History Of mTBI Research Articles

Adverse Outcomes among Veterans who Screen Positive for TBI/do not Complete a TBI Evaluation

<h3>Research Objectives</h3> To examine whether Veterans who screened positive for mild traumatic brain injury (mTBI), but did not complete a Veterans Health Administration (VHA) Comprehensive TBI Evaluation (CTBIE), were at higher risk for adverse outcomes compared to Veterans who screened negative for TBI. <h3>Design</h3> Retrospective longitudinal study that included data from Department of Veterans Affairs (VA), Department of Defense (DoD), and National Death Index. DoD data ranged from October 1, 1999, to September 30, 2019 (Fiscal Years [FYs]2000-2019) and VHA data ranged from October 1, 2001, to September 30, 2019 (FYs2002-2019). The follow-up review period was within 3 years of TBI screening. <h3>Setting</h3> Veterans Health Administration. <h3>Participants</h3> Post-9/11 Veterans who were screened for deployment-related mTBI. <h3>Interventions</h3> None. <h3>Main Outcome Measures</h3> Incident diagnoses of substance use disorder (SUD), alcohol use disorder (AUD), opioid use disorder (OUD), overdose, and homelessness within 3 years of TBI screening. <h3>Results</h3> Compared to Veterans who screened negative for TBI, Veterans who screened positive for mTBI but never completed a CTBIE were at increased risk for incident SUD (HR=1.40, 95% CI=1.27-1.54), AUD (HR=1.32, 95% CI=1.19-1.45), OUD (HR=1.68, 95% CI=1.35-2.09), overdose (HR=1.39, 95% CI=1.13-1.70), and homelessness (HR=1.47, 95% CI=1.32-1.65) within 3 years following their TBI screening, after controlling for demographic, military, and regional covariates. <h3>Conclusions</h3> Veterans who screened positive for mTBI but did not receive a CTBIE were at increased risk for incident SUD, AUD, OUD, overdose, and homelessness relative to Veterans who screened negative for TBI. This potentially represents missed opportunities for access to interdisciplinary care to identify and address mTBI history and/or other conditions that can diminish health, safety, and quality of life. Prior to military discharge, the DoD should increase educational efforts to discuss the importance of follow-up health care. In VHA, there should be similar messaging, as well as targeted outreach to Veterans who screen positive for mTBI but do not complete a CTBIE within 30 days of screening to minimize the risk of adverse outcomes. <h3>Author(s) Disclosures</h3> The authors have no conflicts to disclose.

Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden

Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson’s disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden.

A pilot study of olfactory function in veterans with a history of deployment-related mild traumatic brain injury

ABSTRACT Olfactory impairment in military populations is highly prevalent and often attributed to the long-term effects of mild traumatic brain injury (mTBI) and chronic psychiatric disorders. The main goal of this investigation was to examine olfactory function in a cohort of combat veterans using a quantitative smell test. Participants underwent a neurological examination, completed performance validity testing (PVT), provided deployment history, and their medical records were reviewed. Participants were 38 veterans with a deployment-related mTBI who passed the PVT and did not have ongoing substance misuse issues. Olfactory examination revealed normosmia in 20 participants and various degrees of deficit in 18. The groups did not differ in demographics, post-injury interval, or current clinical (non-psychiatric) conditions. Participants with hyposmia frequently reported being exposed to a higher number of blasts and being positioned closer to the nearest primary blast, and more often endorsed a period of loss of consciousness after the most serious mTBI. In addition, they more often reported tympanic membrane perforation, extracranial injuries, and histories of both blast and blunt force mTBI. Comorbid diagnoses of posttraumatic stress disorder, depression, chronic headaches, and pain were more common among them as well. Several blast exposure and injury-related characteristics increase the likelihood of long-term olfactory impartments, comorbid psychiatric conditions, and chronic pain among veterans with history of deployment-related mTBI. Notably, none of the participants with hyposmia had a clinical diagnosis of olfactory dysfunction or were receiving service-connected disability for loss of sense of smell at the time of their assessment.

Risk factors for the presence and persistence of posttraumatic stress symptoms following traumatic brain injury in U.S. service members and veterans.

