Mild Blast Traumatic Brain Injury Research Articles

Neuropsychiatric Outcomes in UK Military Veterans With Mild Traumatic Brain Injury and Vestibular Dysfunction.

To estimate the frequency of vestibular dysfunction following blunt, blast, and combined blunt and blast mild traumatic brain injury (mTBI) and thereon assess the long-term impact of vestibular dysfunction on neurobehavioral function and disability independently of comorbid psychiatric symptoms. Combat Stress residential and Veterans' Outreach drop-in centers for psychological support. One hundred sixty-two help-seeking UK military veterans. Self-reported frequency and severity of mTBI (using the Ohio State TBI Identification Method), Vertigo Symptom Scale, PTSD Checklist for DSM-5, Kessler Psychological Distress Scale (K10), Neurobehavioral Symptom Inventory, Headache Impact Test (HIT6), Memory Complaints Inventory, World Health Organization Disability Assessment Schedule II short version (WHODAS 2.0). Seventy-two percent of the sample reported 1 or more mTBIs over their lifetime. Chi-square analyses indicated that vestibular disturbance, which affected 69% of participants, was equally prevalent following blunt (59%) or blast (47%) injury and most prevalent following blunt and blast combined (83%). Mediation analysis indicated that when posttraumatic stress disorder, depression, and anxiety were taken into account, vestibular dysfunction in participants with mTBI was directly and independently associated with increased postconcussive symptoms and functional disability. Vestibular dysfunction is common after combined blunt and blast mTBI and singularly predictive of poor long-term mental health. From a treatment perspective, vestibular rehabilitation may provide relief from postconcussive symptoms other than dizziness and imbalance.

Opioid Use among Individuals with Traumatic Brain Injury: A Perfect Storm?

Journal of NeurotraumaVol. 37, No. 1 Short CommunicationOpioid Use among Individuals with Traumatic Brain Injury: A Perfect Storm?Rachel Sayko Adams, John D. Corrigan, and Kristen Dams-O'ConnorRachel Sayko AdamsInstitute for Behavioral Health, The Heller School for Social Policy and Management, Brandeis University, Waltham, Massachusetts.VHA Rocky Mountain Mental Illness Research Education and Clinical Center, Aurora, Colorado.Search for more papers by this author, John D. CorriganDepartment of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, Columbus, Ohio.Search for more papers by this author, and Kristen Dams-O'ConnorAddress correspondence to: Kristen Dams-O'Connor, PhD, Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1163, New York, NY 10029 E-mail Address: Kristen.Dams-O'Connor@mountsinai.orgDepartment of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.Search for more papers by this authorPublished Online:11 Dec 2019https://doi.org/10.1089/neu.2019.6451AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byCaring again: Support for parent caregivers of wounded, ill, and/or injured adult children veteransNeuroRehabilitation, Vol. 52, No. 1Associations between early sleep-disordered breathing following moderate-to-severe traumatic brain injury and long-term chronic pain status: a Traumatic Brain Injury Model Systems studyJournal of Clinical Sleep Medicine, Vol. 19, No. 1Association between traumatic brain injury and suicidality using a mediation approach and MarketScan5 December 2022 | Injury Prevention, Vol. 26Association of pre-admission opioid abuse and/or dependence on major complications in traumatic brain injury (TBI) patientsJournal of Clinical Anesthesia, Vol. 79Peer Support at the Intersection of Disability and Opioid (Mis)Use: Key Stakeholders Provide Essential Considerations5 August 2022 | International Journal of Environmental Research and Public Health, Vol. 19, No. 15Preinjury Health Status of Adults With Traumatic Brain Injury: A Preliminary Matched Case-Control Study15 June 2021 | Journal of Head Trauma Rehabilitation, Vol. 37, No. 3Repeated blast mild traumatic brain injury and oxycodone self‐administration produce interactive effects on neuroimaging outcomes18 January 2022 | Addiction Biology, Vol. 27, No. 2Impact of opioid use disorder on resource utilization and readmissions after operative traumaSurgery, Vol. 171, No. 2Pregnancy, Fetal, and Neonatal Outcomes Among Women With Traumatic Brain Injury14 October 2022 | Journal of Head Trauma Rehabilitation, Vol. Publish Ahead of PrintExamining differences in prescription opioid use behaviors among U.S. adults with and without disabilitiesPreventive Medicine, Vol. 153Reported History of Traumatic Brain Injury Among Suicide Decedents: National Violent Death Reporting System, 2003–2017American Journal of Preventive Medicine, Vol. 61, No. 4When triggers become tigers: taming the autonomic nervous system via sensory support system modulation7 September 2021 | Journal of Social Work Practice in the Addictions, Vol. 37Risk Factors Associated With the Prescription of Opioids Among Service Members Following a First Mild Traumatic Brain InjuryJournal of Head Trauma Rehabilitation, Vol. 36, No. 5Opioid and Sedative-Hypnotic Prescriptions Among Post-9/11 Veteran VA Users Nationwide With Traumatic Brain Injury, 2012-2020Journal of Head Trauma Rehabilitation, Vol. 36, No. 5Scoping Review of Opioid Use After Traumatic Brain InjuryJournal of Head Trauma Rehabilitation, Vol. 36, No. 5Receipt of Concurrent VA and Non-VA Opioid and Sedative-Hypnotic Prescriptions Among Post-9/11 Veterans With Traumatic Brain InjuryJournal of Head Trauma Rehabilitation, Vol. 36, No. 5Association of Lifetime History of Traumatic Brain Injury With Prescription Opioid Use and Misuse Among AdultsJournal of Head Trauma Rehabilitation, Vol. 36, No. 5Traumatic Brain Injury and Opioid Use: Additional Evidence Supporting the “Perfect Storm” of Cascading VulnerabilitiesJournal of Head Trauma Rehabilitation, Vol. 36, No. 5Association between Lifetime History of Traumatic Brain Injury, Prescription Opioid Use, and Persistent Pain: A Nationally Representative Study Raj G. Kumar, Katherine A. Ornstein, John D. Corrigan, Rachel Sayko Adams, and Kristen Dams-O'Connor26 July 2021 | Journal of Neurotrauma, Vol. 38, No. 16Addressing Pain for a Proper Rehabilitation Process in Patients With Severe Disorders of Consciousness17 February 2021 | Frontiers in Pharmacology, Vol. 12 Volume 37Issue 1Jan 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Rachel Sayko Adams, John D. Corrigan, and Kristen Dams-O'Connor.Opioid Use among Individuals with Traumatic Brain Injury: A Perfect Storm?.Journal of Neurotrauma.Jan 2020.211-216.http://doi.org/10.1089/neu.2019.6451Published in Volume: 37 Issue 1: December 11, 2019Online Ahead of Print:August 16, 2019Online Ahead of Editing: July 23, 2019PDF download

