Contributions of human amygdala nuclei to resting-state networks

Uriel K. A. Elvira; Sara Seoane; Joost Janssen; Niels Janssen

doi:10.1371/journal.pone.0278962

Peer Review History

Original SubmissionAugust 29, 2022
11 Oct 2022 Decision Letter - Irene Cristofori, Editor PONE-D-22-24147Contributions of human amygdala nuclei to resting-state networksPLOS ONE Dear Dr. Janssen, 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 25 2022 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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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: 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: 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 work by Arguinzones et al is an interesting contribution to the functional connectivity of the different amygdaloid nuclei in resting conditions. Surprinsingly, to my view, the contributions of the different nuclei to the functional networks identified do not correspond to the classical amygdaloid subdivisions. These subdivision are defined mainly based on work in rodents and (to a lesser extent) in non-human primates. I have only minor comments: - In the abstract, the abbreviations of the amygdaloid subnuclei are not that common to be identified by the readers. I suggest either spelling them out at first use or avoid using abbreviations in the abstract. - In the Discussion, it may be worth to include a few lines about possible limitations of the study or limitations with the comparisond with the animal data, which may contribute to explain such important differences with previously defined functional subdivisions. For example, I am not really sure to what extent the medial amygdala or the anterior amygdaloid area in humans are the same structures as those identified with the same names in rodents. Something similar with the cortical nucleus, which in rodents is divided in two olfactory nuclei (anterior cortical and posterolateral cortical) and one vomeronasal (pheromonal) nucleus (posteromedial cortical). To what extent is the functional role of the cortical nucleus in humans comparable to these cortical nuclei in rodents is not an easy question. A different kind of caveat is the small size of some of the structures, such as the medial amygdala (as represented in Fig 1). How is this affecting to the data? I guess that the results in this nucleus may not be as robust as those in the larger nuclei. Finally, the fact that the lateral nucleus, which is the largest nucleus in the human amygdala and one of the best characterized in the literature in non-human animals, is not involved in any of the functional networks may also deserve a word in the Discussion. Page 14, line 5 from the bottom: "contribution each amygdala nucleus" should probably be "contribution OF each amygdala nucleus" Reviewer #2: The study used a data-driven approach to investigate the functional connectivity (FC) patterns of the amygdaloid nuclei with existing whole-brain resting state networks. The methods are sound and the results interesting. However, in my opinion, the manuscript needs substantial work in the introduction. A description of the functional role of the amygdala (and the amygdaloid nuclei) in the introduction is completely lacking. For example, when listing the main objectives of their work, the authors mention “In addition, we tested whether the self-reported fear of the participants was associated with co-activity in the amygdaloid nuclei”. This comes unexpected, without any description of why this is relevant. What is the proposed functional role of the amygdala and its sub-regions/nuclei? What does self-reported fear mean? Why self-reported fear should be associated with FC of the amygdala? What are the specific hypotheses/predictions concerning the different amygdaloidal nuclei? Please expand the introduction according to these relevant questions. This will allow you to make the introduction more coherent with the discussion, where possible implications of the current results in the clinical field are discussed (but should be maybe more specific). It is not clear if the spatial resolution of fMRI data used in previous studies was lower with respect to HCP data or simply no previous study looked at the single nuclei. ICA allowed to identify 3 seeds within the amygdala region. Do they overlap, at least partially, with the large-scale sections previously considered (LB, CM and SF)? rsfMRI, QC, CSF and WM. Please spell out all acronyms the first time you use them. Page 7. Last lines. “These subdivisions do not take into account the concept of the "extended amygdala". Please explain. Please provide additional details for the segmentation method: “by combining prior information about the average structural location of the amygdaloid nuclei and its surrounding tissue with specific structural information from a given participant’s brain”. What specific structural information? For example? Page 11, first line: “Finally, we explored whether self-reported measures of fear affected co-activity of the amygdala nuclei”. I would rather talk about “exploring a possible relationship between fear and FC”, without further hypothesis about the direction of the effect. I don’t think we can assume that behavior affects FC. ****** 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". 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Revision 1
4 Nov 2022 Author Response Reviewer #1: The work by Arguinzones et al is an interesting contribution to the functional connectivity of the different amygdaloid nuclei in resting conditions. Surprinsingly, to my view, the contributions of the different nuclei to the functional networks identified do not correspond to the classical amygdaloid subdivisions. These subdivision are defined mainly based on work in rodents and (to a lesser extent) in non-human primates. I have only minor comments: - In the abstract, the abbreviations of the amygdaloid subnuclei are not that common to be identified by the readers. I suggest either spelling them out at first use or avoid using abbreviations in the abstract. We thank the reviewer for this comment. We have rewritten the abstract and improved the abbreviations for nuclei throughout the manuscript. - In the Discussion, it may be worth to include a few lines about possible limitations of the study or limitations with the comparisons with the animal data, which may contribute to explain such important differences with previously defined functional subdivisions. For example, I am not really sure to what extent the medial amygdala or the anterior amygdaloid area in humans are the same structures as those identified with the same names in rodents. Something similar with the cortical nucleus, which in rodents is divided in two olfactory nuclei (anterior cortical and posterolateral cortical) and one vomeronasal (pheromonal) nucleus (posteromedial cortical). To what extent is the functional role of the cortical nucleus in humans comparable to these cortical nuclei in rodents is not an easy question. A different kind of caveat is the small size of some of the structures, such as the medial amygdala (as represented in Fig 1). How is this affecting to the data? I guess