PCSY-D-24-00165

Dynamics evaluation of brain signals through information geometry

PLOS Complex Systems

Dear Dr. Choong,

Thank you for submitting your manuscript to PLOS Complex Systems. After careful consideration, we feel that it has merit but does not fully meet PLOS Complex Systems's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript within 60 days Apr 26 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at complexsystems@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcsy/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

* An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Kimberly Glass

Section Editor

PLOS Complex Systems

Kimberly Glass

Section Editor

PLOS Complex Systems

Hocine Cherifi

Editor-in-Chief

PLOS Complex Systems

Journal Requirements:

1. We ask that a manuscript source file is provided at Revision. Please upload your manuscript file as a .doc, .docx, .rtf or .tex.

2. In the online submission form, you indicated that "The data used in this work is available in OpenNeuro with details stated in the manuscript. The code used for this work will be available upon request.". 

All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 

1. In a public repository, 

2. Within the manuscript itself, or 

3. Uploaded as supplementary information.

This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons by return email and your exemption request will be escalated to the editor for approval. Your exemption request will be handled independently and will not hold up the peer review process, but will need to be resolved should your manuscript be accepted for publication. One of the Editorial team will then be in touch if there are any issues.

Additional Editor Comments (if provided):

Both reviewers have multiple excellent points on how to improve this publication. Please especially consider their feedback regarding performing replication on multiple data sets (at least two), evaluating the method in that broader context, presenting the results in a more intuitive manner, and explaining the relevance of this approach to a broader audience.

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Reviewers' Comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does this manuscript meet PLOS Complex Systems’s publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Complex Systems does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I enjoyed reading this technical summary of the analysis of open source EEG data from healthy participants and people with dementia. I thought that your analysis — using information rates and their distributions — was interesting and described clearly.

My main suggestions are to make it easier for the reader to understand the potential importance of the results — and to make the results easier to understand. Perhaps you could consider the following:

Stylistic points

Although your English is extremely good, there are a few lapses in English grammar and occasional odd use of words. It would be useful if you could have your text revised by someone with English as their first language. I have identified a few illustrative examples in my minor comments (please see below).

Major points

I would recommend that you streamline the reporting of your results so that people can get a clear picture of the basic differences the information rate analysis detected. This can be done in several ways.

First, only report the significant differences in the figures containing the bar plots and put the rest of the figures in supplementary material. Second, just use the distributions of information rates over subjects and do not duplicate the same information using the ensemble averages. In other words, choose whether to present Figures 4 through to 8 or, Figures 9 through to 13. I would prefer to see the latter.

Second, I think you need to include hypotheses, so people can evaluate your findings. I would recommend including the following in the introduction:

“There are many analyses of the EEG correlates of dementia and related disorders. Generally speaking, in neurodegenerative disorders and related brain states with reduced levels of consciousness, there is a loss of complexity; sometimes characterised in terms of the emergence of slow rhythms (e.g., slow-wave sleep and enhanced theta activity). A complementary perspective on these characteristic differences is an increased complexity with arousal and attentive neuronal processing (e.g., event related desynchronisation and induced gamma in the occipital regions). These descriptions suggest that in Alzheimer's disease and frontotemporal dementia, we would expect to see a reduced complexity or itinerancy in neuronal dynamics. This speaks to a reduction in the information rate of density dynamics. We therefore hypothesised a reduction in the mean and variance of information rates in the two patient groups. In particular, we predicted that the frontal regions should show a loss of itinerancy in terms of a reduced mean information rate — and its fluctuations as measured by higher order statistical moments (such as variance). We anticipated that these differences would be expressed across frequency bands in a scale-invariant fashion. Furthermore, given the different regional specificity of frontotemporal dementia and Alzheimer’s disease, we predicted a complementary pattern of changes in the posterior brain regions; particularly the parietal, temporal and occipital regions."

When you could discuss your results, you can then comment upon whether these predictions were fulfilled or not. Having predictions helps the reader make sense of the results and links your observations to previous work, upon which these predictions have been based.

