Feasibility of a Combined Neuromodulation and Yoga Intervention for Veterans With Mild Traumatic Brain Injury and Chronic Pain
Phase: NA
Conditions: Mild Traumatic Brain Injury, Chronic Pain
Sponsor: VA Office of Research and Development

Protocol Title 
 
Feasibility of a Combined Neuromodulation and Yoga Intervention for 
Veterans with Mild Traumatic Brain Injury and Chronic Pain 
  
Funding Agency 
or Sponsor VA ORD 
  
Principal Investigator 
 
Amy A. Herrold, PhD / Bella Etingen, PhD 
 
  
Version Number  
and Date Version 5, 2.1.2022 
 
Contents 
1.0 
Background ...................................................................................................................... 2 
2.0 
Testable Hypothesis ......................................................................................................... 6 
3.0 
Specific Aims .................................................................................................................... 7  
4.0 
Study Design and Methods............................................................................................... 7 
5.0 
Research and Data Collection .......................................................................................... 9 
6.0 
Benefits of participation in the study ............................................................................... 13 
7.0 
Compensation ................................................................................................................ 13 
8.0 
Alternatives to Participatoin ............................................................................................ 13 
9.0 
Data Analysis ................................................................................................................. 13 
10.0 
Confidentiality Plan ......................................................................................................... 15 
11.0 
Monitoring and Reporting Serious Adverse Events ......................................................... 16 
12.0 
References ..................................................................................................................... 17 
 
 
 
 

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1.0 
Background 
Clinical Problem:    
Over 340,000 mild traumatic brain injuries (mTBI) have occurred as a result of the military 
conflicts in Iraq and Afghanistan1. mTBI leads to a host of poor rehabilitation outcomes including 
impairments in cognition, physical health, and psychological health. These impairments among 
people with TBI lead to poor quality of life (QOL)2. Worsening this clinical picture, the prevalence 
of chronic pain is estimated to be between 43.1-70% among Veterans with TBI3. Recent 
research by the Chronic Effects of Neurotrauma Consortium (CENC) indicates that mTBI is 
strongly associated with increased pain intensity and pain interference4.  While there is a clear 
need for effective treatments for mTBI and chronic musculoskeletal pain, such treatment options 
are lacking. Despite clinical practice guidelines (CPG) recommending against opioid treatment 
for people with TBI, this patient cohort remains at increased risk of receiving opioid therapy for 
chronic musculoskeletal pain5. Given the ongoing opioid epidemic in the United States, it is very 
timely to develop alternative, non-pharmacologic treatments for chronic musculoskeletal pain 
among Veterans with mTBI. 
 
Yoga, Pain, and TBI: Yoga is an activity and mindfulness-based intervention that may be a 
promising alternative treatment for mTBI and chronic musculoskeletal pain. Yoga classes are 
generally comprised of breathing exercises, gentle stretching/yoga, and meditation. Evidence 
suggests that participating in yoga is helpful for individuals who experience chronic 
musculoskeletal pain. For example, a RCT of yoga conducted in Veterans with chronic low back 
pain found that participating n yoga led to reduced disability, pain, and opioid use6. Further, a 
systematic review of yoga interventions for chronic low back pain concluded that participating 
in yoga (compared to non-exercise controls) results in advances in function at 3 and 6 
months7. Based on this burgeoning evidence, the American College of Physicians Clinical 
Practice Guideline recommends yoga as a non-pharmacological treatment for chronic low back 
pain8. 
An adapted yoga program, LoveYourBrain Yoga, was created and tested specifically for 
TBI. Led by sets of activities recorded in a program manual, LoveYourBrain Yoga is a 6-session 
group-based yoga intervention that incorporates breathing exercises, yoga, meditation, and 
psychoeducation. LoveYourBrain Yoga is feasible and acceptable to people with TBI, and 
preliminary evidence suggests participating in LoveYourBrain Yoga leads to improvements in 
many outcomes, including QOL, among people with TBI of all severities 9-11. However, the 
impact of LoveYourBrain Yoga on pain outcomes in this population is yet to be tested. 
 
TMS, iTBS and Pain: Neuromodulation through transcranial magnetic stimulation (TMS) is a 
promising non-invasive, non-pharmacological treatment for TBI and chronic pain. A recent 
systematic review of repetitive TMS (rTMS) for chronic pain12 and a recent meta-analysis for 
rTMS for neuropathic pain13 demonstrated that high frequency rTMS (>1%) applied to the motor 
cortex (MC) effectively reduces pain. Additionally, high frequency rTMS applied to the left MC of 
patients with mTBI-related headache resulted in reductions in headache symptoms14. 
Collectively, these studies indicate that high frequency, excitatory rTMS applied to the MC is 
beneficial for alleviating pain and can be safely and effectively applied to TBI populations. 
Intermittent theta burst stimulation (iTBS) is a type of patterned, excitatory rTMS. A practical 
advantage of iTBS over rTMS is that iTBS protocols are typically 3 min. in length vs. 30 min. 
with rTMS. Yet, the research on iTBS for pain and TBI treatment is in its infancy. A recent trial of 
a single session of iTBS applied to the MC among patients with chronic orofacial pain 
demonstrated significant, yet transient, improvement in self-reported pain15. These promising 
results may be improved with repeated provision of iTBS treatments over time. Furthermore, 
evidence suggests that iTBS applied to the dorsolateral prefrontal cortex (DLPFC) may 

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significantly decrease frequency, duration, and severity of migraine headaches16. Another RCT 
conducted among patients with multiple sclerosis and lower spastic paraparesis examined 
effects of iTBS, high frequency rTMS (20 Hz), and placebo on spasticity. While researchers 
found that high-frequency rTMS resulted in better short-term outcomes, iTBS resulted in longer-
lasting improvements in outcomes17. 
A single case study utilizing iTBS as a potential treatment for TBI has been reported. This 
study details the case of a 25-year-old man with TBI who underwent 3 weeks of cerebellar iTBS 
combined with rehabilitation. This patient experienced improvements in balance performance, 
motor recovery, step length, and walking speed after iTBS 18. Importantly, this report suggests 
that iTBS can be used among individuals with TBI.  
 
iTBS Properties Make it Ideal for Combined Treatment: The effects of iTBS stimulation, 
typically quantified by increased MC excitability can last up to 60 min.19 Thus, iTBS can induce a 
window of neuroplasticity, making it ideally suited to magnify the effects of behavioral treatments 
provided after it. For example, iTBS provided prior to high frequency (10Hz) rTMS to the MC 
provided greater analgesia than rTMS alone among patients with chronic refractory neuropathic 
pain (without iTBS priming)20. iTBS has also been successfully combined with cognitive-
behavioral therapy to promote smoking cessation21. Collectively, emerging evidence suggests 
that iTBS shows promise to prime the brain for combined interventions and may magnify the 
impacts that these interventions would have when used alone, leading to an improvement in 
outcomes.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Conceptual Model (Fig 1): Our proposal is guided by Day et al.’s conceptual model of how 
mindfulness-based interventions are useful for chronic pain management22. We chose this 
model because it is evidence-based and because it incorporates brain state as a specific 
mechanism/mediator. This is particularly fitting because we hypothesize that iTBS will enhance 
this brain state to further improve the beneficial effects of the LoveYourBrain yoga program on 
pain management. This model informed our selection of outcomes, which, for this SPiRE 
application will include pain intensity, pain interference, QOL, physical functioning, pain 
medication use, and participation. We will also use this conceptual model to tailor the 
Figure 1. Adapted 
conceptual model of 
the mechanisms of 
mindfulness-based 
interventions for 
chronic pain 
management (Day et 
al. 2014).