This study aimed to identify risk factors predictive of the presence and persistence of posttraumatic stress disorder (PTSD) symptom reporting following traumatic brain injury (TBI). Participants were 1,301 U.S. service members and veterans (SMVs) divided into four groups: uncomplicated mild TBI (mTBI; n = 543); complicated mild, moderate, severe, and penetrating TBI (n = 230); injured controls (n = 340); and noninjured controls (n = 188). We examined 25 factors related to demographic, injury-related, military-specific, treatment/health care need, and mental health/social support variables. Seven factors were statistically associated with the presence of DSM-IV-TR symptom criteria for PTSD: premorbid IQ, combat exposure, depression, social participation, history of mTBI, need for managing mood and stress, and need for improving memory and attention, p < .001 (51.3% variance). When comparing the prevalence of these risk factors in a longitudinal cohort (n = 742) across four PTSD trajectory groups (i.e., asymptomatic, improved, developed, persistent), a higher proportion of participants in the persistent PTSD group reported worse depression, a lack of social participation, and history of mTBI. Additionally, a higher proportion of participants in the persistent and developed PTSD groups reported the need for managing mood/stress and improving memory/attention. When considered simultaneously, the presence of ≥ 1 or ≥ 2 risk factors was associated with a higher proportion of participants in the developed and persistent PTSD groups, ps < .001. These risk factors may be useful in identifying SMVs at risk for the development and/or persistence of PTSD symptoms who may need intervention.

Volitional Head Movement Deficits and Alterations in Gait Speed Following Mild Traumatic Brain Injury.

Unconstrained head motion is necessary to scan for visual cues during navigation, for minimizing threats, and to allow regulation of balance. Following mild traumatic brain injury (mTBI) people may experience alterations in head movement kinematics, which may be pronounced during gait tasks. Gait speed may also be impacted by the need to turn the head while walking in these individuals. The aim of this study was to examine head kinematics during dynamic gait tasks and the interaction between kinematics and gait speed in people with persistent symptoms after mTBI. A clinical assessment laboratory. A cross-sectional, matched-cohort study. Forty-five individuals with a history of mTBI and 46 age-matched control individuals. All participants were tested at a single time point and completed the Functional Gait Assessment (FGA) while wearing a suite of body-mounted inertial measurement units (IMUs). Data collected from the IMUs were gait speed, and peak head rotation speed and amplitude in the yaw and pitch planes during the FGA-1, -3, and -4 tasks. Participants with mTBI demonstrated significantly slower head rotations in the yaw ( P = .0008) and pitch ( P = .002) planes. They also demonstrated significantly reduced amplitude of yaw plane head rotations ( P < .0001), but not pitch plane head rotations ( P = .84). Participants with mTBI had significantly slower gait speed during normal gait (FGA-1) ( P < .001) and experienced a significantly greater percent decrease in gait speed than healthy controls when walking with yaw plane head rotations (FGA-3) ( P = .02), but not pitch plane head rotations (FGA-4) ( P = .11). Participants with mTBI demonstrated smaller amplitudes and slower speeds of yaw plane head rotations and slower speeds of pitch plane head rotations during gait. Additionally, people with mTBI walked slower during normal gait and demonstrated a greater reduction in gait speed while walking with yaw plane head rotations compared with healthy controls.

The influence of self-reported history of mild traumatic brain injury on cognitive performance

The long-term cognitive consequences of mild traumatic brain injury (mTBI) are poorly understood. Studies investigating cognitive performance in the chronic stage of injury in both hospital-based and population-based samples have revealed inconsistent findings. Importantly, population-based mTBI samples remain under-studied in the literature. This study investigated cognitive performance among individuals with a history of self-reported mTBI using a battery of cognitively demanding behavioural tasks. Importantly, more than half of the mTBI participants had experienced multiple mild head injuries. Compared to control participants (n = 49), participants with a history of mTBI (n = 30) did not demonstrate deficits in working memory, multitasking ability, cognitive flexibility, visuospatial ability, response inhibition, information processing speed or social cognition. There was moderate evidence that the mTBI group performed better than control participants on the visual working memory measure. Overall, these findings suggest that even multiple instances of mTBI do not necessarily lead to long-term cognitive impairment at the group level. Thus, we provide important evidence of the impact of chronic mTBI across a number of cognitive processes in a population-based sample. Further studies are necessary to determine the impact that individual differences in injury-related variables have on cognitive performance in the chronic stage of injury.

Investigating the Link between Later-Life Brain Volume and Cardiorespiratory Fitness after Mild Traumatic Brain Injury Exposure

Introduction: Evidence suggests that maintaining a higher level of cardiorespiratory fitness (CRF) later in life can offer some protection against brain volume loss as we age. By contrast, mild traumatic brain injury (mTBI) could accelerate age-related cortical atrophy. The current study sought to examine whether variations in the CRF level modified the association between mTBI history and brain volumetric measures in a sample of older adults. Methods: Seventy-nine community-dwelling older adults (mean age 68.7 ± 4.3 years, 54.4% female) were assessed for their mTBI history: 25 participants (32%) reported sustaining at least one lifetime mTBI. Participants also underwent a CRF assessment and magnetic resonance imaging (MRI) to obtain global and region-of-interest volumes. Results: Analysis of covariance, controlling for age, sex, education, and apolipoprotein (APOE) ε4 allele carriage, revealed that participants with a history of mTBI had a significantly larger total mean grey matter volume (582.21 ± 12.46 cm³) in comparison to participants with no mTBI history (571.08 ± 17.21 cm³, p = 0.01 after correction for multiple comparisons). However, no differences between groups based on mTBI history were found for total white matter volume or in any other cortical or subcortical structures examined. A subsequent moderation analysis found that CRF was predominantly non-influential on the association between mTBI history and the MRI-quantified measures of brain volume. Conclusion: While unexpected, the findings suggest that a history of mTBI can lead to grey matter alterations in the ageing brain. However, concurrent variations in the CRF level did not influence the differences in brain volume found based on mTBI exposure status.

Association of War Zone–Related Stress With Alterations in Limbic Gray Matter Microstructure

Military service members returning from theaters of war are at increased risk for mental illness, but despite high prevalence and substantial individual and societal burden, the underlying pathomechanisms remain largely unknown. Exposure to high levels of emotional stress in theaters of war and mild traumatic brain injury (mTBI) are presumed factors associated with risk for the development of mental disorders. To investigate (1) whether war zone-related stress is associated with microstructural alterations in limbic gray matter (GM) independent of mental disorders common in this population, (2) whether associations between war zone-related stress and limbic GM microstructure are modulated by a history of mTBI, and (3) whether alterations in limbic GM microstructure are associated with neuropsychological functioning. This cohort study was part of the TRACTS (Translational Research Center for TBI and Stress Disorders) study, which took place in 2010 to 2014 at the Veterans Affair Rehabilitation Research and Development TBI National Network Research Center. Participants included male veterans (aged 18-65 years) with available diffusion tensor imaging data enrolled in the TRACTS study. Data analysis was performed between December 2017 to September 2021. The Deployment Risk and Resilience Inventory (DRRI) was used to measure exposure to war zone-related stress. The Boston Assessment of TBI-Lifetime was used to assess history of mTBI. Stroop Inhibition (Stroop-IN) and Inhibition/Switching (Stroop-IS) Total Error Scaled Scores were used to assess executive or attentional control functions. Diffusion characteristics (fractional anisotropy of tissue [FAT]) of 16 limbic and paralimbic GM regions and measures of functional outcome. Among 384 male veterans recruited, 168 (mean [SD] age, 31.4 [7.4] years) were analyzed. Greater war zone-related stress was associated with lower FAT in the cingulate (DRRI-combat left: P = .002, partial r = -0.289; DRRI-combat right: P = .02, partial r = -0.216; DRRI-aftermath left: P = .004, partial r = -0.281; DRRI-aftermath right: P = .02, partial r = -0.219), orbitofrontal (DRRI-combat left medial orbitofrontal cortex: P = .02, partial r = -0.222; DRRI-combat right medial orbitofrontal cortex: P = .005, partial r = -0.256; DRRI-aftermath left medial orbitofrontal cortex: P = .02, partial r = -0.214; DRRI-aftermath right medial orbitofrontal cortex: P = .005, partial r = -0.260; DRRI-aftermath right lateral orbitofrontal cortex: P = .03, partial r = -0.196), and parahippocampal (DRRI-aftermath right: P = .03, partial r = -0.191) gyrus, as well as with higher FAT in the amygdala-hippocampus complex (DRRI-combat: P = .005, partial r = 0.254; DRRI-aftermath: P = .02, partial r = 0.223). Lower FAT in the cingulate-orbitofrontal gyri was associated with impaired response inhibition (Stroop-IS left cingulate: P < .001, partial r = -0.440; Stroop-IS right cingulate: P < .001, partial r = -0.372; Stroop-IS left medial orbitofrontal cortex: P < .001, partial r = -0.304; Stroop-IS right medial orbitofrontal cortex: P < .001, partial r = -0.340; Stroop-IN left cingulate: P < .001, partial r = -0.421; Stroop-IN right cingulate: P < .001, partial r = -0.300; Stroop-IN left medial orbitofrontal cortex: P = .01, partial r = -0.223; Stroop-IN right medial orbitofrontal cortex: P < .001, partial r = -0.343), whereas higher FAT in the mesial temporal regions was associated with improved short-term memory and processing speed (left amygdala-hippocampus complex: P < .001, partial r = -0.574; right amygdala-hippocampus complex: P < .001, partial r = 0.645; short-term memory left amygdala-hippocampus complex: P < .001, partial r = 0.570; short-term memory right amygdala-hippocampus complex: P < .001, partial r = 0.633). A history of mTBI did not modulate the association between war zone-related stress and GM diffusion. This study revealed an association between war zone-related stress and alteration of limbic GM microstructure, which was associated with cognitive functioning. These results suggest that altered limbic GM microstructure may underlie the deleterious outcomes of war zone-related stress on brain health. Military service members may benefit from early therapeutic interventions after deployment to a war zone.

