What Are the Predictors for and Psychosocial Correlates of Chronic Headache After Moderate to Severe Traumatic Brain Injury?

OBJECTIVE: Although headache (HA) is a common sequela of traumatic brain injury (TBI), early predictors of chronic HA after moderate to severe TBI are not well established, and the relationship chronic HA has with psychosocial functioning is understudied. Thus, we sought to (1) determine demographic and injury predictors of chronic HA 1 or more years after moderate to severe TBI and (2) examine associations between chronic HA and psychosocial outcomes. SETTING: Community. PARTICIPANTS: Participants in the TBI Model System (TBIMS) with moderate to severe TBI who consented for additional chronic pain questionnaires at the time of TBIMS follow-up. DESIGN: Multisite, observational cohort study using LASSO (least absolute shrinkage and selection operator) regression for prediction modeling and independent t tests for psychosocial associations. MAIN OUTCOME MEASURES: Chronic HA after TBI at year 1 or 2 postinjury and more remotely (5 or more years). RESULTS: The LASSO model for chronic HA at 1 to 2 years achieved acceptable predictability (cross-validated area under the curve [AUC] = 0.70). At 5 or more years, predictability was nearly acceptable (cross-validated AUC = 0.68), but much more complex, with more than twice as many variables contributing. Injury characteristics had stronger predictive value at postinjury years 1 to 2 versus 5 or more years, especially sustained intracranial pressure elevation (odds ratio [OR] = 3.8) and skull fragments on head computed tomography (CT) (OR = 2.5). Additional TBI(s) was a risk factor at both time frames, as were multiple socioeconomic characteristics, including lower education level, younger age, female gender, and Black race. Lower education level was a particularly strong predictor at 5 or more years (OR up to 3.5). Emotional and participation outcomes were broadly poorer among persons with chronic HA after moderate to severe TBI. CONCLUSIONS: Among people with moderate to severe TBI, chronic HA is associated with significant psychosocial burden. The identified risk factors will enable targeted clinical screening and monitoring strategies to enhance clinical care pathways that could lead to better outcomes. They may also be useful as stratification or covariates in future clinical trial research on treatments.

Relationship Between Extreme Pain Phenotypes and Psychosocial Outcomes in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To examine the relationship between extreme pain phenotypes (interference and improvement) and psychosocial outcomes among those with chronic pain after traumatic brain injury (TBI). SETTING: Community. PARTICIPANTS: In total, 1762 TBI Model Systems (TBIMS) participants 1 to 30 years postinjury reporting chronic pain. DESIGN: Multisite, cross-sectional, observational cohort study. PRIMARY MEASURES: Life satisfaction, posttraumatic stress, depression and anxiety symptoms, sleep and participation, the Brief Pain Inventory (BPI) interference scale, and the Patient's Global Impression of Change (PGIC). RESULTS: Persons in the extreme high interference phenotype (vs extreme low interference phenotype) and/or extreme no change phenotype (vs extreme improvement phenotype) had poorer psychosocial outcomes, with extreme pain interference phenotypes having a larger effect on outcomes than extreme perceived improvement phenotypes. After controlling for covariates, large effect sizes (ES) related to pain interference were observed for posttraumatic stress symptoms (ES = -1.14), sleep quality (ES = -1.10), depression (ES = -1.08), anxiety (ES = -0.82), and life satisfaction (ES = 0.76); effect sizes for participation outcomes, although significant, were relatively small (ES = 0.21-0.36). Effect sizes related to perceived improvement were small for life satisfaction (ES = 0.20) and participation (ES = 0.16-0.21) outcomes. Pain intensity was identified as a meaningful confounding factor of the relationships between extreme phenotypes and posttraumatic stress, depression, anxiety, and sleep quality. CONCLUSIONS: Examination of extreme phenotypes provides important insights into the experience of individuals living with chronic pain and TBI. Results suggest that the relationships among a variety of characteristics of the person, their experience with pain, and treatment of pain are complex. Further research is needed to better understand these complex relationships and how differences in pain interference and perceived improvement from treatment can assist in assessment and treatment of chronic pain after TBI.

The Effects of Repetitive Head Impact Exposure on Mental Health Symptoms Following Traumatic Brain Injury.