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psychoeducation provided as part of the LoveYourBrain Yoga program. Psychoeducation will 
integrate domains identified as non-specific mechanism mediators in the model (e.g., pain 
acceptance and pain beliefs). The LoveYourBrain Yoga psychoeducation is already focused on 
resilience, which this model identifies as a non-specific mechanism/mediator as well. Our future 
RCT building on the results of this SPiRE will investigate moderators and mediators of improved 
outcomes as a result of participating in iTBS+yoga and will also be guided by this model. 
 
Knowledge Gaps Filled by this SPiRE Project This project will determine how a combined 
iTBS and the LoveYourBrain Yoga program impacts veterans with mTBI and chronic 
musculoskeletal pain. First, we will determine if we can combine iTBS with LoveYourBrain Yoga 
in a manner that is feasible and acceptable. Each of these interventions have been assessed in 
people with TBI. However, neither of these interventions have been studied among people with 
mTBI and chronic musculoskeletal pain. The preliminary outcome data on chronic 
musculoskeletal pain, collected in this study, will establish the foundation for determining the 
merits of continuing the development of iTBS+yoga as a treatment to attenuate mTBI-related 
chronic musculoskeletal pain and improve function. To advance our understanding of effects of 
iTBS+yoga, we can also build on the LoveYourBrain foundation data built by our consultant 
(Donnelly). Specifically, we selected outcomes for this SPiRE to enable comparisons of 
iTBS+yoga outcomes with the same QOL, feasibility and quantitative acceptability data (i.e., 
satisfaction rating scale) collected from individuals with mTBI who completed the LoveYourBrain 
yoga program without iTBS9-11,23. Comparing these same outcomes for our prospective 
iTBS+yoga cohort with the retrospective yoga alone cohort will allow us to determine the 
potential differential effects of iTBS+yoga on QOL, acceptability and feasibility. 
 
SPiRE Project Knowledge Advancements in Rehabilitation Research This SPiRE project 
will advance knowledge by determining if combining iTBS and the LoveYourBrain Yoga program 
is feasible and acceptable to Veterans with mTBI and chronic musculoskeletal pain. If the 
results are promising, this research will provide critical preliminary data for a VA RR&D Merit/IIR 
application for an RCT assessing the impacts of iTBS+yoga in a larger sample of Veterans. In 
addition, this project will provide novel information about the impacts of a combined 
neuromodulation and yoga program, specifically, whether iTBS can enhance the impacts of 
subsequent participation in an activity-based intervention (i.e., yoga). If we find that iTBS does, 
in fact, magnify the impacts of a subsequent intervention, this combinatorial model can be 
applied to and tested with other interventions (e.g., meditation, exercise) and among other 
outcomes (e.g., sleep) within rehabilitation populations, as well.  
 
Significance of the Research and How it Relates to RR&D Priority Areas This SPiRE aligns 
with the mission of RR&D to maximize functional recovery and has clearly evident potential for 
translation to clinical rehabilitation. This SPiRE project includes aims that address non-
pharmacological activity-based interventions for chronic musculoskeletal pain impacting 
outcomes that include pain reduction, medication use, function, and QOL. 
 
Importance and Health Relevance By demonstrating the feasibility and acceptability of 
iTBS+yoga, we will be a step closer to providing a novel, non-pharmacologic treatment for 
Veterans with mTBI and chronic musculoskeletal pain. If the SPiRE aims are achieved, the 
effectiveness of iTBS and LoveYourBrain Yoga can be further explored. Achieving the SPiRE 
aims are essential first steps towards carrying out a large-scale RCT to test for treatment 
efficacy. This will represent great progress for the 43-70% of Veterans with TBI3 who live with 
chronic pain.  
 

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Direct Benefit to Veterans and VA Services This SPiRE project will directly benefit Veterans 
and VA Services by developing a new, non-pharmacological neurorehabilitation treatment for 
Veterans with mTBI and chronic musculoskeletal pain in need of non-opioid treatment options or 
who do not find existing options to be effective or preferable. If efficacious, our proposed 
iTBS+yoga intervention is primed for diffusion across the VA system of care. TMS is now 
offered at 30 VA hospitals nationwide for depression, and yoga is among the complementary 
and integrative health (CIH) programs being rolled out as a part of the VAs nation-wide Whole 
Health implementation efforts24, with classes offered through VA services such as recreational 
therapy. Thus, should iTBS+yoga ultimately proves to be efficacious and effective, VA facilities 
will be well-poised to offer this treatment.  
 
2.0 
Testable Hypotheses 
 
Recent evidence suggests that non-invasive neuromodulation through repetitive transcranial 
magnetic stimulation (rTMS) is a promising non-pharmacological treatment for chronic 
musculoskeletal pain. Specifically, high frequency rTMS applied to the motor cortex (MC) 
reduces pain among people with chronic and neuropathic pain12,13. A type of patterned, 
excitatory rTMS, called intermittent theta burst stimulation (iTBS), is thought to be particularly 
promising as it can increase excitability of the MC19 that lasts after the cessation of iTBS. This 
time-period of post-iTBS enhanced MC excitability makes iTBS ideally suited to magnify the 
effects of behavioral treatments. More specifically, iTBS shows promise to prime the brain to 
magnify the impacts and benefits of interventions provided during this time-period of enhanced 
MC excitability20,21. Yoga is an activity and mindfulness-based behavioral intervention ideally 
suited for this purpose.  
In this study, we will test the idea that for mTBI-related chronic musculoskeletal pain the 
beneficial effects of yoga can be magnified if it is provided immediately after provision of iTBS 
(iTBS+yoga). LoveYourBrain Yoga is an adapted yoga program that was created and tested 
specifically for people with TBI. LoveYourBrain Yoga is a 6-session, manualized, group-based 
yoga intervention incorporating breathing exercises, yoga, meditation, and psychoeducation. 
LoveYourBrain Yoga is feasible and acceptable to people with TBI, and evidence suggests 
participating in LoveYourBrain Yoga leads to improvements in outcomes including QOL among 
people with TBI of all severities9-11. However, effects of LoveYourBrain Yoga on pain outcomes 
among Veterans with mTBI and chronic musculoskeletal pain are yet to be tested.  
Our long-term goal is to demonstrate efficacy of iTBS+yoga on improving QOL, function, 
and pain among Veterans with mTBI and chronic musculoskeletal pain. The objectives of this 
pilot study, essential first steps towards this goal, are to develop a combined iTBS+yoga 
intervention, assess the intervention’s feasibility and acceptability, and to gather preliminary 
clinical outcome data on QOL, function and pain that will guide future studies.  
Our central hypothesis is that our combined iTBS+yoga intervention will be feasible and 
acceptable for Veterans with mTBI and chronic musculoskeletal pain. This hypothesis is based 
on existing literature and our preliminary data demonstrating that iTBS18 and the LoveYourBrain 
yoga program9, provided separately, are each feasible and acceptable among people with TBI.  
We will address these objectives and hypothesis with the following specific aims conducted 
in a single group, within subject design wherein all 20 Veterans with mTBI and chronic 
musculoskeletal pain will receive iTBS+yoga: 
 
 
 

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3.0 
Specific Aims 
 
Aim 1: Develop a novel, combined iTBS+yoga neurorehabilitation intervention for 
Veterans with mTBI and chronic musculoskeletal pain. The intervention will combine iTBS 
treatment (3min), which will be provided prior to the established LoveYourBrain Yoga program 
(90min). iTBS+yoga treatment sessions will be conducted once a week for 6-weeks. We will 
finalize logistics for combining iTBS with LoveYourBrain Yoga and offering it to Veterans with 
mTBI and chronic musculoskeletal pain. This will include determining how many participants 
can be accommodated in small group sessions, tailoring the psychoeducation of the yoga 
component, and other safety and logistical considerations. 
 
