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To examine the functioning of military service members 5 years after completing a randomized controlled trial (RCT) of cognitive rehabilitation for mild traumatic brain injury (mTBI).Home-based telephonic interview and internet-based self-ratings.Sixty-nine of the 126 (55%) active-duty service members who were enrolled in a 4-arm RCT of cognitive rehabilitation 3 to 24 months after mTBI and were successfully contacted by phone 5 years later. Original and 5-year follow-up participants in each of 4 RCT treatment arms included: psychoeducation ( n = 32 original, n = 17 follow-up), computer ( n = 30 original, n = 11 follow-up), therapist-directed ( n = 30 original, n = 23 follow-up), integrated ( n = 34 original, n = 18 follow-up).Inception cohort evaluated 5 years after completion of an RCT of cognitive rehabilitation.Postconcussion symptoms (Neurobehavioral Symptom Inventory total score), psychological distress (Symptom Checklist-90-revised Global Severity Index score), and functional cognitive/behavioral symptoms (Key Behaviors Change Inventory total average score).Participants' postconcussive symptoms and psychological distress improved at the 5-year follow-up. Functional cognitive/behavioral symptoms were not significantly improved, but therapeutic gains were maintained across time, to 5 years after completing the RCT.In this sample of military personnel, postconcussive symptoms and psychological distress significantly improved from posttreatment to 5 years after cognitive rehabilitation, regardless of treatment arm. Functional cognitive/behavioral symptoms significantly improved with treatment while treatment gains were maintained at the 5-year follow-up. Replication of these results with a larger sample and interim data between 18 weeks and 5 years post-treatment is needed.

Background and ObjectivesRecent 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.MethodsA 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.ResultsData 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.DiscussionIndividuals 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.

To determine whether cognitive and psychological symptom profiles differentiate clinical diagnostic classifications (eg, history of mild traumatic brain injury [mTBI] and posttraumatic stress disorder [PTSD]) in military personnel.US Active-Duty Service Members ( N = 209, 89% male) with a history of mTBI ( n = 56), current PTSD ( n = 23), combined mTBI + PTSD ( n = 70), or orthopedic injury controls ( n = 60) completed a neuropsychological battery assessing cognitive and psychological functioning. Latent profile analysis was performed to determine how neuropsychological outcomes of individuals clustered together. Diagnostic classifications (ie, mTBI, PTSD, mTBI + PTSD, and orthopedic injury controls) within each symptom profile were examined.A 5-profile model had the best fit. The profiles differentiated subgroups with high (34.0%) or normal (21.5%) cognitive and psychological functioning, cognitive symptoms (19.1%), psychological symptoms (15.3%), and combined cognitive and psychological symptoms (10.0%). The symptom profiles differentiated participants as would generally be expected. Participants with PTSD were mainly represented in the psychological symptom subgroup, while orthopedic injury controls were mainly represented in the high-functioning subgroup. Further, approximately 79% of participants with comorbid mTBI and PTSD were represented in a symptomatic group (∼24% = cognitive symptoms, ∼29% = psychological symptoms, and 26% = combined cognitive/psychological symptoms). Our results also showed that approximately 70% of military personnel with a history of mTBI were represented in the high- and normal-functioning groups.These results demonstrate both overlapping and heterogeneous symptom and performance profiles in military personnel with a history of mTBI, PTSD, and/or mTBI + PTSD. The overlapping profiles may underscore why these diagnoses are often difficult to diagnose and treat, but suggest that advanced statistical models may aid in identifying profiles representing symptom and cognitive performance impairments within patient groups and enable identification of more effective treatment targets.

OBJECTIVES: The objective of this work was to assess TBI-related risks factors for early-onset dementia (EOD). BACKGROUND: Young Post-9/11 Veterans may be at elevated risk for EOD because they experience high rates of traumatic brain injury (TBI) in early/mid adulthood. However, few studies have explored the longitudinal relationship between traumatic brain injury (TBI) and the emergence of EOD subtypes. METHODS: This matched case-control study used data from the Veterans Health Administration (VHA) to identify Veterans with EOD. To address the low positive predictive value (PPV=0.27) of dementia algorithms in VHA records, we identified Alzheimer’s disease (AD) and frontotemporal dementia (FTD) with PPV of 0.88 and 0.96 as our outcomes. Logistic regression was employed to assess the adjusted risks for dementia subtypes. RESULTS: The EOD cohort was comprised of Veterans with AD (n=689) and FTD (n=284). There were no significant demographic differences between the EOD cohort and their matched controls. After adjustment, EOD odds ratio increased given prior history of TBI (OR: 3.05, 2.42–3.83). Other significant prior exposures included epilepsy (OR: 4.8, 3.3–6.97), other neurological conditions (OR: 2.0, 1.35–2.97), depression (OR: 1.35, 1.12–1.63) and cardiac disease (OR: 1.36, 1.1–1.67). CONCLUSION: Post-9/11 Veterans have higher odds of EOD following TBI. A sensitivity analysis across TBI severity confirmed this trend, indicating that the odds for both AD and FTD increased after more severe TBIs.

