Review Reports - Perspectives Among Veterans with Chronic Pain and Co-Occurring Mild Traumatic Brain Injury: Mixed-Method Findings from a Neuromodulation and Yoga Intervention

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study has an innovative, non-invasive and non-pharmacological intervention approach for post-mTBI chronic pain, which has a potential for future scalable intervention. However, several issues, including methodological and conceptual concerns, limit the interpretability of the findings and also scientific rigor.

Please provide more and clearer clinical characterization of participants, particularly regarding musculoskeletal pain in terms of whether it was directly related to and/or influenced by mTBI (or other conditions). More detailed clinical information would be needed, including pain etiology, duration, severity, comorbidities, and relevant exclusion criteria (e.g., considerations related to participation in yoga and/or TMS).
The rationale for the "iTBS + LoveYourBrainYoga" combination needs stronger empirical justification with underlying scientific mechanisms (theoretical justification). Please consider expanding the background to better explain those mechanisms through which these interventions are expected to impact chronic pain, mTBI-related symptoms (physical, emotional, social, and cognitive), and more importantly, why combining the two is appropriate.
The methods and approach section lacks sufficient detail to ensure reproducibility, particularly regarding intervention procedures and study design classification. Given the novelty of the combined intervention, this study may be more appropriately framed as a feasibility study rather than a pilot study.
The authors' report relies heavily on qualitative and subjective findings. While this may be acceptable for a feasibility study (again not a pilot), the authors should avoid over-interpreting the preliminary findings as indicative of the intervention effects. The findings should be presented as preliminary only.
The study may be better positioned as a description of a novel intervention development with detailed scientific justification for the combined intervention and thorough description of the procedures, along with the limited preliminary findings from a small sample. This way can still highlight the innovative integration of iTBS and yoga, with "initial" acceptability and feasibility outcomes.

Author Response

IJERPH Manuscript ID: ijerph-4278252

Both Reviewer #1 and #2 made comments that led us to reframe the paper to sharpen the purpose, which is to explore relationships between patient-reported outcomes and experiences among Veterans who completed our iTBS+yoga intervention. We previously published a protocol paper (Krese et al. 2022 JMIR Res Protocols), outlining the rationale for our combined intervention and detailing our methods. We recently published our primary findings on safety, feasibility and pain (Krese et al. 2026 Journal of Head Trauma Rehabil). We have an article in press for a special issue of FOCUS: The Journal of Lifelong Learning in Psychiatry, on combined treatments providing rationale for a treatment that pairs iTBS with yoga, highlights the recently published pilot study that combines these treatments, and describes limitations and future directions. We were also recently funded for a large-scale, randomized, multi-site clinical trial (NCT07158567) that will compare the following 3 groups: (1) active-iTBS+yoga, (2) sham-iTBS+yoga, (3) active-iTBS alone.

The revised manuscript is reframed to better emphasize the paper’s purpose in the context of previous and future work in this line of research.

Reviewer #1

Please provide more and clearer clinical characterization of participants, particularly regarding musculoskeletal pain in terms of whether it was directly related to and/or influenced by mTBI (or other conditions). More detailed clinical information would be needed, including pain etiology, duration, severity, comorbidities, and relevant exclusion criteria (e.g., considerations related to participation in yoga and/or TMS).

Response: We appreciate this feedback and the opportunity to provide clarifying details.

The pain did not have to be related to the mTBI, though in some circumstances the event that caused the mTBI was also the inciting event for the chronic pain in another body part. Of note, our criteria for chronic musculoskeletal pain were not inclusive of headaches, though some patients had history of headaches related or unrelated to the mTBI event.

We added a new Table 1 Patient Demographics and Pain Characteristics that includes pain etiology, severity, and comorbidities and more clearly reference the published inclusion/exclusion criteria from Krese et al 2025 (Supplemental Table 1).

Regarding pain duration: detailed characterization of pain duration beyond the eligibility criteria of >/6 months threshold was not collected. In this sample, many participants had complex clinical presentations, including multiple concurrent pain sites and pain histories extending over prolonged and variable timeframes. As such, reliance on retrospective self-report was considered unlikely to yield precise or reliable estimates of onset or duration for specific pain conditions. Additionally, comprehensive longitudinal medical records were not consistently available to corroborate pain history. Future studies will incorporate more structured approaches to capturing pain duration at screening to improve characterization of chronicity.

Baseline pain severity (Table 1): We defined pain severity as the average score for questions 3 through 6 [pain at its worst (Q3), least (Q4), average (Q5) in the last week, and current (Q6)] on the Brief Pain Inventory. The average baseline pain severity reported by all participants was 5.4 (moderate).

