-->PONE-D-25-42878-->-->Altered Brain–Behavior Coupling during Inhibitory Control in Ankylosing Spondylitis: ERP Evidence from N2 and P3b Components-->-->PLOS One

Dear Dr. Yu,

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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-->5. Review Comments to the Author

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Reviewer #1:

This study makes a compelling case for a nuanced understanding of the cognitive impairment associated with ankylosing spondylitis (AS). The authors go beyond a simple deficit model and propose a compensation mechanism, which is an important and novel contribution. The use of event-related potentials (ERPs) and time frequency analysis provides a reliable neurophysiological basis for their behavioral findings.

Here is a detailed analysis of the text, outlining its strengths and areas for improvement.

Strengths

• Novelty and clinical relevance: The main hypothesis of the study, which indicates that cognitive changes in AS reflect compensatory processes and not simple deficits, is very novel and clinically relevant.

• Integrated Multi-modal Analysis: A combination of behavioral data (time and accuracy of response), analysis of ERP components (N2 and P3b) and time frequency analysis provides a powerful multi-modal approach. The convergence of these findings - where behavioral, ERP, and oscillatory data all indicate a compensatory mechanism - is an important strength that supports the conclusions of the authors.

• Robust Brain-Behavior Coupling: The key finding of a strong and exclusive brain-behavioral association in patients with AS during NoGo is convincing. A specific relationship between P3b amplitude and inhibitory specificity provides a robust neural signature of this compensation process that is not present in healthy controls.

• Clear Behavioral Characterization: The authors effectively describe a strategy of a slower but safer response in patients with AS. By demonstrating that patients have a slower response time in both correct Go and wrong NoGo trials, they convincingly argue against simple motor impairment and for a more deliberate and effortful cognitive strategy.

Weaknesses and Recommendations

• Group Differences and Statistical Reporting: The authors repeatedly note that while there are visually apparent trends in ERP waveforms and topographies, statistical tests (t-tests) show no significant group differences (all p-values > 0.10). This is a critical point that requires more explicit discussion, especially since the core of the paper relies on within-group correlations.

• Limited N2 Component Discussion: The abstract and introduction refer to the N2 component, which is linked to Conflict Tracking. However, the results and discussion sections contain no relevant findings concerning N2. This leaves a gap in the narrative and may mislead readers who expect a more balanced account of the two strands.

• Figure Clarity and Presentation: Although the ERP waveforms (Figures 2, 4) and topographic maps (Figures 3, 5 and 6) are informative, their accuracy could be improved. The font size of the labels and the axes is very small and is difficult to read. Also, the color graduations on topographic maps are not uniform for all figures, which may be confusing.

• Contextualization of the "Slower-but-Safer" Strategy: The authors introduce a slower but safer strategy and align it with the principle of speed-accuracy trade-off. However, they do not discuss how that particular compromise may be specific to AS. Given the nature of chronic inflammatory diseases, it would be of great value to discuss in more detail how fatigue, pain and other symptoms might affect this cognitive strategy.

This manuscript is a high-quality study offering a new and convincing perspective on the cognitive impairment of ankylosing spondylitis. The methodology is sound and the findings are well supported by converging behavioral and neurophysiological evidence. The recommendations outlined above aim to improve the presentation of the manuscript, clarify key points and deepen its contextual discussion, ultimately making it a more impactful and accessible contribution to the field. I recommend acceptance pending a few minor revisions.

Respectfully yours,

Sobhan Khodadadi.

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Reviewer #1: No

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-->PONE-D-25-42878R1-->-->Altered Brain–Behavior Coupling during Inhibitory Control in Ankylosing Spondylitis: ERP Evidence from N2 and P3b Components-->-->PLOS One

Dear Dr. Yu,

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 Apr 18 2026 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 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,

John Adeolu Falode

Academic Editor

PLOS One

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Reviewer #2: (No Response)

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Reviewer #2: Yes

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

Reviewer #2: Yes

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Reviewer #2: Yes

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-->6. Review Comments to the Author

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Reviewer #2:   Reviewer #1 Report

Manuscript title: Altered Brain–Behavior Coupling during Inhibitory Control in Ankylosing Spondylitis: ERP Evidence from N2 and P3b Components

Recommendation: Major Revision

Confidential comments to the Editor

This manuscript addresses a clinically relevant and under-explored topic—executive control alterations in ankylosing spondylitis (AS)—using a Go/NoGo ERP design and a brain–behavior coupling framework. The central idea (task-contingent coupling in AS, potentially consistent with compensatory recruitment) is interesting and could be suitable for a high-impact outlet.