Complex oteneurological evaluation of vestibular disoders in mild blast traumatic brain injury

Due to the non-specific character of the symptoms complex and certain difficulties in clinical evaluation, it is important to develop diagnostic criteria for the vestibular symptoms in patients with blast traumatic brain injury due to the explosive effect for maintaining high quality of life and full social adaptation. Objective . To analyze the vestibular symptoms in those injured during a military traumatic injury due to an explosive effect. Materials and methods: the results of clinical and instrumental studies of 39 patients who were examined and treated in the neurotrauma department of the State Institution “Romodanov Neurosurgery Institute of National Academy of Medical Sciences of Ukraine”, with documented mine-explosive head injury obtained in the armed conflict in Eastern Ukraine during the period of 2014–2017 were analyzed. Results: Most often and most clearly there is a certain stable clinical symptom complex; the statistically significant criteria of stabilographic indicators of quantitative assessment of the state of the vestibular system in patients with combat TBI caused by explosion were determined; the development and implementation of standardized evaluation and analysis of vestibular violations in combat TBI caused by explosions have an important clinical and expert value in the evaluation of vestibular dysfunction for medical-social and forensic medical examinations, timely adequate rehabilitation and social adaptation of participants of armed conflicts. Conclusions: According to the data of subjective audiometry, among examined patients with combat TBI caused by explosions, sensorineural hearing loss of various degrees of severity, including deafness was diagnosed in 29 (74.4 %) patients. Tonic audiometric curves of patients had mostly descending, or often a broken type. The complex of diagnostic criteria was based on the analysis of stabilographic indicators, specifically, the general center of gravity, the frequency-amplitude spectrum of the stabilogram, the integral index of the quality of the vestibular function for the definition of the vestibular system state of patients with combat TBI caused by explosions, that helps to determine the level of damage for the vestibular analyzer , the level of preservation of function and compensation of central regulatory mechanisms of the static-kinetic system. Violation of the vestibular function in combat TBI caused by explosions is an important military-civilian problem

SUN-477 Chronic Variable Stress Worsens Effects of Mild Blast Traumatic Brain Injury on the Stress Response

Traumatic brain injury (TBI) affects 10 million people annually, attributes to major psychiatric disorders, and is among the leading causes of death and disability. Blast-induced TBI (bTBI) accounts for approximately 80% of all TBIs. These numbers are rapidly rising due, in part, to the increasing frequency of terrorist bombing attacks. The least studied form of bTBI, perhaps because of delayed symptom onset, is mild bTBI (mbTBI). Nonetheless, mbTBI increases the prevalence of psychiatric disorders, including memory impairment, anxiety, and mood disorders. Virtually every mbTBI in the battlefield is preceded and followed by a constant period of stress. However, how stress can prime the brain to deal with an insult, such as mbTBI, remains unknown. This work aims to identify the brain targets affected by mbTBI and elucidate how chronic stress could prime the brain for worse outcomes after mbTBI. In the first experiment, we examined the effect of mbTBI on resting and restraint-induced limbic-HPA axis reactivity in male and female mice 7-10 days post-injury. Mild bTBI increased anxiety-like behaviors (p<0.05) and dysregulated the stress response in a sex-specific manner. In the paraventricular nucleus of the hypothalamus, mbTBI decreased (p<0.05) activation of non-neuroendocrine corticotropin releasing factor neurons in females, but not males, suggesting a potential link to autonomic dysregulation. To further examine the impact of mbTBI on HPA axis-relevant limbic structures, we assessed neuronal activation via c-Fos-ir or EGR-1-ir markers in the medial prefrontal cortex (mPFC). Mild bTBI blunted the restraint induced neuronal activation observed in male and female infralimbic and prelimbic regions of the mPFC. These data suggest that the mPFC is a potential target of mbTBI in both sexes. In a second experiment, we used the Thy1-eGFP transgenic mouse model to elucidate the effects of mbTBI during a chronic variable stress (CVS) paradigm. This paradigm consisted of two weeks of CVS prior to our single mbTBI model and followed by another week of CVS after the single blast. The adverse effects of mbTBI on anxiety-like behaviors observed following a single mbTBI were further worsened in the animals exposed to CVS when compared to no-CVS animals. These data suggest that CVS makes the system more vulnerable to the effects of mbTBI. Thus, future experiments should consider implementing a stress component when assessing the impact of mbTBI. Our ongoing experiments aim to elucidate the effects of CVS and mbTBI on the dendritic spine architecture of the mPFC. These data will help us understand the mbTBI effects observed in the mPFC and whether the psychiatric disorders seen following mbTBI result from changes in the dendritic connectivity and architecture on the mPFC.

Low-Level Primary Blast Induces Neuroinflammation and Neurodegeneration in Rats.

Mild blast traumatic brain injury is commonly prevalent in modern combat casualty care and has been associated with the development of neurodegenerative conditions. However, whether primary lower level blast overpressure (LBOP) causes neurodegeneration and neuroinflammation remains largely unknown. The aim of our present study was to determine whether LBOP can cause neuroinflammation and neurodegeneration. Anesthetized rats were randomly assigned to LBOP group (70 kPa, n = 5) or sham group (without blast, n = 5). Histopathological and cytokine changes in brain tissue at 5 days post-injury were evaluated by hematoxylin-eosin staining and Bioplex assay, respectively. Histopathological assessment revealed neuronal degeneration and increased density of inflammatory cells in frontal and parietal cortex, hippocampus and thalamus in rats exposed to LBOP. LBOP exposure significantly elevated levels of pro-inflammatory cytokines (EPO, IL-1β, IL-6, IL-12, IL-18, and TNF-α) and chemokines (GRO and RANTES) as well as of an anti-inflammatory cytokine (IL-13) in the frontal cortex. This study reveals a role of neuroinflammation in neurodegeneration after mild blast traumatic brain injury. Therapies that target this process might in warfighters might function either by attenuating the development of post-traumatic stress disorder, chronic traumatic encephalopathy and Alzheimer's disease, or by slowing their progression.

Association Between 5-Year Clinical Outcome in Patients With Nonmedically Evacuated Mild Blast Traumatic Brain Injury and Clinical Measures Collected Within 7 Days Postinjury in Combat

Although previous work has examined clinical outcomes in combat-deployed veterans, questions remain regarding how symptoms evolve or resolve following mild blast traumatic brain injury (TBI) treated in theater and their association with long-term outcomes. To characterize 5-year outcome in patients with nonmedically evacuated blast concussion compared with combat-deployed controls and understand what clinical measures collected acutely in theater are associated with 5-year outcome. A prospective, longitudinal cohort study including 45 service members with mild blast TBI within 7 days of injury (mean 4 days) and 45 combat deployed nonconcussed controls was carried out. Enrollment occurred in Afghanistan at the point of injury with evaluation of 5-year outcome in the United States. The enrollment occurred from March to September 2012 with 5-year follow up completed from April 2017 to May 2018. Data analysis was completed from June to July 2018. Concussive blast TBI. All patients were treated in theater, and none required medical evacuation. Clinical measures collected in theater included measures for concussion symptoms, posttraumatic stress disorder (PTSD) symptoms, depression symptoms, balance performance, combat exposure intensity, cognitive performance, and demographics. Five-year outcome evaluation included measures for global disability, neurobehavioral impairment, PTSD symptoms, depression symptoms, and 10 domains of cognitive function. Forward selection multivariate regression was used to determine predictors of 5-year outcome for global disability, neurobehavior impairment, PTSD, and cognitive function. Nonmedically evacuated patients with concussive blast injury (n = 45; 44 men, mean [SD] age, 31 [5] years) fared poorly at 5-year follow-up compared with combat-deployed controls (n = 45; 35 men; mean [SD] age, 34 [7] years) on global disability, neurobehavioral impairment, and psychiatric symptoms, whereas cognitive changes were unremarkable. Acute predictors of 5-year outcome consistently identified TBI diagnosis with contribution from acute concussion and mental health symptoms and select measures of cognitive performance depending on the model for 5-year global disability (area under the curve following bootstrap validation [AUCBV] = 0.79), neurobehavioral impairment (correlation following bootstrap validation [RBV] = 0.60), PTSD severity (RBV = 0.36), or cognitive performance (RBV = 0.34). Service members with concussive blast injuries fared poorly at 5-year outcome. The results support a more focused acute screening of mental health following TBI diagnosis as strong indicators of poor long-term outcome. This extends prior work examining outcome in patients with concussive blast injury to the larger nonmedically evacuated population.

Effects of Mild Blast Traumatic Brain Injury on Cognitive- and Addiction-Related Behaviors

Traumatic brain injury (TBI) commonly results in cognitive and psychiatric problems. Cognitive impairments occur in approximately 30% of patients suffering from mild TBI (mTBI), and correlational evidence from clinical studies indicates that substance abuse may be increased following mTBI. However, understanding the lasting cognitive and psychiatric problems stemming from mTBI is difficult in clinical settings where pre-injury assessment may not be possible or accurate. Therefore, we used a previously characterized blast model of mTBI (bTBI) to examine cognitive- and addiction-related outcomes. We previously demonstrated that this model leads to bilateral damage of the medial prefrontal cortex (mPFC), a region critical for cognitive function and addiction. Rats were exposed to bTBI and tested in operant learning tasks several weeks after injury. bTBI rats made more errors during acquisition of a cue discrimination task compared to sham treated rats. Surprisingly, we observed no differences between groups in set shifting and delayed matching to sample, tasks known to require the mPFC. Separate rats performed cocaine self-administration. No group differences were found in intake or extinction, and only subtle differences were observed in drug-primed reinstatement 3–4 months after injury. These findings indicate that bTBI impairs acquisition of a visual discrimination task and that bTBI does not significantly increase the ability of cocaine exposure to trigger drug seeking.

Differential Responses of the HPA Axis to Mild Blast Traumatic Brain Injury in Male and Female Mice.

Traumatic brain injury (TBI) affects 10 million people worldwide, annually. TBI is linked to increased risk of psychiatric disorders. TBI, induced by explosive devices, has a unique phenotype. Over one-third of people exposed to blast-induced TBI (bTBI) have prolonged neuroendocrine deficits, shown by anterior pituitary dysfunction. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is linked to increased risk for psychiatric disorders. Not only is there limited information on how the HPA axis responds to mild bTBI (mbTBI), sex differences are understudied. We examined central and peripheral HPA axis reactivity, 7 to 10 days after mbTBI in male and female mice. Males exposed to mbTBI had increased restraint-induced serum corticosterone (CORT), but attenuated restraint-induced corticotropin-releasing factor (CRF)/c-Fos-immunoreactivity (ir) in the paraventricular nucleus of the hypothalamus (PVN). Females displayed an opposite response, with attenuated restraint-induced CORT and enhanced restraint-induced PVN CRF/c-Fos-ir. We examined potential mechanisms underlying this dysregulation and found that mbTBI did not affect pituitary (pro-opiomelanocortin and CRF receptor subtype 1) or adrenal (11β-hydroxylase, 11β-dehydrogenase 1, and melanocortin 2 receptor) gene expression. mbTBI did not alter mineralocorticoid or glucocorticoid gene expression in the PVN or relevant limbic structures. In females, but not males, mbTBI decreased c-Fos-ir in non-neuroendocrine (presumably preautonomic) CRF neurons in the PVN. Whereas we demonstrated a sex-dependent link to stress dysregulation of preautonomic neurons in females, we hypothesize that mbTBI may disrupt limbic pathways involved in HPA axis coordination in males. Overall, mbTBI altered the HPA axis in a sex-dependent manner, highlighting the importance of developing therapies to target individual strategies that males and females use to cope with mbTBI.

Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular, Histopathological, and Behavioral Outcomes in Rats.

To determine the effects of mild blast-induced traumatic brain injury (bTBI), several groups of rats were subjected to blast injury or sham injury in a compressed air-driven shock tube. The effects of bTBI on relative cerebral perfusion (laser Doppler flowmetry [LDF]), and mean arterial blood pressure (MAP) cerebral vascular resistance were measured for 2 h post-bTBI. Dilator responses to reduced intravascular pressure were measured in isolated middle cerebral arterial (MCA) segments, ex vivo, 30 and 60 min post-bTBI. Neuronal injury was assessed (Fluoro-Jade C [FJC]) 24 and 48 h post-bTBI. Neurological outcomes (beam balance and walking tests) and working memory (Morris water maze [MWM]) were assessed 2 weeks post-bTBI. Because impact TBI (i.e., non-blast TBI) is often associated with reduced cerebral perfusion and impaired cerebrovascular function in part because of the generation of reactive oxygen and nitrogen species such as peroxynitrite (ONOO−), the effects of the administration of the ONOO− scavenger, penicillamine methyl ester (PenME), on cerebral perfusion and cerebral vascular resistance were measured for 2 h post-bTBI. Mild bTBI resulted in reduced relative cerebral perfusion and MCA dilator responses to reduced intravascular pressure, increases in cerebral vascular resistance and in the numbers of FJC-positive cells in the brain, and significantly impaired working memory. PenME administration resulted in significant reductions in cerebral vascular resistance and a trend toward increased cerebral perfusion, suggesting that ONOO− may contribute to blast-induced cerebral vascular dysfunction.

Primary Blast Brain Injury Mechanisms: Current Knowledge, Limitations, and Future Directions.

Mild blast traumatic brain injury (bTBI) accounts for the majority of brain injury in United States service members and other military personnel worldwide. The mechanisms of primary blast brain injury continue to be disputed with little evidence to support one or a combination of theories. The main hypotheses addressed in this review are blast wave transmission through the skull orifices, direct cranial transmission, skull flexure dynamics, thoracic surge, acceleration, and cavitation. Each possible mechanism is discussed using available literature with the goal of focusing research efforts to address the limitations and challenges that exist in blast injury research. Multiple mechanisms may contribute to the pathology of bTBI and could be dependent on magnitudes and orientation to blast exposure. Further focused biomechanical investigation with cadaver, in vivo, and finite element models would advance our knowledge of bTBI mechanisms. In addition, this understanding could guide future research and contribute to the greater goal of developing relevant injury criteria and mandates to protect our soldiers on the battlefield.

Exendin-4 attenuates blast traumatic brain injury induced cognitive impairments, losses of synaptophysin and in vitro TBI-induced hippocampal cellular degeneration

Mild blast traumatic brain injury (B-TBI) induced lasting cognitive impairments in novel object recognition and less severe deficits in Y-maze behaviors. B-TBI significantly reduced the levels of synaptophysin (SYP) protein staining in cortical (CTX) and hippocampal (HIPP) tissues. Treatment with exendin-4 (Ex-4) delivered by subcutaneous micro-osmotic pumps 48 hours prior to or 2 hours immediately after B-TBI prevented the induction of both cognitive deficits and B-TBI induced changes in SYP staining. The effects of a series of biaxial stretch injuries (BSI) on a neuronal derived cell line, HT22 cells, were assessed in an in vitro model of TBI. Biaxial stretch damage induced shrunken neurites and cell death. Treatment of HT22 cultures with Ex-4 (25 to 100 nM), prior to injury, attenuated the cytotoxic effects of BSI and preserved neurite length similar to sham treated cells. These data imply that treatment with Ex-4 may represent a viable option for the management of secondary events triggered by blast-induced, mild traumatic brain injury that is commonly observed in militarized zones.

Clinical and Magnetic Resonance Spectroscopic Imaging Findings in Veterans With Blast Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder.

