Diagnostic and Therapeutic Approaches in Neurorehabilitation after Traumatic Brain Injury and Disorders of Consciousness

Round 1

Reviewer 1 Report

The authors of this review aimed to write a comprehensive work about patients with disorders of consciousness after traumatic brain injury. This topic is meaningful due to its tremendous impact on medical services and public health. The article is well-written and has an adequate length and an appropriate structure. I also appreciate that it addresses this subject from several points of view – epidemiology, clinical and paraclinical diagnostic methods, and treatment options.

However, there are a couple of things I would recommend to improve.

In the abstract, there are some mentions of network-based mechanisms of consciousness and modulation of neural networks. I consider that these issues should be broadened in a separate section, along with an emphasis on the pathophysiology process of traumatic brain injuries at all levels – cellular and molecular level, circuitries level, and dynamic network level. 

Also, a few paragraphs about mechanisms and factors involved in the complex process of neurorehabilitation should be considered before presenting the treatment options and approaches.

In the pharmacologic therapies chapter, I recommend adding neurotrophic factor-like drugs. Several publications illustrate the pleiotropic and multimodal effects of these specific molecules, and some trials highlight the positive outcome of Cerebrolysin treatment in patients with traumatic brain injury. Including some knowledge about these therapeutic approaches would enrich the content of the article. 

Finally, the abstract should reflect all the adjustments made in the article. 

Author Response

Dear Editor-in-Chief,

thank you for informing us that our review article entitled “Diagnostic and therapeutic approaches in neurorehabilitation after traumatic brain injury and disorders of consciousness” has been received and currently been reviewed.

We are pleased that the reviewer found our article intriguing, and we would like to extend our appreciation to the reviewers for their valuable and insightful comments and suggestions. We have diligently taken their feedback into account and conducted a major revision to enhance the overall quality of our manuscript.

According to the reviewer’s comments, we did the following step-wise revision and the changes could be tracked in the _CORRECT-version incl. lines:

Reviewer 1:

• Separate section encompassing network-based mechanisms of consciousness and modulation of neural networks. I consider that these issues should be broadened in a separate section, along with an emphasis on the pathophysiology process of traumatic brain injuries at all levels – cellular and molecular level, circuitries level, and dynamic network level. 

 

- We included a separate section which focuses on network-based mechanisms and depicts in detail pathophysiological alteration both on network and circuitry as well as on cellular level in TBI.

  Network-based mechanisms and their dysfunction on circuitry and cellular levels after TBI

(see line 172-259_CORRECT)

 

• Few paragraphs about mechanisms and factors involved in the complex process of neurorehabilitation before presenting the treatment options and approaches.

- The above mentioned paragraph also includes structures such as intrinsic connectivity networks (ICNs) as neuroanatomic correlates involved in neurorehabilitation (see line 202-206_CORRECT) and also includes mechanisms of neurodegeneration and inflammation which might further interfere with the rehabilitation outcome.   

 

• Pharmacologic therapies chapter, adding neurotrophic factor-like drugs with highlighting the positive outcome of Cerebrolysin treatment

- The pharmacologic chapter was broadened by adding various studies investigating the therapeutic potential of neurotrophic and discussing the effect of Cerebrolysin in restoring neurocognitive functions (see line 456 – 499_CORRECT).

 

We look forward to hearing whether the journal Clinical and Translational Neuroscience is interested in accepting this article for publication. Both authors have read and approved the review article and agree with its submission to MDPI/CTN.  

Reviewer 2 Report

Dear Dr. Lippert, ,

thank you very much for relevant review article on Diagnostic and therapeutic approaches in neurorehabilitation after traumatic brain injury and disorders of consciousness.

Overall, it is an important contribution highlighting the multidisciplinary rehabilitation needs for patients suffering from traumatic brain injury (TBI) and disorders of consciousness (DoC).

Taken together, this review article is relatively broad and would benefit from more specificity, added references on current evidence. As you have included mild TBI, it would be interesting to mention the percentage of treatment needs regarding intensive care, neurosurgical interventions, and even mortality after initial classified mild TBI based on the GCS.

 Please find my point-by-point suggestions for your major revisions:

 • The article should be marked as a review article.

• The article would benefit from a more concise language throughout the manuscript by using the same wording instead of various terms e.g. in the abstract brain injury versus traumatic brain injury

• Abstract: the authors should double check the phrase on recovery of consciousness and should clarify their message

• Intro: The paragraph on characterization of TBI patients based on biomarkers and neuroimaging need to be more specific and should be underlined by references

• Intro: The paragraph on TBI epidemiology and variances should be revised and the authors should include the high annual incidence among the young and in the elderely as well as stated e.g. in DOI: 10.1097/HTR.0b013e3181ccc8b4

• The authors should add references, when ever they state current evidence and add relevant papers in the field on 

- Lack of neurorehab needs in Europe after moderate to severe and mild TBI (CENTER-TBI) (Andelic et al., J Clin Med. 2021; Howe et al., BMC Health Services Research 2022)

- HRQoL outcome after TBI using the QOLIBRI instrument)

- DTI on an individual level and correlation to multidimensional outcomes (GOSE, PSQI, cognition (memory, executive funciton) by Jolly et al., Brain 2021

- HD-EEG section

• The authors should be careful mentioning the practice guidelines in neurorehab, which have not been published yet. I suggest to rename the paragraph 6 into "The need of practice guidelines in neurorehabilitation", and thereafter current evidence with original citations can be added.