Aim 2: Examine the feasibility and acceptability of iTBS+yoga for Veterans with mTBI and 
chronic musculoskeletal pain. All Veterans (N=20) will receive 6 weekly sessions of 
iTBS+yoga. We hypothesize that iTBS+yoga will be feasible as indicated by Veteran’s initiation 
and completion of all 6 weeks of the intervention. Acceptability will be assessed quantitatively 
through satisfaction ratings and qualitatively using semi-structured interviews.  
 
Aim 3: Establish the foundation for sample size and power considerations for a future 
clinical trial to examine the effectiveness of iTBS+yoga on Veterans’ QOL, function and 
pain outcomes. This will be achieved by collecting preliminary data of Veterans self-reported 
QOL, function and pain outcomes before (baseline) and after (endpoint) the 6-week iTBS+yoga 
intervention. 
4.0 
Study Design and Methods 
 
The proposed research involves human subjects and will NOT involve animals. 
Design: Prospective within-subject pilot study to develop iTBS+yoga intervention, examine the 
feasibility and acceptability of 6 sessions of iTBS+yoga over 6 weeks, and gather preliminary 
data on pain, function and QOL.  
 
Veteran Sample: Twenty Veterans above the age of 22 with mTBI and chronic musculoskeletal 
pain will be included. Veteran participants must perceive themselves as able to participate in 
gentle physical movements and will be cleared for gentle exercise by a study team physician. 
mTBI will be defined according to the VA/DoD CPG25 utilizing the mTBI symptom attribution and 
classification algorithm (SACA)26. Chronic musculoskeletal pain will be operationally defined as 
pain in the muscles, bones, ligaments, tendons and/or nerves that persists for >6 months and is 
of moderate to severe intensity as indicated by a score of >5 on specific items on the Brief Pain 
Inventory (BPI)27. For safety, we will exclude persons with contraindications to TMS or MRI. 
Detailed eligibility criteria are provided in Table 1. We will include both males and females. We 
will not exclude participants based on gender, ethnicity or race.  Subjects with major depressive 
disorder and other psychological disorders will not be excluded and these diagnoses will be 
documented as potential covariates. 
 
Participant Recruitment Plan: We will recruit Veterans from the TBI/Polytrauma program at 
Edward Hines Jr., VA Hospital (Hines VA). TBI/Polytrauma program personnel will inform 
TBI/Polytrauma program members about the study through routine staff meetings. The PI will 
also present updates on this study on a quarterly basis. Dr. Herrold and research team 
members will be added as Co-Signers in the electronic medical record of TBI/Polytrauma 
patients that may be a good fit for this study. Research team members will then be able to 

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screen these for eligibility and send eligible Veterans an informational letter about the study. 
Research team members will then make follow-up screening phone calls. 
We will also mail informational letters to Veterans who have completed our past studies and 
permitted us to contact them about future studies through a TBI Data Repository (Hines 
IRB#14-003, Co-PIs Herrold & Pape) created for recruitment purposes. This repository currently 
includes over 300 Veterans and continues to grow with ongoing studies.   
 
 
 
 
 
 
Recruitment Feasibility at Hines VA Recruitment Site: In 2019 at Hines VA there were 1,737 
unique Veteran patients with ICD-10 diagnostic codes for mTBI or chronic musculoskeletal pain 
within the TBI/Polytrauma program. Given that chronic pain co-occurs 43-70% among Veterans 
with TBI3, we conservatively estimate that 694 (40% of 1,737) unique Veterans who received 
TBI/Polytrauma services in 2019 alone would meet study eligibility criteria. Thus, enrolling 10 
Veterans a year for 2 years for this SPiRE project is quite feasible.  
 
Initial Eligibility Screening: A partial HIPAA waiver and waiver of informed consent for 
screening purposes will provide regulatory approval to screen candidates to determine study 
eligibility prior to obtaining informed consent. Veterans identified as research candidates will 
Table 1. Participant Eligibility Criteria 
Inclusion Criteria 
• 22+ years of age 
• Can read and speak English 
• Perceive themselves as able to participate in gentle physical movements and cleared by 
study physician to do so.    
• mTBI Criteria: Symptom Attribution and Classification (SACA) criteria for mTBI 
(without requirement of clinical neuropsychological impairment) 
• Chronic musculoskeletal pain: pain (in muscles, bones, ligaments, tendons and/or 
nerves) that persists for >6 months and is of moderate to severe intensity with a 
score of >5 on specific items on the Brief Pain Inventory (BPI)  
• Fully vaccinated against COVID-19 prior to study participation 
Exclusion Criteria 
• Contraindications to iTBS/TMS (e.g. epilepsy, history of anoxic brain injury or heart 
disease) 
• Contraindications to MRI (e.g., claustrophobia, ferromagnetic metal implants) 
• Pain believed to be associated with cardiac or ischemic conditions 
• Active seizure disorder, or if they are taking psychostimulants (e.g. amphetamines), 
anticholinergics or other medications that may increase their risk of having seizures. 
• History of moderate to severe TBI 
• History of or current psychosis not due to an external cause (e.g., due to illicit drug 
use) 
• Are pregnant or nursing 
• Within 12 weeks of a major surgery/operation 
• Have questionably valid test profiles 

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complete an initial phone screening for the following: (1) probable mTBI, using the Ohio State 
University TBI Identification Method (a TBI Common Data Element, CDE)28, (2) MRI safety, 
using the Hines VA safety form, and (3) self-reported age and ability to read and speak English. 
(4) Age will be verified in the EMR (i.e., CPRS or CAPRI). (5) A list of prescribed and over-the 
counter medications and the length of time the participant has been on each medication will also 
be collected over the telephone.  Current medications will be cross-referenced with study 
eligibility criteria and the EMR to identify any antiepileptics, and any medications known to lower 
seizure threshold. The electronic medical record (EMR) will also be reviewed for study eligibility 
criteria. In response to the global SARS-CoV-2 (COVID-19) pandemic, documentation of full 
COVID-19 vaccination will be confirmed. If review findings indicate possible contraindications to 
rTMS or MRI related to a metal implant, then the model and manufacturer of the implant will be 
obtained to determine whether or not it is safe to expose the implant to a strong magnet. 
Manufacturer recommendations regarding safety will be followed. If potential participants meet 
all eligibility criteria, they will be scheduled for the first research visit. They will be mailed a copy 
of the informed consent form to review, and an appointment reminder of the appointment date 
and time. 
5.0 
Research and Data Collection Procedures (Fig 3):  
 
Due to the COVID-19 pandemic, the PI may elect to increase social distancing measures and 
utilize telehealth to complete portions of the protocol via phone or VA-approved telehealth 
technologies. 
 
Informed Consent: Authorized clinical researchers will meet eligible participants at a 
designated entrance, closest in proximity to a private room, where the study visit is to take 
place. The researcher will provide all documentation, to include the study consent form and all 
assessments the participant will need to complete. All participants will be able to make their own 
decisions regarding research participation. They will be encouraged to discuss the study with a 
family member or friend before agreeing to participate. The participant will not be openly 
encouraged to participate in the research or told that there is any expected benefit from the 
experimental interventions during participation.  Research participants will have access to 
research staff to assist with any questions or concerns until understanding is achieved to the 
judgement of the individual asking the question.  If a participant refuses participation, no further 
contact will be made.  If signed informed consent forms are completed, a note will be made in 
the Hines VA EMR, and the original consent will be kept in a locked cabinet in a locked research 
office behind swipe-access doors in Bldg. 1, Room B-351 or B-318 of Hines VA.  Copies of the 
Figure 3. Study Timeline 

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signed consent forms will be provided to the Hines VA IRB Office.  Additionally, a copy will be 
provided to the participant.  After informed consent processes are concluded,  
participants will complete a saliva alcohol test, a urine drug screen and pregnancy test for 
females to confirm eligibility. 
 