OBJECTIVE: This study aimed to characterize the types and timing of repetitive head impact (RHI) exposures in individuals with moderate to severe traumatic brain injury (TBI) and to examine the effects of RHI exposures on mental health outcomes. SETTING: TBI Model Systems National Database. PARTICIPANTS: 447 patients with moderate to severe TBI who reported RHI exposure between 2015 and 2022. DESIGN: Secondary data analysis. MAIN MEASURES: RHI exposures reported on the Ohio State University TBI Identification Method (OSU TBI-ID) were characterized by exposure category, duration, and timing relative to the index TBI. Mental health outcomes were evaluated at the 5-year follow-up assessment using the Patient Health Questionnaire-9 (PHQ-9) for depression symptoms and the Generalized Anxiety Disorder-7 (GAD-7) for anxiety symptoms. RESULTS: The majority of RHI exposures were sports-related (61.1%), followed by other causes (20.8%; including falls), repetitive violence/assault (18.8%), and military exposures (6.7%). Males predominantly reported sports and military exposures, while a larger proportion of females reported violence and falls. Sports exposures were most common before the index TBI, while exposures from falls and violence/abuse were most common after TBI. RHI exposures occurring after the index TBI were associated with higher levels of depression (ß = 5.05; 95% CI, 1.59-8.50) and anxiety (ß = 4.53; 95% CI, 1.02-8.05) symptoms than exposures before the index TBI. CONCLUSION: The findings emphasize the need to consider RHI exposures and their interaction with TBI when assessing mental health outcomes. Understanding the prevalence and challenges associated with RHI post-TBI can inform targeted interventions and improve the well-being of individuals with TBI. Preventive measures and ongoing care should be implemented to address the risks posed by RHI, particularly in individuals with prior TBI, especially surrounding fall and violence/abuse prevention.

Characterizing Extreme Phenotypes for Pain Interference in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To define and characterize extreme phenotypes based on pain interference for persons with chronic pain following traumatic brain injury (TBI). SETTING: Eighteen Traumatic Brain Injury Model System (TBIMS) Centers. PARTICIPANTS: A total of 1762 TBIMS participants 1 to 30 years post-injury reporting chronic pain at their most recent follow-up interview. PRIMARY MEASURES: The Brief Pain Inventory (BPI) interference scale, sociodemographic, injury, functional outcome, pain, and treatment characteristics. RESULTS: Participants were predominantly male (73%), White (75%), middle-aged (mean 46 years), and who were injured in motor vehicle accidents (53%) or falls (20%). Extreme phenotypes were identified based on upper and lower 25th percentiles to create low-interference ( n = 441) and high-interference ( n = 431) extreme phenotypes. Bivariate comparisons found several sociodemographic, injury, function, pain, and treatment differences between extreme phenotype groups, including significant differences ( P < .001) on all measures of concurrent function with those in the low-interference extreme phenotype experiencing better function than those in the high-interference extreme phenotype. Lasso regression combined with logistic regression identified multivariable predictors of low- versus high-interference extreme phenotypes. Reductions in the odds of low- versus high-interference phenotypes were significantly associated with higher pain intensity (odds ratio [OR] = 0.33), having neuropathic pain (OR = 0.40), migraine headache (OR = 0.41), leg/feet pain (OR = 0.34), or hip pain (OR = 0.46), and more pain catastrophizing (OR = 0.81). CONCLUSION: Results suggest that for those who experience current chronic pain, there is high variability in the experience and impact of pain. Future research is needed to better understand how pain experience impacts individuals with chronic pain and TBI given that pain characteristics were the primary distinguishing factors between phenotypes. The use of extreme phenotypes for pain interference may be useful to better stratify samples to determine efficacy of pain treatment for individuals with TBI.

