Early Brain Amyloid Accumulation at PET in Military Instructors Exposed to Subconcussive Blast Injuries.

Background Traumatic brain injury (TBI) is the leading cause of disability in young adults. Recurrent TBI is associated with a range of neurologic sequelae, but the contributing factors behind the development of such chronic encephalopathy are poorly understood. Purpose To quantify early amyloid ß deposition in the brain of otherwise healthy adult men exposed to repeated subconcussive blast injury using amyloid PET. Materials and Methods In this prospective study from January 2020 to December 2021, military instructors who were routinely exposed to repeated blast events were evaluated at two different points: baseline (before blast exposure from breacher or grenade) and approximately 5 months after baseline (after blast exposure). Age-matched healthy control participants not exposed to blasts and without a history of brain injury were evaluated at similar two points. Neurocognitive evaluation was performed with standard neuropsychologic testing in both groups. Analysis of PET data consisted of standardized uptake value measurements in six relevant brain regions and a whole-brain voxel-based statistical approach. Results Participants were men (nine control participants [median age, 33 years; IQR, 32-36 years] and nine blast-exposed participants [median age, 33 years; IQR, 30-34 years]; P = .82). In the blast-exposed participants, four brain regions showed significantly increased amyloid deposition after blast exposure: inferomedial frontal lobe (P = .004), precuneus (P = .02), anterior cingulum (P = .002), and superior parietal lobule (P = .003). No amyloid deposition was observed in the control participants. Discriminant analysis on the basis of regional changes of amyloid accumulation correctly classified the nine healthy control participants as healthy control participants (100%), and seven of the nine blast-exposed participants (78%) were correctly classified as blast exposed. Based on the voxel-based analysis, whole-brain parametric maps of early abnormal early amyloid uptake were obtained. Conclusion Early brain amyloid accumulation was identified and quantified at PET in otherwise healthy adult men exposed to repetitive subconcussive traumatic events. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Haller in this issue.

Close proximity to blast: No long-term or lasting effect on cognitive performance in service members with and without TBI during blast exposure.

OBJECTIVE: Blast related characteristics may contribute to the diversity of findings on whether mild traumatic brain injury sustained during war zone deployment has lasting cognitive effects. This study aims to evaluate whether a history of blast exposure at close proximity, defined as exposure within 30 feet, has long-term or lasting influences on cognitive outcomes among current and former military personnel. METHOD: One hundred participants were assigned to one of three groups based on a self-report history of blast exposure during combat deployments: 47 close blast, 14 non-close blast, and 39 comparison participants without blast exposure. Working memory, processing speed, verbal learning/memory, and cognitive flexibility were evaluated using standard neuropsychological tests. In addition, assessment of combat exposure and current post-concussive, posttraumatic stress, and depressive symptoms, and headache was performed via self-report measures. Variables that differed between groups were controlled as covariates. RESULTS: No group differences survived Bonferroni correction for family-wise error rate; the close blast group did not differ from non-close blast and comparison groups on measures of working memory, processing speed, verbal learning/memory, or cognitive flexibility. Controlling for covariates did not alter these results. CONCLUSION: No evidence emerged to suggest that a history of close blast exposure was associated with decreased cognitive performance when comparisons were made with the other groups. Limited characterization of blast contexts experienced, self-report of blast distance, and heterogeneity of injury severity within the groups are the main limitations of this study.

Remote blast-related mild traumatic brain injury is associated with differential expression of exosomal microRNAs identified in neurodegenerative and immunological processes.

BACKGROUND: Blast traumatic brain injury (TBI) and subconcussive blast exposure have been associated, pathologically, with chronic traumatic encephalopathy (CTE) and, clinically, with cognitive and affective symptoms, but the underlying pathomechanisms of these associations are not well understood. We hypothesized that exosomal microRNA (miRNA) expression, and their relation to neurobehavioral outcomes among Veterans with blunt or blast mild TBI (mTBI) may provide insight into possible mechanisms for these associations and therapeutic targets. METHODS: This is a subanalysis of a larger Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project. Participants (n = 152) were divided into three groups: Controls (n = 35); Blunt mTBI only (n = 54); and Blast/blast+blunt mTBI (n = 63). Postconcussive and post-traumatic stress symptoms were evaluated using the NSI and PCL-5, respectively. Exosomal levels of 798 miRNA expression were measured. RESULTS: In the blast mTBI group, 23 differentially regulated miRNAs were observed compared to the blunt mTBI group and 23 compared to controls. From the pathway analysis, significantly dysregulated miRNAs in the blast exposure group correlated with inflammatory, neurodegenerative, and androgen receptor pathways. DISCUSSION: Our findings suggest that chronic neurobehavioral symptoms after blast TBI may pathomechanistically relate to dysregulated cellular pathways involved with neurodegeneration, inflammation, and central hormonal regulation.

Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort.

Mild traumatic brain injury (mTBI) is among the most common injuries sustained by post-9/11 veterans; however, these injuries often occur within the context of psychological trauma. Blast exposure, even in the absence of a diagnosable TBI, leads to changes in neural connectivity and congitive functioning. Therefore, considering clinical comorbidities and injury characteristics is critical to understanding the long-term effects of mTBI. Research is moving towards identifying diagnostic and prognostic blood-based biomarkers for TBI; however, few studies include other prevalent clinical and medical comorbidities related to deployment. Here, we present the initial cross-sectional relationships between plasma biomarkers, clinical, and medical comorbidities in a well-characterized longitudinal sample of 550 post-9/11 veteran men and women. We examined biomarkers associated with inflammation (interleukin 6 and 10, tumor necrosis factor α, and eotaxin) and neurodegeneration (neurofilament light, glial fibrillary acidic protein (GFAP), tau, brain derived neurotrophic factor, amyloid ß 40 and 42, phosphorylated neurofilament heavy chain, and neuron specific enolase). Univariate analyses of covariance (ANCOVA) were conducted to determine mean level differences between close blast (blasts that occur within 0-10 meters) and mTBI groups. Our primary findings were twofold: (1) Inflammatory markers were consistently higher in participants exposed to close blasts and were strongly related to deployment-related psychopathology. (2) GFAP was consistently lower in participants exposed to blast and mTBI and lower GFAP was associated with more severe psychological symptoms. More research is clearly needed; however, our findings indicate that chronic increased inflammation and decreased GFAP may be related to close blast exposure.

The association between blast exposure and transdiagnostic health symptoms on systemic inflammation.

Chronic elevation of systemic inflammation is observed in a wide range of disorders including PTSD, depression, and traumatic brain injury. Although previous work has demonstrated a link between inflammation and various diagnoses separately, few studies have examined transdiagnostic symptoms and inflammation within the same model. The objective of this study was to examine relationships between psychiatric and health variables and systemic inflammation and to determine whether mild traumatic brain injury (mTBI) and/or exposure to blast munitions moderate these relationships. Confirmatory factor analysis in a large sample (N = 357) of post-9/11 Veterans demonstrated a good fit to a four-factor model reflecting traumatic stress, affective, somatic, and metabolic latent variables. Hierarchical regression models revealed that each of the latent variables were associated with higher levels of systemic inflammation. However, the strongest relationship with inflammation emerged among those who had both war-zone blast exposures and metabolic dysregulation, even after adjusting for mental health latent variables. Exploratory analyses showed that blast exposure was associated with metabolic dysregulation in a dose-response manner, with self-reported closer blast proximity associated with the greatest metabolic dysregulation. Together, these results provide a greater understanding of the types of symptoms most strongly associated with inflammation and underscore the importance of maintaining a healthy lifestyle to reduce the impact of obesity and other metabolic symptoms on future chronic disease in younger to middle-aged Veterans.

Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury.

Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7-16 post injury and again from day 35-43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.

Animal model of repeated low-level blast traumatic brain injury displays acute and chronic neurobehavioral and neuropathological changes.

Blast-induced neurotrauma (BINT) is not only a signature injury to soldiers in combat field and training facilities but may also a growing concern in civilian population due to recent increases in the use of improvised explosives by insurgent groups. Unlike moderate or severe BINT, repeated low-level blast (rLLB) is different in its etiology as well as pathology. Due to the constant use of heavy weaponry as part of combat readiness, rLLB usually occurs in service members undergoing training as part of combat readiness. rLLB does not display overt pathological symptoms; however, earlier studies report chronic neurocognitive changes such as altered mood, irritability, and aggressive behavior, all of which may be caused by subtle neuropathological manifestations. Current animal models of rLLB for investigation of neurobehavioral and neuropathological alterations have not been adequate and do not sufficiently represent rLLB conditions. Here, we developed a rat model of rLLB by applying controlled low-level blast pressures (<10 psi) repeated successively five times to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also examined levels of superoxide-producing enzyme NADPH oxidase, microglial activation, and reactive astrocytosis as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic anxiety-like symptoms, motor and short-term memory impairments. These changes were paralleled by increased microglial activation and reactive astrocytosis. Conversely, animals exposed to a single low-level blast did not display significant changes. Collectively, this study demonstrates that, unlike a single low-level blast, rLLB exerts a cumulative impact on different brain regions and produces chronic neuropathological changes in so doing, may be responsible for neurobehavioral alterations.

