PONE-D-23-37867Advancing 7T perfusion imaging by Arterial Spin Labeling: Using parallel transmit for enhanced labeling efficiency and image quality.PLOS ONE

Dear Dr. Oliveira,

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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Additional Editor Comments:

Reviewers generally considered the manuscript of moderate interest because of limitations of the approach and  mild innovation.

The manuscript can be considered for publication only if methodological concerns rasied by all reviewers are fully addressed. Moreover, methodology must be described with more details and greater clarity. Appropriate quantitative measuremens should be introduced, following reviewers suggestions.

Regarding data availability, I don't share the authors view. GDPR allows publication of raw data if they are de-identified, that is if any connection between data and individual are broken. If MR images can't be associated to a person, then they are not perosnal data and are not regulated by GDPR. Of course, any personal feature (including faces in anatomical data) must be deleted.

I understand the concerns (I am an UE citizen and work in EU), but the open data principles must be adhered to. I suggest to check with the local privacy officer.

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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

Reviewer #3: No

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: No

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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: No

Reviewer #3: No

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

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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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 work, the authors compared the effects of different transmit coils (two-channel v.s. 8-channel) on multi-slice cerebral pulsed arterial spin labeling (pASL) at 7T. The comparison was applied to both baseline with three different inversion slab thicknesses and functional ASL of the hand region in the motor cortex with a finger-tapping functional task. The author found lower coefficient of variance (CoV) between the perfusion signal and the inversion slab thickness using 8-channel transmit than two-channel, which represents a higher robustness. The author also demonstrated higher temporal SNR and comparable capabilities for functional ASL using the 8-channel transmit coil.

The experiments in this work were well-designed. The novelty of this manuscript is moderate since pASL has not been a preferred method for brain perfusion mapping in recent years. This manuscript is well written with a clear structure and proper language. Here are some minor tips:

1. The title ‘Advancing 7T perfusion imaging by Arterial Spin Labeling: Using parallel transmit for enhanced labeling efficiency and image quality’. It is recommended to specify ‘Pulsed’ Arterial Spin Labeling. Also, ‘enhanced labeling efficiency and image quality’ is too general since there are no results involving labeling efficiency as a metric. It is better to specify ‘higher robustness’ and ‘higher temporal SNR’. Besides, the running title does not even mention ‘parallel transmit’, which is the key of this manuscript.

2. ‘Perfusion’ labeled in the color bar of Figure 2 is not appropriate, which should be a normalized value such as ml/100g/min. It is better labeled as ‘Perfusion signal’ or ‘Perfusion weighted signal’. Besides, Figure 3 should also come with a color bar.

Reviewer #2: This study investigates the effects of two transmit coils configuration on ASL perfusion imaging with FAIR using TR-FOCI for labeling and background suppression. The two configurations were: a) a parallel transmit system (pTX) with 32 Rx and 8 Tx channels, and b) a standard setup of 32Rx and 3Tx channels. This work showed that a pTx configuration is advantageous in ASL imaging at ultra-high magnetic fields given its less inhomogenous B1 field; however, CBF quantification is missing which would have given a more illustrative example of why it is better to use a pTx system. The two configurations were also tested in functional imaging. Both coils yielded robust fMRI measurements, and the tSNR was higher using the pTX system.

Major Issues

1. To validate that a pTX setting was better than the standard system two quantitative measures were used: coefficient of variance (CoV) and temporal signal-to-noise ratio (SNR); however, as shown in equation two these two measurements are dependent from each other (or basically the same measurement i.e., CoV = 1/tSNR). CBF maps should be quantified in order to add robustness to the study.

2. Line 74: it would also allow for higher perfusion imaging resolution as seen in https://doi.org/10.1371/journal.pone.0215998

3. Line 152: I would show here in a figure the coils b1 maps or give a reference to the b1 maps showed in the supplementary material. Also, for this figure in the supplementary materials the scale and color bar are missing.

4. Was whole brain coverage achieved? If yes, it will be worth to show those images, or a comparison of maximum brain coverage achieved with both systems (pTx versus standard), as whole brain coverage is also specified in the introduction as one of the advantages of acquiring ASL at ultra high magnetic fields.

5. What correction method for multiple comparisons was used for the fMRI study?

6. Line 233 : were t-test comparisons corrected for multiple comparisons?

7. Line 240 in the caption of figure 4 caption: the wording of two different ROIs is confusing; these are the same right/left hemisphere gray matter masks, right?

