Investigating sensory response to physical discomfort in children with autism spectrum disorder using near-infrared spectroscopy

Larissa C. Schudlo; Evdokia Anagnostou; Tom Chau; Krissy Doyle-Thomas

doi:10.1371/journal.pone.0257029

Peer Review History

Original SubmissionFebruary 23, 2021
30 Mar 2021 Decision Letter - Manabu Sakakibara, Editor PONE-D-21-06009 Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscopy PLOS ONE Dear Dr. Doyle-Thomas, 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. Two experts in the field have carefully reviewed the manuscript entitled, "Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscopy". Their comments are appended below. The first reviewer acknowledged the manuscript is considerably well written pointing out some important suggestions which will be strengthen the manuscript. The reviewer #2 is also well evaluated the manuscript, however, this reviewer raised several critical issues to be considered before publication. Judging from these favorable comments, I would like to be revised the manuscript according to each critique. Please submit your revised manuscript by May 14 2021 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. 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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, Manabu Sakakibara, Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. 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Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. 3. You indicated that you had ethical approval for your study. In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent. [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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: No Reviewer #2: Yes ****** 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 ****** 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: Well written study with valid clinical foundation. The use of the cold challenge is established as safe with children and used in pain research. Findings are important to the development of this area of research. Limitations: 1) As noted by the authors, the effects of medication on these children were not controlled for or reported. This may have a significant impact of the perception of pain and the attentional abilities of the child. 2) The authors site the work of Dunn, Schoen, and Miller demonstrating an understanding of sensory processing disorder and it's classifications. There is no description of the sensory processing disorder diagnosis or severity in this manuscript. Children with over- and under-responsive types of SPD will naturally respond differently to stimuli. 3) Since children with SPD may occur in the general population, often without co-morbid diagnoses, control group children should have been screened for SPD as well. Suggestions to consider in future studies: 1) Children with SPD have altered reactions to sensory habituation based on the type of stimuli and the presentation timing of the stimuli. Single modal stimulation often has a muted response, while multi-modal stimuli has a delayed response that is typically additive across trials. See the Sensory Challenge Protocol studies from Schaaf and Miller. 2) Another consideration would be the effect of decreased vagal tone on the physiologic response to pain. Typically children with SPD demonstrate lower heart rate at rest. When in pain, most individuals will show an increase in HR due to parasympathetic responses to noxious stimuli. By measuring HR while looking at the blood flow to the brain, there may be a way to determine physiologic response vs. perception of pain. 3) Electrodermal measurements have also been shown to be a reliable indicator of sensory over- or under-arousal status. Overall, I think this is a good article. I would add data on the SPD sub-type with which the children present, or list it as a limitation of this study. Reviewer #2: PONE-D-21-06009_reviewer Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscopy Recommendation: Major revision In the present manuscript the authors report on their findings of male children with autism spectrum disorder (ASD) their response to painful stimulus and the utility of near infrared spectroscopy (NIRS) to identify focal changes in brain oxygenation, correlating with a cortical response to the painful stimulus. Overall the authors observed a blunted reaction to the painful stimulus in patients with ASD, relative to typically developing children. This study was well performed and the resulting manuscript is overall well written, with a well researched and lengthy discussion section. The conclusions appear well supported by the data and are certainly relevant to the scientific community. However, several critiques should be considered prior to publication. 1. While well written, the manuscript is too long. Specifically, the introduction and discussion should be abbreviated to include only the most pertinent information. Most of the background information should be made more concise. In general, any claim should be supported by a relevant citation. The first several paragraphs of the introduction have many claims without citation and are quite verbose. Recommend making the introduction much more concise. 2. A full discussion of the subject inclusion and exclusion is recommended. This should include both demographic inclusion criteria as well as clinical. Furthermore, the recruitment strategy should be discussed. Also, if any compensation was involved. Please describe the consenting process and other ethical considerations, including the parental roles. 