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. 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. 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. 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.

Neuroimaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) have been widely adopted in the clinical diagnosis and management of traumatic brain injury (TBI), particularly at the more acute and severe levels of injury. Additionally, a number of advanced applications of MRI have been employed in TBI-related clinical research with great promise, and researchers have used these techniques to better understand underlying mechanisms, progression of secondary injury and tissue perturbation over time, and relation of focal and diffuse injury to later outcome. However, the acquisition and analysis time, the cost of these and other imaging modalities, and the need for specialized expertise have represented historical barriers in extending these tools in clinical practice. While group studies are important in detecting patterns, heterogeneity among patient presentation and limited sample sizes from which to compare individual level data to well-developed normative data have also played a role in the limited translatability of imaging to wider clinical application. Fortunately, the field of TBI has benefitted from increased public and scientific awareness of the prevalence and impact of TBI, particularly in head injury related to recent military conflicts and sport-related concussion. This awareness parallels an increase in federal funding in the United States and other countries allocated to investigation in these areas. In this article we summarize funding and publication trends since the mainstream adoption of imaging in TBI to elucidate evolving trends and priorities in the application of different techniques and patient populations. We also review recent and ongoing efforts to advance the field through promoting reproducibility, data sharing, big data analytic methods, and team science. Finally, we discuss international collaborative efforts to combine and harmonize neuroimaging, cognitive, and clinical data, both prospectively and retrospectively. Each of these represent unique, but related, efforts that facilitate closing gaps between the use of advanced imaging solely as a research tool and the use of it in clinical diagnosis, prognosis, and treatment planning and monitoring.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.TeaserWe present a global effort to devise harmonization procedures necessary to meaningfully leverage big data.

Traumatic brain injury (TBI), a significant concern in military populations, is associated with alterations in brain structure and function, cognition, as well as physical and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) is particularly sensitive to changes in brain structure following TBI, as alterations in white matter (WM) microstructure are common. However, dMRI studies in mild TBI (mTBI) are conflicting, likely due to relatively small samples, sample heterogeneity (demographics, pre- and comorbidities) and injury characteristics (mechanism; chronicity). Furthermore, few studies account for brain asymmetry, which may impact cognitive functions subserved by WM tracts. Examining brain asymmetry in large samples may increase sensitivity to detect heterogeneous areas of subtle WM alteration in mTBI.Through the Enhancing Neuroimaging and Genetics through Meta-analysis (ENIGMA) 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=2,598; 2,321 males/277 females; age 19-85 years). 1,080 reported a deployment-related TBI, 480 had a history of only non-military-related TBI, 823 reported no history of TBI, and 215 did not differentiate between military and non-military TBI. dMRI data were processed in a harmonized manner along with harmonized demographic, injury, psychiatric, and cognitive measures. Hemispheric asymmetry of fractional anisotropy (FA, a common proxy for myelin organization) was calculated for 19 WM tracts and compared between those with and without TBI history.FA in the cingulum showed greater asymmetry in individuals with a history of deployment-related TBI; this effect was driven by greater left lateralization in the group with TBI. There was a trend towards lower FA of the right cingulum in the TBI group. These results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness and were driven primarily by individuals who had sustained their worst TBI before age 40. We further found that alterations in the cingulum were associated with slower processing speed and poorer set shifting.The results indicate an enhancement of the previously reported natural left laterality, possibly due to vulnerability of the non-dominant 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.

