PONE-D-23-20713Short Communication:

Lifetime Musical Activity and Resting-State Functional Connectivity in Cognitive NetworksPLOS ONE

Dear Dr. Liebscher, First, let me apologize on behalf of Plos ONE for the time needed to review this manuscript. It was very difficult to secure reviewers, also because a few reviewers with specific experience in the field were in conflict of interest. Reviewers 2 and 3 made a number of methodological comments that authors must consider, but not necessarily address by changing the processing strategy or study design. In particolar, I think that the "matched pair" experimental design is acceptable in this context; probably authors, rather than changing study design, can discuss the limitations of the approach in the relavant section of the manuscript.

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PLOS ONE

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“O. Peters received fees for consultation from Abbvie, Biogen, Eisai, Griffols, MSD Roche, and Schwabe. J. Priller received fees for consultation, lectures, and patents from Neurimmune, Axon, Desitin, and Epomedics. J. Wiltfang is an advisory board member of Abbott, Biogen, Boehringer Ingelheim, Immunogenetics, Lilly, MSD Sharp & Dohme, and Roche Pharma and received honoraria for lectures from Actelion, Amgen, Beeijing Yibai Science and Technology Ltd., Janssen Cilag, Med Update GmbH, Pfizer, Roche Pharma and holds the following patents: PCT/EP 2011 001724 and PCT/EP 2015 052945. J. Wiltfang is supported by an Ilidio Pinho professorship, iBiMED (UIDB/04501/2020) at the University of Aveiro, Portugal. E. Düzel received fees for consultation from Roche, Biogen, RoxHealth and holds shares in neotiv. F. Jessen received fees for consultation from Eli Lilly, Novartis, Roche, BioGene, MSD, Piramal, Janssen, and Lundbeck. The remaining authors report no conflicts of interest.”

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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: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: N/A

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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

Reviewer #3: 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: Yes

Reviewer #3: Yes

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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: RE: PONE-D-23-20713

The current manuscript describes an interesting and relevant cross-sectional study investigating the relationship between lifetime musical activity and resting-state functional connectivity (RSFC) in higher-order cognitive networks in the brain (i.e., the default mode network, frontoparietal, and salience networks).

Specifically, Dr. Liebscher and colleagues assessed n=130 cognitive unimpaired older adult individuals (age=>60 years) from the longitudinal DZNE-DELCODE cohort study on risk for dementia and cognitive decline. Individuals, who reported to have participated in musical instrument playing during early, middle, and late life stages (n=65) were compared to matched control subjects, who reported never to have played a musical instrument (n=65), in seed-to-voxel and within-networks RSFC patterns. Individuals with lifetime musical activity displayed higher local RSFC between medial prefrontal cortex, temporal, and frontal regions (right temporal pole and right precentral gyrus) versus control subjects.

The authors conclude that playing a musical instrument during life is related to a higher RSFC of medial prefrontal cortex with brain regions involved in higher-order cognitive and motor processes.

The manuscript is well-written and relevant. I only have the following minor points:

Abstract

- Since it is indeed a strength and relevant for interpretation of the observed findings that the two participant groups were matched on several demographic factors, please write these out already in the abstract (i.e., highlight that groups were matched on: age, sex, educational years, crystallized intelligence etc. (cf., Table 1))

Methods, 2.1 Participants:

- Please provide details on how you specifically operationalized “cognitively unimpaired”? It is unclear how this was assessed with standard neuropsychological tests. Providing information on the criteria for fulfilling this categorization (e.g., performing within certain cut-off values) would be beneficial.

Methods, 2.2 Measurements, 2.2.1 Self-reported assessment of musical activity:

- Although detailed information on the specific categorization process and the one-to-one matching procedure are provided in another REF and in the Supplementary Material, the manuscript would benefit from including these descriptions in the main text. Currently, it is unclear how often participants were to have played a musical instrument during life stages to be categorized as ‘having a lifetime history of musical activity’ (i.e., their musical activity ‘frequency’) from the only brief description provided in the current version of chapter 2.2.1. Please include these details from the reference and the supplementary materials here to enhance clarity. Indeed, this would equip the reader with enhanced ability to derive more nuanced conclusions of the identified association.

Methods, 2.2.4 Additional measures:

- How did you specifically operationalize socioeconomic status? Currently, it only says that SES was assessed using the International Socioeconomic Index of Occupational Information. Please specify what the specific items measure.

Discussion:

- Although the authors have ensured that there were no differences between musical activity participants and matched controls on several demographic variables (cf., Table 1), a more extensive examination of other unaccounted variables in the RSFC association analyses would be beneficial. Please provide a more comprehensive discussion of the potential factors that could also be linked to a history of musical activity and might have influenced the observed differences in local and global functional connectivity patterns (such as potential differences in functional capacity including autonomy, social activity/interpersonal relationships, and occupational functioning that may not be captured by the SES measure applied).

