Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a strong, timely, and conceptually ambitious Perspective that integrates several bodies of literature that are too often considered separately, including transdiagnostic emotion regulation, neuroimaging, individual differences, developmental adversity, and neuromodulation. I found the manuscript engaging, well structured, and genuinely useful. In particular, the proposed Layered Transdiagnostic Model of Emotion Regulation (LTM-ER) provides a clear organizing framework that distinguishes a shared transdiagnostic core, disorder-specific neural fingerprints, and individual-difference moderators while generating explicit and testable predictions.

I also appreciated the translational orientation of the manuscript. Rather than stopping at a descriptive synthesis, the author derives practical implications for research design, neuromodulation studies, and clinical assessment. The emphasis on multimodal outcomes and individual heterogeneity is particularly valuable. Overall, I view the manuscript very positively. My comments below are minor and are primarily intended to improve conceptual precision and calibrate a few claims.

1. Calibration of some claims. A few expressions, such as “essentially settled” and similarly strong formulations regarding the maturity of the evidence, could be slightly moderated. Given the methodological heterogeneity across diagnoses, measures, tasks, and neuroimaging paradigms, formulations such as “strongly supported by converging evidence” may provide a more appropriately calibrated interpretation without weakening the central argument.

2. Behavioral versus neural transdiagnostic evidence. The manuscript could distinguish somewhat more explicitly between the particularly robust behavioral evidence for transdiagnostic emotion-regulation impairment and the necessarily more heterogeneous evidence supporting a common neural core. A brief clarification that Layer 1 represents a convergent model rather than an invariant neural circuit across all disorders would strengthen the framework.

3. Scope of emotion-regulation strategies. Much of the neural and neuromodulation evidence discussed concerns cognitive reappraisal. Although explicit and implicit regulation are considered, it may be useful to acknowledge briefly that the proposed neural architecture is currently most strongly supported for reappraisal-related processes and should not necessarily be generalized to all emotion-regulation strategies.

4. “Disorder-specific fingerprints.” This is a useful and intuitive concept, but I suggest clarifying that these fingerprints refer to relative patterns of divergence superimposed on the shared core rather than validated diagnostic biomarkers or uniquely identifying neural signatures.

5. Clinical translation. The practical recommendations are a particular strength of the manuscript. However, some proposals—for example, transdiagnostic screening of ER capacity or the prioritization of shared-core interventions—might be framed explicitly as model-derived recommendations requiring prospective validation rather than current standards of clinical care.

6. Layer 3 moderators. The conceptual status of the variables included in Layer 3 could be clarified slightly. Developmental history and dispositional characteristics are person-level moderators, whereas stimulation parameters are intervention-level characteristics. Distinguishing these two categories within Layer 3 could make the model conceptually cleaner without requiring structural changes.

7. Early adversity and neural mechanisms. The section on early adversity is valuable. I suggest distinguishing more explicitly between evidence directly linking adversity to neural ER circuitry and evidence linking adversity to behavioral or psychological mediators of dysregulation, for which a neural pathway may currently be plausible but not directly demonstrated.

8. Neuromodulation. I appreciated the balanced treatment of parameter-dependent and null findings. It may nevertheless be useful to state more explicitly that the current evidence arguably supports NIBS particularly strongly as a mechanistic probe of ER circuitry, whereas its role as an established transdiagnostic therapeutic intervention remains less mature.

9. Testability of the LTM-ER. The five predictions are an important strength because they move the model beyond descriptive synthesis. The manuscript could briefly distinguish predictions that already receive indirect support from existing evidence from those that represent genuinely prospective hypotheses requiring direct empirical testing.

10. Minor wording issue regarding novelty. I recommend a light editorial check of expressions implying priority or exclusivity, such as “the first disorder-by-disorder reading,” unless these claims can be comprehensively substantiated. More cautious formulations such as “to our knowledge” would preserve the novelty claim while avoiding unnecessary overstatement.

