A Review of Transcranial Electrical and Magnetic Stimulation Usefulness in Major Depression Disorder—Lessons from Animal Models and Patient Studies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. Line 35  I would suggest "feelings of worthlessness, guilty feelings, and suicidal thoughts"
2. Line 34.  What type of mood?
3. Line 52.  I would suggest deleting "but" as it's not needed.
4. Line 20 vs. Line 30.  Why use MD and MDD?  Would not MDD be better?
5. Line 65.  Even though it's defined in the abstract, the first time tDCS is used, I would suggest explaining it - and this should be true for all other abbreviations.
6. Line 87  A spacing issue here.
7. Line 108.  This implies that only one medicine is approved but I thought there were several medicines for MDD.  I know of a case where sertraline was tried and failed but then duoloxetrine (spelled wrong I am sure) was used and worked well.
8. Lines 232-234 and 239-241 seem to be redundant.
9. Line 430.  The difference between long-term effect and long-term impact might be clarified; otherwise it's like saying A leads to A. 
10. Line 507.  What does BDNF stand for?

Author Response

We would like to thank the reviewer for the positive comments regarding our paper and we have addressed the issues raised below.

Comment 1
Line 35 I would suggest "feelings of worthlessness, guilty feelings, and suicidal thoughts"
Response 1
Thank you for your suggestions, we agreed and updated the manuscript.

Comment 2
Line 34. What type of mood?
Response 2
We added: “Depression is a mental disorder affecting both mental and physical health. It is a heterogeneous group of pathological conditions with different etiologies that, according to DSM-V-TR, might include symptoms such as depressed mood, loss of enjoyment, difficulty concentrating, lack of energy, sleep and appetite disturbances, feelings of worthless-ness, guilty feelings, and suicidal thoughts”.

Comment 3
Line 52. I would suggest deleting "but" as it's not needed.

Response 3
We modified according to the suggestion.

Comment 4
Line 20 vs. Line 30. Why use MD and MDD? Would not MDD be better?
Response 4
We agreed to correct as MDD, thank you for pointing it out.

Comment 5
Line 65. Even though it's defined in the abstract, the first time tDCS is used, I would suggest explaining it - and this should be true for all other abbreviations.
Response 5
We have checked all the abbreviations in the manuscript and made sure to explain them when they first appear in the manuscript.

Comment 6
Line 87 A spacing issue here.
Response 6
Thank you for your feedback, we checked and corrected.

 

Comment 7
Line 108. This implies that only one medicine is approved but I thought there were several medicines for MDD. I know of a case where sertraline was tried and failed but then duoloxetrine (spelled wrong I am sure) was used and worked well.
Response 7
We paraphrased to exclude the fact that vortioxetine is the only one medicine for treating MDD. “Currently, vortioxetine is among the approved pharmacological treatments for MDD with demonstrated direct and independent pro-cognitive benefits [9].”

Comment 8
Lines 232-234 and 239-241 seem to be redundant.
Response 8
Thank you for your attentive review. We deleted the redundant sentence.

 

Comment 9

Line 430. The difference between long-term effect and long-term impact might be clarified; otherwise it's like saying A leads to A.
Response 9
Thank you for pointing this out. To respond to your recommendation, we rephrased in the introduction.

 

Comment 10
Line 507. What does BDNF stand for?
Response 10
We explained the abbreviation and “Brain-Derived Neurotrophic Factor (BDNF) expression”.

We would like to thank you again for your efforts in reviewing our manuscript and we are grateful for this opportunity to refine and strengthen our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors presented a review entitled “A Review of Transcranial Electrical and Magnetic Stimulation Usefulness in Major Depression Disorder - Lessons from Animal Models and Patient Studies” to analyze the current knowledge of using tDCS and tMS in animal models and clinical studies, both as monotherapy and/or combined with other therapeutic approaches”, as they declared in the last lines of the abstract. I think it is a potentially interesting paper. However, when you get to the abstract section and continue through all sections of the manuscript except for a few exceptions, the difficulties begin. The manuscript takes a confusing, uncertain path that leads to not easily and directly understanding what the authors intended, what purpose, and what methods are used.