White Matter Perivascular Space Burden Is Associated With Mild Traumatic Brain Injury History In Soldiers

Mild traumatic brain injury (mTBI) exposure in military Service Members may lead to impaired brain waste clearance which increases neurological disease risk including amyloidopathies. Perivascular spaces (PVS) are part of the glymphatic pathway which support brain waste clearance, especially during sleep. Greater magnetic resonance imaging (MRI)-visible PVS burden has been previously observed in patients with neurodegenerative diseases and animal TBI models. PURPOSE: To determine the association between PVS burden (number and volume) and mTBI history in Special Operations Forces (SOF) combat Soldiers. METHODS: In this cross-sectional study, participants underwent neuroimaging to capture T2-weighted (T2w) whole brain three dimensional volumes obtained on a Siemens 3T Biograph mMR or 3T MAGNETOM Prisma scanner (TR/TE = 3200/400ms, slice thickness = 1mm, FoV = 256mm x 256 mm). The PVS segmentation was performed using a previously validated, multi-scale deep convolutional encoder-decoder neural network. All T2w images were skull stripped and a custom T2w atlas with segmented cerebral white matter and subcortical gray matter labels was registered to each subject using Advanced Normalization Tools to minimize misidentifying thin tubular structures in the skull, brainstem, cerebellum, and cortex as PVS. Only PVS clusters within the white matter mask were quantified for analyses. Binary mTBI history was self-reported (“yes” or “no”). Due to non-normal PVS metric distribution, non-parametric Mann-Whitney U tests were used to determine group differences in PVS outcomes. RESULTS: In total, 223 healthy SOF combat Soldiers (age = 33.1±4.3yrs) were included for analysis and 123 (55.16%) reported mTBI history. Soldiers with mTBI history had greater PVS number (z = 2.506, P = 0.013) and PVS volume (z = 2.419, P = 0.016). CONCLUSIONS: We found mTBI history is associated with increased PVS burden in SOF combat Soldiers that are clinically recovered from mTBI. This may indicate ongoing physiological post-mTBI changes that could lead to impaired waste clearance via the glymphatic system. Future studies should determine how sleep influences PVS burden following mTBI exposure and if PVS number and volume are meaningful neurobiological outcomes for neurodegenerative disease risk. Funded by US Special Operations Command

A-178 18F-Fluorodeoxyglucose Positron Emission Tomography Findings Are Not Related to Cognitive Functioning in Service Members with Remote History of Traumatic Brain Injury

Abstract Objective: Determine whether glucose uptake as measured by 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is associated with cognitive performance and mild neurocognitive disorder (MNCD) in active-duty service members with a history of mild traumatic brain injury (mTBI). Method: 287 patients with a history of mTBI underwent FDG-PET scans at rest and neuropsychological testing at the National Intrepid Center of Excellence at Walter Reed National Military Medical Center. Glucose uptake in bilateral frontal, parietal, occipital, and temporal lobes, and 58 cortical/cerebellar regions were correlated with seven neuropsychological composite scores, with and without relevant covariates. Results: Prior to correction for multiple comparisons, perceptual reasoning correlated with bilateral hippocampi glucose uptake (rs:.141-.165, ps&amp;lt;.03), processing speed was inversely related to glucose uptake in the left temporal lobe (r=-.134, p=.034), working memory was related to glucose uptake in the left parietal, temporal, and occipital lobes (rs:.128-.140, ps&amp;lt;.05). Partial correlations between cognition and the 56 cortical/cerebellar regions of interest (ROIs) were not significant after correction for multiple comparisons. Increased glucose uptake in the bilateral pericalcarine, left superior temporal, and right occipital, superior parietal, transverse temporal, precuneus, and lingual cortices was related to increased likelihood of MNCD (ORs:41.02-2263.7, ps&amp;lt;.05); however, did not survive correction for multiple comparisons. Conclusions: After correction for multiple comparisons, there was no significant relationship between regional glucose uptake and neurocognitive performance or MNCD. Glucose uptake as measured by FDG-PET is not related to cognitive performance in active-duty service members with a remote history of mTBI and may have limited clinical utility for these individuals.

Factors associated with recovery from posttraumatic stress disorder in combat veterans: The role of deployment mild traumatic brain injury (mTBI).

Examine factors associated with recovery from posttraumatic stress disorder (PTSD) and evaluate the role of deployment mild traumatic brain injury (mTBI) in the relationship between PTSD recovery and functional outcomes. Post 9/11 combat veterans with lifetime history of PTSD (N = 124, 84.7% male) completed the Mid-Atlantic MIRECC Assessment of Traumatic Brain Injury (MMA-TBI), Salisbury Blast Interview (SBI), Clinician Administered PTSD scale (CAPS-5), cognitive assessment battery, and measures of depression, PTSD symptoms, neurobehavioral symptoms, sleep quality, pain interference, and quality of life. Analyses of variance (ANOVA) results revealed significant differences in most behavioral health outcomes based on PTSD recovery, with participants who have recovered from PTSD showing less severe neurobehavioral and depressive symptoms, better sleep quality, less functional pain interference, and higher quality of life. No differences were found in cognitive functioning between those who have recovered from PTSD and those who have not. History of deployment mTBI did not significantly moderate the relationship between PTSD recovery and most functional and cognitive outcomes with the exception of 2 measures of processing speed. Specifically, among participants with history of deployment mTBI, those who have recovered from PTSD displayed better cognitive functioning than those who have not. Additionally, participants who have not recovered from PTSD had higher levels of blast exposure during military service. PTSD recovery was associated with better psychological functioning and higher quality of life, but not with objective cognitive functioning. Deployment mTBI history moderated only the relationship between PTSD recovery status and tests of processing speed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Test–retest reliability of the neurotracker compared to the impact test for the management of mild traumatic brain injuries during two consecutive university sport seasons

ABSTRACT Introduction Neurocognitive assessment tools such as the Neurotracker and ImPACT have been proposed to optimize sports-related mild traumatic brain injury (mTBI) management. Baseline testing is recommended with such assessments to individualize monitoring of athletes' remission. While the ideal timeframe between baseline updates has been studied for the ImPACT, these data are missing for the Neurotracker. Objective The current study aimed to compare the test–retest reliability of the ImPACT and Neurotracker for two consecutive seasons in university athletes participating in sports at risk for mTBI. Methods At the start of two consecutive seasons, 30 athletes with no recent history of mTBI completed a baseline assessment including the Neurotracker and the ImPACT. The test–retest reliability of the results was analyzed by considering intra-class correlation (ICC), Becker’s standardized mean difference (dB) and Bland-Altman’ plot of each outcome. Results The Neurotracker and the Visual Motor Speed composite score of the ImPAC were the only outcomes with significative ICCs and acceptable d B between the two seasons. Neurotracker was the only outcome with a significative bias (+0.179). Conclusion Our research suggests that the Neurotracker has an acceptable level of test–retest reliability after one year in comparison to the ImPACT.

Mild Traumatic Brain Injuries and Future Risk of Developing Alzheimer's Disease: Systematic Review and Meta-Analysis.

Traumatic brain injury (TBI) increases the risk of future dementia and Alzheimer's disease (AD). However, it is unclear whether this is true for mild TBI (mTBI). To explore the association between mTBI and subsequent risk of developing AD. We systematically searched four electronic databases from January 1954 to April 2020. We included studies reporting primary data and where mTBI preceded AD by≥5 years. We meta-analyzed included studies for both high quality studies and studies with a follow up of > 10 years. We included 5 of the 10,435 results found. Meta-analysis found a history of mTBI increased risk of AD (pooled relative risk = 1.18, 95% CI 1.11-1.25, N = 3,149,740). The sensitivity analysis including only studies in which mTBI preceded AD by > 10 years, excluded two very large studies and resulted in wider confidence intervals (RR = 2.02, 95% CI 0.66-6.21, N = 2307). There is an increased risk of AD following mTBI. Our findings of increased risk even with mTBI means it cannot be assumed that mild head injuries from sports are harmless. The sensitivity analysis suggests that we cannot exclude reverse causation, and longer follow up times are needed. Implementation of policy to reduce mTBIs, including in children and sportsmen, are urgently needed. Further research is needed on the effect of frequency and age at injury of mTBIs.

Sex differences in outcomes from mild traumatic brain injury eight years post-injury.

The long-term effects of mild TBI (mTBI) are not well understood, and there is an ongoing debate about whether there are sex differences in outcomes following mTBI. This study examined i) symptom burden and functional outcomes at 8-years post-injury in males and females following mTBI; ii) sex differences in outcomes at 8-years post-injury for those aged <45 years and ≥45 years and; iii) sex differences in outcomes for single and repetitive TBI. Adults (≥16 years at injury) identified as part of a population-based TBI incidence study (BIONIC) who experienced mTBI 8-years ago (N = 151) and a TBI-free sample (N = 151) completed self-report measures of symptoms and symptom burden (Rivermead Post-Concussion Symptom Questionnaire, Hospital Anxiety and Depression Scale, Post-traumatic Stress Disorder Checklist), and functional outcomes (Participation Assessments with Recombined Tools, Work Limitations Questionnaire). The mTBI group reported significantly greater post-concussion symptoms compared to the TBI-free group (F(1,298) = 26.84, p<.01, ηp2 = .08). Females with mTBI were twice as likely to exceed clinical cut-offs for post-concussive (X2 (1)>5.2, p<.05, V>.19) and PTSD symptoms (X2(1) = 6.10, p = .014, V = .20) compared to the other groups, and reported their health had the greatest impact on time-related work demands (F(1,171) = 4.36, p = .04, ηp2 = .03. There was no interaction between sex and age on outcomes. The repetitive mTBI group reported significantly greater post-concussion symptoms (F(1,147) = 9.80, p<.01, ηp2 = .06) compared to the single mTBI group. Twice the proportion of women with repetitive mTBI exceeded the clinical cut-offs for post-concussive (X2(1)>6.90, p<.01, V>.30), anxiety (X2(1)>3.95, p<.05, V>.23) and PTSD symptoms (X2(1)>5.11, p<.02, V>.26) compared with males with repetitive TBI or women with single TBI. Thus, at 8-years post-mTBI, people continued to report a high symptom burden. Women with mTBI, particularly those with a history of repetitive mTBI, had the greatest symptom burden and were most likely to have symptoms of clinical significance. When treating mTBI it is important to assess TBI history, particularly in women. This may help identify those at greatest risk of poor long-term outcomes to direct early treatment and intervention.

