Developmental Neurotoxicity of Alcohol from Neuronal Basis to Behavioural Outcomes: A Comprehensive Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript presents a timely and potentially valuable conceptual synthesis of prenatal alcohol exposure (PAE) and fetal alcohol spectrum disorders (FASD), proposing a network-neuroscience framework that links molecular, cellular, and systems-level alterations to behavioral outcomes. The topic is relevant and the review is generally well organized. However, several substantial issues limit its current suitability for publication. These concern methodology, conceptual overreach, balance of evidence, and numerous language and editorial deficiencies. 

 Major problems:

 1. The manuscript is repeatedly described as a "systematic review" (including in the title), yet no systematic review methodology is presented - no literature search strategy is reported, no databases, search terms, date ranges, inclusion/exclusion criteria, or screening procedures are described, no PRISMA framework or study selection flow diagram is provided, finally, no assessment of study quality or risk of bias is included. As written, the article is a narrative review with a conceptual framework rather than a systematic review. The title, abstract, and manuscript type should be revised accordingly unless a proper systematic methodology is added.

 2. Central conceptual model remains largely speculative - the manuscript's principal novelty is the proposal that FASD should be viewed as a "disorder of emerging neuro-computational architecture." While intellectually attractive, the framework is largely inferential. Most cited evidence demonstrates cellular injury, structural abnormalities, or altered connectivity. Direct evidence linking these findings to the proposed network-level developmental trajectory is limited. Several statements imply causal relationships that exceed the available data. The distinction between established findings and author-generated hypotheses is insufficiently clear. The authors should explicitly identify which aspects are evidence-based and which represent theoretical extrapolation.

 3. Insufficient critical evaluation of the literature - the review predominantly presents supportive evidence. Missing are discussions of: conflicting neuroimaging findings,
 inconsistencies across DTI and fMRI studies, methodological heterogeneity, limitations of graph-theoretical analyses, variability introduced by exposure timing, dose, and comorbid exposures, replication challenges in connectomics studies. A balanced review should critically discuss limitations and controversies rather than mainly supporting the proposed model.

 4. Overreliance on animal studies for mechanistic claims. Many mechanistic sections rely heavily on rodent and zebrafish data. The manuscript should more clearly discuss: translational limitations, species-specific developmental timing differences, uncertainty regarding extrapolation to human fetal development, which mechanisms are strongly supported in humans versus inferred from animal models.

 5. Figures 1–3 are largely schematic and summarize proposed mechanisms, so figures Are conceptual rather than Evidence-Based. Please clearly indicate that these are conceptual illustrations, avoid presenting speculative pathways as established facts, improve figure legends by specifying the evidence supporting each pathway.

 6. Clinical and translational implications require more caution. Sections discussing biomarkers, EEG screening, connectomics, neuromodulation, and network-guided interventions sometimes imply near-future clinical applicability. Currently no validated network biomarker exists for FASD diagnosis, connectomic measures remain research tools, evidence for neuromodulation in FASD is very limited. The clinical translation section should be rewritten with a more cautious tone and stronger emphasis on current limitations.

 7. Missing discussion of confounding factors - the review insufficiently addresses major confounders frequently present in PAE populations (prenatal tobacco exposure,
 cannabis and other substance use, maternal stress, socioeconomic adversity, nutritional deficiencies, postnatal environmental influences). These factors significantly influence neurodevelopment and complicate interpretation of network-level findings.

Minor Concerns

1. The bibliography contains 177 entries. Please consider reducing the number of citations by removing those that are not essential.

 2. Inconsistent terminology - the manuscript alternates between: PAE, prenatal alcohol exposure, fetal alcohol exposure and between: FASD, fetal alcohol spectrum disorders. Terminology should be standardized throughout.

 3. Formatting problems - numerous missing spaces occur throughout the manuscript, for example: "PI3KAkt", "brain-derived", "frontoparietal", "school-age", "long-range".
Spacing and hyphenation should be carefully checked.

 4. Citation density is uneven. Some sections contain extensive citation support, whereas others—particularly the conceptual framework and predictive sections—contain relatively sparse referencing considering the strength of the claims.

