Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I am sorry to say, but I have spent many hours trying to understand the real purpose of the presents article.

The authors present here something that is not new. Although they try to give a new approach to the physicological mechanisms, which contribute to the horizontal nystagmus complex operate under cerebelar tuning. This is point is rather vaguw and more references on the point must included.

The text lacks any statistical analysis and is rather confusing. Inj my opinion is hard to read and must be re-organized.

With the exception of some pictures, there is no diagram or any other table on which results of previous studies are presented. 

The conclusions are also difficult to understand . Hondsestly, I don't see any mechanistic interpretation, as they propose, in this text. 

The references must be more up-to-date and try to apply the questions and notifications which have been presented previously. There are quidelines for the reviewers but some texts make them extreme difficult ti imply....

 

Author Response

Response to Reviewer 1

Comment: I have spent many hours trying to understand the real purpose of the present article.

Response: Thank you for this important comment. I recognize that the purpose of the original manuscript may not have been stated with sufficient clarity. The Introduction has been revised to clarify that the manuscript is not intended to present a new diagnostic algorithm or a systematic review, but rather a narrative clinical-conceptual framework for interpreting selected horizontal nystagmus phenotypes as the observable output of interacting vestibulo-ocular mechanisms. A new subsection, “Literature selection and scope of the review,” has also been added to define the purpose and boundaries of the paper.

Comment: The authors present here something that is not new. Although they try to give a new approach to the physiological mechanisms, which contribute to the horizontal nystagmus complex operate under cerebellar tuning. This point is rather vague and more references on the point must included.

Response: I agree that the individual mechanisms discussed in the paper, including gaze holding, velocity storage, and cerebellar modulation, are not new. The novelty of the manuscript lies in integrating these established mechanisms into a single clinician-facing framework for interpreting mixed or discordant horizontal nystagmus phenotypes. The text has been revised to make this point explicit. The language around cerebellar tuning has also been clarified by replacing some uses of “supervisory control” with “cerebellar regulatory influence,” and additional references have been added, including recent and consensus-based work on vestibular signs, acute vestibular syndromes, and bedside testing.

Comment: The text lacks any statistical analysis and is rather confusing. In my opinion it is hard to read and must be re-organized.

Response: This manuscript is a narrative clinical-conceptual review and does not present original patient data or a quantitative meta-analysis; therefore, statistical analysis is not applicable. This has now been stated explicitly in the new literature selection and scope subsection. The manuscript has also been reorganized and streamlined to improve readability, and repetitions have been reduced.

Comment: With the exception of some pictures, there is no diagram or any other table on which results of previous studies are presented.

Response: Thank you. In response, I added a new table entitled “Table 1. Operational bedside and laboratory correlates of the proposed framework.” This table summarizes observable features, suggested dominant functional processes, accessible bedside signs, candidate quantitative readouts, and interpretative cautions. This addition is intended to make the framework more transparent and clinically usable.

Comment: The conclusions are also difficult to understand. Honestly, I do not see any mechanistic interpretation, as they propose, in this text.

Response: The Conclusion has been revised to make the mechanistic interpretation more explicit. The revised text emphasizes that horizontal nystagmus is interpreted not as a simple directional label, but as the observable output of interacting functional processes: gaze-holding stability, storage-related vestibular persistence, and cerebellar regulatory influence. The framework is now clearly described as an interpretative structure rather than as a rigid localization scheme.

Comment: The references must be more up-to-date.

Response: The reference list has been checked, corrected, renumbered, and expanded. Recent and consensus-based references have been added, including work on vestibular sign classification, acute unilateral vestibulopathy/vestibular neuritis diagnostic criteria, bedside testing in acute vestibular syndrome, and higher-order vestibular-cerebellar control.

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very attractive point of view. It aligns with some abnormalities in real life situations. However, the proof of concept suffers from oversimplification excluding other known pathways of oculomotor control. A brief mention of higher control influence must be mentioned.

The article is more of a reflective logical framework rather than a narrative clinical-conceptual synthesis with no explanation of literature selection methodology.

It significantly lacks operational criteria for clinical application and the suggested clinical pathway is more confusing than helpful. It would be more appropriate to   define clear decision rules based on established easily accessible bedside tests.