• Fig 1 would benefit from using the precise terms of the CRS-R assessemnt

• Fig 2 would benefit from a legend on the colored arrows.

• Fig 2 would benefit from detailed explanation on all shown items e.g. the  zolpidem mechanism

• The artcile needs a Native Proofread

• The article needs formatting regarding the citations

• The article needs revision regarding format on the use of abbreviations (e.g. DOC vs DoC; UWS was not explained when used at the first time          

Thank you very much for your valuable work and effort in the field.

Author Response

Dear Editor-in-Chief,

thank you for informing us that our review article entitled “Diagnostic and therapeutic approaches in neurorehabilitation after traumatic brain injury and disorders of consciousness” has been received and currently been reviewed.

 

We are pleased that the reviewer found our article intriguing, and we would like to extend our appreciation to the reviewers for their valuable and insightful comments and suggestions. We have diligently taken their feedback into account and conducted a major revision to enhance the overall quality of our manuscript.

According to the reviewer’s comments, we did the following step-wise revision and the changes could be tracked in the _CORRECT-version incl. lines:

Reviewer 2:

• The article should be marked as a review article.
• The title is adapted and marked as a review article (see line 1_CORRECT)
• The article would benefit from a more concise language throughout the manuscript by using the same wording instead of various terms e.g. in the abstract brain injury versus traumatic brain injury
• The article has been systematically revised in terms of language style and the consistent use of abbreviations (e.g. TBI, UWS, etc.)
• Abstract: the authors should double check the phrase on recovery of consciousness and should clarify their message
• The sentence was rephrased (see line 13-15_CORRECT). Moreover, the abstract highlights the main topics concerning identification and prognostication of consciousness recovery as well as new techniques and therapeutic recommendations (see line 30-34_CORRECT).
• Intro: The paragraph on characterization of TBI patients based on biomarkers and neuroimaging need to be more specific and should be underlined by references
• The authors should add references, when ever they state current evidence and add relevant papers in the field on 

- Lack of neurorehab needs in Europe after moderate to severe and mild TBI (CENTER-TBI) (Andelic et al., J Clin Med. 2021; Howe et al., BMC Health Services Research 2022)

- HRQoL outcome after TBI using the QOLIBRI instrument)

- DTI on an individual level and correlation to multidimensional outcomes (GOSE, PSQI, cognition (memory, executive funciton) by Jolly et al., Brain 2021

- HD-EEG section

- The introduction has been fundamentally revised and revised. Both the aspects of imaging and biomarkers are discussed in detail. The references mentioned ((Andelic et al., J Clin Med. 2021; Howe et al., BMC Health Services Research 2022) have been included (see line 47_CORRECT and see line 95_CORRECT). Moreover, studies investigating MRI findings and its correlation with neurocognitive performance has been introduced (Jolly et al., Brain 2021) – (see line 105-109_CORRECT – ref. 19).

- Studies investigating HRQoL outcome after TBI using the QOLIBRI instrument were added (see line 81-95_CORRECT) as well as HD-EEG (see line 112_CORRECT).

 

• Intro: The paragraph on TBI epidemiology and variances should be revised and the authors should include the high annual incidence among the young and in the elderely as well as stated e.g. in DOI: 10.1097/HTR.0b013e3181ccc8b4

- The paragraph on the epidemiology of TBI was revised accordingly and information on the age distribution was added. In addition, information on the YLL was added as a key parameter for estimating the socio-economic consequences, especially in the younger population. (see line 143 – 163_CORRECT).

• The authors should be careful mentioning the practice guidelines in neurorehab, which have not been published yet. I suggest to rename the paragraph 6 into "The need of practice guidelines in neurorehabilitation", and thereafter current evidence with original citations can be added.

 

- The practice guidelines in neurorehabilitation has been previously published at the end of Dec. 2022.

080-006l_S3_Neurologische-Rehabilitation-bei-Koma-und-schwerer-Bewusstseinsstoerung-im-Erwachsenenalter_2022-12.pdf (awmf.org)

- Therefore, we adopted this paragraph and added some key references upon which the guideline is based on.

• Fig 2 would benefit from a legend on the colored arrows.

- A legend is added in Fig 2.

• Fig 2 would benefit from detailed explanation on all shown items e.g. the  zolpidem mechanism

- Further explanation on the mechanism of zolpidem in the mesocircuit model were added (see line 672-674_CORRECT)

We look forward to hearing whether the journal Clinical and Translational Neuroscience is interested in accepting this article for publication. Both authors have read and approved the review article and agree with its submission to MDPI/CTN.  

Round 2

Reviewer 2 Report

Dear Dr. Lippert, dear Dr. Guggisberg, thanks for your great effort that improved your manuscript. All points have been addressed and no further revisions are needed from my perspective.