Testing Biological and Psychological Pathways of Emotion Regulation as a Primary Mechanism of Action in Yoga Interventions for Chronic Low Back Pain: Protocol for a Randomized Controlled Trial

Background Interventions that promote adaptive emotion regulation (ER) skills reduce pain in patients with chronic pain; however, whether the effects of yoga practice on chronic low back pain (CLBP) are due to improvements in ER remains to be examined. Objective This study will test whether the effects of yoga on CLBP (improved pain severity and interference) are mediated by improved ER, the extent to which effects are related to specific aspects of ER, and the role of pain sensitization as a mediator or moderator of effects. In this study, pain sensitization will be assessed by quantitative sensory testing and gene expression profiles to examine whether pain sensitization moderates yoga’s effects on pain or whether yoga and ER abilities reduce pain sensitization, leading to decreased pain severity and interference. Methods For this 2-arm parallel group blinded randomized controlled trial, we will enroll 204 adults with CLBP who will be randomized to receive the yoga (n=102) or a control stretching and strengthening (n=102) intervention, which are delivered via web-based synchronous biweekly 75-minute sessions over 12 weeks. Participants are encouraged to practice postures or exercises for 25 minutes on other days using accessible prerecorded practice videos that are sent to participants digitally. Participants will be assessed at 5 time points: baseline, midintervention (6 weeks), postintervention (12 weeks), and 3- and 6-month follow-ups. Assessments of ER, pain severity and interference, pain sensitivity including somatosensory and gene expression profiles, and physical strength and flexibility will be conducted at each visit. The fidelity of the interventions is assessed using a manualized checklist to evaluate recorded group sessions to ensure consistent instructor delivery. Results The primary outcome will be the mean change in pain severity as measured by the Brief Pain Inventory-Short Form at 12 weeks. The primary mechanism of action is ER measured by change in the Difficulties in Emotion Regulation Scale total score. Secondary outcomes include pain sensitivity, physical strength and flexibility, pain interference, and quality of life. A mediation path analysis and series of moderated mediation path analyses will be conducted to test the study hypotheses. As of January 2024, we have enrolled 138 participants. We expect the study to be completed by May 2025. Conclusions The study will provide important data for evaluating whether improvements in ER are responsible for reduced pain perception and pain sensitivity as well as increased quality of life in the context of chronic pain. The study findings have important implications for determining the mechanism of action for yoga and possibly other mind-body interventions as nonpharmacological therapies for pain management. The results of the study will inform the content, delivery, and measures for intervention trials involving yoga as a modality for relieving pain and improving function. Trial Registration ClinicalTrials.gov NCT04678297; https://clinicaltrials.gov/study/NCT04678297 International Registered Report Identifier (IRRID) DERR1-10.2196/56016

1R01AT010555-01A1 Park, Crystal RESUME AND SUMMARY OF DISCUSSION: This application proposes to test whether yoga improves chronic low back pain (CLBP) by enhancing emotion regulation (ER) and will evaluate whether reduced pain sensitization mediates the pain-reducing effects of yoga-induced improved ER.The study was considered innovative in testing ER as a mediator of yoga's pain-reducing effects.Both the environment and investigators are excellent and were very responsive to prior critiques.Rigor was noted by: use of RCT; well-developed yoga intervention; adequate control condition; strong recruitment and retention plan; use of blinding; inclusion of an intermediate and long-term assessments; and a validated battery for assessment of pain sensitization.There were very few weaknesses noted.In summary, the committee concluded that the potential overall impact was very high.