- Did the authors consider running sensitivity analyses with respect to individuals, who have reported only engaging in solo instrument performance, as compared to participation in musical bands as part of their lifetime musical activities? It would be of interest to explore this aspect and/or discuss the plausible associations potentially emanating from differences in musical instrument engagement on the identified neural benefits associated with participating in musical activities throughout life in older age.

- Additionally, it would be interesting to assess and/or discuss whether differences would emerge when accounting for the specific musical instruments played by the individuals (e.g., potential disparities between individuals engaged solely in vocal performance/singing, individuals exclusively playing instrument like the piano or violin, which additionally require intricate fine motor skills involving both the left and right hands). This would be particularly interesting with regards to the identified nodes of precentral gyrus and superior frontal gyrus found to be involved in motor processing and motor control tasks (cf., lines 362-365).

- Please also highlight that the samples sizes were modest and the findings need replication before firm conclusions can be drawn (before specifically highlighting the need for future longitudinal studies)

Figure 1

- In Figure 1C (FC cluster 1) and 1E (FC cluster 2), please provide value units on the Y-axis (currently, only values are reported)

Reviewer #2: I have some methodological concerns about this paper. Here are my comments:

1. The preprocessing of MRI is too concise. Please describe clearly what has been done. Since subjects were required to be registered to a template, the registration accuracy is very important for this seed-based analysis. Please demonstrate the quality of registration.

2. The seed-definition is too arbitrary. I think some studies have suggested the seed location of DMN is in around the PCC area. To confirm the accuracy to these seeds and determine if these seeds could be used to form networks, please generate network map based on these selected seeds.

3. Please give clear definition of local FC and global FC.

4. Statistical analysis is confusing. In the method section, three different threshold are mentioned as significant. For example, "p-values of < .05 were considered statistically significant", "using a voxel-

277 level threshold of p < .005 (uncorrected)", "a cluster extend threshold of p < .05 corrected for

278 multiple comparisons using False Discovery Rate". Please clarify the statistical significance level and ensure all the reported results could pass FDR.

5. Why not also compare the inter-network FC between two groups.

6. Image quality is not good.

Reviewer #3: The authors investigated the impact of playing musical instruments on the functional connectivity of cognitive neural networks. Utilizing the DELCODE Study database and employing a one-to-one matching procedure based on described characteristics, the authors compared FPN, DMN, SAL differences, revealing that "Higher RSFC has been related to protective lifestyle factors and preserved cognitive abilities in the context of brain pathology, supporting a contribution of these neural correlates to cognitive reserve". As suggested by the authors, the higher RSFC discovered in this study between higher-order cognitive and motor processes may represent neuroprotective correlates underlying musical activity in older adults (OA). However, the study design exhibits certain shortcomings. If possible, it is strongly recommended that the authors supplement essential data.

1. The issue of sample representativeness is raised. The text only mentions a one-to-one matching procedure, which introduces a considerable arbitrary selection component. It is strongly advised that the authors employ a 1:1 randomization approach to select samples, thus better eliminating differences in confounding factors (including those mentioned in the text, but not limited to only those) between the two groups.

2. It is strongly recommended that the authors supplement data on cognitive function, executive function, emotional changes, and relevant behavioral differences between the two groups in addition to the differences in resting-state brain functional connectivity. Calculating the correlation between brain functional connectivity differences and behavioral differences and conducting mediation analysis models or pathway analysis is preferable to establish persuasive evidence. It is crucial to demonstrate the specific aspects of cognitive function differences caused by the impact of playing musical instruments on the functional connectivity of cognitive neural networks. Therefore, the manuscript requires substantial data supplementation for a major revision.

3. The study lacks strict control over confounding factors. In addition to the factors mentioned in the text such as Age, Education, Crystallized Intelligence, Sex, Diagnostic group, Lifetime Physical Activity, Current Physical Activity, and LEQ, there may be other potential factors such as underlying diseases, nutritional status, emotional conditions, interpersonal relationships, etc. Adhering to the principle of random sampling is essential, and the sample size should ideally reach several thousand individuals.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Short communication

Lifetime musical activity and resting-state functional connectivity in cognitive networks

PONE-D-23-20713R1

Dear Dr. Liebscher,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Federico Giove, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes

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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 satisfactorily responded to the comments and suggestions raised by the undersigned, which has improved the quality of the manuscript. I therefore recommend that the manuscript should be accepted for publication and wish to congratulate the authors on this piece of work.

Reviewer #2: (No Response)

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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

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