PONE-D-21-12168

Altered resting-state functional connectivity of the frontal-striatal circuit in elderly with apathetic state

PLOS ONE

Dear Dr. Hamada,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Academic Editor

PLOS ONE

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2. Please consider rephrasing "apathetic people" to "patients/people with apathy", as our our submission guidelines (http://journals.plos.org/plosone/s/submission-guidelines) suggest changing potentially stigmatizing labels should be changed to more current, acceptable terminology.

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4. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://direct.mit.edu/jocn/article/24/11/2186/27852/Decreased-Functional-Connectivity-by-Aging-Is

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

Additional Editor Comments (if provided):

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The present study compared resting state striatal functional connectivity between the apathy and non-apathy groups. The connectivity between the ventral rostral putamen and the right dorsal anterior cingulate cortex/supplementary motor area was found decreased in the apathetic group while the connectivity between the dorsal caudate and the left sensorimotor area was increased. The ROI-to-ROI analysis revealed reduction of functional connectivity between the ventral regions and dorsal regions of the striatum in the apathy group. These results may help us to under stand the neural alteration associated with apathy. This reviewer has several concerns as below.

The description of data preprocessing on page 8 is not clear. The phrase of ‘scrubbing parameter with a band-pass filter of 0.01-0,08Hz’ is confusing. Considering the later sentence stated that the scrubbing parameter was used to identify the outlier scans, did the authors want to express in the first sentence that a band pass filtering was used and a scrubbing strategy was used to cutoff outlier scans using a ‘parameter’ generated by the toolbox? If so, what parameter and threshold was used to determine an outlier scan? For example, the frame-displacement (FD >0.5mm) was used in many previous studies.

The description of “functional connectivity analysis” is not clear. It was said that ‘In the first-level analysis, a multiple regression analysis was performed for each individual subject using the general linear model for correlation connectivity estimation’. My understanding of the procedure is that ‘the multiple regression analysis’ was used in the preprocessing stage to regress out nuisance variables including head motions and others. Then the resultant errors were band-pass filtered. The time course of each seed mask was extracted and correlated with the time course of each voxel. The correlation coefficients were then transferred with Fisher’s Z-transformation.

The FWHM of 8 mm seem too big as the seed ROIs are close to each other. In literature, 5 or 6mm is a typical FWHM and may be more proper for the current study.

The left and right homologous ROIs were combined to one seed when calculating functional connectivity maps. But the human brain laterization is well known. It’s better to conduct a 2-by-2 ANOA for the second level analysis with GROUP and HEMISHPERE as factors.

When reporting results, the functional connectivity of several seeds seems to have no difference between the two groups. But it was not explicitly stated.

The readability of Figure 2b is poor. I suggest a different font color or change the back groud color.

Reviewer #2: I understand from this manuscript that elderly individuals with apathy show decreased functional connectivity between the striatal structures (i.e., ventral rostral putamen), and frontal areas (i.e., dACC/pre SMA). Besides, increased functional connectivity between the striatal structures (i.e., dorsal caudate) and sensorimotor area was reported in elderly individuals with apathy as compared to elderly individuals without apathy.

Functional neuroanatomy studies are important for a better understanding of apathy which increases disability and caregiver burden in elderly population. This is a powerful study in terms of using fMRI analysis methods. I think if the authors strengthen the presentation of their study, it will contribute to the literature and colleagues of the field.

Major points:

1) The areas associated with apathy in AD are not just the ACC and OFC, or the entire ACC or OFC. If it is desired to exemplify some of the related brain regions, it may be more appropriate to reconstruct the sentence (Introduction section- Line 26).

2) 7th reference seems to be missing in the main text.

3) Extended sentences with conjunctions make it difficult to follow, and in some there may be errors in tense suffixes. In this sense, I would suggest that the manuscript be reviewed by the authors.

4) The authors may consider to edit the flow of Introduction section. The paragraph starting with "Apathy is also observed in older adults with..." from line 43 does not seem to be compatible with the previous paragraph. In the previous paragraph, the conceptualization of the apathy and the functional neuroanatomical correlates corresponding to this conceptualization are presented. However, the first sentence containing the word "also" causes the expectation for continuum of a topic.

5) I think, the first paragraph of the Materials and Methods/Participants section also need to be reconsidered. Especially these two sentences are hard to follow: "335 people in the database were screened on the levels of apathy and the exclusion criteria. Exclusion criteria were: current or past presence of neurological or psychiatric disorders such as cerebrovascular disease, Mini-mental State Examination (MMSE) score less than 26 or dementia, diffuse or multiple cerebral white matter lesions on T2-weighted image, obvious cerebral atrophy, head motion > 2.0 mm during the scan of rs-fMRI". Since this section contains basic information for readers to understand the study, I think it would be more useful to give it in simpler sentences.

