Stress: Influences and Determinants of Psychopathology
Round 1
Reviewer 1 Report (Previous Reviewer 2)
Comments and Suggestions for AuthorsThe article has been significantly improved and now deserves publication
in the Encyclopedia.Tables have been added and the graphics have been
improved. I recommend it for publication.
Author Response
We are very thankful for taking the time to review this manuscript and for your positive comments on it.
Reviewer 2 Report (New Reviewer)
Comments and Suggestions for AuthorsThis review provides a nice summary of the effects of stress and contributing factors to psychopathology, revealing the various connections, viewpoints, and complexities of neurochemistry and cerebral functioning in a brain-region-specific manner.
The review is a relevant contribution to a comprehensive understanding of stress and pathology and is of overall importance as an overview of research work lacking in the field. However, I have several remarks/suggestions that could ameliorate the data presentation/interpretation of the paper:
In Part 2.1.1. Circuits Involved, a schematic diagram of the neural circuits underlying stress would be helpful in better understanding.
In part 2.2.1, authors described decreased HPA activity and repeated exposure to the same homotypic or heterotypic stressors (pp. 266-276), whereby authors state only an increased level of corticosteroids. However, there are studies where adding heterotypic acute stress to already existing chronic stress does not increase corticosterone levels (animal studies) due to compromised HPA activity as a consequence of impaired glucocorticoid receptor (GR)-mediated feedback inhibition in the brain regions (hippocampus and prefrontal cortex, Filipović et al., 2005). Such changes are also supported by clinical evidence, where altered activity of the HPA axis caused by decreased function of GR negative feedback control has been shown in depressive patients (Pariante and Miller 2001). All these references should be cited in the text.
The effects of proinflammatory cytokines on GR function should be described. Also, increased plasma proinflammatory cytokines may be associated with treatment resistance to antidepressants, which should be mentioned.
In Part 3.1. Impact of Stress on the Brain, the mechanism of deregulated GR-negative feedback control in the hippocampus and brain cortex (such as impaired cytoplasmic/nuclear GR shuttling) (Dronjak et al., 2004), should be added.
Given that neural circuits are identified through the expression of c-Fos, the results of c-Fos mapping to characterize brain circuits activated by exposure to stress should be added..
Author Response
We are very thankful for taking the time to review this manuscript and for your positive comments. We took all of it into great attention and tried to follow all recommendations. Please find the detailed responses below and the corresponding revisions/corrections highlighted in grey, in the re-submitted file.
R: part 2.1.1. As you suggested, we included a schematic diagram (original) of the neural circuits underlying stress and their locations as well as the chemical compositions of some important components.
R: part 2.2.1. Thank you for bringing this to our attention. In section 2.2.1, we only described non-pathological cases. However, in Table 1, we referenced the study by Ostrander et al. 2006 (69), which demonstrated hypoactivity of the hypothalamic-pituitary-adrenocortical axis during recovery from chronic variable stress. In response to your suggestions, we have added new lines highlighted in grey to Table 1, including information from other studies that evaluate the impact of chronic psychosocial stress on pathophysiology.
- Part 3.2: Thank you. Following your suggestions we included in the section 3.2 some sentences and new citations, regarding the relationship between stress and immune system (starting in line 455); GRs and cytokines (lines 472-477) and one sentence including the relationship between cytokines and treatment resistance to antidepressants (lines 459-461).
