Insights into Advanced Neurological Dysfunction Mechanisms Following DBS Surgery in Parkinson’s Patients: Neuroinflammation and Pyroptosis

Round 1

Reviewer 1 Report

This paper entitled: “Insight of Advanced Neurological Dysfunction Mechanism after DBS Surgery in Parkinson's Patients: Neuroinflammation and Pyroptosis” aims to discuss the consequences of DBS surgery and uncover the possible mechanisms responsible for side effects such as problems with consciousness and memory. The topic is interesting and important for researches in the field. 

 

But this paper does not bring any “innovative” thoughts or approaches, it simply states that the reason of all side effects is “activation of glial cells” and “neuroinflammation”. Authors often use loose and incoherent statements (see below), they repeat same things in different paragraphs and basically discuss neuroinflammation itself most of the time with loose relation to DBS. The whole discussion seems very superficial to me. In the discussion authors state: “This article aims at these sequelae that appear after surgery, combined with the characteristics of the DBS surgical approach, material selection, anesthesia, etc. combined with the research hotspots of cytokinesis”. But authors never give any information about different materials for DBS electrodes (they just discuss iron, why?) or different anesthesia substances or protocols and its effects. I think authors should rethink the structure of the paper, add more information about different materials which are used to make DBS electrodes, different anesthesia protocols, the exact location of electrode placements, etc. 

 

Some other remarks:

 

Line 19: “Keywords: Parkinson;” Do you mean James Parkinson? Or actually Parkinson's disease (Parkinson’s)? Please, be more accurate. 

 

Line 60: “blood-brain barrier integrity, and providing nutrients for neurons[18].” These are functions commonly related to astrocytes rather than microglial cells. And the reference you put here (Prinz et al., 2019) does not contain information about these two microglial functions. Please, provide correct references.

 

Line 61: “alters the activation of cytokines”. What do you mean by activation of cytokines?

 

Line 66: “Iron will accumulate in the hippocampus as a result of iron homeostasis being affected by the process of implanting a brain pacemaker[23, 24]” - Stimulator is in titanium housing with platinum-iridium electrodes, am I correct?

 

Line 75: “Additionally, anesthesia of DBS surgery may cause the nuclear factor B (NF-κ B) and calcineurin (Ca N) signal pathways to assault mitochondria and break the respiratory chain. ” - Reference needed.

 

Line 100: “Damage-associated molecular patterns (DMAPs)” - DAMPs.

 

Line 119: “up-regulating the expression level of soluble media.” - What is soluble media?

 

Line 120-121: “Inflammatory factors released by microglia

cells have an amplifying effect. These inflammatory agents (TNF-α, IL-1) amplify inflammatory activation through the special physiological structure of astrocytes[45].” - This is very loose and incoherent statement.

 

Line 186: “Inhalation anesthesia affects CAN and NF- κ B pathway[28]” - What about intravenous anesthesia? Does it have other effect? or maybe it depends on specific substance used? 

 

Line 217: “The hippocampus is an important organ for processing memory and consciousness in humans, and it is more susceptible to damage from external sources due to its specific structure[77].” - What kind of specific structure? Why is it specific?

 

Inflammation - is it always a bad thing?

 

 

 

 

English grammar is ok, however there are many loose and incoherent statements in the text.

 

Author Response

Dear Cornea:

On behalf of my co-authors, thank you very much for giving us an opportunity to revise our manuscript. We appreciate all the editor and reviewers very much for the positive and constructive comments and suggestions on our manuscript entitled “Insights into Advanced Neurological Dysfunction Mechanisms following DBS Surgery in Parkinson's Patients: Neuroinflammation and Pyroptosis”. (Manuscript ID: cimb-2389283).

We have studied reviewer’s comments carefully and have made revision which marked in yellow in the paper. We have tried our best to revise our manuscript according to the comments. Attached please find the revised version, which we would like to submit for your kind consideration.

We would like to express our great appreciation to you and reviewers for comments on our paper.

Looking forward to hearing from you.

Thank you and best regards.

Yours sincerely,

Xiaoyu Yan

Responds to the reviewer’s comments:

Reviewer 1

This paper entitled: “Insight of Advanced Neurological Dysfunction Mechanism after DBS Surgery in Parkinson's Patients: Neuroinflammation and Pyroptosis” aims to discuss the consequences of DBS surgery and uncover the possible mechanisms responsible for side effects such as problems with consciousness and memory. The topic is interesting and important for researches in the field.

