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.

Discriminating Mild Traumatic Brain Injury and Posttraumatic Stress Disorder Using Latent Neuroimaging and Neuropsychological Profiles in Active-Duty Military Service Members.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

ENIGMA brain injury: Framework, challenges, and opportunities.

Traumatic brain injury (TBI) is a major cause of disability worldwide, but the heterogeneous nature of TBI with respect to injury severity and health comorbidities make patient outcome difficult to predict. Injury severity accounts for only some of this variance, and a wide range of preinjury, injury-related, and postinjury factors may influence outcome, such as sex, socioeconomic status, injury mechanism, and social support. Neuroimaging research in this area has generally been limited by insufficient sample sizes. Additionally, development of reliable biomarkers of mild TBI or repeated subconcussive impacts has been slow, likely due, in part, to subtle effects of injury and the aforementioned variability. The ENIGMA Consortium has established a framework for global collaboration that has resulted in the largest-ever neuroimaging studies of multiple psychiatric and neurological disorders. Here we describe the organization, recent progress, and future goals of the Brain Injury working group.

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury.

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 < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research.

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.

Research Letter: Long-Term Outcomes Following Cognitive Rehabilitation for Mild Traumatic Brain Injury: A 5-Year Follow-Up of a Cohort From the SCORE Randomized Clinical Trial.

OBJECTIVE: 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). SETTING: Home-based telephonic interview and internet-based self-ratings. PARTICIPANTS: 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). DESIGN: Inception cohort evaluated 5 years after completion of an RCT of cognitive rehabilitation. MAIN MEASURES: 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). RESULTS: 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. CONCLUSION: 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.

Latent Neuropsychological Profiles to Discriminate Mild Traumatic Brain Injury and Posttraumatic Stress Disorder in Active-Duty Service Members.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Traumatic Brain Injury and Early Onset Dementia in Post 9-11 Veterans.

OBJECTIVES: To assess traumatic brain injury (TBI)-related risks factors for early-onset dementia (EOD). BACKGROUND: Younger Post-9/11 Veterans may be at elevated risk for EOD due to high rates of TBI in early/mid adulthood. 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, primary outcomes were Alzheimer's disease (AD) and frontotemporal dementia (FTD). Logistic regression identified conditions associated with dementia subtypes. RESULTS: The EOD cohort included 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 was significantly associated with history of TBI (OR: 3.05, 2.42-3.83), 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.

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.

Resting-State Correlations of Fatigue Following Military Deployment.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Health Phenotypes and Neurobehavioral Symptom Severity Among Post-9/11 Veterans With Mild Traumatic Brain Injury: A Chronic Effects of Neurotrauma Consortium Study.

OBJECTIVE: To evaluate whether neurobehavioral symptoms differ between groups of veterans with mild traumatic brain injury (mTBI) classified by health characteristics. PARTICIPANTS: A total of 71 934 post-9/11 veterans with mTBI from the Chronic Effects of Neurotrauma Consortium Epidemiology warfighter cohort. DESIGN: Cross-sectional analysis of retrospective cohort. MAIN MEASURES: Health phenotypes identified using latent class analysis of health and function over 5 years. Symptom severity measured using Neurobehavioral Symptom Inventory; domains included vestibular, somatic, cognitive, and affective. RESULTS: Veterans classified as moderately healthy had the lowest symptom burden while the polytrauma phenotype group had the highest. After accounting for sociodemographic and injury characteristics, polytrauma phenotype veterans had about 3 times the odds of reporting severe symptoms in each domain compared with moderately healthy veterans. Those veterans who were initially moderately healthy but whose health declined over time had about twice the odds of severe symptoms as consistently healthier Veterans. The strongest associations were in the affective domain. Compared with the moderately healthy group, veterans in other phenotypes were more likely to report symptoms substantially interfered with their daily lives (odds ratio range: 1.3-2.8). CONCLUSION: Symptom severity and interference varied by phenotype, including between veterans with stable and declining health. Ameliorating severe symptoms, particularly in the affective domain, could improve health trajectories following mTBI.

Self-efficacy predicts response to cognitive rehabilitation in military service members with post-concussive symptoms.

