Effects of basic and dual-task training programs on physical function in Parkinson’s disease: The PARKEX study

Juan Carlos Magaña; Silvia Enríquez-Calzada; Roger Prat; Cláudia M. Deus; Susana P. Pereira; Mercè Avellanet; Elvira Gea; Ariadna Laguna; Marta Martinez-Vicente; Ona Perez-Larumbe; Maria Giné-Garriga; Jorge Hernández-Vara; Joel Montane

doi:10.1371/journal.pone.0358534

Peer Review History

Original SubmissionNovember 25, 2025
9 Feb 2026 Decision Letter - Homa Seyedmirzaei, Editor Dear Dr. Montané, 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 Mar 26 2026 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. A 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'. 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Please ensure that you refer to Table 1 in your text; if accepted, production will need this reference to link the reader to the Table. 7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 8. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [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? Reviewer #1: Partly Reviewer #2: Yes Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: No Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** Reviewer #1: 1. Lines 148-151 (Sample Size) and Lines 229–231 (Outcomes): The N=24 calculation is based on a protocol for mitochondrial function, yet this paper reports only clinical outcomes like TUG and PDQ-39. - Why is the original primary endpoint (mitochondrial function) omitted? - Since the study was not powered for clinical scales, please provide a statistical justification for N=24 or reframe these results as exploratory secondary analyses. 2. Lines 369-377 (Results) and Lines 59–63 (Abstract): The authors report medium-to-large effect sizes for specific PDQ-39 subscales (Emotional Well-Being, Bodily Discomfort, Activities of Daily Living) with r_rb values ranging from –0.428 to –0.524. However, these subscale comparisons are not shown in Table 4 or any supplementary table. Table 4 only includes the total PDQ-39 score comparisons. Reporting specific numerical results for subscales without providing the accompanying statistical tests (MD, 95% CI, p-value, r_rb) violates CONSORT guidelines for complete outcome reporting and prevents readers from verifying these claims. 3. Lines 299-304 (Table 2): The legend uses "Median ± IQR." The "±" symbol is reserved for Mean ± SD. Please update the table to standard non-parametric notation: Median (IQR) or Median [Q1, Q3]. 4. Lines 336-340 and Table 4: (Pairwise comparisons): While the permutation tests are appropriate for the small sample, the comparison between BPT and BPT+FE (n=8 per group) is severely underpowered to detect clinically meaningful differences between these two exercise modalities. The non-significant p-values (p > 0.1854 for all outcomes) should not be interpreted as evidence of equivalence or absence of added benefit from dual-task training. Any conclusions regarding the comparative efficacy of BPT versus BPT+FE should be explicitly tempered by this limitation. 5. Lines 124-128 (Study Design): The use of a no-intervention control group (the 3rd arm) introduces significant risk of expectation and attention bias. This is a major limitation for self-reported (PDQ-39, BDI) and effort-dependent (TUG) outcomes. Please discuss how this bias was addressed or acknowledge it as a factor that may inflate the observed benefits. 6. Lines 268-274 (Statistical Analysis): The motor subscale (UPDRS-III) was selected as a covariate. Could you justify why the total UPDRS score was not used? Non-motor symptoms are highly relevant to the quality of life and depression outcomes presented here. Reviewer #2: Dear Editor, I have reviewed the manuscript entitled “Effects of basic and dual-task training programs on physical function in Parkinson’s disease: the PARKEX study”. The authors completed the drug therapy with physical training in Parkinson’s disease. The treated groups were compared with a group without physical training. They followed investigation lasted for 12 weeks. The training was applied three times a week. It was a progressive training. The study is useful, because the effect of training has been shown different from that of drugs. The applied interesting equipment named; “ flywheel device” was used in the course of traditional gymnastic. The description of the training is difficult to understand; I recommend to rewrite it. How many patients with Hoehn-Yahr I, II, III were included in the treated groups? What was the process of dual-task training? Was it applied in the same arrangement for 12 weeks? How many times was it applied? You cited literature of dual-task training, but your results not confirmed them. There has been a publication on a dual-task train for 5 days (J Psychiatry Psychiatric Disord 2023). Can you discuss it comparing