Seizure onset and offset pattern determine the entrainment of the cortex and substantia nigra in the nonhuman primate model of focal temporal lobe seizures

Mark J. Connolly; Sujin Jiang; Lim C. Samuel; Claire-Anne Gutekunst; Robert E. Gross; Annaelle Devergnas

doi:10.1371/journal.pone.0307906

Peer Review History

Original SubmissionMay 7, 2024
24 May 2024 Decision Letter - Ayataka Fujimoto, Editor PONE-D-24-17382Seizure onset and offset pattern determine the entrainment of the cortex and substantia nigra in the nonhuman primate model of focal temporal lobe seizuresPLOS ONE Dear Dr. Devergnas, 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 Jul 08 2024 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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Reviewer #1: Yes Reviewer #2: No ****** 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: Dr. Connolly et al. studied the involvement of the substantia nigra and somatosensory cortex during temporal lobe seizures induced in two nonhuman primates. They found that the involvement of the SN and SI depends on the seizure onset zone and offset pattern. Comments (invitation: May 10, 2024, and submission: May 11, 2024) I want to congratulate the authors’ efforts. The manuscript is well written and easy to follow. None of the following comments are criticisms. 1) Lines 159-162: Would it be possible to provide the location of the electrodes to get the signal from SI in Figure1 or provide a new figure? 2) Lines 256-259: This description differs slightly from Figure 2E, causing confusion. The part stating "These oscillatory activities decreased at the end of the seizures but were still significantly higher in the 13–25 Hz range for both animals" seems to correspond to the blue "Offset" in Figure 2E. However, the part mentioning "in the 8–12 Hz for NHP 1" appears to refer to the green "Post-ictal." Perhaps using "Offset" and "Post-ictal" would clarify the statement, as the term "end of the seizures" is somewhat ambiguous. 3) Line 263-265: What might be the reason for the difference in the duration of SN power between NHP1 and NHP2? Please address this in the Discussion section. 4) Line 343-344: While it's indeed possible that the SN might be involved in the termination of BS patterns, is the SN the cause of BS pattern termination, or are the results obtained in this study a consequence of the termination of the BS pattern? Please elaborate on the authors' thoughts in the Discussion section. 5) Line 380: The authors may want to change from “SI” to “SN”. 6) Line 398-401: What is your interpretation of the fact that only BS seizures, not ARR or RHY, are associated with the SN as observed in the results of this study? Please provide the authors' perspective. Is there a relationship between the termination pattern of BS seizures and the basal ganglia? 7) Section 4.4: In this study, the authors examined the coherence between the HPC and SI, not the relationship between SI and SN. Therefore, it may be challenging to discuss the involvement of the SN and basal ganglia in this paragraph. What are your thoughts on this? 8) Figure 2E: The authors may want to change from 8-12 Hz to 13-25 Hz in the vertical axis of the bottom-right plot. Reviewer #2: The authors have repeatedly shown the mechanism of neural networks in nonhuman models. While the limbic circuits have been a major focus in temporal lobe epilepsy, this study shows the implication of the SN in temporal lobe seizures in NHP. I believe that this study is valuable in elucidating the circuitry of temporal lobe epilepsy. There are a few points that could possibly improve the manuscript with a better representation of data. 1) Why is the penicillin model being used in this study? I understand that the purpose of this study is to investigate how the epileptic activities propagate to the other extralimbic structures in a temporal lobe epilepsy. The penicillin model is closer to a model of acute symptomatic seizures rather than chronic epilepsy. Wouldn't it be more appropriate to evaluate using a model closer to chronic epilepsy, such as kindling? If it is convenient, that is fine. It may be mentioned in the limitation. 2) Ictal DC shifts and ictal high-frequency oscillations (HFOs) are noted as a marker of epileptogenesis in humans. In this study, it was mentioned that the EEG sampling rate was 2 kHz. This analysis focuses on frequencies between 1 and 25 Hz. Is it correct to understand that frequency bands above 25 Hz did not appear during seizures? 3) It would be better to standardize the way abbreviations are noted. In the abstract, "temporal lobe" is abbreviated as "TL," and later it appears as "TLE." Additionally, in the introduction, "hippocampus" is noted as "HPC," but in the abstract, it is immediately referred to as "HPC" without prior introduction. It can be confusing when an abbreviation appears suddenly without prior introduction, so it would be desirable to standardize the notation method. Creating a list of abbreviations somewhere might be a good idea. 4) Is there any mention of data availability? If not, I would like it to be added. ****** 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.0307906.r001
Revision 1