DESCRIPTION (provided by applicant):
Yoga has been shown to have consistent but modest effects in reducing pain and improving function in populations with chronic low back pain (CLBP) in multiple randomized controlled trials.Reviews and practice guidelines support yoga as an evidence-based treatment for CLBP with at least moderate benefit and yoga is being increasingly applied as an integrative therapy.However, the mechanisms through which yoga exerts clinical improvements on pain severity and interference have not been identified; such identification might lead to optimizing yoga interventions to improve their potency.To identify underlying mechanisms associated with yoga interventions  and based on a comprehensive theoretical emotion regulation model of yoga developed by the PI, we aim to test emotion regulation as a primary mechanism of yoga's effects, and to test biological pathways through which yoga's effects on increased adaptive emotion regulation may operate to affect pain-related functioning.Emotions strongly influence perceptions of pain intensity and predict disability, particularly among individuals with CLBP, and interventions that promote emotion regulation skills have been shown to reduce pain.Increasing evidence demonstrates that consistent yoga practice can promote improved emotion regulation, but research has not yet tested whether the effects of yoga practice on CLBP are due to improvements in emotion regulation.To examine this issue, we will conduct a randomized controlled trial of 204 people with CLBP assessed pre-intervention, 6 weeks, post-intervention and at 3-and 6-month follow-up to test the impact of a yoga intervention on emotion regulation relative to stretching/strengthening without meditation or breathwork.Secondarily, we will also assess whether yoga's effects on CLBP (improved pain severity and functioning) are mediated by changes in emotion regulation.We also examine whether the link between emotion regulation and pain severity and functioning is moderated or mediated by pain sensitization, effects that have been theorized and/or demonstrated to account for changes in pain, thereby testing emotion regulation as a key mechanism underlying the clinical effects of yoga on CLBP.

PUBLIC HEALTH RELEVANCE:
By identifying specific mechanisms through which yoga influences pain, the proposed study will advance the scientific study of yoga for multiple pain-related conditions, strengthen the evidence base on yoga for CLBP (facilitating healthcare providers' confidence and likelihood in prescribing yoga), and provide specific directions for optimizing yoga to increase its effectiveness for treating CLBP, one of the most prevalent and costly health conditions in the US.

CRITIQUE 1
Significance: 2 Investigator(s): 1 Innovation: 1 Approach: 2 Environment: 1 Overall Impact: This revised R01 application investigates the mechanisms of yoga as a pain-relieving treatment, via emotional regulation.In 204 people with chronic low back pain, a 12-week yoga intervention is compared with a stretching/strengthening intervention to assess impact on emotional regulation (primary aim), and on pain sensitivity/interference (secondary aim).A second, secondary aim examines the interaction of ER and pain sensitivity/interference.Overall the proposal has very wellexplained and rational Significance, Innovation, and a strong Approach with research strategy having robust design likely to yield clinically impactful results.The environment is superior and supporting materials are well-prepared.The proposal is viewed as having high scientific impact.

Strengths
• A better understanding of the mechanism by which yoga reduces chronic pain would allow for refinement of yoga practices intended as nonpharmacologic pain treatment, focusing on those mechanisms.This might reduce the variability in pain treatment response and make the treatment more viable for broad application, improving health, quality of life, and public health burden.
• Defining yoga mechanisms for low back pain amelioration is also exciting because action via emotional regulation might also help identify patients unlikely to respond, for example patients with apathy.

Weaknesses
• Improved application of yoga as a pain treatment still does not address implementation barriers such as nonadherence, lack of buy-in by third party stakeholders, and shortage of practitionerteachers.

Strengths
• The PIs are experienced investigators.Dr. Park has 2 past R01s and 3 synergistic multi-year funded projects.She is a clinical psychologist who has developed research emphasis in emotional self-regulation and also in yoga, thus this project is the natural outgrowth of her body of work in both areas.Dr. Starkweather is a clinician researcher in nursing and psychosocial stress.
• Dr. Finklestein-Fox is also specialized in psychosocial stress and is a clinical psychologist; Dr. Huedo-Medina supports statistical analysis; Dr. Groessl dds further expertise in clinical psychology and yoga clinical trials.Jie Chen is the graduate student supporting the study.

Strengths
• Dissociating fundamental components (key properties/mechanisms) of yoga is highly novel.
• Addressing emotional regulation as a mediator of chronic low back pain is mildly novel.