While traditionally ignored as a region purely responsible for motor function, the cerebellum is increasingly being appreciated for its contributions to higher order functions through various cerebro-cerebellar networks. Traumatic brain injury (TBI) research generally focuses on the cerebrum, in part because acute pathology is not found in the cerebellum as often. Acute pathology is an important predictor of outcome, but neural disruption also evolves over time in ways that have implications for daily-life functioning. Here we examine these changes in a multi-modal, multi-cohort study.Combining 12 datasets from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Pediatric msTBI (moderate-severe TBI) working group, we measured volume of the total cerebellum and 17 subregions using a state-of-the-art, deep learning-based approach for automated parcellation in 598 children and adolescents with or without TBI (msTBI; n = 314 | non-TBI; n = 284; age M = 14.0 ± 3.1 years). Further, we investigated brain-behavior relations between cerebellar volumes and a measure of executive functioning (i.e., Behavioral Rating Inventory of Executive Function [BRIEF]). In a subsample with longitudinal data, we then assessed whether late changes in cerebellar volume were associated with early white matter microstructural organization using diffusion tensor imaging (DTI).Significantly smaller total cerebellar volume was observed in the msTBI group (Cohen’sd= −0.37). In addition, lower regional cerebellar volume was found in posterior lobe regions including crus II, lobule VIIB, lobule VIIIB, vermis VII, and IX (Cohen’sdrange = −0.22 to −0.43). Smaller cerebellum volumes were associated with more parent-reported executive function problems. These alterations were primarily driven by participants in the chronic phase of injury (> 6 months). In a subset of participants with longitudinal data (n = 80), we found evidence of altered growth in total cerebellum volume, with younger msTBI participants showing secondary degeneration in the form of volume reductions, and older participants showing disrupted development reflected in slower growth rates. Changes in total cerebellum volume over time were also associated with white matter microstructural organization in the first weeks and months post-injury, such that poorer white matter organization in the first months post-injury was associated with decreases in volume longitudinally.Pediatric msTBI was characterized by smaller cerebellar volumes, primarily in the posterior lobe and vermis. The course of these alterations, along with group differences in longitudinal volume changes as well as injury-specific associations between DTI measures and volume changes, is suggestive of secondary cerebellar atrophy, possibly related to supra-tentorial lesions, and/or disruption in cerebellar structural and functional circuits. Moreover, evidence for robust brain-behavior relationships underscore the potential cognitive and behavioral consequences of cerebellar disruption during a critical period of brain development.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) commonly occur among military Service Members and Veterans and have heterogenous, but also overlapping symptom presentations, which often complicate the diagnoses of underlying impairments and development of effective treatment plans. Thus, we sought to examine whether the combination of whole brain gray matter (GM) and white matter (WM) structural measures with neuropsychological performance can aid in the classification of military personnel with mTBI and PTSD.Active-Duty US Service Members (n = 156; 87.8% male) with a history of mTBI, PTSD, combined mTBI+PTSD, or orthopedic injury completed a neuropsychological battery and T1- and diffusion-weighted structural neuroimaging. Cortical, subcortical, ventricular, and WM volumes and whole brain fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were calculated. Latent profile analyses were performed to determine how the GM and WM indicators, together with neuropsychological indicators, classified individuals.For both GM and WM, respectively, a 4-profile model was the best fit. The GM model identified greater ventricular volumes in Service Members with cognitive symptoms, including those with a diagnosis of mTBI, either alone or with PTSD. The WM model identified reduced FA and elevated RD in those with psychological symptoms, including those with PTSD or mTBI and comorbid PTSD. However, contrary to expectation, a global neural signature unique to those with comorbid mTBI and PTSD was not identified.The findings demonstrate that neuropsychological performance alone is more robust in differentiating Active-Duty Service Members with mTBI and PTSD, whereas global neuroimaging measures do not reliably differentiate between these groups.

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.

BackgroundThe cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions.MethodsWe quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640; Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate (p-FDR< .05).ResultsPTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (allp-FDR< 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status.ConclusionsThese findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

While outcome from mild traumatic brain injury (mTBI) is generally favorable, concern remains over potential negative long-term effects, including impaired cognition. This study examined the link between cognitive performance and remote mTBIs within the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) multicenter, observational study of Veterans and service members (SMs) with combat exposure.Baseline data of the participants passing all cognitive performance validity tests (Neither of the mTBI positive groups differed from the mTBI negative control group on any of the cognitive domains in multivariable analyses. Findings were also consistently negative across sensitivity analyses (e.g., mTBIs as a continuous variable, number of blast-related mTBIs, or years since the first and last mTBI).Our findings demonstrate that the average veteran or SM who experienced one or more mTBIs does not have postacute objective cognitive deficits due to mTBIs alone. A holistic health care approach including comorbidity assessment is indicated for patients reporting chronic cognitive difficulties after mTBI(s), and strategies for addressing misattribution may be beneficial. Future study is recommended with longitudinal designs to assess within-subjects decline from potential neurodegeneration. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

