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.

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.

When should an athlete retire or discontinue participating in contact or collision sports following sport-related concussion? A systematic review.

OBJECTIVE: To systematically review the scientific literature regarding factors to consider when providing advice or guidance to athletes about retirement from contact or collision sport following sport-related concussion (SRC), and to define contraindications to children/adolescent athletes entering or continuing with contact or collision sports after SRC. DATA SOURCES: Medline, Embase, SPORTSDiscus, APA PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials were searched systematically. STUDY ELIGIBILITY CRITERIA: Studies were included if they were (1) original research, (2) reported on SRC as the primary source of injury, (3) evaluated the history, clinical assessment and/or investigation of findings that may preclude participation in sport and (4) evaluated mood disturbance and/or neurocognitive deficits, evidence of structural brain injury or risk factors for increased risk of subsequent SRC or prolonged recovery. RESULTS: Of 4355 articles identified, 93 met the inclusion criteria. None of the included articles directly examined retirement and/or discontinuation from contact or collision sport. Included studies examined factors associated with increased risk of recurrent SRC or prolonged recovery following SRC. In general, these were low-quality cohort studies with heterogeneous results and moderate risk of bias. Higher number and/or severity of symptoms at presentation, sleep disturbance and symptom reproduction with Vestibular Ocular Motor Screen testing were associated with prolonged recovery and history of previous concussion was associated with a risk of further SRC. CONCLUSION: No evidence was identified to support the inclusion of any patient-specific, injury-specific or other factors (eg, imaging findings) as absolute indications for retirement or discontinued participation in contact or collision sport following SRC. PROSPERO REGISTRATION NUMBER: CRD42022155121.

What tests and measures accurately diagnose persisting post-concussive symptoms in children, adolescents and adults following sport-related concussion? A systematic review.

OBJECTIVE: To determine what tests and measures accurately diagnose persisting post-concussive symptoms (PPCS) in children, adolescents and adults following sport-related concussion (SRC). DESIGN: A systematic literature review. DATA SOURCES: MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL and SPORTDiscus through March 2022. ELIGIBILITY CRITERIA: Original, empirical, peer-reviewed findings (cohort studies, case-control studies, cross-sectional studies and case series) published in English and focused on SRC. Studies needed to compare individuals with PPCS to a comparison group or their own baseline prior to concussion, on tests or measures potentially affected by concussion or associated with PPCS. RESULTS: Of 3298 records screened, 26 articles were included in the qualitative synthesis, including 1016 participants with concussion and 531 in comparison groups; 7 studies involved adults, 8 involved children and adolescents and 11 spanned both age groups. No studies focused on diagnostic accuracy. Studies were heterogeneous in participant characteristics, definitions of concussion and PPCS, timing of assessment and the tests and measures examined. Some studies found differences between individuals with PPCS and comparison groups or their own pre-injury assessments, but definitive conclusions were not possible because most studies had small convenience samples, cross-sectional designs and were rated high risk of bias. CONCLUSION: The diagnosis of PPCS continues to rely on symptom report, preferably using standardised symptom rating scales. The existing research does not indicate that any other specific tool or measure has satisfactory accuracy for clinical diagnosis. Future research drawing on prospective, longitudinal cohort studies could help inform clinical practice.

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.

Is balance performance reduced after mild traumatic brain injury?: Interim analysis from chronic effects of neurotrauma consortium (CENC) multi-centre study.

OBJECTIVES: Determine if mild traumatic brain injury (mTBI) history is associated with balance disturbances. SETTING: Chronic Effects of Neurotrauma Consortium (CENC) centres. PARTICIPANTS: The CENC multi-centre study enrols post-9/11 era Service Members and Veterans with combat exposure. This sample (n = 322) consisted of enrolees completing initial evaluation by September 2016 at the three sites conducting computerized dynamic post-urography (CDP) testing. DESIGN: Observational study with cross-sectional analyses using structural equation modelling. MAIN MEASURES: Comprehensive structured interviews were used to diagnose all lifetime mild traumatic brain injuries (mTBIs). The outcome, Sensory Organization Test (SOT), was measured on CDP dual-plate force platform. Other studied variables were measured by structured interviews, record review and questionnaires. RESULTS: The overall positive/negative mTBI classification did not have a significant effect on the composite equilibrium score. However, the repetitive mTBI classification showed lower scores for participants with ≥ 3 mTBI versus 1-2 lifetime mTBIs. For repetitive mTBI, pain interference acted as a mediator for the indirect effect, and a direct effect was evident on some sensory condition equilibrium scores. CONCLUSION: These findings show that repeated mTBI, partially mediated by pain, may lead to later balance disturbances among military combatants. Further study of CDP outcomes within this accruing cohort is warranted.