3. This reviewer questions the decision to include the “excluded” subjects in the analysis. Including these subjects, and also analyzing the cohort without them leads to a confusing description of the results. Furthermore, table 2 is quite confusion with these two groups described (with and without usable NIR data). Recommend only reporting results on subjects with a complete dataset. 4. Table 2 should also include p values. 5. The results section should report on the data only. Further description of methods should be placed in the “methods” section, including the section starting on page 15 line 354 ****** 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 Reviewer #2: Yes:** Kurt Yaeger [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/. 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Revision 1
6 May 2021 Author Response Reviewer #1 1. As noted by the authors, the effects of medication on these children were not controlled for or reported. This may have a significant impact of the perception of pain and the attentional abilities of the child. >> We have added these potential effects to our discussion regarding medication. Added text: "Limitations ASD Population It should be noted that medications can potentially affect hemodynamic and/or cortical activity, as well as pain perception and attentional abilities." 2. The authors site the work of Dunn, Schoen, and Miller demonstrating an understanding of sensory processing disorder and its classifications. There is no description of the sensory processing disorder diagnosis or severity in this manuscript. Children with over- and under-responsive types of SPD will naturally respond differently to stimuli. >> Unfortunately, we do not have this information specifically regarding sensory processing diagnoses or severity for the participants of this study. This has been added as a limitation and consideration for future work. Added text: "Limitations ASD population representation It should also be noted that sensory processing disorders can also present in the general population. Participants should be screened explicitly for sensory processing disorders and severity in future work, and considerations of this subgroup ought to be considered." 3. Since children with SPD may occur in the general population, often without co-morbid diagnoses, control group children should have been screened for SPD as well. Suggestions to consider in future studies >> This information has been added to the manuscript. Added text: "Limitations ASD population representation It should also be noted that sensory processing disorders can also in the general population. Participants should be screened explicitly for sensory processing disorders and severity in future work, and considerations of this subgroup ought to be considered." 4. Children with SPD have altered reactions to sensory habituation based on the type of stimuli and the presentation timing of the stimuli. Single modal stimulation often has a muted response, while multi-modal stimuli has a delayed response that is typically additive across trials. See the Sensory Challenge Protocol studies from Schaaf and Miller. >> We have included this information and reference to the work of Schaaf and Miller in the manuscript. Added text: "Assessment of physical pain or discomfort However, Sensory Processing Disorder and an atypical response to ordinary stimuli is believed to stem from brain rather than peripheral nervous system dysfunction (10,11). Specifically, atypical sensory modulation is believed to stem from the brain’s inability to appropriately regulate the received sensory information to produce a suitable output (5). Aberrant sensory processing in the ASD population Individuals with sensory processing disorders can have altered reactions to sensory stimuli that depend on the type of stimulus, its timing, and the number of sensory systems stimulated at once (11). Thus, a larger heterogenous sample of the population and different types of stimuli ought to be considered in future work to evaluate generalizability of these findings. Capturing the heterogeneity in ASD would yield greater understanding of the neurobiological underpinnings of atypical sensory processing and pain perception." 5. Another consideration would be the effect of decreased vagal tone on the physiologic response to pain. Typically children with SPD demonstrate lower heart rate at rest. When in pain, most individuals will show an increase in HR due to parasympathetic responses to noxious stimuli. By measuring HR while looking at the blood flow to the brain, there may be a way to determine physiologic response vs. perception of pain. >>Consideration of vagal tone to evaluate sensory processing in our paradigm has been added to the manuscript. Added text "Clinical relevance of findings and expanded applications Additionally, consideration of other autonomic measurements, such as heart rate, vagal tone, and electrodermal activity, in conjunction with cortical activity may better capture the physiological response to sensory stimuli (53,54). Our focus was on assessing the utility of NIRS to measure a response. However, autonomic measurements have shown to be reliable indicators of hyper or hypo sensitivity and help separate physiological pain from perception. A multi-modal analysis could be considered in future work." 6. Electrodermal measurements have also been shown to be a reliable indicator of sensory over- or under-arousal status. >>Consideration of electrodermal activity to evaluate sensory processing in our paradigm has been added to the manuscript. Added text "Clinical relevance of findings and expanded applications Additionally, consideration of other autonomic measurements, such as heart rate, vagal tone, and electrodermal activity, in conjunction with cortical activity may better capture the physiological response to sensory stimuli (53,54). Our focus was on assessing the utility of NIRS to measure a response. However, autonomic measurements have shown to be reliable indicators of hyper or hypo sensitivity and help separate physiological pain from perception. A multi-modal analysis could be considered in future work." Overall, I think this is a good article. I would add data on the SPD sub-type with which the children present, or list it as a limitation of this study. Reviewer #2 1. While well written, the manuscript is too long. Specifically, the introduction and discussion should be abbreviated to include only the most pertinent information. Most of the background information should be made more concise. In general, any claim should be supported by a relevant citation. The first several paragraphs of the introduction have many claims without citation and are quite verbose. Recommend making the introduction much more concise. >>We have edited the manuscript to shorten it and remove unnecessary information. 2. A full discussion of the subject inclusion and exclusion is recommended. This should include both demographic inclusion criteria as well as clinical. Furthermore, the recruitment strategy should be discussed. Also, if any compensation was involved. Please describe the consenting process and other ethical considerations, including the parental roles. >> We have included additional information regarding recruitment processes, the consent process, parental/guardian involvement and the compensation. Added text "Methods Participants ...Participants in the POND Network who agreed to receive study recruitment emails received a study flyer via email and were invited to contact the study’s research coordinator for more information if interested. ...Participants were given a description of the study and their understanding of the study was assessed through a series of questions. Upon successfully demonstrating their understanding of the study, and if they were still willing to participate, participants and their parent or guardian signed the consent form. As a token of appreciation for their participation, participants were given a gift card (regardless of successful study completion). A parents or guardian was present during the consent process, but not during the experimental protocol." 3. This reviewer questions the decision to include the “excluded” subjects in the analysis. Including these subjects, and also analyzing the cohort without them leads to a confusing description of the results. Furthermore, table 2 is quite confusion with these two groups described (with and without usable NIR data). Recommend only reporting results on subjects with a complete dataset. >>We have modified the statistical results presented to only report on subjects with a complete dataset. Table 2 has also been updated. Added text: "Results Results are presented for the remaining 10 participants in the ASD group. Participant characteristics The two participant groups were not significantly different with respect to age (p = 0.76, t16 = -0.309), but differed significantly with respect to IQ ( p = 0.01, t15 = -3.23). Subjective pain ratings The pain ratings were significantly different between the two task types (p < 0.01, F70 = 241.663) but did not different significantly between the two study groups (p = 0.628, F14 = 0.245). Pain/discomfort tolerance Statistical analysis of the cold-water trial durations showed no significant differences were observed between the two groups or across the three trials (group: p = 0.09, F45 = 7.483; trial: p = 0.406, F31 = 0.929)." 4. Table 2 should also include p values. >> Table 2 has been updated to include p-values. Please see the attached "Response to Reviewers" document for a formatted version of table 2. 5. The results section should report on the data only. Further description of methods should be placed in the “methods” section, including the section starting on page 15 line 354 >>The manuscript has been edited such that the results section only includes data, and the methods have been moved to the methods section. Added text: "Feature extraction Because participants dictated the duration of the cold stimulus trials, the length of the trials varied across participants and task repetition. All control trials were 60s long, while the stimulus trials were up to 180s. To compare the evolution of the hemodynamic response between trial types, trial duration ought to be consistent. Thus, two different comparisons of brain activity were considered for statistical analysis of functional brain measurements: i) maximum [HbO] across the full task intervals and ii) maximum [HbO] within the first 60s of the task intervals." Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0257029.r002