Repetitive Low-Level Blast Exposure Improves Behavioral Deficits and Chronically Lowers Aß42 in an Alzheimer Disease Transgenic Mouse Model.

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aß) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aß42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aß 42 levels and Aß oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.

Alterations in the Topology of Functional Connectomes Are Associated with Post-Traumatic Stress Disorder and Blast-Related Mild Traumatic Brain Injury in Combat Veterans.

Post-traumatic stress disorder (PTSD) is a common condition in post-deployment service members (SM). SMs of the conflicts in Iraq and Afghanistan also frequently experience traumatic brain injury (TBI) and exposure to blasts during deployments. This study evaluated the effect of these conditions and experiences on functional brain connectomes in post-deployment, combat-exposed veterans. Functional brain connectomes were created using 5-min resting-state magnetoencephalography data. Well-established clinical interviews determined current PTSD diagnosis, as well as deployment-acquired mild TBI and history of exposure to blast. Linear regression examined the effect of these conditions on functional brain connectomes beyond covariates. There were significant interactions between blast-related mild TBI and PTSD after correction for multiple comparisons including number of nodes (non-standardized parameter estimate [PE] = -12.47), average degree (PE = 0.05), and connection strength (PE = 0.05). A main effect of blast-related mild TBI was observed on the threshold level. These results demonstrate a distinct functional connectome presentation associated with the presence of both blast-related mild TBI and PTSD. These findings suggest the possibility that blast-related mild TBI alterations in functional brain connectomes affect the presentation or progression of recovery from PTSD. The current results offer mixed support for hyper-connectivity in the chronic phase of deployment TBI.

Psychosocial impairment following mild blast-induced traumatic brain injury in rats.

Traumatic brain injury (TBI) is associated with increased risk for mental health disorders, impacting post-injury quality of life and societal reintegration. TBI is also associated with deficits in psychosocial processing, defined as the cognitive integration of social and emotional behaviors, however little is known about how these deficits manifest and their contributions to post-TBI mental health. In this pre-clinical investigation using rats, a single mild blast TBI (mbTBI) induced impairment of psychosocial processing in the absence of confounding physical polytrauma, post-injury motor deficits, affective abnormalities, or deficits in non-social behavior. Impairment severity correlated with acute upregulations of a known oxidative stress metabolite, 3-hydroxypropylmercapturic acid (3-HPMA), in urine. Resting state fMRI alterations in the acute post-injury period implicated key brain regions known to regulate psychosocial behavior, including orbitofrontal cortex (OFC), which is congruent with our previous report of elevated acrolein, a marker of neurotrauma and 3-HPMA precursor, in this region following mbTBI. OFC of mbTBI-exposed rats demonstrated elevated mRNA expression of metabotropic glutamate receptors 1 and 5 (mGluR1/5) and injection of mGluR1/5-selective agonist in OFC of uninjured rats approximated mbTBI-induced psychosocial processing impairment, demonstrating a novel role for OFC in this psychosocial behavior. Furthermore, OFC may serve as a hotspot for TBI-induced disruption of psychosocial processing and subsequent mental health disorders.

Information Transfer and Multifractal Analysis of EEG in Mild Blast-Induced TBI.

Mild, blast-induced traumatic brain injury (mbTBI) is a common combat brain injury characterized by typically normal neuroimaging findings, with unpredictable future cognitive recovery. Traditional methods of electroencephalography (EEG) analysis (e.g., spectral analysis) have not been successful in detecting the degree of cognitive and functional impairment in mbTBI. We therefore collected resting state EEG (5 minutes, 64 leads) from twelve patients with a history of mbTBI, along with repeat neuropsychological testing (D-KEFS Tower test) to compare two new methods for analyzing EEG (multifractal detrended fluctuation analysis (MF-DFA) and information transfer modeling (ITM)) with spectral analysis. For MF-DFA, we extracted relevant parameters from the resultant multifractal spectrum from all leads and compared with traditional power by frequency band for spectral analysis. For ITM, because the number of parameters from each lead far exceeded the number of subjects, we utilized a reduced set of 10 leads which were compared with spectral analysis. We utilized separate 30 second EEG segments for training and testing statistical models based upon regression tree analysis. ITM and MF-DFA models both generally had improved accuracy at correlating with relevant measures of cognitive performance as compared to spectral analytic models ITM and MF-DFA both merit additional research as analytic tools for EEG and cognition in TBI.

