PONE-D-20-32068

Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis

PLOS ONE

Dear Dr. Koenig,

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.

In addition to the comments from the Reviewers, please also address the following:

- Carefully check all references, as at least one is improperly formatted/referenced (ref. 34) 

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Academic Editor

PLOS ONE

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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: This very interesting paper looks at pathway-based MRI measures of structural and functional connectivity to construct the motor and cognition dysfunction by a composite imaging metric in MS. The topic is of high interest, given the lack of knowledge on relations between structure and function in relation to clinical deficits. Results are related to disability and cognitive dysfunction. Technically the setup is alright, but the descriptive indicators are too strict, headings and theirs order are confusing. Thresholds for the DTI analysis are missing which effects the correlates between the functioning. Hypothesis is misleading. MS has more complex relationships between pathways and functioning than AD. So, the selected pathway may not represent the memory domain functioning only in MS. Likewise, the current study also showed SDMT correlation as well, which is one the most common cognitive test in MS to indicate the processing speed functioning. The recommendations regarding the correction of these descriptions are attached below.

Abstract:

- Well-written

- Add MS cohort

- Perhaps indicate “2-year longitudinal study at four month intervals” info.

Introduction

- Line 46-48 “We reported reduced resting state functional magnetic resonance imaging (rsfMRI) between the bilateral primary motor cortices in patients with MS as compared to controls” is wrong expression. Perhaps rephrase to “reduced connectivity assessed by rsfMRI”?

- Line 48-50 “A follow-up study focused on both structural and functional connectivity, showing that diffusion tensor imaging (DTI) measures in the transcallosal motor pathway are correlated with rsfMRI of the primary sensorimotor cortices (SMC) in MS” How was this correlation? Perhaps indicate “The change of DTI and rs-fMRI measures were positively correlated over …”

- Line 69-72 “The cognitive component of the MSFC is based on the Paced Serial Addition Test (PASAT) [14], or, more recently, the Symbol Digit Modalities Test (SDMT). The metric proposed here was constructed as an analog to these composite measures of neurologic deficit.” Is this indicating the current study? This is very confusing. In the method section, different kind of tests are existed, but no PASAT.

- Line 73-75 “We focus on two common domains of disability in MS, motor function and memory,..” Why memory only? Several cognitive tests are given in the method and results sections. Conclusion also does not indicate this info. Perhaps the term was going to be “cognition” or “cognitive function”? In addition, even if the main idea was to track the memory, PASAT, BVMT and etc would have been chosen to specify, but not SDMT. SDMT more indicates processing speed.

On the other hand, PCC-AMLT is a well-known memory pathway in AD. However, MS has more complicated pathways that are presented by several cognitive dysfunction in it. Based on the results of the current study, it seems that this pathway is related with memory (COWAT) and processing speed (SDMT) domains. Therefore, instead of memory only, representing as “motor and cognitive functions” would be better.

- Line 73-75: The hypothesis is poorly introduced. Referring the previous work does not help to understand the aim. The citation for the ROI selection for the specific domain should be explained in previous paragraph. Than the exact functions and pathways that are going to be investigated in this study should be described in the hypothesis-paragraph. Such as “therefore, we investigated this this this pathway and its relationship with this this functions using SFCI…. over 2 years..”??

Theory

- Line 89-90. Why the metric will decrease with increased disability? It is a fact that both adaptive and maladaptive responses can occur in MS.

- Line 99. Is the “sample means” indicates the mean of the global connectivity for each patient? The equation should be explained better. Such as for Eq.2: fcpop indicates global or individual functional connectivity of healthy controls, �cpop represents the standard deviation of global or individual functional connectivity of healthy controls and Zmotor indicates the effect size of the motor SFC…

- Line 106. Please introduce the terms in the Eq. 3. What kind of notation is the L,R etc.

- Line 109. Again please explain the notation.

Materials and methods:

- Line 118. The term “Data acquisition” sounds like collecting imaging data etc... Perhaps reword as “Participants”?

In this section, it is written that the study includes 25 MS and 12 HC but in the abstract it is written 20 MS and 9 HC. Indication of the only final numbers of the participant (after withdraw) would be better to follow the article. Another way to describe better would be adding the inclusion/exclusion criteria’s and writing the final number of participants was determined based on these criteria’s following neuropsychological examination given in results.

Ethical committee number and chair should be written.

- Sample size is too strict. Is the Power analysis done? If it is not within the acceptable range the calculations should be repeated by applying something like Bootstrapping.

- Line 139. Table 1. SDMT is rather processing speed. Processing speed and working memory functioning should not be combined under the same section titled as “memory”. SDMT and D-KEFS do not represent the components of the memory domains and rather PASAT would have been involved in the neuropsychological tests to show the working memory functioning as described in the introduction.

- Line 148: Numerical indication of the slices would be easier to read: 176 axial slices.

- Line 173. Only “MRI post- processing” heading misleads the readers. This part includes both pre and post processing for the current version. Perhaps the heading would be “Processing of the MRI data”?

Other MRI Measures

- Line 200-203. Please specify the lesion filling procedures/tolls etc. more detailed.

- Line 249: What are the exact values for the thresholding of the structural connectivity construction? FOD cut off, number of fibers etc.?

Results

- Line 335: Table 2 should include the lesion volume information.

- Descriptive statistics that are represented in the Table3&4 are hard to follow in the text. Combining the functional and structural connectivity sections would be better for following the results in the tables that belong to both sections.

