Objective To explore the neural mechanisms of brain impairment in type 2 diabetes mellitus (T2DM), abnormal changes to the functional connections between brain regions in the resting state were investigated based on a meta-analysis. Methods Resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessment were performed on 38 patients with T2DM and 33 healthy controls (HCs). Functional connectivity between regions based on a meta-analysis and other voxels in the brain was calculated and compared between the two groups using a two-samplettest. A correlation analysis was conducted between clinical/cognitive variables and functional connection values from the regions with significant differences in the above comparison. Results Patients in the T2DM group showed a significantly decreased functional connection between the right posterior cerebellum and the right middle/inferior occipital gyrus, left middle temporal gyrus, left superior frontal gyrus, left middle frontal gyrus, left insula, left precuneus, and right paracentral lobule/left precuneus when compared with HC group. The functional connection values between the right insula and left medial frontal gyrus, left supplementary motor area, and between the left lingual gyrus and right middle/inferior occipital gyrus in patients with T2DM were significantly decreased. Moreover, the functional connection values between the right posterior cerebellum and left middle frontal gyrus, and between the right posterior cerebellum and left precuneus were negatively correlated with HbA1c in the T2DM group (r = -.356,p = .03;r = -.334,p = .043). Conclusions Our study showed a wide range of cerebellar-cerebral circuit abnormalities in patients with T2DM, which provides a new direction to investigate the neuropathological mechanisms of T2DM from the perspective of the cerebellum.
Altered functional connectivity of brain regions based on a meta-analysis in patients with T2DM: A resting-state fMRI study
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Decision Letter
2020/05/2424-May-2020
Dear Mr. zhang:
It is a pleasure to accept your manuscript entitled "Altered functional connectivity of brain regions based on a meta-analysis in patients with T2DM: a resting-state fMRI study" in its current form for publication in Brain and Behavior. If there were further comments from the reviewer(s) who read your manuscript, they will be included at the foot of this letter.
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2020/05/21Dear Madam or Sir,
Thank you very much for giving us an opportunity to improve our manuscript entitled “Altered functional connectivity of brain regions based on a meta-analysis in patients with T2DM: a resting-state fMRI study”. We appreciate all the reviewers for their constructive comments and suggestions on our manuscript, which has been revised and shown in the manuscript attached with all changes tracked. The point by point responses to the reviewer’s comments have been listed after this letter. If any other concern exists, please just let me know at your first convenience.
I am looking forward to hear from you.
My very best regards.
Xiaoling Zhang, MD, PhD
Department of MRI, Shaanxi Provincial People’s Hospital
No.256 Youyi West Road, Xi’an, Shaanxi, People’s Republic of China
Postcode: 710068
E-mail address: zxl.822@163.comTo reviewer 1:
Thank you very much for your comments and advices, which are very useful for improving our manuscript. We would like to reply the following questions as below:1.Please provide the units of FOV (230×230 mm2) and full width at half maximum (6 mm).
Reply: Thank for your kind advice. We have made corresponding revised in the manuscript. (in MRI measurements section).
2. Please give more information about the visual impairment in T2DM patients and its relationship with brain aberrations.
Reply: Thank you for your terrific advises. We have added some evidence in the Discussion section to confirm the relationship between visual impairment and brain aberrations in T2DM patients. We hope the revised description as follow would be to your satisfaction.
Multiple studies (Cui, et al., 2014; Wang, et al., 2017) have confirmed the visual processing area of the occipital lobe is the most vulnerable region of the brain to T2DM. Cui et al. found diffusely decreased connectivity in the lingual gyrus-related visual network in patients with T2DM (Cui, et al., 2016). Our results were consistent with their findings. The lingual gyrus and middle occipital gyrus are important nodes of the visual network, which are crucial for the visual information processing relating to visual cognition (Zhen, et al., 2018). Reduced functional connection between the lingual gyrus and middle/inferior occipital gyrus indicates visual impairment in patients with T2DM. However, due to the presence of diabetic retinopathy patients in this study, we cannot determine whether this abnormal functional connection occurs before or reflects the neural basis of retinopathy. In future studies, we will try to clarify the neural mechanism of this abnormality.
To reviewer 2:
Thank you very much for your comments and advices, which are very useful for improving our manuscript. We would like to reply the following questions as below:1. In the sentence “At present, the amplitude...are the two metrics that are commonly...” Remove the word “the”, because other metrics, including ICA are also commonly used.
Reply: Thank for your kind advice. We have revised this statement according to your suggestion.
When reading the introduction section, this was not incorporated yet. This whole sentence could however be removed as the next sentence introduced the meta-analysis of ALFF studies.Reply: Thank for your kind advice. We have removed this sentence according to your suggestion.
2. I saw that in the statistical analysis subsection, a minimum cluster size > 46 voxels was defined for a cluster to be considered of interest. However, in Table 2 5 clusters with a lower number of voxels was presented. It is thus confusing as to whether these 5 clusters are considered of interest or if they are merely presented because the statistical analysis showed them. Please correct.
Reply: We feel sorry for our carelessness. It is a mistake because we did not check carefully. Based on our experience, we think when the voxel p was set at 0.001, with GRF correction at p 0.05, two-tailed, the cluster size should be > 46 voxels, but after examining the original data, we found that cluster size > 29 voxels in this study. We have revised it in the Statistical analysis section and the figure note of the manuscript. We hope to get your understanding.
3. Page 12 pdf: T2DM patients do not necessarily have eating disorders, in the sense of anorexia or bulimia. Maybe it would be better to state that eating patterns in T2DM are commonly altered and sometimes unhealthy.
Reply: You are absolutely right. We have revised the manuscript according to your suggestion.