with your results? I recommend the manuscript for major revision. Reviewer #3: The study is interesting and well-written. It is about the study of a potential new intervention method in people in Parkinson. The author adopted a dual-task intervention associated with a resistance training. Despite the topic is interesting and innovative, the methodology is weak and could be implemented and more and precise information on the dual task setting and protocol. Furthermore, important limits are related to the lack of tests related to the cognitive function, also in dual tasking. The TUG alone is not an indicator of the possible effects of the training, a TUG performed in single and dual task could be of great help. Overall, the manuscript requires major revisions. After these revisions are solved, I will proceed with more detailed comments: -Please, implement the introduction with more information about the dual task concept and the dual task training. There are different reviews on the topic dual task training that could be useful. -Please, implement the details of the dual task within the methods. The videos are not enough, a better explanation of the dual task training is required. -Please, highlight in the limits of the study that no test on the cognitive function have been performed. It is important to evaluate not only the aspects related to questionnaire, but according to my opinion, more information about the cognitive health could be helpful in better understand how the intervention work in this population. ****** 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 Reviewer #3: 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.] To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation. NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications. Attachments Attachment Submitted filename: Review dual PD.docx https://doi.org/10.1371/journal.pone.0358534.r001
Revision 1
11 Mar 2026 Author Response Reviewers' comments: Reviewer #1: 1. Lines 148-151 (Sample Size) and Lines 229–231 (Outcomes): The N=24 calculation is based on a protocol for mitochondrial function, yet this paper reports only clinical outcomes like TUG and PDQ-39. - Why is the original primary endpoint (mitochondrial function) omitted? - Since the study was not powered for clinical scales, please provide a statistical justification for N=24 or reframe these results as exploratory secondary analyses. Response: Thank you for this important comment. The original sample size calculation (n = 24) was based on the primary endpoint of the PARKEX trial, the mitochondrial function, as described in the published study protocol. The present manuscript reports a pre-specified secondary analysis focusing on clinical, motor, non-motor, and quality-of-life outcomes collected within the same randomized controlled trial. While these clinical outcomes were prospectively assessed, the study was not specifically powered to detect clinically meaningful differences in these scales. Therefore, the findings should be considered exploratory in nature. We have clarified this important point in the Introduction, Methods (sample size section), and Limitations to improve transparency and avoid overinterpretation of the clinical results. In the Introduction section: “The PARKEX trial was originally designed to evaluate changes in mitochondrial function as its primary biological endpoint. In addition to these mechanistic outcomes, clinical, motor, non-motor, and quality-of-life measures were prospectively collected to explore the potential functional impact of the intervention.” In the Methods section: “The sample size (N=24) was calculated based on the primary mitochondrial endpoint of the trial, as detailed in the published protocol. Clinical and functional outcomes analyzed in the present manuscript were secondary endpoints and the study was not specifically powered to detect changes in these measures.” “Clinical, motor, non-motor, and quality-of-life measures were prospectively collected as secondary outcomes within the PARKEX trial to explore the broader functional impact of the intervention. The primary endpoint of the overall trial was mitochondrial function, as described in the published protocol. In the present analysis, functional mobility measured by the Timed Up and Go (TUG) was considered the main clinical outcome. Additional outcomes included lower-limb muscular endurance (Squat Test), health-related quality of life (PDQ-39 total and subscales), and depressive symptoms (BDI).” In the Limitations section: “Importantly, the study was powered for the primary mitochondrial endpoint and not for clinical scales. Therefore, the absence of significant differences in some outcomes may reflect limited statistical power rather than true absence of effect.” 