PONE-D-23-04338Functional Correlates of Cognitive Performance and Working Memory in Temporal Lobe Epilepsy: Insights from Task-based and Resting-state fMRIPLOS ONE

Dear Dr. Concha,

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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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

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Reviewer #1: Yes

Reviewer #2: Yes

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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: In this manuscript, Fajardo-Valdez, Camacho-Téllez et al. report interesting findings related to fMRI-derived functional connectivity in temporal lobe epilepsy patients during wakeful resting, and patterns of BOLD activation while performing a working memory task. The paper reports behavioural data (neuropsychological measures, working memory paradigm performance) and functional connectivity in both resting-state (DMN) and neurocognitive networks (TPN), and evaluates the (anti)correlation between them. The authors observe that the TLE patients exhibit decreased functional connectivity in the default mode and temporo-polar networks during rest, and decreased BOLD response in temporo-parietal regions during the working memory task. In my opinion, the findings constitute a valuable contribution to the evolving understanding of the consistently reported altered functional connectivity, in concurrence with neurocognitive deficits, observed in focal epilepsy patients. The manuscript is well-written and communicates well. Pending that the authors adequately address the remarks listed below, I can recommend the manuscript for publication.

Major remarks:

- The authors state that the sample is further described in a previous publication (Rodriguez-Cruces et al., 2020); however, it appears that the size of the sample used in the referenced paper is not identical to what is reported in the current manuscript. I ask the authors to clarify this issue. While I was able to find clinical information about a part (?) of the sample in a previous publication (Rodriguez-Cruces et al,, 2018), I strongly recommend that these data are reported for the current sample in the current manuscript (see the next remark for context). If the clinical data are already included in the published dataset at OpenNeuro - which I was unable to access (see minor comment below) - the authors may disregard this remark.

- Following the previous remark, I would strongly encourage the authors to provide more clinical information pertaining to the study participants, as correlations between such variables and functional connectivity have consistently been reported. In my opinion, the manuscript could be further improved by investigating if the reported effects (e.g., DMN-TPN anticorrelation) are mediated by clinical factors. I ask the authors to, at the very least, comment on if including such variables as confounders in the analyses would be beneficial, and possibly conduct the analyses. Previously reported variables include (but are not limited to):

* Time with epilepsy/time since first seizure. Some studies indicate that epilepsy duration is associated with various functional connectivity-related characteristics (e.g., van Dellen et al., 2019, DOI: 10.1371/journal.pone.0008081).

* Medication. Was the TLE group homogeneous in terms of medication? Would it be possible to create sub-groups based on medications (e.g., Haneef et al., 2015, DOI: 10.1089/brain.2014.0304)?

* Surgery. The authors state that “the majority” of patients had not undergone surgery. Surgery has been demonstrated to alter functional connectivity (e.g., for a review, see Johnson et al., 2022, DOI: 10.1097/WCO.0000000000001008).

- I ask the authors to more clearly describe and justify the data rejection procedures employed in the manuscript. To my understanding, while a relatively large dataset is introduced (TLE = 40; HC = 36), it appears that considerably reduced datasets were used in the resting-state fMRI analysis (TLE = 21; HC = 25), and the task-related fMRI analysis (TLE = 33; HC = 33). The stated reason for the reduction is poor fMRI data quality following visual inspection. Based on the information available, I feel obliged to characterise this approach as questionable from a strict methodological standpoint. Considering that almost half of the TLE patients’ data were rejected for the resting-state analysis, I would strongly encourage the authors to carefully detail the rejection procedures. Ideally, objective metrics should be used to facilitate reproducibility. Please clarify this point carefully.