4. Regarding the limitation section, I would like to see added that blood glucose was not measured directly before neuropsychological assessment and MRI examination. I also think that the remark about cognitive functioning can be removed. The authors have used clinically validated instruments, sometimes their scores simply do not correlate with certain brain alterations.
Reply: Thank for your kind advice. We have modified this sentence according to your suggestion.
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Decision Letter
2020/04/3030-Apr-2020
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Dear Mr. zhang:
Manuscript ID BRB3-2019-12-0822.R1 entitled "Altered functional connectivity of brain regions based on a meta-analysis in patients with T2DM: a resting-state fMRI study" which you submitted to Brain and Behavior, has been reviewed very favorably and minor revisions have been requested. I invite you to respond to the comments appended below and revise your manuscript.
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Reviewer(s)' Comments to Author:
Reviewer: 1
Comments to the Author
1. Please provide the units of FOV (230×230 mm2) and full width at half maximum (6 mm).
2. Please give more information about the visual impairment in T2DM patients and its relationship with brain aberrations.Reviewer: 2
Comments to the Author
I thank the authors for the changes they have made according to my suggestions. I find the paper significantly improved and have not come across any major problems anymore. There are some minor changes that can still be implemented.6. In the sentence “At present, the amplitude...are the two metrics that are commonly...” Remove the word “the”, because other metrics, including ICA are also commonly used.
Reply: Thank for your kind advice. We have revised this statement according to your suggestion.
When reading the introduction section, this was not incorporated yet. This whole sentence could however be removed as the next sentence introduced the meta-analysis of ALFF studies.I saw that in the statistical analysis subsection, a minimum cluster size > 46 voxels was defined for a cluster to be considered of interest. However, in Table 2 5 clusters with a lower number of voxels was presented. It is thus confusing as to whether these 5 clusters are considered of interest or if they are merely presented because the statistical analysis showed them. Please correct.
Page 12 pdf: T2DM patients do not necessarily have eating disorders, in the sense of anorexia or bulimia. Maybe it would be better to state that eating patterns in T2DM are commonly altered and sometimes unhealthy.
Regarding the limitation section, I would like to see added that blood glucose was not measured directly before neuropsychological assessment and MRI examination. I also think that the remark about cognitive functioning can be removed. The authors have used clinically validated instruments, sometimes their scores simply do not correlate with certain brain alterations.
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2020/04/27I thank the authors for the changes they have made according to my suggestions. I find the paper significantly improved and have not come across any major problems anymore. There are some minor changes that can still be implemented.
6. In the sentence “At present, the amplitude...are the two metrics that are commonly...” Remove the word “the”, because other metrics, including ICA are also commonly used.
Reply: Thank for your kind advice. We have revised this statement according to your suggestion.
When reading the introduction section, this was not incorporated yet. This whole sentence could however be removed as the next sentence introduced the meta-analysis of ALFF studies.I saw that in the statistical analysis subsection, a minimum cluster size > 46 voxels was defined for a cluster to be considered of interest. However, in Table 2 5 clusters with a lower number of voxels was presented. It is thus confusing as to whether these 5 clusters are considered of interest or if they are merely presented because the statistical analysis showed them. Please correct.
Page 12 pdf: T2DM patients do not necessarily have eating disorders, in the sense of anorexia or bulimia. Maybe it would be better to state that eating patterns in T2DM are commonly altered and sometimes unhealthy.
Regarding the limitation section, I would like to see added that blood glucose was not measured directly before neuropsychological assessment and MRI examination. I also think that the remark about cognitive functioning can be removed. The authors have used clinically validated instruments, sometimes their scores simply do not correlate with certain brain alterations.
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Reviewer report
2020/04/24- Please provide the units of FOV (230×230 mm2) and full width at half maximum (6 mm).
- Please give more information about the visual impairment in T2DM patients and its relationship with brain aberrations.
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Author Response
2020/04/19Dear Madam or Sir,
We have received your E-mail for guiding us to prepare the revised documents of our manuscript entitled ‘The functional connectivity of robustly impaired regions in T2DM patients: a resting-state fMRI study’ submitted for publication by Brain and Behavior.
Thank you so much for your recommendation and the very specific guideline for us to better present our work. We are also grateful for the reviewer’s comments for us to think deeply and further enhance the paper.
Following these very constructive editorial suggestions and review comments, we have carefully revised our manuscript accordingly. The revised portions are marked in color of red in the Manuscript with Tracked Changes file. The point by point responses to the reviewer’s comments have been listed after this letter. As to the language, we do have asked a native colleague to help us with the revision again. We believe that these revisions and changes will significantly improve the quality of the manuscript.
We are looking forward to your further information about our manuscript.
Thank you very much again for all your great valuable times and efforts in help handling our paper for review and improvement.Xiaoling Zhang, MD, PhD
Department of MRI, Shaanxi Provincial People’s Hospital
No.256 Youyi West Road, Xi’an, Shaanxi, People’s Republic of China
Postcode: 710068
E-mail address: zxl.822@163.comTo reviewer 1:
Thank you very much for your comments and advices, which are very useful for improving our manuscript. We would like to reply the following questions as below:1. The spelling and format in the whole manuscript should be checked carefully. Just for instance,
a. Currently, Abnormal neuronal activity…
b. neural basis of cognitive impairment(De Felice and…
Please check the spaces before and after brackets and other symbols in the whole text.
Reply: Thank you for your careful review of our manuscript. We have carefully checked the spelling and format and invited a native speaker to help us improving the English writing. We hope the revised manuscript would be to your satisfaction.2. “…and right insula were abnormally activated in T2DM patients.” Brain regions are usually activated in task-fMRI studies rather than in resting-state fMRI studies.
Reply: Thank you very much for helping us point out inappropriate wording. We have modified the sentence to “…and right insula were abnormally activity in T2DM patients” and the related descriptions have been revised in the revised manuscript.