Time Since Injury as a Factor in Post-Concussion Symptom Reporting among Military Service Members with Blast-Related Concussion.

Over the last decade, much research has been devoted to concussion among military personnel. Post-concussion symptoms after blast-related concussion are common, but it is unknown whether symptom reporting differs over time. This study's objective was to assess the relationship between time since injury and post-concussion symptom reporting. We conducted a retrospective review of existing records to identify service members who experienced blast-related concussion during deployment between 2007 and 2012 and who responded to a Post-Deployment Health Assessment (PDHA). The study population included 3690 military personnel grouped by time between injury and PDHA completion: 1-90 days (45.3%, n = 1,673), 91-180 days (33.0%, n = 1,216), or 181-365 days (21.7%, n = 801). Post-concussion symptoms assessed on the PDHA included headache, tinnitus, memory problems, concentration problems, difficulty making decisions, irritability, dizziness, and sleep problems. All post-concussion symptoms were higher for 91-180 days and 181-365 days after injury relative to 1-90 days, with the exception of dizziness. After adjustment for loss of consciousness, mental health comorbidity, and other covariates, the odds of reporting three or more post-concussion symptoms were significantly higher in those who completed the PDHA 91-180 days (odds ratio: 1.29; 95% confidence interval: 1.09-1.51) or 181-365 days after injury (odds ratio: 1.33; 95% confidence interval: 1.09-1.61), compared with the 1-90 days group. These findings suggest that refinements to in-theater medical care may be needed to reduce post-concussion symptom burden and improve the prospect of concussion recovery.

Performance validity and symptom validity tests: Are they measuring different constructs?

OBJECTIVE: To evaluate the relationships among performance validity, symptom validity, symptom self-report, and objective cognitive testing. METHOD: Combat Veterans (N = 338) completed a neurocognitive assessment battery and several self-report symptom measures assessing depression, posttraumatic stress disorder (PTSD) symptoms, sleep quality, pain interference, and neurobehavioral complaints. All participants also completed two performance validity tests (PVTs) and one stand-alone symptom validity test (SVT) along with two embedded SVTs. RESULTS: Results of an exploratory factor analysis revealed a three-factor solution: performance validity, cognitive performance, and symptom report (SVTs loaded on the third factor). Results of t tests demonstrated that participants who failed PVTs displayed significantly more severe symptoms and significantly worse performance on most measures of neurocognitive functioning compared to those who passed. Participants who failed a stand-alone SVT also reported significantly more severe symptomatology on all symptom report measures, but the pattern of cognitive performance differed based on the selected SVT cutoff. Multiple linear regressions revealed that both SVT and PVT failure explained unique variance in symptom report, but only PVT failure significantly predicted cognitive performance. CONCLUSIONS: Performance and symptom validity tests measure distinct but related constructs. SVTs and PVTs are significantly related to both cognitive performance and symptom report; however, the relationship between symptom validity and symptom report is strongest. SVTs are also differentially related to cognitive performance and symptom report based on the utilized cutoff score. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Laterality and region-specific tau phosphorylation correlate with PTSD-related behavioral traits in rats exposed to repetitive low-level blast.

Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.

Distinct and dementia-related synaptopathy in the hippocampus after military blast exposures.

Explosive shockwaves, and other types of blast exposures, are linked to injuries commonly associated with military service and to an increased risk for the onset of dementia. Neurological complications following a blast injury, including depression, anxiety, and memory problems, often persist even when brain damage is undetectable. Here, hippocampal explants were exposed to the explosive 1,3,5-trinitro-1,3,5-triazinane (RDX) to identify indicators of blast-induced changes within important neuronal circuitries. Highly controlled detonations of small, 1.7-gram RDX spherical charges reduced synaptic markers known to be downregulated in cognitive disorders, but without causing overt neuronal loss or astroglial responses. In the absence of neuromorphological alterations, levels of synaptophysin, GluA1, and synapsin IIb were significantly diminished within 24 hr, and these synaptic components exhibited progressive reductions following blast exposure as compared to their stable maintenance in control explants. In contrast, labeling of the synapsin IIa isoform remained unaltered, while neuropilar staining of other markers decreased, including synapsin IIb and neural cell adhesion molecule (NCAM) isoforms, along with evidence of NCAM proteolytic breakdown. NCAM180 displayed a distinct decline after the RDX blasts, whereas NCAM140 and NCAM120 exhibited smaller or no deterioration, respectively. Interestingly, the extent of synaptic marker reduction correlated with AT8-positive tau levels, with tau pathology stochastically found in CA1 neurons and their dendrites. The decline in synaptic components was also reflected in the size of evoked postsynaptic currents recorded from CA1 pyramidals, which exhibited a severe and selective reduction. The identified indicators of blast-mediated synaptopathy point to the need for early biomarkers of explosives altering synaptic integrity with links to dementia risk, to advance strategies for both cognitive health and therapeutic monitoring.