To compare magnetic resonance spectroscopic imaging (MRSI) findings from the hippocampal regions of military veterans with blast-related mild traumatic brain injury (blast mTBI) and post-traumatic stress disorder (PTSD) to those with PTSD only; and to examine the relationship of MRSI findings to cognitive and neuromotor impairment. 35 military veterans-23 with blast mTBI and PTSD (blast mTBI/PTSD) and 12 with PTSD only participated in the study. Whole plane MRSI data including N-acetyl aspartate (NAA) and choline (Ch) were acquired at 7T for the hippocampus. Concurrent cognitive and neuromotor data were collected using established assessments. General linear models (GLMs) with Bonferroni correction were used to compare the two groups on NAA/Ch ratios across regions of the hippocampus. Spearman's correlations were used to examine correlations between NAA/Ch and cognitive and neuromotor impairment. The NAA/Ch results for the left hippocampus were lower in the blast mTBI/PTSD group than the PTSD-only group. The blast mTBI/PTSD group also scored worse on the WAIS-IV-vocabulary. Significant correlations between NAA/Ch and neuromotor outcomes-including vestibular impairment-were supported. Combined MRSI and cognitive and neuromotor data may help inform more objective and accurate diagnoses and effective treatments for patients with blast mTBI and PTSD.

Resting-State Magnetoencephalography Reveals Different Patterns of Aberrant Functional Connectivity in Combat-Related Mild Traumatic Brain Injury.

Blast mild traumatic brain injury (mTBI) is a leading cause of sustained impairment in military service members and veterans. However, the mechanism of persistent disability is not fully understood. The present study investigated disturbances in brain functioning in mTBI participants using a source-imaging-based approach to analyze functional connectivity (FC) from resting-state magnetoencephalography (rs-MEG). Study participants included 26 active-duty service members or veterans who had blast mTBI with persistent post-concussive symptoms, and 22 healthy control active-duty service members or veterans. The source time courses from regions of interest (ROIs) were used to compute ROI to whole-brain (ROI-global) FC for different frequency bands using two different measures: 1) time-lagged cross-correlation and 2) phase-lock synchrony. Compared with the controls, blast mTBI participants showed increased ROI-global FC in beta, gamma, and low-frequency bands, but not in the alpha band. Sources of abnormally increased FC included the: 1) prefrontal cortex (right ventromedial prefrontal cortex [vmPFC], right rostral anterior cingulate cortex [rACC]), and left ventrolateral and dorsolateral prefrontal cortex; 2) medial temporal lobe (bilateral parahippocampus, hippocampus, and amygdala); and 3) right putamen and cerebellum. In contrast, the blast mTBI group also showed decreased FC of the right frontal pole. Group differences were highly consistent across the two different FC measures. FC of the left ventrolateral prefrontal cortex correlated with executive functioning and processing speed in mTBI participants. Altogether, our findings of increased and decreased regionalpatterns of FC suggest that disturbances in intrinsic brain connectivity may be the result of multiple mechanisms, and are associated with cognitive sequelae of the injury.

Role of Pre-Morbid Factors and Exposure to Blast Mild Traumatic Brain Injury on Post-Traumatic Stress in United States Military Personnel.

Mild traumatic brain injury (mTBI), the signature injury of the recent wars in Afghanistan and Iraq, is a prevalent and potentially debilitating condition that is associated with symptoms of post-traumatic stress/post-traumatic stress disorder (PTS/PTSD). Prior mTBI, severity and type of injury (blast vs. non-blast), and baseline psychiatric illness are thought to impact mTBI outcomes. It is unclear if the severity of pre-morbid PTS/PTSD is a risk factor of post-injury levels of PTS and mTBI symptoms. The objective of the study was to examine predictors of post-injury PTS/PTSD, including pre-morbid PTS symptoms, and physical and cognitive symptoms in the sub-acute phase (1 week-3 months) following an acute mTBI. A retrospective review of medical records was performed of 276 servicemen assigned to the United States Army Special Operations Command referred for mTBI evaluation between December 2009 and March 2011. Post-Concussion Symptom Scale and PTSD Checklist scores were captured pre- and post-injury. A total of 276 records were reviewed. Pre-morbid and post-injury data were available for 91% (251/276). Of the 54% (136/251) of personnel with mTBI, 29% (39/136) had positive radiology findings and 11% (15/136) met criteria for clinical PTS symptoms at baseline. Logistic regression analysis found baseline PTS symptoms predicted personnel who met clinical levels of PTSD. Receiver operating characteristic curve analysis revealed that baseline PTS (p = 0.001), baseline mTBI symptoms (p = 0.001), and positive radiology (magnetic resonance imaging or computed tomography) findings for complicated mTBI (p = 0.02) accurately identified personnel with clinical levels of PTSD following mTBI. Years of military service, combat deployment status, age, and injury mechanism (blast vs. non-blast) were not associated with increased risk of PTS following mTBI. Pre-morbid PTS symptoms are associated with an increased risk for clinical levels of PTS following a subsequent mTBI. Symptom severity and positive radiologic findings may amplify this risk. At-risk personnel may benefit from early identification and intervention.