3. The paragraph two in Introduction is too lengthy.
Reply: Thank you for your terrific advises. We have revised this paragraph to make it more concise and logical. We hope the revised sentences descripted clearly and could be to your satisfaction.
4. The duration of recruitment is missing.
Reply: We are sorry for our mistake. We have added the recruitment date in the Methods section.
5. Why the latest version of DPABI is not applied in the present study?
Reply: We regret that the latest DPABI version is not currently available in our hospital. The DPABI software is installed on the computing server of our department. The computing server is managed by a specific administrator and the DPABI has not been updated to the latest version. Nevertheless, the DPABI V2.3 is still used in many departments and the results are recognized by many professionals. Anyway, we will try to adopt the latest version of DPABI in our future research. We hope to get your understanding.
6. How were the masks of ROIs obtained from the previous study (Zhang DS et al., 2018)?
Reply: It is a good question. This is an achievement of our previous work (Zhang DS et al., 2018). We performed an ALE-meta analysis to estimate the altered spontaneous brain activity in type 2 diabetes mellitus and the masks of ROIs were generated. Data processing was completed in the MNI standard space coordinate system, and the results were corrected by FDR (P < 0.05, cluster size > 200mm3). We presented the corrected ALE-image results in the MNI standard space using DPABI software, and save the 4 clusters in the results map as MASK, the 4 ROIs were left lingual gyrus (-4, -74,- 2, cluster size = 800mm3), right cerebellum posterior lobe (28, -184, -14, cluster size = 488mm3), left postcentral gyrus (-16, -30,76, cluster size = 368mm3) and right insula (46,- 18,10, cluster size = 256mm3) respectively. Detailed information could be found in the previous publication (Zhang DS et al., 2018). We have added the above to the Method section of the revised manuscript.
7. You may summarize the results in the first paragraph in Discussion rather than repetition.
Reply: Thank you very much for your advices. We have revised the first paragraph of the Discussion as follows and presented it in the revised manuscript. We hope the revised description would be to your satisfaction.
The present study used brain regions from the previous meta-analysis as the ROIs to explore the functional connectivity patterns of these ROIs with the whole brain in patients with T2DM. We found multiple abnormal connections between different brain regions, especially the right cerebellar posterior lobe and extensive cerebral regions. In addition, the functional connectivity between the right posterior cerebellum and left middle frontal gyrus and left precuneus was negatively correlated with HbA1c in patients with T2DM. This suggests that the cerebellar–cerebral loop may be involved in neuropathological mechanisms of brain function in T2DM.
8. “However, in recent years, several studies…”However, you listed references decades ago.
Reply: We feel sorry for our mistake. We have revised this sentence and cited literature reasonably.
9. The fourth paragraph in Discussion is poorly organized. I could not get the points.
Reply: We feel sorry for our lack of clarity. We have revised this paragraph and listed some literature that were related to our research. Our study showed the decreased functional connection between the right posterior cerebellum and left precuneus negative correlations with HbA1c, which was consistent to some of the previous studies. This suggested disconnection between the right posterior cerebellum and left precuneus might be related to T2DM emotional abnormalities.
10. “Buckner RL et al(Buckner et al., 2011) noted that…” “Espeland et al.(Espeland et al., 2011) have found…” It seems strange.
Reply: Thank you for your terrific suggestion. We have revised our manuscript and invited a native speaker to help us improving the English writing. We hope the revised manuscript would be to your satisfaction.
11. “…might cause clinical symptoms of…” It is not appropriate to claim causality in a cross-sectional study.
Reply: Thanks so much for your valuable comments. We have adopted a more cautious statement as follows “Thus, the reduced functional connection between the insula and the medial frontal gyrus may be associated with the decreased ability to control food intake and abnormal eating behaviors in patients with T2DM”.
12. Did you take the least disease duration into consideration in the present study?
Reply: Thank you very much for your constructive comments. The subjects included in this study were all hospitalized patients. Most patients were re-visiting instead of first visit, so the duration of disease was longer. This may render our results unusable in patients with shorter durations. What’s more, we have discussed this concern in the Limitations of our study. We hope to get your understanding.
To reviewer 2:
Thank you very much for your comments and advices, which are very useful for improving our manuscript. We would like to reply the following questions as below:1. First, I want to highlight that the manuscript is thoughtfully written and that the English is of a high quality. Here and there I found some places where words were missing or where grammar was used in the wrong way. If the authors wish they could have a native speaker check for such minimal errors to further improve the quality of their manuscript. However, the manuscript is already good as is.
Reply: Thanks for your good comments. We have revised our manuscript and invited a native speaker to help us improving the English writing. We hope the revised manuscript would be to your satisfaction.
2. I had some trouble understanding the term “robustly impaired regions”, because to me it is not clear 1) when a region is robustly impaired, and 2) what damage would be necessary for the region to be robustly impaired. I understand that the authors wish to highlight that the selected seeds are data-driven rather than hypothesis-driven, but the chosen term did not do that for me. It might be something such as “regions based on a meta-analysis” or “data-driven region” or “regions previously found in other studies”. I realize it is not as catchy as “robustly impaired regions”, but it does help understanding where the regions came from.
Reply: Thanks so much for your valuable comments. In the original manuscript, we chose to use the term "robustly impaired regions" due to the ALE-meta analysis uses a probability algorithm. These brain regions derived from meta-analysis were the most stable vulnerable brain regions in previous multiple resting fMRI studies. However, this expression does not allow the reader to clearly understand the origin of these ROIs, so we chose to modify the term to "regions based on a meta-analysis".
3. The last sentence of the Abstract is somewhat generic. Firstly, because of the cross-sectional nature of this study, hyperglycemia is correlated, but it cannot be determined that hyperglycemia may affect connectivity. Second, what would the new perspectives be?