Major comments

Overall, the manuscript has notable weaknesses. The most severe concerns are at the conceptual/methodological perspective according to which authors have conceived their review. A very important aspect is to declare and use the objective of the research as a guiding element.

The authors first described Major Depressive Disorder (MDD) and the cognitive decline in depression as diagnostic criterion (lines 54-79). In lines 76-80 they wrote that “the most complex cases of the association between cognitive impairment and depression can already be addressed using methods that allow for an early differential diagnosis between reversible forms of cognitive impairment and degenerative dementia”…Because they cite only the cognitive decline, I feel that their purpose was studying the relationship between MDD and cognitive impairment. But, on the next page, the introduction shifts toward structural brain abnormalities in MDD and brain stimulation techniques. But in the title only transcranial electrical and magnetic stimulation are reported.

In this regard, the suggestion is that a specific topic concerning a specific population and an objective statement be proposed, and that said statement be used verbatim every time the objective is mentioned. This gives coherence to the work.

 The manuscript observes the use of and reference to the DSM-V (line 33). Currently, there is a new revised version of the manual, the DSM-5-TR (APA, 2022). It is advisable to modify the citations/references and consult the revised text.

- Generally, a review addresses an appropriate and focused question. If the question is not clear, the systematic review is unlikely to be a good one because it is difficult to be systematic in addressing an unclear question. In the present manuscript, no reference was given to the question research.

- A review uses explicit and systematic methods to identify, appraise, and summarize the literature according to predetermined criteria. If the methods and criteria used to do this are not described or are not sufficiently detailed, it is not possible to make a thorough evaluation of the quality of the review. In this manuscript, it is not reported any of these criteria.

- The review should give a clear description of the population considered, paper types, interventions, and outcomes evaluated. The inclusion and exclusion criteria for the paper should be clearly described. The outcomes considered should be clearly illustrated within the methodology. In the present manuscript, no reference was suggested for search and inclusion/exclusion criteria. Without exact rules, the papers included can be biased. Ideally, the search strategy used should be reported in sufficient detail so that the process can be replicated.

Authors are suggested to use the PRISMA reporting guidelines, which are designed to help authors transparently report why their systematic review was done, what methods they used, and what they found. By doing the Database Search for Records Identification and adding a flowchart, the quality of the review will increase.

Therefore, I strongly recommend they revise the manuscript in its entirety.

I hope that the Authors will continue in this important line of research and use my comments to help shape their efforts.

Author Response

The authors presented a review entitled “A Review of Transcranial Electrical and Magnetic Stimulation Usefulness in Major Depression Disorder - Lessons from Animal Models and Patient Studies” to analyze the current knowledge of using tDCS and tMS in animal models and clinical studies, both as monotherapy and/or combined with other therapeutic approaches”, as they declared in the last lines of the abstract. I think it is a potentially interesting paper. However, when you get to the abstract section and continue through all sections of the manuscript except for a few exceptions, the difficulties begin. The manuscript takes a confusing, uncertain path that leads to not easily and directly understanding what the authors intended, what purpose, and what methods are used.

Major comments

Comment 1.

Overall, the manuscript has notable weaknesses. The most severe concerns are at the conceptual/methodological perspective according to which authors have conceived their review. A very important aspect is to declare and use the objective of the research as a guiding element.

Response 1.

We appreciate the reviewers’ comments regarding the need for a stronger conceptual and methodological framework. In response, we have refined our research aim and included it in the end of the introduction section, as follows:

“The present study has been designed to evaluate the therapeutic potential of two non-invasive interventions for MDD. The interventions under scrutiny are tDCS and tMS. An exploratory review of the extant evidence from both animal models and clinical studies has been undertaken to determine the efficacy of these interventions as standalone treatments and in combination with conventional therapies such as anti-depressants and psychotherapy.”

 

Comment 2.

