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.

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.

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.

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.

Postconcussion symptom reporting is not associated with diffusion tensor imaging findings in the subacute to chronic phase of recovery in military service members following mild traumatic brain injury.

INTRODUCTION: The purpose of this study was to examine the relation between white matter integrity of the brain and postconcussion symptom reporting following mild traumatic brain injury (MTBI). METHOD: Participants were 109 U.S. military service members (91.7% male) who had sustained a MTBI (n = 88) or orthopedic injury without TBI (trauma controls, TC, n = 21), enrolled from the Walter Reed National Military Medical Center, Bethesda, Maryland. Participants completed a battery of neurobehavioral symptom measures and underwent diffusion tensor imaging (DTI; General Electric 3T) of the whole brain, on average 44.9 months post injury (SD = 42.3). Measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were generated for 18 regions of interest (ROIs). Participants in the MTBI group were divided into two subgroups based on International Classification of Diseases-10th Revision (ICD-10) Category C criteria for postconcussion syndrome (PCS): PCS-present (n = 41) and PCS-absent (n = 47). RESULTS: The PCS-present group had significantly worse scores on all 13 neurobehavioral measures than the PCS-absent group (p < .001, d = 0.87-2.50) and TC group (p < .003, d = 0.84-2.06). For all ROIs, there were no significant main effects across the three groups for FA, MD, AD, and RD (all ps >.03). Pairwise comparisons revealed no significant differences for all ROIs when using FA and RD, and only two significant pairwise differences were found between PCS-present and PCS-absent groups when using MD and AD [i.e., anterior thalamic radiation and cingulate gyrus (supracallosal) bundle]. CONCLUSIONS: Consistent with past research, but not all studies, postconcussion symptom reporting was not associated with white matter integrity in the subacute to chronic phase of recovery following MTBI.

Plasma Tau and Amyloid Are Not Reliably Related to Injury Characteristics, Neuropsychological Performance, or White Matter Integrity in Service Members with a History of Traumatic Brain Injury.

The aim of this study was to examine the relationship between plasma tau and amyloid beta-42 (Aß42), neuropsychological functioning, and white matter integrity in U.S. military service members with (n = 155) and without (n = 42) a history of uncomplicated mild (n = 83), complicated mild (n = 26), or moderate, severe, or penetrating (n = 46) traumatic brain injury (TBI). We hypothesized that higher levels of tau and Aß42 would be related to reduced neurocognitive performance and white matter integrity. Participants were enrolled prospectively from Walter Reed National Military Medical Center. Participants completed a blood draw, neuropsychological assessment, and diffusion tensor imaging (General Electric 3T) of the whole brain. From 20 neuropsychological test scores, five cognitive domain scores were computed. Measures of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were generated for 18 regions of interest (ROIs). There was no relationship found between the plasma biomarkers and neurocognitive performance in any of the three TBI groups (all ps >0.05; all R2 changes <0.146). Although not reaching statistical significance after correction for multiple comparisons, higher tau and Aß42 tended to be related to higher FA and lower MD, RD, and AD in patients with a history of moderate, severe, or penetrating TBI. There was no consistent relationship between either of the biomarkers and white matter integrity in the complicated and uncomplicated mild TBI groups. In addition, there was no significant relationship between the biomarkers and age, education, sex, race, bodily injury severity, time since injury, TBI severity, or number of TBIs (all ps >0.15). Future investigation in larger samples of moderate, severe, and penetrating TBI are needed. Other plasma biomarkers, including phosphorylated tau, exosomal tau, and interleukin-10, may be more promising measures to use in the diagnosis, management, and treatment of TBI.

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.

Decreases in White Matter Integrity of Ventro-Limbic Pathway Linked to Post-Traumatic Stress Disorder in Mild Traumatic Brain Injury.

Post-traumatic stress disorder (PTSD) is commonly observed in military service members with mild traumatic brain injury (mTBI); however, the relationship between mTBI and PTSD is complex and not well understood. The present study aims to elucidate a link between the degree of alteration in limbic system-related white matter tracts and PTSD symptoms in an mTBI population. Diffusion-tensor imaging (DTI) with probabilistic tractography of the fronto-limbic pathways revealed decreased white matter integrity in the uncinate fasciculus in those with co-morbid mTBI and PTSD (n = 34), relative to those with only mTBI (n = 35). Additionally, fractional anisotropy (FA) and radial diffusivity (RD) measures in the bilateral uncinate fasciculus correlated with Post-Traumatic Stress Disorder Checklist Civilian version (PCL-C) scores, and primarily within the avoidance and re-experiencing domains. Findings from this study suggest the degree of traumatic injury within the limbic system could be directly related to post-traumatic stress and post-concussive symptoms, with disrupted white matter leading to significant PTSD outcomes.

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.

Findings from Structural MR Imaging in Military Traumatic Brain Injury.

PURPOSE: To describe the initial neuroradiology findings in a cohort of military service members with primarily chronic mild traumatic brain injury (TBI) from blast by using an integrated magnetic resonance (MR) imaging protocol. MATERIALS AND METHODS: This study was approved by the Walter Reed National Military Medical Center institutional review board and is compliant with HIPAA guidelines. All participants were military service members or dependents recruited between August 2009 and August 2014. There were 834 participants with a history of TBI and 42 participants in a control group without TBI (not explicitly age- and sex-matched). MR examinations were performed at 3 T primarily with three-dimensional volume imaging at smaller than 1 mm(3) voxels for the structural portion of the examination. The structural portion of this examination, including T1-weighted, T2-weighted, before and after contrast agent administrtion T2 fluid attenuation inversion recovery, and susceptibility-weighted images, was evaluated by neuroradiologists by using a modified version of the neuroradiology TBI common data elements (CDEs). Incident odds ratios (ORs) between the TBI participants and a comparison group without TBI were calculated. RESULTS: The 834 participants were diagnosed with predominantly chronic (mean, 1381 days; median, 888 days after injury) and mild (92% [768 of 834]) TBI. Of these participants, 84.2% (688 of 817) reported one or more blast-related incident and 63.0% (515 of 817) reported loss of consciousness at the time of injury. The presence of white matter T2-weighted hyperintense areas was the most common pathologic finding, observed in 51.8% (432 of 834; OR, 1.75) of TBI participants. Cerebral microhemorrhages were observed in a small percentage of participants (7.2% [60 of 834]; OR, 6.64) and showed increased incidence with TBI severity (P < .001, moderate and severe vs mild). T2-weighted hyperintense areas and microhemorrhages did not collocate by visual inspection. Pituitary abnormalities were identified in a large proportion (29.0% [242 of 834]; OR, 16.8) of TBI participants. CONCLUSION: Blast-related injury and loss of consciousness is common in military TBI. Structural MR imaging demonstrates a high incidence of white matter T2-weighted hyperintense areas and pituitary abnormalities, with a low incidence of microhemorrhage in the chronic phase.

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.

Exploring variations in functional connectivity of the resting state default mode network in mild traumatic brain injury.

A definitive diagnosis of mild traumatic brain injury (mTBI) is difficult due to the absence of biomarkers in standard clinical imaging. The brain is a complex network of interconnected neurons and subtle changes can modulate key networks of cognitive function. The resting state default mode network (DMN) has been shown to be sensitive to changes induced by pathology. This study seeks to determine whether quantitative measures of the DMN are sensitive in distinguishing mTBI subjects. Resting state functional magnetic resonance imaging data were obtained for healthy (n=12) and mTBI subjects (n=15). DMN maps were computed using dual-regression Independent Component Analysis (ICA). A goodness-of-fit (GOF) index was calculated to assess the degree of spatial specificity and sensitivity between healthy controls and mTBI subjects. DMN regions and neuropsychological assessments were examined to identify potential relationships. The resting state DMN maps indicate an increase in spatial coactivity in mTBI subjects within key regions of the DMN. Significant coactivity within the cerebellum and supplementary motor areas of mTBI subjects were also observed. This has not been previously reported in seed-based resting state network analysis. The GOF suggested the presence of high variability within the mTBI subject group, with poor sensitivity and specificity. The neuropsychological data showed correlations between areas of coactivity within the resting state network in the brain with a number of measures of emotion and cognitive functioning. The poor performance of the GOF highlights the key challenge associated with mTBI injury: the high variability in injury mechanisms and subsequent recovery. However, the quantification of the DMN using dual-regression ICA has potential to distinguish mTBI from healthy subjects, and provide information on the relationship of aspects of cognitive and emotional functioning with their potential neural correlates.

Serial longitudinal magnetic resonance imaging data indicate non-linear regional gray matter volume recovery in abstinent alcohol-dependent individuals.