ImportanceTraumatic brain injury (TBI) was common among US service members deployed to Iraq and Afghanistan. Although there is some evidence to suggest that TBI increases the risk of cardiovascular disease (CVD), prior reports were predominantly limited to cerebrovascular outcomes. The potential association of TBI with CVD has not been comprehensively examined in post-9/11–era veterans.ObjectiveTo determine the association between TBI and subsequent CVD in post-9/11–era veterans.Design, Setting, and ParticipantsThis was a retrospective cohort study conducted from October 1, 1999, to September 30, 2016. Participants were followed up until December 31, 2018. Included in the study were administrative data from the US Department of Veterans Affairs and the Department of Defense from the Long-term Impact of Military-Relevant Brain Injury Consortium–Chronic Effects of Neurotrauma Consortium. Participants were excluded if dates did not overlap with the study period. Data analysis was conducted between November 22, 2021, and June 28, 2022.ExposuresHistory of TBI as measured by diagnosis in health care records.Main Outcomes and MeasuresComposite end point of CVD: coronary artery disease, stroke, peripheral artery disease, and cardiovascular death.ResultsOf the 2 530 875 veterans from the consortium, after exclusions, a total of 1 559 928 veterans were included in the analysis. A total of 301 169 veterans (19.3%; median [IQR] age, 27 [23-34] years; 265 217 male participants [88.1]) with a TBI history and 1 258 759 veterans (80.7%; median [IQR] age, 29 [24-39] years; 1 012 159 male participants [80.4%]) without a TBI history were included for analysis. Participants were predominately young (1 058 054 [67.8%] P P P Conclusions and RelevanceResults of this cohort study suggest that US veterans with a TBI history were more likely to develop CVD compared with veterans without a TBI history. Given the relatively young age of the cohort, these results suggest that there may be an increased burden of CVD as these veterans age and develop other CVD risk factors. Future studies are needed to determine if the increased risk associated with TBI is modifiable.

The variety of instruments used to assess posttraumatic stress disorder (PTSD) allows for flexibility, but also creates challenges for data synthesis. The objective of this work was to use a multisite mega analysis to derive quantitative recommendations for equating scores across measures of PTSD severity.Empirical Bayes harmonization and linear models were used to describe and mitigate site and covariate effects. Quadratic models for converting scores across PTSD assessments were constructed using bootstrapping and tested on hold out data.We aggregated 17 data sources and compiled anThese methods allow PTSD symptom severity to be placed on multiple scales and offers interesting empirical perspectives on the role of harmonization in the behavioral sciences. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mild traumatic brain injury (mTBI) is highly prevalent in military populations, with many service members suffering from long-term symptoms. Posttraumatic stress disorder (PTSD) often co-occurs with mTBI and predicts worse clinical outcomes. Functional neuroimaging research suggests there are both overlapping and distinct patterns of resting-state functional connectivity (rsFC) in mTBI versus PTSD. However, few studies have directly compared rsFC of cortical networks in military service members with these two conditions. In the present study, U.S. service members (n = 137; ages 19–59; 120 male) underwent resting-state fMRI scans. Participants were divided into three study groups: mTBI only, PTSD only, and orthopedically injured (OI) controls. Analyses investigated group differences in rsFC for cortical networks: default mode (DMN), frontoparietal (FPN), salience, somatosensory, motor, auditory, and visual. Analyses were family-wise error (FWE) cluster-corrected and Bonferroni-corrected for number of network seeds regions at the whole brain level (pFWE

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium brings together researchers from around the world to try to identify the genetic underpinnings of brain structure and function, along with robust, generalizable effects of neurological and psychiatric disorders. The recently-formed ENIGMA Brain Injury working group includes 10 subgroups, based largely on injury mechanism and patient population. This introduction to the special issue summarizes the history, organization, and objectives of ENIGMA Brain Injury, and includes a discussion of strategies, challenges, opportunities and goals common across 6 of the subgroups under the umbrella of ENIGMA Brain Injury. The following articles in this special issue, including 6 articles from different subgroups, will detail the challenges and opportunities specific to each subgroup.