Is sentence ambiguity comprehension affected after mild traumatic brain injury? Results suggest cognitive control is more important than diagnosis.

Individuals with mild traumatic brain injury (mTBI) may experience chronic cognitive-linguistic impairments that are difficult to evaluate with existing measures. Garden path sentences are linguistically complex sentences that lead readers down a path to an incorrect interpretation. Previous research indicates many individuals, with or without mTBI, may have difficulty fully resolving the ambiguity of garden path sentences, a skill which may require cognitive control. Evidence suggests cognitive control can be impacted by mTBI. Thus, impairments in cognitive control are expected to correlate with interpreting ambiguous sentences. To examine the relationship between cognitive control and the processing of ambiguous garden path sentences in adults with mTBI. We predict individuals with mTBI will perform more poorly on ambiguous sentence tasks compared with a control group. Further, we predict that performance on this task will correlate with measures of cognitive control and working memory. A total of 20 adults with mTBI history and 44 adults with no significant neurological history were recruited from the community. Participants completed a computerized, ambiguous sentence measure with carefully designed comprehension questions and an abbreviated neuropsychological battery of cognitive-linguistic tasks. Participants performed similarly on sentence ambiguity resolution measures across groups with a wide range in performance. A comprehension measure aimed at identifying full ambiguity resolution correlated with cognitive control across groups. A link between cognitive control and linguistic ambiguity is confirmed in a comprehension measure by the current findings. mTBI history did not appear to change the nature of the relationship between cognitive control and ambiguity resolution. High individual variability on sentence and cognitive control measures across groups suggest that if an impairment were present, it would affect both types of tasks. Thus, testing cognitive communication following mTBI should specifically examine complex cognitive and linguistic processing. What is already known on the subject Cognitive control and ambiguous sentence processing are known to be linked, but the circumstances and individual variability associated with when cognitive control is recruited to support sentence processing are not fully understood. Very little is known about sentence processing following TBI history, despite cognitive control commonly being impaired following mild TBI. Thus, our study was necessary to explore the theoretical and clinical relationships between cognitive control and ambiguous sentence processing in individuals with mild TBI history. What this paper adds to existing knowledge This study adds to our understanding of how cognitive control and ambiguous sentence processing are linked in those with mild TBI history, and similar to the few previous studies, there were no group differences in cognitive or sentence measures. The positive correlation between cognitive control on Stroop and a particular ambiguous sentence comprehension question targeting inhibitory control highlights that any relationship between abilities or assessment tasks must be very specific to tasks with overlapping requirements, such as inhibition. What are the potential or actual clinical implications of this work? The relationship between cognitive and ambiguous sentence measures highlights the need to assess all areas of cognition and communication in those with mild TBI history without assuming that impairments in cognitive performance will relate to communication. The overlap between abilities is highly specific and must be explored on a case-by-case basis in those with mild TBI. Evaluation and treatment should still be individualized based on the functional communication profile of the client.

0282 Elevated levels of Extracellular Vesicle Cytokines are Associated with Poor Sleep Quality in Warfighters with Chronic Mild TBI