The trajectory of regional volume changes during the first year of sustained abstinence in those recovering from an alcohol use disorder is unclear because previous research typically employed only two assessment points. To better understand the trajectory of regional brain volume recovery in treatment-seeking alcohol-dependent individuals (ALC), regional brain volumes were measured after 1 week, 1 month and 7.5 months of sustained abstinence via magnetic resonance imaging at 1.5 T. ALC showed significant volume increases in frontal, parietal and occipital gray matter (GM) and white matter (WM), total cortical GM and total lobar WM, thalamus and cerebellum, and decreased ventricular volume over 7.5 months of abstinence. Volume increases in regional GM were significantly greater over 1 week to 1 month than from 1 month to 7.5 months of abstinence, indicating a non-linear rate of change in regional GM over 7.5 months. Overall, regional lobar WM showed linear volume increases over 7.5 months. With increasing age, smoking ALC showed lower frontal and total cortical GM volume recovery than non-smoking ALC. Despite significant volume increases, ALC showed smaller GM volumes in all regions, except the frontal cortex, than controls after 7.5 months of abstinence. ALC and controls showed no regional WM volume differences at any assessment point. In non-smoking ALC only, increasing regional GM and WM volumes were related to improving processing speed. Findings may indicate a differential rate of recovery of cell types/cellular components contributing to GM and WM volume during early abstinence, and that GM volume deficits persist after 7.5 months of sustained sobriety in this ALC cohort.

Postconcussional disorder and PTSD symptoms of military-related traumatic brain injury associated with compromised neurocircuitry.

Traumatic brain injury (TBI) is a common combat injury, often through explosive blast, and produces heterogeneous brain changes due to various mechanisms of injury. It is unclear whether the vulnerability of white matter differs between blast and impact injury, and the consequences of microstructural changes on neuropsychological function are poorly understood in military TBI patients. Diffusion tensor imaging (DTI) techniques were used to assess the neurocircuitry in 37 U.S. service members (29 mild, 7 moderate, 1 severe; 17 blast and 20 nonblast), who sustained a TBI while deployed, compared to 14 nondeployed, military controls. High-dimensional deformable registration of MRI diffusion tensor data was followed by fiber tracking and tract-specific analysis along with region-of-interest analysis. DTI results were examined in relation to post-concussion and post-traumatic stress disorder (PTSD) symptoms. The most prominent white matter microstructural injury for both blast and nonblast patients was in the frontal fibers within the fronto-striatal (corona radiata, internal capsule) and fronto-limbic circuits (fornix, cingulum), the fronto-parieto-occipital association fibers, in brainstem fibers, and in callosal fibers. Subcortical superior-inferiorly oriented tracts were more vulnerable to blast injury than nonblast injury, while direct impact force had more detrimental effects on anterior-posteriorly oriented tracts, which tended to cause heterogeneous left and right hemispheric asymmetries of white matter connectivity. The tractography using diffusion anisotropy deficits revealed the cortico-striatal-thalamic-cerebellar-cortical (CSTCC) networks, where increased post-concussion and PTSD symptoms were associated with low fractional anisotropy in the major nodes of compromised CSTCC neurocircuitry, and the consequences on cognitive function were explored as well.

Perfusion deficits in patients with mild traumatic brain injury characterized by dynamic susceptibility contrast MRI.

Perfusion deficits in patients with mild traumatic brain injury (TBI) from a military population were characterized by dynamic susceptibility contrast perfusion imaging. Relative cerebral blood flow (rCBF) was calculated by a model-independent deconvolution approach from the tracer concentration curves following a bolus injection of gadolinium diethylenetriaminepentaacetate (Gd-DTPA) using both manually and automatically selected arterial input functions (AIFs). Linear regression analysis of the mean values of rCBF from selected regions of interest showed a very good agreement between the two approaches, with a regression coefficient of R = 0.88 and a slope of 0.88. The Bland-Altman plot also illustrated the good agreement between the two approaches, with a mean difference of 0.6 ± 12.4 mL/100 g/min. Voxelwise analysis of rCBF maps from both approaches demonstrated multiple clusters of decreased perfusion (p < 0.01) in the cerebellum, cuneus, cingulate and temporal gyrus in the group with mild TBI relative to the controls. MRI perfusion deficits in the cerebellum and anterior cingulate also correlated (p < 0.01) with neurocognitive results, including the mean reaction time in the Automated Neuropsychological Assessment Metrics and commission error and detection T-scores in the Continuous Performance Test, as well as neurobehavioral scores in the Post-traumatic Stress Disorder Checklist-Civilian Version. In conclusion, rCBF calculated using AIFs selected from an automated approach demonstrated a good agreement with the corresponding results using manually selected AIFs. Group analysis of patients with mild TBI from a military population demonstrated scattered perfusion deficits, which showed significant correlations with measures of verbal memory, speed of reaction time and self-report of stress symptoms.