Characterizing Extreme Phenotypes for Perceived Improvement From Treatment in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To define and characterize extreme phenotypes based on perceived improvement in pain for persons with chronic pain following traumatic brain injury (TBI). SETTING: Eighteen Traumatic Brain Injury Model System (TBIMS) Centers. PARTICIPANTS: A total of 1762 TBIMS participants 1 to 30 years post-injury reporting chronic pain at their most recent follow-up interview. PRIMARY MEASURES: The Patient's Global Impression of Change (PGIC) related to pain treatment. Sociodemographic, injury, functional outcome, pain, and pain treatment characteristics. RESULTS: Participants were mostly male (73%), White (75%), middle-aged (mean 46 years), injured in motor vehicle accidents (53%), or falls (20%). Extreme phenotypes were created for an extreme improvement phenotype ( n = 512, 29.8%) defined as "moderately better" or above on the PGIC and an extreme no-change group ( n = 290, 16.9%) defined as no change or worse. Least absolute shrinkage and selection operator (LASSO) regression combined with logistic regression identified multivariable predictors of improvement versus no-change extreme phenotypes. Higher odds of extreme improvement phenotype were significantly associated with being female (odds ratio [OR] = 1.85), married versus single (OR = 2.02), better motor function (OR = 1.03), lower pain intensity (OR = 0.78), and less frequent pain, especially chest pain (OR = 0.36). Several pain treatments were associated with higher odds of being in the extreme improvement versus no-change phenotypes including pain medication (OR = 1.85), physical therapy (OR = 1.51), yoga (OR = 1.61), home exercise program (OR = 1.07), and massage (OR = 1.69). CONCLUSION: Investigation of extreme phenotypes based on perceived improvement with pain treatment highlights the ability to identify characteristics of individuals based on pain treatment responsiveness. A better understanding of the biopsychosocial characteristics of those who respond and do not respond to pain treatments received may help inform better surveillance, monitoring, and treatment. With further research, the identification of risk factors (such as pain intensity and frequency) for treatment response/nonresponse may provide indicators to prompt changes in care for individuals with chronic pain after TBI.

Characterization and Treatment of Chronic Pain After Traumatic Brain Injury-Comparison of Characteristics Between Individuals With Current Pain, Past Pain, and No Pain: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To estimate the prevalence of chronic pain after traumatic brain injury (TBI) and identify characteristics that differ from those without chronic pain. SETTING: Community. PARTICIPANTS: A total of 3804 TBI Model Systems (TBIMS) participants who completed the Pain Survey at TBIMS follow-up. DESIGN: A multisite, cross-sectional observational cohort study. MAIN OUTCOME MEASURES: Functional outcomes, pain experience, and treatment. RESULTS: 46% reported current chronic pain, 14% reported past (post-injury) chronic pain, and 40% reported no chronic pain. Bivariate differences in sociodemographic and injury characteristics between the 3 pain groups were generally small in effect size, reflecting little clinical difference. However, medium effect sizes were seen for all functional outcomes, such that individuals with current chronic pain had worse functional outcomes compared with individuals in the past pain or no pain groups. Treatment utilization rates were higher for individuals with current chronic pain compared with past pain, with medical treatments being most frequently utilized. Individuals with past pain perceived more improvement with treatment than did those with current chronic pain as represented by a large effect size. CONCLUSIONS: Chronic pain affects approximately 60% of those living with TBI. The implications of chronic pain for functional outcomes support inclusion of pain metrics in prognostic models and observational studies in this population. Future research is needed to proactively identify those at risk for the development of chronic pain and determine the efficacy and access to pain treatment.

