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We examined whether females with a history of traumatic brain injury (TBI) and intimate partner violence (IPV) have greater exposure to lifetime trauma relative to females with TBI but no IPV history. Further, we assessed the effects of lifetime trauma on psychological outcomes after TBI. Female participants (n = 70; age M [standard deviation–SD] = 50.5 [15.2] years) with TBI (time since injury median [interquartile range –IQR] = 10.2 [5.3–17.8] years) completed a structured assessment of lifetime history of TBI, including an IPV module to query head injuries from physical violence by an intimate partner. We characterized lifetime trauma exposure with the Adverse Childhood Experiences (ACEs) questionnaire and Survey of Exposure to Community Violence (CV). We evaluated psychological functioning with self-report questionnaires of post-traumatic stress disorder (PTSD), depression, and anxiety symptoms. Compared with those with no IPV history (n = 51), participants reporting IPV-related head injuries (n = 19; 27.1%) reported more ACEs (M[SD] IPV: 4.5[2.9]; No IPV: 1.6[1.8], p < 0.001, d = 1.08) and greater CV (IPV: 17.5[8.4]; No IPV: 7.6[6.1], p < .0001, d = 1.26). Within the full sample, ACEs (β = 0.21, 95% confidence interval [CI] = 0.04–0.39) and CV (β = 0.07, 95% CI = 0.01–0.13) predicted worse PTSD symptoms, while IPV alone did not. Exposure to all three sources of trauma (ACEs, CV, and IPV) was associated with worse PTSD symptoms relative to fewer traumas. The results highlight the scope of traumatic exposures among TBI survivors and the importance of considering IPV and other lifetime trauma exposure in assessing and managing TBI. Trauma-informed interventions that are modified for TBI-related impairment may offer improved outcomes in managing psychological symptoms. [ABSTRACT FROM AUTHOR]

For many years, experts have recognized the importance of studying traumatic brain injury (TBI) among active-duty service members and veterans. A majority of this research has been conducted in Veterans Administration (VA) or Department of Defense settings. However, far less is known about military personnel who seek their medical care outside these settings. Studies that have been conducted in civilian settings have either not enrolled active duty or veteran participants, or failed to measure military history, precluding study of TBI outcomes by military history. The purpose of the present study was to determine associations between military history and medical (prevalence of 25 comorbid health conditions), cognition (Brief Test of Adult Cognition by Telephone), and psychological health (Patient Health Questionnaire-9 [PHQ-9], Generalized Anxiety Disorder-7, suicidality [9th item from PHQ-9]) in the first 5 years after TBI. In this prospective study, we analyzed data from the TBI Model Systems National Database. Participants were 7797 individuals with TBI admitted to one of 21 civilian inpatient rehabilitation facilities from April 1, 2010, to November 19, 2020, and followed up to 5 years. We assessed the relationship between military history (any versus none, combat exposure, service era, and service duration) and TBI outcomes. We found specific medical conditions were significantly more prevalent 1 year post-TBI among individuals who had a history of combat deployment (lung disorders, post-traumatic stress disorder [PTSD], and sleep disorder), served in post-draft era (chronic pain, liver disease, arthritis), and served >4 years (high cholesterol, PTSD, sleep disorder). Individuals with military history without combat deployment had modestly more favorable cognition and psychological health in the first 5 years post-injury relative to those without military history. Our data suggest that individuals with TBI with military history are heterogeneous, with some favorable and other deleterious health outcomes, relative to their non-military counterparts, which may be driven by characteristics of service, including combat exposure and era of service. [ABSTRACT FROM AUTHOR]

Several studies have characterized comorbidities among individuals with traumatic brain injury (TBI); however, there are few validated TBI comorbidity indices. Widely used indices (e.g., Elixhauser Comorbidity Index [ECI]) were developed in other patient populations and anchor to mortality or healthcare utilization, not functioning, and notably exclude conditions known to co-occur with TBI. The objectives of this study were to develop and validate a functionally relevant TBI comorbidity index (Fx-TBI-CI) and to compare prognostication of the Fx-TBI-CI with the ECI. We used data from the eRehabData database to divide the sample randomly into a training sample (N = 21,292) and an internal validation sample (N = 9166). We used data from the TBI Model Systems National Database as an external validation sample (N = 1925). We used least absolute shrinkage and selection operator (LASSO) regression to narrow the list of functionally relevant conditions from 39 to 12. In internal validation, the Fx-TBI-CI explained 14.1% incremental variance over an age and sex model predicting the Functional Independence Measure (FIM) Motor subscale at inpatient rehabilitation discharge, compared with 2.4% explained by the ECI. In external validation, the Fx-TBI-CI explained 4.9% incremental variance over age and sex and 3.8% over age, sex, and Glasgow Coma Scale score,compared with 2.1% and 1.6% incremental variance, respectively, explained by the ECI. An unweighted Sum Condition Score including the same conditions as the Fx-TBI-CI conferred similar prognostication. Although the Fx-TBI-CI had only modest incremental variance over demographics and injury severity in predicting functioning in external validation, the Fx-TBI-CI outperformed the ECI in predicting post-TBI function. [ABSTRACT FROM AUTHOR]