However, the current submission has important methodological and inferential weaknesses that preclude acceptance in its present form: (i) insufficient control of multiple comparisons across ERP, time–frequency, and correlation analyses; (ii) questionable component labeling/interpretation of “P3b” given the topography and condition; (iii) reliance on “significant in one group but not the other” without formal group-difference tests; and (iv) potentially low NoGo trial counts after artifact rejection. These issues are addressable, but require substantial re-analysis and reframing.

________________________________________

Comments to the Authors

1) Summary of the work and contribution

The authors compare male AS patients (n=16) and age-matched controls (n=23) on a Go/NoGo task with 32-channel EEG. They focus on N2 (200–300 ms), a late positivity labeled “P3b” (400–600 ms), and theta-band power (4–7 Hz) within the 400–600 ms window. Behaviorally, AS participants show slower responses and reduced Go accuracy, with a trend toward higher NoGo accuracy. The main claim is that NoGo accuracy is coupled with late ERP amplitude at FCz/Cz in AS but not in controls, accompanied by enhanced theta power during inhibition, interpreted as compensatory control recruitment.

The topic is timely and the brain–behavior coupling angle is potentially valuable. Nevertheless, several core claims are not yet supported at the evidentiary standard expected for a Q1 journal.

________________________________________

Major concerns (must be addressed)

2) Component identification: the “P3b” label is likely not justified

The manuscript interprets a 400–600 ms positivity as P3b, yet the reported coupling is maximal at FCz/Cz, and the condition of interest is NoGo inhibition. In the Go/NoGo literature, the NoGo-related late positivity often has a more fronto-central distribution (frequently discussed as NoGo-P3 and/or P3a-like control engagement), whereas canonical P3b is typically centro-parietal (often maximal at Pz/CPz) and linked to context updating.

Requested actions:

• Provide quantitative justification for labeling the component as P3b (e.g., scalp distribution of peak/mean activity; demonstrate parietal maximum if claiming P3b).

• Alternatively (and likely more appropriate), relabel the effect as NoGo-P3 (or clarify P3a vs P3b distinction) and update the title/abstract accordingly.

• Include a figure showing scalp topography in the relevant window for each condition/group, and report where the component peaks.

3) Multiple comparisons: correction strategy is currently insufficient/unclear

The analysis includes many statistical tests (ERP across electrodes and conditions; numerous correlations; theta across many channels). The manuscript and supplement currently mix uncorrected p-values with statements implying correction (e.g., Bonferroni in the figure caption) without a coherent family-wise strategy.

Requested actions:

• Define families of tests and apply appropriate correction (e.g., FDR or Bonferroni) consistently for:

1. ERP group comparisons (components × electrodes × conditions),

2. Brain–behavior correlation matrices,

3. Theta topography/channel tests.

• Consider a more Q1-appropriate approach such as:

o a priori ROI analyses (confirmatory) + corrected exploratory analyses, and/or

o mixed ANOVA / linear mixed modeling (Group × Condition × Electrode) for ERP, and/or

o cluster-based permutation testing for time–frequency topographies.

Important: Several key inferences (e.g., Cz correlation p=.035) may not survive correction; conclusions must match corrected results.

4) “Coupling present in AS but absent in controls” requires a formal group-difference test

The manuscript repeatedly interprets significance in AS and non-significance in controls as evidence of group differences. This is not statistically valid without directly testing whether the correlations differ between groups.

Requested actions:

• Compare correlation coefficients between groups using Fisher r-to-z, or

• Fit an interaction model: Accuracy ~ ERP + Group + ERP×Group (robust SEs recommended).