Associations of Chronic Pain With Psychosocial Outcomes After Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To examine the differences in participation, life satisfaction, and psychosocial outcomes among individuals with traumatic brain injury (TBI) endorsing current, past, or no chronic pain. SETTING: Community. PARTICIPANTS: Three thousand eight hundred four TBI Model Systems participants 1 to 30 years of age postinjury classified into 1 of 3 groups based on their pain experience: current pain, past pain, no pain completed a Pain Survey at their usual follow-up appointment which on average was approximately 8 years postinjury. DESIGN: Multisite, cross-sectional observational cohort study. MAIN OUTCOME MEASURES: Sociodemographic and injury characteristics and psychosocial outcomes (ie, satisfaction with life, depression, anxiety, posttraumatic stress disorder [PTSD], sleep quality, community participation). RESULTS: Persons with current chronic pain demonstrated higher scores on measures of PTSD, anxiety, and depression, and the lower scores on measures of sleep quality, community participation and satisfaction with life. Those with resolved past pain had mean scores for these outcomes that were all between the current and no chronic pain groups, but always closest to the no pain group. After adjusting for sociodemographic and function in multivariate analysis, having current chronic pain was associated with more negative psychosocial outcomes. The largest effect sizes (ES; in absolute value) were observed for the PTSD, depression, anxiety, and sleep quality measures (ES = 0.52-0.81) when comparing current pain to past or no pain, smaller ES were observed for life satisfaction (ES = 0.22-0.37) and out and about participation (ES = 0.16-0.18). When comparing past and no pain groups, adjusted ES were generally small for life satisfaction, PTSD, depression, anxiety, and sleep quality (ES = 0.10-0.23) and minimal for participation outcomes (ES = 0.02-0.06). CONCLUSIONS: Chronic pain is prevalent among individuals with TBI and is associated with poorer psychosocial outcomes, especially for PTSD, depression, anxiety, and sleep disturbance. The results from this study highlight the presence of modifiable comorbidities among those with chronic pain and TBI. Persons who experience persistent pain following TBI may be at greater risk for worse psychosocial outcomes.

Altered lateralization of the cingulum in deployment-related traumatic brain injury: An ENIGMA military-relevant brain injury study.

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.

Alternative Structure Models of the Traumatic Brain Injury Rehabilitation Needs Survey: A Veterans Affairs TBI Model Systems Study.

OBJECTIVE: To explore the factor structure of the Rehabilitation Needs Survey (RNS). DESIGN: Secondary analysis of observational cohort study who were 5-years post-traumatic brain injury (TBI). SETTING: Five Inpatient Rehabilitation Facilities. PARTICIPANTS: Veterans enrolled in the TBI Model Systems longitudinal study who completed the RNS at 5-year follow-up (N=378). MAIN OUTCOME MEASURE(S): RNS. RESULTS: RNS factor structure was examined with exploratory factor analysis (EFA) with oblique rotation. Analyses returned 2- and 3-factor solutions with Cronbach alphas ranging from 0.715 to 0.905 and corrected item-total correlations that ranged from 0.279 to 0.732. The 2-factor solution accounted for 61.7% of the variance with ≥3 exclusively loading items on each factor with acceptable internal consistency metrics and was selected as the most parsimonious and clinically applicable model. Ad hoc analysis found the RNS structure per the EFA corresponded with elements of the International Classification of Functioning, Disability and Health (ICF) conceptual framework. All factors had adequate internal consistency (α≥0.70) and 20 of the 21 demonstrated good discrimination (corrected item-total correlations≥0.40). CONCLUSIONS: The 2-factor solution of the RNS appears to be a useful model for enhancing its clinical interpretability. Although there were cross-loading items, they refer to complex rehabilitation needs that are likely influenced by multiple factors. Alternatively, there are items that may require alteration and redundant items that should be considered for elimination.

Cross-Walk Comparison of the DVBIC-TBICoE and LIMBIC-CENC Combat-Related Concussion Prospective Longitudinal Study Datasets.

OBJECTIVE: To describe and compare cohorts between 2 large, longitudinal, federally-funded TBI studies of Service members and veterans across demographic, self-report, and neuropsychological variables. DESIGN: Analysis of data from the DVBIC-TBICoE and LIMBIC-CENC prospective longitudinal studies (PLS). SETTING: Recruitment locations spanning Department of Defense and Veterans Affairs hospitals across the U.S. PARTICIPANTS: 1463 participants (N=1463) enrolled in the DVBIC-TBICoE study and divided among non-injured (NIC) (n=191), injured control (IC) (n=349), mild TBI (mTBI) (n=682), and (severe, moderate, penetrating, and complicated mild traumatic brain injury (smcTBI) (n=241) subgroups. 1550 participants enrolled in the LIMBIC-CENC study and divided between IC (n=285) and mTBI (n=1265) subgroups. IC and mTBI study groups were compared across demographic and military characteristics, self-reported symptoms, and neuropsychological test scores. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Neurobehavioral Symptom Inventory, PTSD Checklist-Military Version, TBI quality of life, Test of Premorbid Functioning, Wechsler Adult Intelligence Scale-IV Visual Puzzles, Symbol Search, Coding, Letter-Number Sequencing, and Digit Span, Trail Making Test, Delis-Kaplan Executive Functioning System Verbal Fluency, Letter Fluency, and Category Fluency, California Verbal Learning Test-II, and Grooved Pegboard. RESULTS: Compared with DVBIC-TBICoE, LIMBIC-CENC participants have higher enrollment age, education level, proportion of Black race, and time from injury as well as less combat deployments and are less likely to be married. The distribution of military service branches also differed. Further, symptom profiles differed between cohorts. LIMBIC-CENC participants endorsed higher posttraumatic stress disorder symptomatology. DVBIC-TBICoE study IC participants endorsed higher somatosensory and vestibular symptoms (medium effect sizes). Other symptom measure differences had very small effect sizes (≤0.2). Differences were found on many cognitive test results, but are difficult to interpret given the demographic differences and generally very small effect sizes. CONCLUSIONS: The heavy use of National Institutes of Health common data elements in both studies and collaboration with the DVBIC-TBICoE study team on development of the LIMBIC-CENC assessment battery enabled this comparative analysis. Results highlight unique differences in study cohorts and add perspective and interpretability for assimilating past and future findings.

