Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: Secondary analysis of a randomised clinical trial

Hanna Lu; Xi Ni; Sandra Sau Man Chan; Calvin Pak Wing Cheng; Waichi Chan; Linda Chiu Wa Lam

doi:10.1371/journal.pone.0317700

Peer Review History

Original SubmissionFebruary 1, 2024
17 May 2024 Decision Letter - Xu-Qiao Chen, Editor PONE-D-24-02411Pre-treatment subjective sleep quality as a predictive biomarker in preclinical Alzheimer’s disease patients treated with transcranial direct current stimulationPLOS ONE Dear Dr. Lu, 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 submit your revised manuscript by Jul 01 2024 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 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information . [Note: HTML markup is below. Please do not edit.] 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: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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 ****** 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 ****** 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 manuscript presents an interesting study investigating the effects of transcranial direct current stimulation (tDCS) on sleep quality and cognition in mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) patients. With some revisions to improve clarity, organization, and presentation, the manuscript could significantly enhance its impact and readability The introduction provides a comprehensive background on the topic, but it would benefit from clearly stating the primary objectives and hypotheses. The discussion interprets the study findings well and relates them to existing literature. However, it could be structured more clearly to address each key finding separately and discuss its implications in greater detail . The manuscript would benefit from a thorough proofreading to improve sentence structure and ensure clarity of expression. Reviewer #2: Dear Editor, Thank you for the opportunity to provide a review of Manuscript PONE-D-24-02411 entitled "Pre-treatment subjective sleep quality as a predictive biomarker in preclinical Alzheimer’s disease patients treated with transcranial direct current stimulation." My comments relate primarily to the adequacy of the implementation and reporting of epidemiologic and statistical procedures. The quality of the technical English was variable. The authors must perform a thorough round of copyediting to correct the many instances of grammatical and syntactical errors in the text. These errors offered no bar to my evaluation of the manuscript. # Incomplete reporting The authors cannot cite previous papers when reporting key elements of the methods. For example, they state "details of randomization, masking, treatment modality, inclusion and exclusion criteria have been reported elsewhere." This paper must stand alone. The authors must provide a description of these important methodologic procedures, as is required by CONSORT. # Identification of the primary outcome The authors must identify the primary outcome of this manuscript and place it in the context of the trial and its protocol. # No safety endpoints The authors describe how safety assessments were to be conducted but fail to report any results on this outcome. # R is not published by IBM The authors cite R as being published by IBM. This is wrong. # Lack of justification of correlation matrix The authors do not justify the use of correlation techniques. What research questions were being posed here? Are these questions pre-planned? They seem opportunistic. # DO NOT TEST significance at baseline The authors should not perform formal statistical tests on the baseline characteristics of participants in a randomised controlled trial. This is a major error and is highly inappropriate. It sets up a statistical tautology. Table 1's last two columns must be deleted. Any mention of statistical significance relating to Table 1 should be removed. # Report confidence intervals The authors should report confidence intervals. These intervals should accompany the point estimates. # Recommendation I cannot support the acceptance of this manuscript for publication in the Journal until the issues identified above are considered. Thank you. ****** 6. 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 https://doi.org/10.1371/journal.pone.0317700.r001
Revision 1
19 Dec 2024 Author Response Point-by-point responses to the reviewer’s comments on the manuscript "Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trial" Comments from editors Comment 1: Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. Response 1: Thank you for the suggestion. The contents have been modified as “The written informed consent was obtained from all participants or their legal guardian(s) before any assessment.” on Page 4. Comment 2: Thank you for stating the following financial disclosure: "This clinical trial was supported by the Hong Kong Research Grant Council (RGC) - General Research Fund (GRF) (GRF14108214)." Please state what role the funders took in the study. Response 2: Yes. We have stated the role of funders in the cover letter as “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”. Comment 3: Please update your Data Availability statement in the submission form accordingly. Response 3: Yes. Data Availability statement has been updated in the submission form. Comment 4: Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Response 4: The “Ethics declarations” on Page 12 have been removed. Comment 5: Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Response 5: Yes. The captions for supporting documents have been updated on Page 19. Reviewer 1 General Comments Comment: The manuscript presents an interesting study investigating the effects of transcranial direct current stimulation (tDCS) on sleep quality and cognition in mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) patients. With some revisions to improve clarity, organization, and presentation, the manuscript could significantly enhance its impact and readability Response: Thank you for reviewing our paper. We also thank you for considering our study to be interesting. Based on your thoughtful and valuable comments, we have answered each of your points as follows and revised the manuscript for your further evaluation. Specific Comment 1: The authors state that patients with a DSM-5 diagnosis of major neurocognitive disorder were recruited and that the participants who had a history of primary bipolar or other psychotic disorders, and major neurological disorders, including stroke, transient ischemic attack or traumatic brain injury. However, the neuropathological backgrounds of the subject group are not still clear, making interpretation of the results difficult. Were they mostly Alzheimer’s disease patients? Please clarify their neurological diagnosis of the subjects in ‘Study design’ section. Response 1: Thank you very much for this suggestion. We totally agree with your opinion. Neuropathological backgrounds are critical for preclinical AD patients. Due to limited research funding, either structural MRI or plasma/saliva Aβ and tau testing is unavailable in this study, thus, we gave a diagnosis of mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) based on the AD-signatured impaired domains of cognition (i.e., working memory). For better describing the neurological diagnosis of the subjects, the have been updated as “The following criteria were used to define mild NCD-AD participants: (1) evidence of modest cognitive decline in one or more cognitive domains, as indicated by a box score of ≤0.5 on the Clinical Dementia Rating (CDR) subcategory and a Cantonese Mini Mental State Examination (CMMSE) score ranging from 22 to 27; (2) no interference with daily activities that require independence; (3) with a score of episodic memory as measured by delay recall in list learning; and (4) no better explanation by other psychiatric disorders. In addition to meeting the criteria for NCD, patients with mild NCD-AD did not have uncontrolled hypertension, diabetes, or hyperlipidemia (vascular risk factors).” on Page 4. Meanwhile, we are fully acknowledged the absence of neuropathological markers in the limitations and highlighted this part as “On the other hand, although a sizeable sample size and low dropout rate were achieved, the diagnosis of mild NCD-AD was mainly based on the performance of cognitive assessments, without neuropathological backgrounds (i.e., levels of Aβ and tau) or neuroimaging information (i.e., medial temporal lobe atrophy score), which may decrease the interpretation of the results.” on Page 11. Specific Comment 2: The introduction provides a comprehensive background on the topic, but it would benefit from clearly stating the primary objectives and hypotheses. The discussion interprets the study findings well and relates them to existing literature. However, it could be structured more clearly to address each key finding separately and discuss its implications in greater detail. Response 2: Yes. In the introduction part, we highlighted our primary aim of this secondary analysis as “Therefore, in order to make significant progress in comprehending the reciprocal relationship between subjective sleep quality and cognitive functions, our primary objective was to present a thorough picture of subjective sleep quality, global cognition and domain-specific cognitive functions related to tDCS treatments. The secondary objective was to identify the links between pre-treatment subjective sleep quality and the treatment-induced cognitive changes.” on page 4. The discuss parts have been structured and separated with sub-titles. Specific Comment 3: The manuscript would benefit from thorough proofreading to improve sentence structure and ensure clarity of expression. Response 3: Thank you very much for the suggestion. We have modified some of the descriptions for clearly explaining our viewpoints. The proofreading of this revised manuscript has been done. Reviewer 2 General Comments Comment: Thank you for the opportunity to provide a review of Manuscript PONE-D-24-02411 entitled "Pre-treatment subjective sleep quality as a predictive biomarker in preclinical Alzheimer’s disease patients treated with transcranial direct current stimulation." My comments relate primarily to the adequacy of the implementation and reporting of epidemiologic and statistical procedures. The quality of the technical English was variable. The authors must perform a thorough round of copyediting to correct the many instances of grammatical and syntactical errors in the text. These errors offered no bar to my evaluation of the manuscript. Response: Thank you very much for taking the time to review our manuscript. The detailed comments are very thoughtful and helpful. In this revision, we have done thorough proofreading to improve the quality of this manuscript. Major Concerns Specific Comment 1: The authors cannot cite previous papers when reporting key elements of the methods. For example, they state "details of randomization, masking, treatment modality, inclusion and exclusion criteria have been reported elsewhere." This paper must stand alone. The authors must provide a description