But this paper does not bring any “innovative” thoughts or approaches, it simply states that the reason of all side effects is “activation of glial cells” and “neuroinflammation”. Authors often use loose and incoherent statements (see below), they repeat same things in different paragraphs and basically discuss neuroinflammation itself most of the time with loose relation to DBS. The whole discussion seems very superficial to me. In the discussion authors state: “This article aims at these sequelae that appear after surgery, combined with the characteristics of the DBS surgical approach, material selection, anesthesia, etc. combined with the research hotspots of cytokinesis”. But authors never give any information about different materials for DBS electrodes (they just discuss iron, why?) or different anesthesia substances or protocols and its effects. I think authors should rethink the structure of the paper, add more information about different materials which are used to make DBS electrodes, different anesthesia protocols, the exact location of electrode placements, etc.

Response: Thank you for your letter and for the reviewers’ comments concerning our manuscript. Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our research. We have studied comments carefully and have made correction which we hope meet with approval. We have re-edited the language with the help of native English speakers. And we added a section to discuss hardware issues and anesthesia options in DBS surgery in page 8.

Some other comments:

1. Line 19: “Keywords: Parkinson;” Do you mean James Parkinson? Or actually Parkinson's disease (Parkinson’s)? Please, be more accurate.

 Response: We are sorry for the inaccurate expression. I mean Parkinson's disease  in this manuscript and we have corrected the key words.

2. Line 60: “blood-brain barrier integrity, and providing nutrients for neurons[18].” These are functions commonly related to astrocytes rather than microglial cells. And the reference you put here (Prinz et al., 2019) does not contain information about these two microglial functions. Please, provide correct references.

Response: We are sorry for the incorrect references. We have re-edited paragraph 1 of section 2.1 in page 2 and added reference 19 to discuss this part.

3. Line 61: “alters the activation of cytokines”. What do you mean by activation of cytokines?

Response: We thank the reviewer for bringing this to our attention. Anesthetic and electrode locations can promote the activation of pro-inflammatory factors in the peripheral immune system after DBS surgery in patients with Parkinson’s disease, which induces neuroinflammation. Inflammatory factors including TNF-α, IL-1β, IL-6, etc. And we have added this part in line 61-65.

4. Line 66: “Iron will accumulate in the hippocampus as a result of iron homeostasis being affected by the process of implanting a brain pacemaker[23, 24]” - Stimulator is in titanium housing with platinum-iridium electrodes, am I correct?

Response: We are grateful to the reviewer for raising this point. It is believed that brain is the most metabolically active organ in the body and has a high demand for iron. Iron serves as a cofactor in myelination, neurotransmission, oxygen transport, cellular division, and mitochondrial energy generation. Microglia are the immune cells of the central nervous system (CNS), and brain inflammatory status is thought to be largely determined by their action. Proteins involved in iron metabolism identified in microglia include divalent metal transporter-1 (DMT1), transferrin receptor (TfR), ferritin, and ferroportin (Fpn). Transcripts and protein levels of iron transporter genes are differentially altered in response to pro- and anti-inflammatory stimuli. The platinum-iridium electrodes of the stimulator will interact with brain cells. The process of implanting a brain pacemaker increases the pro-inflammatory response in the brain. Non-transferrin–bound iron (NTBI) uptake is enhanced by the proinflammatory response;McCarthy study shows that the labile iron pool (LIP) is also increased under these conditions, suggesting that microglia sequester both intracellular iron released by heme catabolism and extracellular iron taken up by DMT1. We re-edited this part in lines 68-71.

5. Line 75: “Additionally, anesthesia of DBS surgery may cause the nuclear factor B (NF-κ B) and calcineurin (Ca N) signal pathways to assault mitochondria and break the respiratory chain. ” - Reference needed.

Response: We are sorry for the mistakes and we have added reference 29 in line 81 to discuss this part.

6. Line 100: “Damage-associated molecular patterns (DMAPs)” - DAMPs.

Response: We are sorry for the mistakes and we have corrected it in line 105.

7. Line 119: “up-regulating the expression level of soluble media.” - What is soluble media?

Response: We are sorry for the inaccurate expression. The soluble media refers to TNF-α and we have re-edited in line 122.

8. Line 120-121: “Inflammatory factors released by microglia cells have an amplifying effect. These inflammatory agents (TNF-α, IL-1) amplify inflammatory activation through the special physiological structure of astrocytes[45].” - This is very loose and incoherent statement.

Response: We are grateful to reviewer’s suggestion. We added more examples to make clarify our ideas. For examples, studies shown that microglia rapidly release small amounts of ATP, and astrocytes, in turn, amplify this release, thereby increasing the frequency of excitatory postsynaptic currents through the ATP receptor P2Y1. We re-edited the section in lines 127 to 130.

