PONE-D-22-03109S.M.A.R.T. F.U.S: Surrogate Model of Attenuation and Refraction in Transcranial Focused Ultrasound.PLOS ONE

Dear Dr. Cain,

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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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: Partly

Reviewer #3: No

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

Reviewer #1: I Don't Know

Reviewer #2: N/A

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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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: The SMART FUS toolbox software that numerically models the acoustic propagation of low-intensity focused ultrasound (LIFU) is reported. The authors explained that users receive an estimation of the degree of refraction/attenuation expected for the given FUS parameters through rapid estimation of beam properties of LIFU transmitted through bone (skull).

The rationale behind the work is strongly justified and praiseworthy. The software is available to public, favoring dissemination of their work.

As authors indicated, the acoustic propagation through skull is complicated phenomena. Thus, any numerical model is desired to be supported by in vitro validation (not just modelling through models).

The following additional contents can strengthen their work;

1. Comparisons among existing simulation software and algorithms (although the work utilizes part of the 'k-wave' functions) in terms of performances indices.

2. Comparisons of simulation with respect to actual hydrophone mapping of the acoustic field, using quantifiable attenuators with different materials and shapes.

3. Considerations of modeling through inhomogeneous skull properties (although mentioned in the discussion).

4. As the work seems to be heavily dependent on the performance of k-wave algorithms, narrowing the scope of the report, for example, to a 'technical report', can be considered, if PlosOne supports such submissions.

5. Explanation of differential technical elements of their work from the k-wave and their separate performance validation.

Reviewer #2: The authors present a method for estimating the attenuation and aberration of focused ultrasound after propagating through a slab of bone. This uses a large dataset of pre-computed simulations, and interpolates between these values to give estimates of the attenuation and aberration given the transducer parameters and bone thickness. For people not familiar with running simulations, the idea is to give a quick way of estimating the effect of the bone.

Major comments:

1. There is no validation provided for the simulations. Particularly for the higher frequencies, I am not convinced that 3 points per wavelength is sufficient. Some validation must be provided. I would suggest at least the following:

(a) Transducer model in water: For a range of transducer sizes, angles, and frequencies (which relates to PPW in this study), verify that the axial pressure in water agrees with a suitable reference solution (e.g., computed using the O'Neil solution, the Rayleigh integral, or the FOCUS toolbox, etc).

(b) Propagation through bone: A convergence test should be performed to show that the results don't depend on the sampling parameters. In other words, run a subset of simulations (particularly for the highest frequency) at higher points per wavelength and smaller CFL, and show the predicted field doesn't change.

(c) Do the predictions match the data presented in https://doi.org/10.48550/arXiv.2202.04552? It should be straightforward to compare the precomputed field from BM3-SC1 (single layer bone) with BM1-SC1 (water), and compare them with the values returned by SMART_FUS. I intended to do this, but couldn't run the SMART_FUS software (see comment below).

2. No evidence is given that a single layer flat bone is a good surrogate for estimating the attenuation / aberration through a real skull (e.g., which has non-uniform thickness and interior structure). Some justification / evidence should be provided.

Minor comments:

3. If the simulations only take 10s, is there an argument for end users just running the simulations themselves for their specific parameters?

4. How is the distance between the transducer and the bone surface determined? Is it fixed?

5. What about the attenuation within the skin and brain?

6. I was unable to run the SMART_FUS functions from the Zenodo link as the data files .\\data\\5d_mats\\attentuation_matrix.mat and .\\data\\5d_mats\\refraction_matrix.mat are missing.

7. Do you have permission to redistribute the imdistline function from the MATLAB image processing toolbox in an open repository?

8. In Fig 1B, should the right plot title be refraction?

9. DS appears in the author contributions but is not in the author list.

Reviewer #3: This is a short manuscript that introduces two matlab functions to aid in transcranial focused ultrasound. The functions are idealized functions of a single bone type of a flat configuration. As such a simplified model of bone, it is not clear what the application for these matlab functions would be. A better understanding of the intended use of the functions is needed here. A clear use case would be helpful.

In addition, some details of the functions are not clear. What is “trajectory?” Is this angle with respect to the bone surface?

What was the rationale and references for the choices of bone acoustic properties?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PONE-D-22-03109R1S.M.A.R.T. F.U.S: Surrogate Model of Attenuation and Refraction in Transcranial Focused Ultrasound.PLOS ONE

Dear Dr. Cain,

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.

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

Please submit your revised manuscript by Sep 12 2022 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,

Talib Al-Ameri, Ph.D

Academic Editor

PLOS ONE

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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 #2: (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 #2: Partly

**********

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

Reviewer #2: N/A

**********

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 #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 #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 #2: Accuracy: I thank the authors for their revision. However, my fundamental concern from the previous version - are the simulations correct? - has still not been adequately addressed. While k-Wave as a solver may have previously been validated under certain conditions, it is essential that you validate its use under the conditions in which you use it for this study. As a minimum, I would like to see a comparison of the axial pressure from the transducer at the lowest sampling used (3 points per wavelength) against an analytical solution (e.g., the O'Neil solution). This is easy to do, as the O'Neil solution is also implemented in k-Wave.

Convergence test: The convergence tests mentions data in an appendix, but I couldn't see an appendix?

Flat skull bone: There is still no evidence provided that the use of a flat skull bone is a good surrogate for a real skull which varies in thickness. I appreciate that there might be some computational difficulties as discussed, and I'm happy with the homogeneous vs heterogeneous justification, but flat vs real is still not justified. If you took a real skull, and a flat skull with the same nominal thickness, what errors might be introduced? I could imagine in some scenarios they might be be considerable. Quantifying the errors is a important concern if the authors intend the toolbox to be used by other (non-computational) groups.

Attenuation in the brain: While the density and sound speed are similar, the acoustic attenuation in soft tissue is 2 orders of magnitude higher, so the question remains.

Do the predictions match the data presented in ...: This was intended as a suggestion to validate the results of the paper, not as a homework problem for the reviewers.

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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 #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.]

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.

S.M.A.R.T. F.U.S: Surrogate Model of Attenuation and Refraction in Transcranial Focused Ultrasound.

PONE-D-22-03109R2

Dear Dr. Cain,

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,

Talib Al-Ameri, Ph.D

Academic Editor

PLOS ONE

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