- Line 417-418: “In the interest of space, only behavioral measures that showed significant relationships are included.” Which relationship? Did you mean that only those that show a significant correlation between at least one of the SFCI components and one of the neuropsychological tests are given in the table?

- Line 431-446: Instead of the terms “positively/negatively”, explaining like “lower performance by SDMT or etc related with the lower/stronger/higher connectivity” may be easier to read.

Discussion

-Line 448-449: “This work demonstrates that a combined structural and functional connectivity metric can be a sensitive tool for identification of neurological disease” there is no other type of neurological disease that shows different patterns etc than MS or identify MS. So this sentence may be confusing. Rather it can be “This work demonstrates that a combined structural and functional connectivity metric can be a sensitive tool for identification of clinical impairment in neurological disease such as MS.”

-Methodological limitations must be discussed

-Line 497-500: I respectfully disagree with the authors that normalization is not necessary to compensate bias field effect (i.e noise) either it is region based or not. Before the calculation of the ROIs, registration to a standard atlas is mandatory which the current study also involved registration. This issue should be discussed more. Perhaps, exemplify the order of the analysis for this study compared to other studies.

Reviewer #2: The authors propose a composite MRI index, made out from MRI connectivity metrics relative to motor and cognitive domains, to relate to functional status and its decline in MS, tested in a 2-year longitudinal dataset.They focus on the transcallosal motor pathway connectivity and the connectivity mediated by the posterior cingulum bundle.

The authors theorize three different models to obtain the index and they test them both on simulated and real data.

line 150 : 256 x 128 might be a matrix error? ( siemens has this 50% distance factor - or gap- of the voxel on MPRAGE sequences in the direction of acquisition , but this does not change the matrix). I suppose also axial acquisition has to be verified, because 176 slices is typical of sagittal acquisitions.

liines 148-171 : please keep same order in the parameter description of each sequence (e.g. slice number,, thickness, FOV, matrix, voxel size etc). Also please report the acquisition duration, confirm that this is the order of acquisition and describe experimental setting , paradigm , pre-scan instructions and training.

line 172 MRI data analysis:: please provide all tools that you use in every step i.e. to apply Gaussian filter, fitting the boxcar model, the LV and on. I suppose that this can be provided as supplementary info. Also more info is needed for the experimental set, e.g. bite bar, physiological parameter acquisition. This is to ameliorate reproducibility.

line 219-220: How did you manually modify ROIs, e.g. by erosion of the voxels found in CSF?

line 230-242 : please add details for registration and transformation of images and refer to different spaces in a more explicit way: individual space can be functional , DTI, T13D or FLAIR. What kind of interpolation did you use to apply a transformation matrix to a flat ROI?

Fig3 : the 3D glass brain image appears blurred and does not permit a good evaluation of the localization.

line 265: by "cluster size 60" do you mean cluster size threshold of 60 voxels?please rephrase.

line 475-476: some grammar error, please rephrase

line 479 : rather than finding it is a missed relationship or no finding.

Conclusion:

This study can be included among the efforts in the advanced neuroimaging in neurological disease to identify connectivity biomarkers of disease status and progression. The small sample size may determine type I statistical error, as might be the case of the discussed missing PCC-AMTL association to memory. It is comprehensible that producing data for a power analysis at this point is too much to ask, therefore the value of this study can only be considered as in an exploratory study. It is valuable however for the longitudinal design, the right choice to focus on specific function-structure target, the sane methodology and for the correct admission and description of the limits. It is a valid scientific contribution in the search of viable imaging targets to obtain biomarkers that can translate into clinic, after validation in an adequately large study, so it should be considered as such.

It would be desired the availability, when published, of anonymized metadata of the group analysis, for example z-score maps and demographic, clinical and the other metrics that have been used, upon which to make a power analysis by anyone interested: itwould be an important addition for the usefullness of the paper and would fulfill the journal's policy and mission.

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Reviewer #1: No

Reviewer #2: Yes: Nikolaos Petsas

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PONE-D-20-32068R1

Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis

PLOS ONE

Dear Dr. Koenig,

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.

As you will see below, most of the remaining comments raised from Reviewer are matters of preference. As such, I leave you some leeway in deciding which to specifically address. However, please justify your responses, accordingly. I do recommend, though, that you update some of the references, as suggested. 

Please submit your revised manuscript by Apr 24 2021 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 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: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Niels Bergsland

Academic 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.

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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. 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: Yes

**********

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

**********

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: Overall the review was performed well, the paper has certainly improved. Some remaining points:

Although the authors improved readability of the paper a lot, the references are too old. Cognition in MS is highly topic in recent years and I believe there are more updated relevant works in the literature.

Abstract:

- 3 digits after decimal point is enough for the p value description and 2 digits for r values.

Materials and methods:

- Line 176: Please rephrased as “176 axial slices and 0.94 mm slice thickness”

-“Acquisition time (TA)” would be better instead of “Scan length”

-Please provide abbreviations such as inversion time (TI), TE, TR ….

Results:

In general each table and figure caption should include the abbreviations.

-Figure 4: Please provide all abbreviations MS, SMC… and descriptions like (A) shows sensorimotor cortex etc. in the figure caption.

Reviewer #2: All my questions have been successfully addressed. The only concern of mine remaining is that full data availability has not been definitely addressed

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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: Yes: Arzu Ceylan Has Silemek

Reviewer #2: Yes: Nikolaos Petsas

[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.]

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.

Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis

PONE-D-20-32068R2

Dear Dr. Koenig,

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.

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Kind regards,

Niels Bergsland

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: