PONE-D-25-03889Multiplex Nodal Modularity: A novel network metric for the regional analysis of amnestic mild cognitive impairment during a working memory binding taskPLOS ONE

Dear Dr. Campbell-Cousins, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’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.

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Section Editor

PLOS ONE

Journal requirements: 1. When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Thank you for stating the following financial disclosure: ACC is funded by the Principal’s Career Development Scholarship (PCDS) for his PHD from the University of Edinburgh. This funder spent no role in the manuscript's creation/data collection. https://institute-academic-development.ed.ac.uk/postgraduate/doctoral/career-management/principals-scholarshipsMAP received funding from the Alzheimer’s Society towards the Longitudinal Study of MCI through the Grants AS-R42303 and AS-SF-14-008. This funding was for the collection of MCI data (used in the manuscript) and specifically in conjunction with this research article 10.1186/s13195-022-01082-9. For the previously mentioned article, the funders only supported the study (proposed research) financially and monitored progress.https://www.alzheimers.org.uk/   Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: Avalon Campbell-Cousins was supported by Edinburgh University’s Principle’s Career Development PhD Scholarship. The authors also acknowledge the support from the Alzheimer’s Society towards the Longitudinal Study of MCI through the Grants AS-R42303 and AS-SF-14-008 awarded to MAP. Additionally, the support of NHS Scotland (both Lothian and Forth Valley boards) in recruiting MCI patients and the Volunteer Panel for healthy controls at the University of Edinburgh. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: ACC is funded by the Principal’s Career Development Scholarship (PCDS) for his PHD from the University of Edinburgh. This funder spent no role in the manuscript's creation/data collection. https://institute-academic-development.ed.ac.uk/postgraduate/doctoral/career-management/principals-scholarshipsMAP received funding from the Alzheimer’s Society towards the Longitudinal Study of MCI through the Grants AS-R42303 and AS-SF-14-008. This funding was for the collection of MCI data (used in the manuscript) and specifically in conjunction with this research article 10.1186/s13195-022-01082-9. For the previously mentioned article, the funders only supported the study (proposed research) financially and monitored progress.https://www.alzheimers.org.uk/  Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 4. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.  Before we proceed with your manuscript, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. 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Additional Editor Comments:

After careful consideration by 2 Reviewers and an Academic Editor, all of the critiques of the Reviewers must be addressed in detail in a revision to determine publication status. If you are prepared to undertake the work required, I would be pleased to reconsider my decision, but revision of the original submission without directly addressing the critiques of the Reviewers does not guarantee acceptance for publication in PLOS ONE. If the authors do not feel that the queries can be addressed, please consider submitting to another publication medium. A revised submission will be sent out for re-review. The authors are urged to have the manuscript given a hard copyedit for syntax and grammar.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

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?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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: No

Reviewer #2: No

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

PLOS ONE 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: In this paper, Authors propose a new metric for assessing community structure in various single-and multi-layer networks, called nodal modularity (nQ). Contrary to the more traditionally used modularity, nQ not only quantifies community structure at a global level in a network, but also provides some information about community structure at a meso-scale level (i.e. at level of single regions). NQ was tested for calculation using functional MRI (fMRI) and diffusion tensor MRI (DT MRI) data from a group of mild cognitive impairment (MCI) patients and healthy controls, calculating multiplex nQ across functional/structural layers. Results suggest that observed changes in nQ in MCI align with expected trajectories of changes in alzheirmer’s disease, suggesting applicability of nQ as a biomarker for the disease.

The paper is of interest, but it overall very long, with several redundant and unnecessary information being reported; several sections can be considerably condensed. Following major issues should be addressed.

1) The Abstract repeatedly states that nQ is very useful (compared to standard modularity) because it is a more fine-grained metric giving information not only at global level but a mesoscale level. Despite this, the results reported in the Abstract are very generic and do not describe which are the regions showing abnormal nQ. Since Authors claim that this is one of the major novelty of their study, I think that results should be expanded in this direction.

2) The first section of the introduction is excessively long and includes a lot of information about Alzheimer's pathology (unrelated to neuroimaging) that is mostly background and not necessary for the paper. This section should be shortened. In general, the methods section is also overly detailed and can be significantly condensed. The same applies to the number of figures and tables.

3) The end of the Introduction is not really introduction, it anticipates already results and conclusions. All the last paragraph of the introduction reporting results and conclusions should be deleted.

4) One of the main limitations of the paper is the very small sample size of HC and MCI groups included. This should be clearly stated in the paper.

5) It is not clear which version of SPM software was used for fMRI analysis, some paragraphs mention SPM8 and other paragraphs mention SPM12. SPM8 is a very old software, so it is surprising that Authors use it for some analysis. To be sure that Authors are using appropriate software for the analysis, please also report software versions for Freesurfer and FSL.

6) The paragraph in the method about modularity is very long and can be condensed. The same applies for the description of the very standard network metrics (e.g. degree, clustering coefficient, centrality..). these are all very standard metrics which were described in details in hundreds of previous publications.