Effect of Post-traumatic Amnesia Duration on Traumatic Brain Injury (TBI) First Year Hospital Costs: A Veterans Affairs Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To examine the association between severity of traumatic brain injury (TBI) as measured by duration of post-traumatic amnesia (PTA) and first year hospitalization costs for service members and veterans (SMVs) treated for TBI at Polytrauma Rehabilitation Centers (PRCs) within the Veterans Health Administration (VHA). DESIGN: Multivariable models of merged datasets from the VA TBI Model Systems (VA TBIMS) national database containing TBI clinical characterization including PTA with VHA hospital cost data. SETTING: Five VA PRCs. PARTICIPANTS: VA TBIMS participants with known PTA who received inpatient rehabilitation within 1 year of their TBI at any of 5 PRCs between 2010 and 2020 (N=717). INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Total, acute care, rehabilitation, intensive care unit (ICU), and surgery costs across all VA hospitals. RESULTS: A total of 717 SMVs (mean age 36.9 years, 94.1% men, 76.8% non-Hispanic White, 7.8% active duty) met inclusion criteria for the unadjusted analyses. Unadjusted mean total hospital costs in the first-year post TBI were approximately $201,214 higher for those with PTA duration ≥24 hours ($351,157) than PTA <24 hours ($149,943). In adjusted models (n=583), each additional day of PTA duration incrementally increased total ($1453), rehabilitation ($1324), ICU ($78), and surgery ($39) costs. Other significant covariates included age, acute care length of stay, Disability Rating Scale on rehabilitation admission, penetrating violent cause of injury, and drug abuse. CONCLUSIONS: This study demonstrates that PTA as a quantitative measure of TBI severity significantly affects first-year hospitalization costs of SMVs treated at PRCs. Each additional day of PTA was associated with higher total, rehabilitation, ICU, and surgery costs. Mean first year hospital costs were also found to exceed the highest budget allocation to VHA facilities for a veteran treated at a PRC. These findings have possible implications for hospital care provision for those receiving inpatient rehabilitation in VHA settings.

The American Congress of Rehabilitation Medicine Diagnostic Criteria for Mild Traumatic Brain Injury.

OBJECTIVE: To develop new diagnostic criteria for mild traumatic brain injury (TBI) that are appropriate for use across the lifespan and in sports, civilian trauma, and military settings. DESIGN: Rapid evidence reviews on 12 clinical questions and Delphi method for expert consensus. PARTICIPANTS: The Mild Traumatic Brain Injury Task Force of the American Congress of Rehabilitation Medicine Brain Injury Special Interest Group convened a Working Group of 17 members and an external interdisciplinary expert panel of 32 clinician-scientists. Public stakeholder feedback was analyzed from 68 individuals and 23 organizations. RESULTS: The first 2 Delphi votes asked the expert panel to rate their agreement with both the diagnostic criteria for mild TBI and the supporting evidence statements. In the first round, 10 of 12 evidence statements reached consensus agreement. Revised evidence statements underwent a second round of expert panel voting, where consensus was achieved for all. For the diagnostic criteria, the final agreement rate, after the third vote, was 90.7%. Public stakeholder feedback was incorporated into the diagnostic criteria revision prior to the third expert panel vote. A terminology question was added to the third round of Delphi voting, where 30 of 32 (93.8%) expert panel members agreed that 'the diagnostic label 'concussion' may be used interchangeably with 'mild TBI' when neuroimaging is normal or not clinically indicated.' CONCLUSIONS: New diagnostic criteria for mild TBI were developed through an evidence review and expert consensus process. Having unified diagnostic criteria for mild TBI can improve the quality and consistency of mild TBI research and clinical care.