Abstract Introduction Sleep disorders are common in military populations and frequently occur comorbidly with mild traumatic brain injury (mTBI), resulting in substantial health risks. Although inflammation and cytokine elevations have independently been reported both after traumatic brain injury (mTBI) and in association with sleep dysfunction, the impact of these factors on inflammatory processes in a combined context (i.e. post-mTBI sleep dysfunction) has yet to be explored. Extracellular vesicles (EVs) are a particularly promising source of these cytokines; EVs are lipid bilayer-enclosed particles released by cells to the extracellular environment, constituting a newly discovered form of cell-to-cell communication that may afford improved signal-to-noise ratio and more functionally specific protein biomarkers than free (soluble) sources. To determine whether mTBI and sleep dysfunction may bidirectionally regulate inflammatory processes, the present study examined associations between plasma and EV levels of cytokines and sleep quality in a cohort of warfighters with and without chronic mTBI. Methods Participants (n=182) were enrolled in the Chronic Effects of Neurotrauma Consortium (CENC) Multicenter Prospective Longitudinal Study/ Long-Term Impact of Military Brain Injury Consortium (LIMBIC). They were divided into control (no TBI history) or mTBI groups (positive history of mTBI). EV and plasma levels of interleukin (IL)-10, IL-6, and tumor necrosis factor-alpha (TNFα) were analyzed using a Simoa HD-1 analyzer. Sleep quality was evaluated using Pittsburgh Sleep Quality Index (PSQI). Results Within the mTBI group, patients reporting poor sleep quality (PSQI ≥10) had elevated EV levels of IL-10 (ß(SE) = 0.12(0.04), p&amp;lt;0.01) when compared to those reporting good sleep (PSQI&amp;lt;10). Sleep quality was associated with EV levels of IL-10 (ß(SE)=0.11(0.04), p=0.01) and TNFα (ß(SE)=0.07(0.03), p&amp;lt; 0.01) in mTBI patients. Plasma levels of cytokines were not significantly associated with sleep quality. Conclusion Our findings suggest that EV levels of IL-10 and TNFα, but not their plasma levels, are associated with self-reported sleep quality warfighters with history of mTBI. Our results suggest that EVs are relevant signaling mechanisms in sleep-related inflammatory responses following mTBI. Larger prospective studies are needed to further investigate the links between EV cytokines and sleep quality in participants with mTBI. Support (If Any) This work was supported by grant funding from: Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01 CX001135.

0625 Characterization of Obstructive Sleep Apnea in Active-Duty US Military Personnel Receiving Interdisciplinary Care at the National Intrepid Center of Excellence

Abstract Introduction Among active-duty service members (ADSMs), obstructive sleep apnea (OSA) is associated with decreased quality of life and military readiness/retention. Limited evidence suggests mild traumatic brain injury (mTBI) patients have increased OSA incidence, but little is known about the underlying physiology. This study aims to characterize OSA in treatment-seeking ADSMs with a history of remote mTBI and/or persistent neurobehavioral symptoms to improve detection and early intervention. Methods This is a retrospective analysis of data collected from ADSMs attending the National Intrepid Center of Excellence Intensive Outpatient Program for persistent symptoms associated with mTBI. Sleep assessment included overnight polysomnography and self-report assessments of sleep quality, somatic and mood symptoms. OSA severity was determined by apnea-hypopnea index (negative: &amp;lt;5, mild: 5-15, moderate/severe: ≥15). Group differences were assessed using analysis of covariance and pairwise least squares regression, controlling for age and body mass index, and corrected for multiple comparisons. Results Analyses included 574 ADSMs, mostly male (99%), with a mean age of 39.7. The majority (n=288; 50.2%) were OSA negative (OSA-neg); a third had mild OSA (m-OSA) (n=216; 38%); and a tenth were diagnosed with moderate/severe OSA (mod/s-OSA) (n=70; 12%). Mod/s-OSA patients had increased arousal index (p&amp;lt;0.01), hypoxia time (p&amp;lt;0.001), reduced total sleep time (p&amp;lt;0.01) and sleep efficiency (p&amp;lt;0.001) compared to m-OSA and OSA-neg patients. M-OSA patients had an increased arousal index compared to OSA-neg patients (p&amp;lt;0.01). Patient groups did not significantly differ on subjective measures of sleep (i.e., quality, sleepiness), post-concussive, or behavioral health symptoms (anxiety, depression, post-traumatic stress symptoms, alcohol misuse). Conclusion In our sample of treatment-seeking ADSMs, nearly half presented with OSA according to cut-scores derived for AHI, greater than that expected in the general population. As reported in civilian populations, mod/s-OSA patients demonstrated worse objective sleep measures compared to m-OSA and OSA-neg patients, yet in our sample their self-reported symptom severity did not differ. These findings suggest a low threshold for OSA screening is needed in the symptomatic mTBI population and that multiple factors other than OSA likely contribute to perceived sleep disturbances and neurobehavioral symptoms. Support (If Any) None.