The authors first described Major Depressive Disorder (MDD) and the cognitive decline in depression as diagnostic criterion (lines 54-79). In lines 76-80 they wrote that “the most complex cases of the association between cognitive impairment and depression can already be addressed using methods that allow for an early differential diagnosis between reversible forms of cognitive impairment and degenerative dementia”…Because they cite only the cognitive decline, I feel that their purpose was studying the relationship between MDD and cognitive impairment. But, on the next page, the introduction shifts toward structural brain abnormalities in MDD and brain stimulation techniques. But in the title only transcranial electrical and magnetic stimulation are reported.

Response 2.

We are grateful for the reviewer's observations regarding the shift in focus from cognitive impairment in MDD to structural brain abnormalities and brain stimulation techniques. In order to ensure consistency with the study's scope, we have revised the introduction to clarify the relationship between cognitive impairment, brain structure, and the therapeutic role of tDCS and tMS. We included the following:

“MDD is associated with structural and functional brain abnormalities that contribute to its debilitating effects, including significant cognitive impairment… Research suggests that cognitive deficits are more pronounced in melancholic depression compared to non-melancholic subtypes. Additionally, factors such as symptom severity, cumulative duration of depressive episodes, and comorbid conditions can further exacerbate cognitive decline. The most complex cases require differential diagnosis techniques to distinguish between reversible cognitive impairment related to depression and neurodegenerative conditions such as dementia. However, despite advances in neuroscience, no definitive biomarkers exist for diagnosing MDD or guiding individualized treatment selection…Traditional therapeutic approaches, including antidepressant medications and psychotherapy, remain the primary treatment options for MDD. However, these interventions are not universally effective, with up to 30% of patients experiencing treatment resistance. Furthermore, barriers such as limited access to care, treatment-related side effects, and social stigma often prevent individuals from receiving adequate support. Given these limitations, there is a growing interest in alternative and adjunctive treatment strategies, particularly non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (tMS)…tDCS and tMS have emerged as promising neuromodulatory interventions that modulate cortical excitability and functional connectivity in key brain regions implicated in MDD. These techniques offer potential advantages over traditional treatments, including fewer systemic side effects and greater accessibility.”

 

Comment 3.

In this regard, the suggestion is that a specific topic concerning a specific population and an objective statement be proposed, and that said statement be used verbatim every time the objective is mentioned. This gives coherence to the work.

Response 3.

To respond to your concerns, we included study aim and objectives, to provide readers with enough information on what was intended in this review.

“This study aims to evaluate the effectiveness of tDCS and tMS as alternative or adjunctive treatments for MDD, particularly in patients resistant to conventional therapies. By analyzing evidence from both clinical studies and animal models, the study seeks to assess the potential of these neuromodulation techniques in improving treatment outcomes, cognitive function, and neuroplasticity in individuals with MDD.

Research Objectives:

1. To investigate the neurobiological mechanisms through which tDCS and tMS modulate brain activity in the treatment of MDD.
2. To explore findings from animal models and their translational relevance to clinical applications for MDD treatment.
3. To provide recommendations for integrating tDCS and tMS into personalized treatment approaches for patients with treatment-resistant depression.”

 

Comment 4.

In this regard, the suggestion is that a specific topic concerning a specific population and an objective statement be proposed, and that said statement be used verbatim every time the objective is mentioned. This gives coherence to the work.

Response 4.

Thank you for your valuable feedback. To enhance the coherence of our manuscript, we have refined the research objective to explicitly define the specific population and focus of the study.

“This study aims to evaluate the effectiveness of transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (tMS) as alternative or adjunctive treatments for Major Depressive Disorder (MDD), particularly in patients resistant to conventional therapies.”

So, we focused on patients with MDD, resistant to conventional therapies.

 

Comment 5.

The manuscript observes the use of and reference to the DSM-V (line 33). Currently, there is a new revised version of the manual, the DSM-5-TR (APA, 2022). It is advisable to modify the citations/references and consult the revised text.