As you suggested we included several references:
- Filipović, D., Zlatković, J., Gass, P., & Inta, D. The differential effects of acute vs. chronic stress and their combination on hippocampal parvalbumin and inducible heat shock protein 70 expression. Neuroscience 2013, 236, 47–54. https://doi.org/https://doi.org/10.1016/j.neuroscience.2013.01.033
- Bartolomucci, A., Palanza, P., Parmigiani, S., Pederzani, T., Merlot, E., Neveu, P. J., & Dantzer, R. (2003). Chronic psychosocial stress down-regulates central cytokines mRNA. Brain Research Bulletin, 62, 173–178. https://doi.org/10.1016/j.brainresbull.2003.09.009
- Dronjak, S., Gavrilovic´, L., Dragana, G., Filipovic´, F., & Radojčicradojčic´, M. B. Immobilization and cold stress affect sympatho-adrenomedullary system and pituitary-adrenocortical axis of rats exposed to long-term isolation and crowding. Physiol Behav. 2004, 81 (3):409-415. https://doi.org/10.1016/j.physbeh.2004.01.011)
- Almutabagani L.F., Almanqour R.A., Alsabhan J.F., et al. Inflammation and Treatment-Resistant Depression from Clinical to Animal Study: A Possible Link?. Neurol Int. 2023;15(1):100-120. doi:10.3390/neurolint15010009
- Carmine M. Pariante, Bradley D. Pearce, Tracy L. Pisell, Carmen I. Sanchez, Cecilia Po, Cindy Su, Andrew H. Miller, The Proinflammatory Cytokine, Interleukin-1α, Reduces Glucocorticoid Receptor Translocation and Function, Endocrinology, 1999, 140 (9), 1 4359–4366, https://doi.org/10.1210/endo.140.9.6986
Round 2
Reviewer 2 Report (New Reviewer)
Comments and Suggestions for AuthorsThe authors have answered all of my questions, and the paper has been improved. Therefore, it can be accepted for publication.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe reviewed manuscript is devoted to the main aspects of stress, which can make a decisive contribution to the pathogenesis of socially significant pathological conditions and diseases.An attractive side of the manuscript is the author’s attempt to consider this problem in a comprehensive, multidisciplinary manner. The review brings together the main reliable results obtained in the field of psychophysiology, neurobiology, pharmacology, endocrinology, genetics, psychology, sociology, and healthy lifestyle. The strength of the study is the successful rethinking of early ideas about the nature and mechanisms of stress, taking into account the experimental and clinical results of the last period, highlighting a personalized approach to overcoming the negative consequences of stress.
The manuscript may be of interest to a wide range of specialists; it gives a good integral view of the problem under discussion.
Author Response
We are very thankful for your positive comments on our Entry manuscript. Nevertheless , to improving the quality of this Entry I invited a colleague (Umeoka, E. H de Lima.) that was very helpful in updating and confirming all the literature.
Reviewer 2 Report
Comments and Suggestions for Authors
This manuscript addresses a hot topic that touches on the neurobiology of stress. Although a comprehensive overview on stress was described relatively recently in 2018 by the authors Godoy, L. D., Rossignoli, M. T., Delfino-Pereira, P., Garcia-Cairasco, N., & de Lima Umeoka, E. H. (Godoy, L. D., Rossignoli, M. T., Delfino-Pereira, P., Garcia-Cairasco, N., & de Lima Umeoka, E. H. (2018). A Comprehensive Overview on Stress Neurobiology: Basic Concepts and Clinical Implications. Frontiers in behavioural neuroscience, 12, 127. https://doi.org/10.3389/fnbeh.2018.00127), the author refers to them. It should be noted, however, that the references are duplicated: 28 and 70 references are identical. The strength of the review is that, as there are difficulties in understanding stress, the author, based on historical data, deciphers the concept of "stress" on a time scale and all the related terms: allostasis, homeostasis, adaptation, etc. The author mentions all the famous names of allostasis, homeostasis, adaptation and adjustment. The author mentions all the famous names that are still famous today (Walter Cannon, Hans Sellier, Bruce McEwen, Eliot Stellar, etc.) in the field of stress research.
- The manuscript is clear and well structured. However, we would like to see more figures and precision in the development of certain pathologies related to stress (perhaps to list which ones), in paragraph 4.1 we would like to see more clarifying material, for example, what is the determinacy of genetic factors of stress resistance?