0320 Sex Differences in Sleep Quality and Biomarker Levels in Service Members and Veterans with Chronic Mild Traumatic Brain Injury

Abstract Introduction Sleep disorders are highly prevalent in military populations and are frequently associated with a history of traumatic brain injury (TBI). Despite the recent increase in female representation in the military, few studies have focused on sex differences in sleep quality in military populations. In this study, we examined biological sex differences in self-reported sleep quality and blood levels of protein biomarkers of TBI in a cohort of service members and veterans with chronic mild TBI (mTBI). Methods Participants (n=1,121) were enrolled in the Chronic Effects of Neurotrauma Consortium (CENC)/Long Term Impact of Military Brain Injury Consortium (LIMBIC) study. Females (n=147) and males (n=974) were classified into control (n=192, no TBI history) or mTBI (n=929, positive history of mTBI) groups. Self-reported sleep quality was assessed using PSQI (Pittsburgh Sleep Quality Index). Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), Tau, interleukin (IL)-10, IL-6, and tumor necrosis factor-alpha (TNFα) were analyzed using a Simoa HD-X analyzer. Results Regression models revealed higher PSQI scores in females than males (ß(SE)=1.36(0.40), p =0.001) and in the TBI group (ß(SE)=1.97(0.36), p&amp;lt;0.001) in comparison to controls. TBI x sex interaction was not statistically significant. Within the mTBI group, females had higher PSQI scores (p=0.031) and GFAP levels (p&amp;lt;0.001) than males, which remained significant when controlling for demographics, number of mTBIs, and time since last mTBI. No other significant differences in biomarker levels were observed. In men, but not women, higher levels of GFAP were associated with lower PSQI scores (ß(SE)=-1.38(0.43), p=0.001). Conclusion Our findings suggest sex differences in sleep quality after mTBI, providing insights into possible mechanisms underlying the development of chronic symptoms in military populations. Our results support the need for considering biological sex in the development of personalized therapeutic strategies for chronic TBI-related sleep disorders. Support (If Any) This work was supported by grant funding from: The U.S. Army Medical Research and Material Command, from the U.S. Department of Veterans Affairs Long-term Impact of Military-related Brain Injury Consortium/Chronic Effects of Neurotrauma Consortium under Award No.1I01CX002097-01 and the U.S Department of Defense under Award No.W81XWH-18-PH/TBIRP-LIMBIC.

Personality disorder and mild traumatic brain injury.

Mild traumatic brain injury (mTBI) poses risk to the neurocognitive, emotional, and financial well-being of affected individuals. While aggression and impulsivity have been examined in relation to mTBI, little work has been done to evaluate the relationship between history of mTBI and personality disorder (PD). The authors examined the associations between history of mTBI and PD in a control group without history of mTBI (N = 1189) and individuals with history of mTBI (N = 267). Results demonstrated that any PD diagnosis is a significant risk factor for mTBI (p < 0.001). Cluster B diagnoses, particularly borderline and antisocial PD, were independently significant risk factors for mTBI. These data suggest a role for screening for a history of mTBI in patients with PDs and associated traits.

Sensory Phenotypes for Balance Dysfunction After Mild Traumatic Brain Injury.

Recent team-based models of care use symptom subtypes to guide treatments of individuals with chronic effects of mild traumatic brain injury (mTBI). However, these subtypes, or phenotypes, may be too broad, particularly for balance (e.g., vestibular subtype). To gain insight into mTBI-related imbalance, we (1) explored whether a dominant sensory phenotype (e.g., vestibular impaired) exists in the chronic mTBI population, (2) determined the clinical characteristics, symptomatic clusters, functional measures, and injury mechanisms that associate with sensory phenotypes for balance control in this population, and (3) compared the presentations of sensory phenotypes between individuals with and without previous mTBI. A secondary analysis was conducted on the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. Sensory ratios were calculated from the sensory organization test, and individuals were categorized into 1 of the 8 possible sensory phenotypes. Demographic, clinical, and injury characteristics were compared across phenotypes. Symptoms, cognition, and physical function were compared across phenotypes, groups, and their interaction. Data from 758 Service Members and Veterans with mTBI and 172 individuals with no lifetime history of mTBI were included. Abnormal visual, vestibular, and proprioception ratios were observed in 29%, 36%, and 38% of people with mTBI, respectively, with 32% exhibiting more than 1 abnormal sensory ratio. Within the mTBI group, global outcomes (p < 0.001), self-reported symptom severity (p < 0.027), and nearly all physical and cognitive functioning tests (p < 0.027) differed across sensory phenotypes. Individuals with mTBI generally reported worse symptoms than their non-mTBI counterparts within the same phenotype (p = 0.026), but participants with mTBI in the vestibular-deficient phenotype reported lower symptom burdens than their non-mTBI counterparts (e.g., mean [SD] Dizziness Handicap Inventory = 4.9 [8.1] for mTBI vs 12.8 [12.4] for non-mTBI, group × phenotype interaction p < 0.001). Physical and cognitive functioning did not differ between the groups after accounting for phenotype. Individuals with mTBI exhibit a variety of chronic balance deficits involving heterogeneous sensory integration problems. While imbalance when relying on vestibular information is common, it is inaccurate to label all mTBI-related balance dysfunction under the vestibular umbrella. Future work should consider specific classification of balance deficits, including specific sensory phenotypes for balance control.