The Center for Disease Control and Prevention (CDC)'s 2018 Guideline for current practices in pediatric mild traumatic brain injury (mTBI; also referred to as concussion herein) systematically identified the best up-to-date practices based on current evidence and, specifically, identified recommended practices regarding computed tomography (CT), magnetic resonance imaging (MRI), and skull radiograph imaging. In this article, we discuss types of neuroimaging not discussed in the guideline in terms of their safety for pediatric populations, their potential application, and the research investigating the future use of certain modalities to aid in the diagnosis and treatment of mTBI in children. The role of neuroimaging in pediatric mTBI cases should be considered for the potential contribution to children's neural and social development, in addition to the immediate clinical value (as in the case of acute structural findings). Selective use of specific neuroimaging modalities in research has already been shown to detect aspects of diffuse brain injury, disrupted cerebral blood flow, and correlate physiological factors with persistent symptoms, such as fatigue, cognitive decline, headache, and mood changes, following mTBI. However, these advanced neuroimaging modalities are currently limited to the research arena, and any future clinical application of advanced imaging modalities in pediatric mTBI will require robust evidence for each modality's ability to provide measurement of the subtle conditions of brain development, disease, damage, or degeneration, while accounting for variables at both non-injury and time-post-injury epochs. Continued collaboration and communication between researchers and healthcare providers is essential to investigate, develop, and validate the potential of advanced imaging modalities in pediatric mTBI diagnostics and management.

Objective The study objective was to determine whether number of concussions would affect symptom improvement following cognitive rehabilitation (CR) interventions. Method Service members (N = 126) with concussion history completed a 6-week randomized control trial of CR interventions. Participants were stratified based on self-reported lifetime concussion frequency. Outcome measures included the Paced Auditory Serial Addition Test (PASAT), the Global Severity Index (GSI) from the Symptom Checklist-90-Revised, and the Key Behaviors Change Inventory (KBCI). Results Mixed-model analyses of variance revealed a significant main effect for time on cognitive, psychological, and neurobehavioral functioning. A significant main effect for the number of concussions was observed for GSI and KBCI, but not PASAT. Interactions between the number of concussions and time were not significant for any of the outcome variables. Conclusions Over the 6-week interval, improvements were found for all participants across all outcome measures. Number of concussions did not affect improvements over time.

Traumatic brain injury (TBI) is a major cause of death and disability in children in both developed and developing nations. Children and adolescents suffer from TBI at a higher rate than the general population, and specific developmental issues require a unique context since findings from adult research do not necessarily directly translate to children. Findings in pediatric cohorts tend to lag behind those in adult samples. This may be due, in part, both to the smaller number of investigators engaged in research with this population and may also be related to changes in safety laws and clinical practice that have altered length of hospital stays, treatment, and access to this population. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric Moderate/Severe TBI (msTBI) group aims to advance research in this area through global collaborative meta-analysis of neuroimaging data. In this paper, we discuss important challenges in pediatric TBI research and opportunities that we believe the ENIGMA Pediatric msTBI group can provide to address them. With the paucity of research studies examining neuroimaging biomarkers in pediatric patients with TBI and the challenges of recruiting large numbers of participants, collaborating to improve statistical power and to address technical challenges like lesions will significantly advance the field. We conclude with recommendations for future research in this field of study.

Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are prevalent among military populations, and both have been associated with working memory (WM) impairments. Previous resting-state functional connectivity (rsFC) research conducted separately in PTSD and mTBI populations suggests that there may be similar and distinct abnormalities in WM-related networks. However, no studies have compared rsFC of WM brain regions in participants with mTBI versus PTSD. We used resting-state fMRI to investigate rsFC of WM networks in U.S. Service Members (n = 127; ages 18-59) with mTBI only (n = 46), PTSD only (n = 24), and an orthopedically injured (OI) control group (n = 57). We conducted voxelwise rsFC analyses with WM brain regions to test for differences in WM network connectivity in mTBI versus PTSD. Results revealed reduced rsFC between ventrolateral prefrontal cortex (vlPFC), lateral premotor cortex, and dorsolateral prefrontal cortex (dlPFC) WM regions and brain regions in the dorsal attention and somatomotor networks in both mTBI and PTSD groups versus controls. When compared to those with mTBI, individuals with PTSD had lower rsFC between both the lateral premotor WM seed region and middle occipital gyrus as well as between the dlPFC WM seed region and paracentral lobule. Interestingly, only vlPFC connectivity was significantly associated with WM performance across the samples. In conclusion, we found primarily overlapping patterns of reduced rsFC in WM brain regions in both mTBI and PTSD groups. Our finding of decreased vlPFC connectivity associated with WM is consistent with previous clinical and neuroimaging studies. Overall, these results provide support for shared neural substrates of WM in individuals with either mTBI or PTSD.