Weaknesses
• None noted.• Further supporting the past scientific study rigor are four other studies reviewed, including two pilot studies performed by Dr Park and colleagues and a study by Co-I Groessel consistent with the study purpose, showing improved emotional self-management and reduced pain, including reduced use of opioid medications with yoga in Groessel's study • The rigor of the current study method is supported by randomized assignment to treatment or control conditions; subjects will be recruited continuously and run in cohorts of 34 to help control for seasonal confounds to effects.
• The active control is designed to stimulate the same muscle groups without relying upon the core components of yoga as identified in the PI's model.Its use is validated by previous yoga studies in which it was used as a comparison condition.
• The study examines changes in gene expression as a biological biomarker of stress and inflammatory changes.

Weaknesses
• The investigators themselves note that this project privileges internal validity in its translational aim of clarifying mechanism for yoga pain reduction.This is true in that pain sensitivity and interference are definitely not equivalent to an adverse experience of pain, or limitations in social participation because of pain.
• For recruitment, we are not given numbers in the Form E section.

Strengths
• U Conn provides a strong environment for the study.Clinical resources seem adequate; the recruitment and retention plan lists.Thus, it is difficult to know whether the resources provided for recruitment are satisfactory.

Weaknesses Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • 16% Black/AA, 1% Native, 6% Asian, 3% more than one race and 19% Hispanic/Latinex.These estimates are based on population demographics.An excellent racial and cultural outreach plan is provided.
• Age 18 through [no age limit], satisfactory for age-inclusion.

Vertebrate Animals:
Not Applicable (No Vertebrate Animals)

Resubmission:
• This revised application is highly responsive to the previous reviewer critique.Among the many changes which strengthened the application are improved clarity of the reason why mechanistic investigation is the primary goal of the study, better description of the role of the PI and team in past research demonstrating the rigor of this scientific line of thinking, clarification of relationships among the study team, a more detailed analysis plan including sex as a biological variable, and a well-justified sample size estimation.An additional follow-up point at 6 weeks has been added to be responsive to reviewer critique.

Acceptable
• Both data on pain and emotional regulation, and data on RNA sequencing, will be made available through data use agreements and manuscripts.

Acceptable
• Describes 4 key practices to authenticate resources.

Budget and Period of Support:
Recommend as Requested Overall Impact: The primary goal of this resubmitted R01 proposal is to test the effects of yoga (vs.stretching/strengthening) on emotion regulation (ER), a potential mechanism of action in the effects of yoga on pain intensity/interference.Secondary aims will focus on examining whether yoga-related improvements in ER reduce pain severity/interference and evaluating the role of pain sensitization as a moderator (Model 1) or mediator (Model 2) of these effects.Participants will be 204 individuals with chronic low back pain (CLBP) who are yoga-naïve and recruited from the local community.Interventions will be conducted with 6 cohorts of patients (n = 34 per cohort), while simultaneously running a stretching and a yoga group (n = 17 each).Outcomes will be assessed at baseline, midintervention (6 weeks), end of interventions, and at 3-and 6-month post-intervention follow-ups.CLBP is a significant and costly public health problem, and although yoga is already widely used in the context of pain, mechanisms of action remain poorly understood.The investigators were very responsive to previous reviews, and the resubmitted proposal clarifies why emotional regulation is the primary outcome, more thoroughly addresses the rigor (including strengths and limitations) of extant research on yoga and CLBP, better integrates biological measures in the study conceptualization, and adds a mid-intervention assessment (6-wks).There remains, however, some question as to whether results of the proposed research would lead to greater utilization of yoga for pain in clinical practice.The investigative team is collectively very strong, and the scientific environment at the University of Connecticut Health Center should contribute to the likelihood of a successful outcome.Novel aspects include the study of mechanisms -in general (and ER specifically) -in the effects of yoga on pain, though application of yoga to the context of chronic pain is less innovative.Scientifically rigorous aspects of the approach include utilization of a randomized controlled trial and incorporation of QST pain testing and a behavioral laboratory-based assessment of ER.Despite a few concerns in the approach, including a possible missed opportunity to examine opioid use trajectories and apparent failure to account for other substance use, the potential overall impact of this project remains in the high range.

Strengths
• CLBP is a significant, prevalent, and costly public health problem.
• There is mounting empirical evidence that yoga can improve ER.
• The rigor of the prior work, including strengths and limitations of extant research examining effects of yoga on chronic pain, was adequately addressed.
• If successful, this research may increase understanding of specific mechanisms by which yoga may influence chronic pain intensity/interference.