9. Line 186: “Inhalation anesthesia affects CAN and NF- κ B pathway[28]” - What about intravenous anesthesia? Does it have other effect? or maybe it depends on specific substance used?

Response: We are grateful to the reviewer for raising this point. We found the current reports maunly focused on the inhaled anesthetic isoflurane, there were rarely researches on intravenous anesthetics and we will continue follow up on future research progress.

10. Line 217: “The hippocampus is an important organ for processing memory and consciousness in humans, and it is more susceptible to damage from external sources due to its specific structure[77].” - What kind of specific structure? Why is it specific?

Response: Thank you for pointing out this question. It is known that damage to specific neuronal populations in the hippocampus is highly correlated with glucocorticoid overdose/dysfunctioning hypothalamic-pituitary adrenal axis with neuroinflammatory associations. Specifically，during the stress response, GCs modulate the hippocampal function, affecting numerous signaling and metabolic systems . It is also important that, unlike other brain structures, the basal membrane covers only 30% of the vascular surface in the hippocampus, which facilitates the penetration of hormones and inflammatory factor into hippocampal neurons. We re-edited the section in lines 225 to 228.

11. Inflammation - is it always a bad thing?

Response: We thank the reviewer for this question. In our opinion, neuroinflammation is the friend and foe of neurological diseases. The neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. Microglia produce various neurotrophic factors that promote neurogenesis and plasticity. Astrocytes activated after neuroinflammation are also housekeeping cells essential for the maintenance of the central nervous system. They are actively involved in controlling ion and water homeostasis, releasing neurotrophins, clearing transmitters released during synaptic activity, shuttle metabolites and wastes, and participating in BBB formation.

Reviewer 2 Report

Thank you very much for giving me the opportunity to review an article with such an interesting topic, such as new perspective and new ideas for the clinical  rehabilitation and treatment of patients after Parkinson's surgery.

This is a review article which presents a new perspective and new ideas for the clinical rehabilitation and treatment of patients after Parkinson's surgery and the main purpose is to review the mechanisms of consciousness and speech impairment occurring after DBS from the perspective of neuroinflammation and to offer solutions in the field of neuroprotection. The authors provide the advantages of DBS surgery over drug therapy and the relationship between disturbance of consciousness and neuroinflammation and pyroptosis after DBS.

The topic is relevant in this field because the deeper molecular mechanisms remain unexplored. This article mainly reviews the advantages of DBS surgery over drug therapy and the relationship between disturbance of consciousness and neuroinflammation and pyroptosis after DBS.

The conclusions are mostly consistent with the evidence and arguments presented.

The authors have used appropriate references through which they support their study.

In my opinion, the manuscript is adequately written, it offers new information, so it is suitable for publication.

Author Response

We are grateful for reviewers' comments.

Round 2

Reviewer 1 Report

Dear authors, 

 

line 60: 2.1 … “Microglia serve as the brain's primary immune effector cells and are involved in the immune response, blood-brain barrier integrity, and nutrient provision for neurons[18,19]. ”

 

I still do not get how microglia are involved in BBB integrity and why you include reference for astrocytes here (#19) if you talk about microglial functions?

 

Line 61: Do you mean production of cytokines then? Which kind of "activation"?

 

“ Specifically, unlike other brain structures, the basal membrane covers only 30% of the vascular surface in the hippocampus , which facilitates the penetration of hormones and inflammatory factor into hippocampal neurons [80].”

 

Please refer to the original reference, which is not Komoltsev, but Licht.

 

Author Response

1. line 60: 2.1 … “Microglia serve as the brain's primary immune effector cells and are involved in the immune response, blood-brain barrier integrity, and nutrient provision for neurons[18,19]. ”

I still do not get how microglia are involved in BBB integrity and why you include reference for astrocytes here (#19) if you talk about microglial functions?

Response: We are sorry for the inappropriate expression. We have replaced the references and deleted the part about astrocytes and blood-brain barrier in lines 61-62

2. Line 61: Do you mean production of cytokines then? Which kind of "activation"?

Response: We thank the reviewer for this question. And yes we mean cytokines production and release. In our opinion neuroinflammation enhances the immune system and increases the penetration of endothelial tissues by immune cells. NF-κB promotes inflammatory cytokines, such as IL-6, TNF-α, and IL-1β. We have replaced the “activation” to “production and release” in line 63.

3.“ Specifically, unlike other brain structures, the basal membrane covers only 30% of the vascular surface in the hippocampus , which facilitates the penetration of hormones and inflammatory factor into hippocampal neurons [80].”

Please refer to the original reference, which is not Komoltsev, but Licht.

Response: We are sorry for the mistakes. And we have corrected the reference in line 227.