of these important methodologic procedures, as is required by CONSORT. Response 1: Thank you for your suggestion. We have updated the inclusion criteria of mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) on Page 4. The sentence of “The details of randomization, masking, treatment modality, inclusion and exclusion criteria have been reported elsewhere.” has been removed from the main contents. Specific Comment 2: The authors must identify the primary outcome of this manuscript and place it in the context of the trial and its protocol. Response 2: Thank you for your comment. We apologize for any confusion that we did not explain the contents clearly in this paper. This study is a secondary analysis of our previous randomized clinical trial. Thus, for clearly presenting the primary aims of this paper, we modified the title as “Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trial”. Meanwhile, we highlighted the study aims as “In order to make significant progress in comprehending the reciprocal relationship between subjective sleep quality and cognitive functions, our primary objective was to present a thorough picture of subjective sleep quality, global cognition and domain-specific cognitive functions related to tDCS treatments. The secondary objective was to identify the links between pre-treatment subjective sleep quality and the treatment-induced cognitive changes.” on Page 4 Specific Comment 3: The authors describe how safety assessments were to be conducted but fail to report any results on this outcome. Response 3: Thank you for this suggestion. We have reported the adverse events and safety on Page 8 as “All patients reported that the treatments were well-tolerated following twelve sessions of treatments. In tDCS groups, the most significant adverse events were mild skin injury under cathodal electrode in three patients. However, the above skin injuries were recovered after one week. None of the patients reported other adverse events, such as nausea, seizures, headache, or dizziness.”. Specific Comment 4: The authors cite R as being published by IBM. This is wrong. Response 4: Thank you for pointing out this issue. We apologize for the confusion. The sentence has been revised as “The computations were performed using R package.” on Page 6. Specific Comment 5: The authors do not justify the use of correlation techniques. What research questions were being posed here? Are these questions pre-planned? They seem opportunistic. Response 5: Yes. Thank you very much for this comment. We apologize for the confusion. In this revision, we highlight the aim of this study as “The secondary objective was to identify the links between pre-treatment subjective sleep quality and the treatment-induced cognitive changes.” on Page 4. Thus, we examined the correlation matrices in the three treatment groups. Specific Comment 6: The authors should not perform formal statistical tests on the baseline characteristics of participants in a randomised controlled trial. This is a major error and is highly inappropriate. It sets up a statistical tautology. Table 1's last two columns must be deleted. Any mention of statistical significance relating to Table 1 should be removed. Response 6: Thank you for this comment. The last two columns in table 1 have been removed. Attachments Attachment Submitted filename: Responses to reviewers.pdf https://doi.org/10.1371/journal.pone.0317700.r002
27 Dec 2024 Decision Letter - Xu-Qiao Chen, Editor PONE-D-24-02411R1Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trialPLOS ONE Dear Dr. Lu, 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. The authors have addressed all the comments raised by the reviewers, but the English needs to be refined before acceptance. Please submit your revised manuscript by Feb 10 2025 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 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. 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, Xu-Qiao Chen Academic Editor PLOS ONE Journal Requirements: 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. Additional Editor Comments: Kindly follow the reviewer's recommendations to refine the English language. [Note: HTML markup is below. Please do not edit.] 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 #2: (No Response) ******** 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #2: Yes ****** 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 #2: No ****** 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 #2: Dear Editor, Thank you for the opportunity to provide a review of Manuscript PONE-D-24-02411R1 entitled "Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trial." My comments relate primarily to the adequacy of the implementation and reporting of epidemiologic and statistical procedures. I understand that the manuscript underwent a previous round of peer-review. The quality of the technical English remains variable, despite the authors' attempt at identifying and correcting them. The authors must perform another round of copyediting to correct grammatical and syntactical errors in the text. I strongly suggest that they engage the services of a native English language speaker. I am satisfied that the issues I raised in the previous round were addressed satisfactorily. Thank you. ****** 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 #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/ https://doi.org/10.1371/journal.pone.0317700.r003