 5. Figure quality - the visual quality and readability of several figures could be improved: text size is small, some labels are difficult to read, figure 3 is visually, to much text, uneven font size, crowded and would benefit from simplification.

 6. Abstract requires greater precision. The abstract occasionally presents the proposed framework as an established interpretation rather than a conceptual synthesis. The distinction between evidence and hypothesis should be made clearer.

 7. Conclusion is overstated. Statements such as the framework providing a "unifying explanation" may be overly strong given the current evidence base. A more balanced conclusion would improve scientific rigor.

This manuscript addresses an important topic and offers an interesting integrative perspective linking developmental neurobiology and network neuroscience in FASD. However, the work currently functions as a narrative/conceptual review rather than a systematic review, and the proposed neuro-computational architecture framework is presented with greater certainty than the available evidence supports. Substantial revisions are required to improve methodological transparency, strengthen critical analysis, moderate speculative claims, and correct numerous language and formatting issues.

Comments on the Quality of English Language

Numerous language and grammar problems - the manuscript contains many typographical, grammatical, and formatting errors (e.g.: "systemic review" instead of "systematic review" (title), "class (I ADH and CYP2E1)", "brain growth spurt triggers widespread", "cytochromec release", "binge like", "largescale", "scalingdown", "corpus callosume specially", "graph based measure stend", "visuo cortical", "trophicfactor deficits"). A thorough professional English-language revision is required. 

Author Response

The manuscript presents a timely and potentially valuable conceptual synthesis of prenatal alcohol exposure (PAE) and fetal alcohol spectrum disorders (FASD), proposing a network-neuroscience framework that links molecular, cellular, and systems-level alterations to behavioral outcomes. The topic is relevant and the review is generally well organized. However, several substantial issues limit its current suitability for publication. These concern methodology, conceptual overreach, balance of evidence, and numerous language and editorial deficiencies. 

 Major problems:

-The manuscript is repeatedly described as a "systematic review" (including in the title), yet no systematic review methodology is presented - no literature search strategy is reported, no databases, search terms, date ranges, inclusion/exclusion criteria, or screening procedures are described, no PRISMA framework or study selection flow diagram is provided, finally, no assessment of study quality or risk of bias is included. As written, the article is a narrative review with a conceptual framework rather than a systematic review. The title, abstract, and manuscript type should be revised accordingly unless a proper systematic methodology is added.

Response: We thank the reviewer for this important comment. The title is now revised in the current version of the manuscript

-Central conceptual model remains largely speculative - the manuscript's principal novelty is the proposal that FASD should be viewed as a "disorder of emerging neuro-computational architecture." While intellectually attractive, the framework is largely inferential. Most cited evidence demonstrates cellular injury, structural abnormalities, or altered connectivity. Direct evidence linking these findings to the proposed network-level developmental trajectory is limited. Several statements imply causal relationships that exceed the available data. The distinction between established findings and author-generated hypotheses is insufficiently clear. The authors should explicitly identify which aspects are evidence-based and which represent theoretical extrapolation.

Response: We thank the reviewer for this important comment. the manuscript has been revised to more clearly distinguish established evidence from theoretical extrapolations and to explicitly indicate where further empirical validation is needed.

-Insufficient critical evaluation of the literature - the review predominantly presents supportive evidence. Missing are discussions of: conflicting neuroimaging findings,
 inconsistencies across DTI and fMRI studies, methodological heterogeneity, limitations of graph-theoretical analyses, variability introduced by exposure timing, dose, and comorbid exposures, replication challenges in connectomics studies. A balanced review should critically discuss limitations and controversies rather than mainly supporting the proposed model.

Response: We thank the reviewer for this valuable comment. The manuscript has been revised to provide a more balanced and critical appraisal of the literature, including conflicting findings and methodological limitations in current connectomic approaches in PAE research as suggested.

 -Overreliance on animal studies for mechanistic claims. Many mechanistic sections rely heavily on rodent and zebrafish data. The manuscript should more clearly discuss: translational limitations, species-specific developmental timing differences, uncertainty regarding extrapolation to human fetal development, which mechanisms are strongly supported in humans versus inferred from animal models.