This study examined whether self-efficacy differentiated treatment responders from non-responders in a trial of cognitive rehabilitation (CR) for postconcussive symptoms. 126 service members with mild TBI seen on average 9.5 months since injury completed one of four cognitive rehabilitation treatments for 6 weeks. The four treatment arms were: (1) Psychoeducation control, (2) Self-administered computerized CR, (3) Interdisciplinary CR, and (4) Interdisciplinary CR integrated with CBT. Outcome was assessed across time (baseline, and 6, 12, and 18 weeks post-treatment) for three domains: psychological (Symptom Checklist-90-Revised; SCL-90-R), cognitive (Paced Auditory Serial Addition Test; PASAT), and functional/behavioural (Key Behaviors Change Inventory; KBCI). Mixed model ANOVAs tested for self-efficacy differences across time in treatment responders versus non-responders, as defined by reliable change indices. A significant interaction was found on the SCL-90 such that responders had increasing self-efficacy with respect to psychological symptoms across four time points, whereas non-responders' self-efficacy did not change. Perceived self-efficacy at the beginning of treatment was associated with treatment engagement within the psychological domain for responders only, suggesting a mediating role in treatment outcome. Overall, results suggest that increasing patients' level of self-efficacy may be important for successful treatment of psychological distress in those with remote concussion.

Neuropsychological Performance and Subjective Symptom Reporting in Military Service Members With a History of Multiple Concussions: Comparison With a Single Concussion, Posttraumatic Stress Disorder, and Orthopedic Trauma.

OBJECTIVE: To examine differences in objective neurocognitive performance and subjective cognitive symptoms in individuals with a history of a single concussion, multiple concussions, orthopedic injuries, and posttraumatic stress disorder (PTSD). METHOD: Participants included 116 military service members who sustained a mild traumatic brain injury (mTBI) during combat deployment. Subjects were subdivided into groups based on concussion frequency: a single concussion (n = 42), 2 concussions (n = 21), and 3 or more concussions (n = 53). Eighty-one subjects sustained an orthopedic injury (n = 60) during deployment or were diagnosed with PTSD (n = 21), but had no history of mTBI. Subjects completed a battery of neuropsychological tests and self-report measures of postconcussive symptoms, PTSD symptoms, and psychopathology. RESULTS: No differences were found among the concussion groups on a composite neuropsychological measure. The PTSD group had the highest number of symptom complaints, with the 2-concussion and 3-plus-concussion groups being most similar to the PTSD group. The concussion groups showed a nonsignificant pattern of increasing distress with increasing number of concussions. CONCLUSIONS: The current findings are consistent with meta-analytic results showing no differential effect on neuropsychological functioning due to multiple concussions. Results also support the burden of adversity hypothesis suggesting increasing symptom levels with increasing psychological or physically traumatic exposures.

Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury.

OBJECTIVE: To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. PARTICIPANTS: Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High-dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. RESULTS: Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. CONCLUSION: Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population.

Diffusion Imaging Findings in US Service Members With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

OBJECTIVE: Use diffusion tensor imaging to investigate white matter microstructure attributable to mild TBI (mTBI) and/or posttraumatic stress disorder (PTSD). PARTICIPANTS: Twenty-seven individuals with mTBI only, 16 with PTSD only, 42 with mTBI + PTSD, and 43 service members who sustained orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Clinical diffusion tensor imaging sequence to assess fractional anisotropy, mean, axial, and radial diffusivity within selected regions of interest. RESULTS: Corrected analyses revealed a pattern of lower white matter integrity in the PTSD group for several scalar metrics. Regions affected included primarily right hemisphere areas of the internal capsule. These differences associated with the PTSD only cohort were observed in relation to all 3 comparison groups, while the mTBI + PTSD group did not exhibit any notable pattern of white matter abnormalities. CONCLUSION: Results suggest that lower resolution scan sequences are sensitive to post-acute abnormalities associated with PTSD, particularly in the right hemisphere. In addition, these findings suggest that ongoing PTSD symptoms are associated with differences in white matter diffusion that are more readily detected in a clinical scan sequence than mTBI abnormalities. Future studies are needed to prospectively assess service members prior to onset of injury to verify this pattern of results.

Assessment of quantitative magnetic resonance imaging metrics in the brain through the use of a novel phantom.

OBJECTIVE: Multisite and longitudinal neuroimaging studies are important in uncovering trajectories of recovery and neurodegeneration following traumatic brain injury (TBI) and concussion through the use of diffusion tensor imaging (DTI) and other imaging modalities. This study assessed differences in anisotropic diffusion measurement across four scanners using a human and a novel phantom developed in conjunction with the Chronic Effects of Neurotrauma Consortium. METHOD: Human scans provided measurement within biological tissue, and the novel physical phantom provided measures of anisotropic intra-tubular diffusion to serve as a model for intra-axonal water diffusion. Intra- and inter-scanner measurement variances were compared, and the impact on effect size was calculated. RESULTS: Intra-scanner test-retest reliability estimates for fractional anisotropy (FA) demonstrated relative stability over testing intervals. The human tissue and phantom showed similar FA ranges, high linearity and large within-device effect sizes. However, inter-scanner measures of FA indicated substantial differences, some of which exceeded typical DTI effect sizes in mild TBI. CONCLUSION: The diffusion phantom may be used to better elucidate inter-scanner variability in DTI-based measurement and provides an opportunity to better calibrate results obtained from scanners used in multisite and longitudinal studies. Novel solutions are being evaluated to understand and potentially overcome these differences.