Consent documents will be stored in locked file cabinet, behind a locked door at the Hines VA 
Bldg. 1, Room B-351 or B-318.  
 
Drug and Alcohol Screening: Abstinence from alcohol and illicit substances will be requested 
for each visit and will be confirmed with a saliva alcohol test and urine drug screen (breathalyzer 
testing will not be utilized at this time due to aerosolization concerns – in compliance with 
COVID-19 safety precautions). On Visit 1, the urine drug screen will be completed by Hines VA 
clinical laboratory using a manual requisition with the participant’s unique subject ID number. All 
Table 2. Study Assessments 
Assessment Name  
Assessment Purpose 
Screening Assessments: 
Structured Diagnostic Interview (STDI)138 with the 
Neurobehavioral Symptom Inventory (NSI, TBI-CDE)141 
mTBI eligibility 
California Verbal Learning Test-II (CVLT-II)142 
Memory and performance effort validity 
Minnesota Multiphasic Personality Inventory-2-RF (MMPI-2-RF)144 Symptom reporting validity 
Brief Pain Inventory (BPI) 139 
Preliminary pain data & eligibility 
Hines VA MRI Safety Form and TMS Safety Form 
MRI & TMS safety compatibility 
Demographics 
Sample characterization 
Baseline and Endpoint Assessments for Study Outcomes: 
TBI-QOL (TBI-CDE) 
Preliminary quality of life data 
Mayo-Portland Adaptability Index (TBI-CDE) 
Preliminary function and participation data 
Pain Interference scale (PROMIS) 
Preliminary pain data 
Therapy Activity Data Collection 
Preliminary Therapeutic Activity data 
Session completion rates 
Feasibility (Endpoint only) 
Structured qualitative interviews 
Acceptability (Endpoint only) 
Satisfaction ratings 
Acceptability (Endpoint only) 
Home & community yoga & meditation diaries 
Covariate (each weekly session) 

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subsequent urine drug screens will be conducted using a urine test kit by research staff. No 
results from the urine drug screen will be entered into the Veteran participant’s medical record. 
These results will be for research purposes only. Any participant testing positive for alcohol, or 
illicit drugs (with the exception of prescribed opiates) will be asked to re-schedule research 
procedures, and safe transportation will be arranged (e.g., taxi) or participants will be escorted 
to the ER or mental health intake as appropriate. 
 
All female participants will complete a pregnancy test during the Visit 1 screening visit.  If a 
pregnancy test is positive, then participation in the study will stop.  
 
 
Table 2 Summarizes assessments conducted during the study. 
 
 
Visit 1 (Individual Screening Visit):   
 
Pre-visit / Post-visit screening:  Authorized clinical researchers will contact study participants 
to review procedures for accessing Hines VA facility prior to the scheduled study visit date. 
Research staff will complete a COVID-19 screening questionnaire with the participant over the 
phone 1 day prior to the visit date.   
 
Potential participants will first complete a finite set of assessments from the mTBI SACA (Pape, 
Herrold et al. 2016)138. The Structured Diagnostic Interview (STDI), included in the SACA, will 
be used to establish the mTBI history including duration of loss of consciousness (LOC), 
alteration of consciousness (AOC), and post-traumatic amnesia (PTA)138. The Brief Pain 
Inventory (Short Form) will be used to identify and confirm inclusion criteria related to 
participant’s reports of musculoskeletal pain. The interview ends with the Neurobehavioral 
Symptom Inventory [NSI, a TBI Common Data Element (CDE)141]. The California Verbal 
Learning Test-II (CVLT-II)142 will be used to assess verbal memory, a cognitive domain affected 
by mTBI. To determine validity of test profiles, the CVLT-II forced choice component will be 
used, with a cutoff score of 15, as a measure of effort performance143. To determine validity of 
symptom reporting, the Minnesota Multiphasic Personality Inventory-2-RF (MMPI-2-RF)144 will 
be used  to identify abnormal symptom reporting via this criteria: F: T score ≥ 107; F(p): T score 
≥ 85; TRIN: T score ≥ 80; VRIN: T score ≥ 80)138.  
 
During the screening process, a study physician will evaluate the Veteran's ability to engage in 
gentle exercise and their pain management strategy including OTC analgesics that they might 
take during the intervention. On the screening visit the participant will be instructed to bring in 
all medications with them to complete the Medication Inventory including OTC analgesics. We 
will also screen the electronic medical record for medical history criteria. Participants will still 
be able to receive other potential treatments to assist with the management of chronic 
musculoskeletal pain. These pain management strategies/treatments must remain stable during 
study participation. Other treatments for chronic musculoskeletal pain that the participant’s 
provider may discuss with them could include physical therapy, occupational therapy, 
chiropractic care, acupuncture, injections (steroid, prolotherapy, trigger point injections) if these 
are appropriate. Participants will remain on their usual pain medications while participating in 
the study. Upon the initial evaluation, all medication dosage and frequency will be documented. 
All subjects will have their medication dosage and frequency documented at the completion of 

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the study. 
 
Once the study visit is completed, authorized clinical researchers will complete a follow up 
phone call with each participant, which will include completion of an additional COVID-19 
screening form. 
 
 
Visit 2 (Individual MRI): A high-resolution, structural MRI scan will be collected in order to 
allow for iTBS treatment site neuronavigation for each participant. The MRI will take place at 
Hines VAH and this visit will last approximately 30 minutes. 
All established COVID-19 safety precautions will be followed, as identified by Edward Hines Jr. 
VA Hospital administration. 
 
MRI Scan 
 
• 
Participant will also undergo a magnetic resonance imaging scan (MRI) to look at the 
brain. An MRI is a type of scan that uses magnetic fields and radio waves to take a 
picture of the brain. The MRI will last about 15 minutes. 
 
In order to make sure the MRI procedure will be safe; participant will be asked to fill out a 
screening form before starting the study. It is important that participants tell the researchers in 
this study if they have any history of:  
 
• 
Metal fragments in the eyes or face. 
 
• 
Implantation of any electronic devices such as (but not limited to) cardiac pacemakers, 
cardiac defibrillators, cochlea implants or nerve stimulators. 
 
• 
Surgery on the blood vessels of the brain or the valves of the heart 
 
• 
Claustrophobia (fear of enclosed places) 
 
• 
Body piercing or tattoos  
 
Participants will be asked to change into a hospital gown or surgical scrubs and remove any 
metal, such as earrings. 
 
An MRI technician will give participants instructions outside the MRI scanner about the 
scanning. Next, participants will be asked to lie still on the MRI patient table and their heads will 
be placed in a specially designed head holder. The participant’s head will be cushioned by a 
firm foam pillow. The table will then slide into the enclosed space of the MRI scanner.  
 
The information from the MRI scanner is only useful if participants are able to complete the 
whole imaging session and hold their heads very still the whole time. Therefore, participant will 
be encouraged to hold as still as possible, and to let the investigators know if they are 
uncomfortable in any way as soon as possible after the imaging session begins. 
 
The front of the head-holder will be open, which lets participants look through a special mirror 
and see pictures presented to them on a projection screen near their feet. Sounds may also be 

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presented to participants using specially designed headphones. Participants will be asked to 
hold their heads as still as possible and to respond to the pictures or sounds by pushing a 
button or thinking quietly to themselves.  
 