Intracranial venous injury, thrombosis and repair as hallmarks of mild blast traumatic brain injury in rats: Lessons from histological and immunohistochemical studies of decalcified sectioned heads and correlative microarray analysis

BackgroundMany previous experimental studies of blast wave effects have reported vascular and parenchymal injury in brains extracted from the skulls prior to histopathological assessment. Brain removal disrupts vasculature and structural features of the meninges that may be sources of signs and symptoms of mild traumatic brain injury, particular at lower blast overpressures (<5psi peak). New methodImmunohistochemical and histopathological studies have been conducted in sections from decalcified, paraffin embedded, histologically sectioned whole rat heads. These sections preserve the entire cranial contents in situ, and permit evaluation of the inner ear, central nervous system and associated vasculature. The findings could also be correlated with mRNA expression patterns from whole brains subjected to similar treatment. ResultsLower levels of blast wave exposure produce primarily vascular effects in rats. Messenger RNA profiles of the whole brains showed evidence of both blast intensity and time dependent effects on vascular wound healing markers. The rats exposed to 10–11psi overpressure tended to show a similar pattern of mRNA expression changes in these vascular repair and inflammatory pathways as rats exposed to approximately 5psi overpressure, but the changes were greater. The changes in mRNA expression after a 14–15psi exposure were different and suggestive of more severe injury, particularly for DNA repair, lymphocyte activation and lymphocyte migration pathways. Histopathological examination of decalcified heads revealed that even 2.5–7.9psi blast exposures produced a high prevalence of mild venous hemorrhage and thrombosis (accompanied by inflammatory markers) in the inner ear, vertebrobasilar circulation, hippocampal choroidal fissure and the veins associated with velum interpositum. Comparison with existing method(s)The sites of vascular injury would not have been included in specimens extracted from the skull prior to processing. ConclusionsThe isolated regions of intravascular coagulation in small veins and the isolated, very small venous hemorrhages in the subarachnoid space are worthy of consideration as factors in both healing and chronic sequelae of mild blast concussion. Although small, remnants persisted in the subarachnoid space even 42 days after a single blast exposure. The high prevalence of very mild subdural and subarachnoid hemorrhage may be a target for clinical management.

White matter abnormalities in blast mild traumatic brain injury in the military

ABSTRACTMild traumatic brain injury (mTBI) has been labeled the “signature injury” of the wars in Iraq and Afghanistan, and approximately half of mTBIs that occur in combat are due to explosive blasts. The rapid change in pressure that results from an explosion may make blast injury distinct from mTBI due to other causes. Persistent symptoms following blast mTBI may be related to white matter damage that has recently been identified using innovative neuroimaging techniques, such as diffusion tensor imaging (DTI). By comparing the DTI findings in blast mTBI to studies of the effects of white matter structure on functional performance, hypotheses can be developed about the implications of the injury for engagement in occupation. Incorporation of neuroscience evidence about the effects of blast mTBI may provide objective evidence of underlying damage that correlates with deficits in occupational engagement of military service members and veterans who are affected by these injuries.

Comparing the Neuropsychological Test Performance of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans with and without Blast Exposure, Mild Traumatic Brain Injury, and Posttraumatic Stress Symptoms.

To compare neuropsychological test performance of Veterans with and without mild traumatic brain injury (MTBI), blast exposure, and posttraumatic stress disorder (PTSD) symptoms. We compared the neuropsychological test performance of 49 Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans diagnosed with MTBI resulting from combat blast-exposure to that of 20 blast-exposed OEF/OIF Veterans without history of MTBI, 23 OEF/OIF Veterans with no blast exposure or MTBI history, and 40 matched civilian controls. Comparison of neuropsychological test performance across all four participant groups showed a complex pattern of mixed significant and mostly nonsignificant results, with omnibus tests significant for measures of attention, spatial abilities, and executive function. The most consistent pattern was the absence of significant differences between blast-exposed Veterans with MTBI history and blast-exposed Veterans without MTBI history. When blast-exposed Veteran groups with and without MTBI history were aggregated and compared to non-blast-exposed Veterans, there were significant differences for some measures of learning and memory, spatial abilities, and executive function. However, covariation for severity of PTSD symptoms eliminated all significant omnibus neuropsychological differences between Veteran groups. Our results suggest that, although some mild neurocognitive effects were associated with blast exposure, these neurocognitive effects might be better explained by PTSD symptom severity rather than blast exposure or MTBI history alone.