Reply: Thank you for your kind advices. We have revised the manuscript and adopted a more euphemistic statement as follows.
Conclusions: Our study showed a wide range of cerebellar–cerebral circuit abnormalities in patients with T2DM, which provides a new direction to investigate the neuropathological mechanisms of T2DM from the perspective of the cerebellum.
4. In the first paragraph of the Introduction section please add the word “potentially” to the sentence “…, increasing the risk of dementia.” It is not a given that cognitive decrements, especially mild decrements associated with type 2 diabetes increase the risk of dementia.
Reply: Thank for your kind advice. We have modified this sentence according to your suggestion.
5. In the second paragraph the second sentence about functional MRI talks about resting-state. Please add this.
Reply: Thank for your kind advice. We have added this statement according to your suggestion.
6. In the sentence “At present, the amplitude...are the two metrics that are commonly...” Remove the word “the”, because other metrics, including ICA are also commonly used.
Reply: Thank for your kind advice. We have revised this statement according to your suggestion.
7. On page 4, “These brain regions are not only correlated with cognitive functions,...” References are missing suggesting a connections between these brain regions and clinical manifestations.
Reply: Thank you for your great comments. We have modified this statement and added the corresponding references. Details could be found in the revised manuscript.
8. On the same page, the sentence that ALE uses to identify brain regions is difficult to understand and it also is somewhat out of context. Either remove this sentence of explain it in more detail.
Reply: Thank you for your great comments. We have made modifications to this sentence to make it more coherent.
9. Was a hypoglycemia protocol available for the testing day? What was the required blood glucose range during testing? How was a hyperglycemia event treated? Hypoglycemia within 24 hours before testing, did that lead to rescheduling? All could affect the fMRI outcomes as it is a functional scan and should be described.
Reply: The patients we included were all hospitalized patients, and their blood glucose was measured 5 times a day at regular intervals, including fasting blood glucose, 2 hours blood glucose after 3 meals, and blood glucose levels at 10 pm. By consulting the medical records, we can clearly understand the daily blood glucose levels of patients during hospitalization. Patients with any hypoglycemia (blood glucose < 3.9mmol / L) or hyperglycemia (blood glucose > 33.3mmol / L) during the hospital stay were excluded from the study and the examination will not be rescheduled. Patients underwent MRI within 2 hours after dinner and required postprandial blood glucose <33.3mmol/L. The postprandial blood glucose concentration of patients in this study ranged from 7.9 mmol/L to 21.8 mmol/L. We add the detailed description in the Methods section. We hope the revised manuscript would be to your satisfaction.
10. What was the blood glucose level right before testing?
Reply: We regret that data for blood glucose levels before testing is not available. In clinical practice all patients arrived at the department of MRI between 06:30 pm and 7: 00 pm after dinner. After a 30-minute neuropsychological test and a 30-minute MRI scan, patients returned to the ward and then measured the postprandial blood glucose. We hope to get your understanding.
11. It would be helpful to report the number of patients with complications and what medication they used in Table 1.
Reply: Thank you for your terrific advices. We have been added them in Table 1 according to your suggestion.
12. The clock drawing test is not necessarily a test for visuospatial skills. In fact, many more functions are needed to execute this test, including but not limited to executive functions. It is more a measure of global integrated cognitive ability.
Reply: We greatly admire your profound knowledge. As doctors of radiology, we know relatively little about the cognitive scale. After received your comments, we consulted the relevant literature and found that CDT can not only evaluate visual spatial functions, but also evaluate various cognitive functions such as visual memory, executive functions, and abstract thinking. We have made corresponding revised in the manuscript.
13. MRI analysis details are clear, but the seeds and the seed-based methods are not clearly described in the Methods section. Please provide the names of all seeds, from what space to what space they were transformed and how, and if their time-course was extracted in native space or in standard space. A figure with the seeds, or an additional image of the seed in the current figures would be helpful.
Reply: Thank you for your terrific advices. The ROIs acquisition was done in our previous study (Zhang DS et al., 2018). Zhang et al. performed an ALE-meta analysis study to estimate the most stable vulnerable brain regions in type 2 diabetes mellitus and the masks of ROIs were generated accordingly. The ALE-meta analysis data processing was completed in the MNI standard space coordinate system, and the results were corrected by FDR (P < 0.05, cluster size > 200mm3). We presented the corrected ALE-image results in the MNI standard space using DPABI software, and saved the 4 clusters in the results map as MASK, and the 4 ROIs were left lingual gyrus (-4, -74,- 2, cluster size = 800mm3), right cerebellum posterior lobe (28, -184, -14, cluster size = 488mm3), left postcentral gyrus (-16, -30,76, cluster size = 368mm3) and right insula (46,- 18,10, cluster size = 256mm3) respectively. All above had been added to the revised manuscript and the ROI map were showed in the corresponding Figure 1-3.
14. I am not familiar with how DPABI executes a GRF analysis, but generally a minimum cluster size is a priori determined and the cluster threshold (p=0.001 in SPM or z=3.1 in FSL are standard). Am I correct to assume that the cluster p was set at 0.001, with FWE correction at p 0.05? Then the only thing that is missing is the minimum cluster size. Please revise the text.
Reply: GRF correction is a multiple comparison correction method based on a Gaussian random field. This study voxel p was set at 0.001, with GRF correction at p 0.05, two-tailed and cluster size > 46. we have revised it in the Statistical analysis section and the figure note of the manuscript.
15. Education level is different between the groups. Adding this as an additional confounding factor, does this alter the results?
Reply: Thank you for your terrific advices. We have added education level as a covariate in the inter-group analysis to avoid its impact on the results in the original manuscript and highlighted it here in yellow in the Statistical analysis section of the revised manuscript. The results given in the original manuscript were after eliminating this confounding factor.
