PONE-D-22-14162Feasibility of flow-related enhancement brain perfusion MRIPLOS ONE

Dear Dr. Julian Glandorf,

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Additional Editor Comments:

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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: 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?

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: Yes

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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: The authors present a novel method for measuring brain perfusion using MRI. This so-called FREE sequence does not require the administration of contrast medium and was originally developed to determine the perfusion of the lung parenchyma. The results are promising and can be used to measure brain perfusion. The work is highly relevant for clinical application. The manuscript is clearly written without substantial errors. I suggest publication of the manuscript after a minor revision.

1. The presented perfusion maps are similar to the classic CBF maps. Is it possible to give quantitative values of the blood flow. Does the methode allow to calculate the cerebral blood volume (CBV) based an the kinetics of the signal?

2. Two patients with metastasis of a melanoma were examined. Due to the content of melanin, these metastasis appear hyperintense on T1-weighted images without contrast media. Does this effect influence the perfusion contrast?

3. Fig. 4 b: Were the measurements performed before or after radiotherapy?

4. In the discussion section (in line 244) the dependency of the perfusion signal on the angle of blood flow is mentioned. In perspective, is it possible to quantify the directional dependence of perfusion using the method presented (e.g. in the sense of a perfusion tensor)?

5. In the stroke patient only the basal ganglia are hypointense on CT while the M1-segment is occludet. In such a case, the vessel is usually immediately recanalized by thrombectomy without delay by MRI. This should be commented on. What was the outcome of the patient. Did you perform a thrombectomy?

Reviewer #2: Summary of article:

Dr. Glandorf et al. have investigated the methodological validity of the new technique for flow-related enhancement brain perfusion MRI. The authors applied a method to describe perfusion-weighted maps without contrast media, which was reported in the research on lung MRI, into brain MRI. Specifically, the authors conducted three following experiments: (1) Determination of the best flip angles and slice thickness using the data of one health volunteer; (2) Correlation of classification of with-matter/gray matter between arterial spin labeling (ASL) method and their new method using the data of 25 healthy volunteer; (3) Investigation for the usefulness in pathologies using the data of three patients with cerebral metastases and one ischemic stroke patient. As a result, the authors found that (1) Perfusion contrast and its corticomedullary differentiation increased with flip angle; (2) classification in ASL and their new method was highly correlated (correlation coefficient: 0.36 in Pearson correlation test); (3) the results of the new technique were similar with the results of T1 weighted image with gadolinium enhancement. They concluded that their new technique without using contrast media would be safe and feasible.

Comments (Invitation on Aug 31, 2022, and comment submission on Sep 6, 2022)

This study addressed an interesting methodological paper for a new technique of enhancement brain MRI without using contrast media. This study could have a great impact on investigating less-invasive examinations. The authors’ motivation is reasonable because gadolinium enhancement MRI is known to cause rare but critical complications. I would like to congratulate all authors’ efforts in this paper. Please consider addressing some concerns as shown below.

Here are my comments and suggestions about this manuscript.

Major points:

[1] “Introduction”

This study consists of three experiments. Therefore, it is better to describe the purpose/aim and motivation of each experiment in the introduction, such as the followings:

[Aim 1]

[Aim 2]

[Aim 3]

[2] “Methods”

It is helpful for broad readers to add a brief explanation of what Sorensen-Dice coefficients means or how it is calculated in 1-2 sentence.

[3] “Results”

Please consider describing the time required for imaging in every experiment, although the authors show the required time only in a patient with an ischemic stroke.

[4] “Discussion”

It is better to summarize the characteristics or strengths/weaknesses of the new technique compared with those of ASL and gadolinium enhancement MRI in a table.

[5] “Discussion”

Please add the following limitations: (1) This study confirmed the similarity of the results between the new technique and gadolinium enhancement MRI only in the condition of brain metastases and large vessel occlusion. The feasibility for other diseases such as high-grade glioma, encephalitis, vasculitis, or minor ischemic stroke is still uncertain; (2) This study did not consider the artifact effects. Some patients (i.g. with V-P shunt) would have artifacts that would affect the MR imaging.

Minor points:

[6] “Figure 2”

Please add the explanation of (c) in the figure legend.

[7] “Results”

Please rewrite the subsection title “FREE vs pCASL” because this part does not show which is better or superior but the correlation/concordance of two different methods.

[8] “Results”

It is helpful to show the scatter plot of Pearson correlation.

[9] “Results”

Please explain or define what “Dice match” means. I guess that means the “spatial overlap assessed by Sorensen-Dice coefficients,” but it should be defined in the manuscript.

[10] “Results”

The explanation of (a)-(g) in Figure 5 should be in the figure legend, not in the main text.

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Reviewer #1: Yes: Christian Ziener

Reviewer #2: Yes: Naoto Kuroda

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Feasibility of flow-related enhancement brain perfusion MRI

PONE-D-22-14162R1

Dear Dr. Julian Glandorf,

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,

Ayataka Fujimoto

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear authors,

Thank you very much for the revision.

Al reviewers accepted the latest version.

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

**********

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: Yes

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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: All points have been carefully edited. The manuscript is clearly written. I recommend publication of the manuscript.

Reviewer #2: I appreciate the authors taking my suggestions and incorporating them into the manuscript.

I would like to congratulate their effort in the revision.

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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: Christian Ziener

Reviewer #2: Yes: Naoto Kuroda

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