Finally, I think it would be nice to unpack the notion of information rate for the general reader. For example, on Page 4 (line 128) you can say:

“Time-dependent changes in the probability distribution over measured brain states can then be thought of as a path or movement on a statistical manifold, where each point on the manifold corresponds to a probability distribution. The information rate scores the rate of change of information distance with movement on the statistical manifold. Technically, this can be measured as a path integral of infinitesimal differences in probability distributions, as measured with (a function of) the KL divergence. This information rate reduces to a simple expression — in terms of the rate of change of the probability distributions as described below — and captures the density dynamics in a way that static measures do not. It is this density dynamics that underwrites the complexity and itinerancy of transitions through successive brain states."

Minor points

Page 2, line 10: please say: "leads to behavioural change and the loss of the ability…"

Page 2, line 28: please say "with the brain in a state of concentration"

Page 2, line 33: please replace "Personnel" with "Patients"

Page 2, line 35: please say "healthy person due to the loss of synapses within the brain"

Page 4, line 110: please replace "can hardly" with "cannot"

Page 5, line 138. I am assuming that the window size is in units of seconds. If so, please make this explicit.

In Table 1 (page 8) please include the alpha, beta, gamma, … designations of the frequency bands you use in Table 2.

I did not understand the Latin placeholder text in the Acknowledgements.

I hope that these suggestions help, should any revision be required.

Reviewer #2: Dear Authors,

Thank you for providing this thoughtful examination of EEG and signal processing in the context of a disease with major social relevance.  I've been reading papers with a similar structure to this one for the past 20 years, and it's always interesting to see how novel (in the Alzheimer's space) signal processing methods play out in EEG or other neuroimaging methods.  I think the greatest challenges to this class of literature is not so much the novelty of signal processing - (which I understand is likely your immediate focus when writing) but replication and contextualization.  The good news is that with some feasible updates, this paper could become a star in the field.  I think there are two major classes of replicability and contextualization concerns - within EEG and then vs other imaging modalities.  Additionally, the manuscript is with lip service to underlying cellular mechanisms of AD, and while there are many potential readers who will be coming from that perspective, that aspect of the paper deserves further serious development.  

Within EEG replication

I'm sympathetic to the difficulties of data access, and how patience and persistence is required in obtaining datasets.  That being said, given the long history of weak replication of EEG findings in AD, it's essential for you to find at least two other datasets in which to explore.  The current dataset likely isn't large enough for train/test/validation and given heterogeneity of EEG cohorts, it's very important to show that you've established a reliable biomarker.  So start emailing everyone with related data, get access and rerun what you've already set up.  To that point, I'd expect a github repo with all code to reproduce figures, so please link to that.  To provide context to your point I would like to see a review of literature - I understand these metrics haven't been generally deployed, but perhaps you find that they co-vary with some more primitive analysis, so one might infer that your results would hold in those cases as well.  Of course directly demonstrating it in as many datasets as possible is certainly the superior solution.  In particular, I'm interested in to what extent this relates to various network analysis perspectives on EEG that largely originated from Stam's group, and if this metric on communication supports (or not) selective effects on long range links.

Between neuroimaging modality comparisons

The authors state: "The patients would need to go through medical history, physical examination, laboratory test, and utilizing a few visual diagnostic tools like CT scan, fMRI, and EEG."  That is unfortunately inaccurate - it would likely be helpful if such data were routinely acquired, but in 99% of cases there are no brainscans of any type acquired.  The point is not just to correct this statement, but that I think the motivation is to justify the importance of sensitive and specific diagnostic measures.  As it's much easier to get someone in an MRI machine, as you don't have to deal with goopy electrodes applied to likely confused individuals who may not fully realize why they are there, I think there should be discussion of the relative merits of EEG diagnostics vs MRI-based methods.  This should cover not just the usual temporal resolution issues but the average classification accuracies found by well-cited papers on each type, the type of features found to be distinct in each approach, and the specificity (or not) to AD vs other neurodegenerative diseases.  The purpose of this discussion is to give readers newer to the field an important range of performance to expect, and to understand why EEG is (or is not) going to offer superior classification accuracy, and if not, what additional value the analysis may have.