16. The results would benefit from some additional subheadings. Breaking up the fMRI analysis into seed-specific subheading will make it clearer to understand what clusters were found by using which seed.
Reply: This is indeed a very good suggestion. We have revised our manuscript with additional subheadings. We wish the revised manuscript was clearer for understanding.
17. Also, if this is a cluster methods, it would be good to discuss the results in terms of the areas pertaining to the clusters. For example, the connectivity with the right posterior cerebellum might consist of 1 big cluster, but could also comprise 4 separate clusters. From the text this is unclear.
Reply: We feel sorry for our vague description. As shown in Figure 1-3, the result of the functional connection includes multiple separate clusters instead of 1 big cluster. Each cluster includes one or two brain regions, so our discussion is based on the important regions included in the cluster. We added subtitles to the discussion section to make the article well-organized.
18. This is also important for the post-hoc correlation analysis. If all regions that correlated with the seed are taken separately, a large number of tests was carried out and a form of correction for multiple comparisons should be applied to increase reliability of the found correlations. If it all is 1 cluster, correlation results are reliable, but very unspecific. Therefore, please detail the clusters, and if the correlations are really carried out with all regions separately, please take measures to make them more reliable.
Reply: Thank you for your great comments. There are 7 clusters had different functional connections to the right posterior cerebellum, including right middle/inferior occipital gyrus, left middle temporal gyrus, left superior frontal gyrus, left middle frontal gyrus, left insula, left precuneus, right paracentral lobule / left precuneus. Correlation analysis was performed between all the different regions with cognitive scores and clinical variables. The significant correlation presented in the manuscript have not been corrected, since all correlations do not significant after Bonferroni correction. This suggests that these correlations may be just a trend. What’s more, we have added detailed explanations in the revised manuscript.
19. Correlations with cognitive tests were not studied? Or were there no correlations?
Reply: It is our mistake for not listing these results. All abnormal functional connections were analyzed for correlation with cognitive tests. However, there were no statistical associations observed. We have added the declaration in the revised manuscript (in the Correlation analysis section of Results).
20. When it comes to the cerebellum, scan coverage is sometimes limited and signal can sometimes be distorted due to its location. Given that most of the results are with the right posterior cerebellum seed, it is important to verify that all participants showed sufficient cerebellar coverage, and that all had undistorted signal.
Reply: It is quite a good question. First, the MRI technicians were fixed during the data collection. After the data collection, an experienced researcher was responsible for quality control to ensure that the data in the group included the whole brain tissue. Secondly, during data pre-processing, we examined the registration images of each subject and eliminated the subjects with poor registration and incomplete cerebellar scanning. Ensure that the cerebellum of all subjects included were complete.
21. On page 9 in the Discussion section, the sentence about connectivity with the right posterior cerebellum suggesting a related functional impairment is extrapolating the results to a large extent. As this was not tested, it would be better to delete this sentence from the text. It would be interesting to briefly discuss literature that has studied posterior cerebellum functions.
Reply: We absolutely agree with you. We have revised this section according to your suggestion. We hope the revised manuscript would be to your satisfaction.
22. On page 10, one cannot say that hyperglycemia might lead to cognitive dysfunction by affecting the prefrontal-cerebellar loop, because 1) this is a cross-sectional study, 2) correlations between HbA1c and cognition, and between cognition and connectivity were not studied, and 3) there were more alterations found than only those in the prefrontal-cerebellar loop. Please remove.
Reply: You are absolutely right. We have revised these statements according to your suggestion. We hope the revised manuscript would be to your satisfaction.
23. In the next paragraph, which is about the precuneus, it is stated that connectivity between the posterior cingulate and the left middle temporal gyrus is related to HbA1c. This is not was is presented in the Results section. Is this an error?
Reply: We are sorry for our unclear statement. This is a finding of a previous study (Yang et al., 2016). Thus it is unlikely to present in our results. We have revised this statement to make it more clear. We hope to get your understanding.
24. Furthermore, I have difficulty understanding this paragraph, because it lacks focus and also presents causal relations in the last sentence. Deleting this whole paragraph will, in my opinion, improve the Discussion section.
Reply: This paragraph discussed the relationship between connection of precuneus and posterior cerebellum and levels of HbA1c, which was an important finding for our research. We have made substantial modifications as follows to make this section clearer and more coherent. We hope to get your understanding.
The precuneus and middle temporal gyrus belong to default mode networks (DMN) and the posterior cerebellum is functionally coupled to DMN (Buckner et al., 2011). Multiple studies (Musen et al., 2012; Yang et al., 2016; Zhang et al., 2015) confirm abnormal functional connections within DMN and between DMN and other regions in patients with T2DM. In addition, one study (Yang et al., 2016) found that the connection between the bilateral posterior lobe of the cerebellum and DMN decreased and was negatively correlated with HbA1c in patients with T2DM. Our study found similar results and suggested that the decreased functional connection between the right posterior cerebellum and left precuneus was negatively correlated with HbA1c, which provides further evidence for the destruction of the connection between the cerebellum and DMN in patients with T2DM, especially the disconnection between the right posterior cerebellum and left precuneus. Patients with depression have abnormal functional connections between the cerebellum and precuneus and may predict suicidal tendencies (Zhang et al., 2016). Several studies (O'Connor et al., 2009; Stuart & Baune, 2012) suggest that the relationship between depression and T2DM is bidirectional or co-morbidity. Therefore, we speculate that disconnection between the right posterior cerebellum and left precuneus may be related to emotional abnormalities in patients with T2DM.
25. In the third paragraph on the same page, abnormal feeding behavior is one of the typical symptoms of T2DM. I do not think this is correct. Abnormal feeding behavior, in the sense of overeating and not eating healthy food can lead to type 2 diabetes, but I would not consider this a symptom of type 2 diabetes.