Distal and Proximal Predictors of Rehospitalization Over 10 Years Among Survivors of TBI: A National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To describe the rates and causes of rehospitalization over a 10-year period following a moderate-severe traumatic brain injury (TBI) utilizing the Healthcare Cost and Utilization Project (HCUP) diagnostic coding scheme. SETTING: TBI Model Systems centers. PARTICIPANTS: Individuals 16 years and older with a primary diagnosis of TBI. DESIGN: Prospective cohort study. MAIN MEASURES: Rehospitalization (and reason for rehospitalization) as reported by participants or their proxies during follow-up telephone interviews at 1, 2, 5, and 10 years postinjury. RESULTS: The greatest number of rehospitalizations occurred in the first year postinjury (23.4% of the sample), and the rates of rehospitalization remained stable (21.1%-20.9%) at 2 and 5 years postinjury and then decreased slightly (18.6%) at 10 years postinjury. Reasons for rehospitalization varied over time, but seizure was the most common reason at 1, 2, and 5 years postinjury. Other common reasons were related to need for procedures (eg, craniotomy or craniectomy) or medical comorbid conditions (eg, diseases of the heart, bacterial infections, or fractures). Multivariable logistic regression models showed that Functional Independence Measure (FIM) Motor score at time of discharge from inpatient rehabilitation was consistently associated with rehospitalization at all time points. Other factors associated with future rehospitalization over time included a history of rehospitalization, presence of seizures, need for craniotomy/craniectomy during acute hospitalization, as well as older age and greater physical and mental health comorbidities. CONCLUSION: Using diagnostic codes to characterize reasons for rehospitalization may facilitate identification of baseline (eg, FIM Motor score or craniotomy/craniectomy) and proximal (eg, seizures or prior rehospitalization) factors that are associated with rehospitalization. Information about reasons for rehospitalization can aid healthcare system planning. By identifying those recovering from TBI at a higher risk for rehospitalization, providing closer monitoring may help decrease the healthcare burden by preventing rehospitalization.

Predictors of Missed Follow-up Visits in the National Traumatic Brain Injury Model Systems Cohort Study.

OBJECTIVE: To identify key variables that could predict risk of loss to follow-up (LTFU) in a nationally funded longitudinal database of persons with traumatic brain injury. DESIGN: Secondary analysis of a prospective longitudinal cohort study. SETTING: Traumatic Brain Injury Model System (TBIMS) Centers in the US. PARTICIPANTS: A total of 17,956 TBIMS participants (N=17,956) with interview status data available were included if eligible for 1-, 2-, 5-, 10-, 15-, or 20-year follow-ups between October 31, 1989, and September 30, 2020. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Follow-up data collection completion status at years 1, 2, 5, 10, 15, and 20. RESULTS: Information relevant to participants' history, injury characteristics, rehabilitation stay, and patterns of follow-up across 20 years were considered using a series of logistic regression models. Overall, LTFU rates were low (consistently <20%). The most robust predictors of LTFU across models were missed earlier follow-ups and demographic factors including Hispanic ethnicity, lower education, and lack of private health insurance. CONCLUSIONS: Efforts to retain participants in such social disadvantaged or minority groups are encouraged given their disproportionate rate of LTFU. Repeated attempts to reach participants after a previously missed assessment are beneficial because many participants that missed 1 or more follow-ups were later recovered.

Relation of Mild Traumatic Brain Injury history to abnormalities on a preliminary Neuroendocrine screen; A multicenter LIMBIC-CENC analysis.

