White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury.

Importance: 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 (ß = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (ß = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (ß = 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 (ß = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (ß = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (ß = 1.2 × 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.

Lifetime Blast Exposure Is Not Related to White Matter Integrity in Service Members and Veterans With and Without Uncomplicated Mild Traumatic Brain Injury.

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 (ßs = -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.

Military-related mild traumatic brain injury: clinical characteristics, advanced neuroimaging, and molecular mechanisms.

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.

Development of the Blast Ordnance and Occupational Exposure Measure for Self-Reported Lifetime Blast Exposures.

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.

White Matter Integrity Relates to Cognition in Service Members and Veterans after Complicated Mild, Moderate, and Severe Traumatic Brain Injury, But Not Uncomplicated Mild Traumatic Brain Injury.

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.

¹8F-fluorodeoxyglucose-positron emission tomography findings are not related to cognitive functioning in service members with remote history of mild traumatic brain injury.

OBJECTIVE: Determine whether glucose uptake as measured by 18F-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. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

An examination of volumetric and cortical thickness correlates of posttraumatic nightmares in male active duty service members.

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.

Longitudinal changes of white matter microstructure following traumatic brain injury in U.S. military service members.

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.

Altered Metabolic Interrelationships in the Cortico-Limbic Circuitry in Military Service Members with Persistent Post-Traumatic Stress Disorder Symptoms Following Mild Traumatic Brain Injury.

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 18F-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 statement This is the first 18F-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.

White Matter Hyperintensities Are Not Related to Symptomatology or Cognitive Functioning in Service Members with a Remote History of Traumatic Brain Injury.

This study aimed to determine whether magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) are associated with symptom reporting and/or cognitive performance in 1202 active-duty service members with prior single or multiple mild traumatic brain injury (mTBI). Patients with mTBI evaluated at the National Intrepid Center of Excellence (NICoE) at Walter Reed National Military Medical Center (WRNMMC) were divided into those with (n = 632) and without (n = 570) WMHs. The groups were compared on several self-report scales including the Neurobehavioral Symptom Inventory (NSI), Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version (PCL-C), Satisfaction with Life Scale (SWLS), and Short Form-36 Health Survey (SF-36). They were also compared on several neuropsychological measures, including tests of attention, working memory, learning and memory, executive functioning, and psychomotor functioning. After correction for multiple comparisons, there were no significant differences between the two groups on any self-reported symptom scale or cognitive test. When comparing a subgroup with the highest (20+) WMH burden (n = 60) with those with no WMHs (n = 60; matched on age, education, sex, race, rank, and TBI number), only SF-36 Health Change significantly differed between the subgroups; the multiple WMH subgroup reported worsening health over the past year (t[53] = 3.52, p = 0.001, d = 0.67) compared with the no WMH subgroup. These findings build on prior research suggesting total WMHs are not associated with significant changes in self-reported symptoms or cognitive performance in patients with a remote history of mTBI. As such, clinicians are encouraged to use caution when reporting such imaging findings.

Cerebrovascular Reactivity Measures Are Associated With Post-traumatic Headache Severity in Chronic TBI; A Retrospective Analysis.

OBJECTIVE: To characterize the relationship between persistent post-traumatic headache (pPTH) and traumatic cerebrovascular injury (TCVI) in chronic traumatic brain injury (TBI). Cerebrovascular reactivity (CVR), a measure of the cerebral microvasculature and endothelial cell function, is altered both in individuals with chronic TBI and migraine headache disorder (Amyot et al., 2017; Lee et al., 2019b). The pathophysiologies of pPTH and migraine are believed to be associated with chronic microvascular dysfunction. We therefore hypothesize that TCVI may contribute to the underlying migraine-like mechanism(s) of pPTH. MATERIALS AND METHODS: 22 moderate/severe TBI participants in the chronic stage (>6 months) underwent anatomic and functional magnetic resonance imaging (fMRI) scanning with hypercapnia gas challenge to measure CVR as well as the change in CVR (ΔCVR) after single-dose treatment of a specific phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, which potentiates vasodilation in response to hypercapnia in impaired endothelium, as part of a Phase2a RCT of sildenafil in chronic TBI (NCT01762475). CVR and ΔCVR measures of each participant were compared with the individual's pPTH severity measured by the headache impact test-6 (HIT-6) survey. RESULTS: There was a moderate correlation between HIT-6 and both CVR and ΔCVR scores [Spearman's correlation = -0.50 (p = 0.018) and = 0.46 (p = 0.03), respectively], indicating that a higher headache burden is associated with decreased endothelial function in our chronic TBI population. CONCLUSION: There is a correlation between PTH and CVR in chronic moderate-severe TBI. This relationship suggests that chronic TCVI may underlie the pathobiology of pPTH. Further, our results suggest that novel treatment strategies that target endothelial function and vascular health may be beneficial in refractory pPTH.

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

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

Post-Traumatic Stress Disorder Is Associated with Neuropsychological Outcome but Not White Matter Integrity after Mild Traumatic Brain Injury.

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.

Cortical thinning in military blast compared to non-blast persistent mild traumatic brain injuries.

In the military, explosive blasts are a significant cause of mild traumatic brain injuries (mTBIs). The symptoms associated with blast mTBIs causes significant economic burdens and a diminished quality of life for many service members. At present, the distinction of the injury mechanism (blast versus non-blast) may not influence TBI diagnosis. However, using noninvasive imaging, this study reveals significant distinctions between the blast and non-blast TBI mechanisms. A cortical whole-brain thickness analysis was performed using structural high-resolution T1-weighted MRI to identify the effects of blasts in persistent mTBI (pmTBI) subjects. A total of 41 blast pmTBI subjects were individually age- and gender-matched to 41 non-blast pmTBI subjects. Using FreeSurfer, cortical thickness was quantified for the blast group, relative to the non-blast group. Cortical thinning was identified within the blast mTBI group, in two clusters bilaterally. In the left hemisphere, the cluster overlapped with the lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, superior frontal, rostral anterior cingulate and frontal pole cortices (p < 0.02, two-tailed, size = 1680 mm2). In the right hemisphere, the cluster overlapped with the lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, pars orbitalis, pars triangularis and insula cortices (p < 0.002, two-tailed, cluster size = 2453 mm2). Self-report assessments suggest significant differences in the Post-Traumatic Stress Disorder Checklist-Civilian Version (p < 0.05, Bonferroni-corrected) and the Neurobehavioral Symptom Inventory (p < 0.01, uncorrected) between the blast and non-blast mTBI groups. These results suggest that blast may cause a unique injury pattern related to a reduction in cortical thickness within specific brain regions which could affect symptoms. No other study has found cortical thickness difference between blast and non-blast mTBI groups and further replication is needed to confirm these initial observations.

Assessment of Brain Venous Structure in Military Traumatic Brain Injury Patients using Susceptibility Weighted Imaging and Quantitative Susceptibility Mapping.

Brain venous volume above the lateral ventricle in military patients with traumatic brain injury (TBI) was assessed using two segmentation approaches on susceptibility weighted images (SWI) and quantitative susceptibility maps (QSM). This retrospective study included a total of 147 subjects: 14 patients with severe TBI; 38 patients with moderate TBI, 58 patients with mild TBI (28 with blast-related injuries and 30 with non-blast-related injuries), and 37 control subjects without history of TBI. Using the multiscale vessel enhancement filter on SWI images, patients with severe TBI demonstrated significantly higher segmented venous volumes compared with controls. Using a threshold approach on QSM images, TBI patients with different severities all demonstrated increased segmented volumes compared with control subjects: in the whole brain (severe, p = 0.001; moderate, p = 0.008; mild, p = 0.042, compared with controls), in the left hemisphere (severe, p = 0.01; moderate, p = 0.038, compared with controls), in the right hemisphere (severe, p = 0.001; moderate, p = 0.013; mild, p = 0.027, compared with controls). While segmented volumes on SWI appear to overlay directly on the visualized venous structures, the QSM-derived segments also encompass some perivascular and deep white matter areas. This might represent the damage in the perivascular regions associated with iron deposition or astroglial scarring.

Acquired Sleep-Related Hypermotor Epilepsy with Disrupted White Matter Tracts Assessed by Multishell Diffusion Magnetic Resonance Imaging.

Sleep-related hypermotor epilepsy (SHE) (previously frontal lobe epilepsy) is a rare seizure disorder commonly misdiagnosed or unrecognized, causing negative patient sequelae. While usually reported in familial studies, it is more commonly acquired. Diagnosis is a challenge due to its low incidence in comparison with the more common sleep disorders or psychogenic etiologies in the differential diagnosis. Diagnosis is scaled on degree of certainty based on described or clinically documented semiology, with video EEG as a helpful, but not necessary, adjunct. Current treatment is similar to other focal epilepsies. We studied a 36-year-old active duty male soldier who presented with 2 years of predominantly sleep related, abrupt, short, and anamnestic hyperkinetic movements with unstructured vocalizations. Prior workup included non-contributory video electroencephalograph (EEG) and polysomnography as well as normal brain magnetic resonance imaging (MRI). Treatments for presumed psychiatric and parasomnia disturbances were not effective in establishing diagnosis or relief. Evaluation at our tertiary, multidisciplinary care institution recorded events consistent with the diagnosis of clinical SHE. He was enrolled in an advanced multishell diffusion-weighted imaging MRI research study to evaluate white matter tracts, given his history of mild, repetitive, non-penetrating traumatic brain injury, not otherwise requiring hospitalization. Multishell diffusion MRI tractography found changes not previously described in the right frontal lobe white matter tracts. These changes were consistent with neurological localization and serve as a potential nidus for this patient's seizure disorder. Misdiagnosis of SHE can result in detrimental biopsychosocial sequelae of untreated epilepsy, unnecessary or harmful intervention, or the stigmata of a behavioral disorder. Further investigation into diagnosis and etiology of acquired SHE is needed. Assessment for white matter abnormalities can potentially provide information into pathogenesis of epilepsy disorders.

Compromised Neurocircuitry in Chronic Blast-Related Mild Traumatic Brain Injury.

The aim of this study was to apply recently developed automated fiber segmentation and quantification methods using diffusion tensor imaging (DTI) and DTI-based deterministic and probabilistic tractography to access local and global diffusion changes in blast-induced mild traumatic brain injury (bmTBI). Two hundred and two (202) male active US service members who reported persistent post-concussion symptoms for more than 6 months after injury were recruited. An additional forty (40) male military controls were included for comparison. DTI results were examined in relation to post-concussion and post-traumatic stress disorder (PTSD) symptoms. No significant group difference in DTI metrics was found using voxel-wise analysis. However, group comparison using tract profile analysis and tract specific analysis, as well as single subject analysis using tract profile analysis revealed the most prominent white matter microstructural injury in chronic bmTBI patients over the frontal fiber tracts, that is, the front-limbic projection fibers (cingulum bundle, uncinate fasciculus), the fronto-parieto-temporal association fibers (superior longitudinal fasciculus), and the fronto-striatal pathways (anterior thalamic radiation). Effects were noted to be sensitive to the number of previous blast exposures, with a negative association between fractional anisotropy (FA) and time since most severe blast exposure in a subset of the multiple blast-exposed group. However, these patterns were not observed in the subgroups classified using macrostructural changes (T2 white matter hyperintensities). Moreover, post-concussion symptoms and PTSD symptoms, as well as neuropsychological function were associated with low FA in the major nodes of compromised neurocircuitry. Hum Brain Mapp 38:352-369, 2017. © 2016 Wiley Periodicals, Inc.

Imaging Cerebral Microhemorrhages in Military Service Members with Chronic Traumatic Brain Injury.

PURPOSE: To detect cerebral microhemorrhages in military service members with chronic traumatic brain injury by using susceptibility-weighted magnetic resonance (MR) imaging. The longitudinal evolution of microhemorrhages was monitored in a subset of patients by using quantitative susceptibility mapping. MATERIALS AND METHODS: The study was approved by the Walter Reed National Military Medical Center institutional review board and is compliant with HIPAA guidelines. All participants underwent two-dimensional conventional gradient-recalled-echo MR imaging and three-dimensional flow-compensated multiecho gradient-recalled-echo MR imaging (processed to generate susceptibility-weighted images and quantitative susceptibility maps), and a subset of patients underwent follow-up imaging. Microhemorrhages were identified by two radiologists independently. Comparisons of microhemorrhage number, size, and magnetic susceptibility derived from quantitative susceptibility maps between baseline and follow-up imaging examinations were performed by using the paired t test. RESULTS: Among the 603 patients, cerebral microhemorrhages were identified in 43 patients, with six excluded for further analysis owing to artifacts. Seventy-seven percent (451 of 585) of the microhemorrhages on susceptibility-weighted images had a more conspicuous appearance than on gradient-recalled-echo images. Thirteen of the 37 patients underwent follow-up imaging examinations. In these patients, a smaller number of microhemorrhages were identified at follow-up imaging compared with baseline on quantitative susceptibility maps (mean ± standard deviation, 9.8 microhemorrhages ± 12.8 vs 13.7 microhemorrhages ± 16.6; P = .019). Quantitative susceptibility mapping-derived quantitative measures of microhemorrhages also decreased over time: -0.85 mm(3) per day ± 1.59 for total volume (P = .039) and -0.10 parts per billion per day ± 0.14 for mean magnetic susceptibility (P = .016). CONCLUSION: The number of microhemorrhages and quantitative susceptibility mapping-derived quantitative measures of microhemorrhages all decreased over time, suggesting that hemosiderin products undergo continued, subtle evolution in the chronic stage.

Tract Orientation and Angular Dispersion Deviation Indicator (TOADDI): A framework for single-subject analysis in diffusion tensor imaging.

The purpose of this work is to develop a framework for single-subject analysis of diffusion tensor imaging (DTI) data. This framework is termed Tract Orientation and Angular Dispersion Deviation Indicator (TOADDI) because it is capable of testing whether an individual tract as represented by the major eigenvector of the diffusion tensor and its corresponding angular dispersion are significantly different from a group of tracts on a voxel-by-voxel basis. This work develops two complementary statistical tests based on the elliptical cone of uncertainty, which is a model of uncertainty or dispersion of the major eigenvector of the diffusion tensor. The orientation deviation test examines whether the major eigenvector from a single subject is within the average elliptical cone of uncertainty formed by a collection of elliptical cones of uncertainty. The shape deviation test is based on the two-tailed Wilcoxon-Mann-Whitney two-sample test between the normalized shape measures (area and circumference) of the elliptical cones of uncertainty of the single subject against a group of controls. The False Discovery Rate (FDR) and False Non-discovery Rate (FNR) were incorporated in the orientation deviation test. The shape deviation test uses FDR only. TOADDI was found to be numerically accurate and statistically effective. Clinical data from two Traumatic Brain Injury (TBI) patients and one non-TBI subject were tested against the data obtained from a group of 45 non-TBI controls to illustrate the application of the proposed framework in single-subject analysis. The frontal portion of the superior longitudinal fasciculus seemed to be implicated in both tests (orientation and shape) as significantly different from that of the control group. The TBI patients and the single non-TBI subject were well separated under the shape deviation test at the chosen FDR level of 0.0005. TOADDI is a simple but novel geometrically based statistical framework for analyzing DTI data. TOADDI may be found useful in single-subject, graph-theoretic and group analyses of DTI data or DTI-based tractography techniques.