Exploring the factor structure of a battery of neuropsychological assessments among the CENC cohort.

OBJECTIVE: The goal of the Chronic Effects of Neurotrauma Consortium (CENC) study is to explore the effects of concussions among Service Members and Veterans. A factor model was fit to selected neuropsychological measures to identify potentially useful relationships between assessments collected on CENC-enrolled participants. METHOD: 492 post-9/11 participants with combat exposure were enrolled across four VA study sites. Participants completed assessments including concussion history, neurocognitive functioning, and self-report questionnaires. Exploratory factor analyses (EFA) using four different methods with varimax and promax rotations were used to analyse the cognitive variables. Final model selection was based on factor loadings towards simple structure. RESULTS: The scree plot suggested the number of factors to be extracted was between 4 and 5. EFA produced a 5-factor MINRES model with promax rotation that resulted in a factor loading with variables loading on only one factor with a predefined threshold (0.40). Variables loaded on five cognition domains: list learning, working memory/executive skills, cognitive control, fluency, and memory. CONCLUSION: These results provide reasonable evidence that data collected from the CENC neuropsychological battery can be reduced to five clinically useful factors. This will enable us to use the factors for further study of the impact of concussion on neurodegeneration.

Functional brain connectivity and cortical thickness in relation to chronic pain in post-911 veterans and service members with mTBI.

OBJECTIVES: Investigate the relation of chronic pain interference to functional connectivity (FC) of brain regions and to cortical thickness in post-911 Veterans and Service Members (SMs) who sustained a mild traumatic brain injury (mTBI). METHODS: This is an observational study with cross-sectional analyses. A sample of 65 enrollees completing initial evaluation at a single site of the Chronic Effects of Neurotrauma Consortium (CENC) reported pain interference ratings on the TBI QOL. Functional connectivity and cortical thickness were measured. RESULTS: Severity of pain interference was negatively related to FC of the default mode network (DMN), i.e., participants who reported more severe pain interference had less FC between mesial prefrontal cortex and posterior regions of the DMN including posterior cingulate cortex and precuneus. Cortical thickness of specific regions was positively related to severity of pain interference. CONCLUSION: The more that pain was perceived to interfere with daily life, the less the FC between regions in a network associated with self-referential thought and mind wandering. Although cortical thickness in specific brain regions was positively related to severity of pain interference, follow-up longitudinal data, control group data, and study of individual differences in this cohort will expand this initial report and replicate these findings.

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.

Cognitive Rehabilitation for Military Service Members With Mild Traumatic Brain Injury: A Randomized Clinical Trial.

OBJECTIVE: To compare cognitive rehabilitation (CR) interventions for mild traumatic brain injury (mTBI) with standard of care management, including psychoeducation and medical care for noncognitive symptoms. SETTING: Military medical center. PARTICIPANTS: A total of 126 service members who received mTBI from 3 to 24 months before baseline evaluation and reported ongoing cognitive difficulties. INTERVENTIONS: Randomized clinical trial with treatment outcomes assessed at baseline, 3-week, 6-week, 12-week, and 18-week follow-ups. Participants were randomly assigned to one of four 6-week treatment arms: (1) psychoeducation, (2) computer-based CR, (3) therapist-directed manualized CR, and (4) integrated therapist-directed CR combined with cognitive-behavioral psychotherapy (CBT). Treatment dosage was constant (10 h/wk) for intervention arms 2 to 4. MEASURES: Paced Auditory Serial Addition Test (PASAT); Symptom Checklist-90 Revised (SCL-90-R); Key Behaviors Change Inventory (KBCI). RESULTS: No differences were noted between treatment arms on demographics, injury-related characteristics, or psychiatric comorbidity apart from education, with participants assigned to the computer arm having less education. Using mixed-model analysis of variance, all 4 treatment groups showed a significant improvement over time on the 3 primary outcome measures. Treatment groups showed equivalent improvement on the PASAT. The therapist-directed CR and integrated CR treatment groups had better KBCI outcomes compared with the psychoeducation group. Improvements on primary outcome measures during treatment were maintained at follow-up with no differences among arms. CONCLUSIONS: Both therapist-directed CR and integrated CR with CBT reduced functional cognitive symptoms in service members after mTBI beyond psychoeducation and medical management alone.