Dataset Information

Detection of blast-related traumatic brain injury in U.S. military personnel.

ABSTRACT: Blast-related traumatic brain injuries have been common in the Iraq and Afghanistan wars, but fundamental questions about the nature of these injuries remain unanswered.We tested the hypothesis that blast-related traumatic brain injury causes traumatic axonal injury, using diffusion tensor imaging (DTI), an advanced form of magnetic resonance imaging that is sensitive to axonal injury. The subjects were 63 U.S. military personnel who had a clinical diagnosis of mild, uncomplicated traumatic brain injury. They were evacuated from the field to the Landstuhl Regional Medical Center in Landstuhl, Germany, where they underwent DTI scanning within 90 days after the injury. All the subjects had primary blast exposure plus another, blast-related mechanism of injury (e.g., being struck by a blunt object or injured in a fall or motor vehicle crash). Controls consisted of 21 military personnel who had blast exposure and other injuries but no clinical diagnosis of traumatic brain injury.Abnormalities revealed on DTI were consistent with traumatic axonal injury in many of the subjects with traumatic brain injury. None had detectable intracranial injury on computed tomography. As compared with DTI scans in controls, the scans in the subjects with traumatic brain injury showed marked abnormalities in the middle cerebellar peduncles (P<0.001), in cingulum bundles (P=0.002), and in the right orbitofrontal white matter (P=0.007). In 18 of the 63 subjects with traumatic brain injury, a significantly greater number of abnormalities were found on DTI than would be expected by chance (P<0.001). Follow-up DTI scans in 47 subjects with traumatic brain injury 6 to 12 months after enrollment showed persistent abnormalities that were consistent with evolving injuries.DTI findings in U.S. military personnel support the hypothesis that blast-related mild traumatic brain injury can involve axonal injury. However, the contribution of primary blast exposure as compared with that of other types of injury could not be determined directly, since none of the subjects with traumatic brain injury had isolated primary blast injury. Furthermore, many of these subjects did not have abnormalities on DTI. Thus, traumatic brain injury remains a clinical diagnosis. (Funded by the Congressionally Directed Medical Research Program and the National Institutes of Health; ClinicalTrials.gov number, NCT00785304.).

SUBMITTER: Mac Donald CL

PROVIDER: S-EPMC3146351 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Detection of blast-related traumatic brain injury in U.S. military personnel.

Mac Donald Christine L CL Johnson Ann M AM Cooper Dana D Nelson Elliot C EC Werner Nicole J NJ Shimony Joshua S JS Snyder Abraham Z AZ Raichle Marcus E ME Witherow John R JR Fang Raymond R Flaherty Stephen F SF Brody David L DL

The New England journal of medicine 20110601 22

<h4>Background</h4>Blast-related traumatic brain injuries have been common in the Iraq and Afghanistan wars, but fundamental questions about the nature of these injuries remain unanswered.<h4>Methods</h4>We tested the hypothesis that blast-related traumatic brain injury causes traumatic axonal injury, using diffusion tensor imaging (DTI), an advanced form of magnetic resonance imaging that is sensitive to axonal injury. The subjects were 63 U.S. military personnel who had a clinical diagnosis of ...[more]

PMID: 21631321

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Project description:Blast-related traumatic brain injury (TBI) has been one of the "signature injuries" of the wars in Iraq and Afghanistan. However, neuroimaging studies in concussive 'mild' blast-related TBI have been challenging due to the absence of abnormalities in computed tomography or conventional magnetic resonance imaging (MRI) and the heterogeneity of the blast-related injury mechanisms. The goal of this study was to address these challenges utilizing single-subject, module-based graph theoretic analysis of resting-state functional MRI (fMRI) data. We acquired 20min of resting-state fMRI in 63 U.S. military personnel clinically diagnosed with concussive blast-related TBI and 21 U.S. military controls who had blast exposures but no diagnosis of TBI. All subjects underwent an initial scan within 90days post-injury and 65 subjects underwent a follow-up scan 6 to 12months later. A second independent cohort of 40 U.S. military personnel with concussive blast-related TBI served as a validation dataset. The second independent cohort underwent an initial scan within 30days post-injury. 75% of the scans were of good quality, with exclusions primarily due to excessive subject motion. Network analysis of the subset of these subjects in the first cohort with good quality scans revealed spatially localized reductions in the participation coefficient, a measure of between-module connectivity, in the TBI patients relative to the controls at the time of the initial scan. These group differences were less prominent on the follow-up scans. The 15 brain areas with the most prominent reductions in the participation coefficient were next used as regions of interest (ROIs) for single-subject analyses. In the first TBI cohort, more subjects than would be expected by chance (27/47 versus 2/47 expected, p<0.0001) had 3 or more brain regions with abnormally low between-module connectivity relative to the controls on the initial scans. On the follow-up scans, more subjects than expected by chance (5/37, p=0.044) but fewer subjects than on the initial scans had 3 or more brain regions with abnormally low between-module connectivity. Analysis of the second TBI cohort validation dataset with no free parameters provided a partial replication; again more subjects than expected by chance (8/31, p=0.006) had 3 or more brain regions with abnormally low between-module connectivity on the initial scans, but the numbers were not significant (2/27, p=0.276) on the follow-up scans. A single-subject, multivariate analysis by probabilistic principal component analysis of the between-module connectivity in the 15 identified ROIs, showed that 31/47 subjects in the first TBI cohort were found to be abnormal relative to the controls on the initial scans. In the second TBI cohort, 9/31 patients were found to be abnormal in identical multivariate analysis with no free parameters. Again, there were not substantial differences on the follow-up scans. Taken together, these results indicate that single-subject, module-based graph theoretic analysis of resting-state fMRI provides potentially useful information for concussive blast-related TBI if high quality scans can be obtained. The underlying biological mechanisms and consequences of disrupted between-module connectivity are unknown, thus further studies are required.