Response: Thank you for this helpful comment. The manuscript has been revised to better distinguish between mechanisms supported by human data and those primarily inferred from animal studies.

 -Figures 1-3 are largely schematic and summarize proposed mechanisms, so figures Are conceptual rather than Evidence-Based. Please clearly indicate that these are conceptual illustrations, avoid presenting speculative pathways as established facts, improve figure legends by specifying the evidence supporting each pathway.

Response: We thank the reviewer for this helpful suggestion. The figure legends have been now revised, and the mechanistic illustrations have been also improved in the revised version of the manuscript.

-Clinical and translational implications require more caution. Sections discussing biomarkers, EEG screening, connectomics, neuromodulation, and network-guided interventions sometimes imply near-future clinical applicability. Currently no validated network biomarker exists for FASD diagnosis, connectomic measures remain research tools, evidence for neuromodulation in FASD is very limited. The clinical translation section should be rewritten with a more cautious tone and stronger emphasis on current limitations.

Response: We thank the reviewer for this valuable comment. We have now revised the “Clinical and Translational Implications” section.

Missing discussion of confounding factors - the review insufficiently addresses major confounders frequently present in PAE populations (prenatal tobacco exposure,
 cannabis and other substance use, maternal stress, socioeconomic adversity, nutritional deficiencies, postnatal environmental influences). These factors significantly influence neurodevelopment and complicate interpretation of network-level findings.

Response: We thank the reviewer for this important point. We agree that multiple confounding factors are commonly present in PAE populations and can influence neurodevelopment and interpretation of network-level findings.  However, such factors is beyond the scope of the present review.

Minor Concerns

-The bibliography contains 177 entries. Please consider reducing the number of citations by removing those that are not essential. Inconsistent terminology the manuscript alternates between: PAE, prenatal alcohol exposure, fetal alcohol exposure and between: FASD, fetal alcohol spectrum disorders. Terminology should be standardized throughout.

Response: We thank the reviewer for this helpful observation. We agree that consistent terminology is important for clarity. We have carefully revised the manuscript to standardize the terminology throughout, using “PAE (prenatal alcohol exposure)” and “FASD (fetal alcohol spectrum disorders)” consistently, and ensuring uniform usage across the text.

 -Formatting problems - numerous missing spaces occur throughout the manuscript, for example: "PI3K/Akt", "brain-derived", "frontoparietal", "school-age", "long-range".
Spacing and hyphenation should be carefully checked.

Response: We thank the reviewer for highlighting these spelling mistakes which all been now corrected in the current version of manuscript/

 -Citation density is uneven. Some sections contain extensive citation support, whereas others particularly the conceptual framework and predictive sections contain relatively sparse referencing considering the strength of the claims.

Response: We thank the reviewer for this comment. We have now revised the references list.

 -Figure quality - the visual quality and readability of several figures could be improved: text size is small, some labels are difficult to read, figure 3 is visually, to much text, uneven font size, crowded and would benefit from simplification.

Response: We thank the reviewer for this helpful comment. We have now revised this figure and enhanced its quality.

- Abstract requires greater precision. The abstract occasionally presents the proposed framework as an established interpretation rather than a conceptual synthesis. The distinction between evidence and hypothesis should be made clearer.

Response: We thank the reviewer for this helpful comment. The abstract is now revised in the text.

 -Conclusion is overstated. Statements such as the framework providing a "unifying explanation" may be overly strong given the current evidence base. A more balanced conclusion would improve scientific rigor.

Response: We thank the reviewer for this helpful comment. The discussion section is now revised in the current version of the manuscript.

This manuscript addresses an important topic and offers an interesting integrative perspective linking developmental neurobiology and network neuroscience in FASD. However, the work currently functions as a narrative/conceptual review rather than a systematic review, and the proposed neuro-computational architecture framework is presented with greater certainty than the available evidence supports. Substantial revisions are required to improve methodological transparency, strengthen critical analysis, moderate speculative claims, and correct numerous language and formatting issues.

 

Comments on the Quality of English Language

Numerous language and grammar problems - the manuscript contains many typographical, grammatical, and formatting errors (e.g.: "systemic review" instead of "systematic review" (title), "class (I ADH and CYP2E1)", "brain growth spurt triggers widespread", "cytochromec release", "binge like", "largescale", "scalingdown", "corpus callosume specially", "graph based measure stend", "visuo cortical", "trophicfactor deficits"). A thorough professional English-language revision is required. 