Military-related risk factors for dementia.

INTRODUCTION: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post-traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans. METHODS: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. RESULTS: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia. DISCUSSION: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.

Approach to investigation and treatment of persistent symptoms following sport-related concussion: a systematic review.

OBJECTIVE: To conduct a systematic review of the literature regarding assessment and treatment modalities in patients with persistent symptoms following sport-related concussion (SRC). DATA SOURCES: We searched Medline, Embase, SPORTSDiscus, PsycINFO, CINAHL, Cochrane library and ProQuest Dissertation & Theses Global electronic databases. STUDY ELIGIBILITY CRITERIA: Studies were included if they were original research, reported on SRC as the primary source of injury, included patients with persistent postconcussive symptoms (>10 days) and investigated the role of assessment or treatment modalities. RESULTS: Of 3225 articles identified in the preliminary search, 25 articles met the inclusion criteria. 11 articles were concerned with assessment and 14 articles with treatment of persistent symptoms following SRC. There were three randomised control trials and one quasi-experimental study. The remainder consisting of cross-sectional studies, historical cohorts and case series. SUMMARY: 'Persistent symptoms' following SRC can be defined as clinical recovery that falls outside expected time frames (ie, >10-14 days in adults and >4 weeks in children). It does not reflect a single pathophysiological entity, but describes a constellation of non-specific post-traumatic symptoms that may be linked to coexisting and/or confounding pathologies. A detailed multimodal clinical assessment is required to identify specific primary and secondary processes, and treatment should target specific pathologies identified. There is preliminary evidence supporting the use of symptom-limited aerobic exercise, targeted physical therapy and a collaborative approach that includes cognitive behavioural therapy. Management of patients with persistent symptoms is challenging and should occur in a multidisciplinary collaborative setting, with healthcare providers with experience in SRC.

A sustainable training strategy for improving health care following a catastrophic radiological or nuclear incident.

The detonation of a nuclear device in a US city would be catastrophic. Enormous loss of life and injuries would characterize an incident with profound human, political, social, and economic implications. Nevertheless, most responders have not received sufficient training about ionizing radiation, principles of radiation safety, or managing, diagnosing, and treating radiation-related injuries and illnesses. Members throughout the health care delivery system, including medical first responders, hospital first receivers, and health care institution support personnel such as janitors, hospital administrators, and security personnel, lack radiation-related training. This lack of knowledge can lead to failure of these groups to respond appropriately after a nuclear detonation or other major radiation incident and limit the effectiveness of the medical response and recovery effort. Efficacy of the response can be improved by getting each group the information it needs to do its job. This paper proposes a sustainable training strategy for spreading curricula throughout the necessary communities. It classifies the members of the health care delivery system into four tiers and identifies tasks for each tier and the radiation-relevant knowledge needed to perform these tasks. By providing education through additional modules to existing training structures, connecting radioactive contamination control to daily professional practices, and augmenting these systems with just-in-time training, the strategy creates a sustainable mechanism for giving members of the health care community improved ability to respond during a radiological or nuclear crisis, reducing fatalities, mitigating injuries, and improving the resiliency of the community.

Explainable machine learning for predicting conversion to neurological disease: Results from 52,939 medical records.

Objective: This study assesses the application of interpretable machine learning modeling using electronic medical record data for the prediction of conversion to neurological disease. Methods: A retrospective dataset of Cleveland Clinic patients diagnosed with Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, or Parkinson's disease, and matched controls based on age, sex, race, and ethnicity was compiled. Individualized risk prediction models were created using eXtreme Gradient Boosting for each neurological disease at four timepoints in patient history. The prediction models were assessed for transparency and fairness. Results: At timepoints 0-months, 12-months, 24-months, and 60-months prior to diagnosis, Alzheimer's disease models achieved the area under the receiver operating characteristic curve on a holdout test dataset of 0.794, 0.742, 0.709, and 0.645; amyotrophic lateral sclerosis of 0.883, 0.710, 0.658, and 0.620; multiple sclerosis of 0.922, 0.877, 0.849, and 0.781; and Parkinson's disease of 0.809, 0.738, 0.700, and 0.651, respectively. Conclusions: The results demonstrate that electronic medical records contain latent information that can be used for risk stratification for neurological disorders. In particular, patient-reported outcomes, sleep assessments, falls data, additional disease diagnoses, and longitudinal changes in patient health, such as weight change, are important predictors.

