A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain

Xue Ying Zhang; Marta Diaz-delCastillo; Lingsi Kong; Natasha Daniels; William MacIntosh-Smith; Aya Abdallah; Dominik Domanski; Denis Sofrenovic; Tsz Pui (Skel) Yeung; Diego Valiente; Jan Vollert; Emily Sena; Andrew S. Rice; Nadia Soliman

doi:10.1371/journal.pone.0290382

Peer Review History

Original SubmissionMarch 6, 2023
15 May 2023 Decision Letter - Dragan Hrncic, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-23-05023A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent painPLOS ONE Dear Dr. Soliman, 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. 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Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide." 6. Please amend the manuscript submission data (via Edit Submission) to include author "Kong L, Soliman N, Daniels NF, Macinotash-Smith W, Abdallah A, Domanski D, Sofrenovic D, Yeung TP, Valient J., Rice ASC [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? 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 ****** 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 ****** 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: This manuscript by Zhang and colleagues is a systematic review and meta-analysis of thigmotaxis in models of pain. I am impressed by the still rather novel attempt to meta-analyze preclinical data, although this paper again shows why it doesn’t really show much: simply not enough variability in methods (e.g., use of different sexes, strains, multiple drugs). I’m also a bit underwhelmed by the stakes here; 30+ figures and long, overly detailed tables in service of what most people in the field view as a rather secondary issue (pain comorbidities, or potential confounds). That said, I realize PLoS One is not concerned about how important this all is, but rather whether it’s solid. It clearly is. This group is absolutely at the forefront of preclinical pain meta-analysis. I have two major pieces of advice to improve things. The first is that to my mind the group failed to analyze what I think is probably the most important issue: time. They conclude that thigmotaxis is caused by persistent pain. Um, duh. We knew this. The outstanding question in the field is how long does it take for the anxiety (which is driving the thigmotaxis) to develop after the injury. This information (time of anxiety testing post-injury) is in every paper they analyzed, but I see no evidence that it was looked at here. The second is that I don’t like the introduction at all. The citations are utterly arbitrary, in some cases randomly picking a few papers when much better reviews exist, and in others using arbitrarily chosen reviews instead of citing primary literature proving a point. But the bigger problem is that the discussion is about predictive validity of outcome measures of pain, when the paper is actually meta-analyzing not an outcome measure of pain, but rather a measure of a pain-induced comorbidity: anxiety. No one in the preclinical pain field is pretending that thigmotaxis is a measure of pain itself, however indirect. They are using it specifically to address the presence or absence of the comorbidity. Thus, I think this paper would be a lot better set up by a discussion of the prevalence of pain comorbidities and their modelling in animals. ****** 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.0290382.r001
Revision 1
28 Jul 2023 Author Response Reviewer #1: This manuscript by Zhang and colleagues is a systematic review and meta-analysis of thigmotaxis in models of pain. I am impressed by the still rather novel attempt to meta-analyze preclinical data, although this paper again shows why it doesn’t really show much: simply not enough variability in methods (e.g., use of different sexes, strains, multiple drugs). I’m also a bit underwhelmed by the stakes here; 30+ figures and long, overly detailed tables in service of what most people in the field view as a rather secondary issue (pain comorbidities, or potential confounds). That said, I realize PLoS One is not concerned about how important this all is, but rather whether it’s solid. It clearly is. This group is absolutely at the forefront of preclinical pain meta-analysis. I have two major pieces of advice to improve things. We share the reviewer’s underwhelm and agree that this review hasn’t led to the insights one would hope for to progress the field. There remains an ethical and societal obligation to continue to examine the use of animal models in pain research and given the volume and exponential production of data, systematic reviews are likely to play an important role. However, the lack of variability in experimental designs and the paucity of reporting experimental details are limiting. We know pain studies are affected by a range of factors including methodological rigour, animal characteristics, experimental paradigms and the environment, however, as this review demonstrates, we are yet to see the changes in the field that would improve our appreciation of these factors. The first is that to my mind the group failed to analyze what I think is probably the most important issue: time. They conclude that thigmotaxis is caused by persistent pain. Um, duh. We knew this. The outstanding question in the field is how long does it take for the anxiety (which is driving the thigmotaxis) to