The MRI scanner makes loud banging noises while taking a measurement, so either ear plugs 
or specially designed headphones will be used to reduce the noise. The researchers will be in 
communication with the participant through an intercom system to tell them how the study is 
going. The earplugs or headphones should not get in the way of communicating with the 
researchers. Participant can speak to the technician by talking out loud. If at any time or for any 
reason, participants wish to stop the exam, they may do so by squeezing a rubber ball. This will 
signal the MRI technician to stop the scanner. 
 
The MRI pictures in this study will be reviewed by a neuroradiologist.  If an abnormality is 
detected during the processing of the scan, participants will be contacted, and the information 
will be provided.  Participants will be asked to provide us with the name and address of the 
provider of their choice. Appropriate Release of Information documentation and processes will 
be used to transport the records. Participants will be encouraged to schedule a visit with their 
provider for appropriate medical advice. 
 
Visit 3 (Individual Baseline & Motor Threshold): Individual baseline assessments will be 
completed during this study visit. These will include self-report questionnaires about TBI-related 
quality of life (TBI-QOL), function (Mayo Portland Adaptability Index) and pain (Pain Interference 
Scale). Participants will also be instructed to keep diaries of utilization of pain medication and 
other pain management strategies. Participants will also complete weekly diaries detailing the 
time they spent at home or in the community engaging in meditation or yoga practices. 
Individual Motor Threshold (MT): Each participant’s T1 MRI, will be loaded into a Localite 
TMS Neural Navigator system. A MagVenture C-B60 coil will be used to deliver single pulse 
TMS to the non-dominant MC to identify the abductor pollicis brevis (APB) muscle coordinates. 
Stimulation intensity that will be used in iTBS will be determined by collecting each participant’s 
motor threshold (MT) using the finger representations of the motor cortex.  The consensus in 
the literature is that iTBS can be safely provided at 80% of active motor threshold (AMT).  Since 
there is more within and between subject variability with AMT (e.g, different gripping strengths), 
relative to resting motor threshold (RMT), scientifically the RMT is preferred. There is also 
recent evidence that motor threshold estimates using RMT and AMT are equivalent.201 This 
means that treatment intensity, based on these two MT estimation procedures, would be 
equivalent, we will use RMT to estimate MT and compute treatment intensity. RMT will be 
defined as the lowest stimulus intensity necessary to produce motor-evoked potentials (MEPs) 
≥50µV in 5/10 trials. Thus, the standard iTBS parameters will be used in this trial to maximize 
safety.  iTBS will be provided at 80% of RMT. 
 
The electrodes used in this process will be placed using a gel or sticky paste.   
The test will take about 1 hour. 
 
Visits 4-9 (iTBS+Yoga Treatment Sessions): iTBS+Yoga sessions will occur once a week for 
6 weeks. These sessions will occur at Hines VAH, with only essential research staff present,    
and take approximately 1.5 hours. Each session will start with individual iTBS (3 min.). Then, 

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small group yoga sessions will occur. All reasonable precautions will be made to prevent 
contact with/spread of SARS COV-19, per Hines Hospital policy. 
Because of potential pain (see POSSIBLE RISKS OR DISCOMFORTS below), we recommend 
that participants bring an over the counter pain reliever of their choice to take prior to each iTBS 
session. We will ask participants when they took the medication and the amount. 
 
Pre-iTBS Assessments: 
 
• 
Participants will be asked to complete a saliva alcohol test to help the research team 
determine the amount of alcohol that may be in the participant’s bloodstream. During this 
alcohol screening, participant will be asked to blow into a tube attached to a special 
hand-held machine. No results will be entered into participant’s electronic medical 
record.  
 
• 
Participants will be asked to provide a urine sample to allow the research team to 
determine if certain drugs are in participant’s body. This includes pain medications like 
morphine and Vicodin; benzodiazepines such as Valium, Librium, Xanax and Ativan, that 
are usually used to treat anxiety or alcohol withdrawal; and substances like cocaine, 
marijuana/cannabis, heroin, amphetamine or speed and barbiturates.  
 
It is important to know that any alcohol tests or urine drug screening results are used to 
determine if participants are eligible to continue in this research study and will NOT be entered 
into participant’s medical record or reported to legal authorities. 
Intermittent Theta Burst Stimulation (iTBS) Treatment Sessions: 
 
Neuromodulation through transcranial magnetic stimulation (TMS) is a promising non-invasive, 
non-pharmacological treatment for TBI and chronic musculoskeletal pain. A recent systematic 
review of repetitive TMS (rTMS) for chronic pain6 and a recent meta-analysis for rTMS for 
neuropathic pain7 demonstrated that high frequency rTMS (>1%) applied to the motor cortex 
(MC) effectively reduces pain. Additionally, high frequency rTMS applied to the left MC of 
patients with mTBI-related headache resulted in reductions in headache symptoms18. 
Collectively, these studies indicate that high frequency, excitatory rTMS applied to the MC is 
beneficial for alleviating pain and can be safely and effectively applied to TBI populations.  
 
iTBS Properties Make it Ideal for Combined Treatment: The effects of iTBS stimulation, typically 
quantified by increased MC excitability can last up to 60 min.8 Thus, iTBS can induce a window 
of neuroplasticity, making it ideally suited to magnify the effects of behavioral treatments 
provided after it. For example, iTBS provided prior to high frequency (10Hz) rTMS to the MC 
provided greater analgesia than rTMS alone among patients with chronic refractory neuropathic 
pain (without iTBS priming)9. iTBS has also been successfully combined with cognitive-
behavioral therapy to promote smoking cessation10. Collectively, emerging evidence suggests 
that iTBS shows promise to prime the brain for combined interventions and may magnify the 
impacts that these interventions would have when used alone, leading to an improvement in 
outcomes.  
 
iTBS+Yoga Intervention: Intervention sessions will occur once a week for 6 weeks. Each 
session will start with individual iTBS (3 min.). We will use the T1 MRI to localize the stimulation 
site, which will be each participant’s dominant trunk representation area of the MC. iTBS will be 
delivered utilizing the MagVentrure Mag-Pro X100 with MagOption stimulator that includes 

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active and placebo coils (C-B60 Butterfly coils). Only the active setting will be used. iTBS 
parameters include 3 pulses of stimulation given at 50Hz, repeated every 200ms at 80% of the 
resting MT18. The inter-pulse-interval is 20ms. A 2s train of TBS, is repeated every 10s for a 
total of 190s, which equates to a total of 600 pulses32.  
 
During the iTBS treatments, ear buds will be placed in subject’s ears because the magnetic 
stimulator makes a loud clicking noise. Tape may be placed over the ear buds to make sure the 
ear buds stay in place.  
 
Each complete session will take about 15 minutes to allow for set-up and take-down. 
Appropriate surfaces will be sanitized before and after each study participant. The weekly 
schedule for iTBS will be one session of iTBS every week (on the same weekday and time if 
possible) for 6 weeks. In order to monitor for safety, all iTBS sessions will be videotaped. All 
security procedures for data will apply. Acknowledgement for picture and video will be 
completed as part of HIPAA Authorization documentation. A total of 6 iTBS sessions will be 
provided over six weeks.  
Love Your Brain Yoga Sessions: After the iTBS sessions, participant will complete a small 
group (approximately 3-6 people) yoga session. Each yoga session includes 10 minutes of 
breathing exercises, 45 minutes of gentle yoga/stretching, 15 minutes of guided meditation, and 
20 minutes of facilitated discussion with psychoeducation. 
Safety Measures:  Subjects will participate in safety monitoring using the Data Safety 
Monitoring Scale (DSMS). This scale rates changes from baseline vital signs (temperature, 
blood pressure, heart rate, oxygen saturation levels), fatigue, tinnitus (ringing in the ears), sleep, 
dizziness, nausea, vomiting, confusion, seizure, syncope (fainting), headache, neck pain, skin 
integrity of the scalp, and substance use. 
 