Author Response

Reviewer 1

 

 

This is a strong, timely, and conceptually ambitious Perspective that integrates several bodies of literature that are too often considered separately, including transdiagnostic emotion regulation, neuroimaging, individual differences, developmental adversity, and neuromodulation. I found the manuscript engaging, well structured, and genuinely useful. In particular, the proposed Layered Transdiagnostic Model of Emotion Regulation (LTM-ER) provides a clear organizing framework that distinguishes a shared transdiagnostic core, disorder-specific neural fingerprints, and individual-difference moderators while generating explicit and testable predictions.

I also appreciated the translational orientation of the manuscript. Rather than stopping at a descriptive synthesis, the author derives practical implications for research design, neuromodulation studies, and clinical assessment. The emphasis on multimodal outcomes and individual heterogeneity is particularly valuable. Overall, I view the manuscript very positively. My comments below are minor and are primarily intended to improve conceptual precision and calibrate a few claims.

 

 

I sincerely thank the reviewer for the thoughtful and encouraging assessment of the manuscript and for recognizing the value of the Layered Transdiagnostic Model of Emotion Regulation (LTM-ER). The suggestions have helped me clarify the evidential status of the model, distinguish levels of explanation, and frame its translational implications more precisely. I have addressed each comment below.

 

Comment #1: Calibration of some claims. A few expressions, such as “essentially settled” and similarly strong formulations regarding the maturity of the evidence, could be slightly moderated. Given the methodological heterogeneity across diagnoses, measures, tasks, and neuroimaging paradigms, formulations such as “strongly supported by converging evidence” may provide a more appropriately calibrated interpretation without weakening the central argument.

 

Response #1: I agree that several formulations conveyed greater certainty than warranted by the methodological diversity of the literature. I have moderated these statements in the Introduction, Section 3, and Conclusions. In particular, I have replaced language suggesting that the empirical question is “essentially settled” or that neural convergence is “established rather than provisional” with wording that recognizes substantial support while preserving uncertainty about mechanisms, generalizability, and clinical application.

 

 

Comment #2: Behavioral versus neural transdiagnostic evidence. The manuscript could distinguish somewhat more explicitly between the particularly robust behavioral evidence for transdiagnostic emotion-regulation impairment and the necessarily more heterogeneous evidence supporting a common neural core. A brief clarification that Layer 1 represents a convergent model rather than an invariant neural circuit across all disorders would strengthen the framework.

 

Response #2: I have clarified that the extensive behavioral evidence, particularly evidence based on self-reported ER difficulties and habitual strategy use, does not by itself establish a common neural substrate. Layer 1 is now described explicitly as a model of partial convergence across the populations and paradigms studied, rather than an invariant circuit present in every disorder or individual. This distinction is reflected in Sections 3 and 6 and in the description of Figure 1.

 

 

Comment #3: Scope of emotion-regulation strategies. Much of the neural and neuromodulation evidence discussed concerns cognitive reappraisal. Although explicit and implicit regulation are considered, it may be useful to acknowledge briefly that the proposed neural architecture is currently most strongly supported for reappraisal-related processes and should not necessarily be generalized to all emotion-regulation strategies.

 

Response #3: Although the manuscript discusses explicit and implicit regulation, much of the neural and interventional evidence informing the proposed architecture concerns cognitive reappraisal. I have added a scope clarification in Section 2 and qualified the generalization of the model in Section 6. This preserves the broader conceptual relevance of the LTM-ER while making clear that its applicability across strategies requires further testing.

 

Comment #4: “Disorder-specific fingerprints.” This is a useful and intuitive concept, but I suggest clarifying that these fingerprints refer to relative patterns of divergence superimposed on the shared core rather than validated diagnostic biomarkers or uniquely identifying neural signatures.

 

Response #4: I appreciate this clarification. I retain the term “fingerprints” as an organizing concept but now define it as referring to relative, diagnosis-associated patterns of divergence superimposed on the proposed shared core. These patterns are not presented as validated diagnostic biomarkers, uniquely identifying signatures, or established tools for individual classification. I have also clarified that some examples concern familial risk or broader emotional processing, which limits their interpretation as abnormalities of ER in diagnosed patients.

 

Comment #5: Clinical translation. The practical recommendations are a particular strength of the manuscript. However, some proposals—for example, transdiagnostic screening of ER capacity or the prioritization of shared-core interventions—might be framed explicitly as model-derived recommendations requiring prospective validation rather than current standards of clinical care.