24 Jun 2024 Author Response Reviewer #1: 1) Lines 159-162: Would it be possible to provide the location of the electrodes to get the signal from SI in Figure1 or provide a new figure? Response: We added a sagittal representation on figure 1 to provide the location of the electrode placement in SI. No histological verification could be done as these electrodes were not located inside the brain. Figure 1: Electrode targeting. (A) Schematic representation of the electrode placement in the SN and PCN injection site in the HPC as well as electrode placement in the HPC and SI. The signal from the red contacts located in the ventral and dorsal part of the structure and in SI were subtracted from each other to obtain a bipolar recording signal in each structure. (B) Nissl stained sections showing the PCN injection site (black arrow) and electrode insertion tracts in the HPC for NHP 1 and 2. (C) TH staining showing the electrode tract in the SN for NHP 1 and 2. Abbreviations: Substantia nigra pars reticulata (SN), Hippocampus (HPC), Penicillin (PCN). Scale bars: B: 9 mm, C: 6 mm. 2) Lines 256-259: This description differs slightly from Figure 2E, causing confusion. The part stating "These oscillatory activities decreased at the end of the seizures but were still significantly higher in the 13–25 Hz range for both animals" seems to correspond to the blue "Offset" in Figure 2E. However, the part mentioning "in the 8–12 Hz for NHP 1" appears to refer to the green "Post-ictal." Perhaps using "Offset" and "Post-ictal" would clarify the statement, as the term "end of the seizures" is somewhat ambiguous. Response: Thanks for noticing, we corrected the error and replace “end of the seizure” by “offset period” or “post-ictal” when appropriate in the revised manuscript. 3) Line 263-265: What might be the reason for the difference in the duration of SN power between NHP1 and NHP2? Please address this in the Discussion section. Response: We added a section in the discussion to address this difference between animals. “This increase of activity in the SN was also significant during the offset period for NHP 2 but did not reach significance for NHP 1. We believe that this difference between the 2 animals might be explained by the lower number of seizures for NHP 1 (14 seizures) compared to NHP 2 (59 seizures).” 4) Line 343-344: While it's indeed possible that the SN might be involved in the termination of BS patterns, is the SN the cause of BS pattern termination, or are the results obtained in this study a consequence of the termination of the BS pattern? Please elaborate on the authors' thoughts in the Discussion section. Response: Thanks, this is an interesting point, we added a section in the discussion to address it. “However, we cannot exclude the possibility that the difference in HPC/SN coherence obtained for the BS pattern might only reflect the difference in activity at the HPC level. This study serves as an initial step to demonstrate the role of the substantia nigra (SN) in temporal lobe (TL) seizures. However, inhibiting the SN should be pursued further to investigate its function in terminating burst suppression (BS) offset patterns. Additionally, the implication of the other BG structures should be evaluated to better understand the role of these nuclei in the propagation and termination of TL seizures. Special attention should be given to the unique roles of the direct and indirect basal ganglia pathways. A recent study has shown separate implication of these pathways in frontal lobe seizure 1 while another one found no difference between chemogenetic inhibition of direct and indirect pathway 2. Exploring the network involvement in function of seizure focus but also the seizure pattern is a necessary step for novel individualized therapy development. “ 5) Line 380: The authors may want to change from “SI” to “SN”. Response: Thanks, this has been corrected. 6) Line 398-401: What is your interpretation of the fact that only BS seizures, not ARR or RHY, are associated with the SN as observed in the results of this study? Please provide the authors' perspective. Is there a relationship between the termination pattern of BS seizures and the basal ganglia? Response: We added a section in the discussion to address this “ However, we cannot exclude the possibility that the difference in HPC/SN coherence obtained for the BS pattern might only reflect the difference in activity at the HPC level. This study serves as an initial step to demonstrate the role of the substantia nigra (SN) in temporal lobe (TL) seizures. However, inhibiting the SN should be pursued further to investigate its function in terminating burst suppression (BS) offset patterns. Additionally, the implication of the other BG structures should be evaluated to better understand the role of these nuclei in the propagation and termination of TL seizures. Special attention should be given to the unique roles of the direct and indirect basal ganglia pathways. A recent study has shown separate implication of these pathways in frontal lobe seizure 1 while another one found no difference between chemogenetic inhibition of direct and indirect pathway 2. Exploring the network involvement in function of seizure focus but also the seizure pattern is a necessary step for novel individualized therapy development. “ 7) Section 4.4: In this study, the authors examined the coherence between the HPC and SI, not the relationship between SI and SN. Therefore, it may be challenging to discuss the involvement of the SN and basal ganglia in this paragraph. What are your thoughts on this? Response: It has been suggested that BG involvement during TL seizure originated from the cortex however we recognize that our current SI data set does not allow for a conclusion on BG involvement. We added this in the discussion. “However, we understand the limitation of this study and further simultaneous recordings of the cortex and BG during TL seizure should be performed. Such study would allow for a better understanding of the propagation of each seizure type through this network and a dynamic analysis of the changes in network causality throughout the seizure 3.” 