The ENIGMA‐DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder‐oriented working groups used the ENIGMA‐DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA‐defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross‐diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large‐scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross‐diagnosis features.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n= 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q&nbsp

INTRODUCTION: Impairments in cognitive performance after sports-related concussion (SRC) typically resolve within weeks of the injury, whereas alterations to white matter (WM) organization have been found to persist longer into the chronic injury stage. However, longer-term associations between cognition and WM organisation following SRC have not been studied. The objective of this study was to compare WM organisation and cognitive performance in collegiate athletes an average of almost 4 years post-SRC to athletes with no history of SRC. METHOD: National Collegiate Athletic Association Division III athletes (n = 71, age = 19.3 +/− 1.2; 14 with self-reported SRC) completed a neurocognitive assessment and diffusion tensor imaging (DTI). WM organisation was assessed by extracting measures of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) from 20 WM regions of interest (ROIs). Multivariate partial least squares analyses were used to compare athletes with and without a history of SRC and assess relationships between DTI-derived metrics of WM organisation and cognitive measures. RESULTS: Cognitive performance and ROI metrics did not differ between athletes with and without prior SRC. However, among athletes with a history of SRC, better executive function, processing speed, and memory but worse choice reaction time were associated with higher FA and lower MD and RD in several WM tracts. CONCLUSION: Athletes with a history of SRC demonstrated greater associations between cognitive performance and WM organization, but also variability in the domains showing associations. Taken together, the findings demonstrate the importance of examining brain-behaviour relationships several years after SRC to better gauge how WM organisation supports cognition.

Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose of this study was to characterize fatigue following deployment using the Multidimensional Fatigue Inventory (MFI), a multidimensional self-report instrument. The study was developed to test the hypothesis that if fatigue involves disrupted effort/reward processing, this should manifest as altered basal ganglia functional connectivity as observed in other amotivational states.Twenty-eight current and former servicemembers were recruited and completed the MFI. All 28 participants had a history of at least one mTBI during deployment. Twenty-six participants underwent resting-state functional MRI. To test the hypothesis that fatigue was associated with basal ganglia functional connectivity, the investigators measured correlations between MFI subscale scores and the functional connectivity of the left and right caudate, the putamen, and the globus pallidus with the rest of the brain, adjusting for the presence of depression.The investigators found a significant correlation between functional connectivity of the left putamen and bilateral superior frontal gyri and mental fatigue scores. No correlations with the other MFI subscales survived multiple comparisons correction.This exploratory study suggests that mental fatigue in military servicemembers with a history of deployment with at least one mTBI may be related to increased striatal-prefrontal functional connectivity, independent of depression. A finding of effort/reward mismatch may guide future treatment approaches.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,426 individuals with PTSD and 1,621 controls (2174 males/873 females) between ages 18–83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen’s d=−0.11, p=0.0055). The tapetum connects the left and right hippocampus, structures for which structure and function have been consistently implicated in PTSD. Results remained significant/similar after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Background and ObjectivesEpilepsy is defined by the occurrence of multiple unprovoked seizures, but quality of life (QOL) in people with epilepsy is determined by multiple factors, in which psychiatric comorbid conditions play a pivotal role. Therefore, understanding the interplay between comorbid conditions and QOL across epilepsy phenotypes is an important step toward improved outcomes. Here, we report the impact of QOL across distinct epilepsy phenotypes in a cohort of post-9/11 veterans with high rates of traumatic brain injury (TBI).MethodsThis observational cohort study from the Veterans Health Administration included post-9/11 veterans with epilepsy. A process integrating an epilepsy identification algorithm, chart abstraction, and self-reported measures was used to classify patients into 1 of 4 groups: (1) epilepsy controlled with medications, (2) drug-resistant epilepsy (DRE), (3) posttraumatic epilepsy (PTE), or (4) drug-resistant PTE (PT-DRE). Summary scores for 6 QOL measures were compared across the groups after adjustment for age, sex, and number of comorbid conditions.ResultsA total of 529 survey respondents with epilepsy were included in the analysis: 249 controls (i.e., epilepsy without DRE or PTE), 124 with DRE, 86 with PTE, and 70 with PT-DRE. DRE was more common in those with PTE compared with those with nontraumatic epilepsy (45% vs 33%, odds ratio 1.6 [95% CI 1.1–2.4], p = 0.01). Patients with PTE and PT-DRE had significantly more comorbid conditions in health records than those with nontraumatic epilepsy. Those with both PTE and DRE reported the lowest QOL across all 6 measures, and this persisted after adjustment for comorbid conditions and in further linear analyses.DiscussionAmong those with PTE, DRE prevalence was significantly higher than prevalence of nontraumatic epilepsies. PTE was also associated with higher burden of comorbidity and worse overall QOL compared to nontraumatic epilepsies. People with PTE are distinctly vulnerable to the comorbid conditions associated with TBI and epilepsy. This at-risk group should be the focus of future studies aimed at elucidating the factors associated with adverse health outcomes and developing antiepileptogenic therapies.