PRIMARY OBJECTIVES: Determine if an abnormal preliminary neuroendocrine disorder (NED) blood test screen is associated with mild TBI (mTBI) history or post-concussiveclinical features. RESEARCH DESIGN: Observational. METHODS: Among 1,520 participants with military combatexposure, we measured randomly timed serum levels of insulin-likegrowth factor-1, thyroid stimulating hormone (TSH), and total testosterone as a preliminary NED screen. Using multivariable models, we analyzed relation of screen results in mTBI group membership and post-concussiveclinical features (fatigue, depression, cognitive symptoms, executive function, processing speed). RESULTS: None of the mTBI positive groups, including repetitive (≥3 mTBI) and blast-related,differed from the non-TBIcontrols on rates of abnormal lab screen or rates of growth hormone deficiency (GHD), hypothyroidism or male hypogonadism in treatment records. Lab screen findings were also not associated with any clinical feature. CONCLUSIONS: This study shows no evidence that remote mTBI(s) or implicated post-concussiveclinical features are linked to GHD, hypothyroidism or male hypogonadism. Large case-controlstudies incorporating more definitive neuroendocrine disorder NED testing (TSH plus thyroxine, early morning testosterone, LH, FSH, prolactin and GH provocative testing) are needed to determine whether mTBI(s) alone elevate one's risk for chronic NED and how best to select patients for comprehensive testing.

Randomized trial of rTMS in traumatic brain injury: improved subjective neurobehavioral symptoms and increases in EEG delta activity.

PRIMARY OBJECTIVE: While repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for cognitive difficulties accompanying depression, it is unknown if it can improve cognition in persons with traumatic brain injury. RESEARCH DESIGN: Using a sham-controlled crossover design, we tested the capacity of high frequency rTMS of the prefrontal cortex to improve neuropsychological performance in attention, learning and memory, and executive function. METHODS: Twenty-six participants with cognitive complaints and a history of mild-to-moderate traumatic brain injury were randomly assigned to receive first either active or sham 10 Hz stimulation for 20 minutes (1200 pulses) per session for five consecutive days. After a one-week washout, the other condition (active or sham) was applied. Pre- and post-treatment measures included neuropsychological tests, cognitive and emotional symptoms, and EEG. MAIN OUTCOMES AND RESULTS: Results indicated no effect of treatment on cognitive function. Subjective measures of depression, sleep dysfunction, post-concussive symptoms (PCS), and executive function showed significant improvement with stimulation, retaining improved levels at two-week follow-up. EEG delta power exhibited elevation one week after stimulation cessation. CONCLUSIONS: While there is no indication that rTMS is beneficial for neuropsychological performance, it may improve PCS and subjective cognitive dysfunction. Long-term alterations in cortical oscillations may underlie the therapeutic effects of rTMS.

Demographic, military, and health comorbidity variables by mild TBI and PTSD status in the LIMBIC-CENC cohort.

OBJECTIVE: To describe associations of demographic, military, and health comorbidity variables between mild traumatic brain injury (mTBI) history and posttraumatic stress disorder (PTSD) status in a sample of Former and current military personnel. SETTING: Participants recruited and tested at seven VA sites and one military training facility in the LIMBIC-CENC prospective longitudinal study (PLS), which examines the long-term mental health, neurologic, and cognitive outcomes among previously combat-deployed U.S. Service Members and Veterans (SM/Vs). PARTICIPANTS: A total of 1,540 SM/Vs with a history of combat exposure. Data were collected between 1/1/2015 through 3/31/2019. DESIGN: Cross-sectional analysis using data collected at enrollment into the longitudinal study cohort examining demographic, military, and health comorbidity variables across PTSD and mTBI subgroups. MAIN MEASURES: PTSD Checklist for DSM-5 (PCL-5), mTBI diagnostic status, Patient Health Questionnaire 9-item (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), AUDIT-C, and other self-reported demographic, military, and health comorbidity variables. RESULTS: Ten years following an index date of mTBI exposure or mid-point of military deployment, combat-exposed SM/Vs with both mTBI history and PTSD had the highest rates of depression symptoms, pain, and sleep apnea risk relative to SM/Vs without both of these conditions. SM/Vs with PTSD, irrespective of mTBI history, had high rates of obesity, sleep problems, and pain. CONCLUSION: The long-term symptom reporting and health comorbidities among SM/Vs with mTBI history and PTSD suggest that ongoing monitoring and intervention is critical for addressing symptoms and improving quality of life.