Neurotransmitter Systems in a Mild Blast Traumatic Brain Injury Model: Catecholamines and Serotonin.

Exposure to improvised explosive devices can result in a unique form of traumatic brain injury--blast-induced traumatic brain injury (bTBI). At the mild end of the spectrum (mild bTBI [mbTBI]), there are cognitive and mood disturbances. Similar symptoms have been observed in post-traumatic stress disorder caused by exposure to extreme psychological stress without physical injury. A role of the monoaminergic system in mood regulation and stress is well established but its involvement in mbTBI is not well understood. To address this gap, we used a rodent model of mbTBI and detected a decrease in immobility behavior in the forced swim test at 1 d post-exposure, coupled with an increase in climbing behavior, but not after 14 d or later, possibly indicating a transient increase in anxiety-like behavior. Using in situ hybridization, we found elevated messenger ribonucleic acid levels of both tyrosine hydroxylase and tryptophan hydroxylase 2 in the locus coeruleus and the dorsal raphe nucleus, respectively, as early as 2 h post-exposure. High-performance liquid chromatography analysis 1 d post-exposure primarily showed elevated noradrenaline levels in several forebrain regions. Taken together, we report that exposure to mild blast results in transient changes in both anxiety-like behavior and brain region-specific molecular changes, implicating the monoaminergic system in the pathobiology of mbTBI.

Chapter 20 - Advances in imaging explosive blast mild traumatic brain injury

In the past, direct physical evidence of mild traumatic brain injury (mTBI) from explosive blast has been difficult to obtain through conventional imaging modalities such as T1- and T2-weighted magnetic resonance imaging (MRI) and computed tomography (CT). Here, we review current progress in detecting evidence of brain injury from explosive blast using advanced imaging, including diffusion tensor imaging (DTI), functional MRI (fMRI), and the metabolic imaging methods such as positron emission tomography (PET) and magnetic resonance spectroscopic imaging (MRSI), where each targets different aspects of the pathology involved in mTBI. DTI provides a highly sensitive measure to detect primary changes in the microstructure of white matter tracts. fMRI enables the measurement of changes in brain activity in response to different stimuli or tasks. Remarkably, all three of these paradigms have found significant success in conventional mTBI where conventional clinical imaging frequently fails to provide definitive differences. Additionally, although used less frequently for conventional mTBI, PET has the potential to characterize a variety of neurotransmitter systems using target agents and will undoubtedly play a larger role, once the basic mechanisms of injury are better understood and techniques to identify the injury are more common. Finally, our MRSI imaging studies, although acquired at much lower spatial resolution, have demonstrated selectivity to different metabolic and physiologic processes, uncovering some of the most profound differences on an individual by individual basis, suggesting the potential for utility in the management of individual patients.

Concussive brain injury from explosive blast.

ObjectiveExplosive blast mild traumatic brain injury (mTBI) is associated with a variety of symptoms including memory impairment and posttraumatic stress disorder (PTSD). Explosive shock waves can cause hippocampal injury in a large animal model. We recently reported a method for detecting brain injury in soldiers with explosive blast mTBI using magnetic resonance spectroscopic imaging (MRSI). This method is applied in the study of veterans exposed to blast.MethodsThe hippocampus of 25 veterans with explosive blast mTBI, 20 controls, and 12 subjects with PTSD but without exposure to explosive blast were studied using MRSI at 7 Tesla. Psychiatric and cognitive assessments were administered to characterize the neuropsychiatric deficits and compare with findings from MRSI.ResultsSignificant reductions in the ratio of N-acetyl aspartate to choline (NAA/Ch) and N-acetyl aspartate to creatine (NAA/Cr) (P < 0.05) were found in the anterior portions of the hippocampus with explosive blast mTBI in comparison to control subjects and were more pronounced in the right hippocampus, which was 15% smaller in volume (P < 0.05). Decreased NAA/Ch and NAA/Cr were not influenced by comorbidities – PTSD, depression, or anxiety. Subjects with PTSD without blast had lesser injury, which tended to be in the posterior hippocampus. Explosive blast mTBI subjects had a reduction in visual memory compared to PTSD without blast.InterpretationThe region of the hippocampus injured differentiates explosive blast mTBI from PTSD. MRSI is quite sensitive in detecting and localizing regions of neuronal injury from explosive blast associated with memory impairment.