The suggestion of clinical/laboratory confirmation is very important and it would have been helpful to clearly suggest which tests would be more suitable detect which level and what are the established norms.

Although one of the main issue is to "oppose" the traditional "peripheral vs central" concept, other attempts of blurring this distinction should be mentioned and the novelty of the preset concept highlighted.

The article is too long and suffers many repetitions. There are some unusual expressions : dominant dynamical networks, network phenotypes, supervisory control 

Comments on the Quality of English Language

minor semantic corrections.

Author Response

Comment: This is a very attractive point of view. It aligns with some abnormalities in real life situations. However, the proof of concept suffers from oversimplification excluding other known pathways of oculomotor control. A brief mention of higher control influence must be mentioned.

Response: Thank you for the positive and constructive assessment. I agree that the original framework risked appearing overly simplified. The section “Beyond the nodulus-uvula” has been expanded to acknowledge higher-order ocular motor and vestibular influences, including cortical, thalamic, basal ganglia, brainstem reticular, vestibulo-cerebellar, visual-vestibular, pursuit, fixation-suppression, and spatial-orientation networks. The manuscript now clarifies that the proposed model is a simplified core framework for clinical usability, not an exhaustive circuit map.

Comment: The article is more of a reflective logical framework rather than a narrative clinical-conceptual synthesis with no explanation of literature selection methodology.

Response: I agree. A new subsection entitled “Literature selection and scope of the review” has been added. It clarifies that the article is a narrative clinical-conceptual review rather than a systematic review and explains which categories of literature were prioritized: anatomical, physiological, experimental, lesion-based, and clinically relevant studies addressing vestibular nuclei circuitry, gaze holding, velocity storage, optokinetic after-nystagmus, periodic alternating nystagmus, Alexander-law behavior, and bedside evaluation of acute vestibular syndromes.

Comment: It significantly lacks operational criteria for clinical application and the suggested clinical pathway is more confusing than helpful. It would be more appropriate to define clear decision rules based on established easily accessible bedside tests.

Response: This is an important point. The clinical interpretation section has been revised to make the bedside criteria more operational. The examiner is now guided to document whether nystagmus is present in primary position, whether it is modified by fixation, whether it changes with eccentric gaze, and whether slow-phase velocity shows exponential drift, periodic reversal, or disproportionate persistence. These criteria are summarized in the new operational table. The clinical pathway is now framed as decision-support rather than rigid localization.

Comment: The suggestion of clinical/laboratory confirmation is very important and it would have been helpful to clearly suggest which tests would be more suitable to detect which level and what are the established norms.

Response: I expanded the instrumented assessment and future directions sections. Candidate readouts are now specified for each functional process: video-oculographic assessment of gaze dependence and post-saccadic drift for gaze-holding dysfunction; low-frequency rotational responses and OKAN-related metrics for storage-related behavior; and cycle duration, reversal pattern, fixation dependence, and slow-phase velocity time series for periodic or regulatory-instability phenotypes. The manuscript also states that universal thresholds are not yet established for all proposed correlates and that future studies should define normative ranges and clinically meaningful thresholds.

Comment: Although one of the main issues is to oppose the traditional peripheral vs central concept, other attempts of blurring this distinction should be mentioned and the novelty of the present concept highlighted.

Response: The Introduction has been revised to clarify that the paper does not oppose the peripheral-versus-central distinction, which remains clinically important. Rather, the proposed framework aims to complement established reasoning and bedside algorithms in selected mixed or discordant cases. Additional references have been added to acknowledge previous work on vestibular sign classification, acute vestibular syndrome bedside testing, and peripheral-appearing central phenotypes. The novelty is now stated as the integration of these observations into a coupled gaze-holding/storage/cerebellar-regulatory framework.

Comment: The article is too long and suffers many repetitions. There are some unusual expressions: dominant dynamical networks, network phenotypes, supervisory control.

Response: I have streamlined several sections and reduced repetitions. Some terminology has been softened or clarified. For example, “supervisory control” has been partly replaced by “cerebellar regulatory influence,” and “dominant dynamical domain” is now used operationally to mean the functional process that best explains the observed waveform behavior. The purpose is to improve readability while preserving the conceptual value of the framework.

