Neuroanatomical Correlates of Anxiety Disorders and Their Implications in Manifestations of Cognitive and Behavioral Symptoms

1

“the article doesn't summarize and clarify the specific anatomical changes in the different regions: with only a few exceptions, "alterations" and "differences" are mentioned generally but are not explained - changes in white or grey matter, is it about increased or decreased volume, etc.”

We appreciate the reviewer pointing out the lack of clarification on the types of changes sometimes presented. The information got lost during one of the editing steps before submission, and the mistake has been corrected.

“The selection process of the reviewed studies is unclear. The authors mention that they selected 17 studies but do not provide information on the initial number of studies (17 out of how many?). What were the search criteria? What databases were used? What were the criteria for refinement, i.e. on what was the final decision for inclusion or exclusion based?”

This information was indeed missing, and we appreciate the comment. We have corrected this by addressing methodology and adding the specific considerations for the search criteria; lines 105-137.

“The text (line 118) and Table 1. describing the included studies contradict each other. According to the text, patients with SAD were n=300, and GAD were n=139. The numbers in the table, however, sum up to 268 patients with SAD and 158 patients with GAD”

Thank you for pointing this out. The calculation error was due previous editing of the text before submission. The numbers have been corrected.

“The age range in line 119 is unclear: "17,86 to 58,70 years old" is a bizarre way of describing an age range.”

 We agree that the numbers are odd. They represent the result of statistical analysis, that was not properly described. The statement has been reformulated in the text; line 149

“The authors pay a lot of attention to the number of patients in the different studies, but later in the review, these numbers are not discussed. Their significance for the review remains unclear and should be clarified: Were they part of the selection procedure? Did the authors intend to assess the incidence and/or importance of the reviewed alterations?”

Thank you for pointing this out. The exact numbers were not particularly relevant for the conclusion. They should indicate the representative value surrounding congruencies in results, as the main goal of the paper was to “filter” congruent findings in literature.

“The presence of comorbidities and the number of patients with comorbidities in the reviewed studies are thoroughly described. Yet, it remains unclear what is the significance of these numbers for the reviewed topic.”

This is indeed an issue that could possibly lead to confusion, and we are thankful for this note. The lack of clarity mentioned by the reviewer has occurred during editing before submission. To address that issue, we added to “limitations”, explaining how these comorbidities could act as confounders, interfering with symptomology and differential diagnose.

“In section "2. Changes in prefrontal areas" and the subsequent sections 3 to 5 (describing the findings on specific regions (parietal lobe, temporal lobe, insular cortex), the nature of the structural changes or the connectivity alterations are not explained. It is only mentioned that there are "structural changes" and "connectivity alterations", but for most areas, there is no indication of their character (at least increase or decrease of grey matter, cortical thickness or white matter volume).”

This issue has been addressed by the changes made to accommodate the first comment.

"7. Limits and future perspectives" mentions variations and incoherence between studies. However, these variations and incoherence are not discussed in the text, i.e. it is unclear how much different studies agree or contradict each other and on what findings specifically.”

Thank you for pointing this out. The inconsistencies mentioned relate to the appearance of tendencies, instead of significant volumetric differences, from one paper to another, which is why they were not described in detail. This issue has been addressed by emphasizing this in both the introduction and section 7, as pointed by the reviewer. The incoherence on the reports of AM volumetric changes was poorly described in the text. The term incoherence is indeed not appropriate in this context and the paragraph in question has been restructured to enhance clarity.

“Section "5. Conclusions" is wrongly numbered in the text. It should be 8. as it follows after 7.”

We apologize for this overlooking this before submission and thank the reviewer for pointing this out. The mistake has been corrected.

“The citation "7 . Tyrer, P.; Baldwin, D. Generalised Anxiety Disorder. 2006, 368, 11. " is incomplete. Probably, the authors meant this one:
Tyrer, P. and Baldwin, D. S. (2006). Generalized anxiety disorder. The Lancet, 368(9553), 2156-2166. https://doi.org/10.1016/s0140-6736(06)69865-6”

Thank you for pointing this out. The citation in question has been corrected. We apologize for this overlooking.

2

“Page 1, Paragraph 3: The manuscript should incorporate the most recent classification system, DSM-5-TR (APA, 2022), instead of DSM-5”

We thank the reviewer for pointing this out. The mistake has been corrected.