Behavioral and Myelin-Related Abnormalities after Blast-Induced Mild Traumatic Brain Injury in Mice.

In civilian and military settings, mild traumatic brain injury (mTBI) is a common consequence of impacts to the head, sudden blows to the body, and exposure to high-energy atmospheric shockwaves from blast. In some cases, mTBI from blast exposure results in long-term emotional and cognitive deficits and an elevated risk for certain neuropsychiatric diseases. Here, we tested the effects of mTBI on various forms of auditory-cued fear learning and other measures of cognition in male C57BL/6J mice after single or repeated blast exposure (blast TBI; bTBI). bTBI produced an abnormality in the temporal organization of cue-induced freezing behavior in a conditioned trace fear test. Spatial working memory, evaluated by the Y-maze task performance, was also deleteriously affected by bTBI. Reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis for glial markers indicated an alteration in the expression of myelin-related genes in the hippocampus and corpus callosum 1-8 weeks after bTBI. Immunohistochemical and ultrastructural analyses detected bTBI-related myelin and axonal damage in the hippocampus and corpus callosum. Together, these data suggest a possible link between blast-induced mTBI, myelin/axonal injury, and cognitive dysfunction.

Progressive Cognitive and Post-Traumatic Stress Disorder-Related Behavioral Traits in Rats Exposed to Repetitive Low-Level Blast.

Many military veterans who experienced blast-related traumatic brain injuries (TBI) in the conflicts in Iraq and Afghanistan currently have chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Besides static symptoms, new symptoms may emerge or existing symptoms may worsen. TBI is also a risk factor for later development of neurodegenerative diseases. In rats exposed to repetitive low-level blast overpressure (BOP), robust and enduring cognitive and PTSD-related behavioral traits develop that are present for at least one year after blast exposure. Here we determined the time-course of the appearance of these traits by testing rats in the immediate post-blast period. Three cohorts of rats examined within the first eight weeks exhibited no behavioral phenotype or, in one cohort, features of anxiety. None showed the altered cued fear responses or impaired novel object recognition characteristic of the fully developed phenotype. Two cohorts retested 36 to 42 weeks after blast exposure exhibited the expanded behavioral phenotype including anxiety as well as altered cued fear learning and impaired novel object recognition. Combined with previous work, the chronic behavioral phenotype has been observed in six cohorts of blast-exposed rats studied at 3-4 months or longer after blast injury, and the three cohorts studied here document the progressive nature of the cognitive/behavioral phenotype. These studies suggest the existence of a latent, delayed emerging and progressive blast-induced cognitive and behavioral phenotype. The delayed onset has implications for the evolution of post-blast neurobehavioral syndromes in military veterans and its modeling in experimental animals.

Repetitive Blast Promotes Chronic Aversion to Neutral Cues Encountered in the Peri-Blast Environment.

Repetitive mild traumatic brain injury (mTBI) has been called the "signature injury" of military service members in the Iraq and Afghanistan wars and is highly comorbid with post-traumatic stress disorder (PTSD). Correct attribution of adverse blast-induced mTBI and/or PTSD remains challenging. Pre-clinical research using animal models can provide important insight into the mechanisms by which blast produces injury and dysfunction-but only to the degree by which such models reflect the human experience. Avoidance of trauma reminders is a hallmark of PTSD. Here, we sought to understand whether a mouse model of blast reproduces this phenomenon, in addition to blast-induced physical injuries. Drawing on well-established work from the chronic stress and Pavlovian conditioning literature, we hypothesized that even while one is anesthetized during blast exposure, environmental cues encountered in the peri-blast environment could be conditioned to evoke aversion/dysphoria and re-experiencing of traumatic stress. Using a pneumatic shock tube that recapitulates battlefield-relevant open-field blast forces, we provide direct evidence that stress is inherent to repetitive blast exposure, resulting in chronic aversive/dysphoric-like responses to previous blast-paired cues. The results in this report demonstrate that, although both single and repetitive blast exposures produce acute stress responses (weight loss, corticosterone increase), only repetitive blast exposure also results in co-occurring aversive/dysphoric-like stress responses. These results extend appreciation of the highly complex nature of repetitive blast exposure; and lend further support for the potential translational relevance of animal modeling approaches currently used by multiple laboratories aimed at elucidating the mechanisms (both molecular and behavioral) of repetitive blast exposure.