8. Line 255 : was the tSNR significant higher for the pTX coil compared to the 2Tx coil?

9. Line 272: it might be worth to address in the discussion why do you think P04 displayed decreased z-values for pTX relative to 2Tx (something that was not really expected).

10. Caption in Figure 1 of the supplementary material does not specify the preinversion thickness used for these FAIR acquisitions.

Minor issues

1. Line 22: A in arterial spin labeling should not be capitalized. Overall, there is no consistency between capitalized and non-capitalized description of abbreviations, e.g., (line 27) flow-sensitive alternating inversion recovery (FAIR) or (line 28) Time-Resolved Frequency Offset corrected Inversion (TR-FOCI). Please choose a style and keep it constant throughout the manuscript.

2. Line 45: BOLD fMRI has not been previously described or spelled out.

3. References are missing in line 63 and 65.

4. Line 66: It is recommended not to use contractions in formal writing (i.e., ASL’s)

5. Line 145: C in Control should be in low case

6. Line 170: G in Gray-matter should be in low case. These style errors are constant through-out the document please correct.

7. Line 231: I think the sentence should read: …, meaning that there is more perfusion signal loss at larger inversion slab widths in the 2Tx compared to the pTx coil.

8. Line 298: add citation

9. Line 302-308: very interesting

10. Line 317: capitalize ROIs

11. Line 319-320: UP definition is missing.

Reviewer #3: This manuscript presents a pTx implementation of a pulsed arterial spin labeling technique at ultra-high field for brain perfusion imaging. They demonstrate a comparison of two coil system setups: 2 channel transmit and 8 channel transmit pTx. Two different experiments were performed to evaluate the coil performances. Authors claim the pTx system produces a more homogenous transmit field which translated into improved perfusion signal acquisition.

I agree that ASL can greatly benefit from ultra-high field strength. The use of pTx is becoming a popular approach to combat the challenges which are more evident at 7T. However, there are several technical problems and gaps in the proposed methodology which lack clarity and are of major concern. This leads to many assumptions which readers may need to make. It appears the manuscript focuses more on a coil comparison rather than the potential capabilities of pTx as implied in the title. It is unclear where the capabilities of using pTx are showcased beyond using the 8Tx pTx coil. I suggest the following concerns are addressed prior to recommendation of publication.

Major comments:

1. There are various ASL labeling schemes which can be broadly categorized as spatially selective or velocity selective. Select statements made in the introduction regarding spatial coverage and dependence on arterial transit times is generally only applicable to spatially selective ASL schemes (PASL and pCASL). It will be insightful to elaborate and acknowledge in the introduction other ASL techniques which exist that are not spatially selective such as velocity selective ASL and their progress with using pTx.

2. Line 118 – In section 2.2 Data acquisition, it is briefly mentioned that B1-shimming was implemented over the entire brain. I understand separate volunteer data was used to achieve the B1-shim however there is ambiguity in the description. Please provide more detail on the size of volunteer data to calculate the shim parameters and whether this was a universal B1-shim applied for all subjects scanned for the study. Did you consider using a subject tailored shim or tailored pTx pulses for better B1 correction? If not, why? Please also specify in what aspect of the full ASL FAIR sequence was this shim applied to?

3. Line 120 – This next point follows on from comment 2. It is unclear where pTx capabilities is utilized despite the use of a pTx coil. The authors describe adiabatic tr-FOCI pulses are used for the labeling and two background suppression pulses. Adiabatic pulses are insensitive to B1 variation. They don’t require a pTx coil to be implemented effectively. My understanding is that these adiabatic pulse elements is what contributes significantly to the efficiency of the labeling and as a result the perfusion signal. This then only leaves the 2D-EPI excitation pulses and saturation modules. It is not mentioned and therefore unclear where exactly the pTx was applied to benefit the ASL technique evaluated.

4. Line 152 – Was there any verification in the setup to ensure a fair comparison of the two coils? Authors mentioned a different maximum B1 limit was applied for the two coils respectively. There is a significant difference between the maximum B1 limit. This leads me to assume significantly lower/capped reference voltage was used for the 2Tx coil. Using a lower reference voltage may result in an overall lower flip angle distribution. This appeared to translate in the B1 maps shown in the supplementary material. Could you explain how experiments were performed to give a fair comparison. It would be ideal to consider a baseline calibration of the reference voltage prior to acquisition of perfusion protocols.