 

Response #5: I agree that the distinction between model-derived proposals and established clinical practice needed to be more explicit. I have reframed the recommendations in Sections 7 and 8.3 and Table 3 as directions for prospective evaluation. In particular, I have removed the suggestion that shared-core interventions should already be considered first-line across diagnoses. The revised text emphasizes that the clinical value of the proposed assessment and treatment-selection framework remains to be established.

 

Comment #6: Layer 3 moderators. The conceptual status of the variables included in Layer 3 could be clarified slightly. Developmental history and dispositional characteristics are person-level moderators, whereas stimulation parameters are intervention-level characteristics. Distinguishing these two categories within Layer 3 could make the model conceptually cleaner without requiring structural changes.

 

Response #6: Thank you for this helpful observation. I have clarified the distinction between person-level characteristics and characteristics of the task, intervention, and measurement context. Developmental history and dispositional tendencies remain person-level factors, whereas stimulation settings are intervention-level factors. Regulatory mode is treated as a task or process characteristic, and the outcome channel as a measurement characteristic. These distinctions retain the three-layer structure while avoiding the implication that all sources of variability are individual traits or empirically established moderators.

 

Comment #7:  Early adversity and neural mechanisms. The section on early adversity is valuable. I suggest distinguishing more explicitly between evidence directly linking dversity to neural ER circuitry and evidence linking adversity to behavioral or psychological mediators of dysregulation, for which a neural pathway may currently be plausible but not directly demonstrated.

 

Response #7:   I agree that the previous wording moved too quickly from psychological mediation findings to a neural interpretation. I have revised Section 4 to distinguish statistical associations involving behavioral and psychological variables from direct evidence concerning neural ER circuitry. The proposed connection between these levels is now identified as a hypothesis. I have also moderated causal wording in the discussion of the cohort findings and in the Conclusions.

 

Comment #8:  Neuromodulation. I appreciated the balanced treatment of parameter-dependent and null findings. It may nevertheless be useful to state more explicitly that the current evidence arguably supports NIBS particularly strongly as a mechanistic probe of ER circuitry, whereas its role as an established transdiagnostic therapeutic intervention remains less mature.

Response #8:  Although Section 5 already discusses NIBS as a mechanistic probe, I agree that the distinction between mechanistic information and therapeutic efficacy should be clearer. I have strengthened this distinction and qualified language suggesting established efficacy. The revised text emphasizes that changes in laboratory ER performance, neural activity, or autonomic measures do not by themselves establish durable clinical benefit across diagnoses.

 

Comment #9:  Testability of the LTM-ER. The five predictions are an important strength because they move the model beyond descriptive synthesis. The manuscript could briefly distinguish predictions that already receive indirect support from existing evidence from those that represent genuinely prospective hypotheses requiring direct empirical testing.

 

Response #9: I agree that the five predictions should be distinguished according to the evidence currently motivating them. I have clarified that existing studies provide indirect support for aspects of the predictions rather than validation of the LTM-ER as an integrated model. Predictions 1 and 4 are motivated by findings of cross-diagnostic convergence and parameter-dependent stimulation effects. Predictions 2, 3, and 5 involve further inferential steps concerning residual diagnostic information, neural developmental pathways, and differential treatment transfer. All five require direct testing in their stated form.

 

 

Comment #10: Minor wording issue regarding novelty. I recommend a light editorial check of expressions implying priority or exclusivity, such as “the first disorder-by-disorder reading,” unless these claims can be comprehensively substantiated. More cautious formulations such as “to our knowledge” would preserve the novelty claim while avoiding unnecessary overstatement.

 

Response #10: I agree and have removed priority and exclusivity claims that would require a comprehensive historical comparison to substantiate. Rather than describing the manuscript as providing “the first disorder-by-disorder reading,” the revised Introduction states its contribution in terms of the organization and integration offered by the LTM-ER.

I thank the reviewer again for these constructive suggestions, which have improved the conceptual precision of the manuscript while preserving its central argument and translational aims.