that the results in this nucleus may not be as robust as those in the larger nuclei. We thank the reviewer for these crucial insights. We agree with the reviewer that overall comparisons between humans and animal studies are not straightforward and we believe that future studies that examine the amygdala nuclei with task fMRI (instead of resting-state fMRI) may be beneficial in resolving some of these questions. We discuss these issues in a new paragraph in the general discussion where we go into detail about the comparison between our results and those obtained in non-human animal studies. See page 16, line 444 Finally, the fact that the lateral nucleus, which is the largest nucleus in the human amygdala and one of the best characterized in the literature in non-human animals, is not involved in any of the functional networks may also deserve a word in the Discussion. We thank the reviewer for pointing this out. In the added paragraph we also speculate as to why we did not find activity in the LA nucleus. In our opinion this may be related to the nature of the resting-state study that we conducted which by definition only relies on minimal amounts on sensory input. Under such conditions no LA activity may be observed. As we also mentioned before, fMRI studies using tasks (which require strong sensory input) may be able to shed further light on this issue. We again thank the reviewer for bringing up this inspiring point. See page 16, line 444 Page 14, line 5 from the bottom: "contribution each amygdala nucleus" should probably be "contribution OF each amygdala nucleus" Fixed. Reviewer #2: The study used a data-driven approach to investigate the functional connectivity (FC) patterns of the amygdaloid nuclei with existing whole-brain resting state networks. The methods are sound and the results interesting. However, in my opinion, the manuscript needs substantial work in the introduction. A description of the functional role of the amygdala (and the amygdaloid nuclei) in the introduction is completely lacking. For example, when listing the main objectives of their work, the authors mention “In addition, we tested whether the self-reported fear of the participants was associated with co-activity in the amygdaloid nuclei”. This comes unexpected, without any description of why this is relevant. What is the proposed functional role of the amygdala and its sub-regions/nuclei? What does self-reported fear mean? Why self-reported fear should be associated with FC of the amygdala? What are the specific hypotheses/predictions concerning the different amygdaloidal nuclei? Please expand the introduction according to these relevant questions. This will allow you to make the introduction more coherent with the discussion, where possible implications of the current results in the clinical field are discussed (but should be maybe more specific). We thank the reviewer for bringing this up. We have now largely rewritten the Introduction and parts of the Discussion to accommodate the reviewer’s concerns. It is not clear if the spatial resolution of fMRI data used in previous studies was lower with respect to HCP data or simply no previous study looked at the single nuclei. Indeed the spatial resolution in previous studies was lower (2 to 4 mm) compared to that of the HCP (1.6 mm). It is likely that previous studies have not looked at amygdala nuclei because of this insufficient spatial resolution. We hope to have clarified this issue in the current manuscript. ICA allowed to identify 3 seeds within the amygdala region. Do they overlap, at least partially, with the large-scale sections previously considered (LB, CM and SF)? We thank the reviewer for highlighting this important point. We have largely rewritten the first two paragraphs of the Discussion section to better highlight this issue in the current version of the manuscript. In the current manuscript we highlight that the relationship between the specific clusters we have found (and the nuclei that are involved in each cluster) and the classical division of the amygdala into LB, CM and SF sections. We hope to have improved our manuscript with respect to this issue. rsfMRI, QC, CSF and WM. Please spell out all acronyms the first time you use them. Fixed. Page 7. Last lines. “These subdivisions do not take into account the concept of the "extended amygdala". Please explain. The extended amygdala refers to the bed nucleus of the stria terminalis (BNST) in the basal forebrain. There is debate in the literature about whether to consider this structure as part of the amygdala (e.g., Lebow & Chen, 2016). The current parcellation of the amygdala into its constituent nuclei (Saygin et al., 2017) does not include this structure. We have added some words to better explain this issue. We thank the reviewer for pointing this out. Methods page 5, line 177 Please provide additional details for the segmentation method: “by combining prior information about the average structural location of the amygdaloid nuclei and its surrounding tissue with specific structural information from a given participant’s brain”. What specific structural information? For example? Specific structural information that is used is the relative position of the surrounding structures (coming from the aparc+aseg file) as well as the specific intensity values present in the T1w file. We have updated the manuscript to better explain this issue. Methods, page 5, line 180 Page 11, first line: “Finally, we explored whether self-reported measures of fear affected co-activity of the amygdala nuclei”. I would rather talk about “exploring a possible relationship between fear and FC”, without further hypothesis about the direction of the effect. I don’t think we can assume that behavior affects FC. We completely agree with the reviewer about this issue and we apologize for the slip up. We did not wish to imply any causality here. We have rewritten these sections. We thank the reviewer for the insightful comments! Attachments Attachment Submitted filename: response_to_comments_24102022_plosone.pdf https://doi.org/10.1371/journal.pone.0278962.r002
25 Nov 2022 Decision Letter - Irene Cristofori, Editor Contributions of human amygdala nuclei to resting-state networks PONE-D-22-24147R1 Dear Dr. Janssen, 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: 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 #2: 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 #2: 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 #2: 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 adequately addressed the reviewers' comments. I have no further suggestions. Reviewer #2: The authors have addressed all the comments I made during the first revision run. I recommend the manuscript for publication. ****** 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: Enrique Lanuza Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0278962.r003
Formally Accepted
14 Dec 2022 Acceptance Letter - Irene Cristofori, Editor PONE-D-22-24147R1 Contributions of human amygdala nuclei to resting-state networks Dear Dr. Janssen: 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.0278962.r004

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