Reviewer 3 Report

Comments and Suggestions for Authors

I believe this is a well-written paper that effectively synthesizes previously scattered knowledge. However, I have some reservations regarding its practical applicability.

1. While the paper presents several criteria intended to make it usable in actual clinical practice, I find these criteria to be vague. Please provide more detailed information regarding these criteria.
2. I believe that quantitative assessment of nystagmus is necessary for practical clinical use. Please address this point in the “Future Directions” section.
3. Please simplify the figures.
4. There is an error in the reference number.

Author Response

Comment: I believe this is a well-written paper that effectively synthesizes previously scattered knowledge. However, I have some reservations regarding its practical applicability.

Response: Thank you for this positive assessment and helpful concern. The manuscript has been revised to strengthen practical applicability. I added more explicit bedside criteria, a new operational table, and clearer links between observable nystagmus features and candidate quantitative assessments.

Comment: While the paper presents several criteria intended to make it usable in actual clinical practice, I find these criteria to be vague. Please provide more detailed information regarding these criteria.

Response: I agree. The clinical interpretation section has been expanded with more specific descriptions of gaze dependence, eccentric gaze instability, post-saccadic drift, periodicity, direction reversals, fixation effects, Alexander-law mismatch, and dissociation between rapid and sustained vestibular paradigms. These criteria are summarized in Table 1.

Comment: I believe that quantitative assessment of nystagmus is necessary for practical clinical use. Please address this point in the Future Directions section.

Response: I agree entirely. The “Priorities for future validation” section has been expanded to emphasize quantitative nystagmus assessment, including slow-phase velocity, gaze-dependent drift slope, post-saccadic drift metrics, fixation suppression effects, head-shaking response, low-frequency vestibular persistence, OKAN time constants, rotatory-chair decay measures, periodicity measures, reversal dynamics, and reproducibility across platforms and operators.

Comment: Please simplify the figures.

Response: The figure captions and the textual references to the figures have been revised to clarify the distinct purpose of each figure: Fig. 1 presents the minimal architecture, Fig. 2 the integrated framework, Fig. 3 schematic waveform phenotypes, and Fig. 4 the bedside flowchart. Terminology has also been simplified in the manuscript where possible.

Comment: There is an error in the reference number.

Response: Thank you for noting this. The reference numbering has been checked and corrected throughout the manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

This version is better, but I believe that some diagrams, and not only tables, can be helpful. An additional comment/paragraph on clinical tests, such as VEMPS, must be added. 

Author Response

Dear reviewer

Thank you again for your helpful suggestion. To make the framework more clinically usable and visually clear, I added a new diagram, now included as Figure 5, entitled “Complementary vestibular and ocular motor tests for applying the framework.” This figure summarizes how bedside examination, video-oculography, vHIT, rotatory/optokinetic measures, VEMPs, and neurologic assessment can be used together to interrogate different clinical questions within the proposed framework.

In addition, I added a new subsection in the manuscript:

4.4. Complementary clinical vestibular tests, including VEMPs. This paragraph clarifies that VEMPs are complementary to horizontal nystagmus analysis. It explains that cVEMPs and oVEMPs do not directly measure horizontal gaze holding or velocity storage, but provide important information about otolith-dependent vestibular pathways and may help contextualize peripheral otolith input to the vestibular nuclei in patients with mixed or discordant vestibular-ocular findings.

The Future Directions section was also updated to mention VEMP amplitude and latency/asymmetry patterns among the candidate quantitative variables for future validation. Three references related to VEMPs and otolithic testing were added to support this addition.

Changes made in the manuscript:

Added new subsection 4.4: Complementary clinical vestibular tests, including VEMPs.

Added new Figure 5 as an additional diagram mapping clinical tests to the main functional questions of the framework.

Added specific discussion of cVEMPs and oVEMPs as complementary tests of otolith-dependent vestibular pathways.

Expanded Future Directions to include VEMP amplitude and latency/asymmetry patterns as candidate quantitative variables.

Added new references 25–27 on VEMPs and otolithic testing.

Renumbered the following subsections accordingly.

I hope that these changes address the reviewer’s remaining concerns and make the manuscript clearer and more clinically applicable.