Comparison of Clinical Outcomes 1 and 5 Years Post-Injury Following Combat Concussion.

OBJECTIVE: To compare 1-year and 5-year clinical outcomes in 2 groups of combat-deployed service members without brain injury to those of 2 groups with combat-related concussion to better understand long-term clinical outcome trajectories. METHODS: This prospective, observational, longitudinal multicohort study examined 4 combat-deployed groups: controls without head injury with or without blast exposure and patients with combat concussion arising from blast or blunt trauma. One-year and 5-year clinical evaluations included identical batteries for neurobehavioral, psychiatric, and cognitive outcomes. A total of 347 participants completed both time points of evaluation. Cross-sectional and longitudinal comparisons were assessed. Overall group effect was modeled as a 4-category variable with rank regression adjusting for demographic factors using a 2-sided significance threshold of 0.05, with post hoc Tukey p values calculated for the pairwise comparisons. RESULTS: Significant group differences in both combat concussion groups were identified cross-sectionally at 5-year follow-up compared to controls in neurobehavioral (Neurobehavioral Rating Scale-Revised [NRS]; Cohen d, -1.10 to -1.40, confidence intervals [CIs] [-0.82, -1.32] to [-0.97, -1.83] by group) and psychiatric domains (Clinician-Administered PTSD Scale for DSM-IV [CAPS]; Cohen d, -0.91 to -1.19, CIs [-0.63, -1.19] to [-0.76, -1.62] by group) symptoms with minimal differences in cognitive performance. Both combat concussion groups also showed clinically significant decline from 1- to 5-year evaluation (66%-76% neurobehavioral NRS; 41%-54% psychiatric CAPS by group). Both control groups fared better but a subset also had clinically significant decline (37%-50% neurobehavioral NRS; 9%-25% psychiatric CAPS by group). CONCLUSIONS: There was an evolution, not resolution, of symptoms from 1- to 5-year evaluation, challenging the assumption that chronic stages of concussive injury are relatively stable. Even some of the combat-deployed controls worsened. The evidence supports new considerations for chronic trajectories of concussion outcome in combat-deployed service members.

Examining posttraumatic stress disorder as a key postinjury risk factor in OIF/OEF veterans with blast-induced mild traumatic brain injury.

OBJECTIVE: To explore the neuropsychological sequelae of blast-induced mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD), several neuropsychological tests and self-reported measures of cognitive and emotional functioning were administered to 138 Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) veterans. We hypothesized that veterans affected by mTBI and PTSD would manifest differences in neuropsychological testing and self-report measures compared to a group of healthy veteran controls and to veterans with only PTSD. METHOD: Participants included 3 groups of veterans: (a) healthy controls (n = 43); (b) PTSD only (n = 48); and (c) comorbid blast-induced mTBI and PTSD (n = 47). An exploratory factor analysis (EFA) was used to extract a smaller number of latent dimensions for group comparison. RESULTS: The EFA supported an 8-factor model. A multivariate analysis of variance on the 8 factor scores demonstrated 3 significant factor mean differences: (a) perceived cognitive complications (PCC), (b) perceived emotional distress (PED), and (c) processing speed (PS). Post hoc analyses showed significant group mean difference in PS between the comorbid and the control groups. In addition, the comorbid group presented with the highest levels of PCC and PED. CONCLUSIONS: Results suggest that among OIF/OEF veterans with blast-induced mTBI, PTSD with its accompanying emotional distress may be a significant determinant of subjective sense of well-being both cognitively and emotionally. The objective discrepancy in PS between the comorbid group and the healthy controls also appears largely due to PTSD more so than the remote blast-induced mTBI, as the group mean difference in PS became negligible after controlling for PTSD levels. (PsycInfo Database Record (c) 2020 APA, all rights reserved).