Response 5.

Thank you for your update, we have checked the DSM-V revision, and we updated the symptomatology based on the revised version, we also changed the reference as well.

We have added:

“It is a heterogeneous group of pathological conditions with different etiologies that, according to DSM-5-TR, might include symptoms such as depressed mood, loss of enjoyment, difficulty concentrating, lack of energy, sleep and appetite disturbances, feelings of worthlessness, guilty feelings, and suicidal thoughts [2]. MDD is diagnosed when an individual exhibits a minimum of five symptoms over the course of two consecutive weeks, denoting a substantial deterioration in functioning. At least one of these symptoms must be a depressed mood or an absence of interest or pleasure in activities.”

 

Comment 6.

Generally, a review addresses an appropriate and focused question. If the question is not clear, the systematic review is unlikely to be a good one because it is difficult to be systematic in addressing an unclear question. In the present manuscript, no reference was given to the question research.

Response 6.

Thank you for your recommendation, based on our aim and objectives, we have formulated a research question:

“Our review was guided by the following research question:

1. How do tDCS and tMS modulate brain activity and improve treatment outcomes in patients with MDD, particularly those resistant to conventional therapies?”

 

Comment 7.

A review uses explicit and systematic methods to identify, appraise, and summarize the literature according to predetermined criteria. If the methods and criteria used to do this are not described or are not sufficiently detailed, it is not possible to make a thorough evaluation of the quality of the review. In this manuscript, it is not reported any of these criteria.

Response 7.

We appreciate the reviewer’s feedback and understand the importance of clear reporting of the methodology and criteria used in a review. We would like to point out that the manuscript employs a scoping review methodology rather than a systematic review. Our goal was to explore and map the breadth of literature on a specific topic, often without stringent criteria for study selection and quality appraisal that are characteristic of systematic reviews. In our study, we aimed to provide an overview of existing research on tDCS and tMS in the context of treatment-resistant major MDD by identifying and summarizing relevant studies across both animal models and clinical trials. As such, we did not apply the same explicit, systematic approach required for a systematic review, where studies are rigorously assessed for methodological quality, bias, and other specific criteria. Instead, our focus was on exploring a broad range of papers to gather insights and answer our research question regarding the potential therapeutic role of these neuromodulation techniques.

We acknowledge that the lack of a detailed description of criteria might lead to confusion, and we will revise the manuscript to make it clearer that we employed a scoping review approach, outlining that our aim was to provide an overview and not to evaluate the quality of individual studies systematically.

We have introduced in our introduction section, after stating the review aim and question, the clarification of the type of review done.

“This study employed a scoping review methodology to evaluate the effectiveness of tDCS and tMS as alternative or adjunctive treatments for MDD, particularly in patients resistant to conventional therapies. By analyzing evidence from both clinical studies and animal models, the study seeks to assess the potential of these neuromodulation techniques in improving treatment outcomes, cognitive function, and neuroplasticity in individuals with MDD”.

 

Comment 8.

The review should give a clear description of the population considered, paper types, interventions, and outcomes evaluated. The inclusion and exclusion criteria for the paper should be clearly described. The outcomes considered should be clearly illustrated within the methodology. In the present manuscript, no reference was suggested for search and inclusion/exclusion criteria. Without exact rules, the papers included can be biased. Ideally, the search strategy used should be reported in sufficient detail so that the process can be replicated.

Response 8.

Thank you for pointing it out, we have added the following paragraph to make it more transparent the methodology of the study

“ This study employed a scoping review methodology to evaluate the effectiveness of tDCS and tMS as alternative or adjunctive treatments for MDD, particularly in patients resistant to conventional therapies. By analyzing evidence from both clinical studies and animal models, the study seeks to assess the potential of these neuromodulation techniques in improving treatment outcomes, cognitive function, and neuroplasticity in individuals with MDD.