Intimate partner violence perpetration among veterans: associations with neuropsychiatric symptoms and limbic microstructure.

Background: Intimate partner violence (IPV) perpetration is highly prevalent among veterans. Suggested risk factors of IPV perpetration include combat exposure, post-traumatic stress disorder (PTSD), depression, alcohol use, and mild traumatic brain injury (mTBI). While the underlying brain pathophysiological characteristics associated with IPV perpetration remain largely unknown, previous studies have linked aggression and violence to alterations of the limbic system. Here, we investigate whether IPV perpetration is associated with limbic microstructural abnormalities in military veterans. Further, we test the effect of potential risk factors (i.e., PTSD, depression, substance use disorder, mTBI, and war zone-related stress) on the prevalence of IPV perpetration. Methods: Structural and diffusion-weighted magnetic resonance imaging (dMRI) data were acquired from 49 male veterans of the Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom; OEF/OIF) of the Translational Research Center for TBI and Stress Disorders (TRACTS) study. IPV perpetration was assessed using the psychological aggression and physical assault sub-scales of the Revised Conflict Tactics Scales (CTS2). Odds ratios were calculated to assess the likelihood of IPV perpetration in veterans with either of the following diagnoses: PTSD, depression, substance use disorder, or mTBI. Fractional anisotropy tissue (FA) measures were calculated for limbic gray matter structures (amygdala-hippocampus complex, cingulate, parahippocampal gyrus, entorhinal cortex). Partial correlations were calculated between IPV perpetration, neuropsychiatric symptoms, and FA. Results: Veterans with a diagnosis of PTSD, depression, substance use disorder, or mTBI had higher odds of perpetrating IPV. Greater war zone-related stress, and symptom severity of PTSD, depression, and mTBI were significantly associated with IPV perpetration. CTS2 (psychological aggression), a measure of IPV perpetration, was associated with higher FA in the right amygdala-hippocampus complex (r = 0.400, p = 0.005). Conclusion: Veterans with psychiatric disorders and/or mTBI exhibit higher odds of engaging in IPV perpetration. Further, the more severe the symptoms of PTSD, depression, or TBI, and the greater the war zone-related stress, the greater the frequency of IPV perpetration. Moreover, we report a significant association between psychological aggression against an intimate partner and microstructural alterations in the right amygdala-hippocampus complex. These findings suggest the possibility of a structural brain correlate underlying IPV perpetration that requires further research.

Persistent MRI Findings Unique to Blast and Repetitive Mild TBI: Analysis of the CENC/LIMBIC Cohort Injury Characteristics.

INTRODUCTION: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) are mixed, making the findings difficult to interpret. As such, additional research is needed to continue to elucidate the relationship between the clinical features of mTBI and quantitative MRI measurements. MATERIAL AND METHODS: Volumetric and diffusion imaging data in a sample of 976 veterans and service members from the Chronic Effects of Neurotrauma Consortium and now the Long-Term Impact of Military-Relevant Brain Injury Consortium observational study of the late effects of mTBI in combat with and without a history of mTBI were examined. A series of regression models with link functions appropriate for the model outcome were used to evaluate the relationships among imaging measures and clinical features of mTBI. Each model included acquisition site, participant sex, and age as covariates. Separate regression models were fit for each region of interest where said region was a predictor. RESULTS: After controlling for multiple comparisons, no significant main effect was noted for comparisons between veterans and service members with and without a history of mTBI. However, blast-related mTBI were associated with volumetric reductions of several subregions of the corpus callosum compared to non-blast-related mTBI. Several volumetric (i.e., hippocampal subfields, etc.) and diffusion (i.e., corona radiata, superior longitudinal fasciculus, etc.) MRI findings were noted to be associated with an increased number of repetitive mTBIs versus. CONCLUSIONS: In deployment-related mTBI, significant findings in this cohort were only observed when considering mTBI sub-groups (blast mechanism and total number/dose). Simply comparing healthy controls and those with a positive mTBI history is likely an oversimplification that may lead to non-significant findings, even in consortium analyses.

