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Congratulations, the manuscript can be accepted now!
[# PeerJ Staff Note - this decision was reviewed and approved by Jafri Abdullah, a PeerJ Section Editor covering this Section #]
One reviewer has still raised major concerns, and the authors should carefully address them.
The revised manuscript has significantly improved in its basic reporting. The authors have addressed all the previous concerns related to clarity and completeness of the methods, results, and conclusions.
The experimental design section has been strengthened considerably in the revised version. The authors have provided clear and detailed information on the methodology, including appropriate controls and justification for the chosen approach. The revisions demonstrate a robust experimental design that supports the validity and reliability of the findings.
The concerns regarding the validity of the findings have been effectively addressed in the revised manuscript.
The author has made efforts to address all the comments I provided earlier, implementing the suggested revisions to improve the overall quality of the manuscript. However, upon further review, it appears that the manuscript still requires some revisions to fully address the remaining issues and meet the necessary standards.
1. Have previous studies reported any changes in hypothalamic brain function or structure associated with insomnia disorder? Please provide relevant information on this topic in the Introduction.
2. Please summarize the final paragraph of the Introduction.
3. The study explored the relationship between FC values and serum levels of arousal-promoting neurotransmitters (orexin-A and histamine) in ID patients. However, the discussion in this section is insufficient. You should supplement the discussion on the relevance between FC and neurotransmitters.
4. To ensure consistency, you should standardize the abbreviation for "litre" across lines 199-201. For instance, if you use "L" for "litre" in one instance, make sure it’s applied uniformly throughout those lines.
5. In the abstract, you used the abbreviation "RS-fMRI" for Resting-state functional magnetic resonance imaging. The same abbreviation should be defined in the main text to maintain consistency.
6. In the third paragraph of the Discussion, "neurotransmitter (histamine and orexin-A)" should be changed to "neurotransmitters (histamine and orexin-A)".
7. The abbreviations in some of the figures do not match their corresponding terms. Please verify and correct them.
no comment
The study has several limitations, primarily including a small sample size, which should be reflected in the conclusion.
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All the reviewers raised several critical concerns. The authors should carefully address them.
1. The study mentioned using PSG over two nights, with the second night aimed at eliminating the first-night effect. Please clarify what is meant by the "first-night effect."
2. In the conclusion, the authors stated that ID patients showed aberrant functional connectivity in brain arousal-promoting regions. Please clarify what constitutes "arousal-promoting regions" and provide relevant references.
3. The authors conducted correlations between FC values and scales/PSG indices but did not discuss these correlations in the manuscript. Please explain what insights these correlations might provide.
4. Please ensure attention to spelling details. All abbreviations used for the first time should be clearly defined.
1. The authors measured neurotransmitter levels in peripheral blood rather than in cerebrospinal fluid or brain tissue. It is generally believed that insomnia disorder correlates more closely with central rather than peripheral neurotransmitter levels. Please provide a rationale for measuring peripheral arousal-promoting neurotransmitters, such as evidence demonstrating the correlation between central and peripheral neurotransmitter levels.
2. The study included assessments beyond sleep: emotional and cognitive scales, revealing differences between ID patients and the control group. Please explain how incorporating these assessments contribute to the understanding in this study.
Please describe how confounding factors were controlled throughout the entire study process, including study design and statistical analysis.
Authors found that insomnia disorder patients exhibited aberrant functional connectivity, which correlated with elevated peripheral levels of histamine. The topic is attractive but he authors need to provide clear information regarding the study's design and other details.
1. The sentence "the changes of the PH FC value may reflect alterations in arousal" (line 264) contains two consecutive abbreviations, which impairs readability. You should rewrite the sentence to describe it more clearly.
2. Please provide references for the hypotheses you propose (lines 99-101).
1. Although the reasons for using peripheral arousal-promoting neurotransmitters are explained, analyzing correlations with central arousal-promoting neurotransmitters and brain function would better demonstrate their association. The lack of analysis using central neurotransmitters should be acknowledged as a limitation in your study, and this should be clarified in the manuscript.
2. You investigated several scales in your study (lines 125-130). We understand that the two sleep scales were used to assess sleep status and correlate it with brain function. However, given that comorbid mood disorders were excluded in the criteria, why were mood scales still used? Please clarify the purpose. Additionally, regarding the MOCA scale, please explain the reason for its inclusion in your study.
3. Please explain the reason for including BMI in your study.
4. More detailed information is needed regarding the MRI acquisition process.
5. Please provide a clear description of the sequence in which blood samples and MRI scans were collected.
Your study only examined the correlation between neurotransmitters and functional connectivity. In my opinion, the conclusions drawn appear overly definitive. I suggest that you rephrase the sentence at lines 329-331.
Insomnia disorder can be classified into different subtypes according to various criteria. Please indicate whether your study considered the impact of different insomnia subtypes on brain function and neurotransmitters. Addressing this would enhance the design of study.
The article investigated the functional connectivity of the anterior and posterior hypothalamus with the whole brain in insomnia disorder patients, and explored the relationship between functional connectivity values and serum levels of arousal-promoting neurotransmitters. It is well written and will deepen our understanding of the potential neuro-imaging and neuro-humoral mechanisms underlying insomnia disorders.
No comment.
No comment.
Although the findings sound reasonable and interesting, there are still some issues that need to be addressed and clarified.
1. The foundational research on hypothalamus as ROI cited in the article is sparse, relying on references from only two studies. Have other researchers conducted brain functional studies utilizing the hypothalamus as a ROI?
2. How long did the EPI sequences and T1 sequences last, respectively? The author should include details in the MRI data acquisition section.
3. Regarding Figure 5, are the deviations reported as standard deviation (SD) or standard error (SE)? This should be specified in the figure.
4. Were the samples in the ELISA measurement tested in duplicates? Was a single standard curve or a double standard curve employed?
5. This study involved several assessments/measurements including PSG, blood sampling, and MRI scans. How were these assessments/measurements sequence in time? Was there a standardized order?
6. Arousal-promoting neurotransmitters include more than orexin-A and histamine. Why were these two chosen for measurement? Please provide further elaboration.
7. When comparing functional connectivity between the ID group and HC group, were covariates used to control for biases?
8. Provide additional details about the scale used in the study, including a more comprehensive description.
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