14 Jun 2021 Decision Letter - Manabu Sakakibara, Editor PONE-D-21-06009R1 Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscopy PLOS ONE Dear Dr. Doyle-Thomas, 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. Two experts in the field, one is the same, have carefully reviewed the revision. The original #1 reviewer is satisfied with the revised manuscript, while the newly participated reviewer #3 is almost satisfied with the revision leaving some minor concerns which should be clarified before publication. I am looking forward receiving the necessary revision and the replies to the critiques. Please submit your revised manuscript by Jul 29 2021 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: http://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, Manabu Sakakibara, Ph.D. Academic Editor PLOS ONE Journal Requirements: 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. [Note: HTML markup is below. Please do not edit.] 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 #3: All comments have been addressed ******** 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: (No Response) Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #3: 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: (No Response) Reviewer #3: Yes ****** 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: (No Response) Reviewer #3: 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: (No Response) Reviewer #3: The authors explored the objective pain assessment tools in ASD by using NIRS and achieved some results. This study was well written after revision. There were some concerns about the methods as follow: 1. The effects of using psychotropic drugs and cognitive level in ASD children should be considered in this study. The IQ level differed significantly between 2 groups, so the authors should discuss the influence of IQ level as a confounding factor. 2. The authors expressed that self-reporting of pain can be difficult in ASD children and "no history of chronic pain" was one of the inclusion/exclusion criteria. How to confirm "no history of chronic pain" in ASD children？ ****** 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:** Rhonda Manning, PT, DPT Reviewer #3: 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.0257029.r003
Revision 2
23 Jul 2021 Author Response Response - Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscopy Reviewer #3: The authors explored the objective pain assessment tools in ASD by using NIRS and achieved some results. This study was well written after revision. There were some concerns about the methods as follow: 1. The effects of using psychotropic drugs and cognitive level in ASD children should be considered in this study. The IQ level differed significantly between 2 groups, so the authors should discuss the influence of IQ level as a confounding factor. Regarding the potential effect of medication on the hemodynamic response, this limitation was already addressing in the Limitation section on page 21, Ln 496. Regarding IQ, while the two groups differed significantly in IQ, the task did not have a significant cognitive component. As addressed in section Sample Size, previous work has shown that cognitive level does not significantly affect sensory reactivity. The text has been modified to clarify this. Added text: Sample Size Additionally, study groups were not matched for IQ in this work. Although this is a potential confounding factor, it has been found that cognitive level (IQ) or overall developmental level is not related to abnormal sensory reactivity in children with ASD2. 2. The authors expressed that self-reporting of pain can be difficult in ASD children and "no history of chronic pain" was one of the inclusion/exclusion criteria. How to confirm "no history of chronic pain" in ASD children？ “No chronic history of pain” was confirmed by the participant and their caregiver during the consent process. Added text: Method Participants It was also confirmed that participants met the inclusion/exclusion criterion during the consent process and were eligible to participate. Upon successfully demonstrating their understanding of the study and confirming eligibly criterion were met, and if they were still willing to participate, participants and their parent or guardian signed the consent form. Attachments Attachment Submitted filename: Response_July2021.docx https://doi.org/10.1371/journal.pone.0257029.r004
23 Aug 2021 Decision Letter - Manabu Sakakibara, Editor Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscopy PONE-D-21-06009R2 Dear Dr. Doyle-Thomas, 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, Manabu Sakakibara, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): 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 #3: All comments have been addressed ******** 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: 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 #3: Yes ****** 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 #3: 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: Study manuscript is significantly improved. A possible explanation for the hemispheric differences note may be the altered connectivity of the brains in children with ASD. Decreased inter-hemispheric connectivity with increased intra-hemispheric connections may account for this altered pattern. The data presented in the tables and figures is easy to follow and read. Well done! Reviewer #3: (No Response) ****** 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:** Rhonda Manning, PT, DPT, PCS Reviewer #3: No https://doi.org/10.1371/journal.pone.0257029.r005
Formally Accepted
26 Aug 2021 Acceptance Letter - Manabu Sakakibara, Editor PONE-D-21-06009R2 Investigating Sensory Response to Physical Discomfort in Children with Autism Spectrum Disorder using Near-Infrared Spectroscop Dear Dr. Doyle-Thomas: 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. Manabu Sakakibara Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0257029.r006

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