Response: We thank the reviewer for this helpful comment. The manuscript has now undergone a thorough English editing for grammar and spelling mistakes.

Reviewer 2 Report

Comments and Suggestions for Authors

In this systematic review, the authors integrate developmental neurobiology and network neuroscience to conceptualize prenatal alcohol exposure as a disorder of emerging neural and functional architecture. In particular, they summarize the pharmacokinetics of ethanol during pregnancy, critical windows of vulnerability, and neuroimaging studies, and discuss implications for biomarkers, early identification, and network-informed interventions. The authors provide a comprehensive review of the literature, including recent reports published up to 2025, thereby offering an updated overview of prenatal alcohol exposure. However, several minor issues should be addressed to improve clarity and scholarly rigor.

 

1. In this article, the authors describe this comprehensive review as a systematic review in the title. However, the reviewer could not find any section describing the literature search strategy, inclusion and exclusion criteria, databases searched, or timeframe considered. The reviewer suggests that the authors follow accepted systematic review standards by referencing the widely accepted PRISMA 2020 Statement. The primary goal of a systematic review is to minimize selection bias and accurately summarize recent findings.
2. The figure legends are relatively simplistic. The reviewer suggests that the figure legends should be expanded substantially to provide more detailed descriptions and improve readability. Moreover, higher-quality mechanistic illustrations integrating cellular and network-level alterations would further strengthen the manuscript.
3. In Line 500, Section 6, “Mechanistic Consequences and Testable Predictions,” is important but currently reads more like a conceptual perspective article. The reviewer suggests that the authors either explicitly state that these are theoretical predictions requiring future validation or strengthen this section with more direct empirical evidence to support the proposed concepts.
4. The title describes the article as a “systemic review,” which should likely be corrected to “systematic review.” Please revise accordingly.
5. Several spacing and typographical inconsistencies throughout the manuscript should be revised. For example, in Line 175, “cytochromec release” should be corrected to “cytochrome c release.” In Line 224, “planarcellpolarity” should also be revised. In addition, multiple grammatical and formatting issues are present throughout the manuscript and require careful proofreading.

Author Response

Comments and Suggestions for Authors

In this systematic review, the authors integrate developmental neurobiology and network neuroscience to conceptualize prenatal alcohol exposure as a disorder of emerging neural and functional architecture. In particular, they summarize the pharmacokinetics of ethanol during pregnancy, critical windows of vulnerability, and neuroimaging studies, and discuss implications for biomarkers, early identification, and network-informed interventions. The authors provide a comprehensive review of the literature, including recent reports published up to 2025, thereby offering an updated overview of prenatal alcohol exposure. However, several minor issues should be addressed to improve clarity and scholarly rigor.

 

-In this article, the authors describe this comprehensive review as a systematic review in the title. However, the reviewer could not find any section describing the literature search strategy, inclusion and exclusion criteria, databases searched, or timeframe considered. The reviewer suggests that the authors follow accepted systematic review standards by referencing the widely accepted PRISMA 2020 Statement. The primary goal of a systematic review is to minimize selection bias and accurately summarize recent findings.

Response: We thank the reviewer for this pertinent remark. In fact, our study is a narrative review rather than “systematic review”, we have now replaced it with “comprehensive review”.

-The figure legends are relatively simplistic. The reviewer suggests that the figure legends should be expanded substantially to provide more detailed descriptions and improve readability. Moreover, higher-quality mechanistic illustrations integrating cellular and network-level alterations would further strengthen the manuscript.

Response: We thank the reviewer for this helpful suggestion. The figure legends are now revised and expanded, and the mechanistic illustrations have been also improved in the revised manuscript as suggested.

-In Line 500, Section 6, “Mechanistic Consequences and Testable Predictions,” is important but currently reads more like a conceptual perspective article. The reviewer suggests that the authors either explicitly state that these are theoretical predictions requiring future validation or strengthen this section with more direct empirical evidence to support the proposed concepts.