Weaknesses
• Yoga is already widely used in the context of pain and there is some question as to whether identification of specific mechanisms of action would lead to greater utilization/dissemination in clinical practice.

Strengths
• The investigative team is collectively very strong with relevant and complementary expertise that should support the proposed research.
• MPIs have a demonstrated record of collaboration on topics relevant to the proposal, including a pilot study to optimize yoga for low back pain.
• The inclusion of a biostatistician with expertise in multi-level analysis, moderation, mediation, and mixed-effects modeling is a strength.

Weaknesses
• No major limitations noted.

Strengths
• Examination of mechanisms underlying the effects of yoga is novel.
• No previous work has examined the effects of yoga on ER in the context of chronic pain.

Weaknesses
• Although mechanisms of action remain poorly understood, the application of yoga to pain in general and CLBP in particular is not innovative.

Strengths
• Scientifically rigorous aspects of the approach include use of a two-arm randomized interventional design, inclusion of QST pain testing, and the selection of a control condition (stretching/strengthening) that can account for nonspecific effects such as time, attention, and effort, along with general improvements in strength and flexibility.
• Preliminary studies examining the effects of yoga for back pain (a well as potential mediators) provide important support for the proposed approach.
• The inclusion of a behavioral laboratory-based assessment of ER (The Negative Affective Priming Task) to complement the primary Difficulties in Emotion Regulation Scale is another notable strength.

Weaknesses
• The application notes that medication is the primary treatment among CLBP patients, and preliminary work conducted by Co-I Dr. Groessl demonstrated a main effect of yoga in terms of decreased use of opioid medications.Although inclusion criteria require that medication use must be stable for 30 days and that participants will be asked to take their lowest usual dose of pain medication within 24 hours of each assessment, there may be a missed opportunity to examine the effects of yoga and ER on pain medication use trajectories.
• It does not appear that concurrent substance use (e.g., nicotine, alcohol, cannabis) will be assessed or accounted for despite evidence that prolonged and acute use of such substances can uniquely influence self-reported pain intensity/interference and reactivity to QST assessment.

Strengths
• The scientific environment at the University of Connecticut Health Center (UCHC) is strong and should support the proposed research.
• Yoga sessions will take place at the UCHC Outpatient Pavilion building, and a letter of support was provided.

Weaknesses
• No major limitations noted.

Strengths
• Study timeline and milestones were described in detail.

Weaknesses
• No major limitations noted.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • Potential Risks and Adequacy of Protection against risks were described in detail.
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable o An acceptable data and safety monitoring plan were provided.A Data Safety and Monitoring Board will also be assembled.

Inclusion Plans:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion Based on Age: Distribution justified scientifically • 50% Female, 68% White, 15% Black or African American, 6% Asian, 14% Hispanic or Latino • men and women age 18+ years of age will be included

Acceptable
• All study staff will complete Biohazard and Transportation of Biohazard training through UConn Environmental Safety Department.Collection, storage and assays of biohazardous samples will be performed in accordance with established safety guidelines and regulatory requirements. Resubmission: • Investigators were very responsive to the previous reviews.

Acceptable
• Data and resource sharing plan were provided.

Acceptable
• In order to ensure the identity and validity of key biological and/or chemical resources used in RNA sequencing as proposed in this application, the research team has established the following practices: 1.All chemicals and reagents are purchased tracking catalog numbers from well-established companies/vendors; 2. Batch numbers and other detailed product information are recorded in electronic lab notes for reference and future purchase orders; 3. Quality control analyses are performed for all key biological and/or chemical resources that could influence the research data (RNA quality, RIN >7.0); 4. Quality controls are performed for all experiments and reported to the PI.All decisions made by the PI are reported on the raw data output for analysis and reporting of results in research publications and presentations.