2. Lines 369-377 (Results) and Lines 59–63 (Abstract): The authors report medium-to-large effect sizes for specific PDQ-39 subscales (Emotional Well-Being, Bodily Discomfort, Activities of Daily Living) with r_rb values ranging from –0.428 to –0.524. However, these subscale comparisons are not shown in Table 4 or any supplementary table. Table 4 only includes the total PDQ-39 score comparisons. Reporting specific numerical results for subscales without providing the accompanying statistical tests (MD, 95% CI, p-value, r_rb) violates CONSORT guidelines for complete outcome reporting and prevents readers from verifying these claims. Response: To address this concern and ensure complete outcome reporting, we have revised the manuscript to explicitly include, within the results main text, the corresponding mean differences (MD), 95% confidence intervals (95% CI), and p-values for the referenced PDQ-39 subscales. 3. Lines 299-304 (Table 2): The legend uses "Median ± IQR." The "±" symbol is reserved for Mean ± SD. Please update the table to standard non-parametric notation: Median (IQR) or Median [Q1, Q3]. Response: The table has been revised accordingly. The notation “Median ± IQR” has been replaced with the standard non-parametric format “Median (IQR)” throughout Table 2 to ensure correct statistical reporting. 4. Lines 336-340 and Table 4: (Pairwise comparisons): While the permutation tests are appropriate for the small sample, the comparison between BPT and BPT+FE (n=8 per group) is severely underpowered to detect clinically meaningful differences between these two exercise modalities. The non-significant p-values (p > 0.1854 for all outcomes) should not be interpreted as evidence of equivalence or absence of added benefit from dual-task training. Any conclusions regarding the comparative efficacy of BPT versus BPT+FE should be explicitly tempered by this limitation. Response: We thank the reviewer for this important methodological consideration. We agree that the sample size limits the statistical power to detect clinically meaningful differences between the BPT and BPT+FE groups, and that non-significant results should not be interpreted as evidence of equivalence. Accordingly, we have removed the sections of the manuscript where conclusions were drawn regarding the comparative efficacy between BPT and BPT+FE under these conditions. The revised manuscript now avoids any interpretation suggesting equivalence or absence of added benefit and more appropriately reflects the exploratory nature of these comparisons given the limited sample size. 5. Lines 124-128 (Study Design): The use of a no-intervention control group (the 3rd arm) introduces significant risk of expectation and attention bias. This is a major limitation for self-reported (PDQ-39, BDI) and effort-dependent (TUG) outcomes. Please discuss how this bias was addressed or acknowledge it as a factor that may inflate the observed benefits. Response: We agree that the use of a no-intervention control group may introduce expectation and attention bias, particularly for self-reported and effort-dependent outcomes. The choice of this design was based on the aim to evaluate the added effect of structured exercise compared with usual care. However, we acknowledge that this approach may inflate perceived benefits. We have now addressed this issue in the Limitations section, clarifying the potential influence of expectation and attention bias on PDQ-39, BDI, and TUG outcomes, and cautioning against overinterpretation of between-group differences. The added text reads as follows: “In addition, the inclusion of a usual-care control group without an attention-matched intervention may have further increased the risk of expectation and attention bias. This factor may be particularly relevant for self-reported outcomes (PDQ-39, BDI) and effort-dependent measures such as the TUG” 6. Lines 268-274 (Statistical Analysis): The motor subscale (UPDRS-III) was selected as a covariate. Could you justify why the total UPDRS score was not used? Non-motor symptoms are highly relevant to the quality of life and depression outcomes presented here. Response: We used UPDRS-III as a covariate because it is a specific, validated measure of motor severity and is the component most directly related to our functional outcomes (TUG and Squat Test). Using the UPDRS total score would have mixed motor and non-motor domains and could have introduced variance not directly relevant to the primary motor/functional outcomes. We have clarified this rationale in the Statistical analysis section and the modified text reads as follows: “UPDRS-III was selected instead of the UPDRS total score because it provides a specific and validated measure of motor severity, directly linked to functional mobility and strength outcomes. The total score combines motor and non-motor domains, which may reflect broader disease burden rather