Response: We thank the reviewer for this insightful comment. This section is now revised to explicitly state that the proposed mechanisms and predictions are theoretical and require further validation in future studies.

-The title describes the article as a “systemic review,” which should likely be corrected to “systematic review.” Please revise accordingly.

Response: We thank the reviewer for this pertinent remark. We apologies for any inconsistencies, in fact, our study is a narrative review rather than “systematic review”, we have now replaced it with “comprehensive review”.

-Several spacing and typographical inconsistencies throughout the manuscript should be revised. For example, in Line 175, “cytochromec release” should be corrected to “cytochrome c release.” In Line 224, “planarcellpolarity” should also be revised. In addition, multiple grammatical and formatting issues are present throughout the manuscript and require careful proofreading.

We thank the reviewer for this helpful comment. The manuscript has now undergone a thorough English editing for grammar and spelling mistakes.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript entitled “Developmental Neurotoxicity of Alcohol from Neuronal Basis to Behavioural Outcomes: a Systematic Review” is generally well written and organized, and the topic is undoubtedly relevant to the field of developmental neurobiology and neuropsychiatry. However, several conceptual and structural issues should be addressed before the manuscript can be considered for publication.

First, despite being presented as a systematic review, the manuscript does not appear to follow the methodological standards required for a true systematic review. I advise removing this term from the title.

In addition, the manuscript does not provide substantially novel insights or conceptual advances beyond what is already extensively available in the current literature regarding alcohol-induced developmental neurotoxicity and FASD-related mechanisms. The proposed integrative framework has potential value, but its  translational relevance should be more clearly articulated. Furthermore, the conception of this integrative framework should be explicitly summarized in the abstract.

Several issues related to figures and organization also require attention:

• All abbreviations used in figures should be fully described in the corresponding figure legends.
• Figure 2 contains text in Spanish.
• Figure 3 is not properly cited within the main text. Moreover, the lower portion of the figure is not sufficiently illustrative, and its explanatory purpose remains unclear. The authors should reconsider its structure.

The manuscript also presents considerable redundancy in multiple sections. Human electrophysiological and imaging findings are repeatedly discussed across different sections, generating unnecessary overlap that affects readability. Similarly, the beginning of Section 6 contains repetitive information that could be condensed to improve clarity and flow.

One of the most potentially interesting aspects of the manuscript concerns the discussion of “critical windows of vulnerability.” However, this topic is not developed in a sufficiently systematic or mechanistic manner. In particular, the final paragraph of Section 5 raises highly relevant concepts that deserve deeper discussion and should ideally be accompanied by a dedicated illustrative figure. In fact, the conceptual construction presented in this paragraph is substantially more informative and compelling than the textual content currently presented in the lower portion of Figure 3.

Importantly, the pathophysiology of FASD is deeply rooted in the vulnerability of the developing central nervous system. A critical factor determining this vulnerability is the developmental switch of GABAergic signaling from depolarizing (excitatory) to hyperpolarizing (inhibitory), commonly referred to as the “GABA shift.” The temporal dynamics of the GABA shift should be integrated into the construction of any comprehensive pathophysiological framework. Incorporating this perspective would significantly strengthen the mechanistic depth and developmental relevance of the review.

Author Response

The manuscript entitled “Developmental Neurotoxicity of Alcohol from Neuronal Basis to Behavioural Outcomes: a Systematic Review” is generally well written and organized, and the topic is undoubtedly relevant to the field of developmental neurobiology and neuropsychiatry. However, several conceptual and structural issues should be addressed before the manuscript can be considered for publication.

-First, despite being presented as a systematic review, the manuscript does not appear to follow the methodological standards required for a true systematic review. I advise removing this term from the title.

Response: We thank the reviewer for this pertinent remark. We apologies for any inconsistencies, in fact, our study is a narrative review rather than “systematic review”, we have now replaced it with “comprehensive review”.

