with single-trial precision" for publication as a Methods and Resources Article at PLOS Biology. This revised version of your manuscript has been evaluated by the PLOS Biology editors, the Academic Editor and the original reviewers.

Based on the reviews, I am pleased to say that we are likely to accept this manuscript for publication, provided you address the following data and other policy-related requests that I have provided below (A-F):

(A)We would like to suggest the following minor modification to the title:

“A multi-channel electrophysiology approach to non-invasively and precisely record human spinal cord activity”

(B) You may be aware of the PLOS Data Policy, which requires that all data be made available without restriction: http://journals.plos.org/plosbiology/s/data-availability. For more information, please also see this editorial: http://dx.doi.org/10.1371/journal.pbio.1001797

Note that we do not require all raw data. Rather, we ask that all individual quantitative observations that underlie the data summarized in the figures and results of your paper be made available in one of the following forms:

-Supplementary files (e.g., excel). Please ensure that all data files are uploaded as 'Supporting Information' and are invariably referred to (in the manuscript, figure legends, and the Description field when uploading your files) using the following format verbatim: S1 Data, S2 Data, etc. Multiple panels of a single or even several figures can be included as multiple sheets in one excel file that is saved using exactly the following convention: S1_Data.xlsx (using an underscore).

-Deposition in a publicly available repository. Please also provide the accession code or a reviewer link so that we may view your data before publication.

Regardless of the method selected, please ensure that you provide the individual numerical values that underlie the summary data displayed in the following figure panels as they are essential for readers to assess your analysis and to reproduce it:

Figure 2A-B, 3A-H, 4A-H, 5A-B, 6A-B, 7A-H, 8A-D, S1

NOTE: the numerical data provided should include all replicates AND the way in which the plotted mean and errors were derived (it should not present only the mean/average values).

(C) Please make the data uploaded in EEG-BIDS format to OpenNeuro publicly available at this stage.

(D) Please also ensure that each of the relevant figure legends in your manuscript include information on *WHERE THE UNDERLYING DATA CAN BE FOUND*, and ensure your supplemental data file/s has a legend.

(E) Please ensure that your Data Statement in the submission system accurately describes where your data can be found and is in final format, as it will be published as written there.

(F) Please note that we cannot accept sole deposition of code in GitHub, as this could be changed after publication. However, you can archive this version of your publicly available GitHub code to Zenodo. Once you do this, it will generate a DOI number, which you will need to provide in the Data Accessibility Statement (you are welcome to also provide the GitHub access information). See the process for doing this here: https://docs.github.com/en/repositories/archiving-a-github-repository/referencing-and-citing-content

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As you address these items, please take this last chance to review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the cover letter that accompanies your revised manuscript.

We expect to receive your revised manuscript within two weeks.

To submit your revision, please go to https://www.editorialmanager.com/pbiology/ and log in as an Author. Click the link labelled 'Submissions Needing Revision' to find your submission record. Your revised submission must include the following:

- a cover letter that should detail your responses to any editorial requests, if applicable, and whether changes have been made to the reference list

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NOTE: If Supporting Information files are included with your article, note that these are not copyedited and will be published as they are submitted. Please ensure that these files are legible and of high quality (at least 300 dpi) in an easily accessible file format. For this reason, please be aware that any references listed in an SI file will not be indexed. For more information, see our Supporting Information guidelines:

https://journals.plos.org/plosbiology/s/supporting-information

*Published Peer Review History*

Please note that 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:

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*Press*

Should you, your institution's press office or the journal office choose to press release your paper, please ensure you have opted out of Early Article Posting on the submission form. We ask that you notify us as soon as possible if you or your institution is planning to press release the article.

*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. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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

Kind regards,

Richard

Richard Hodge, PhD

Senior Editor, PLOS Biology

rhodge@plos.org

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Reviewer remarks:

Reviewer #1: I would like to thank the authors for comprehensively addressing my concerns.

Dear Falk,

On behalf of my colleagues and the Academic Editor, Simon Hanslmayr, I am pleased to say that we can accept your manuscript for publication, provided you address any remaining formatting and reporting issues. These will be detailed in an email you should receive within 2-3 business days from our colleagues in the journal operations team; no action is required from you until then. Please note that we will not be able to formally accept your manuscript and schedule it for publication until you have completed any requested changes.

During the production process, I would also be grateful if you could please ensure that the OpenNeuro data depositions are made publicly available. The weblink provided in the Data Availability Statement for Study 3 appears to work fine, but the links for Study 1 and 2 do not?

Please take a minute to log into Editorial Manager at http://www.editorialmanager.com/pbiology/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with biologypress@plos.org. If you have previously opted in to the early version process, we ask that you notify us immediately of any press plans so that we may opt out on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

Thank you again for choosing PLOS Biology for publication and supporting Open Access publishing. We look forward to publishing your study. 

Best wishes, 

Richard

Richard Hodge, PhD

Senior Editor, PLOS Biology

rhodge@plos.org

PLOS

Empowering researchers to transform science

Carlyle House, Carlyle Road, Cambridge, CB4 3DN, United Kingdom

ORCiD I plosbio.org I @PLOSBiology I Blog

California (U.S.) corporation #C2354500, based in San Francisco