than motor severity per se.” Reviewer #2: Dear Editor, I have reviewed the manuscript entitled “Effects of basic and dual-task training programs on physical function in Parkinson’s disease: the PARKEX study”. The authors completed the drug therapy with physical training in Parkinson’s disease. The treated groups were compared with a group without physical training. They followed investigation lasted for 12 weeks. The training was applied three times a week. It was a progressive training. The study is useful, because the effect of training has been shown different from that of drugs. The applied interesting equipment named; “ flywheel device” was used in the course of traditional gymnastic. The description of the training is difficult to understand; I recommend to rewrite it. Response: Thank you for your positive evaluation of our study and for highlighting the relevance of combining pharmacological treatment with structured physical training in Parkinson’s disease. We appreciate your comment regarding the clarity of the training description. The Methods section has been thoroughly revised and restructured to improve clarity, logical flow, and readability. We simplified the explanation of the periodization model, clarified the distinction between BPT and BPT+FE (dual-task condition), and provided a more concise description of intensity progression and task integration. We have also provided a Supplementary Table (see S Table 1) detailing the structure progression of the Dual Task training. How many patients with Hoehn-Yahr I, II, III were included in the treated groups? Response: As shown in Table 2, all participants included in the study were classified as Hoehn–Yahr stage II. We have clarified this in the text to make the disease severity of the sample more explicit. The new text in the Results section reads as following: “The sample consisted of 24 participants, all classified as Hoehn–Yahr stage II, reflecting a clinically homogeneous group with mild-to-moderate disease severity.” What was the process of dual-task training? Was it applied in the same arrangement for 12 weeks? How many times was it applied? Response: The dual-task training was applied three times per week over the 12-week intervention period, following the same overall structure throughout the program. Each session combined flywheel-based resistance exercises with structured cognitive tasks performed simultaneously (dual-task condition). While the session format remained consistent across the 12 weeks, task complexity and motor–cognitive demands were progressively increased according to participants’ performance and adaptation. This progression involved increasing resistance load, modifying coordination demands, and introducing more challenging cognitive tasks to ensure continued stimulus and engagement. We have clarified these aspects in the revised Methods section to improve transparency and reproducibility of the intervention protocol. We have also provided a Supplementary Table (see S Table 1) detailing the structure progression of the Dual Task training. You cited literature of dual-task training, but your results not confirmed them. There has been a publication on a dual-task train for 5 days (J Psychiatry Psychiatric Disord 2023). Can you discuss it comparing with your results? I recommend the manuscript for major revision. Response: We acknowledge your concern about the methodological detail of the dual-task intervention. We have substantially expanded the Methods section to provide a clearer and more precise description of the dual-task setting, including task type, structure, progression, frequency, and how cognitive and motor components were combined during training (see Methods section). We have also expanded the Introduction section. The new introduction section reads as follows: “Given the close interaction between motor and cognitive systems, targeting both domains together offers advantages beyond those achieved with motor training alone. Randomized controlled trials have implemented dual-task interventions combining locomotor activities with concurrent cognitive tasks (e.g., mental arithmetic, verbal fluency) or coordinated motor demands (e.g., obstacle negotiation, manipulative tasks), reporting improvements in mobility, balance, and selected executive domains such as divided attention, inhibitory control, working memory, and set-shifting (e.g., obstacle negotiation, manipulative tasks). [10-16]” For this, we have added the following new references, including the reference that was suggested in the comment: 10. Dalma Szögedi, Trevor W. Stone, Elek Dinya , Judit Málly. Dual-task performance testing as an indicator of cognitive deterioration in Parkinson's disease: A pilot study. Journal of Psychiatry and Psychiatric Disorders. 