19 Dec 2024 Author Response Point-by-point responses to the reviewer’s comments on the manuscript "Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trial" Comments from editors Comment 1: Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. Response 1: Thank you for the suggestion. The contents have been modified as “The written informed consent was obtained from all participants or their legal guardian(s) before any assessment.” on Page 4. Comment 2: Thank you for stating the following financial disclosure: "This clinical trial was supported by the Hong Kong Research Grant Council (RGC) - General Research Fund (GRF) (GRF14108214)." Please state what role the funders took in the study. Response 2: Yes. We have stated the role of funders in the cover letter as “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”. Comment 3: Please update your Data Availability statement in the submission form accordingly. Response 3: Yes. Data Availability statement has been updated in the submission form. Comment 4: Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Response 4: The “Ethics declarations” on Page 12 have been removed. Comment 5: Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Response 5: Yes. The captions for supporting documents have been updated on Page 19. Reviewer 1 General Comments Comment: The manuscript presents an interesting study investigating the effects of transcranial direct current stimulation (tDCS) on sleep quality and cognition in mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) patients. With some revisions to improve clarity, organization, and presentation, the manuscript could significantly enhance its impact and readability Response: Thank you for reviewing our paper. We also thank you for considering our study to be interesting. Based on your thoughtful and valuable comments, we have answered each of your points as follows and revised the manuscript for your further evaluation. Specific Comment 1: The authors state that patients with a DSM-5 diagnosis of major neurocognitive disorder were recruited and that the participants who had a history of primary bipolar or other psychotic disorders, and major neurological disorders, including stroke, transient ischemic attack or traumatic brain injury. However, the neuropathological backgrounds of the subject group are not still clear, making interpretation of the results difficult. Were they mostly Alzheimer’s disease patients? Please clarify their neurological diagnosis of the subjects in ‘Study design’ section. Response 1: Thank you very much for this suggestion. We totally agree with your opinion. Neuropathological backgrounds are critical for preclinical AD patients. Due to limited research funding, either structural MRI or plasma/saliva Aβ and tau testing is unavailable in this study, thus, we gave a diagnosis of mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) based on the AD-signatured impaired domains of cognition (i.e., working memory). For better describing the neurological diagnosis of the subjects, the have been updated as “The following criteria were used to define mild NCD-AD participants: (1) evidence of modest cognitive decline in one or more cognitive domains, as indicated by a box score of ≤0.5 on the Clinical Dementia Rating (CDR) subcategory and a Cantonese Mini Mental State Examination (CMMSE) score ranging from 22 to 27; (2) no interference with daily activities that require independence; (3) with a score of episodic memory as measured by delay recall in list learning; and (4) no better explanation by other psychiatric disorders. In addition to meeting the criteria for NCD, patients with mild NCD-AD did not have uncontrolled hypertension, diabetes, or hyperlipidemia (vascular risk factors).” on Page 4. Meanwhile, we are fully acknowledged the absence of neuropathological markers in the limitations and highlighted this part as “On the other hand, although a sizeable sample size and low dropout rate were achieved, the diagnosis of mild NCD-AD was mainly based on the performance of cognitive assessments, without neuropathological backgrounds (i.e., levels of Aβ and tau) or neuroimaging information (i.e., medial temporal lobe atrophy score), which may decrease the interpretation of the results.” on Page 11. Specific Comment 2: The introduction provides a comprehensive background on the topic, but it would benefit from clearly stating the primary objectives and hypotheses. The discussion interprets the study findings well and relates them to existing literature. However, it could be structured more clearly to address each key finding separately and discuss its implications in greater detail. Response 2: Yes. In the introduction part, we highlighted our primary aim of this secondary analysis as “Therefore, in order to make significant progress in comprehending the reciprocal relationship between subjective sleep quality and cognitive functions, our primary objective was to present a thorough picture of subjective sleep quality, global cognition and domain-specific cognitive functions related to tDCS treatments. The secondary objective was to identify the links between pre-treatment subjective sleep quality and the treatment-induced cognitive changes.” on page 4. The discuss parts have been structured and separated with sub-titles. Specific Comment 3: The manuscript would benefit from thorough proofreading to improve sentence structure and ensure clarity of expression. Response 3: Thank you very much for the suggestion. We have modified some of the descriptions for clearly explaining our viewpoints. The proofreading of this revised manuscript has been done. Reviewer 2 General Comments Comment: Thank you for the opportunity to provide a review of Manuscript PONE-D-24-02411 entitled "Pre-treatment