Understanding the effects of age on longitudinal traumatic brain injury (TBI) outcomes requires attention to both chronic and evolving TBI effects and age-related changes in health and function. The present study examines the independent and interactive effects of aging and chronicity on functional outcomes after TBI. We leveraged a well-defined cohort of individuals who sustained a moderate/severe TBI and received acute inpatient rehabilitation at specialized centers with high follow up rate as part of their involvement in the TBI Model Systems longitudinal study. We selected individuals at one of two levels of TBI chronicity (either 2 or 10 years post-injury) and used an exact matching procedure to obtain balanced chronicity groups based on age and other characteristics (N = 1993). We found that both older age and greater injury chronicity were related to greater disability, reduced functional independence, and less community participation. There was a significant age by chronicity interaction, indicating that the adverse effects of greater time post-injury were most pronounced among survivors who were age 75 or older. The inflection point at roughly 75 years of age was corroborated by post hoc analyses, dividing the sample by age at 75 years and examining the interaction between age group and chronicity. These findings point to a need for provision of rehabilitation services in the chronic injury period, particularly for those who are over 75 years old. Future work should investigate the underlying mechanisms of this interaction towards the goal of developing interventions and models of care to promote healthy aging with TBI. [ABSTRACT FROM AUTHOR]

Pain is common among adults with traumatic brain injury (TBI), yet little data exist regarding prevalence of opioid use in this population. The objective of this retrospective cohort study was to evaluate the association between lifetime TBI exposure, opioid use, and pain in a nationally representative sample of 1022 adults aged 50+ who participated in the Health and Retirement Study (HRS). Our primary exposure was lifetime TBI history measured via the Ohio State University TBI Identification Method. We evaluated three alternate TBI exposures (years since most recent TBI, age at first TBI, and number of lifetime TBIs) in sensitivity analyses. We evaluated two outcomes: recent opioid medication use, and moderate-to-severe pain measured over two HRS waves. We classified three pain groups (persistent, intermittent, and no pain). Prevalences of opioid use among individuals with and without TBI were 19.7% and 13.6%, respectively. After adjustment for age, sex, and race, individuals with TBI had a 52% increased risk for opioid use compared with individuals without TBI (relative risk = 1.52, 95% confidence interval: 1.11, 2.04). Individuals with recent TBI (1–10 years ago), first TBI after age 40+, and 2+ lifetime TBIs had greatest risk for opioid use. Compared with individuals without TBI, individuals with TBI had 4.9-times increased odds for persistent versus no pain, and 1.9-times increased odds of intermittent versus no pain. Persistent pain among adults with lifetime TBI is elevated compared with the general population, which may contribute to increased opioid use among persons with TBI, particularly those with recent injuries or multiple lifetime TBIs. [ABSTRACT FROM AUTHOR]

Severe traumatic brain injury (TBI) activates a robust systemic response that involves inflammatory and other factors, including estradiol (E2), associated with increased deaths. Tumor necrosis factor-alpha (TNFα) is a significant mediator of systemic shock, and it is an extra-gonadal transcription factor for E2 production. The study objectives were to test the hypotheses: (1) a positive feedback relationship exists between acute serum TNFα and E2; and (2) acute concentrations of E2 and TNFα are prognostic indicators of death after severe TBI. This prospective cohort study included N = 157 adults with severe TBI. Serum samples were collected for the first five days post-injury. The TNFα and E2 levels were averaged into two time epochs: first 72 h (T1) and second 72 h post-injury (T2). A cross-lag panel analysis conducted between T1 and T2 TNFα and E2 levels showed significant cross-lag effects: T1 TNFα and T1 E2 were related to T2 E2 and T2 TNFα, respectively. Cox proportional hazards multi variable regression models determined that increases in T1 E2 (hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.15, 2.81), but not T2 E2 (HR = 0.91, 95% CI: 0.56, 1.47), were associated with increased risk of death. Increased T2 TNFα (HR = 2.47, 95% CI: 1.35, 4.53), and T1 TNFα (HR = 1.47, 95% CI: 0.99, 2.19), to a lesser degree, were associated with increased risk of death. Relationships of death with T2 TNFα and T1 E2 were mediated partially by cardiovascular, hepatic, and renal dysfunction. Both E2 and TNFα are systemic, reciprocally related biomarkers that may be indicative of systemic compromise and increased risk of death after severe TBI. [ABSTRACT FROM AUTHOR]