- Of the 120 sources cited, only 2 were self-citations (1.7%) and only 7.5% were actual sources (sources from the last 5 years, 2019-2023).
- There is a need to improve the quality and originality of the illustrative material when presenting data and describing figures. For example, the quality of Figure 2 could be improved. Classification of stressors - can be demonstrated. That is, schemes could be added to make the text easier to understand.
- I didn't see a clear purpose for this review in the review itself, is it just abstract?
I would like to see new reviews that bring novelty to the topic at hand, but for now this review should be supplemented with facts and think about novelty that would distinguish this review from the previous one. Undoubtedly, the topic is relevant, but I would like to see improvement of new articles, perhaps based on recent events (COVID 19), formation of new non-technical stressors mentioned by the author (visual and auditory), and so on.
Author Response
We are very thankful for your positive comments on our Entry manuscript. We took all of it into great attention and tried to follow all recommendations. To improving the quality of this Entry I invited a colleague (Umeoka, E. H de Lima.) that was very helpful in updating and confirming all the literature.
We sent the article to be reviewed on grammar and style by our translation team from the University of Salamanca
The manuscript has been profoundly revised, and we updated some of the references cited.
We included in Definition the purpose of this Entry (From lines 18 to 20).
We included in this entry several sentences and paragraphs, all highlighted in gray. We took into consideration your suggestions and included a new paragraph with data about novelty to the topic and based on recent events (COVID 19, wars and natural disasters) (From lines 99 to 112).
We edited and improved the quality of the Figure.
in paragraph 2.2.2 Severity and timeframe of the stressor we included a paragraph about other stressor factors determining stress response
As suggested, in paragraph 3.2. Pathophysiology of stress-related disorders, we included a table describing the most common Stress Protocols conducted in studies with animal models, key findings, and related psychopathology to make the text easier to understand. And also, a paragraph about human studies
in paragraph 4.1. Genetic and environmental factors we included a paragraph about the determinacy of genetic factors of stress resistance 478 to 481 and also more about the early stress ( beginning in line 500)
in paragraph 4.2. Factors contributing to resilience to stress we included several sentences and paragraphs, all highlighted in gray.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe manuscript is extremely difficult to read because of grammar issues. Also, statements are made carelessly and there are factual errors. A reviewer's job is not to edit a manuscript, so I stopped reviewing on Page 6 due to difficulty in reading. I will provide a few examples of careless or unsupported statements and factual errors though so the author can look for similar instances in the rest of the manuscript.
The two sentences starting on line 30 and ending on line 34. What does "stress is not punctual" mean? "Its desires..."? Whose desires? Stress can't have desires. "The capacity or incapacity to cope with stress has profound consequences...unltimately leading to an allostatic overload..." The capacity to cope shouldn't lead to overload.
Do not use Roman numerals for century. It should be 21st or 18th, etc. Likewise, terms like "last century" are confusing.
Are the statements made in lines 102-106 supported by any evidence?
Line 118: "The effect of the stress response...involves a response..."?
Line 144: Should be the "hypothalamic-pituitary-adrenal" axis. The adrenal gland has a medullary and a cortical region and both are involved in the stress response.
Figure 1. The NAc line is pointing to the mammillary bodies, not the nucleus accumbens. The insula is depicted as a small, capsular object but it is actually a part of the cerebral cortex larger than this object and it has sulci and gyri like other cortical regions.
It would be better not to use so many abbreviations, especially HIPPO
The sentence beginning on line 198 and ending on line 201 does not make sense. How do these features determine the importance of a structure?
For the sentence that begins on line 208, the last phrase on lines 209-210 does not make sense.
Lines 245-251: glutamate is not a monoamine, neither are GABA or taurine.
Line 251: What does "stabilizing nerve activity" mean?
Comments on the Quality of English LanguageThe manuscript is extremely difficult to read because of grammar issues. The author should have the manuscript edited by a professional before submitting it again for review.