Visit 10 (Endpoint Assessments): Individual endpoint assessments will be completed during 
this study visit. These will include repeating self-report questionnaires about TBI-related quality 
of life (TBI-QOL), function (Mayo Portland Adaptability Index) and pain (Brief Pain Inventory and 
Pain Interference Scale). Additionally, we will ask participants to complete satisfaction ratings of 
the iTBS+Yoga sessions and to turn in participants’ pain management and yoga/meditiatation 
diaries. 
Visit 11 (Qualitative Interviews): Participants will be asked to take part in semi-structured 
interviews that will be audio-recorded. Interviews will elicit feedback about Veteran experiences 
with iTBS+yoga intervention participation, barriers and facilitators to participation, perceptions of 
the intervention, how participation may have impacted key pain-related outcomes and quality of 
life, and suggestions for improvement.  
Study Outcomes – Individual Baseline & Endpoint Assessments: Feasibility will be defined 
by enrollment and the number of sessions completed by each participant. Acceptability will be 
quantitatively assessed using satisfaction ratings9 and qualitatively assessed via semi-
structured interviews with all study participants. Interviews will elicit feedback about Veteran 
experiences with intervention participation, barriers and facilitators to participation, perceptions 
of the intervention, how participation may have impacted key pain-related outcomes and their 
QOL, and suggestions for improvement. TBI CDE outcomes will include: the TBI-QOL scale and 

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Mayo-Portland Adaptability Index. 
 
The Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 
scale and the BPI will also be used, along with utilization of pain medication and other pain 
management strategies collected via self-report and chart review. Participants will also complete 
weekly diaries detailing the time they spent at home or in the community engaging in meditation 
or yoga practices, which will be used as a potential covariate in analyses. 
 
5.1 Possible Risks or Discomforts 
 
Intermittent Theta Burst Stimulation (iTBS - TMS) The biggest concern for magnetic 
stimulation is seizure induction.  Other known side effects of iTBS include headache, dizziness, 
tinnitus, nausea, neck pain or scalp burns (Rossi et al, 2009)32.  Alcohol use and alcohol 
withdrawal may introduce an unknown seizure risk as both of these circumstances lower the 
seizure threshold32. For this reason, any participant with a positive saliva alcohol test result will 
not be stimulated and iTBS will be re-scheduled.  
 Additional Known risks are: 
• 
Possible electrocution during iTBS due to insufficient insulation of the coil.  The coils will 
be inspected before and after each iTBS session to ensure that the coil does not have 
any cracks or loss of integrity.  
• 
Physical discomfort, facial numbness, headache or dental pain. Mechanical vibrations 
that occur within the coil while a TMS pulse is being generated, for example, may result 
in discomfort or headache  
• 
Device failure due to overheating, electrical short-circuiting or mechanical breakdown 
from force on the device.  All precautions will be taken to prevent device breakdown that 
may affect the welfare of the participant.  The TMS device will be inspected routinely and 
safety guidelines from the manufacturer will be followed. 
• 
Contamination transferred from one participant to another following treatment.  The 
device will be disinfected after every use to prevent spread of germs between 
participants. 
• 
Mania, depression, anxiety and suicidality, although rare and usually associated with 
depression or bipolar depression. Repeat measures are collected to monitor for 
emergence of new mental health conditions and worsening of existing conditions.  If new 
conditions emerge or existing conditions worsen, then the participant will be withdrawn 
and follow up with their established care team will be recommended. 
 
Behavioral Assessments: The participant may experience some distress when completing 
behavioral assessments. The participant will be asked to notify study staff if these questions or 
questionnaires make them feel uncomfortable in order to make sure that the participant has 
timely access to mental health resources or information for organizations they can contact for 
support.  Participants will be questioned about mTBI symptoms, and circumstances related to 
chronic musculoskeletal pain they are experiencing, routinely during study participation.  Safety 
management of adverse responses to these measures is outlined below.  
 
Neuroimaging:  There are no known risks associated with the MRI procedures, although some 
participants experience mild discomfort from trying to keep still during the MRI, and some 
participants feel anxious or claustrophobic in the scanner.  This is minimized by having the 
researchers in constant communication (via headphones) with the participant. 

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Unknown TMS Risks:  There may be other unknown and/or unanticipated side effects that 
could occur.  An adverse events (AE) log and daily study monitor log will be used to monitor the 
occurrence of any AE including unanticipated events (A response plan to unanticipated AE in 
delineated in section 11.0   Monitoring and Reporting Serious Adverse Events). 
Confidentiality: Loss of confidentiality is a potential risk. This research study involves collection 
of self-report measures.  Participant’s responses to self-report questionnaires will be 
documented.  To protect confidentiality, all hard copies of questionnaires and behavioral 
assessments as well as urine screens and saliva alcohol test screens will be assigned a unique 
participant identification number and the date the assessment was completed.   
Precautions Taken to Minimize Risks: 
 
iTBS Safety Monitoring: The iTBS (TMS) Safety Sheet (DSMS) contains a customized 
severity indicator scale.  Additionally, an Adverse Events Tracking Log has been developed for 
this project.  Both are integrated into the safety monitoring of this study.  All serious and non-
serious adverse events will be tracked on the Adverse Event Tracking Log.  
 
For each safety variable specified on the DSMS, change from baseline is rated according to 
severity and for each severity rating there is a specified medical response to be followed. The 
ratings are on a scale of 1 to 5 with a higher number indicating more deleterious change. This 
scale rates changes from baseline in vital signs (temperature, blood pressure, heart rate, 
oxygen saturation levels), fatigue, tinnitus, sleep, dizziness, nausea, vomiting, confusion, 
seizure, syncope (fainting), headache, neck pain, skin integrity of the scalp, substance use, and 
PTSD symptoms.  This scale will be completed at baseline and then weekly thereafter.  
 
Participants will be clinically monitored for seizure by trained research staff. Should a seizure 
occur, the following response plan would occur:  
1) Research team member to activate emergency code for Hines RRT 
2) Other research team member to call 911. 
3) Trained research staff to assess airway, breathing and circulation (ABC) 
4) When RRT arrives, their staff will take over, assess and treat the participant if needed 
5) RRT emergency team will transport participant to Hines ED 
a. For participants treated at Hines VA ED, the PI will contact the participant within 
a week and encourage them to follow-up with their Primary Care Physician (it is 
Hines VA policy that patients treated in the ED follow up with their Primary Care 
Physician within 2 weeks). 
6) As outlined below, any seizure will result in stopping treatment and withdrawal from 
study.  
 
All female participants will complete a pregnancy test during study participation.  If a pregnancy 
test is positive, then participation in the study will stop.  
 