Project description:As a result of armed conflict, head trauma from exposure to blasts is an increasing critical health issue, particularly among military service members. Whilst numerous studies examined the burden of blast-related brain injuries on service members', few systematic reviews have been published. This work provides a comprehensive summary of the evidence on blast-related mild traumatic brain injury (mTBI) burden in active U.S. military service members and inactive Veterans, describing characteristics and outcomes. Records published up to April 2017 were identified through a search of PubMed, Web of Science, Scopus, Ovid MEDLINE, and Cochrane Library. Records-based and original research reporting on U.S. military service members and Veterans with mild blast TBI were included. Data on subject characteristics, exposure, diagnostic criterion, and outcomes were extracted from included studies using a standardized extraction form and were presented narratively. Of the 2,290 references identified by the search, 106 studies with a total of 37,515 participants met inclusion criteria for blast-related mTBI. All but nine studies were based out of military or Veteran medical facilities. Unsurprisingly, men were over-represented (75-100%). The criteria used to define blast-related mTBI were consistent; however, the methodology used to ascertain whether individuals met those criteria for diagnosis were inconsistent. The diagnosis, most prevalent among the Army, heavily relied on self-reported histories. Commonly reported adverse outcomes included hearing disturbances and headaches. The most frequently associated comorbidities were post-traumatic stress disorder, depression, anxiety, sleep disorders, attention disorders, and cognitive disorders. The primary objective of this review was to provide a summary of descriptive data on blast-related mTBI in a U.S. military population. Low standardization of the methods for reaching diagnosis and problems in the study reporting emphasize the importance to collect high-quality data to fill knowledge gaps pertaining to blast-related mTBI.

Project description:OBJECTIVE: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated. METHODS: To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05). RESULTS: There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis. CONCLUSION: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms.

Project description:BackgroundMild traumatic brain injury (mTBI) occurs at a higher frequency among military personnel than among civilians. A common symptom of mTBIs is cognitive dysfunction. Health care professionals use neuropsychological assessments as part of a multidisciplinary and best practice approach for mTBI management. Such assessments support clinical diagnosis, symptom management, rehabilitation, and return-to-duty planning. Military health care organizations currently use computerized neurocognitive assessment tools (NCATs). NCATs and more traditional neuropsychological assessments present unique challenges in both clinical and military settings. Many research gaps remain regarding psychometric properties, usability, acceptance, feasibility, effectiveness, sensitivity, and utility of both types of assessments in military environments.ObjectiveThe aims of this study were to explore evidence regarding the use of NCATs among military personnel who have sustained mTBIs; evaluate the psychometric properties of the most commonly tested NCATs for this population; and synthesize the data to explore the range and extent of NCATs among this population, clinical recommendations for use, and knowledge gaps requiring future research.MethodsStudies were identified using MEDLINE, Embase, American Psychological Association PsycINFO, CINAHL Plus with Full Text, Psych Article, Scopus, and Military & Government Collection. Data were analyzed using descriptive analysis, thematic analysis, and the Randolph Criteria. Narrative synthesis and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews) guided the reporting of findings. The psychometric properties of NCATs were evaluated with specific criteria and summarized.ResultsOf the 104 papers, 33 met the inclusion criteria for this scoping review. Thematic analysis and NCAT psychometrics were reported and summarized.ConclusionsWhen considering the psychometric properties of the most commonly used NCATs in military populations, these assessments have yet to demonstrate adequate validity, reliability, sensitivity, and clinical utility among military personnel with mTBIs. Additional research is needed to further validate NCATs within military populations, especially for those living outside of the United States and individuals experiencing other conditions known to adversely affect cognitive processing. Knowledge gaps remain, warranting further study of psychometric properties and the utility of baseline and normative testing for NCATs.

Project description:Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression. Aberrant regulation of gene expression is associated with behavioral abnormalities, where DNA methylation bridges environmental signals to sustained changes in gene expression. We assessed DNA methylation changes in the brains of rats exposed to three 74.5 kPa blast overpressure events, conditions that have been associated with long-term anxiogenic manifestations weeks or months following the initial exposures. Rat frontal cortex eight months post-exposure was used for cell sorting of whole brain tissue into neurons and glia. We interrogated DNA methylation profiles in these cells using Expanded Reduced Representation Bisulfite Sequencing. We obtained data for millions of cytosines, showing distinct methylation profiles for neurons and glia and an increase in global methylation in neuronal versus glial cells (p<10(-7)). We detected DNA methylation perturbations in blast overpressure-exposed animals, compared with sham blast controls, within 458 and 379 genes in neurons and glia, respectively. Differentially methylated neuronal genes showed enrichment in cell death and survival and nervous system development and function, including genes involved in transforming growth factor β and nitric oxide signaling. Functional validation via gene expression analysis of 30 differentially methylated neuronal and glial genes showed a 1.2 fold change in gene expression of the serotonin N-acetyltransferase gene (Aanat) in blast animals (p<0.05). These data provide the first genome-based evidence for changes in DNA methylation induced in response to multiple blast overpressure exposures. In particular, increased methylation and decreased gene expression were observed in the Aanat gene, which is involved in converting serotonin to the circadian hormone melatonin and is implicated in sleep disturbance and depression associated with traumatic brain injury.

Dataset Information

Detection of blast-related traumatic brain injury in U.S. military personnel.

Publications

Detection of blast-related traumatic brain injury in U.S. military personnel.

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