Author Response
We are very thankful for your positive comments on our Entry manuscript. We took all of it into great attention and tried to follow all recommendations. To improving the quality of this Entry I invited a colleague (Umeoka, E. H de Lima.) that was very helpful in updating and confirming all the literature.
We sent the article to be reviewed on grammar and style by our translation team from the University of Salamanca
The manuscript has been profoundly revised, and we updated some of the references cited.
We included in Definition the purpose of this Entry (From lines 18 to 20).
We included in this entry several sentences and paragraphs, all highlighted in gray. We took into consideration your suggestions and included a new paragraph with data about novelty to the topic and based on recent events (COVID 19, wars and natural disasters) (From lines 99 to 112).
We edited and improved the quality of the Figure.
in paragraph 2.2.2 Severity and timeframe of the stressor we included a paragraph about other stressor factors determining stress response
As suggested, in paragraph 3.2. Pathophysiology of stress-related disorders, we included a table describing the most common Stress Protocols conducted in studies with animal models, key findings, and related psychopathology to make the text easier to understand. And also, a paragraph about human studies
in paragraph 4.1. Genetic and environmental factors we included a paragraph about the determinacy of genetic factors of stress resistance 478 to 481 and also more about the early stress ( beginning in line 500)
in paragraph 4.2. Factors contributing to resilience to stress we included several sentences and paragraphs, all highlighted in gray.
We took away some abbreviations, Hippocampus (HIPPO) and Raphe nuclei (RN)
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsThis version of the manuscript remains very difficult to read and understand. The language is also loose and careless.
The very first sentence of the manuscript is: "Few terms are currently as confusing as the "stress" description. What term? "Stress description"? A description is not a term. Or is "stress" the confusing term, in which case why is the sentence ended with "description"?
The second sentence: "Stress is traditionally defined as a reaction or threat, as a stimulus acting on a person, or as a feeling, characterized by physiological arousal or negative emotions [1,2]." When has stress been defined as threat?
The third sentence: "But this has not always been the case. The concept of stress is relatively old and...used to express the suffering deprivation, or adversity experience by individuals [3]." How is this different than how the concept was described in the second sentence?
Second paragraph, third sentence: "During the 18th century, the concept ceased to refer to the emotional consequences of the individual to be understood as the triggering factor of such reactions." Although this sentence needs a reference, it does not make sense. What reactions? And how do emotional consequences (which are reactions) trigger "such" reactions?
There are likely other examples throughout the remainder of the manuscript.
Careless and inaccurate reference citations. A few examples: Reference 27 is cited on line 184. This manuscript discusses BDNF and uses the term "anhedonia" once. Reference 52 (line 185) does not mention sexual arousal or recreational drugs. The term "anxiety" is used once, in a Figure caption. Reference 31 (line 188) is a manuscript about the insula, which does not discuss the VTA, the nucleus accumbens, or stress. References 54 and 55 (line 192) do not include the terms LC, the periaqueductal gray, solitary tract, or brainstem. Reference 93 (Table 1) is a manuscript that describes effects on caudate and nucleus accumbens in rats, not hypothalamus, PFC, or hippocampus. Reference 87 (Table 1 and Line 343) is not a review article and does not mention early life stress or deprivation. It also does not discuss early postnatal development. It is a study comparing adults in the early stages of schizophrenia with age-matched controls. These are just a few examples.
Section 2.1.2. Activation of the sympathetic nervous system results in release of adrenaline and noradrenaline from the adrenal medulla. Noradrenaline is also released in the brain.
Lines 466-468: "However, despite the initial draft for brain and neural systems development is specified by the genome, all details are subtly worked out with each one's experience and environmental interaction by non-genomic and epigenetic mechanisms [28]." All details? Reference 28 also includes genomic mechanisms in addition to non-genomic and epigenetic mechanisms (Figure 1 caption).
Comments on the Quality of English Language
Grammar is ok.
