Post-Concussion Musculoskeletal Injury Risks

Musculoskeletal injuries (MSKI) and traumatic brain injury (TBI) are the signature injuries of the ongoing military conflicts. MSKI affect 800,000 Service Members annually and TBI have impacted more than 350,000 in the past 19 years and account for 22% of all combat casualties. Concussion, a mild form of TBI, increases MSKI risk in physically active individuals, including Service Members.

The overall goal of the study is to identify the neuromuscular control mechanisms that increase MSKI risk following concussion. It is hypothesized that concussed individuals will display abnormal neuromuscular function that increases MSKI risk, as compared to non-concussed controls. The study will employ a multi-center, prospective, case-matched control observational study to identify the differences in neuromuscular function following concussion that may contribute to increased MSKI risk. Once the neuromuscular control mechanisms that increase MSKI risk following concussion are identified, targeted risk mitigation strategies can be developed to reduce MSKI risk.

Musculoskeletal injuries are the greatest unsolved public health problem facing the military and significantly diminish Service member's medical readiness. MSKI affect 800,000 Service members and result in 25 million limited-duty days annually. Additionally, among civilians peers, sport-related MSKI affect as many as 12 million people annually. In total, MSKI place a significant burden on military and civilian populations, with a combined financial burden of more than $980 billion per year in the US alone.

Traumatic brain injuries (TBI), specifically concussions a mild form of TBI, have been classified by the National Institutes of Health and Centers for Disease Control as a "serious health problem" in the US. TBIs have impacted more than 350,000 Service members in the past 19 years. Concussions negatively affect individuals' quality of life, as assessed by patient report outcome (PRO) psychosocial measures, including worse scores for measures of anxiety, depression, fatigue, anger, and pain immediately following concussion, as compared to when they are cleared to return-to-duty/activity (RTD/A).

Musculoskeletal injury (MSKI) risk is increased following RTD/A after concussion. However, despite the well-documented increased MSKI risk following concussion, the underlying neuromuscular mechanisms contributing to this increased risk have yet to be definitively determined. The underlying mechanism contributing to increased MSKI risk is likely a multifaceted issue that requires a comprehensive study to identify all of the factors.

Understanding the neuromuscular control deficits that persist after concussion and how these deficits change over time (longitudinally) will greatly expand the existing knowledge of why individuals are at greater MSKI risk following concussion. Thus, the overall objective is to elucidate the neuromuscular control mechanisms that contribute to increase MSKI risk following concussion so that effective MSKI risk mitigation strategies can be developed. The study team hypothesizes that concussed individuals will display aberrant neuromuscular control function that increases MSKI risk, as compared to non-concussed controls.

This study will address the following specific aims:

Specific Aim #1: Determine the neuromuscular control factors that differ between concussed and non-concussed military Service Members and physically active civilians that may contribute to MSKI risk after concussion.

Hypothesis #1: Concussed individuals will display aberrant neuromuscular functioning (e.g., atypical joint loading, slower time to stabilization, lower muscular twitch interpolation) that increases MSKI risk after reporting asymptomatic as compared to non-concussed controls.

Specific Aim #2: Determine the differences in patient reported outcome (PRO) measures between military Service Members and physically active civilians with and without concussion.

Hypothesis #2: Concussed individuals will report worse functioning on PRO measures (e.g., National Institutes of Health Patient-Reported Outcomes Measurement Information System \[PROMIS\] and psychological resiliency) as compared to non-concussed matched controls.

Exploratory Aim #1: Determine the time-dependent changes in neuromuscular control factors following concussion (initial, 6-week post-initial, 12-week post-initial) for concussed and non-concussed military Service Members and physically active civilians.

Exploratory Hypothesis #1: Concussed individuals will display greater changes, regressing toward the non-concussed population, in neuromuscular control (e.g., joint loading, time to stabilization, muscular twitch interpolation) from initial-to-6-week and initial-to-12-week measures as compared to non-concussed controls (anticipate non-significant changes).

This is a multi-center prospective, case-matched control observational study to identify the differences in neuromuscular function following concussion that may contribute to increased MSKI risk. A convenience sample of concussed Service Members and physically active civilians who self-report being asymptomatic and gender, age, occupation, and physical activity matched non-concussed controls will complete the study procedures described below: 1) within 5 days of being asymptomatic ("initial"); 2) 6 weeks post-initial neuromuscular control assessment ("6-week post-initial"; ±72 hours); and 3) 12 weeks post-initial neuromuscular control assessment ("12-week post-initial"; ±72 hours).

Concussed and non-concussed matched control participants will complete the same dynamic movement assessment, neuromuscular testing, and sensory assessment batteries. Control participants will complete the battery at the same time intervals as their concussed counterpart, ± 72 hours. Full-body kinematics will be tracked via stereophotogrammetric motion capture systems and kinetic measures will be captured via 6-degree-of-freedom force platforms. Peak isometric strength and voluntary muscle activation, via the interpolated twitch technique (ITT), and muscular ramp contraction assessment of the dominant and non-dominant knee extensors and plantar flexors will be assessed via a dynamometer (WRNMMC: Baltimore Therapeutic Equipment (BTE) Primus RS \[Baltimore Therapeutic Equipment, Maryland and Colorado, USA\]; UGA: Biodex System 4 \[Biodex Medical Systems, Shirley, New York, USA\]). The sensory assessments will examine proprioception (sensation of joint movement) and light touch sensation. The proprioception assessments will utilize the three-dimensional motion capture equipment (closed chain) and the dynamometer (passive joint repositioning). The light touch sensation will utilize Semmes-Weinstein Monofilaments to assess the participant's ability to detect various sensory thresholds on the foot. Additionally, study participants will self-report any MSKI they sustain and psychosocial measures monthly for up to 1-year following the initial neuromuscular control assessment.