Automated neuroimaging methods like FreeSurfer ( https://surfer.nmr.mgh.harvard.edu/ ) have revolutionized quantitative neuroimaging analyses. Such analyses provide a variety of metrics used for image quantification, including magnetic resonance imaging (MRI) volumetrics. With the release of FreeSurfer version 6.0, it is important to assess its comparability to the widely-used previous version 5.3. The current study used data from the initial 249 participants in the ongoing Chronic Effects of Neurotrauma Consortium (CENC) multicenter observational study to compare the volumetric output of versions 5.3 and 6.0 across various regions of interest (ROI). In the current investigation, the following ROIs were examined: total intracranial volume, total white matter volume, total ventricular volume, total gray matter volume, and right and left volumes for the thalamus, pallidum, putamen, caudate, amygdala and hippocampus. Absolute ROI volumes derived from FreeSurfer 6.0 differed significantly from those obtained using version 5.3. We also employed a clinically-based evaluation strategy to compare both versions in their prediction of age-mediated volume reductions (or ventricular increase) in the aforementioned structures. Statistical comparison involved both general linear modeling (GLM) and random forest (RF) methods, where cross-validation error was significantly higher using segmentations from FreeSurfer version 5.3 versus version 6.0 (GLM: t = 4.97, df = 99, p value = 2.706e-06; RF: t = 4.85, df = 99, p value = 4.424e-06). Additionally, the relative importance of ROIs used to predict age using RFs differed between FreeSurfer versions, indicating substantial differences in the two versions. However, from the perspective of correlational analyses, fitted regression lines and their slopes were similar between the two versions, regardless of version used. While absolute volumes are not interchangeable between version 5.3 and 6.0, ROI correlational analyses appear to yield similar results, suggesting the interchangeability of ROI volume for correlational studies.

Objective: While Spencer's verbal incidental learning (IL) task-from Vocabulary and Similarities subtests of the WAIS-has been validated relative to traditional memory measures and Alzheimer's disease (AD) pathology, the effectiveness of the particular scoring method used has not been assessed relative to alternative scoring weightings. The purpose of this study was to compare original and alternative scoring methods of this IL task by using an AD biomarker-benchmark to arrive at an optimal approach. Methods: Fifty-five memory-clinic patients aged 59-87 received neuropsychological assessment, measures of IL, and quantitative brain imaging. Partial correlation coefficients with total hippocampal volume-controlling for age, sex, and intracranial volume-were assessed across several IL scoring methods, and partial correlations with measures of memory were examined to evaluate convergent validity.Results: IL scoring methods maximizing the contribution of paired-associate-recall-performance were significantly correlated with both hippocampal volumes and traditional memory measures, whereas discrimination-emphasized scoring methods were not.Conclusions: IL scoring methods emphasizing memory paired-associate recall appeared to be preferable to those emphasizing memory discrimination. Administration of the IL- Similarities subtest alone, without IL- Vocabulary, may strike a balance between strength of relationships with both hippocampal volumes and standard memory measures, while also limiting administration time.

Proton ((1)H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo (1)H magnetic resonance spectroscopy and review (1)H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic (1)H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of (1)H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.

Introduction Sporadic duodenal adenomas (SDAs) are a rare but important finding at gastroscopy due to their malignant potential. Although endoscopic resection (ER) is generally advocated this carries significant risk related to the relatively thin, vascular and fixed duodenal wall. The lack of guidelines related to SDAs leads to variability in their management with potential implications for patient outcomes. This descriptive study aimed to evaluate current practice regarding the management of non-ampullary SDAs and assess the need for a consensus. Methods 40 internationally renowned advanced endoscopists from multiple international centres were surveyed regarding their management of non-ampullary SDAs. 12 questions investigating factors influencing whether to offer ER, pre-ER work-up, procedural risk and post-ER management were evaluated. Results The survey was completed by 19 endoscopists with 18 confirming they endoscopically manage non-ampullary SDAs. Most endoscopists offered ER on a case-by-case basis with patient age (72%), comorbidities (44%) and lesion size (39%) reported as integral to decision making. No guidelines were used by 94% but multi-disciplinary team discussion prior to ER was arranged routinely by 67% and in select cases by 22% of endoscopists. Endoscopists completed further investigation prior to ER including endoscopic ultrasound (39%) and cross-sectional imaging (22%). The degree of risk involved in duodenal resection quoted to patients including haemorrhage (range 1–50%, median 15%) and perforation (0.7–10%, median 3%) was variable. Both anti-coagulation and anti-platelets were restarted a median of 3 days (IQR 2–7 days) following duodenal resection. Post-procedural proton pump inhibitors (PPIs) were routinely prescribed by 94% of endoscopists however therapy duration was variable (median 29 days, IQR 14–30 days). Post-procedure patients were admitted routinely by 39% and in specific cases by 56% of endoscopists. Two endoscopists reported prescribing rectal non-steroidal anti-inflammatory drugs following ER of D2 adenomas. Conclusions There is widespread variability in the pre- and post-procedural management of non-ampullary SDAs in major international centres. The majority of endoscopists manage patients on a case by case basis following MDT discussion and advocate PPI therapy post resection. There is a need to develop a consensus of opinion to help standardise the management of non-ampullary SDAs