6) It is not common to use cut-off points on apathy scales. In general higher scores indicate higher levels of apathy. Was the cut-off point for the apathy scale used in a single study? Are there any other examples in recent studies, supporting the validation of this cut-off score other than the relevant reference (#32)?

7) Explaining the scoring of depression scale will make it possible to understand the results and the table. Does this depression scale involves any cognitive tasks? If not, I would strongly recommend not to cluster depression scale under the neuropsychological assessment.

8) Line 151. Giving an analysis result and comparative reference information in the Method section may not be very appropriate. I recommend to relocate that sentence to Discussion.

9) Under the figure: A)... Red and blue foci indicate areas showing significant positive and negative connectivity.

It is better to clarify the color and connectivity direction.

10) Creating a table with peak Talairach coordinates for ROIs can make it easier for the readers to understand the results. It will also be convenient for the study to be repeated by other researchers.

11) The authors drew attention to the overlap in symptoms of apathy and depression. However, if apathy and depression comorbidly present; it may not be easy to draw a line between these two syndrome as we can do between an internal disease and a psychiatric condition. It is known that both depression and apathy are the neuropsychiatric conditions that have independent effects on the molecular structure and physiological functioning of the brain. Statistically controlling the depression score may not result with subtracting the effect of depression from the brain activation as intended here in this study. I find the study's functional imaging analysis approach correct (controlling depression by adding the scores to analysis as covariant). However, adding multi covariates in fMRI analysis may suppress the overall activation which can cause underestimating the findings. In my opinion, in order to be able to say that the results were clearly independent of depression, a group of apathetic participants without depression should have been included. I would recommend the authors to discuss their method and findings stronger, in this context. Also, if the researchers have used any other tools or measurements, those can be included to manuscript in terms of increasing internal consistency.

Minor points:

Line 41. Mistyping of striatum as stratum

Line 60. I would suggest using "study of cognitively normal aged people" instead of "study of cognitive- normal aged people"

Line 85. I would suggest using "cranial MRI" instead of "head MRI"

Line 104. This long sentence "Furthermore, all participants conducted the following neuropsychological assessments: Cognitive functions, assessed by the MMSE [29], the Frontal Assessment Battery (FAB) [30], and the Kohs Block Design Test (KOHS) [31]; depressive symptoms were evaluated using the Japanese version of Zung’s self-rating depression scale (SDS) [32]." can be simply expressed like "Furthermore, all participants conducted the following neuropsychological assessments: MMSE [29], Frontal Assessment Battery (FAB) [30], and Kohs Block Design Test (KOHS) [31]. Depressive symptoms were evaluated using the Japanese version of Zung’s self-rating depression scale (SDS)"

Line 126. Could the authors have meant "adjust" by using the phrase "to agree with" in this sentence: Next, the functional images were normalized to the standard space defined by a template T1-weighted image and resliced with a voxel size of 3x3x3 mm3 to agree with the gray matter probability maps.

Line 209. If the intended meaning is not the process of aging; authors may consider using "elderly" instead of using the expression "aged people".

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-12168R1Altered resting-state functional connectivity of the frontal-striatal circuit in elderly with apathyPLOS ONE

Dear Dr. Hamada,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please address the comment of reviewer #1.   

Please submit your revised manuscript by Dec 26 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Satoshi Ikemoto

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed most of my concerns well. However, in line 139, the bandpass filter COULD NOT be 0.08-0.09Hz, the typic one should be 0.01-0.09Hz. If this work was done with 0.08-0.09Hz, I do not think these is any signal left for functional connectivity calculation. Please Check.

Reviewer #2: Recommendations were found to be considered by the authors. According to my opinion, with the contributions of the editor and the other referee, this valuable study has become better presented. Since the significance intervals of the scores from the depression scale has not been explained, I think it is still not clear how pure is the patient group with apathy in the diagnostic sense. However, the authors were also showed sensitive approach to this point and took the recommendation into account by reporting this as a limitation. In this sense, there is nothing else I would like to point out. I hope that the authors will continue their work on this topic and replicate the results in further studies.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Altered resting-state functional connectivity of the frontal-striatal circuit in elderly with apathy

PONE-D-21-12168R2

Dear Dr. Hamada,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Satoshi Ikemoto

Academic Editor

PLOS ONE

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