Remote blast-related mild traumatic brain injury is associated with differential expression of exosomal microRNAs identified in neurodegenerative and immunological processes.

BACKGROUND: Blast traumatic brain injury (TBI) and subconcussive blast exposure have been associated, pathologically, with chronic traumatic encephalopathy (CTE) and, clinically, with cognitive and affective symptoms, but the underlying pathomechanisms of these associations are not well understood. We hypothesized that exosomal microRNA (miRNA) expression, and their relation to neurobehavioral outcomes among Veterans with blunt or blast mild TBI (mTBI) may provide insight into possible mechanisms for these associations and therapeutic targets. METHODS: This is a subanalysis of a larger Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project. Participants (n = 152) were divided into three groups: Controls (n = 35); Blunt mTBI only (n = 54); and Blast/blast+blunt mTBI (n = 63). Postconcussive and post-traumatic stress symptoms were evaluated using the NSI and PCL-5, respectively. Exosomal levels of 798 miRNA expression were measured. RESULTS: In the blast mTBI group, 23 differentially regulated miRNAs were observed compared to the blunt mTBI group and 23 compared to controls. From the pathway analysis, significantly dysregulated miRNAs in the blast exposure group correlated with inflammatory, neurodegenerative, and androgen receptor pathways. DISCUSSION: Our findings suggest that chronic neurobehavioral symptoms after blast TBI may pathomechanistically relate to dysregulated cellular pathways involved with neurodegeneration, inflammation, and central hormonal regulation.

Clinical features of dementia cases ascertained by ICD coding in LIMBIC-CENC multicenter study of mild traumatic brain injury.

OBJECTIVE: Describe dementia cases identified through International Classification of Diseases (ICD) coding in the Long-term Impact of Military-relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) multicenter prospective longitudinal study (PLS) of mild traumatic brain injury (mTBI). DESIGN: Descriptive case series using cross-sectional data. METHODS: Veterans Affairs (VA) health system data including ICD codes were obtained for 1563 PLS participants through the VA Informatics and Computing Infrastructure (VINCI). Demographic, injury, and clinical characteristics of Dementia positive and negative cases are described. RESULTS: Five cases of dementia were identified, all under 65 years old. The dementia cases all had a history of blast-related mTBI and all had self-reported functional problems and four had PTSD symptomatology at the clinical disorder range. Cognitive testing revealed some deficits especially in the visual memory and verbal learning and memory domains, and that two of the cases might be false positives. CONCLUSIONS: ICD codes for early dementia in the VA system have specificity concerns, but could be indicative of cognitive performance and self-reported cognitive function. Further research is needed to better determine links to blast exposure, blast-related mTBI, and PTSD to early dementia in the military population.

Advanced brain age in deployment-related traumatic brain injury: A LIMBIC-CENC neuroimaging study.

OBJECTIVE: To determine if history of mild traumatic brain injury (mTBI) is associated with advanced or accelerated brain aging among the United States (US) military Service Members and Veterans. METHODS: Eight hundred and twenty-two participants (mean age = 40.4 years, 714 male/108 female) underwent MRI sessions at eight sites across the US. Two hundred and one participants completed a follow-up scan between five months and four years later. Predicted brain ages were calculated using T1-weighted MRIs and then compared with chronological ages to generate an Age Deviation Score for cross-sectional analyses and an Interval Deviation Score for longitudinal analyses. Participants also completed a neuropsychological battery, including measures of both cognitive functioning and psychological health. RESULT: In cross-sectional analyses, males with a history of deployment-related mTBI showed advanced brain age compared to those without (t(884) = 2.1, p = .038), while this association was not significant in females. In follow-up analyses of the male participants, severity of posttraumatic stress disorder (PTSD), depression symptoms, and alcohol misuse were also associated with advanced brain age. CONCLUSION: History of deployment-related mTBI, severity of PTSD and depression symptoms, and alcohol misuse are associated with advanced brain aging in male US military Service Members and Veterans.