Posttraumatic survivor guilt is associated with white matter microstructure alterations.

BACKGROUND: Military veterans with posttraumatic stress disorder (PTSD) commonly experience posttraumatic guilt. Guilt over commission or omission evolves when responsibility is assumed for an unfortunate outcome (e.g., the death of a fellow combatant). Survivor guilt is a state of intense emotional distress experienced by the weight of knowing that one survived while others did not. METHODS: This study of the Translational Research Center for TBI and Stress Disorders (TRACTS) analyzed structural and diffusion-weighted magnetic resonance imaging data from 132 male Iraq/Afghanistan veterans with PTSD. The Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV) was employed to classify guilt. Thirty (22.7 %) veterans experienced guilt over acts of commission or omission, 34 (25.8 %) experienced survivor guilt, and 68 (51.5 %) had no posttraumatic guilt. White matter microstructure (fractional anisotropy, FA), cortical thickness, and cortical volume were compared between veterans with guilt over acts of commission or omission, veterans with survivor guilt, and veterans without guilt. RESULTS: Veterans with survivor guilt had significantly lower white matter FA compared to veterans who did not experience guilt (p < .001), affecting several regions of major white matter fiber bundles. There were no significant differences in white matter FA, cortical thickness, or volumes between veterans with guilt over acts of commission or omission and veterans without guilt (p > .050). LIMITATIONS: This cross-sectional study with exclusively male veterans precludes inferences of causality between the studied variables and generalizability to the larger veteran population that includes women. CONCLUSION: Survivor guilt may be a particularly impactful form of posttraumatic guilt that requires specific treatment efforts targeting brain health.

Role of Deployment History on the Association Between Epilepsy and Traumatic Brain Injury in Post-9/11 Era US Veterans.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is a well-established epilepsy risk factor and is common among service members. Deployment-related TBI, where combat/blast may be more common, may have different outcomes than nondeployment-related TBI. This work examined associations of all TBI exposures (not just combat), and epilepsy, while adjusting for comorbidities associated with epilepsy, among veterans by deployment status. METHODS: The cohort included post-9/11 veterans with ≥2 years of care in both Veterans Health Administration and Defense Health Agency systems. We identified epilepsy using ICD-9/10-CM codes, antiseizure medication, and service-connected disability for epilepsy. We conducted a logistic regression model with interaction terms for conditions by deployment history that adjusted for demographics and military characteristics. RESULTS: The cohort (n = 938,890) included post-9/11 veterans of whom 27,436 (2.92%) had epilepsy. Most veterans had a history of deployment (70.64%), referred to as "deployed." Epilepsy was more common among veterans who were never deployed ("nondeployed") (3.85% vs 2.54%). Deployed veterans were more likely to have had TBI, compared with the nondeployed veterans (33.94% vs 14.24%), but nondeployed veterans with moderate/severe TBI had higher odds of epilepsy compared with deployed veterans (adjusted odds ratio [aOR] 2.92, 95% CI 2.68-3.17 vs aOR 2.01, 95% CI 1.91-2.11). Penetrating TBI had higher odds of epilepsy among the deployed veterans (aOR 5.33, 95% CI 4.89-5.81), whereas the odds of epilepsy for mild TBI did not significantly differ by deployment status. Although most neurologic conditions were more prevalent among the nondeployed veterans, they were often associated with higher odds of epilepsy in the deployed veterans. DISCUSSION: Deployment history had a significant differential impact on epilepsy predictors. As expected, penetrating TBI had a greater epilepsy impact among deployed veterans perhaps due to combat/blast. Some epilepsy predictors (moderate/severe TBI, multiple sclerosis, and Parkinson disease) had a stronger association in the nondeployed veterans suggesting a potential healthy warrior effect in which such conditions preclude deployment. Other neurologic conditions (e.g., brain tumor, Alzheimer disease/frontotemporal dementia) had a greater epilepsy impact in the deployed veterans. This may be attributable to deployment-related exposures (combat injury, occupational exposures). A better understanding of deployment effects is critical to provide targeted epilepsy prevention in veterans and military service members.

Sleep Quality Disturbances Are Associated with White Matter Alterations in Veterans with Post-Traumatic Stress Disorder and Mild Traumatic Brain Injury.