Data and Statistical Analysis Plan

Data will be collapsed across trials for all for multi-trial assessments for each data collection time point (initial, 6-Week post-initial, 12-Week post-initial). The time from initial concussion diagnosis until the first data collection time point ("initial"), over-ground gait velocity, and potentially limb dominance will be utilized as a covariates for all statistical analyses. Other covariates, including gender, age, occupation, and physical activity will be explicitly controlled between groups by the matching procedure used in the study design and will therefore be unlikely to contribute to any observed effects; however, the study team will evaluate the importance of these variables in each analysis. These covariates will initially be included in each model, when appropriate; however, if a covariate accounts for little or no variance (p \> 0.2), it will be removed from the models. For all statistical analyses, statistical significance will be set a priori as α ≤ 0.05.

For Specific Aim #1, generalized linear mixed effects models including the fixed effects of study group (concussed group; non-concussed control group) and the random (subject-level) effect of participant will determine whether there is a statistically significant difference between concussed and non-concussed matched controls in each biomechanical outcome collected during the movement assessments, while accounting for the aforementioned covariates. Models will be generated for each movement assessment. Additionally, the models exploring gait variables will include task complexity (single-task vs dual-task) to determine whether there is a statistically significant difference in performance in regards to task complexity.

For Specific Aim #2, generalized linear models including group (concussed group; non-concussed control group) as the independent variable and each PRO as the dependent variable to determine whether there is a statistically significant difference in self-reported function and symptoms between concussed and non-concussed matched controls for each PRO. These models will include similar covariates as were used to analyze Specific Aim #1. For ordinal outcomes, the study team will use cumulative link models.

For Exploratory Aim #1, generalized linear mixed effects models treating time as both a fixed effect and including a random slope of time by participant, and fixed effects of group (concussed and non-concussed matched control), time point (initial, 6-Week post-initial, 12-Week post-initial), the interaction of group and time, as well as other covariates as previously described will determine whether there is a statistically significant difference between concussed and non-concussed matched controls in the outcomes of interest over time. Planned comparisons will evaluate between group differences at each time point. The study team will also analyze loss to follow up ("attrition"), to identify if any trends in performance on any of the biomechanical measures or PRO relate to the likelihood of study dropout. If no trends in missing data are observed, participants with at least one follow-up session will be included in all analyses.

Eligibility Criteria:
Inclusion Criteria:

Concussed Cohort

* 18-40 years old.
* Self-reported asymptomatic post-concussion following enrollment into the study and monitoring of symptoms by research personnel via daily self-reported symptom questionnaires.
* Recruited within 5 days following being diagnosed with a concussion, and at least 72 hours prior to self-reporting as asymptomatic.
* Access to a functional email address and the internet for completion of patient reported outcomes (PROs) and musculoskeletal injury measures.

Non-Concussed Cohort

* 18-40 years old.
* Active duty Service members and physically active civilians.
* No self-report history of concussion within the previous 5 years.
* No lingering post-concussion signs/symptoms.
* Same gender as the matched concussed participant.
* Within ±5% of the matched concussed participant's height, weight, and body mass index.
* Within ±2 years of age of the matched concussed participant.
* Participant in the same physical activities (work, recreational sports, average type \[no impact, low-impact, high-impact\] and duration of physical activity)

Exclusion Criteria:

* Post-Concussion Cohort AND Healthy Non-Concussed Cohort

  * Unable to read or comprehend the English language.
  * Admitted to the hospital following concussion.
  * Sustained a concussion not related to physical activity participation (e.g., blast-related injury, fall from a ladder, motor vehicle accident).
  * Loss of consciousness longer than 30 minutes.
  * Alteration in consciousness longer than 24 hours.
  * Post-traumatic amnesia lasting longer than 1 day.
  * Glasgow Coma Scale below 13.
  * Abnormal brain imaging findings.
  * Sustained a concussion that took longer than 21 days for the individual to report as asymptomatic.
  * A MSKI within the last 6 months that resulted in altered or missed physical activity for 3 or more consecutive days.
  * History of MSKI surgery.
  * Pregnant females (will be eligible for participation in the study once medically cleared to RTD/A by a qualified and licensed healthcare provider following the end of the pregnancy).
  * Participants will be excluded if they present any known contraindications for electrical stimulation. These contraindications include conditions such as: active deep vein thrombosis/thrombophlebitis, any acute injury with concurrent inflammation, hemorrhagic conditions, impaired circulation, impaired local sensations, presence of infection (osteomyelitis, tuberculosis), malignancy, recently radiated tissue, skin disease/damage and/or at-risk skin.
  * Present with any implanted pacemaker, electronic device, or plastic/cement material