Reply: You are absolutely right. We have revise this sentence according to your suggestion.
26. On page 11, how would connectivity between the insula and the SMA impair motor functions in type 2 diabetes? Was this tested by the authors?
Reply: We are sorry for our irresponsible statement. We have not tested it, the expression that decreased functional connectivity between the insula and the supplementary motor area (BA 6) affects motor function is inappropriate and we have revised this statement in our manuscript.
27. The last sentence of that paragraph should be deleted. Now this study does not provide neuroimaging evidence of motor impairment, because it was not tested in any way. Be very careful with such causal and strong statements in cross-sectional studies.
Reply: Thank you for your terrific advices. We have removed this sentence according to your suggestion.
28. In the limitations, it is mentioned that this study lacks assessment scales for evaluating cognitive functions. In the Methods section, however, cognitive tests are mentioned. Are they used and applied or not?
Reply: We are sorry for our ambiguous statement. What we're trying to say is that current cognitive functions scales cannot well reflect the behavioral manifestations of brain abnormalities, more suitable scales should be developed. We have revised this sentence in the Limitations of our manuscript.
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- pre-publication peer review (ROUND 1)
Decision Letter
2020/02/2323-Feb-2020
Dear Mr. zhang:
Manuscript ID BRB3-2019-12-0822 entitled "The functional connectivity of robustly impaired regions in T2DM patients: a resting-state fMRI study" which you submitted to Brain and Behavior, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.
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Reviewer(s)' Comments to Author:
Reviewer: 1
Comments to the Author
This study explored the functional connectivity of T2DM patients taking robustly impaired regions as seeds. The functional connectivity anchoring the seeds were decreased and negatively correlated with HbA1c in T2DM group. The results may provide a new perspective for exploring brain function impairment in patients with T2DM. There are some points in the manuscript, which have to be addressed and possibly corrected before publication in this form.
1. The spelling and format in the whole manuscript should be checked carefully. Just for instance,
a. Currently, Abnormal neuronal activity…
b. neural basis of cognitive impairment(De Felice and…
Please check the spaces before and after brackets and other symbols in the whole text.
2. “…and right insula were abnormally activated in T2DM patients.” Brain regions are usually activated in task-fMRI studies rather than in resting-state fMRI studies.
3. The paragraph two in Introduction is too lengthy.
4. The duration of recruitment is missing.
5. Why the latest version of DPABI is not applied in the present study?
6. How were the masks of ROIs obtained from the previous study (Zhang DS et al., 2018)?
7. You may summarize the results in the first paragraph in Discussion rather than repetition.
8. “However, in recent years, several studies…”However, you listed references decades ago.
9. The fourth paragraph in Discussion is poorly organized. I could not get the points.
10. “Buckner RL et al(Buckner et al., 2011) noted that…” “Espeland et al.(Espeland et al., 2011) have found…” It seems strange.
11. “…might cause clinical symptoms of…” It is not appropriate to claim causality in a cross-sectional study.
12. Did you take the least disease duration into consideration in the present study?Reviewer: 2
Comments to the Author
In this manuscript, the authors report the results of a seed-based connectivity analysis comparing connectivity patterns of seeds selected from a meta-analysis between patients with type 2 diabetes and controls. The results showed that connectivity between most seeds and the rest of the brain was decreased in the patient group versus the control group. Additionally, lower connectivity between the right posterior cerebellum and the left middle frontal gyrus and the left precuneus was related to higher HbA1c in type 2 diabetes. This is an interesting article, especially because the chosen seeds were all found in a meta-analysis of Chinese articles studying forms of functional connectivity in type 2 diabetes. I do have several questions and observations.First, I want to highlight that the manuscript is thoughtfully written and that the English is of a high quality. Here and there I found some places where words were missing or where grammar was used in the wrong way. If the authors wish they could have a native speaker check for such minimal errors to further improve the quality of their manuscript. However, the manuscript is already good as is.
I had some trouble understanding the term “robustly impaired regions”, because to me it is not clear 1) when a region is robustly impaired, and 2) what damage would be necessary for the region to be robustly impaired. I understand that the authors wish to highlight that the selected seeds are data-driven rather than hypothesis-driven, but the chosen term did not do that for me. It might be something such as “regions based on a meta-analysis” or “data-driven region” or “regions previously found in other studies”. I realize it is not as catchy as “robustly impaired regions”, but it does help understanding where the regions came from.
The last sentence of the Abstract is somewhat generic. Firstly, because of the cross-sectional nature of this study, hyperglycemia is correlated, but it cannot be determined that hyperglycemia may affect connectivity. Second, what would the new perspectives be?
In the first paragraph of the Introduction section please add the word “potentially” to the sentence “…, increasing the risk of dementia.” It is not a given that cognitive decrements, especially mild decrements associated with type 2 diabetes increase the risk of dementia.
In the second paragraph the second sentence about functional MRI talks about resting-state. Please add this.
In the sentence “At present, the amplitude...are the two metrics that are commonly...” Remove the word “the”, because other metrics, including ICA are also commonly used.
On page 4, “These brain regions are not only correlated with cognitive functions,...” References are missing suggesting a connections between these brain regions and clinical manifestations.
On the same page, the sentence that ALE uses to identify brain regions is difficult to understand and it also is somewhat out of context. Either remove this sentence of explain it in more detail.
Was a hypoglycemia protocol available for the testing day? What was the required blood glucose range during testing? How was a hyperglycemia event treated? Hypoglycemia within 24 hours before testing, did that lead to rescheduling? All could affect the fMRI outcomes as it is a functional scan and should be described.
What was the blood glucose level right before testing?
It would be helpful to report the number of patients with complications and what medication they used in Table 1.
The clock drawing test is not necessarily a test for visuospatial skills. In fact, many more functions are needed to execute this test, including but not limited to executive functions. It is more a measure of global integrated cognitive ability.