Warm regards,

Sandra Carvalho

 

Reviewer 2 Report

Comments and Suggestions for Authors

This Perspective offers a useful integration of transdiagnostic emotion-regulation research, individual differences, and neuromodulation. The three-layer framework and five predictions provide a constructive organising structure. However, the manuscript sometimes presents a proposed synthesis as an established mechanism and moves too quickly from group-level findings to clinical recommendations.

1) The manuscript treats amygdala/insula hyperactivation and anterior cingulate hypoactivation as a robust transdiagnostic pattern. Importantly, Wong et al. (2026) found no significant hypoactivation using canonical ALE; the ACC finding emerged through exploratory Bayesian thresholding and did not survive standard cluster-level family-wise error correction. The text, Figure 1, and Table 2 should reflect this distinction consistently. More generally, emotional reactivity, habitual strategy use, self-reported dysregulation, and task-based regulatory performance should not be treated as interchangeable evidence for one mechanism. 

2) Layer 3 currently combines person-level characteristics with experimental variables, including stimulation parameters and outcome measures. Separate individual moderators from intervention and measurement factors. Furthermore, specify how shared and diagnosis-associated neural components would be estimated, what would falsify their proposed separation, and how diagnostic classification would be evaluated in independent data while accounting for symptom severity, comorbidity, medication, and site effects. These clarifications would strengthen the model without requiring new empirical analyses in a Perspective.

3) Section 4 interprets the Portuguese cohort findings as showing how early adversity produces subsequent regulatory difficulties. However, the cited study of emotion regulation, coping, and personality is cross-sectional and explicitly acknowledges that it cannot draw causal conclusions. Describe these results as statistical indirect associations compatible with—but not establishing—the proposed developmental pathway. Also, Prediction 3 is labelled “Developmental Moderation” but specifies mediation; these are different hypotheses and require different analyses.

4) Although Section 7 acknowledges limited biomarker validation, Section 8.3 recommends shared-core interventions as first-line options across diagnoses. Present this as a research proposition rather than an established treatment-selection rule. Likewise, the reported heart-rate reduction also occurred without explicit reappraisal, while the cited P3 findings concern oddball and working-memory tasks. Neither observation, by itself, establishes an ER-specific biomarker. Clearly separate physiological modulation, target engagement, improved regulatory performance, and clinically meaningful benefit.

5) Include a brief explanation of the narrative evidence-selection approach, reduce repeated claims of novelty and convergence, and separate the dmPFC and IFG in Figure 1 rather than representing them as a single anatomical node. The figure’s numerical citations should also match the reference list.

6) Sleep-related physiological variation may represent an additional source of individual differences relevant to Layer 3. Goldstein and Walker (2014) proposed a framework linking sleep, particularly rapid-eye-movement sleep, to affective homeostasis. Federico et al. (2022) found that poorer self-reported sleep quality was associated with altered resting-state connectivity in limbic and fronto-temporo-parietal networks, alongside greater anxiety and depressive symptoms in healthy adults. Complementing this observational evidence, Tamm et al. (2019) found that sleep restriction reduced self-rated regulation success during a cognitive-reappraisal task in young adults, without detectable changes in brain activation or connectivity. Together, these findings motivate prospective tests of whether sleep quality helps explain individual differences in regulatory performance and neural measures, rather than assuming a fixed relationship between the two.

References

Federico, G., et al. (2022). Self-Reported Sleep Quality Across Age Modulates Resting-State Functional Connectivity in Limbic and Fronto-Temporo-Parietal Networks: An Exploratory Cross-Sectional fMRI Study. Frontiers in Aging Neuroscience, 14, 806374. DOI: 10.3389/fnagi.2022.806374.

Goldstein, A. N., & Walker, M. P. (2014). The role of sleep in emotional brain function. Annual Review of Clinical Psychology, 10, 679–708. DOI: 10.1146/annurev-clinpsy-032813-153716. 

Tamm, S., et al. (2019). Sleep restriction caused impaired emotional regulation without detectable brain activation changes—a functional magnetic resonance imaging study. Royal Society Open Science, 6(3), 181704. DOI: 10.1098/rsos.181704.