subjective sleep quality as a predictive biomarker in preclinical Alzheimer’s disease patients treated with transcranial direct current stimulation." My comments relate primarily to the adequacy of the implementation and reporting of epidemiologic and statistical procedures. The quality of the technical English was variable. The authors must perform a thorough round of copyediting to correct the many instances of grammatical and syntactical errors in the text. These errors offered no bar to my evaluation of the manuscript. Response: Thank you very much for taking the time to review our manuscript. The detailed comments are very thoughtful and helpful. In this revision, we have done thorough proofreading to improve the quality of this manuscript. Major Concerns Specific Comment 1: The authors cannot cite previous papers when reporting key elements of the methods. For example, they state "details of randomization, masking, treatment modality, inclusion and exclusion criteria have been reported elsewhere." This paper must stand alone. The authors must provide a description of these important methodologic procedures, as is required by CONSORT. Response 1: Thank you for your suggestion. We have updated the inclusion criteria of mild neurocognitive disorder due to Alzheimer’s disease (NCD-AD) on Page 4. The sentence of “The details of randomization, masking, treatment modality, inclusion and exclusion criteria have been reported elsewhere.” has been removed from the main contents. Specific Comment 2: The authors must identify the primary outcome of this manuscript and place it in the context of the trial and its protocol. Response 2: Thank you for your comment. We apologize for any confusion that we did not explain the contents clearly in this paper. This study is a secondary analysis of our previous randomized clinical trial. Thus, for clearly presenting the primary aims of this paper, we modified the title as “Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trial”. Meanwhile, we highlighted the study aims as “In order to make significant progress in comprehending the reciprocal relationship between subjective sleep quality and cognitive functions, our primary objective was to present a thorough picture of subjective sleep quality, global cognition and domain-specific cognitive functions related to tDCS treatments. The secondary objective was to identify the links between pre-treatment subjective sleep quality and the treatment-induced cognitive changes.” on Page 4 Specific Comment 3: The authors describe how safety assessments were to be conducted but fail to report any results on this outcome. Response 3: Thank you for this suggestion. We have reported the adverse events and safety on Page 8 as “All patients reported that the treatments were well-tolerated following twelve sessions of treatments. In tDCS groups, the most significant adverse events were mild skin injury under cathodal electrode in three patients. However, the above skin injuries were recovered after one week. None of the patients reported other adverse events, such as nausea, seizures, headache, or dizziness.”. Specific Comment 4: The authors cite R as being published by IBM. This is wrong. Response 4: Thank you for pointing out this issue. We apologize for the confusion. The sentence has been revised as “The computations were performed using R package.” on Page 6. Specific Comment 5: The authors do not justify the use of correlation techniques. What research questions were being posed here? Are these questions pre-planned? They seem opportunistic. Response 5: Yes. Thank you very much for this comment. We apologize for the confusion. In this revision, we highlight the aim of this study as “The secondary objective was to identify the links between pre-treatment subjective sleep quality and the treatment-induced cognitive changes.” on Page 4. Thus, we examined the correlation matrices in the three treatment groups. Specific Comment 6: The authors should not perform formal statistical tests on the baseline characteristics of participants in a randomised controlled trial. This is a major error and is highly inappropriate. It sets up a statistical tautology. Table 1's last two columns must be deleted. Any mention of statistical significance relating to Table 1 should be removed. Response 6: Thank you for this comment. The last two columns in table 1 have been removed. https://doi.org/10.1371/journal.pone.0317700.r004
Revision 2
3 Jan 2025 Decision Letter - Xu-Qiao Chen, Editor Pre-treatment subjective sleep quality as a predictive biomarker of tDCS effects in preclinical Alzheimer’s disease patients: secondary analysis of a randomised clinical trial PONE-D-24-02411R2 Dear Dr. Lu, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. 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, Xu-Qiao Chen 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 #2: (No Response) ******** 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #2: Yes ****** 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 #2: No ****** 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 #2: See response to the editor. See response to the editor. See response to the editor. See response to the editor. ****** 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 #2: No ******** https://doi.org/10.1371/journal.pone.0317700.r005
Formally Accepted
Acceptance Letter - Xu-Qiao Chen, Editor PONE-D-24-02411R2 PLOS ONE Dear Dr. Lu, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Xu-Qiao Chen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0317700.r006

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