MRI analysis details are clear, but the seeds and the seed-based methods are not clearly described in the Methods section. Please provide the names of all seeds, from what space to what space they were transformed and how, and if their time-course was extracted in native space or in standard space. A figure with the seeds, or an additional image of the seed in the current figures would be helpful.
I am not familiar with how DPABI executes a GRF analysis, but generally a minimum cluster size is a priori determined and the cluster threshold (p=0.001 in SPM or z=3.1 in FSL are standard). Am I correct to assume that the cluster p was set at 0.001, with FWE correction at p 0.05? Then the only thing that is missing is the minimum cluster size. Please revise the text.
Education level is different between the groups. Adding this as an additional confounding factor, does this alter the results?
The results would benefit from some additional subheadings. Breaking up the fMRI analysis into seed-specific subheading will make it clearer to understand what clusters were found by using which seed.
Also, if this is a cluster methods, it would be good to discuss the results in terms of the areas pertaining to the clusters. For example, the connectivity with the right posterior cerebellum might consist of 1 big cluster, but could also comprise 4 separate clusters. From the text this is unclear.
This is also important for the post-hoc correlation analysis. If all regions that correlated with the seed are taken separately, a large number of tests was carried out and a form of correction for multiple comparisons should be applied to increase reliability of the found correlations. If it all is 1 cluster, correlation results are reliable, but very unspecific. Therefore, please detail the clusters, and if the correlations are really carried out with all regions separately, please take measures to make them more reliable.
Correlations with cognitive tests were not studied? Or were there no correlations?
When it comes to the cerebellum, scan coverage is sometimes limited and signal can sometimes be distorted due to its location. Given that most of the results are with the right posterior cerebellum seed, it is important to verify that all participants showed sufficient cerebellar coverage, and that all had undistorted signal.
On page 9 in the Discussion section, the sentence about connectivity with the right posterior cerebellum suggesting a related functional impairment is extrapolating the results to a large extent. As this was not tested, it would be better to delete this sentence from the text. It would be interesting to briefly discuss literature that has studied posterior cerebellum functions.
On page 10, one cannot say that hyperglycemia might lead to cognitive dysfunction by affecting the prefrontal-cerebellar loop, because 1) this is a cross-sectional study, 2) correlations between HbA1c and cognition, and between cognition and connectivity were not studied, and 3) there were more alterations found than only those in the prefrontal-cerebellar loop. Please remove.
In the next paragraph, which is about the precuneus, it is stated that connectivity between the posterior cingulate and the left middle temporal gyrus is related to HbA1c. This is not was is presented in the Results section. Is this an error?
Furthermore, I have difficulty understanding this paragraph, because it lacks focus and also presents causal relations in the last sentence. Deleting this whole paragraph will, in my opinion, improve the Discussion section.
In the third paragraph on the same page, abnormal feeding behavior is one of the typical symptoms of T2DM. I do not think this is correct. Abnormal feeding behavior, in the sense of overeating and not eating healthy food can lead to type 2 diabetes, but I would not consider this a symptom of type 2 diabetes.
On page 11, how would connectivity between the insula and the SMA impair motor functions in type 2 diabetes? Was this tested by the authors?
The last sentence of that paragraph should be deleted. No this study does not provide neuroimaging evidence of motor impairment, because it was not tested in any way. Be very careful with such causal and strong statements in cross-sectional studies.
In the limitations, it is mentioned that this study lacks assessment scales for evaluating cognitive functions. In the Methods section, however, cognitive tests are mentioned. Are they used and applied or not?
Decision letter by
Cite this decision letter
Reviewer report
2020/02/21In this manuscript, the authors report the results of a seed-based connectivity analysis comparing connectivity patterns of seeds selected from a meta-analysis between patients with type 2 diabetes and controls. The results showed that connectivity between most seeds and the rest of the brain was decreased in the patient group versus the control group. Additionally, lower connectivity between the right posterior cerebellum and the left middle frontal gyrus and the left precuneus was related to higher HbA1c in type 2 diabetes. This is an interesting article, especially because the chosen seeds were all found in a meta-analysis of Chinese articles studying forms of functional connectivity in type 2 diabetes. I do have several questions and observations.
First, I want to highlight that the manuscript is thoughtfully written and that the English is of a high quality. Here and there I found some places where words were missing or where grammar was used in the wrong way. If the authors wish they could have a native speaker check for such minimal errors to further improve the quality of their manuscript. However, the manuscript is already good as is.
I had some trouble understanding the term “robustly impaired regions”, because to me it is not clear 1) when a region is robustly impaired, and 2) what damage would be necessary for the region to be robustly impaired. I understand that the authors wish to highlight that the selected seeds are data-driven rather than hypothesis-driven, but the chosen term did not do that for me. It might be something such as “regions based on a meta-analysis” or “data-driven region” or “regions previously found in other studies”. I realize it is not as catchy as “robustly impaired regions”, but it does help understanding where the regions came from.
The last sentence of the Abstract is somewhat generic. Firstly, because of the cross-sectional nature of this study, hyperglycemia is correlated, but it cannot be determined that hyperglycemia may affect connectivity. Second, what would the new perspectives be?
In the first paragraph of the Introduction section please add the word “potentially” to the sentence “…, increasing the risk of dementia.” It is not a given that cognitive decrements, especially mild decrements associated with type 2 diabetes increase the risk of dementia.
In the second paragraph the second sentence about functional MRI talks about resting-state. Please add this.
In the sentence “At present, the amplitude...are the two metrics that are commonly...” Remove the word “the”, because other metrics, including ICA are also commonly used.
On page 4, “These brain regions are not only correlated with cognitive functions,...” References are missing suggesting a connections between these brain regions and clinical manifestations.