“Page 3, Paragraph 2: The manuscript lacks clarity on inclusion and exclusion criteria. Additionally, quantitative information pertaining to the grouping of studies should be excluded from a narrative review, as it is more indicative of a systematic review.”

We appreciate the input. This issue has been addressed by the corrections done as answer to the second comment of the first reviewer.

“Page 3, Paragraph 3: The final sentence regarding the number of different scales should be relocated to the limitations section.”

Thank you for the comment. We have added this to “limitations” with further clarification.

“The overall structure of the section deviates from the pertinent research question. The inclusion of irrelevant information on functional characteristics of healthy individuals and patients detracts from the paper's focus. Moreover, there is a notable absence of references to the type of anatomical change identified and the method employed for identification.”

Thank you for the comment, and we agree that an excess of exemplification may diverge from the main focus of the paper. We tried to re-edit the text to accommodate this view.

Regarding the second part of this comment, in the editing process prior to the first submission, some references were removed to avoid redundancy. We also clarified this following the first comment of the first reviewer.

“The section lacks substantive discussion on the findings of the paper and fails to draw comparisons with background knowledge.”

Thank you for pointing that out, this issue was already addressed in accordance with the comments of the first reviewer.

I strongly recommend updating the references, as there is a significant gap of knowledge in the field under investigation. Here are a couple of suggestions the authors can check:

Disrupted brain gray matter connectome in social anxiety disorder: a novel individualized structural covariance network analysis [2023]

https://pubmed.ncbi.nlm.nih.gov/37381581/ 

Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder [2017]

https://pubmed.ncbi.nlm.nih.gov/30140607/  

Subcortical brain volumes, cortical thickness and cortical surface area in families genetically enriched for social anxiety disorder - A multiplex multigenerational neuroimaging study [2018]

https://pubmed.ncbi.nlm.nih.gov/30266294/ 

From anatomy to function: the role of the somatosensory cortex in emotional regulation

[2019]

https://pubmed.ncbi.nlm.nih.gov/30540029/ 

We appreciate and agree with the suggestions on updating references. We would like to thank the reviewer for recommending those papers. The text was edited to integrate up-to-date findings.

See highlighted addition

“The organization of this section, segmented by aspects of brain function affected by anxiety disorders, deviates from the main body's organization by brain region, resulting in a considerable degree of confusion.”

The authors completely agree with this comment, and we appreciate the congruence of thought between us and the reviewer as an expert on the field. This section has been re-structured to provide a clearer image of the issues addressed in the paper.

“Page 1, Paragraph 3: The manuscript should incorporate the most recent classification system, DSM-5-TR (APA, 2022), instead of DSM-5”

We thank the reviewer for pointing this out. The mistake has been corrected.

Comment v.2. The respective reference in the reference list has not been corrected.

“Page 3, Paragraph 2: The manuscript lacks clarity on inclusion and exclusion criteria. Additionally, quantitative information pertaining to the grouping of studies should be excluded from a narrative review, as it is more indicative of a systematic review.”

We appreciate the input. This issue has been addressed by the corrections done as answer to the second comment of the first reviewer.

Comment v.2. Inclusion and exclusion criteria are now included in the manuscript. The methodology remains that of a systematic and not a narrative review. Please proceed with the appropriate adjustments.

“Page 3, Paragraph 3: The final sentence regarding the number of different scales should be relocated to the limitations section.”

Thank you for the comment. We have added this to “limitations” with further clarification.

“The overall structure of the section deviates from the pertinent research question. The inclusion of irrelevant information on functional characteristics of healthy individuals and patients detracts from the paper's focus. Moreover, there is a notable absence of references to the type of anatomical change identified and the method employed for identification.”

Thank you for the comment, and we agree that an excess of exemplification may diverge from the main focus of the paper. We tried to re-edit the text to accommodate this view.

Regarding the second part of this comment, in the editing process prior to the first submission, some references were removed to avoid redundancy. We also clarified this following the first comment of the first reviewer.

Comment v.2. There are problems to be fixed regarding this issue. There are still sections (eg. section 3: Abnormalities in the parietal lobe) where there is no reference at all to anatomical changes, or other (eg. section 4: Changes in the temporal lobe), where structural changes are downgraded in favor of functional characteristics and responses. Given your research question (lines 103-104), anatomical changes should be the core for developing your paper’s sections. The other option is to properly adapt your research question.