Connecting to a broader audience of AD researchers

To have the impact your fine work deserves, it will be helpful to throw a line to the larger contingent of molecular biology researchers of AD who will not be prepared to grasp or imagine how  your findings contribute to a multiscale conceptualization of the disease.  It seems you all agree with this objective, as your final sentence is: "Overall, the insights gained from this study contribute to the expanding field of quantitative EEG analysis, emphasizing the promise of using information rate-based approaches for improved differentiation and understanding of neurological disorders."  What I would like to see is a serious consideration of what molecules and structural brain connectivity might underlie the effects you've seen.  You could pull from simulations, actual ephys data, and other neuroimaging studies.  I think even John Hardy recently had  a piece in neuro talking about how such an integrated perspective is needed, so I think there's currently increased receptivity to your perspective, if you can build out at least a hypothesis of cellular activities possibly mediating your observations.  Now you might say, "we've never seen someone do that", and indeed, it is rare, but witness the lack of progress in the field and need for change.

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6. 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.

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For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

Figure resubmission:

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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. If there are other versions of figure files still present in your submission file inventory at resubmission, please replace them with the PACE-processed versions.

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

PCSY-D-24-00165R1

Dynamics evaluation of brain signals through information geometry

PLOS Complex Systems

Dear Dr. Choong,

Thank you for submitting your manuscript to PLOS Complex Systems. After careful consideration, we feel that it has merit but does not fully meet PLOS Complex Systems's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript within 30 days Jun 18 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at complexsystems@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcsy/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

* A rebuttal letter that responds to each point raised by the editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to any formatting updates and technical items listed in the 'Journal Requirements' section below.

* A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

* An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Kimberly Glass

Section Editor

PLOS Complex Systems

Kimberly Glass

Section Editor

PLOS Complex Systems

Hocine Cherifi

Editor-in-Chief

PLOS Complex Systems

Additional Editor Comments (if provided):

The authors have addressed the majority of the reviewers' comments. However, Reviewer 2 raises an excellent point about replication, which is consistent with comments from the original review. Prior to acceptance, the authors need to address this final concern by applying their method to more than one dataset. If the authors believe this will take longer than 30 days, I am happy to give them additional time to complete their revision. I also optionally suggest that, given the focus of the manuscript, the authors consider slightly updating their title to include a mention of dementia or AD.

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Reviewers' Comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Does this manuscript meet PLOS Complex Systems's publication criteria? Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe methodologically and ethically rigorous research with conclusions that are appropriately drawn based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available (please refer to the Data Availability Statement at the start of the manuscript PDF file)?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS Complex Systems does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Many thanks for attending to my previous comments. And congratulations on a compelling piece of work.

Reviewer #2: Thank you for your revisions in response to my last comments. With regard to your statement, "The problem is compounded by the fact that checking on “reproducibility” requires accessing a similar set of data from Alzheimer’s disease, frontotemporal dementia patients, and healthy controls obtained under similar conditions" as far as "similar conditions" this is resting state data, so it's the easiest set of conditions to replicate. It could well be difficult to find all three conditions in the same dataset, but there are several datasets out there with AD AND control or FTD AND control, so if you can't get all three, then try for at least two conditions to show replication. There are some EEG datasets with an MCI state included, which could also be useful for your purposes.

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7. 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.

Do you want your identity to be public for this peer review? If you choose “no”, your identity will remain anonymous but your review may still be made public.

For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

Figure resubmission:

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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. If there are other versions of figure files still present in your submission file inventory at resubmission, please replace them with the PACE-processed versions.

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies 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. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Evaluating Brain Signal Dynamics Across Cognitive Disorders Using Information Geometry

PCSY-D-24-00165R2

Dear Mr. Choong,

We are pleased to inform you that your manuscript 'Evaluating Brain Signal Dynamics Across Cognitive Disorders Using Information Geometry' has been provisionally accepted for publication in PLOS Complex Systems.

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

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.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact complexsystems@plos.org.

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

Best regards,

Kimberly Glass

Section Editor

PLOS Complex Systems

Hocine Cherifi

Editor-in-Chief

PLOS Complex Systems

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The authors have successfully addressed all reviewer comments. I did note one typo (line 97: "were used to validation of the proposed analyses" --> "were used to validate the proposed analyses") which the authors should fix at the proofing stage.

Reviewer Comments (if any, and for reference):