Sleep disturbances are strongly associated with mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI have been linked to alterations in white matter (WM) microstructure, but whether poor sleep quality has a compounding effect on WM remains largely unknown. We evaluated sleep and diffusion magnetic resonance imaging (dMRI) data from 180 male post-9/11 veterans diagnosed with (1) PTSD (n = 38), (2) mTBI (n = 25), (3) comorbid PTSD+mTBI (n = 94), and (4) a control group with neither PTSD nor mTBI (n = 23). We compared sleep quality (Pittsburgh Sleep Quality Index, PSQI) between groups using ANCOVAs and calculated regression and mediation models to assess associations between PTSD, mTBI, sleep quality, and WM. Veterans with PTSD and comorbid PTSD+mTBI reported poorer sleep quality than those with mTBI or no history of PTSD or mTBI (p = 0.012 to <0.001). Poor sleep quality was associated with abnormal WM microstructure in veterans with comorbid PTSD+mTBI (p < 0.001). Most importantly, poor sleep quality fully mediated the association between greater PTSD symptom severity and impaired WM microstructure (p < 0.001). Our findings highlight the significant impact of sleep disturbances on brain health in veterans with PTSD+mTBI, calling for sleep-targeted interventions.

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

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Exposures: 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. Main Outcomes and Measures: Diffusion characteristics (fractional anisotropy of tissue [FAT]) of 16 limbic and paralimbic GM regions and measures of functional outcome. Results: 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. Conclusions and Relevance: 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.

The Military Injuries: Understanding Post-Traumatic Epilepsy Study: Understanding Relationships among Lifetime Traumatic Brain Injury History, Epilepsy, and Quality of Life.

Understanding risk for epilepsy among persons who sustain a mild (mTBI) traumatic brain injury (TBI) is crucial for effective intervention and prevention. However, mTBI is frequently undocumented or poorly documented in health records. Further, health records are non-continuous, such as when persons move through health systems (e.g., from Department of Defense to Veterans Affairs [VA] or between jobs in the civilian sector), making population-based assessments of this relationship challenging. Here, we introduce the MINUTE (Military INjuries-Understanding post-Traumatic Epilepsy) study, which integrates data from the Veterans Health Administration with self-report survey data for post-9/11 veterans (n = 2603) with histories of TBI, epilepsy and controls without a history of TBI or epilepsy. This article describes the MINUTE study design, implementation, hypotheses, and initial results across four groups of interest for neurotrauma: 1) control; 2) epilepsy; 3) TBI; and 4) post-traumatic epilepsy (PTE). Using combined survey and health record data, we test hypotheses examining lifetime history of TBI and the differential impacts of TBI, epilepsy, and PTE on quality of life. The MINUTE study revealed high rates of undocumented lifetime TBIs among veterans with epilepsy who had no evidence of TBI in VA medical records. Further, worse physical functioning and health-related quality of life were found for persons with epilepsy + TBI compared to those with either epilepsy or TBI alone. This effect was not fully explained by TBI severity. These insights provide valuable opportunities to optimize the resilience, delivery of health services, and community reintegration of veterans with TBI and complex comorbidity.

COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI).

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Coordinating Global Multi-Site Studies of Military-Relevant Traumatic Brain Injury: Opportunities, Challenges, and Harmonization Guidelines.

Traumatic brain injury (TBI) is common among military personnel and the civilian population and is often followed by a heterogeneous array of clinical, cognitive, behavioral, mood, and neuroimaging changes. Unlike many neurological disorders that have a characteristic abnormal central neurologic area(s) of abnormality pathognomonic to the disorder, a sufficient head impact may cause focal, multifocal, diffuse or combination of injury to the brain. This inconsistent presentation makes it difficult to establish or validate biological and imaging markers that could help improve diagnostic and prognostic accuracy in this patient population. The purpose of this manuscript is to describe both the challenges and opportunities when conducting military-relevant TBI research and introduce the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Military Brain Injury working group. ENIGMA is a worldwide consortium focused on improving replicability and analytical power through data sharing and collaboration. In this paper, we discuss challenges affecting efforts to aggregate data in this patient group. In addition, we highlight how "big data" approaches might be used to understand better the role that each of these variables might play in the imaging and functional phenotypes of TBI in Service member and Veteran populations, and how data may be used to examine important military specific issues such as return to duty, the late effects of combat-related injury, and alteration of the natural aging processes.