5. Line 291 – The authors state that labeling is dependent on the distal location selected. I agree that this has an effect as there are associated blood transition times and T1 relaxation effects. However, they conclude pTx is more efficient for inversion. My understanding is adiabatic pulses were used for inversion. When set up to satisfy adiabatic conditions they are insensitive to B1 variation. This leads me to question whether the tr-FOCI pulses were optimised and whether the restriction of maximum B1 limit influenced the overall inversion fidelity of the pulses?

6. It is not easily understandable what the cause of the asymmetry that occurs in your acquired 2Tx data. You refer to the B1 maps supplied in the supplementary material and suggest that the cause is not due to excitation distribution instead it is the RF profile. My understanding of “RF profile of the coils” is that it relates to transmit sensitivity which is the generated B1 distribution. It is unclear whether the right-side bias is caused by coil geometric sensitivities, transmit efficiency or the B1-shim applied. Can you explain what you mean by “RF profile of the coils” incase I have misunderstood.

7. Compared to other regions of the brain, the B1 in the motor cortex at 7T is relatively adequate. This may be one contributing explanation why the fMRI results were comparable between the two coil setups. Did you consider investigating and comparing other areas (e.g. visual cortex or cerebellum) where B1 is less sufficient to showcase the benefits/diversity of pTx?

Minor comments:

8. Line 77 – There may be more suitable references to include that demonstrates comparative implementation of different adiabatic pulses for PASL.

- Zimmer F, O'Brien K, Bollmann S, Pfeuffer J, Heberlein K, Barth M. Pulsed arterial spin labelling at ultra-high field with a B 1 (+) -optimised adiabatic labelling pulse. MAGMA. 2016 Jun;29(3):463-73. doi: 10.1007/s10334-016-0555-2. Epub 2016 Apr 15. PMID: 27084187.

- Wang K, Shao X, Yan L, Ma SJ, Jin J, Wang DJJ. Optimization of adiabatic pulses for pulsed arterial spin labeling at 7 tesla: Comparison with pseudo-continuous arterial spin labeling. Magn Reson Med. 2021 Jun;85(6):3227-3240. doi: 10.1002/mrm.28661.

9. Line 88 – Wording is confusing as two different concepts are trying to be conveyed here. SAR constraints are stringent at UHF whereas sequences can be less SAR intensive compared to others. PASL uses multiple adiabatic pulses which are SAR intensive. Could you please elaborate why you claim PASL may be less SAR intensive compared to other ASL techniques?

10. Figure 1 shows the coverage and location of the labeling and imaging regions. It would benefit to show a full sequence diagram with all sequence elements.

11. It may be insightful to detail the differences in coil configuration and geometry where appropriate since limited pTx pulse capabilities are implemented.

12. Line 299 – Could you please explain what you mean by “calibration of B1”.

13. Line 302 – Wording implies there is a difference map calculated between the two independently acquired B1 maps of the two coils.

14. Line 320 – There was initial insights demonstrated in the benefits of using tailored pTx pulses for velocity selective labelling at 7T which are directly applicable to ASL techniques.

- Wu C-Y, Jin J, Dixon C, Maillet D, Barth M, Cloos MA. Velocity selective spin labeling using parallel transmission. Magn Reson Med. 2024; 91(4): 1576-1585. doi: 10.1002/mrm.29955

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Reviewer #1: No

Reviewer #2: Yes: Maria G. Mora Alvarez

Reviewer #3: No

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PONE-D-23-37867R1Advancing 7T perfusion imaging by pulsed arterial spin labeling: Using a parallel transmit coil for enhanced labeling robustness and temporal SNR.PLOS ONE

Dear Dr. Oliveira,

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.

The work is substantially improved and the authors did their best to take care of the concerns raised by reviewers and to address limitations. There are still some comments, that can be addressed in a minor revision. Regarding the data sharing, if the local privacy officier has this restrictive interpretation of GDPR, authors must take care, in future experiments, to explicitily seek consent by particiapnt to share raw data. In future, limited access to raw data will not be acceptable to PLOS One (and to most funding bodies)

Please submit your revised manuscript by Aug 23 2024 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: 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,

Federico Giove, PhD

Academic Editor

PLOS ONE

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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: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

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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

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

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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

Reviewer #3: 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

Reviewer #3: 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: Thank you for revising your manuscript and including the requested information. My previous concerns were all well addressed but there are a few more comments for the added contents (The following line numbers refer to the manuscript with tracked changes).

