PCOMPBIOL-D-25-00770

Efficient Gaussian Process-based Motor Hotspot Hunting with Concurrent Optimization of TMS Coil Location and Orientation

PLOS Computational Biology

Dear Dr. Schultheiss,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology'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 within 60 days Nov 03 2025 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 ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter

We look forward to receiving your revised manuscript.

Kind regards,

Ming Bo Cai

Academic Editor

PLOS Computational Biology

Joseph Ayers

Section Editor

PLOS Computational Biology

Journal Requirements:

1) Please ensure that the CRediT author contributions listed for every co-author are completed accurately and in full.

At this stage, the following Authors/Authors require contributions: David Luis Schultheiss, Zsolt Turi, Joschka Boedecker, and Andreas Vlachos. Please ensure that the full contributions of each author are acknowledged in the "Add/Edit/Remove Authors" section of our submission form.

The list of CRediT author contributions may be found here: https://journals.plos.org/ploscompbiol/s/authorship#loc-author-contributions

2) We ask that a manuscript source file is provided at Revision. Please upload your manuscript file as a .doc, .docx, .rtf or .tex. If you are providing a .tex file, please upload it under the item type u2018LaTeX Source Fileu2019 and leave your .pdf version as the item type u2018Manuscriptu2019.

3) Please upload all main figures as separate Figure files in .tif or .eps format. For more information about how to convert and format your figure files please see our guidelines:

https://journals.plos.org/ploscompbiol/s/figures

4) Please ensure that all Figure files have corresponding citations and legends within the manuscript. Currently, Figure 4 in your submission file inventory does not have an in-text citation. Please include the in-text citation of the figure.

5) Some material included in your submission may be copyrighted. According to PLOSu2019s copyright policy, authors who use figures or other material (e.g., graphics, clipart, maps) from another author or copyright holder must demonstrate or obtain permission to publish this material under the Creative Commons Attribution 4.0 International (CC BY 4.0) License used by PLOS journals. Please closely review the details of PLOSu2019s copyright requirements here: PLOS Licenses and Copyright. If you need to request permissions from a copyright holder, you may use PLOS's Copyright Content Permission form.

Please respond directly to this email and provide any known details concerning your material's license terms and permissions required for reuse, even if you have not yet obtained copyright permissions or are unsure of your material's copyright compatibility. Once you have responded and addressed all other outstanding technical requirements, you may resubmit your manuscript within Editorial Manager.

Potential Copyright Issues:

i) Figure 4. Please confirm whether you drew the images / clip-art within the figure panels by hand. If you did not draw the images, please provide (a) a link to the source of the images or icons and their license / terms of use; or (b) written permission from the copyright holder to publish the images or icons under our CC BY 4.0 license. Alternatively, you may replace the images with open source alternatives. See these open source resources you may use to replace images / clip-art:

- https://commons.wikimedia.org

- https://openclipart.org/.

6) Your current Financial Disclosure states, "The author(s) received no specific funding for this work."

However, your funding information on the submission form indicates receiving a fund. Please ensure that the funders and grant numbers match between the Financial Disclosure field and the Funding Information tab in your submission form. Note that the funders must be provided in the same order in both places as well.

Please amend your detailed Financial Disclosure statement. This is published with the article. It must therefore be completed in full sentences and contain the exact wording you wish to be published.

1) Please clarify all sources of financial support for your study. List the grants, grant numbers, and organizations that funded your study, including funding received from your institution. Please note that suppliers of material support, including research materials, should be recognized in the Acknowledgements section rather than in the Financial Disclosure

2) State the initials, alongside each funding source, of each author to receive each grant. For example: "This work was supported by the National Institutes of Health (####### to AM; ###### to CJ) and the National Science Foundation (###### to AM)."

3) State what role the funders took in the study. If the funders had no role in your study, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

4) If any authors received a salary from any of your funders, please state which authors and which funders.

7) Thank you for stating "The authors declare no conflict of interest." Please revise your current Competing Interest statement to the standard "The authors have declared that no competing interests exist."

Note: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Reviewers' comments:

Reviewer's Responses to Questions

Reviewer #1: “A systematic review found that over 90% of studies determine rTMS intensity based on motor cortex stimulation, even when the intended cortical target is elsewhere (e.g., the dorsolateral prefrontal cortex) [83]. Our method has the potential to improve rTMS target selection by enhancing spatial precision and reproducibility, ultimately leading to more effective neuromodulatory interventions.“ Here are two argments likely incorrect connected. A more efficient hotspot identification does not solve the problem of using it as a target elsewhere.