Research Objectives:

1. To investigate the neurobiological mechanisms through which tDCS and tMS modulate brain activity in the treatment of MDD.
2. To explore findings from animal models and their translational relevance to clinical applications for MDD treatment.
3. To provide recommendations for integrating tDCS and tMS into personalized treatment approaches for patients with treatment-resistant depression.

Our review was guided by the following research question:

1. How do tDCS and tMS modulate brain activity and improve treatment outcomes in patients with MDD, particularly those resistant to conventional therapies?

The scoping review methodology was chosen to provide a broad synthesis of existing research, particularly in both animal models and human clinical studies, based on the criteria outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for scoping reviews.

The paper extracted for this review, we considered the following criteria: (1) Our study includes pre-clinical animal models and human patients diagnosed with MDD. The clinical studies evaluated include participants with treatment-resistant depression and those undergoing tDCS/tMS as monotherapy or combined with antidepressants or psychotherapy. (2) We considered peer-reviewed journal articles, clinical trials, and preclinical studies investigating the therapeutic use of tDCS and tMS in MDD. Both standalone and combination interventions were included. (3) The primary outcomes analyzed include efficacy in symptom reduction (measured through depression rating scales such as HDRS, MADRS, BDI), cognitive function improvements, and neuroplasticity-related biomarkers (e.g., neuroimaging and neurophysiological data).

Inclusion criteria. Studies published in peer-reviewed journals that assess the effectiveness of tDCS or tMS in MDD, including clinical trials, systematic reviews, meta-analyses, and animal model research.

Exclusion criteria. Studies lacking primary data, case reports, studies on neuromodulation methods other than tDCS/tMS, and non-English publications.

Search strategy and replicability. While this study follows a scoping review approach, we adhered to a structured literature search strategy using PubMed, Scopus, and Web of Science databases. The search terms included “transcranial direct current stimulation,” “transcranial magnetic stimulation,” “Major Depressive Disorder,” and “neuromodulation.” No restrictions were placed on publication year to capture the full scope of available literature.”

 

Comment 8.

The Authors are suggested to use the PRISMA reporting guidelines, which are designed to help authors transparently report why their systematic review was done, what methods they used, and what they found. By doing the Database Search for Records Identification and adding a flowchart, the quality of the review will increase. Therefore, I strongly recommend they revise the manuscript in its entirety.

I hope that the Authors will continue in this important line of research and use my comments to help shape their efforts.

Response 8. Thank you for your insightful feedback. We acknowledge the importance of adhering to the PRISMA guidelines to enhance the transparency and reproducibility of our scoping review. We have updated the manuscript, the main changes cand be found in Response 7.

 

We would like to thank you for your effort and valuable feedback. We proofread and adjust the manuscript to comply with formatting guidelines, including citations, references, headings, tables, and figures.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I have completed my review based on the changes made in response to the noted questions and suggestions. I appreciate the response from the Authors and will refrain from commenting on matters that have already been sufficiently addressed.

In response to my review, the Authors have refined their research purpose and included it at the end of the introduction section. They included the study’s aim and objectives concerning the neurobiological mechanisms, animal models, and recommendations for integrating tDCS and tMS into treatment approaches devoted to individuals with Major Depressive Disorder (MDD) resistant to conventional therapies.

To ensure consistency with the study's aim, the introduction section was revised, and the current version of the manuscript better clarifies the relationship between cognitive impairment, brain structure, and the therapeutic role of tDCS and tMS.

The current version of the manuscript observes the use of the DSM-5-TR (APA, 2022) and focuses on a specific research question.

The authors also specified that the manuscript employs a scoping review methodology rather than a systematic review, exploring the breadth of literature on this topic without constrained criteria with the aim of providing an overview of studies. Finally, The Authors updated the manuscript, adhering to the PRISMA reporting guidelines and adding a flowchart.

They adjusted the manuscript to fulfill formatting guidelines, including citations, references, tables, and figures.

Generally, I feel that the quality of the present review has increased. Therefore, I consider the current version of the manuscript to be a significant topic with implications for individuals, care providers, and policymakers worldwide.

 

Comments for author File: Comments.pdf