- In a remark related to the previous question about the data rejection procedures, I wonder how many participants were included in the analysis of the neuropsychological test scores? If my understanding is correct, the observed (significant) differences in performance on the neuropsychological tests were based on group comparisons using the full dataset (TLE = 40 vs. HC = 36). If this is the case, I would argue that the analysis could be considered misleading, due to the fact that the analysed sample does not match the samples used for the resting-state and task-related fMRI analyses. While I appreciate that the correlation analyses were conducted using only data from subjects whose fMRI data were retained, it is, in my opinion, problematic that the manuscript draws conclusions regarding the TLE patients’ neuropsychological performance based the whole TLE group when only half of the patients are considered in the analyses that are presented as the manuscript’s main findings. If my assumptions are indeed true, I would suggest that the authors compare neuropsychological test performance between TLE patients and healthy controls in the sub-groups, i.e., subjects with retained resting-state data, and subjects with retained task-related data.

- I would also ask the authors to elaborate their methodological choice of flipping the x axis of right TLE patients. E.g., does this choice make the implicit assumption that all activations are bilaterally mirrored? Please justify why it is better methodologically to use the epileptic focus as a reference rather than anatomical structures. Has its applicability been documented anywhere (reference?)? I appreciate that the issue is mentioned in the discussion (towards the end of page 14), but I would encourage the authors to detail assumptions, implications, and limitations associated with this choice. Also, was the flipping done only for the resting-state data? Was the flipping reversed when compared directly with the activation ROIs during the Sternberg task (towards the end of page 7)?

- In Results, “3.3. Associations between functional connectivity and cognitive abilities”, the authors state that “TLE patients showed several significant correlations between FC and cognitive abilities, while healthy subjects did not” while Figure 4 clearly shows several significant correlations for both groups, e.g., in working memory. Please clarify.

Minor remarks:

- A text piece is repeated in Methods. One states that 45 subjects were included for fMRI analysis while the other states 46 subjects.

- While not a strict requirement, I would encourage the authors to use more precise terminology with regards to the neuropsychological data in the manuscript. E.g., neuropsychological test data represents a performance-based cognitive index, not a direct measure of cognitive abilities.

- On the behavioural level, did you observe correlations between any of the neuropsychological working memory indices (e.g., WMI) and performance on the Sternberg task? If not, are they measuring the same cognitive operation?

- For enhanced readability, I recommend restricting the use of the terms “activity” and “activation” to the context of BOLD activation. In the context of functional connectivity, the terms are imprecise, as connectivity is, per definition, the interaction between two spatially separated “activations”.

- I was not able to access the OpenNeuro dataset. While this is not crucial for the review, it is possible that the answer to some of my remarks lie therein.

- While the figures for the most part are informative, the figure captions could benefit from some light revision. Make sure all relevant information is present.

Reviewer #2: Thank you for giving me the opportunity to review this interesting manuscript.

Concha et al. report an fMRI study (resting-state and task-based using a modified Sternberg task) to evaluate anomalies in the working memory (WMem) network in 40 people with TLE and 36 healthy controls, and how WMem network impairments affect overall cognitive performance.

Overall, the results confirm previous findings of reduced connectivity within DMN and/or TPN, an impaired anticorrelation of DMN and TPN and reduced inter-hippocampal connectivity in TLE.

There are some discrepancies to previous reports regarding correlations of BOLD activity/rs connectivity with cognitive scores, e.g. the finding that contralateral hippocampus connectivity to ipsilateral MTG and contralateral PPL correlated negatively with VWMI and processing speed. As the authors state, these differences may in part be attributed to differences in methodological aspects, particularly the analysis of data according to ipsilateral or contralateral to the epileptogenic temporal lobe.

The paper is well written, and the topic itself is of great interest, as cognitive deficits (e.g. memory and language deficits) are frequent concerns in people with TLE with significant detrimental impacts on quality of life. The manuscript is technically sound, the data support the conclusions, methodology and statistical analyses are clearly described and performed appropriately. Data underlying the findings are made available by the authors.