1. Line 110: ‘A FAIR Arterial Spin Labeling sequence was implemented using TR-FOCI RF-pulses [25] with 13ms of pulse duration, nominal flip angle of 2576 degrees, and B1 = 15μT’; Line 143: ‘For the pTx system, a maximum B1+ value of 18μT was used for the excitation pulses’; Line 144: ‘For the 2Tx, a maximum B1 of 12μT was used for the excitation pulses to accommodate amplifier limitations’. Is there a specific reason why the excitation pulses used different B1+ values for the two coils while TR-FOCI RF-pulses used another but the same maximum B1+ value?

2. Line 186: ‘μGM and μWM are the mean signal intensities of white matter and gray matter regions of interest, respectively’ should be ‘of gray matter and white matter regions of interest, respectively.

3. How were the white matter masks generated?

4. Line 197 Equation 4: the CNR is typically defined as abs(S_GM-S_WM)/σ. Here the author tried to use the noise information from both the grey matter and the white matter. I expect the denominator to be sqrt((σ_GM^2+ σ_WM^2)/2) rather than be sqrt(σ_GM^2+ σ_WM^2). Nevertheless, this is only a scaling and will not affect the outcomes.

5. Figure 6B: why were the right and left hemispheres not differentiated for the CNR boxplots?

Reviewer #2: I appreciate the authors addressing my previous comments. This study investigates the effects of two transmit coils configuration on ASL perfusion imaging with FAIR using TR-FOCI for labeling and background suppression. The two configurations were: a) a parallel transmit system (pTX) with 32 Rx and 8 Tx channels, and b) a standard setup of 32Rx and 2Tx channels. This work showed that a pTx configuration is advantageous in ASL imaging at ultra-high magnetic fields given its less inhomogeneous B1 transmit field. Additional, CoV, CNR and SNR measurements were assessed to add robustness to the study. The two configurations were also tested in functional imaging. Both coils yielded robust fMRI measurements, but the tSNR was higher using the pTX system.

Major Issues

1. I think it is important to clarify why SNR was not calculated using the standard deviation of noise in the background (air). Presumably, this is why no statistically significant difference was seen in the SNR assessment between the two coils. I know the use of parallel imaging and transmit coils make this measurement complex, but it will be worth to comment on that.

Minor issues

1. Line 49: This sentence is a phrase and not a complete sentence, it should be connected to the next sentence with a conjunction, in this case using not only…, but also… e.g., Scanning at a higher field strength not only holds the key to improving the intrinsic low SNR of ASL, but also recent research has...

2. Line 341: The should be a semicolon before however instead of a comma, as it is being used as a conjunction.

3. Line 369: I think the flow of the paragraph will be improved if this sentence is start as.. Our fMRI experiment .. since you are previously describing other studies it can be a bit confusing when reading it at a first glance as The fMRI experiment…

Reviewer #3: Thank you for the corrections that you have made in this revision. The authors have mostly addressed my comments satisfactorily.

1. (R3.C5) There is still a concern on clarity with regards to the achieved B1+=15uT for the TR-FOCI RF pulses. The authors clarified that the pulse attributes were kept consistent across both coils. However, there is a discrepancy in the manuscript (line 144) which states, “For the 2Tx, a maximum B1+ of 12uT was used for the excitation pulses to accommodate amplifier limitations”. Given this amplifier limitation, how is the B1+=15uT achieved on the 2Tx?

2. (R3.C6) Is it possible to show multiple slices of the B1 maps (S Fig. 1) which covers the labeling regions highlighted in Figure 1 to verify the claims of potential differences of the B1+ profile of the coil at the level of the tag?

Finally, there are some minor inconsistencies with abbreviations (e.g. B1+ vs B1) used throughout the manuscript. Otherwise, I’m quite satisfied with the authors’ response.

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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: Yes: María Guadalupe Mora Álvarez

Reviewer #3: 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.]

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.

Advancing 7T perfusion imaging by pulsed arterial spin labeling: Using a parallel transmit coil for enhanced labeling robustness and temporal SNR.

PONE-D-23-37867R2

Dear Dr. Oliveira,

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,

Federico Giove, PhD

Academic Editor

PLOS ONE

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