Oxazepam and cognitive reappraisal: A randomised experiment

Gustav Nilsonne; Sandra Tamm; Armita Golkar; Andreas Olsson; Karolina Sörman; Katarina Howner; Marianne Kristiansson; Martin Ingvar; Predrag Petrovic

doi:10.1371/journal.pone.0249065

Peer Review History

Original SubmissionJune 24, 2020
24 Jun 2020 Author Response Attachments Attachment Submitted filename: response_to_reviewers.docx https://doi.org/10.1371/journal.pone.0249065.r001
23 Sep 2020 Decision Letter - Alexandra Kavushansky, Editor PONE-D-20-19162 Oxazepam and cognitive reappraisal: a randomised experiment PLOS ONE Dear Dr. Nilsonne, 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 Nov 07 2020 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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[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 Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: 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: The authors implemented most of my previous suggestions in this revision, which has improved the derivation of research questions, description of the study paradigm, and discussions of findings as well as limitations. A few minor issues need to be resolved before publication however. General: In keeping with general terminology in the manuscript and to avoid confusion, “emotional reappraisal” should be changed to “cognitive reappraisal” throughout the manuscript (see abstract, conclusions, etc.) Materials and Methods, participants: Since PLoS One is a multidisciplinary journal and not all readers may be familiar with substance interactions, please add a short statement as to why participants could not be habitual consumers of nicotine. Are there interactions of oxazepam to be expected? Results: The authors adopted the results section according to my previous comments (variable naming), but did not add information as to whether an effect is statistically significant or not. However, I am of the opinion that it would greatly increase comprehensibility on part of the readers to respectively state before reporting effects and p-values whether an effect/interaction was significant or not. Example for unpleasantness ratings: “The three-way interaction was not significant at -2.7….”. This should be changed for all effects and interactions before I recommend publication. Additionally, for skin conductance, main effect of up-regulation and corrugator activity, main effect of negative stimulus valence, the authors should give a short description of the effect instead of simply stating “… as expected”. Associations between self-rated personality traits (p. 8): Please add that corresponding statistics can be found in Figure 9, as this is not immediately evident. Discussion: p.9: the sentence “It has also been shown that these prefrontal processes interact with processing of emotional information in brain regions such as the amygdala” is missing references. p.9: the sentence “The findings also do not suggest that benzodiazepines […] contribute to poorer emotion regulation performance in patients” needs to be amended. First, the authors did not directly assess emotion regulation performance, which would require objective analysis of number of reappraisal ideas and quality of ideas (see Papousek et al., 2017; Brain Imaging or Behavior, or Rowlands et al., 2019; Neuropsychological Rehabilitation). Much rather, reappraisal of IAPS pictures assesses individuals’ regulation success or reappraisal effectiveness in terms of differences in emotion intensity and physiological variables between two conditions (regulate up/down, etc.). Next, generalizing this study’s findings to “emotion regulation” in general does not seem justified, since only cognitive reappraisal was investigated. For these reasons, this sentence should read “The findings also do not suggest that benzodiazepines […] contribute to poorer cognitive reappraisal in patients.” Reviewer #2: Introduction 1. The authors should draw some stronger connections between the GABAa receptors and frontal lobe activity to help solidify the logic behind by cognitive reappraisal would be impacted by benzodiazepines. Within the final paragraph on page one, the authors suggest this connection, but it could use some stronger connections. 2. The authors present aims related to correlations/associations between measures, yet have a set of analyses related to physiological measures involving higher order cause and effect conclusion that can be made. Results should correspond to the predictions made in the aims section. Method 1. Given that only males were used, the ability to generalize these results is rather limited. Moreover the population of individuals who would take benzodiazepines would likely show the greatest benefit and likely different results for any type of down regulation of emotion as compared to a “normal” sample. 2. What was the average valance and arousal for the sets of IAPS images that were used? 3. How long was each picture shown for? How long did the rating scale appear on the screen for? The authors mention they used 2 second time windows, but it isn’t clear if the stimuli were presented for only 2 seconds or longer. Results a. Much of the results section reported results that were not significant. There were a few interaction effects that were typical and expected. b. The final sample size is reported to be 22, but the table for the placebo condition it appears to say that only 13 participants were in the placebo condition, giving the treatment condition significantly more participants. This could account for a lack of findings in many areas. c. Corrugator activity shows expected increases with unpleasant stimuli in the upregulation condition, but no impact it appears of the