-In addition, the manuscript does not provide substantially novel insights or conceptual advances beyond what is already extensively available in the current literature regarding alcohol-induced developmental neurotoxicity and FASD-related mechanisms. The proposed integrative framework has potential value, but its translational relevance should be more clearly articulated

Response: We thank the reviewer for this comment. We acknowledge that the individual mechanisms described in this review are well established in the literature. However, the novelty of the present work lies in its integrative conceptual framework linking these mechanisms into a unified systems-level model. We have further strengthened the translational perspective by adding a dedicated paragraph in the “Mechanistic Consequences and Testable Predictions” section as suggested.

 

-the conception of this integrative framework should be explicitly summarized in the abstract.

Response: We thank the reviewer for this suggestion. We have revised now the abstract as suggested.

 

-All abbreviations used in the figures should be described in detail in the corresponding legends.

Response: We thank the reviewer for this helpful comment. All abbreviations appearing in the figures are now defined in detail in the corresponding legend as suggested.

 

-Figure 2 contains text in Spanish.

Response: We thank the reviewer for identifying this error. The issue has been corrected, and the figure has been modified accordingly.

 

-Figure 3 is not correctly cited in the body of the text. Moreover, the lower part of the figure is not sufficiently illustrative and its explanatory purpose remains unclear. The authors should rethink its structure

Response: We thank the reviewer for these helpful comments. These issues have been now addressed in the current version of the manuscript.

 

-The manuscript also presents considerable redundancy in multiple sections. Human electrophysiological and imaging findings are repeatedly discussed across different sections, generating unnecessary overlap that affects readability. Similarly, the beginning of Section 6 contains repetitive information that could be condensed to improve clarity and flow.

Response: We thank the reviewer for this valuable comment. We have now revised the manuscript to reduce redundancies as suggested. 

 

-One of the most potentially interesting aspects of the manuscript concerns the discussion of “critical windows of vulnerability.” However, this topic is not developed in a sufficiently systematic or mechanistic manner. In particular, the final paragraph of Section 5 raises highly relevant concepts that deserve deeper discussion and should ideally be accompanied by a dedicated illustrative figure. In fact, the conceptual construction presented in this paragraph is substantially more informative and compelling than the textual content currently presented in the lower portion of Figure 3.

Response: We thank the reviewer for these helpful suggestions. We have therefore revised Section 5 to provide a more systematic and mechanistic discussion, particularly expanding the final paragraph to better integrate underlying biological processes. In addition, we have added a dedicated illustrative figure 4, as suggested.

Importantly, the pathophysiology of FASD is deeply rooted in the vulnerability of the developing central nervous system. A critical factor determining this vulnerability is the developmental switch of GABAergic signaling from depolarizing (excitatory) to hyperpolarizing (inhibitory), commonly referred to as the “GABA shift.” The temporal dynamics of the GABA shift should be integrated into the construction of any comprehensive pathophysiological framework. Incorporating this perspective would significantly strengthen the mechanistic depth and developmental relevance of the review.

Response: We thank the reviewer for this helpful suggestion. We agree that the “GABA shift” is an important developmental mechanism in shaping vulnerability of the developing CNS. We have now slightly mentioned this in the revised section “Ethanol-induced apoptotic neurodegeneration”.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed most of the major concerns raised during the first review round, and the manuscript has improved substantially.

 Major Comments

 1. One important concern remains only partially resolved. The authors state that discussion of confounding factors is beyond the scope of the review. However, prenatal tobacco exposure, maternal stres, socioeconomic adversity, nutritional deficiencies, co-exposure to other substances, and postnatal environmental influences represent major factors affecting neurodevelopment and may substantially influence network-level findings in PAE populations. At minimum, a brief discussion acknowledging these confounders as important limitations of the current literature would strengthen the manuscript.

 2. The revised manuscript more clearlly distinguishes evidence-based findings from theoretical extrapolations, and the figure legends appropriately identify speculative pathways. Nevertheless, the central concept of FASD as a “disorder of emerging neuro-computational architecture” remains primarily a conceptual synthesis rather than a directly validated model. The Discussion and Conclusion sections would benefit from further emphasizing that this framework represents a promising hypothesis that requires future empirical validation.

 Minor Comments

 1. Although the manuscript has undergone language revision, several minor issues remain and should be corrected during final proofreading. Examples that include occasional formatting inconsistencies and residual typographical errors. A final professional language check is recomended.