Before receiving treatment, participants will meet with a study team physician to review their 
pain medications, pain management strategies and to determine whether or not it is safe to 
participate in gentle physical movements. Participants may be advised to take a pain reliever of 
their choice (i.e. Acetaminophen /Tylenol) prior to iTBS sessions if discomfort is anticipated. 
If, in the opinion of the PI, you are no longer appropriate for the study, you may be discontinued 
without regard to your wishes to remain, in order to ensure your safety.  This would apply if you 

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do not comply with the requirements for participation, if it becomes medically unsafe for you to 
continue, if the study is stopped by a sponsor, or if the Department of Health and Human 
Services withdraws approval. 
LoveYourBrain Yoga Program:  As with any exercise program, there is a risk of pain or 
muscle soreness due to increased physical activity. There is also a low risk of falling due to the 
physical activity and balance challenges involved in the yoga group. To minimize the risk of 
unnecessary increases in pain or muscle soreness or falls, you will work with trained 
researchers and clinicians certified in the LoveYourBrain Yoga program. You will have an 
opportunity to rest and you will be monitored for verbal or visual signs of fatigue or discomfort.  
Because psychological symptoms might surface or get worse during the discussion portion of 
the LoveYourBrain Yoga program, you will be monitored for changes in psychological symptoms 
and will be offered resources and follow-up care if needed (i.e. psychological support/follow-up, 
support groups, etc.). 
Structural MRI: There are no known risks associated with MRI, although some people have 
experienced discomfort in trying to remain still. The MRI scanner makes loud banging noises 
while taking a measurement, so earplugs will be used to reduce the noise. The researchers will 
be in communication with you through an intercom system to ask how you are doing.  The 
earplugs should not get in the way of communicating with the researchers. You can speak to the 
technician just by talking out loud. If at any time or for any reason, you wish to stop the exam, 
you may do so by squeezing a rubber ball we provide. Some people have been noted to be 
anxious or claustrophobic during the scan.   
Psychological:  During the study visits, you will complete self-report measures and structured 
interviews related to mTBI, quality of life, pain, and functioning. You may experience distress in 
speaking about these sensitive topics. You will be asked to notify study staff if these questions 
or questionnaires make you feel uncomfortable.  If needed, research staff will make sure you 
have timely access to mental health resources or information on organizations to contact for 
support. If you express extreme distress while completing these assessments, research staff will 
stop the interview. 
Loss of confidentiality:  Loss of confidentiality is a potential risk. You will complete 
questionnaires that discuss mental health symptoms, disability, mTBI symptoms. All of your 
responses will be documented.: To protect you from a breach of confidentiality, you will be 
assigned a unique identification number by the study personnel. This number will be placed on 
all hard forms, and kept in a locked file cabinet in a locked office at Hines VA. Any specimens 
you provide will also be marked with this identification number and the collection date to guard 
against privacy risk. The consent and HIPAA documents you sign will contain protected 
information (i.e., Name, social security number, etc.). To keep them safe, these documents will 
be stored in a different area from the rest of the study rooms, but still in a locked file cabinet 
inside a locked office at Hines VA. All electronic data will be entered in an electronic database 
on the Hines VA secure server.  
 
MRI data will be de-identified and uploaded to a VA secure server. 

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Because this is a new use for the iTBS device, we do not know all of its negative effects; and it 
cannot be guaranteed that you will be able to continue receiving this treatment after this study is 
over.  
 
5.2 
Withdrawal of Subjects 
Study participation is voluntary. However, if the participant withdraws or the PI withdraws 
the participant from the study, the participant will receive a prorated amount based on 
how much of the study they completed.  The participant will be reimbursed in cash from 
the agent cashier’s office at Hines VA.  No existing benefits or services will be lost as a 
result of study withdrawal. 
Any seizure will result in stopping treatment and withdrawal from the study.  The Hines Ready 
Response Team will be contacted for emergency assistance, and the participant will be advised 
to follow up with their established healthcare provider. 
If new conditions emerge or existing conditions worsen, then the participant will be 
withdrawn. The participant will receive pro-rated compensation for the portion of the 
study they have completed.  
Participants will still be able to receive their ongoing treatments to assist with the management 
of existing chronic musculoskeletal pain.  We will encourage participants to work with their 
provider on pain management strategies. While we require participants to adhere to a stable 
pain management strategy while in the study, other treatments for their chronic musculoskeletal 
pain that a provider may discuss with them could include physical therapy, occupational 
therapy, chiropractic care, acupuncture, injections (steroid, prolotherapy, trigger point injections) 
if these are appropriate. 
6.0 
Benefits of Participation in the Study 
The participants may not, themselves, benefit from participation in the first and third aims of the 
research study.  However, the Veteran population as a whole will potentially benefit from 
findings acquired in the research study. It is expected that by receiving iTBS and the 
LoveYourBrain Yoga program, participants may benefit by experiencing an improvement in 
quality of life and/or chronic musculoskeletal pain.   
7.0 
Compensation 
Each participant is eligible to receive up to $190 for participation this payment. This 
compensation is intended to facilitate participation without adding undue influence. If the 
participant withdraws or the PI withdraws them from the study, the participant will receive a 
prorated amount based on how much of the study they completed. Participants are eligible to 
receive $50 for baseline and endpoint visits, $50 for the MRI scan, and $15 for each of the 6 
treatment intervention sessions. Compensation will be disbursed via Electronic Funds Transfer 
(EFT) using the veteran’s preferred method (ex. Direct Deposit or Direct Express Debit card, 
etc.). Veterans who are unable to utilize this option may not be able to receive compensation. 
Participants will have an opportunity to discuss this option prior to consenting to participate in 
the study. 

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8.0 
Alternatives to Participation 
The alternative to participation in this study is not to participate.  Participants may decide at any 
time to stop study participation and withdraw.  There are no consequences for termination of 
study participation. 
 
FUTURE USE OF DATA  
As part of efforts to evaluate the study data for the development of future clinical studies, data 
collected during study participation may be made available upon request to researchers and 
scientists in accordance with federal guidelines and Hines local policy without additional consent 
from the participants. Identifiers will be removed from the identifiable private information and, 
after removal, the information could be used for future research studies or distributed to another 
investigator for future research studies.  
Only authorized research personnel will have access to both identifiable and de-identified study 
data. Safety data and neurobehavioral data will be kept in your folder in a locked cabinet in a 
locked office. 
9.0 
Data Analysis 
 
Data Collection and Analyses by Aim: 
Aim 1: Develop a novel, combined iTBS+yoga intervention for Veterans with mTBI and chronic 
musculoskeletal pain. We will determine 2 main factors to finalize the combined iTBS+yoga 
treatment. First, our study team will conduct mock iTBS and yoga sessions to determine how 
many people we can feasibly provide iTBS to individually before starting the group yoga 
sessions in order to maximize the 60-min of enhanced MC plasticity induced by iTBS. We 
anticipate that we will be able to include 3-6 people per group. Second, based on our 
conceptual model (Fig 1), we will incorporate psychosocial education sessions that focus on 
pain beliefs, acceptance and catastrophizing into each of the 6-existing resilience-based 
psychoeducation sessions. We will engage key stakeholders in developing and finalizing these 
20min. psychoeducation sessions, such as the Shirley Ryan Ability Lab’s pain center, the Hines 
VA TBI/polytrauma and pain clinics, and the Veterans Engagement Panel.  
Aim 2: Examine the feasibility and acceptability of iTBS+yoga Veterans with mTBI and chronic 
musculoskeletal pain. For feasibility, we will track the number of sessions completed and 
compute completion percentage rates as metrics of feasibility. If a participant misses a session, 
they will be contacted within 24 hours to determine reasons for missed sessions, which will also 
be tracked in an activity log. The participant will then be encouraged to make up their missed 
session. If participants miss less than 50% of the sessions (3/6) they will have the opportunity to 
make up the missing sessions. Thus, feasibility completion rates will be described according to 
reasons for participants not completing the 6-week intervention, and rates of missed sessions. 
Regarding acceptability, the semi-structured interviews will be audio-recorded, transcribed 
verbatim and analyzed by 2 qualitative experts using thematic coding and constant comparison 
techniques. Qualitative analysis software will be used to support analyses. Our qualitative 