However, with respect to the existing literature on the topic, research questions and hypotheses should be clarified. In this regard, the Discussion would benefit from rewriting, should clearly highlight the results that go beyond previous findings, and include an elaboration how the current results may impact the future care of people with TLE.

Minor points:

• Typo page 3, section 2.2 „Weschler’s Memory Scale“

• Page 6, section 2.8: „..ANCOVA models can be described with by the following linear model equation“ – suggest to rephrase to „..described using the…“

• Page 7, section 2.10: „Mean BOLD percentage change during the retention phase relative to basal activity was obtained per ROI and was analyzed and compared between groups“

Could the authors elaborate on the baseline condition that was used to assess relative signal change?

• Page 10, 3.3:„TLE patients showed several significant correlations between FC and cognitive abilities, while healthy subjects did not. These associations involved both hicompampi, middle temporal lobe regions, insular cortices and Ipsilateral precentral gyrus“

Could the authors elaborate more on the correlations that were observed in TLE (and which are displayed in Figure 4)? The colour coding in Figure 4 seems a bit confusing: on the upper left, red and blue indicate DMN and TPN, respectively, while in the scatterplots, red and blue indicate TLE vs. controls? In the scatterplots, it is not intuitive which correlations/anticorrelations involve DMN or TPN? Also, the authors state that no correlations were observed in controls, however, some of the scatterplots (e.g. working memory) appear to indicate a correlation in controls rather than TLE?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-04338R1Functional Correlates of Cognitive Performance and Working Memory in Temporal Lobe Epilepsy: Insights from Task-based and Resting-state fMRIPLOS ONE

Dear Dr. Concha, 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 Dec 20 2023 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: https://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,

Florian Ph.S Fischmeister

Academic Editor

PLOS ONE

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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.

Additional Editor Comments: 

Therefore, we invite you to submit a revised version of the manuscript that addresses the two minor points raised by reviewer 2 concering the additional analyses that should be elaborated in the discussion and a minor issue with missing statistical results for S2; c.f. below.

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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: (No Response)

Reviewer #2: (No Response)

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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

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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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

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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

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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 thank the authors for their comprehensive work addressing my remarks to the initial manuscript. I think the analyses considering clinical covariates were an interesting addition to the manuscript. While understandable, it was unfortunate that the heterogeneity with respect to medication prevented any subgroup analyses. Thank you for verifying that none of the patients had undergone surgery. If not very inconvenient for the authors, I would suggest that the medication and epilepsy onset variables are added to the participants.tsv file of the dataset.

Furthermore, I appreciate the authors’ efforts to clarify the dataset and which participants were included in which analyses. The revised manuscript promotes transparency on this issue in much greater extent than the original manuscript. In particular, the supplementary figure S1 was effective in this regard. Especially important was the explicit mentioning that data for the resting-state fMRI analyses were rejected mostly due to the lack of neuropsychological data, and not due to poor fMRI data quality.

I consider all my remarks adequately addressed, also those not explicitly mentioned above. I can recommend the manuscript for publication in its current state. Congratulations to the authors on the work.

Reviewer #2: Thank you for the opportunity to review this manuscript again.

I believe the concerns raised by both reviewers were addressed accordingly, and I only have two minor remarks:

1.) The additional analyses investigating whether clinical factors like age at onset of seizures, age at time of study, birth sex and presence of HS impact the observed effects should be elaborated on in the Discussion.

2.) S2 Fig: The authors state that S2 Fig shows similar/ nearly identical results to Figure 2, however, no statistical results for S2 Fig are presented in the Figure or text/caption.

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Reviewer #1: Yes: Christoffer Hatlestad-Hall

Reviewer #2: No

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Functional Correlates of Cognitive Performance and Working Memory in Temporal Lobe Epilepsy: Insights from Task-based and Resting-state fMRI

PONE-D-23-04338R2

Dear Dr. Concha,

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.

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Kind regards,

Florian Ph.S Fischmeister

Academic Editor

PLOS ONE