All participants underwent a physiatrist evaluation to review medical history, clear them for participation in yoga, determine if mat versus chair yoga would be most appropriate and to review their current pain management strategies (Krese et al 2025).

The rationale for the "iTBS + LoveYourBrainYoga" combination needs stronger empirical justification with underlying scientific mechanisms (theoretical justification). Please consider expanding the background to better explain those mechanisms through which these interventions are expected to impact chronic pain, mTBI-related symptoms (physical, emotional, social, and cognitive), and more importantly, why combining the two is appropriate.

Response: We appreciate the reviewer’s request for additional empirical justification. We have added more information to justify the combination in the Introduction in paragraphs 4 and 5. We also highlighted both the 2022 protocol paper (Krese et al. JMIR Research Protocols ) and our in press FOCUS article that synthesizes evidence for a post-iTBS plasticity window and hypothesizes that this window may prime chronic pain–relevant neural circuits for enhanced engagement with yoga, creating a synergy between top-down neuromodulation and bottom-up mind-body practice.

The methods and approach section lacks sufficient detail to ensure reproducibility, particularly regarding intervention procedures and study design classification. Given the novelty of the combined intervention, this study may be more appropriately framed as a feasibility study rather than a pilot study.

Response: Thank you for the opportunity to provide additional details that will enable greater transparency. We added two sentences about the study design to the beginning of Methods section 2.1 Participants and Intervention. We also added a new second paragraph of section 2.1 to provide more details about the intervention and then the final paragraph of section 2.1 is now honed to focus the reader on the specific contribution of this paper. This study was federally funded by a pilot mechanism and our complementary Journal of Head Trauma Rehabilitation paper was also delineated as a pilot study. Certainly, there are elements of feasibility in the study as a whole and feasibility was the first aim of the funded pilot study. Feasibility was also one area of focus for our 2025 Journal of Head Trauma Rehabilitation paper. As the focus of this paper is around Veteran experiences and examining relationships between quantitively and qualitatively acquired quality of life and function data, we believe it is appropriate to continue to frame this as a pilot study. Given the mixed method nature, these findings are to evaluate the pilot sample’s experience in the intervention and inform future studies to be grounded in Veteran centered outcomes.

The authors' report relies heavily on qualitative and subjective findings. While this may be acceptable for a feasibility study (again not a pilot), the authors should avoid over-interpreting the preliminary findings as indicative of the intervention effects. The findings should be presented as preliminary only.

Response: Thank you for this important comment. We agree that the findings should not be interpreted as evidence of intervention effectiveness. We have revised the manuscript to more clearly characterize the study as a preliminary study and to emphasize that the qualitative and subjective findings are intended to inform how Veterans experienced the pilot study. We also revised the language throughout the section to avoid over-interpreting pre–post changes or participant-reported outcomes as intervention effects.
The study may be better positioned as a description of a novel intervention development with detailed scientific justification for the combined intervention and thorough description of the procedures, along with the limited preliminary findings from a small sample. This way can still highlight the innovative integration of iTBS and yoga, with "initial" acceptability and feasibility outcomes.

Response: We appreciate that the paper needs to be clarified and reframed. As we outlined above, the protocol providing rationale for the combined intervention and detailed methods has been published (Krese et al 2022 JMIR Res Protocol), preliminary feasibility, safety and pain findings were recently published (Krese et al 2025 Journal Head Trauma Rehabil), and in-depth rationale and review on the combined treatments will soon be published (Sabetfakhri et al 2026, Focus). Specifically, we emphasize the qualitative interview findings and quantitative patient-reported outcomes as initial, descriptive data regarding Veterans’ experiences, perceived benefits, acceptability, and feasibility. These data are important for future protocol develop that rely on both the intervention and the patient experience to address complex issues.

Reviewer 2 Report

Comments and Suggestions for Authors

This mixed-methods pilot study directly addresses a significant gap by combining iTBS neuromodulation with a structured yoga program for Veterans with chronic pain and mTBI. The study demonstrates feasibility and safety, registers its protocol, and offers robust qualitative analysis highlighting perceived improvements in pain management, fatigue, and grief. However, the study has key limitations: a small sample size reduces generalizability; a single-arm design limits conclusions about efficacy; a 30% attrition rate may affect participant representativeness; selection bias is likely, as only completers were interviewed; and there are insufficient objective or functional measures to substantiate the findings. Additionally, the study is underpowered to confirm quantitative effects.

A randomised, well-powered three-arm trial including iTBS, LYB-yoga, and a combined group is essential.
Inclusion of a sham or control group with blinding is critical.
Objective functional and motion-related outcomes, along with extended follow-up, must be incorporated to strengthen the study.
Analysing and reporting the reasons and characteristics of participant dropout is required.
Standardising intervention delivery and adverse event reporting, and enhancing sample diversity are also imperative.
The data analysis section should specify the statistical software utilised, including its version. This section should conclude by indicating the selected level of statistical significance.
The discussion section should address section 4.5, which covers the study's clinical implications.
Outdated references must be replaced, as their inclusion diminishes the study's perceived originality.

