Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

MPORTANCE Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. OBJECTIVE To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). DESIGN, SETTING, AND PARTICIPANTS This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. EXPOSURES Remote history of mTBI. MAIN OUTCOMES AND MEASURES White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. RESULTS A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (beta = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (beta = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (beta = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (beta = 5.4 x 10(-3); P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (beta = 4.3 x 10(-4); P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (beta = 1.2 x 10(-3); P = .02). CONCLUSIONS AND RELEVANCE In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

Objective: Determine whether glucose uptake as measured by F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is associated with cognitive performance and cognitive deficits in active duty service members with a history of mild traumatic brain injury (mTBI). Method: 287 patients with a history of mTBI underwent FDG-PET scans at rest and neuropsychological testing at the National Intrepid Center of Excellence at Walter Reed National Military Medical Center. Glucose uptake in the bilateral frontal, parietal, occipital, and temporal lobes, and 58 cortical/cerebellar regions were correlated with seven neuropsychological composite scores, with and without relevant covariates. Results: Perceptual reasoning correlated with bilateral hippocampi glucose uptake (rs = .141-.165, p < .03), processing speed was inversely related to glucose uptake in the left temporal lobe (r = -.134, p = .034), and working memory was related to glucose uptake in the left parietal, temporal, and occipital lobes (rs = .128-.140, p < .05); however, these findings did not survive correction for multiple comparisons. Partial correlations between cognition and the 56 cortical/cerebellar regions of interests were not significant after correction for multiple comparisons. Glucose uptake in the left hippocampus was inversely related to the likelihood of cognitive deficits (OR = .745, p = .041); however, this did not survive correction for multiple comparisons. Conclusions: After correction for multiple comparisons, there was no significant relationship between regional glucose uptake and neurocognitive performance or cognitive deficits. Glucose uptake as measured by FDG-PET is not indicative of cognitive performance in active duty service members with a remote history of mTBI.

This study examines the impact of lifetime blast exposure on white matter integrity in service members and veterans (SMVs). Participants were 227 SMVs, including those with a history of mild traumatic brain injury (mTBI; n?=?124), orthopedic injury controls (n?=?58), and non-injured controls (n?=?45), prospectively enrolled in a Defense and Veterans Brain Injury Center (DVBIC)/Traumatic Brain Injury Center of Excellence (TBICoE) study. Participants were divided into three groups based on number of self-reported lifetime blast exposures: none (n?=?53); low (i.e., 1?9 blasts; n?=?81); and high (i.e., ?10 blasts; n?=?93). All participants underwent diffusion tensor imaging (DTI) at least 11 months post-injury. Tract-of-interest (TOI) analysis was applied to investigate fractional anisotropy and mean, radial, and axial diffusivity (AD) in left and right total cerebral white matter as well as 24 tracts. Benjamini-Hochberg false discovery rate (FDR) correction was used. Regressions investigating blast exposure and mTBI on white matter integrity, controlling for age, revealed that the presence of mTBI history was associated with lower AD in the bilateral superior longitudinal fasciculus and arcuate fasciculus and left cingulum (?s?=??0.255 to ?0.174; ps?<?0.01); however, when non-injured controls were removed from the sample (but orthopedic injury controls remained), these relationships were attenuated and did not survive FDR correction. Regression models were rerun with modified post-traumatic stress disorder (PTSD) diagnosis added as a predictor. After FDR correction, PTSD was not significantly associated with white matter integrity in any of the models. Overall, there was no relationship between white matter integrity and self-reported lifetime blast exposure or PTSD.

The extant literature investigating the relationship between diffusion tensor imaging (DTI) and cognition following traumatic brain injury (TBI) is limited by small sample sizes and inappropriate control groups. The present study examined DTI metric differences between service members and veterans (SMVs) with bodily injury (Trauma Control; TC), uncomplicated mild TBI (mTBI), complicated mild TBI (compTBI), and severe-moderate TBI combined (smTBI), and how DTI metrics related to cognition within each group. Participants were 226 SMVs (56 TC, 112 mTBI, 29 compTBI, 29 smTBI) with valid neuropsychological testing and DTI at least 11 months post-injury. The smTBI group demonstrated decreased fractional anisotropy (FA) and increased axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of the cerebral white matter (CWM) and several individual white matter tracts compared with the TC, mTBI, and compTBI groups (all ps < 0.05; rs = 0.17 to 0.49). The TC, mTBI, and compTBI groups did not differ in terms of any DTI metrics. Within the smTBI group, FA, AD, MD, and RD of the total CWM and several white matter tracts were related to Processing Speed (|rs|: 0.43 to 0.66; ps < 0.05), and/or Delayed Memory (|rs|: 0.41 to 0.67; ps < 0.05). In the compTBI group, Processing Speed was related to left arcuate fasciculus and superior longitudinal fasciculus (SLF) FA, MD, and RD, as well as left uncinate fasciculus MD and RD. In contrast, there were no significant relationships between DTI metrics and cognition/emotional functioning within the mTBI or TC groups. Overall, findings suggest a dose-response relationship between TBI severity and the strength of the relationship between white matter integrity and cognitive performance, with essentially no relationship in mTBI, some findings in compTBI, and several strongly significant relationships in smTBI. In contrast to previously reported findings, there were no differences in DTI metrics between controls, mTBI, and compTBI, and DTI metrics were unrelated to cognition in our relatively large mTBI group.

Mild traumatic brain injury (mTBI) is a significant health burden among military service members. Although mTBI was once considered relatively benign compared to more severe TBIs, a growing body of evidence has demonstrated the devastating neurological consequences of mTBI, including chronic post-concussion symptoms and deficits in cognition, memory, sleep, vision, and hearing. The discovery of reliable biomarkers for mTBI has been challenging due to under-reporting and heterogeneity of military-related mTBI, unpredictability of pathological changes, and delay of post-injury clinical evaluations. Moreover, compared to more severe TBI, mTBI is especially difficult to diagnose due to the lack of overt clinical neuroimaging findings. Yet, advanced neuroimaging techniques using magnetic resonance imaging (MRI) hold promise in detecting microstructural aberrations following mTBI. Using different pulse sequences, MRI enables the evaluation of different tissue characteristics without risks associated with ionizing radiation inherent to other imaging modalities, such as X-ray-based studies or computerized tomography (CT). Accordingly, considering the high morbidity of mTBI in military populations, debilitating post-injury symptoms, and lack of robust neuroimaging biomarkers, this review (1) summarizes the nature and mechanisms of mTBI in military settings, (2) describes clinical characteristics of military-related mTBI and associated comorbidities, such as post-traumatic stress disorder (PTSD), (3) highlights advanced neuroimaging techniques used to study mTBI and the molecular mechanisms that can be inferred, and (4) discusses emerging frontiers in advanced neuroimaging for mTBI. We encourage multi-modal approaches combining neuropsychiatric, blood-based, and genetic data as well as the discovery and employment of new imaging techniques with big data analytics that enable accurate detection of post-injury pathologic aberrations related to tissue microstructure, glymphatic function, and neurodegeneration. Ultimately, this review provides a foundational overview of military-related mTBI and advanced neuroimaging techniques that merit further study for mTBI diagnosis, prognosis, and treatment monitoring.

INTRODUCTION:To address the military gap in the standardized collection of lifetime blast exposures across clinical and research endeavors, researchers at the National Intrepid Center of Excellence (NICoE) completed a quality improvement project that utilized systematic, iterative focus groups that leveraged the input from various stakeholders including subject matter experts, clinical providers, and service members (SMs) to develop a comprehensive, self-report blast exposure inventory that could be completed within 5-10 minutes. This manuscript outlines the process of the development of this inventory.MATERIALS AND METHODS:This project included three phases of focus groups that occurred at the NICoE between August 2020 and March 2021 to collect feedback and input from relevant military stakeholders. The study team utilized related assessments available in the literature, together with clinical experience with the NICoE patient population, to inform the development of an initial draft inventory. Phase 1 consisted of blast injury research subject matter experts who had extensive experience researching and providing clinical care to SMs exposed to blast. Phase 2 consisted of NICoE clinicians across numerous clinical specialties. Phase 3 included current active duty patients in the NICoE intensive outpatient program.RESULTS:Following completion of the focus groups, a lifetime blast exposure inventory was developed in the form of a single page table including incoming, outgoing, training, and operational exposures and broken down by levels of weapon systems as well as breaching and explosive ordnance disposal exposures. In addition, select questions related to the first and most recent blast exposures and experience as an instructor for explosive ordnance disposal- and breaching-related training were included.CONCLUSIONS:Researchers at the NICoE developed a self-report blast exposure inventory through a quality improvement project that included active, ongoing participation and feedback of clinical experts and military SMs. The end result is a brief, single page inventory that can be administered within 5-10 minutes. Although additional research is needed to refine and validate the inventory, the project team believes that the tool begins to address a long-standing gap in the DoD in the standardized collection of lifetime blast exposures.

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.

Military service members (SMs) have an increased risk of developing posttraumatic stress symptoms. Art therapy is a promising intervention that allows SMs with posttraumatic stress to explore their trauma through art-making and reflection in a psychotherapeutic relationship. Thematic analysis of art products may lend itself as a description of visual indicators of an internal state of the brain. We hypothesized that specific neurobiological markers are associated with the theme of psychological closure and/or healing of traumatic memories as represented in the masks created during art therapy. Resting state fMRIs of a convenience sample of 104 SMs who received art therapy as part of the interdisciplinary Intensive Outpatient Program (IOP) at the National Intrepid Center of Excellence were examined. SMs depicting psychological closure and/or healing within their art therapy masks demonstrated greater resting state functional connectivity between regions associated with attention, memory, language, and pain processing. These findings are preliminary in nature therefore causal relationships cannot be assumed between art therapy and neuroimaging metrics, as both art therapy and neuroimaging measures were collected as part of a larger integrative IOP. Future work collecting neuroimaging metrics pre and post an art therapy intervention is warranted to further evaluate these associations.

Introduction: Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common in military service members. The aim of this study is to investigate brain metabolic interrelationships in service members with and without persistent PTSD symptoms after mTBI by using F-18-fluorodeoxyglucose (FDG) positron emission tomography.Methods: Service members (n = 408) diagnosed with mTBI were studied retrospectively. Principal component analysis was applied to identify latent metabolic systems, and the associations between metabolic latent systems and self-report measures of post-concussive and PTSD symptoms were evaluated. Participants were divided into two groups based on DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision) criteria for PTSD, and structural equation modeling was performed to test a priori hypotheses on metabolic interrelationships among the brain regions in the cortico-limbic circuitry responsible for top-down control and bottom-up emotional processing. The differences in metabolic interrelationships between age-matched PTSD-absent (n = 204) and PTSD-present (n = 204) groups were evaluated.Results: FDG uptake in the temporo-limbic system was positively correlated with post-concussive and hyperarousal symptoms. For the bottom-up emotional processing, the insula and amygdala-hippocampal complex in the PTSD-present group had stronger metabolic interrelationships with the bilateral rostral anterior cingulate, left lingual, right lateral occipital, and left superior temporal cortices, but a weaker relationship with the right precuneus cortex, compared with the PTSD-absent group. For the top-down control, the PTSD-present group had decreased metabolic engagements of the dorsolateral prefrontal cortex on the amygdala.Discussion: Our results suggest altered metabolic interrelationships in the cortico-limbic circuitry in mTBI subjects with persistent PTSD symptoms, which may underlie the pathophysiological mechanisms of comorbid mTBI and PTSD. Impact statementThis is the first F-18-fluorodeoxyglucose positron emission tomography study to investigate brain metabolic interrelationships in service members with persistent post-traumatic stress disorder (PTSD) symptoms after mild traumatic brain injury (mTBI). We identified that the temporo-limbic metabolic system was associated with post-concussive and hyperarousal symptoms. Further, brain metabolic interrelationships in the cortico-limbic circuitry were altered in mTBI subjects with significant PTSD symptoms compared with those without them.

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

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.

Identify potential regions of interest (ROIs) that are involved in TBI-related sleep disorders.

Posttraumatic nightmares commonly occur after a traumatic experience. Despite significant deleterious effects on well-being and their role in posttraumatic stress disorder, posttraumatic nightmares remain understudied. The neuroanatomical structures of the amygdala, medial prefrontal cortex, hippocampus, and anterior cingulate cortex constitute the AMPHAC model (Levin and Nielsen, 2007), which is implicated in the neurophysiology of disturbing dreams of which posttraumatic nightmares is a part. However, this model has not been investigated using neuroimaging data. The present study sought to determine whether there are structural differences in the AMPHAC regions in relation to the occurrence of posttraumatic nightmares. Data were obtained from treatment -seeking male active duty service members (N = 351). Posttraumatic nightmares were not significantly related to gray matter volume, cortical surface area, or cortical thickness of any the AMPHAC regions when controlling for age and history of mild traumatic brain injury. Although the present analyses do not support an association between structural measures of AMPHAC regions and posttraumatic nightmares, we suggest that functional differences within and/or between these brain regions may be related to the occurrence of posttraumatic nightmares because functional and structural associations are distinct. Future research should examine whether functional differences may be associated with posttraumatic nightmares.

The purpose of this study was to analyze quantitative diffusion tensor imaging measures across the spectrum of traumatic brain injury severity and evaluate their trajectories in military service members. Participants were 96 U.S. military service members and veterans who had sustained a mild traumatic brain injury [including complicated mild traumatic brain injury (n = 16) and uncomplicated mild traumatic brain injury (n = 68)], moderate-severe traumatic brain injury (n = 12), and controls (with or without orthopaedic injury, n = 39). All participants had been scanned at least twice, with some receiving up to five scans. Both whole brain voxel-wise analysis and tract-of-interest analysis were applied to assess the group differences of diffusion tensor imaging metrics, and their trajectories between time points of scans and days since injury. Linear mixed modelling was applied to evaluate cross-sectional and longitudinal diffusion tensor imaging metrics changes within and between groups using both tract-of-interest and voxel-wise analyses. Participants with moderate to severe traumatic brain injury had larger white matter disruption both in superficial subcortical and deep white matter, mainly over the anterior part of cerebrum, than those with mild traumatic brain injury, both complicated and uncomplicated, and there was no evidence of recovery over the period of follow-ups in moderate-severe traumatic brain injury, but deterioration was possible. Participants with mild traumatic brain injury had white matter microstructural changes, mainly in deep central white matter over the posterior part of cerebrum, with more spatial involvement in complicated mild traumatic brain injury than in uncomplicated mild traumatic brain injury and possible brain repair through neuroplasticity, e.g. astrocytosis with glial processes and glial scaring. Our results did not replicate 'V-shaped' trajectories in diffusion tensor imaging metrics, which were revealed in a previous study assessing the sub-acute stage of brain injury in service members and veterans following military combat concussion. In addition, non-traumatic brain injury controls, though not demonstrating any evidence of sustaining a traumatic brain injury, might have transient white matter changes with recovery afterward. Our results suggest that white matter integrity following a remote traumatic brain injury may change as a result of different underlying mechanisms at the microstructural level, which can have a significant consequence on the long-term well beings of service members and veterans. In conclusion, longitudinal diffusion tensor imaging improves our understanding of the mechanisms of white matter microstructural changes across the spectrum of traumatic brain injury severity. The quantitative metrics can be useful as guidelines in monitoring the long-term recovery.

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

Abstract Introduction Traumatic brain injury (TBI) plagues service members in times of war and training. Diagnosis and management of TBI remain challenging, with many suffering from sleep disorders. We hypothesized that TBI-related damage to the hypothalamus, a master regulator of breathing and sleep, could be related to post-TBI obstructive sleep apnea (OSA) and serve as a pathophysiological biomarker for a subpopulation of OSA patients. Methods This was a retrospective study of warfighters with TBI from the National Intrepid Center of Excellence (NICoE). Subjects were identified by severe TBI on neuroimaging and compared against a control group without TBI. All subjects underwent screening polysomnography (PSG). MRI was acquired via 3T scanner. The hypothalamus was automatically segmented using a diffeomorphic algorithm. DTI scalar values were analyzed with scalar t-tests between subjects and controls. Generalized linear modeling with DTI scalar values was used to predict AHI in subjects. Results 6 subjects and 61 controls were identified. There was significant sleep dysfunction amongst TBI subjects (mean apnea-hypopnea index (AHI) 5.1+/-6.6 events/hour; mild OSA incidence 33.3%; Pittsburgh Sleep Quality Index (PSQI) mean 13.3+/-2.6). Radial diffusivity (RD), axial diffusivity (AD) and mean diffusivity (MD) were significantly higher among subjects (control RD 9.64x10^-10+/-7.54x10^-11 m^2/s, subject RD 1.13x10^-9+/-1.20x10^-10m^2/s, p = 0.023; control AD 1.32x10^-9+/-7.64x10^-11m^2/s, subject AD 1.50x10^-9+/-1.43x10^-10m^2/s, p = 0.029; control MD 1.08x10^-9+/-7.43x10^-11m^2/s, subject MD 1.25x10^-9+/-1.34x10^-10m^2/s, p = 0.025). There were no differences in age or body-mass index. Generalized linear modeling with diffusivity measures as predictors of AHI in subjects was not significant. Conclusion Using a diffeomorphic algorithm to define the hypothalamus reveals significantly elevated scalar DTI measures in chronic, severe TBI compared to controls. DTI differences in the hypothalamus are a novel finding and possibly underlie part of the pathophysiology of TBI. Although this may have potential to serve as a biomarker in severe TBI patients with sleep disorders, these initial data do not support a relationship between DTI and AHI, despite high incidence of OSA and subjective sleep dysfunction. Future studies with more subjects may better elucidate the changes in hypothalamic DTI after TBI for clinical outcomes analysis. Support (if any) This work was supported by grant 130132 from USAMRMC.

The aim of this study was to examine neuropsychological functioning and white matter integrity, in service members and veterans (SMVs) after mild traumatic brain injury (MTBI), with versus without post-traumatic stress disorder (PTSD). Participants were 116 U.S. military SMVs, prospectively enrolled from the Walter Reed National Military Medical Center (Bethesda, MD), who had sustained an MTBI (n = 86) or an injury without TBI (i.e., Injured Control [IC]; n = 30). Participants completed a battery of neuropsychological measures (neurobehavioral and -cognitive), as well as diffusion tensor imaging (DTI) of the brain, on average 6 years post-injury. Based on diagnostic criteria for PTSD, participants in the MTBI group were classified into two subgroups: MTBI/PTSD-Present (n = 21) and MTBI/PTSD-Absent (n = 65). Participants in the IC group were included only if they were classified as PTSD-Absent. The MTBI/PTSD-Present group had a significantly higher number of self-reported symptoms on all neurobehavioral measures (e.g., depression), and lower scores on more than half of the neurocognitive domains (e.g., processing speed), compared to the MTBI/PTSD-Absent and IC/PTSD-Absent groups. There were no significant group differences for the vast majority of DTI measures, with the exception of a handful of regions (i.e., superior longitudinal fascicle and superior thalamic radiation). These results suggest that there is 1) a strong relationship between PTSD and poor neuropsychological outcome after MTBI and 2) a lack of a relationship between PTSD and white matter integrity, as measured by DTI, after MTBI. Concurrent PTSD and MTBI should be considered a risk factor for poor neuropsychological outcome that requires early intervention.