Extensive pre-clinical studies suggest that sex steroids are neuroprotective in experimental traumatic brain injury (TBI). However, clinical trials involving sex hormone administration have not shown beneficial results, and our observational cohort studies show systemic estradiol (E2) production to be associated with adverse outcomes. Systemic E2 is produced via aromatization of testosterone (T) or reduction of estrone (E1). E1, also produced via aromatization of androstenedione (Andro) and is a marker of T-independent E2 production. We hypothesized that E1 would be (1) associated with TBI-related mortality, (2) the primary intermediate for E2 production, and (3) associated with adipose tissue-specific aromatase transcription. We assessed 100 subjects with severe TBI and 8 healthy controls. Serum levels were measured on days 0–3 post-TBI for key steroidogenic precursors (progesterone), aromatase pathway intermediates (E1, E2, T, Andro), and the adipose tissue-specific aromatase transcription factors cortisol, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). E1 was elevated after TBI versus controls. High E1 was associated with higher progesterone, cortisol, and IL-6 (p < 0.05). Multivariable logistic regression demonstrated that those in the highest E1 tertile had increased odds for mortality (adjusted OR = 5.656, 95% CI = 1.102–29.045, p = 0.038). Structural equation models show that early serum E2 production is largely T independent, occurring predominantly through E1 metabolism. Acute serum E1 functions as a mortality marker for TBI through aromatase-dependent E1 production and T-independent E2 production. Further work should evaluate risk factors for high E2 production and how systemic E2 and its key intermediate E1 contribute to the extracerebral consequences of severe TBI. [ABSTRACT FROM AUTHOR]

Early declines in gonadotropin production, despite elevated serum estradiol, among some individuals with severe traumatic brain injury (TBI) suggests amplified systemic aromatization occurs post-injury. Our previous work identifies estradiol (E2) as a potent mortality marker. Androstenedione (A), a metabolic precursor to E2, estrone (E1), and testosterone (T), is a steroid hormone substrate for aromatization that has not been explored previously as a biomarker in TBI. Here, we evaluated serum A, E1, T, and E2 values for 82 subjects with severe TBI. Daily hormone values were calculated, and E2:A and E1:T ratios were generated and then averaged for days 0–3 post-injury. After data inspection, mean E2:A values were categorized as above (high aromatization) and below (low aromatization) the 50th percentile for 30-day mortality assessment using Kaplan-Meier survival analysis and a multivariable Cox proportional hazard model adjusting for age, and Glasgow Coma Scale (GCS) to predict 30-day mortality status. Daily serum T, E1, and E2 were graphed by E2:A category. Serum E1 and E2 significantly differed over time (p < 0.05); the high aromatization group had elevated levels and a significantly lower probability of survival within the first 30 days (p = 0.0274). Multivariable Cox regression showed a significant E2:A*GCS interaction (p = 0.0129), wherein GCS predicted mortality only among those in the low aromatization group. E2:A may be a useful mortality biomarker representing enhanced aromatization after TBI. E2:A ratios may represent non-neurological organ dysfunction after TBI and may be useful in defining injury subgroups in which GCS has variable capacity to serve as an accurate early prognostic marker. [ABSTRACT FROM AUTHOR]

Excitotoxicity contributes to epileptogenesis after severe traumatic brain injury (sTBI). Demographic and clinical risk factors for post-traumatic seizures (PTS) have been identified, but genetic risk remains largely unknown. Thus, we investigated whether genetic variation in astroglial glutamate transporter genes is associated with accelerated epileptogenesis and PTS risk after sTBI. Adults (n = 267) 18–75 years old were assessed over a three-year period post-TBI. Single nucleotide polymorphisms (SNPs) throughout the SLC1A2 and SLC1A3 genes were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure frequencies by genotype. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HRs) for genotypes significant in Kaplan-Meier analyses. Thirty-nine tagging SNPs were examined (SLC1A2: n = 21, SLC1A3: n = 18). PTS developed in 57 (21.4%) individuals. Of those with PTS, n = 20 (35.7%) had an immediate/early seizure within the first seven days, and n = 36 (64.3%) had a late seizure occurring between eight days and three years post-TBI. When adjusting for multiple comparisons, rs4869682 genotypes (SLC1A3, GG vs. T-carriers) were associated with time to first seizure (p = 0.003). Median time until first seizure was 20.4 days for individuals with a GG genotype and 44.8 days for T-carriers. After adjusting for covariates, rs4869682 GG-homozygotes had a 2.05 times increased PTS risk versus T-carriers (aHR = 2.08, 95% confidence interval: 1.20, 3.62, p = 0.009). Variation within SLC1A3 is associated with accelerated epileptogenesis and clinical PTS development after sTBI. Future studies should validate these findings and examine how genetic variation at rs4869682 may be a target for PTS prevention and treatment. [ABSTRACT FROM AUTHOR]