Author Response

IJERPH Manuscript ID: ijerph-4278252

The revised manuscript is reframed to better emphasize the paper’s purpose in the context of previous and future work in this line of research.

Reviewer #2

Response: We agree. This paper represents pilot findings, which by definition, precludes conducting power analysis/sample size determination. We used our published pilot primary outcome pain data (Krese et al 2025 Journal of Head Trauma Rehabil) as one piece of data, along with published literature, to inform power analysis for a recently funded larger scale randomized clinical trial (RCT, NCT07158567) that began in January 2026. This funded RCT includes 3 arms: (1) active-iTBS+yoga, (2) sham-iTBS+yoga, and (3) active-iTBS alone. As mentioned above, we have clarified the pilot study design in Methods section 2.1. We clarified the first sentence of the Limitations section 4.4 to make it more clear that this was a single group study. We appreciate the insight and guide the reader to the limitations for this discussion on future research.

Inclusion of a sham or control group with blinding is critical.

Response: Again, we agree. We have made adjustments to the manuscript text to clarify this is a single group pilot study and reframe and clarify the purpose of this paper. Multiple groups were beyond the scope of the pilot grant that funded this work. We are grateful to now be funded to do as the reviewer suggests. We believe that we have been transparent about the lack of comparison groups in the Limitations section 4.4.
Objective functional and motion-related outcomes, along with extended follow-up, must be incorporated to strengthen the study.

Response: We agree that inclusion of a functional and/or motion-related outcome would have enhanced interpretation of the findings and provided a more comprehensive understanding of the intervention's effects. However, as a pilot study, the primary aims were to evaluate the feasibility, safety, and preliminary effects of the iTBS+yoga intervention. Given the complexity of the intervention and the breadth of safety, feasibility, and exploratory outcomes required, the addition of functional or motion-based assessments or extended follow-up was beyond the scope of the present study. We recognize the importance of these outcomes and have incorporated the Oswestry Disability Index (ODI), a widely accepted and extensively validated measure of low back pain–related function, into our recently funded RCT. The ODI is the most frequently reported disability outcome measure in low back pain research, facilitating comparison with prior studies and future meta-analyses. Additionally, follow-up data acquisition timepoints were outside the scope of a 2-year study for a 6-week intervention. We agree it will be important to understand the durability/sustainability of effects. Our recently funded RCT includes 1-week, 2-weeks, 6-weeks and 6-month post-intervention follow-up data collection timepoints.

Analysing and reporting the reasons and characteristics of participant dropout is required.

Response: We agree that an understanding of participant dropout is important to properly interpreting the results of this paper, given that we were only able to obtain data on those completing the intervention and the nature of the quantitative and qualitative quality of life, and function data we focus on in this paper. We have added this information to section 2.1 of the Methods including a reference to the Krese et al. 2025 Journal of Head Trauma Rehabilitation, Figure 1 CONSORT flow diagram.

Standardising intervention delivery and adverse event reporting, and enhancing sample diversity are also imperative.

Response: We agree. We added additional information to make our standardization and adverse event reporting clear to Methods section 2.1 Participants and Intervention. We also more clearly highlight that additional details on intervention standardization in Krese et al 2022 JMIR Research Protocols and adverse event reporting in Krese et al 2025 Journal of Head Trauma Rehabilitation. Although there was some diversity among the interviewed population, we acknowledge this as a limitation for generalization of the findings of the study. This was added within the manuscript. It should be noted that this study has expanded into a multi-site study with an additional goal of including 50% female participants.
The data analysis section should specify the statistical software utilized, including its version. This section should conclude by indicating the selected level of statistical significance.

RESPONSE: We have updated the software used for both qualitative and quantitative analysis. We have also added the statistical significance used as a guidance for the reader.

7. The discussion section should address section 4.5, which covers the study's clinical implications.

RESPONSE: Thank you for this comment. We added Section 4.5 to more clearly address the clinical implications of the study while maintaining the preliminary mixed-methods framing. We now clarify that the findings should be interpreted as initial Veteran-reported perspectives on feasibility, acceptability, and perceived value, rather than evidence of clinical efficacy.

8. Outdated references must be replaced, as their inclusion diminishes the study's perceived originality.

RESPONSE: We have updated the references to reflect recent research.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have thoroughly addressed all suggestions with exceptional attention to detail. Their systematic approach to compiling scientific material and their unwavering diligence throughout the review process are truly exemplary.