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

ObjectiveOur study addressed aims (1) to test the hypothesis that moderate-severe traumatic brain injury (TBI) in pediatric patients is associated with widespread white matter (WM) disruption, (2) to test the hypothesis that age and sex affect WM organization after injury, and (3) to examine associations between WM organization and neurobehavioral outcomes.MethodsData from 10 previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Pediatric Moderate/Severe TBI (msTBI) working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline.ResultsFive hundred seven children and adolescents (244 with complicated msTBI and 263 controls) were included. Patients were clustered into 3 postinjury intervals: acute/subacute, ConclusionsWM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically meaningful patient subtypes.

The global burden of mortality and morbidity caused by traumatic brain injury (TBI) is significant, and the heterogeneity of TBI patients and the relatively small sample sizes of most current neuroimaging studies is a major challenge for scientific advances and clinical translation. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Adult moderate/severe TBI (AMS-TBI) working group aims to be a driving force for new discoveries in AMS-TBI by providing researchers world-wide with an effective framework and platform for large-scale cross-border collaboration and data sharing. Based on the principles of transparency, rigor, reproducibility and collaboration, we will facilitate the development and dissemination of multiscale and big data analysis pipelines for harmonized analyses in AMS-TBI using structural and functional neuroimaging in combination with non-imaging biomarkers, genetics, as well as clinical and behavioral measures. Ultimately, we will offer investigators an unprecedented opportunity to test important hypotheses about recovery and morbidity in AMS-TBI by taking advantage of our robust methods for large-scale neuroimaging data analysis. In this consensus statement we outline the working group’s short-term, intermediate, and long-term goals. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Annually, approximately 3 million children around the world experience traumatic brain injuries (TBIs), of which up to 20% are characterized as moderate to severe (msTBI) and/or have abnormal imaging findings. Affected children are vulnerable to long-term cognitive and behavioral dysfunction, as injury can disrupt or alter ongoing brain maturation. Post-injury outcomes are highly variable, and there is only limited understanding of how inter-individual differences in outcomes arise. Small sample sizes have also complicated efforts to better understand factors influencing the impact of TBI on the developing brain. White matter (WM) disruption is a critical aspect of TBI neuropathology and diffusion MRI (dMRI) is particularly sensitive to microstructural abnormalities. Here we present the results of a coordinated analysis of dMRI data across ten cohorts from three countries. We had three primary aims: (1) to characterize the nature and extent of WM disruption across key post-injury intervals (acute/subacute - within 2 months, post-acute - 2-6 months, chronic - 6+ months); (2) evaluate the impact of age and sex on WM in the context of injury; and (3) to examine associations between WM and neurobehavioral outcomes. Based on data from 507 children and adolescents (244 with complicated mild to severe TBI and 263 control children), we report widespread WM disruption across all post-injury intervals. As expected, injury severity was a significant contributor to the pattern and extent of WM degradation, but explained less variance in dMRI measures with increasing time since injury, supporting other research indicating that other factors contribute increasingly to outcomes over time. The corpus callosum appears to be particularly vulnerable to injury, an effect that persists years post-TBI. We also report sex differences in the effect of TBI on the uncinate fasciculus (UNC), a structure with a key role in emotion regulation. Females with a TBI had significantly lower fractional anisotropy (FA) in the UNC than those with no TBI, and this phenomenon was further associated with more frequent parent-reported behavioral problems as measured by the Child Behavior Checklist (CBCL). These effects were not detected in males. With future harmonization of imaging and neurocognitive data, more complex modeling of factors influencing outcomes will be possible and help to identify clinically-meaningful patient subtypes.