“Non-Eloquent” brain regions predict neuropsychological outcome in tumor patients undergoing awake craniotomy

Muhammad Omar Chohan; Ranee Ann Flores; Christopher Wertz; Rex Eugene Jung

doi:10.1371/journal.pone.0284261

Peer Review History

Original SubmissionOctober 20, 2022
27 Jan 2023 Decision Letter - Irene Cristofori, Editor PONE-D-22-27442“Non-Eloquent” brain regions predict neuropsychological outcome in tumor patients undergoing awake craniotomyPLOS ONE Dear Dr. Jung, 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 Mar 13 2023 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. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. 3. Please amend your manuscript to include your abstract after the title page. [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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Reviewer #1: Yes ****** 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 retrospective study of 62 patients who underwent awake neurosurgery for brain tumors. They report the effect of brain lesions on the neuropsychological evolution of patients. They conclude that lesions affecting so-called non-eloquent brain regions can affect some high order human functions. I enjoy reading the manuscript as it is well written and organised. I would like the authors to clarify several points before the manuscript can be published. Major: 1) Overall, the manuscript just seems to confirm facts that are all ready well known by the scientific community. Maybe less by neurosurgeons but very well known by some and by neuroscientists. Indeed, the concept of eloquent brain regions as motor, sensory, speech regions is out of date. High order human functions are far more complex and organised in a wide interconnected brain network. For example, the role of the prefrontal/frontal cortex in general has been extensively explored, and even though it is not commonly refered as an "eloquent area" from an "classical" neurosurgical perspective, it known to be a critical brain region for many functions. Therefore, the authors should temper a little the overall novelty of their findings. 2) did the authors use correction for multiple analysis ? Indeed as they are many many brain regions (so many many tests) so the statistical value of significance should be corrected for multiple analysis. Then the authors should confirm or not that the brain region they stated significant "stay" significant with this stastistical methods. minor 1) the authors should give more details on the tumor included (volume, exact localisation (brain region involded)...) 2) why awake was deemed necessary for these patients in the first place ? 3) what was the peroperative testing protocol ? Were high order functions tested during the awake phase (especially since some functions were altered pre operatively)? ****** 6. 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 ******** [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. https://doi.org/10.1371/journal.pone.0284261.r001
Revision 1
14 Mar 2023 Author Response Reviewer #1: The authors present a retrospective study of 62 patients who underwent awake neurosurgery for brain tumors. They report the effect of brain lesions on the neuropsychological evolution of patients. They conclude that lesions affecting so-called non-eloquent brain regions can affect some high order human functions. I enjoy reading the manuscript as it is well written and organised. We thank the reviewer for this positive comment. I would like the authors to clarify several points before the manuscript can be published. Major: 1) Overall, the manuscript just seems to confirm facts that are all ready well known by the scientific community. Maybe less by neurosurgeons but very well known by some and by neuroscientists. Indeed, the concept of eloquent brain regions as motor, sensory, speech regions is out of date. High order human functions are far more complex and organised in a wide interconnected brain network. For example, the role of the prefrontal/frontal cortex in general has been extensively explored, and even though it is not commonly refered as an "eloquent area" from an "classical" neurosurgical perspective, it known to be a critical brain region for many functions. Therefore, the authors should temper a little the overall novelty of their findings. We agree that the term is certainly dated given the knowledge provided by modern neuroscience and neuropsychology. We have attempted to temper the novelty in the manuscript where appropriate, particularly by noting that this term is classically considered to be “non-eloquent” by neurosurgeons, with more modern neuropsychological, neuroimaging, and neuropsychiatric data implicating these regions in numerous higher cognitive processes. 2) did the authors use correction for multiple analysis ? Indeed as they are many many brain regions (so many many tests) so the statistical value of significance should be corrected for multiple analysis. Then the authors should confirm or not that the brain region they stated significant "stay" significant with this stastistical methods. We thank the reviewer for this important comment. We have utilized a family-wise correction for this exploratory paper (we state in the manuscript: “Family-wise p was held to p <.05 to control for Type I error given multiple comparisons”). That is, we adopt a .05 statistical significance threshold under which all major contrasts must fall below (in total) – a family wise error rate (FWER) using ordered p values (the Holm procedure – Holm 1979) Holm, S. (1979). A simple sequentially rejective multiple test procedure. Scandinavian Journal of Statistics, 6, 65-70. Thus, the overall confidence of all contrasts being true is held at 95%. We believe that this, more lenient, correction is appropriate for this exploratory study as compared to the stricter Bonferroni, which allocates the false discovery equally (Bonferroni) across contrasts as opposed to sequentially (Holm)(one contrast can be lenient – i.e., .04, but the rest must be increasingly stricter – i.e., .01 each, until the .05 threshold is reached). We have included the Holm reference to make note of our approach. Minor 1) the authors should give more details on the tumor included (volume, exact localisation (brain region involded)...) Tumor volume was highly skewed, with most being of low volume and a few patients having large volume tumors (Mean = 46,243 mm3, s.d. = 47,197 mm3). Twenty-five lesions were in the left hemisphere, while seventeen were in the right hemisphere. Finally, twenty lesions were within frontal lobe regions (including motor cortex), fourteen were within temporal lobe regions, six were within parietal cortex (including sensory cortex), and one was in “other” cortex (e.g., occipital). We have added this text to the manuscript in the Imaging section. We have added a figure showing the tumor volumes by patient for the reviewer’s information. We do not feel that this figure adds significantly to the manuscript, but are happy to add it if the reviewer feels otherwise. 2) why awake was deemed necessary for these patients in the first place ? Awake surgery was determined to be clinically necessary if behavioral function was determined to be likely to decline significantly due to tumor resection based on 1) location of tumor to so-called “eloquent” tissue, 2) neuropsychological status, and 3) neurosurgical input. Such tissue was often localized to sensory, motor, and language networks in both left and right hemispheres based on fMRI and neuropsychological testing. 3) what was the peroperative testing protocol ? Were high order functions tested during the awake phase (especially since some functions were altered pre operatively)? Primarily language and motor functioning was testing during awake procedure, with stimulation and resection extension progressing to language and motor/sensory networks. Occasional testing was done for other domains (e.g., attention, executive, visual, etc.), although this was not done in as systematic fashion as was language and motor testing across the coho Attachments Attachment Submitted filename: Response to Reviewer.docx https://doi.org/10.1371/journal.pone.0284261.r002
28 Mar 2023 Decision Letter - Irene Cristofori, Editor “Non-Eloquent” brain regions predict neuropsychological outcome in tumor patients undergoing awake craniotomy PONE-D-22-27442R1 Dear Dr. Jung, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Irene Cristofori Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0284261.r003
Formally Accepted
4 Apr 2023 Acceptance Letter - Irene Cristofori, Editor PONE-D-22-27442R1 “Non-Eloquent” brain regions predict neuropsychological outcome in tumor patients undergoing awake craniotomy Dear Dr. Jung: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Irene Cristofori Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0284261.r004

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