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analysis approach will be both deductive and inductive29. We will develop an initial code list a 
priori that reflects categories of interest, based on elements of our conceptual model. Within 
each category, we will inductively develop additional codes and analyze the text for themes and 
patterns. This will be an iterative process where our code list may be revised to account for 
novel instances in the data. We will continue until saturation30 is reached across categories. 
Established qualitative analytic techniques will be used throughout this process, including the 
constant comparative method, which involves identifying key themes and concepts emergent 
from the data to generate meaningful categorization30. We will leverage a team-based approach 
drawing on the breadth of expertise of our team. Dr. Etingen and Ms. Billups will first 
independently review and open-code 2-3 transcripts to identify prominent themes. They will 
compare their codes, develop a set of analytic categories agreed upon through discussion, and 
develop the initial code list. They will continue with the next set of transcripts to develop new 
codes and revise codes applied to all prior transcripts, until they reach saturation with codes and 
themes, and finalize a codebook. They will then code un-coded transcripts until they reach inter-
coder reliability greater than >0.90%31.  
Aim 3: Establish the foundation for sample size and power considerations for a future clinical 
trial to examine the effectiveness of iTBS+yoga on Veterans’ QOL, function and pain outcomes. 
Both sessions completed, and outcomes (QOL, function and pain) will be scrutinized for outliers 
and missing values. We will try to understand causes of missingness and input the missing 
values accordingly. We will perform normality tests for each outcome and transform data to 
obtain normal distributions. For each outcome, we will perform a paired t-test, between baseline 
and endpoint scores (α = .05). To measure the pairwise association between two outcomes, we 
will compute Pearson correlations, and test for significance using the Fisher Z-transformation. 
We will also examine the relationship between number of completed sessions and change score 
(endpoint - baseline) of each outcome with a linear regression model. We hypothesize that the 
relationship will be positive, that is more sessions will provide better change scores. We will 
extract information from this pilot study and compute effect sizes based on change score for 
each outcome and compute sample size for 80% power with a 5% type 1 error rate. To 
determine the effects of iTBS+yoga relative to the LoveYourBrain Yoga program alone, we will 
also complete unpaired t-tests (α=.05) on TBI-QOL and satisfaction ratings between data 
collected with this SPiRE and retrospective published data collected by Dr. Donnelly 
(consultant)9-11. 
 
Expected Outcomes: It is expected that Veterans with mTBI and chronic musculoskeletal pain 
will be able to attend the weekly sessions for six weeks. The quantitative satisfaction ratings will 
improve by the completion of the treatment. The semi-structured interviews and feedback will 
allow for modifications to be made as warranted. While we expect that the 3 outcome domains 
of QOL, function and pain all improve, even if a single domain improves, we consider this 
positive. By exploring the associations between the above outcomes, we will better be able to 
interpret which outcome domain may be driving improvements. 
10.0 Confidentiality Plan  
 
Loss of confidentiality is a potential risk. This research study involves collection of self-report 
questionnaires and assessments. All hard copies of questionnaires and assessments as well as 
urine screens and saliva alcohol test screens will include a unique participant identification 
number and the date the assessment was completed.  Thus, it will be de-identified.  The only 
identifiable information will be the participant’s demographics questionnaire, contact information 
and EFT processing form (VA form 10-7078).  The demographic questionnaire will be kept in a 

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locked filing cabinet in a locked office of the study PI, Dr. Herrold.  The participant’s name and 
contact information will be linked to the unique study identification number and saved 
electronically on a secure VA crosswalk server at Hines VAH.  This secure crosswalk file is the 
only place where the participant’s name will be linked with the unique participant identification 
number.  The study PI, Dr. Herrold will have control over all research team members’ access to 
the crosswalk file. The completed EFT processing form will be stored with the signed consent 
and HIPAA documents within a locked filing cabinet, in a locked office within the secure 
research area, to centralize documentation containing PHI/PII and minimize risk of an 
information breach. 
Any breach in security will be reported to ACOS/Research, Facility Information Security Officer 
(ISO) and facility Privacy Officer within one hour.  To protect from breach of confidentiality, each 
participant will be assigned a unique identification number by the study personnel and the only 
place where this participant identification number will be linked to identifying information (e.g., 
name, address, phone number, date of birth, social security number) will be on a cross-walk file 
within secure Hines VAH servers.   
All urine samples or data will be marked only with the participant’s identification number and 
date of collection in order to guard against privacy risk.  Any hard copies of urine tests or data 
will not include any participant identifiers and will be kept in the participant’s file in a lockable 
filing cabinet located in the PI’s lockable office at Hines VAH.  All urine tests or other data 
entered will be done in an electronic database on the Hines VAH secure data server. No 
information, including results from urine tests will be entered into the electronic medical record. 
All data entry and analysis will be completed and saved on secure Hines VAH data servers.  
The Hines VAH data servers will be accessed at Hines VA Building 1, Room B351, B313, B317, 
and B321.  The study PI, Dr. Amy Herrold, will access secure data servers remotely with an 
encrypted, VA-issued lap top computer.  Data entry and data analysis will be completed on 
desktop computers located at Hines VAH, Building 1, Room B317, B321, and B313 or on Dr. 
Herold’s VA-issued and encrypted lap top computer.  No identifiable information will be saved 
on this laptop.  However, de-identified information will be saved on the hard drive of this laptop 
and will be backed up by transferring data to the secured Hines VAH data server via an 
encrypted memory stick after data from each new subject has been collected.  These laptops, 
therefore, do not contain the only copy of research information.    
All information collected will remain within the VA.  Until a schedule for local research records is 
published, all records including identifiers must be retained.  Once a study team member 
leaves, his/her access to study data will be terminated. 
The storage location for hard copies of all research related materials (e.g., consents, 
questionnaires, neuropsychological assessment forms) will be kept in a locked cabinet in the 
office of the study PI, Dr. Amy Herrold.  Her office is located at Hines VAH in Building 1, Room 
B351, which is behind secured key-card access doors.  All de-identified data and data analyses 
will be stored on a secured data server. 
MRI data will be de-identified and uploaded to Hines VA secure server. 
11.0   Monitoring and Reporting Serious Adverse Events 
An adverse event (AE) is any undesirable experience associated with iTBS measured as a 
deleterious change from baseline on the Data Safety Monitoring Scale (DSMS). AEs can be 
non-serious and serious. A serious AE is when the changes are disabling, life threatening, 

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require hospitalization or requires intervention to prevent impairment. We will measure 
deleterious changes in (1) neurologic status including cognitive symptoms, (2) somatic and 
vestibular symptoms, (3) and depression. AE will be tracked using the AE log.   
Amy Herrold will be responsible for training other research staff of the protocol set forth in this 
IRB application.  All serious, unanticipated adverse events which are related to this research 
study will be reported to the IRB within 5 days. If any unanticipated problem occurs such as 
deviation to this protocol that involve risks or has the potential to recur, this information will be 
reported by the investigator to the IRB as well within 2 business days but no longer than 5 
business days of the investigator or staff becoming aware of the event. 
Finally, any finding of noncompliance, other deficiencies that substantively compromise the 
effectiveness of the facility’s research information protection program, or suspensions or 
terminations will be reported to the ACOS/ACME/Research, Facility Information Security Officer 
(ISO) and facility Privacy Officer within 5 days of becoming aware.  Any loss of confidentiality 
falls under immediate reporting requirements and will be reported within the hour of becoming 
aware.    
This study will not have a Data Safety Monitoring Team. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.0 References 
 

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