develop after the injury. This information (time of anxiety testing post-injury) is in every paper they analyzed, but I see no evidence that it was looked at here. We collected time from model intervention to open field test and have conducted an analysis of time in rat and mouse nerve injury models. The methods, results and discussion have been changed to reflect this. The analysis was performed on rat and mouse nerve injury models (the most frequently reported) and are presented in figures 7 and 20. Results section 2.3.1., “Open field tests were conducted from immediately after model induction to 35 days after nerve injury (for which there were 41 comparisons that reported time since model induction). Time accounted for a significant proportion of heterogeneity (Q = 652.50; d.f. = 13; p <0.0001) (Figure 7A). However, this was not the case when time was analysed in weekly blocks (Q = 3.31; d.f. = 3; p =0.35) (Figure 7B).” Results section 2.3.2., “Open field tests were conducted between 24 h and 180 days after nerve injury (for which there were 46 comparisons that reported time since model induction). All time points accounted for a significant proportion of heterogeneity (Q = 634.39; d.f. = 19; p <0.0001) (Figure 20A). The same was observed in the time block analysis (Q = 16.61; d.f. = 3; p =0.0009) and the 2-3 week time block resulted in the largest observed effect sizes (Figure 20B). However, these findings should be interpreted with caution given the low number of comparisons for each time period.” Discussion, “Given the broad range of timings that the OFTs were conducted and limited comparisons within each period, we were also unable to discern how long after model induction it takes for thigmotactic behaviour to develop.” The second is that I don’t like the introduction at all. The citations are utterly arbitrary, in some cases randomly picking a few papers when much better reviews exist, and in others using arbitrarily chosen reviews instead of citing primary literature proving a point. The introduction has been updated. We have included a broader range of more recent and relevant primary studies and reviews. This includes references to the systematic reviews Currie et al., 2019, Soliman et al., 2021 and narrative reviews Sadler et al., 2022, and Tappe-Theodor et al., 2014. But the bigger problem is that the discussion is about predictive validity of outcome measures of pain, when the paper is actually meta-analyzing not an outcome measure of pain, but rather a measure of a pain-induced comorbidity: anxiety. No one in the preclinical pain field is pretending that thigmotaxis is a measure of pain itself, however indirect. They are using it specifically to address the presence or absence of the comorbidity. Thus, I think this paper would be a lot better set up by a discussion of the prevalence of pain comorbidities and their modelling in animals. We have described thigmotaxis as a behaviour not a measure of pain. Pain cannot be directly measured in humans or animals. We have contextualised thigmotaxis to pain-associated models and whether thigmotactic behaviour can be attenuated by analgesic drugs, thereby distinguishing between pain and anxiety. We appreciate that thigmotaxis can be influenced by other co-morbidities and this was discussed within the introduction e.g., “This behavioural paradigm is commonly used for animal research of psychiatric disorders, particularly anxiety…” and “It could also reflect the clinical observations of exacerbated avoiding behaviours and anxiodepressive disorders that are associated with patients with chronic pain”. Measuring an ethologically relevant behaviour allows us to measure the global affect of a pain-associated intervention. The following sentence has been added to the introduction to further emphasise the points made by the reviewer, “It has been postulated that the behaviour could give insight into the affective, cognitive and sensory dysfunction associated with pain.” Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0290382.r002
8 Aug 2023 Decision Letter - Dragan Hrncic, Editor A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain PONE-D-23-05023R1 Dear Dr. Soliman, 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, Prof. Dr. Dragan Hrncic, 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 ******** 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) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) ****** 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) ****** 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) ****** 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: I am satisfied with the changes. I am satisfied with the changes. I am satisfied with the changes. I am satisfied with the changes. (Why is the minimum character count 100 in this field?!) ****** 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 ******** https://doi.org/10.1371/journal.pone.0290382.r003
Formally Accepted
30 Aug 2023 Acceptance Letter - Dragan Hrncic, Editor PONE-D-23-05023R1 A systematic review and meta-analysis of thigmotactic behaviour in the open field test in rodent models associated with persistent pain Dear Dr. Soliman: 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 Professor Dragan Hrncic Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0290382.r004

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