Author Response

This Perspective offers a useful integration of transdiagnostic emotion-regulation research, individual differences, and neuromodulation. The three-layer framework and five predictions provide a constructive organising structure. However, the manuscript sometimes presents a proposed synthesis as an established mechanism and moves too quickly from group-level findings to clinical recommendations.

 

Response: I thank the reviewer for the careful assessment and constructive suggestions. These comments have helped me distinguish the evidence supporting individual elements of the framework from the hypotheses proposed by the LTM-ER, clarify its empirical testability, and qualify its clinical implications.

 

Comment #1: The manuscript treats amygdala/insula hyperactivation and anterior cingulate hypoactivation as a robust transdiagnostic pattern. Importantly, Wong et al. (2026) found no significant hypoactivation using canonical ALE; the ACC finding emerged through exploratory Bayesian thresholding and did not survive standard cluster-level family-wise error correction. The text, Figure 1, and Table 2 should reflect this distinction consistently. More generally, emotional reactivity, habitual strategy use, self-reported dysregulation, and task-based regulatory performance should not be treated as interchangeable evidence for one mechanism. 

 

Response #1: Thank you for identifying this important error. I have corrected the presentation of Wong et al. (2026), distinguishing the canonical ALE hyperactivation findings from the exploratory Bayesian hypoactivation findings. The ACC result is no longer presented as a robust component of an established transdiagnostic signature. The correction is carried through the text, Figure 1 and its legend, Tables 1 and 2, and Prediction 1. I have also distinguished emotional reactivity, habitual strategy use, self-reported dysregulation, and task-based regulatory performance. These provide related but non-interchangeable evidence, and their correspondence with a shared neural component is now explicitly treated as a hypothesis requiring direct testing.

 

 

Comment #2: Layer 3 currently combines person-level characteristics with experimental variables, including stimulation parameters and outcome measures. Separate individual moderators from intervention and measurement factors. Furthermore, specify how shared and diagnosis-associated neural components would be estimated, what would falsify their proposed separation, and how diagnostic classification would be evaluated in independent data while accounting for symptom severity, comorbidity, medication, and site effects. These clarifications would strengthen the model without requiring new empirical analyses in a Perspective.

 

Response #2: I agree. Layer 3 now distinguishes person-level characteristics from task and intervention factors, while outcome channels are identified separately as measurement characteristics. These variables are not assumed to have equivalent conceptual roles or established moderating effects. I have also added a proposed analytical approach for testing Layers 1 and 2. This describes estimating shared and diagnosis-associated components in participant-level data using matched paradigms, comparing the layered model with simpler alternatives, and evaluating diagnostic information in independent data. The revised text specifies that feature selection, component estimation, and confound adjustment must remain within the training data. It also addresses symptom severity, comorbidity, medication, and site effects and identifies findings that would count against the proposed separation. These additions describe prospective tests rather than analyses performed in this Perspective.

 

Comment #3: Section 4 interprets the Portuguese cohort findings as showing how early adversity produces subsequent regulatory difficulties. However, the cited study of emotion regulation, coping, and personality is cross-sectional and explicitly acknowledges that it cannot draw causal conclusions. Describe these results as statistical indirect associations compatible with—but not establishing—the proposed developmental pathway. Also, Prediction 3 is labelled “Developmental Moderation” but specifies mediation; these are different hypotheses and require different analyses.

 

Response #3: I agree that the original wording implied a developmental causal interpretation not established by the cited cohort findings. Section 4 now describes statistical indirect associations and explicitly acknowledges that cross-sectional mediation cannot establish temporal ordering, causality, or mediation through neural ER circuitry. Prediction 3 has been renamed “Developmental Pathways” and clarified as a prospective mediation hypothesis. The revised text distinguishes this hypothesis from moderation, which would require a separate interaction test. Corresponding wording has also been adjusted in the model description and tables.

 

Comment #4: Although Section 7 acknowledges limited biomarker validation, Section 8.3 recommends shared-core interventions as first-line options across diagnoses. Present this as a research proposition rather than an established treatment-selection rule. Likewise, the reported heart-rate reduction also occurred without explicit reappraisal, while the cited P3 findings concern oddball and working-memory tasks. Neither observation, by itself, establishes an ER-specific biomarker. Clearly separate physiological modulation, target engagement, improved regulatory performance, and clinically meaningful benefit.