7) I don’t understand how the fact that nQ is not correlated with the other graph metrics constitutes a "verification" of nQ. It only tells us that it is independent, but it certainly does not ensure that it is meaningful.

8) Authors should provide a Results section clearly separated from the Discussion section. In the present paper version, the two sections are combined in a very confusing way.

9) Please delete the wording “disease progression” from any result and interpretation; “progression” implies a longitudinal assessment over time, while the present study is cross-sectional.

Reviewer #2: This study introduces nodal modularity (nQ), a novel network metric designed to evaluate particular changes in brain network community architecture, particularly in the context of amnestic mild cognitive impairment (aMCI) and Alzheimer's Disease (AD). The approach employed in this research is both captivating and technically solid, providing significant insights for the realms of neuroimaging and network neuroscience. The authors receive commendation for merging functional and structural data in an innovative analytical model and validating their techniques with established datasets.

However, I would like to highlight several concerns and limitations that I believe require the authors' attention and clarification before this manuscript.

Major Concerns

1. Limited Sample Size and Power

The number of subjects across groups — particularly in the early MCI and MCI converter subgroups — is relatively small. This naturally limits the statistical power and raises concerns about the robustness of the results. While the authors apply permutation testing and ROC analysis, the reliability of node-level inferences across so many comparisons is still questionable in the absence of adequate correction for multiple comparisons.

2. Absence of Multiple Comparison Correction

Given the large number of regions (85 ROIs) evaluated independently for significance, the study is at risk for inflated false positives. The authors have not clearly stated whether false discovery rate (FDR) correction or any other multiple testing correction was applied. For a study aiming to identify diagnostic biomarkers, statistical stringency is crucial.

3. Biological Interpretability of nQ

While nQ is mathematically well-defined, its biological interpretation remains somewhat abstract. It is not clear how variations in nQ values across brain regions translate into functional implications or pathophysiological mechanisms. A clearer, neurobiologically grounded discussion of what an increase or decrease in nQ implies would significantly enhance the manuscript’s impact.

4. Generalizability of Findings

The specificity of the Visual Short-Term Memory Binding Task (VSTMBT) is well established for early AD detection; however, the utility of nQ outside this specific paradigm remains unexplored. The manuscript would benefit from a discussion of how transferable this method might be across tasks, domains, or even other clinical populations.

5. Data Availability and Reproducibility

A portion of the neuroimaging data used in this study is not publicly available due to clinical restrictions. While this is understandable, it poses a challenge to reproducibility — particularly in a journal like PLOS ONE, which emphasizes open science. It would be helpful if the authors could at least share simulated data or a synthetic version of the dataset for validation of their pipeline.

Minor Comments

• The description of nQ is technically dense. Including an more in-depth illustrative figure or schematic could help readers better visualize the interplay of layers, modules, and nodal contributions.

• The discussion of the correlation between nQ and other network metrics (e.g., degree, PageRank, clustering coefficient) is informative; however, the manuscript could further elaborate on the implications of these relationships

Recommendation

Addressing the statistical concerns, clarifying the biological interpretation of the metric, and improving transparency around data availability will enhance the clarity and impact of this study.

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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

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PONE-D-25-03889R1Multiplex Nodal Modularity: A novel network metric for the regional analysis of amnestic mild cognitive impairment during a working memory binding task

PLOS ONE

Dear Dr. Campbell-Cousins,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’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.

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Thank you for resubmitting your work to PLOS ONE. Please make the corrections posed by Reviewer #2 so I can render a decision on this manuscript.

==============================

Please submit your revised manuscript by July 30, 2025. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ 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 academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• 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, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. 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.

We look forward to receiving your revised manuscript.

Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE

Journal Requirements:

Please 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 rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: No

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). 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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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE 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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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: (No Response)

Reviewer #2: 

Upon evaluating the revised submission alongside the authors’ detailed point-by-point responses, I am pleased to acknowledge that the majority of my major concerns have been addressed in a satisfactory and transparent manner. 

Generalizability and Broader Application

The authors have briefly addressed the applicability of the nQ metric to other paradigms and clinical populations. While the discussion could be more detailed, the current additions are appropriate given the manuscript's length and scope.

Correction for Multiple Comparisons

While the authors have correctly implemented the Benjamini–Hochberg false discovery rate (FDR) correction across all node-level statistical tests, the choice of an α threshold of 0.2 raises concerns. This threshold is notably more lenient than the conventional levels (e.g., 0.05 or 0.1) and may substantially increase the risk of false positives, potentially compromising the reliability of the findings. Although the exploratory nature and high dimensionality of the analysis are acknowledged, a threshold of 0.2 should be more thoroughly justified, including discussion of the implications for the interpretation of results. Alternatively, the authors might consider adopting a more stringent FDR threshold to balance sensitivity and specificity more effectively. Without such justification or adjustment, the statistical rigor and robustness of the conclusions remain questionable.

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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.

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

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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. 

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Multiplex Nodal Modularity: A novel network metric for the regional analysis of amnestic mild cognitive impairment during a working memory binding task

PONE-D-25-03889R2

Dear Dr. Campbell-Cousins,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE