The relationship between blast-related mild traumatic brain injury and executive function is moderated by white matter integrity.

Blast-related mild traumatic brain injury (BR mTBI) is a critical research area in recent combat veterans due to increased prevalence of survived blasts. Post-BR mTBI outcomes are highly heterogeneous and defining neurological differences may help in discrimination and prediction of cognitive outcomes. This study investigates whether white matter integrity, measured with diffusion tensor imaging (DTI), could influence how remote BR mTBI history is associated with executive control. The sample included 151 Veterans from the Minneapolis Veterans Affairs Medical Center who were administered a clinical/TBI assessment, neuropsychological battery, and DTI scan as part of a larger battery. From previous research, six white matter tracts were identified as having a putative relationship with blast severity: the cingulum, hippocampal cingulum, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal fasciculus and uncinate. Fractional anisotropy (FA) of the a priori selected white matter tracts and report of BR mTBI were used as predictors of Trail-Making Test B (TMT-B) performance in a multiple linear regression model. Statistical analysis revealed that FA of the hippocampal cingulum moderated the association between report of at least one BR mTBI and poorer TMT-B performance (p < 0.008), such that lower FA value was associated with worse TMT-B outcomes in individuals with BR mTBI. No significant moderation existed for other selected tracts, and the effect was not observed with predictors aside from history of BR mTBI. Investigation at the individual-tract level may lead to a deeper understanding of neurological differences between blast-related and non-blast related injuries.

Persistent MRI Findings Unique to Blast and Repetitive Mild TBI: Analysis of the CENC/LIMBIC Cohort Injury Characteristics.

INTRODUCTION: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) are mixed, making the findings difficult to interpret. As such, additional research is needed to continue to elucidate the relationship between the clinical features of mTBI and quantitative MRI measurements. MATERIAL AND METHODS: Volumetric and diffusion imaging data in a sample of 976 veterans and service members from the Chronic Effects of Neurotrauma Consortium and now the Long-Term Impact of Military-Relevant Brain Injury Consortium observational study of the late effects of mTBI in combat with and without a history of mTBI were examined. A series of regression models with link functions appropriate for the model outcome were used to evaluate the relationships among imaging measures and clinical features of mTBI. Each model included acquisition site, participant sex, and age as covariates. Separate regression models were fit for each region of interest where said region was a predictor. RESULTS: After controlling for multiple comparisons, no significant main effect was noted for comparisons between veterans and service members with and without a history of mTBI. However, blast-related mTBI were associated with volumetric reductions of several subregions of the corpus callosum compared to non-blast-related mTBI. Several volumetric (i.e., hippocampal subfields, etc.) and diffusion (i.e., corona radiata, superior longitudinal fasciculus, etc.) MRI findings were noted to be associated with an increased number of repetitive mTBIs versus. CONCLUSIONS: In deployment-related mTBI, significant findings in this cohort were only observed when considering mTBI sub-groups (blast mechanism and total number/dose). Simply comparing healthy controls and those with a positive mTBI history is likely an oversimplification that may lead to non-significant findings, even in consortium analyses.

Intrusive Traumatic Re-Experiencing Domain: Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium.

Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n= 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology.

Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

Adaptation in Young Military Recruits: Protocol for the Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study.

BACKGROUND: Military services provide a unique opportunity for studying resilience, a dynamic process of successful adaptation (ie, doing well in terms of functioning and symptoms) in response to significant adversity. Despite the tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding the neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential for enhancing the resilience of military service members. OBJECTIVE: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize the trajectories of positive adaptation among young military recruits in response to basic combat training (BCT), a well-defined, uniform, and 10-week period of intense stress (aim 1), and identify promotive and protective processes contributing to individual variations in resilience (aim 2). The secondary objective is to investigate the pathways by which neurobehavioral markers of self-regulation assessed using electroencephalography and magnetic resonance imaging contribute to adaptive trajectories (aim 3). METHODS: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped out for BCT. Participants (N=1201) are assessed at 5 time points over the initial >2 years of military service beginning before BCT (baseline) and followed up at 2 weeks and 6, 12, and 18 months after BCT. Participants complete web-based questionnaires assessing vulnerability and protective factors, mental health, and socioemotional functioning at each time point and a battery of neurocognitive tests at time 0. A subset of participants also complete structured diagnostic interviews and additional self-report measures and perform neurobehavioral tasks before and after BCT during electroencephalography sessions and before BCT only during magnetic resonance imaging sessions. RESULTS: This UG3/UH3 project was initially funded in August 2017, with the UG3 pilot work completed at the end of 2018. The UH3 phase of the project was funded in March 2019. Study enrollment for the UH3 phase began on April 14, 2019, and ended on October 16, 2021. A total of 1201 participants are enrolled in the study. Follow-up data collection for the UH3 phase is ongoing and projected to continue through February 2024. We will disseminate the findings through conferences, webinars, open access publications, and communications with participants and stakeholders. CONCLUSIONS: The ARMOR study provides a rich data set to identify the predictors and mechanisms of resilient and nonresilient outcomes in the context of military stressors, which are intended to empirically inform the development of prevention and intervention strategies to enhance the resilience of military trainees and potentially other young people facing significant life challenges. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51235.

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study of Adaptation in Young Military Recruits: Protocol and rationale for methods and measures.

Background: Military service provides a unique opportunity for studying resilience, a dynamic process of successful adaptation (i.e., doing well in terms of functioning and symptoms) in response to significant adversity. Despite tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential to enhance the resilience of military service members. Objectives: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize trajectories of positive adaptation among young military recruits in response to Basic Combat Training (BCT), a well-defined, uniform, 10-week period of intense stress (Aim 1) and identify promotive and protective processes contributing to individual variations in resilience (Aim 2). The secondary objective is to investigate pathways by which neurobehavioral markers of self-regulation assessed by electroencephalography (EEG) and magnetic resonance imaging (MRI) contribute to adaptive trajectories (Aim 3). Methods: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped for BCT. Participants (N=1,201) are assessed at five timepoints over the initial 2+ years of military service beginning before BCT (baseline) and followed up at 2 weeks, 6, 12, and 18 months post-BCT. At each time point, participants complete online questionnaires assessing vulnerability and protective factors, mental health and social-emotional functioning, and, at Time 0 only, a battery of neurocognitive tests. A subset of participants also complete structured diagnostic interviews, additional self-report measures, and perform neurobehavioral tasks before and after BCT during EEG sessions, and, at pre-BCT only, during MRI sessions. Results: Study enrollment began April 14, 2019 and ended in October 16, 2021. A total of 1,201 participants are enrolled in the study (68.9% male; mean age = 18.9, SD = 3.0). Follow-up data-collection is ongoing and projected to continue through March 2024. We will disseminate findings through conferences, webinars, open access publications, and communications with participants and stakeholders. Conclusions: Results are expected to elucidate how young military recruits adapt to military stressors during the initial years of military service. Understanding positive adaptation of military recruits in the face of BCT has implications for developing prevention and intervention strategies to enhance resilience of military trainees and potentially other young people facing significant life challenges.

A randomized sham-controlled clinical trial of a novel wearable intervention for trauma-related nightmares in military veterans.

STUDY OBJECTIVES: Persistent nightmares are common among individuals exposed to trauma and are especially prevalent among veterans. While behavioral and pharmacological interventions are available, they have demonstrated limited efficacy. Innovations in wearable technology provide a potential avenue to match or exceed these existing treatments by directly targeting nightmare physiology. METHODS: We conducted a randomized, sham-controlled study to determine the efficacy of a novel wearable device-based application in 65 veterans with impaired sleep secondary to trauma-related nightmares. Changes in measures of sleep quality, posttraumatic stress disorder/depression symptoms, and quality of life across the 30-day trial were compared between the Active and Sham systems. RESULTS: Both groups demonstrated statistically significant within-person improvement on all measures. While the Active system was generally associated with stronger magnitude of improvement, none of the comparisons of individual measures across conditions reached statistical significance. However, a post-hoc analysis excluding participants with low frequency of usage demonstrated significantly better improvement in perceived sleep quality with the Active device than Sham. CONCLUSIONS: Overall, these results provide preliminary evidence that a wearable device may improve self-reported sleep quality for veterans reporting frequent trauma-related nightmares, especially in compliant users. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Traumatic Nightmares Treated by NightWare (To Arouse Not Awaken) (TNT/NW); URL: https://www.clinicaltrials.gov/ct2/show/NCT04040387; Identifier: NCT04040387. CITATION: Davenport ND, Werner JK. A randomized sham-controlled clinical trial of a novel wearable intervention for trauma-related nightmares in military veterans. J Clin Sleep Med. 2023;19(2):361-369.

Evaluating resilience in response to COVID-19 pandemic stressors among veteran mental health outpatients.

There is a public health need to understand mental health vulnerabilities to COVID-19 pandemic-related stressors and promote resilience among high-risk populations with preexisting psychiatric conditions. Recent cross-sectional studies suggest increases in mental health distress (e.g., depression and anxiety) during the pandemic. The present study expands upon these emerging findings using longitudinal latent modeling and hierarchical linear regressions. Consistent with the developmental psychopathology literature on resilience, we distinguished between promotive or risk (i.e., main effect), and protective or vulnerability (i.e., moderation) effects on mental health during the pandemic. At a large medical center, 398 veterans receiving outpatient mental health care provided prepandemic (Time 1) and during pandemic (Time 2) assessments of mental and physical health-related distress. Additional Time 2 questionnaires assessed pandemic-related stressors and positive behavioral adaptations in the summer of 2020. As expected, total stressor scores predicted longitudinal worsening of self-reported mental (ß = -.205) and physical health (ß = -.217). Positive behavioral adaptations enacted during the pandemic moderated and protected against stressor effects on mental health (ß = .160). In addition, the presence of substance use disorders moderated and conferred vulnerability to stressor effects on physical health (ß = -.158). Thus, higher COVID-19 pandemic stressor exposure may have exacerbated mental and physical health distress among veterans with common forms of psychopathology. Nevertheless, behavioral activation, purposeful maintenance of social connections, and focused treatment for substance misuse may be important intervention targets for reducing the longitudinal impact of pandemic stressors and enhancing resilience among people with mental illness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.

Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume.

The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10-20), thalamus (p = 7.46 × 10-10), caudate (p = 1.97 × 10-18), putamen (p = 1.7 × 10-12), and nucleus accumbens (p = 1.99 × 10-7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = -0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10-19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10-7) or PTSD (rs10861272; p = 1.78 × 10-6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Posttraumatic stress symptomatology and abnormal neural responding during emotion regulation under cognitive demands: mediating effects of personality.

Posttraumatic stress disorder (PTSD) is often complicated by the after-effects of mild traumatic brain injury (mTBI). The mixture of brain conditions results in abnormal affective and cognitive functioning, as well as maladaptive behavior. To better understand how brain activity explains cognitive and emotional processes in these conditions, we used an emotional N-back task and functional magnetic resonance imaging (fMRI) to study neural responses in US military veterans after deployments to Iraq and Afghanistan. Additionally, we sought to examine whether hierarchical dimensional models of maladaptive personality could account for the relationship between combat-related brain conditions and fMRI responses under cognitive and affective challenge. FMRI data, measures of PTSD symptomatology (PTSS), blast-induced mTBI (bmTBI) severity, and maladaptive personality (MMPI-2-RF) were gathered from 93 veterans. Brain regions central to emotion regulation were selected for analysis, and consisted of bilateral amygdala, bilateral dorsolateral prefrontal (dlPFC), and ventromedial prefrontal/subgenual anterior cingulate (vmPFC-sgACC). Cognitive load increased activity in dlPFC and reduced activity in emotional responding brain regions. However, individuals with greater PTSS showed blunted deactivations in bilateral amygdala and vmPFC-sgACC, and weaker responses in right dlPFC. Additionally, we found that elevated emotional/internalizing dysfunction (EID), specifically low positive emotionality (RC2), accounted for PTSS-related changes in bilateral amygdala under increased cognitive load. Findings suggest that PTSS might result in amygdala and vmPFC-sgACC activity resistant to moderation by cognitive demands, reflecting emotion dysregulation despite a need to marshal cognitive resources. Anhedonia may be an important target for interventions that improve the affective and cognitive functioning of individuals with PTSD.

Longitudinal evaluation of ventricular volume changes associated with mild traumatic brain injury in military service members.

PRIMARY OBJECTIVE: To investigate differences in longitudinal trajectories of ventricle-brain ratio (VBR), a general measure of brain atrophy, between Veterans with and without history of mild traumatic brain injury (mTBI). RESEARCH DESIGN: Structural magnetic resonance imaging (MRI) was used to calculate VBR in 70 Veterans with a history of mTBI and 34 Veterans without such history at two time points approximately 3 and 8 years after a combat deployment. MAIN OUTCOMES AND RESULTS: Both groups demonstrated a quadratic relationship between VBR and age that is consistent with normal developmental trajectories. Veterans with history of mTBI had larger total brain volume, but no interaction between mTBI and age was observed for brain volume, ventricular volume, or VBR. CONCLUSIONS: In our longitudinal sample of deployed Veterans, mTBI was not associated with gross brain atrophy as reflected by abnormally high VBR or abnormal increases in VBR over time.

Abnormal cortical neural synchrony during working memory in schizophrenia.

OBJECTIVE: To better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information. METHODS: We examined time-frequency synchronous energy of cortical source signals that were derived from magnetoencephalography (MEG) localized to cortical regions using WM-related hemodynamic responses and individualized structural head-models. RESULTS: Compared to thirteen healthy controls (HC), twelve PSZ showed performance deficits regardless of WM-load or duration. During encoding, PSZ had early theta and delta event-related synchrony (ERS) deficits in prefrontal and visual cortices which worsened with greater memory load and predicted WM performance. During prolonged maintenance of material, PSZ showed deficient beta event-related desynchrony (ERD) in dorsolateral prefrontal, posterior parietal, and visual cortices. In retrieval, PSZ showed reduced delta/theta ERS in the anterior prefrontal and ventral visual cortices and diminished gamma ERS in the premotor and posterior parietal cortices. CONCLUSIONS: Although beta/gamma cortical neural oscillatory deficits for maintenance/retrieval are evident during WM, the abnormal prefrontal theta-frequency ERS for encoding is most predictive of poor WM in schizophrenia. SIGNIFICANCE: Time-frequency-spatial analysis identified process- and frequency-specific neural synchrony abnormalities underlying WM deficits in schizophrenia.

PTSD confounds detection of compromised cerebral white matter integrity in military veterans reporting a history of mild traumatic brain injury.

PRIMARY OBJECTIVE: Based on high comorbidity between mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) among deployed military service members, this study tested the hypothesis that the presence of PTSD disrupts the association between mTBI and lower white matter integrity identified in non-military samples. Research design/Methods and procedures: In a sample of 124 recent veterans with a range of mTBI and PTSD history, diffusion tensor imaging (DTI) metrics of white matter integrity in 20 regions were compared using multiple mTBI and PTSD contrasts. MAIN OUTCOMES AND RESULTS: Civilian mTBI was associated with lower global anisotropy, higher global diffusivity and higher diffusivity in 17 of 20 regions. No main effects of deployment mTBI were observed, but an interaction between deployment mTBI and lifetime PTSD on FA was observed globally and in 10 regions. Impact and blast mTBI demonstrated similar but weaker effects to those of civilian and deployment mTBI, respectively, demonstrating the context of mTBI is more relevant to white matter integrity than mechanism of injury. CONCLUSIONS: Overall, a main effect of civilian mTBI indicates long-term disruptions to white matter are likely present, while the interaction between deployment mTBI and PTSD indicates that a history of PTSD alters this relationship.

Deficits in Visual System Functional Connectivity after Blast-Related Mild TBI are Associated with Injury Severity and Executive Dysfunction.