treatment. Moreover, any of the results that are main effects should only be reported and not interpreted if there is a significant interaction within that set of analyses (e.g. the corrugator activity analyses). d. The majority of the analyses reported appear to have only correlations. Discussion The analyses that should have resulted in some of the main conclusions about this study appear to be pushed aside as a mere checks and balances set of analyses. The conclusions that are made about the impact of oxazepam appear to impact the subjective emotional experience but not the physiological experience. That is, the results indeed suggest that the participants may interpret that they should feel a particular way without effectively performing the task. 3. The timecourse of cognitive reappraisal is an important thing to note here. Cognitive reappraisal does not unfold over the course of 2 seconds and the measures that the authors are using rely on autonomic nervous system changes. That is, from an EEG perspective the timecourse of changing brain activity as a result of the cognitive reappraisal task is indeed valid; however, the timecourse to change peripheral physiological responses may differ greatly. This leads back to my question within the method related to how long the stimuli were presented for. It is likely the case that if there was a longer timeframe that the physiological measures were captured there may have been changes late in the stimulus presentation for ECG and skin conductance. ****** 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: 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.0249065.r002
Revision 1
13 Feb 2021 Author Response Response to reviewers We thank the reviewers and the editor for the valuable comments, which have improved the manuscript. Responses to the points are provided below. Reviewer #1: The authors implemented most of my previous suggestions in this revision, which has improved the derivation of research questions, description of the study paradigm, and discussions of findings as well as limitations. A few minor issues need to be resolved before publication however. General: In keeping with general terminology in the manuscript and to avoid confusion, “emotional reappraisal” should be changed to “cognitive reappraisal” throughout the manuscript (see abstract, conclusions, etc.) This has been changed throughout. Materials and Methods, participants: Since PLoS One is a multidisciplinary journal and not all readers may be familiar with substance interactions, please add a short statement as to why participants could not be habitual consumers of nicotine. Are there interactions of oxazepam to be expected? We excluded habitual consumers of nicotine to reduce the risk of abstinence symptoms during the experiment. We have now added this into the methods section (page 3, “Participants”). Results: The authors adopted the results section according to my previous comments (variable naming), but did not add information as to whether an effect is statistically significant or not. However, I am of the opinion that it would greatly increase comprehensibility on part of the readers to respectively state before reporting effects and p-values whether an effect/interaction was significant or not. Example for unpleasantness ratings: “The three-way interaction was not significant at -2.7….”. This should be changed for all effects and interactions before I recommend publication. Additionally, for skin conductance, main effect of up-regulation and corrugator activity, main effect of negative stimulus valence, the authors should give a short description of the effect instead of simply stating “… as expected”. This has been changed throughout. Associations between self-rated personality traits (p. 8): Please add that corresponding statistics can be found in Figure 9, as this is not immediately evident. This has been added (page 8, “Associations between self-rated personality traits to responses to stimuli and instructions to perform reappraisal”). Discussion: p.9: the sentence “It has also been shown that these prefrontal processes interact with processing of emotional information in brain regions such as the amygdala” is missing references. We have added references as requested. p.9: the sentence “The findings also do not suggest that benzodiazepines […] contribute to poorer emotion regulation performance in patients” needs to be amended. First, the authors did not directly assess emotion regulation performance, which would require objective analysis of number of reappraisal ideas and quality of ideas (see Papousek et al., 2017; Brain Imaging or Behavior, or Rowlands et al., 2019; Neuropsychological Rehabilitation). Much rather, reappraisal of IAPS pictures assesses individuals’ regulation success or reappraisal effectiveness in terms of differences in emotion intensity and physiological variables between two conditions (regulate up/down, etc.). Next, generalizing this study’s findings to “emotion regulation” in general does not seem justified, since only cognitive reappraisal was investigated. For these reasons, this sentence should read “The findings also do not suggest that benzodiazepines […] contribute to poorer cognitive reappraisal in patients.” This has been edited as suggested. Reviewer #2: Introduction 1. The authors should draw some stronger connections between the GABAa receptors and frontal lobe activity to help solidify the logic behind by cognitive reappraisal would be impacted by benzodiazepines. Within the final paragraph on page one, the authors suggest this connection, but it could use some stronger connections. We have added text to the introduction and discussion to strenghten this connection in light of PET evidence of high concentrations of GABAA receptors in areas of the prefrontal cortex related to emotional processing (page 2, end of 2nd paragraph, and page 9, 4th paragraph of discussion). 