 2. Figure Complexity

The quality and clarity of the figures have improved substantially. Further simplification could improve readability and accessibility for readers.

 3. Critical Evaluation of the Literature

The revised version includes additional discusion of methodological limitations and conflicting findings. Nevertheless, the review still tends to emphasize evidence supporting the proposed framework. A slightly more extensive discussion of inconsistencies across neuroimaging studies, limitations of connectomic analyses, and reproducibility challenges would further improve balance.

Summing up, the authors have successfully addressed the majority of the concernss raised during the previous review. The manuscript is now considerably stronger, particularly with respect to terminology, figure presentation, translational interpretation, and differentiation between established evidence and conceptual hypotheses. The remaining issues are relatively minor, can be addresed without substantial restructuring of the manuscript.

Comments on the Quality of English Language

 1. Although the manuscript has undergone language revision, several minor issues remain and should be corrected during final proofreading. Examples that include occasional formatting inconsistencies and residual typographical errors. A final professional language check is recomended.

Author Response

The authors have addressed most of the major concerns raised during the first review round, and the manuscript has improved substantially.

 Major Comments

1-One important concern remains only partially resolved. The authors state that discussion of confounding factors is beyond the scope of the review. However, prenatal tobacco exposure, maternal stres, socioeconomic adversity, nutritional deficiencies, co-exposure to other substances, and postnatal environmental influences represent major factors affecting neurodevelopment and may substantially influence network-level findings in PAE populations. At minimum, a brief discussion acknowledging these confounders as important limitations of the current literature would strengthen the manuscript.

Response: We thank the reviewer for this important comment. We have added a paragraph to the revised version of the manuscript acknowledging these confounders as significant limitations of the current literature. It is now corrected accordingly.

2-The revised manuscript more clearlly distinguishes evidence-based findings from theoretical extrapolations, and the figure legends appropriately identify speculative pathways. Nevertheless, the central concept of FASD as a “disorder of emerging neuro-computational architecture” remains primarily a conceptual synthesis rather than a directly validated model. The Discussion and Conclusion sections would benefit from further emphasizing that this framework represents a promising hypothesis that requires future empirical validation.

Response: We thank the reviewer for this thoughtful comment. We have revised the Conclusion sections to emphasize the hypothetical nature of this framework and the need for future empirical validation. It is now corrected accordingly.

Minor Comments

1-Although the manuscript has undergone language revision, several minor issues remain and should be corrected during final proofreading. Examples that include occasional formatting inconsistencies and residual typographical errors. A final professional language check is recomended.

Response: We thank the reviewer for this comment. The manuscript has been proofread and corrected by a native English speaker. It is now corrected accordingly.

2-Figure Complexity

The quality and clarity of the figures have improved substantially. Further simplification could improve readability and accessibility for readers.

Response: We sincerely thank the reviewer for this positive assessment and for acknowledging the substantial improvement in the quality and clarity of the figures. We appreciate the suggestion that further simplification may enhance readability for readers. However, at this stage of the revision process, additional modifications to the figures may affect the presentation of essential information.

3-Critical Evaluation of the Literature

The revised version includes additional discusion of methodological limitations and conflicting findings. Nevertheless, the review still tends to emphasize evidence supporting the proposed framework. A slightly more extensive discussion of inconsistencies across neuroimaging studies, limitations of connectomic analyses, and reproducibility challenges would further improve balance.

Response: We thank the reviewer for this valuable observation. We have now added explicit discussion of methodological heterogeneity and reproducibility limitations. These additions are highlighted in the revised manuscript.

Summing up, the authors have successfully addressed the majority of the concernss raised during the previous review. The manuscript is now considerably stronger, particularly with respect to terminology, figure presentation, translational interpretation, and differentiation between established evidence and conceptual hypotheses. The remaining issues are relatively minor, can be addresed without substantial restructuring of the manuscript.

--Comments on the Quality of English Language

-Although the manuscript has undergone language revision, several minor issues remain and should be corrected during final proofreading. Examples that include occasional formatting inconsistencies and residual typographical errors. A final professionallanguage check isrecomended.

Response: We thank the reviewer for this comment. The manuscript has been proofread and corrected by a native English speaker. It is now corrected accordingly.