 

Response #4: Thank you. Section 8.3 and Table 3 now present the proposed clinical applications as questions for prospective evaluation. The suggestion that shared-core interventions should already be prioritized as first-line treatments across diagnoses has been removed. I have also clarified that heart-rate changes and P3 modulation do not, by themselves, establish ER-specific biomarkers. The text now acknowledges that the heart-rate reduction occurred without explicit reappraisal and that the cited P3 findings arose from oddball and working-memory tasks. Physiological modulation, engagement of the intended neural target, improved regulatory performance, and clinically meaningful benefit are distinguished as separate outcomes requiring appropriate evidence. The biomarker discussion in Section 7 has been revised accordingly.

 

 

Comment #5: Include a brief explanation of the narrative evidence-selection approach, reduce repeated claims of novelty and convergence, and separate the dmPFC and IFG in Figure 1 rather than representing them as a single anatomical node. The figure’s numerical citations should also match the reference list.

 

Response #5: I have added a brief account of the narrative scope and evidence-selection rationale, identifying the article as a selective conceptual synthesis rather than a systematic review. I have reduced repeated statements of novelty and convergence and made the distinction between empirical findings and model-derived propositions more explicit. Figure 1 now represents the dmPFC and IFG separately, with the legend distinguishing their anatomical locations and the evidence motivating their inclusion. The figure also differentiates findings according to their evidential status. Its numerical citations have been checked against the revised reference list.

 

Comment #6: Sleep-related physiological variation may represent an additional source of individual differences relevant to Layer 3. Goldstein and Walker (2014) proposed a framework linking sleep, particularly rapid-eye-movement sleep, to affective homeostasis. Federico et al. (2022) found that poorer self-reported sleep quality was associated with altered resting-state connectivity in limbic and fronto-temporo-parietal networks, alongside greater anxiety and depressive symptoms in healthy adults. Complementing this observational evidence, Tamm et al. (2019) found that sleep restriction reduced self-rated regulation success during a cognitive-reappraisal task in young adults, without detectable changes in brain activation or connectivity. Together, these findings motivate prospective tests of whether sleep quality helps explain individual differences in regulatory performance and neural measures, rather than assuming a fixed relationship between the two.

 

Response #6:  I have incorporated sleep as a candidate source of person-level and within-person physiological variation relevant to Layer 3. The added discussion distinguishes the theoretical framework proposed by Goldstein and Walker (2014), the cross-sectional resting-state findings of Federico et al. (2022), and the experimental findings of Tamm et al. (2019) The revised text emphasizes that these studies motivate prospective tests of sleep-related variation rather than establish a fixed relationship between regulatory performance and neural measures. In particular, the absence of detectable neural changes accompanying reduced self-rated regulation success in Tamm et al. is retained as an important qualification. Sleep is therefore presented as a candidate factor to investigate, not an established moderator of the LTM-ER.

 

References were integrated in the manuscript:

Federico, G., et al. (2022). Self-Reported Sleep Quality Across Age Modulates Resting-State Functional Connectivity in Limbic and Fronto-Temporo-Parietal Networks: An Exploratory Cross-Sectional fMRI Study. Frontiers in Aging Neuroscience, 14, 806374. DOI: 10.3389/fnagi.2022.806374.

Goldstein, A. N., & Walker, M. P. (2014). The role of sleep in emotional brain function. Annual Review of Clinical Psychology, 10, 679–708. DOI: 10.1146/annurev-clinpsy-032813-153716. 

Tamm, S., et al. (2019). Sleep restriction caused impaired emotional regulation without detectable brain activation changes—a functional magnetic resonance imaging study. Royal Society Open Science, 6(3), 181704. DOI: 10.1098/rsos.181704.

 

 

I thank the reviewer again for these suggestions, which have improved the accuracy, conceptual clarity, and testability of the manuscript.

Warm regards,

Sandra Carvalho

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

In the opinion of this reviewer, the manuscript can now be accepted for publication.