2. The authors present aims related to correlations/associations between measures, yet have a set of analyses related to physiological measures involving higher order cause and effect conclusion that can be made. Results should correspond to the predictions made in the aims section. We have again reviewed the aims and results for consistency. The main aim was to investigate effects of benzodiazepines, whereas design factors of the experimental paradigm are assumed to have intended effects, e.g. higher unpleasantness to negative compared to neutral images. Validation of the paradigm was not an aim of this study. Method 1. Given that only males were used, the ability to generalize these results is rather limited. Moreover the population of individuals who would take benzodiazepines would likely show the greatest benefit and likely different results for any type of down regulation of emotion as compared to a “normal” sample. These important limitations are noted in the discussion (last paragraph). 2. What was the average valance and arousal for the sets of IAPS images that were used? This has been added under Stimuli and Experimental Paradigm. 3. How long was each picture shown for? How long did the rating scale appear on the screen for? The authors mention they used 2 second time windows, but it isn’t clear if the stimuli were presented for only 2 seconds or longer. We have added this information in the methods section (“Stimuli and experimental paradigm”), please see also figure 1. Results a. Much of the results section reported results that were not significant. There were a few interaction effects that were typical and expected. We agree with the reviewer’s observation. b. The final sample size is reported to be 22, but the table for the placebo condition it appears to say that only 13 participants were in the placebo condition, giving the treatment condition significantly more participants. This could account for a lack of findings in many areas. We agree that this is indeed the case, and we discuss this limitation in the discussion section (last paragraph). c. Corrugator activity shows expected increases with unpleasant stimuli in the upregulation condition, but no impact it appears of the treatment. Moreover, any of the results that are main effects should only be reported and not interpreted if there is a significant interaction within that set of analyses (e.g. the corrugator activity analyses). We have removed interpretations of main effects in the presence of interaction effects throughout the results section. d. The majority of the analyses reported appear to have only correlations. We agree with the reviewer’s observation. Discussion The analyses that should have resulted in some of the main conclusions about this study appear to be pushed aside as a mere checks and balances set of analyses. The conclusions that are made about the impact of oxazepam appear to impact the subjective emotional experience but not the physiological experience. That is, the results indeed suggest that the participants may interpret that they should feel a particular way without effectively performing the task. We agree that effects of oxazepam are evident in self-rated unpleasantness but not in physiological outcomes. The reviewer suggests that this may be due to demand effects. We discuss this possibility in the manuscript (discussion, 2nd paragraph). While we appreciate that the reviewer wishes to further highlight significant effects of the paradigm, this study did not aim to test the validity of the experimental paradigm, which is based on previous research as described in the introduction. 3. The timecourse of cognitive reappraisal is an important thing to note here. Cognitive reappraisal does not unfold over the course of 2 seconds and the measures that the authors are using rely on autonomic nervous system changes. That is, from an EEG perspective the timecourse of changing brain activity as a result of the cognitive reappraisal task is indeed valid; however, the timecourse to change peripheral physiological responses may differ greatly. This leads back to my question within the method related to how long the stimuli were presented for. It is likely the case that if there was a longer timeframe that the physiological measures were captured there may have been changes late in the stimulus presentation for ECG and skin conductance. Effects were measured up to 6 seconds; please see figures 3, 5, and 7. Attachments Attachment Submitted filename: response_to_reviewers_2_2021-02-03.docx https://doi.org/10.1371/journal.pone.0249065.r003
11 Mar 2021 Decision Letter - Alexandra Kavushansky, Editor Oxazepam and cognitive reappraisal: a randomised experiment PONE-D-20-19162R1 Dear Dr. Nilsonne, 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, Alexandra Kavushansky, PhD 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: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: The authors have addressed all my comments to my satisfaction. The manuscript has improved significantly from previous submissions and is now suitable to be published in PLOS One. ****** 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.0249065.r004
Formally Accepted
12 Apr 2021 Acceptance Letter - Alexandra Kavushansky, Editor PONE-D-20-19162R1 Oxazepam and cognitive reappraisal: a randomised experiment Dear Dr. Nilsonne: 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. Alexandra Kavushansky Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0249065.r005

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