• Report the interaction p-value as the basis for claims of differential coupling.

5) N2 polarity and measurement: mismatch between narrative and reported values

The manuscript describes a “pronounced negative deflection” but several N2 means are positive in the tables, raising concerns about measurement choice, referencing, and/or window definition.

Requested actions:

• Clarify reference montage and polarity conventions.

• Confirm whether the N2 window (200–300 ms) truly captures the negative peak for each subject/condition.

• Consider reporting peak negativity or NoGo–Go difference waves for N2 if appropriate.

• Ensure waveforms include a visible zero-line and baseline.

6) Trial numbers: NoGo trial count is likely low and may undermine ERP/theta reliability

With 150 trials and a 4:1 Go:NoGo ratio, there are ~30 NoGo trials before rejection. After artifact rejection, NoGo epochs may be too few for stable ERP/time–frequency estimates.

Requested actions:

• Report, for each group, mean±SD and range of accepted Go and NoGo epochs after preprocessing.

• State any minimum-epoch exclusion threshold (e.g., exclude subjects with <15–20 clean NoGo trials).

• Consider reporting reliability checks (split-half) or at minimum discuss signal stability limitations.

7) Clinical characterization and confounds are insufficient for mechanistic interpretation

The discussion makes inflammation-to-brain mechanistic claims, but the paper does not report key clinical variables (e.g., disease activity indices, CRP/ESR, pain, fatigue, sleep, mood, medication/biologic use).

Requested actions:

• Provide basic clinical descriptors and medication status.

• If available, test whether the proposed neural markers relate to clinical measures (even exploratory).

• If not available, substantially temper mechanistic language and clearly acknowledge confounding factors.

8) Time–frequency (theta) method reporting is too sparse

The theta analysis is described as short-time FFT, but key parameters and normalization details are missing.

Requested actions:

• Specify window length, tapering, step size, frequency resolution, and baseline normalization method (dB vs percent change).

• Justify why FFT is appropriate for theta time-locking in this context or consider standard wavelet/multitaper approaches.

• Apply and report multiple-comparison correction across channels (or use cluster-based permutation).

9) Overstatement of “compensation” and “biomarker” claims

Given cross-sectional design, small sample, and correlation-based inference, the manuscript should not claim strong evidence for compensation or call the effect a biomarker without validation.

Requested actions:

• Rephrase to “consistent with compensatory recruitment” and “candidate marker.”

• Add a limitations paragraph emphasizing cross-sectional design, small n, trial count, and confounds.

10) Recruitment status statement is problematic

The manuscript states recruitment is ongoing “at the time of manuscript preparation.” For a submitted study, the analyzed sample should be clearly defined with a fixed cutoff.

Requested actions:

• Remove/replace with a clear recruitment period and final sample cutoff date.

• If this is an interim analysis, that must be explicitly justified (ideally preregistered), which is uncommon for this type of paper.

________________________________________

Minor comments / presentation

1. Correct typographical issues (e.g., “fRMI” → fMRI; “Yanchen” likely “Yancheng”; “a important role” → “an important role”).

2. Provide descriptive statistics (mean±SD) for behavioral variables alongside inferential tests.

3. Ensure figure captions match statistical procedures (e.g., if Bonferroni is claimed, show corrected p-values or explicitly mark corrected sites).

4. Clarify task details: practice trials, handedness, stimulus mapping, randomization, feedback, and whether ISI is jittered.

5. Consider reducing emphasis on N2 in the title if N2 is not a central supported finding after corrected analysis.

________________________________________

Overall conclusion

The study has promise, but substantial re-analysis and reframing are required. In particular, component identification, trial-count transparency, corrected inference, and proper tests of group differences in coupling are essential for publication in a Q1 venue.

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Reviewer #2: Yes:   soomaayeh heysieattalab

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Altered Brain–Behavior Coupling during Inhibitory Control in Ankylosing Spondylitis: ERP Evidence from NoGo-P3 Component

PONE-D-25-42878R2

Dear Dr. Yu,

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,

John Adeolu Falode

Academic Editor

PLOS One

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