On the same page, the sentence that ALE uses to identify brain regions is difficult to understand and it also is somewhat out of context. Either remove this sentence of explain it in more detail.
Was a hypoglycemia protocol available for the testing day? What was the required blood glucose range during testing? How was a hyperglycemia event treated? Hypoglycemia within 24 hours before testing, did that lead to rescheduling? All could affect the fMRI outcomes as it is a functional scan and should be described.
What was the blood glucose level right before testing?
It would be helpful to report the number of patients with complications and what medication they used in Table 1.
The clock drawing test is not necessarily a test for visuospatial skills. In fact, many more functions are needed to execute this test, including but not limited to executive functions. It is more a measure of global integrated cognitive ability.
MRI analysis details are clear, but the seeds and the seed-based methods are not clearly described in the Methods section. Please provide the names of all seeds, from what space to what space they were transformed and how, and if their time-course was extracted in native space or in standard space. A figure with the seeds, or an additional image of the seed in the current figures would be helpful.
I am not familiar with how DPABI executes a GRF analysis, but generally a minimum cluster size is a priori determined and the cluster threshold (p=0.001 in SPM or z=3.1 in FSL are standard). Am I correct to assume that the cluster p was set at 0.001, with FWE correction at p 0.05? Then the only thing that is missing is the minimum cluster size. Please revise the text.
Education level is different between the groups. Adding this as an additional confounding factor, does this alter the results?
The results would benefit from some additional subheadings. Breaking up the fMRI analysis into seed-specific subheading will make it clearer to understand what clusters were found by using which seed.
Also, if this is a cluster methods, it would be good to discuss the results in terms of the areas pertaining to the clusters. For example, the connectivity with the right posterior cerebellum might consist of 1 big cluster, but could also comprise 4 separate clusters. From the text this is unclear.
This is also important for the post-hoc correlation analysis. If all regions that correlated with the seed are taken separately, a large number of tests was carried out and a form of correction for multiple comparisons should be applied to increase reliability of the found correlations. If it all is 1 cluster, correlation results are reliable, but very unspecific. Therefore, please detail the clusters, and if the correlations are really carried out with all regions separately, please take measures to make them more reliable.
Correlations with cognitive tests were not studied? Or were there no correlations?
When it comes to the cerebellum, scan coverage is sometimes limited and signal can sometimes be distorted due to its location. Given that most of the results are with the right posterior cerebellum seed, it is important to verify that all participants showed sufficient cerebellar coverage, and that all had undistorted signal.
On page 9 in the Discussion section, the sentence about connectivity with the right posterior cerebellum suggesting a related functional impairment is extrapolating the results to a large extent. As this was not tested, it would be better to delete this sentence from the text. It would be interesting to briefly discuss literature that has studied posterior cerebellum functions.
On page 10, one cannot say that hyperglycemia might lead to cognitive dysfunction by affecting the prefrontal-cerebellar loop, because 1) this is a cross-sectional study, 2) correlations between HbA1c and cognition, and between cognition and connectivity were not studied, and 3) there were more alterations found than only those in the prefrontal-cerebellar loop. Please remove.
In the next paragraph, which is about the precuneus, it is stated that connectivity between the posterior cingulate and the left middle temporal gyrus is related to HbA1c. This is not was is presented in the Results section. Is this an error?
Furthermore, I have difficulty understanding this paragraph, because it lacks focus and also presents causal relations in the last sentence. Deleting this whole paragraph will, in my opinion, improve the Discussion section.
In the third paragraph on the same page, abnormal feeding behavior is one of the typical symptoms of T2DM. I do not think this is correct. Abnormal feeding behavior, in the sense of overeating and not eating healthy food can lead to type 2 diabetes, but I would not consider this a symptom of type 2 diabetes.
On page 11, how would connectivity between the insula and the SMA impair motor functions in type 2 diabetes? Was this tested by the authors?
The last sentence of that paragraph should be deleted. No this study does not provide neuroimaging evidence of motor impairment, because it was not tested in any way. Be very careful with such causal and strong statements in cross-sectional studies.
In the limitations, it is mentioned that this study lacks assessment scales for evaluating cognitive functions. In the Methods section, however, cognitive tests are mentioned. Are they used and applied or not?
Reviewed by
Cite this review
Reviewer report
2020/01/14This study explored the functional connectivity of T2DM patients taking robustly impaired regions as seeds. The functional connectivity anchoring the seeds were decreased and negatively correlated with HbA1c in T2DM group. The results may provide a new perspective for exploring brain function impairment in patients with T2DM. There are some points in the manuscript, which have to be addressed and possibly corrected before publication in this form.
1. The spelling and format in the whole manuscript should be checked carefully. Just for instance,
a. Currently, Abnormal neuronal activity…
b. neural basis of cognitive impairment(De Felice and…
Please check the spaces before and after brackets and other symbols in the whole text.
2. “…and right insula were abnormally activated in T2DM patients.” Brain regions are usually activated in task-fMRI studies rather than in resting-state fMRI studies.
3. The paragraph two in Introduction is too lengthy.
4. The duration of recruitment is missing.
5. Why the latest version of DPABI is not applied in the present study?
6. How were the masks of ROIs obtained from the previous study (Zhang DS et al., 2018)?
7. You may summarize the results in the first paragraph in Discussion rather than repetition.
8. “However, in recent years, several studies…”However, you listed references decades ago.
9. The fourth paragraph in Discussion is poorly organized. I could not get the points.
10. “Buckner RL et al(Buckner et al., 2011) noted that…” “Espeland et al.(Espeland et al., 2011) have found…” It seems strange.
11. “…might cause clinical symptoms of…” It is not appropriate to claim causality in a cross-sectional study.
12. Did you take the least disease duration into consideration in the present study?Reviewed by
Cite this review