8) Figure 2E: The authors may want to change from 8-12 Hz to 13-25 Hz in the vertical axis of the bottom-right plot. Response: Thanks, this has been corrected. Reviewer #2: The authors have repeatedly shown the mechanism of neural networks in nonhuman models. While the limbic circuits have been a major focus in temporal lobe epilepsy, this study shows the implication of the SN in temporal lobe seizures in NHP. I believe that this study is valuable in elucidating the circuitry of temporal lobe epilepsy. There are a few points that could possibly improve the manuscript with a better representation of data. 1) Why is the penicillin model being used in this study? I understand that the purpose of this study is to investigate how the epileptic activities propagate to the other extralimbic structures in a temporal lobe epilepsy. The penicillin model is closer to a model of acute symptomatic seizures rather than chronic epilepsy. Wouldn't it be more appropriate to evaluate using a model closer to chronic epilepsy, such as kindling? If it is convenient, that is fine. It may be mentioned in the limitation. Response: The penicillin model was chosen because we needed a large number of seizures exhibiting different onset and offset pattern. Unfortunately, the NHP chronic model do not display as many seizures as the on-demand model 4. In addition, these models are more difficult to manage as most of the time a status epilepticus precede the occurrence of spontaneous recurrent seizures. We added this in our limitation. 2) Ictal DC shifts and ictal high-frequency oscillations (HFOs) are noted as a marker of epileptogenesis in humans. In this study, it was mentioned that the EEG sampling rate was 2 kHz. This analysis focuses on frequencies between 1 and 25 Hz. Is it correct to understand that frequency bands above 25 Hz did not appear during seizures? Response: We intentionally concentrated our analysis on the lower frequencies as they highlighted the differences between various onset and offset patterns. Nevertheless, higher frequencies are also present and could be examined in a subsequent analysis. 3) It would be better to standardize the way abbreviations are noted. In the abstract, "temporal lobe" is abbreviated as "TL," and later it appears as "TLE." Additionally, in the introduction, "hippocampus" is noted as "HPC," but in the abstract, it is immediately referred to as "HPC" without prior introduction. It can be confusing when an abbreviation appears suddenly without prior introduction, so it would be desirable to standardize the notation method. Creating a list of abbreviations somewhere might be a good idea. Response: Thanks for noticing. We corrected the errors in abbreviations and created a list of abbreviation. 4) Is there any mention of data availability? If not, I would like it to be added. Response: Original data are available on the public Dandi repository: Devergnas, Annaelle (2024) SN recording during Temporal lobe seizures (Version 0.240621.2139) [Data set]. DANDI archive. https://doi.org/10.48324/dandi.001069/0.240621.2139 1. Brodovskaya A, Shiono S, Kapur J. Activation of the basal ganglia and indirect pathway neurons during frontal lobe seizures. Brain. Aug 17 2021;144(7):2074-2091. doi:10.1093/brain/awab119 2. Zou W, Guo Z, Suo L, et al. Nucleus accumbens shell modulates seizure propagation in a mouse temporal lobe epilepsy model. Front Cell Dev Biol. 2022;10:1031872. doi:10.3389/fcell.2022.1031872 3. Ilyas A, Toth E, Chaitanya G, Riley K, Pati S. Ictal high-frequency activity in limbic thalamic nuclei varies with electrographic seizure-onset patterns in temporal lobe epilepsy. Clin Neurophysiol. May 2022;137:183-192. doi:10.1016/j.clinph.2022.01.134 4. Croll L, Szabo CA, Abou-Madi N, Devinsky O. Epilepsy in nonhuman primates. Epilepsia. Aug 2019;60(8):1526-1538. doi:10.1111/epi.16089 Attachments Attachment Submitted filename: Plos response_06172024.docx https://doi.org/10.1371/journal.pone.0307906.r002
15 Jul 2024 Decision Letter - Ayataka Fujimoto, Editor Seizure onset and offset pattern determine the entrainment of the cortex and substantia nigra in the nonhuman primate model of focal temporal lobe seizures PONE-D-24-17382R1 Dear Dr. Annaelle delphine Devergnas, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. 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The authors have sincerely addressed the reviewers' comments, and I thank them for that. I will also accept it. 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: N/A 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 replied sufficiently to all my comments. It is a very nice manuscript. Kazuki Sakakura Reviewer #2: The authors have adequately addressed all of the concerns given in the previous review and revised the manuscript accordingly. I have no further comments. ****** 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: Kazuki Sakakura Reviewer #2: Yes: Masaki Izumi ******** https://doi.org/10.1371/journal.pone.0307906.r003
Formally Accepted
19 Jul 2024 Acceptance Letter - Ayataka Fujimoto, Editor PONE-D-24-17382R1 PLOS ONE Dear Dr. Devergnas, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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. Ayataka Fujimoto Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0307906.r004

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