Budget and Period of Support:
Recommend as Requested

CRITIQUE 3
Significance: 2 Investigator(s): 1 Innovation: 1 Approach: 3 Environment: 1 Overall Impact: This resubmission application proposes to test whether yoga improves chronic low back pain (CLBP) by enhancing emotion regulation (ER) and will investigate whether reduced pain sensitization mediates the pain-reducing effects of yoga-induced improved ER.The project addresses a condition of tremendous public health impact, as CLBP is the leading cause of disability worldwide and existing treatments are not particularly effective.The rigor of prior research is addressed, and the proposed research will address important knowledge gaps regarding the mechanisms whereby yoga's beneficial effects in CLBP are achieved.The scientific rationale is well-founded in existing literature as captured in a new integrative model of yoga's therapeutic effects developed by this team.One surprising omission in the model is consideration of baseline ER as an important predictor of treatment response.That is, the investigators emphasize that the yoga interventions in prior studies may have had varying impact on ER, which explains the variable intervention effects.However, it is at least as plausible that dysfunctional ER contributes to CLBP in only a proportion of patients, and these patients are most likely to benefit from yoga.Also, the secondary aims are somewhat dependent on Aim 1, though this is not a major concern given prior findings that yoga improves ER. testing ER as a mediator of yoga's pain-reducing effects, and the addition of pain sensitization as a mediator and moderator of treatment effect is also novel.The strengths of the approach include: use of a well-developed yoga intervention based on considerable preliminary findings, a viable control condition that mimics many of the nonspecific effects of yoga, a strong recruitment and retention plan, use of blinding to enhance rigor, the inclusion of an intermediate assessment timepoint as well as longterm follow-up, and a validated comprehensive battery for assessment of pain sensitization.Rigor will be enhanced by blinding of assessors, video-based assessment of treatment fidelity, assessment of attendance and home practice, and a manualized yoga intervention to promote standardization.Also, the investigators have been quite responsive to prior critiques.A few minor weaknesses in the approach include: lack of information on management of the multiple variables that will be generated by the quantitative sensory testing protocol, no plan to include baseline ER as a potential treatment moderator, and limited attention to managing concomitant therapies in the analytic plan.The environment at the University of Connecticut is ideally suited for the proposed work.However, these do little to detract from the enthusiasm for this novel and exciting application.

Strengths
• The timeline is very detailed, providing a clear and plausible depiction of when study milestones will be accomplished.

Protections for Human Subjects:
Acceptable Risks and/or Adequate Protections • The risks of the project are thoroughly discussed, and adequate protections are in place to mitigate risks.
Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable o The team will establish a DSMB to monitor data and safety.

Inclusion Plans:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion Based on Age: Distribution justified scientifically • Equal numbers of females and males will be enrolled.Racial/ethnic diversity is modest but consistent with the local population: 58% non-Hispanic white, 14% Black or African American, 14% Hispanic, 6% Asian, 8% other.

Vertebrate Animals:
Not Applicable (No Vertebrate Animals)

Resubmission:
None noted by reviewer.

Acceptable
• There is a plan to share the genomic data via the NIH Gene Expression Omnibus repository.

Budget and Period of Support:
Recommended budget modifications or possible overlap identified: • Budget appears appropriate and well-justified.Footnotes for 1 R01 AT010555-01A1; PI Name: Park, Crystal L NIH has modified its policy regarding the receipt of resubmissions (amended applications).See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-074.html.The impact/priority score is calculated after discussion of an application by averaging the overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10.The criterion scores are submitted prior to the meeting by the individual reviewers assigned to an application, and are not discussed specifically at the review meeting or calculated into the overall impact score.Some applications also receive a percentile ranking.For details on the review process, see http://grants.nih.gov/grants/peer_review_process.htm#scoring.

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The rigor of past scientific studies is demonstrated in Dr. Park's past work on a self-regulatory model of yoga's intrinsic actions.

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Acceptable: disclosure and injury.Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion Based on Age: Distribution justified scientifically • 50% women.
THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES: The investigative team is excellent, as the contact PI has strong expertise in clinical intervention studies of yoga and emotion regulation has developed a novel model of yoga's effects on ER.The MPI is a well-established expert in CLBP with valuable experience assessing pain-related biomarkers and pain sensitization.The Co-Is bring important expertise in mind-body interventions and biostatistics.The project is innovative in