7 (2023): 104-117 11. Li Z, Wang T, Liu H, Jiang Y, Wang Z, Zhuang J. Dual-task training on gait, motor symptoms, and balance in patients with Parkinson's disease: a systematic review and meta-analysis. Clin Rehabil. 2020 Nov;34(11):1355-1367. 12. Fernandes, Â., Rocha, N., Santos, R., & Tavares, J. M. R. S. (2015). Effects of dual-task training on balance and executive functions in Parkinson’s disease: A pilot study. Somatosensory & Motor Research, 32(2), 122–127. 13. Salazar RD, Ren X, Ellis TD, Toraif N, Barthelemy OJ, Neargarder S, Cronin-Golomb A. Dual tasking in Parkinson's disease: Cognitive consequences while walking. Neuropsychology. 2017 Sep;31(6):613-623. 14. San Martín Valenzuela C, Moscardó LD, López-Pascual J, Serra-Añó P, Tomás JM. Effects of Dual-Task Group Training on Gait, Cognitive Executive Function, and Quality of Life in People With Parkinson Disease: Results of Randomized Controlled DUALGAIT Trial. Arch Phys Med Rehabil. 2020 Nov;101(11):1849-1856.e1. 15. Wong PL, Cheng SJ, Yang YR, Wang RY. Effects of Dual Task Training on Dual Task Gait Performance and Cognitive Function in Individuals With Parkinson Disease: A Meta-analysis and Meta-regression. Arch Phys Med Rehabil. 2023 Jun;104(6):950-964. 16. Li Z, Wang T, Liu H, Jiang Y, Wang Z, Zhuang J. Dual-task training on gait, motor symptoms, and balance in patients with Parkinson's disease: a systematic review and meta-analysis. Clin Rehabil. 2020 Nov;34(11):1355-1367. 45. Huang YZ, Chang FY, Liu WC, Chuang YF, Chuang LL, Chang YJ. Fatigue and Muscle Strength Involving Walking Speed in Parkinson's Disease: Insights for Developing Rehabilitation Strategy for PD. Neural Plast. 2017;2017:1941980. Reviewer #3: The study is interesting and well-written. It is about the study of a potential new intervention method in people in Parkinson. The author adopted a dual-task intervention associated with a resistance training. Despite the topic is interesting and innovative, the methodology is weak and could be implemented and more and precise information on the dual task setting and protocol. Furthermore, important limits are related to the lack of tests related to the cognitive function, also in dual tasking. The TUG alone is not an indicator of the possible effects of the training, a TUG performed in single and dual task could be of great help. Overall, the manuscript requires major revisions. After these revisions are solved, I will proceed with more detailed comments: -Please, implement the introduction with more information about the dual task concept and the dual task training. There are different reviews on the topic dual task training that could be useful. Response: Thank you for your positive comments regarding the originality and relevance of our study. We acknowledge your concern about the methodological detail of the dual-task intervention. We have substantially expanded the Methods section to provide a clearer and more precise description of the dual-task setting, including task type, structure, progression, frequency, and how cognitive and motor components were combined during training (see Methods section). We have also expanded the Introduction section. The new introduction section reads as follows: “Given the close interaction between motor and cognitive systems, targeting both domains together offers advantages beyond those achieved with motor training alone. Randomized controlled trials have implemented dual-task interventions combining locomotor activities with concurrent cognitive tasks (e.g., mental arithmetic, verbal fluency) or coordinated motor demands (e.g., obstacle negotiation, manipulative tasks), reporting improvements in mobility, balance, and selected execut Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0358534.r002
3 Sep 2026 Decision Letter - Meiling Qi, Editor Effects of basic and dual-task training programs on physical function in Parkinson’s disease: the PARKEX study PONE-D-25-60916R1 Dear Dr. Montané, 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. For questions related to billing, please contact billing support. 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, Meiling Qi Academic Editor PLOS One Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: (No Response) Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: (No Response) Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: (No Response) Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: (No Response) Reviewer #3: Yes ****** Reviewer #1: (No Response) Reviewer #3: Thank you for addressing all my comments. The authors did a very good job and the manuscript has been importantly improved. The manuscript is now suitable for publication. ****** 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 #3: Yes: Luca Petrigna ******** https://doi.org/10.1371/journal.pone.0358534.r003
Formally Accepted
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