INTRODUCTION: Approximately, 275,000 American service members deployed to Iraq or Afghanistan have sustained a mild traumatic brain injury (mTBI), with 75% of these incidents involving an explosive blast. Visual processing problems and cognitive dysfunction are common complaints following blast-related mTBI. METHODS: In 127 veterans, we examined resting fMRI functional connectivity (FC) of four key nodes within the visual system: lateral geniculate nucleus (LGN), primary visual cortex (V1), lateral occipital gyrus (LO), and fusiform gyrus (FG). Regression analyses were performed (i) to obtain correlations between time-series from each seed and all voxels in the brain, and (ii) to identify brain regions in which FC variability was related to blast mTBI severity. Blast-related mTBI severity was quantified as the sum of the severity scores assigned to each of the three most significant blast-related injuries self-reported by subjects. Correlations between FC and performance on executive functioning tasks were performed across participants with available behavioral data (n = 94). RESULTS: Greater blast mTBI severity scores were associated with lower FC between: (A) LGN seed and (i) medial frontal gyrus, (ii) lingual gyrus, and (iii) right ventral anterior nucleus of thalamus; (B) V1 seed and precuneus; (C) LO seed and middle and superior frontal gyri; (D) FG seed and (i) superior and medial frontal gyrus, and (ii) left middle frontal gyrus. Finally, lower FC between visual network regions and frontal cortical regions predicted worse performance on the WAIS digit-symbol coding task. CONCLUSION: These are the first published results that directly illustrate the relationship between blast-related mTBI severity, visual pathway neural networks, and executive dysfunction - results that highlight the detrimental relationship between blast-related brain injury and the integration of visual sensory input and executive processes.

The Chaos of Combat: An Overview of Challenges in Military Mild Traumatic Brain Injury Research.

Mild traumatic brain injury (mTBI), or concussion, is among the most common injuries affecting Veterans of recent combat deployments. Military mTBI differs from civilian mTBI in fundamental ways that make assessment and diagnosis difficult, including a reliance on retrospective self-report and the potential influence of comorbid psychopathology. These unique features and their implications for research and clinical practice are summarized, and neuroimaging studies are discussed in the context of these complicating factors.

Personality and neuroimaging measures differentiate PTSD from mTBI in veterans.

Mild traumatic brain injury (mTBI) is common among recent veterans and often is associated with chronic post-concussive symptoms (PCS). Elevated PCS may also be a consequence of post-traumatic stress disorder (PTSD) which shares symptoms with PCS. Identification of personality, biological, and psychopathology factors that contribute to the relationship between mTBI and PCS could help isolate the sources of chronic post concussive syndrome in veterans. Clinician rated diagnoses (PTSD, Major Depression, Alcohol Dependence), personality characteristics (Multidimensional Personality Questionnaire [MPQ] subscales), white matter brain imaging measures (Mean Diffusivity, Generalized Fractional Anisotropy), and diagnoses of mTBI were collected from 125 American military veterans of Iraq or Afghanistan. Linear and logistic regression models were tested to determine contributions to PCS and whether there were similar contributors to PTSD and mTBI. PCS score was associated with personality characteristics of high Stress Reaction and Traditionalism and low Control as well as mTBI. A diagnosis of PTSD was associated with low Social Closeness, PCS, Alcohol Dependence, and abnormal white matter mean diffusivity. Diagnosis of mTBI was associated with fewer white matter mean diffusivity abnormalities, PCS, and number of deployments. As commonly observed clinically, both PTSD and mTBI were associated with higher rates of PCS, though the contribution of PTSD appears to be secondary to personality traits, particularly Stress Reaction. Furthermore, the observation of factors that are uniquely associated with Blast mTBI (number of deployments) or with PTSD (Lifetime Alcohol Dependence and low Social Closeness), as well as a factor (region of abnormal MD) that had opposite effects on the likelihood of each diagnosis, indicates that the complex relationships between personality, psychopathology, and nature of mTBI need to be considered when interpreting chronic post-concussive symptoms.