Accordingly here “Importantly, the proposed method is not restricted to the motor cortex; it is broadly applicable to other TMS applications requiring parameter optimization, facilitating hotspot identification beyond the motor cortex.“ It should be clearly stated that other outreads such as TMS-EEG are needed.

“is the absence of a CE-certified commercial neuronavigation system capable of defining the next target during neuronavigation“ agreed. However two amendments might be helpful here. 1. An open source availability of the present programm might be helpful (or not??) just by advising “move coil xx cm towards…. and angulate it by xx ° clock- or counterclockwise…. Would the time consumption by manually feeding this program be worth the effort?. 2. Are there any advices for todays researchers without the program simply using conventional hotspot hunting for the moment?

Reviewer #2: The authors propose a Gaussian process Bayesian‐optimization framework that jointly optimizes both TMS coil position and orientation, and compare five acquisition functions on eight subjects’ EMG data and on simulated data. They conclude that Thompson sampling is most robust. The idea is clear, the implementation should be open source, and the work has methodological and practical value. However, there are still some problems in the analysis in this paper. I recommend major revisions to strengthen validation, clarify methods, and temper claims before acceptance.

Individual points:

1. There is a redundant ) in line 96.

2. The results of random sampling is presented in Figure 1. However, in the corresponding analysis of Figure 1 (in text), the random sampling is not mentioned or compared with the other methods.

3. The results in Figure 2 A do not present the data for the first 10 steps. The distribution of the starting point should have an influence on the performance of these methods and should not be omitted in the analysis.

4. In the analysis of Figure 2B, you say

“All acquisition functions outperform random sampling.”

But this is inconsistent with the performance of random sampling in Figure 1.

5. The legend of Figure 3 is not obvious enough.

6. Please clearly states your advantage compared to the previous Bayesian neuronavigation papers. For example:

https://doi.org/10.1016/j.neuroimage.2015.09.013

https://doi.org/10.1016/j.neuroimage.2020.117082

https://doi.org/10.1016/j.neuroimage.2017.04.001

That should be a quantitative comparison that also looks into the mechanisms so that readers could really learn something and not just see yet another Bayesian method for the same without further information why and which one for what.

7. The abstract mentions “generative models” for data augmentation, but the manuscript lacks specifics on model type, parameters, or validation. Describe the simulation pipeline in detail and address potential biases. Moreover, if possible, can you describe the parameters of your 5 acquisition functions?

8. There are previous models for synthetic TMS motor responses with population statistics out there. A comparison would be great. A test with several of some such models would be even better as they might also increase the n, which could be a bit higher.

9. The simulations use 300 stimuli and evaluate ~2800 test points—this is maybe unrealistic in clinical settings. Is it possible to discuss performance under <100 stimuli and the time/cost trade off in conjunction with robotic navigation.

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: None

Reviewer #2: Yes

**********

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

[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.]

Figure resubmission:

While revising your submission, we strongly recommend that you use PLOS’s NAAS tool (https://ngplosjournals.pagemajik.ai/artanalysis) to test your figure files. NAAS can convert your figure files to the TIFF file type and meet basic requirements (such as print size, resolution), or provide you with a report on issues that do not meet our requirements and that NAAS cannot fix.

After uploading your figures to PLOS’s NAAS tool - https://ngplosjournals.pagemajik.ai/artanalysis, NAAS will process the files provided and display the results in the "Uploaded Files" section of the page as the processing is complete. If the uploaded figures meet our requirements (or NAAS is able to fix the files to meet our requirements), the figure will be marked as "fixed" above. If NAAS is unable to fix the files, a red "failed" label will appear above. When NAAS has confirmed that the figure files meet our requirements, please download the file via the download option, and include these NAAS processed figure files when submitting your revised manuscript.

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Schultheiss,

We are pleased to inform you that your manuscript 'Efficient Gaussian Process-based Motor Hotspot Hunting with Concurrent Optimization of TMS Coil Location and Orientation' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology.

Best regards,

Ming Bo Cai

Academic Editor

PLOS Computational Biology

Joseph Ayers

Section Editor

PLOS Computational Biology

***********************************************************

Thanks for addressing the reviewer comments. We apologize for the slow response. Although not all previous reviewers are available to review the revision, the editor reads through the responses and judges that the concerns have been sufficiently addressed. As pointed out by the authors during this process, a related preprint appeared on bioRxiv. You are welcome to include comments about that work in your final manuscript if you desire.

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: none

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: None

**********

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