Diffusive secondary injuries in neuronal networks following a blast impact: A morphological and electrophysiological study using a TBI-on-a-Chip model

Blast-Related Traumatic Brain Injury: What Is Known?

Individuals in violent intimate relationships are at a high risk of sustaining both orthopaedic fractures and traumatic brain injury (TBI), and the fracture clinic may be the first place that concurrent intimate partner violence (IPV) and TBI are recognized. Both IPV and TBI can affect all aspects of fracture management, but prevalence of TBI and comorbid TBI and IPV is unknown. (1) What are the previous-year and lifetime prevalence of IPV and TBI in women presenting to an outpatient orthopaedic fracture clinic? (2) What are the conditional probabilities of TBI in the presence of IPV and the reverse, to explore whether screening for one condition could effectively identify patients with the other? (3) Do patients with TBI, IPV, or both have worse neurobehavioral symptoms than patients without TBI and IPV? The study was completed in the fracture clinic at a community Level 1 trauma center in Southern Ontario from July 2018 to March 2019 and included patients seen by three orthopaedic surgeons. Inclusion criteria were self-identification as a woman, age 18 years or older, and the ability to complete forms in English without assistance from the person who brought them to the clinic (for participant safety and privacy). We invited 263 women to participate: 22 were ineligible (for example, they were patients of a surgeon who was not on the study protocol), 87 declined before hearing the topic of the study, and data from eight were excluded because the data were incomplete or lost. Complete data were obtained from 146 participants. Participants' mean age was 52 ± 16 years, and the most common diagnosis was upper or lower limb fracture. Prevalence of IPV was calculated as the number of women who answered "sometimes" or "often" to direct questions from the Woman Abuse Screening Tool, which asks about physical, emotional, and sexual abuse in the past year or person's lifetime. The prevalence of TBI was calculated as the number of women who reported at least one head or neck injury that resulted in feeling dazed or confused or in loss of consciousness lasting 30 minutes or less on the Ohio State University Traumatic Brain Injury Identification Method, a standardized procedure for eliciting lifetime history of TBI through a 3- to 5-minute structured interview. Conditional probabilities were calculated using a Bayesian analysis. Neurobehavioral symptoms were characterized using the Neurobehavioral Symptom Inventory, a standard self-report measure of everyday emotional, somatic, and cognitive complaints after TBI, with total scores compared across groups using a one-way ANOVA. Previous-year prevalence of physical IPV was 7% (10 of 146), and lifetime prevalence was 28% (41 of 146). Previous-year prevalence of TBI was 8% (12 of 146), and lifetime prevalence was 49% (72 of 146). The probability of TBI in the presence of IPV was 0.77, and probability of IPV in the presence of TBI was 0.36. Thus, screening for IPV identified proportionately more patients with TBI than screening for TBI, but the reverse was not true. Neurobehavioral Symptom Inventory scores were higher (more symptoms) in patients with TBI only (23 ± 16) than those with fractures only (12 ± 11, mean difference 11 [95% CI 8 to 18]; p < 0.001), in those with IPV only (17 ± 11) versus fractures only (mean difference 5 [95% CI -1 to -11]; p < 0.05), and in those with both TBI and IPV (25 ± 14) than with fractures only (mean difference 13 [95% CI 8 to 18]; p < 0.001) or those with IPV alone (17 ± 11, mean difference 8 [95% CI -1 to 16]; p < 0.05). Using a brief screening interview, we identified a high self-reported prevalence of TBI and IPV alone, consistent with previous studies, and a novel finding of high comorbidity of IPV and TBI. Given that the fracture clinic may be the first healthcare contact for women with IPV and TBI, especially mild TBI associated with IPV, we recommend educating frontline staff on how to identify IPV and TBI as well as implementing brief screening and referral and universal design modifications that support effective, efficient, and accurate communication patients with TBI-related cognitive and communication challenges. Level II, prognostic study.

Abstracts from The 35th Annual National Neurotrauma Symposium July 7-12, 2017 Snowbird, Utah.

People experiencing homelessness are at a disproportionately greater risk for developing traumatic brain injury (TBI) than the general population. There has been minimal research to evaluate the prevalence of TBI or the long-term cognitive impacts of TBI among the population experiencing homelessness within the UnitedStates. There is minimal literature that examines individuals who are living unsheltered, especially regardingTBI. This study aimed to assess primarily whether those experiencing unsheltered homelessness had a higher prevalence of TBI than those in shelter. Furthermore, we examined the differences in the prevalence of repeated TBIs, TBI by age of respondent, loss of consciousness (LOC), and cognitive symptoms in people experiencing homelessness across three housing strata (sheltered, low-barrier sheltered, and unsheltered) within a small midwesterncity. Participants were recruited utilizing a convenience sampling of patients who utilized street medicine healthcare services. The study enrolled 102 patients during the interval of October 2022 through March 2024 from three housing strata (sheltered, low-barrier sheltered, and unsheltered) in Lansing, Michigan. We employed the Ohio State TBI Identification Method, abbreviated for ease of use. Results were analyzed for associations between TBI and health conditions utilizing chi-squared tests and a single difference-of-proportionstest. Seventy-five of 102 (73.5 %) of participants reported at least one TBI, with 48 % experiencing their first TBI more than 20years ago. There was a significant difference in TBI prevalence across housing strata. Ninety percent (90 %) of unsheltered survey respondents reported at least one previous TBI, with 50 % reporting three or more previous TBIs. These rates exceeded those of respondents in shelter (58 % prevalence, 21 % 3+ TBIs) and low-barrier shelter (65.1 % prevalence, 26 % 3+ TBIs), all of which exceeded the reported TBI prevalence for the general population (21.7 %). TBI prevalence did not vary significantly by age. LOC following TBI among participants significantly exceeded that of the general population (48 vs. 12 %). The prevalence of severe TBI was significantly greater than the general population for low-barrier shelter (16 vs. 2.6 %) and unsheltered respondents (23 %), but not for sheltered participants. Many respondents (62.6 %) developed cognitive symptoms as a result of TBI, although no statistical difference emerged between the groups. Cognitive sequalae were most common among those with three or moreTBIs. Taken together, these results suggest that the likelihood of TBI and the associated risks present a greater threat to those experiencing homelessness. There is a propensity to most strongly affect those living unsheltered.

Traumatic brain injury: an evidence-based review of management

Background: Traumatic brain injury (TBI) is often under-reported and thus under-recognized by clinicians. Reports of TBI prevalence have been widely variable based on the methods of data collection and definition of TBI. This study investigates the prevalence of TBI using the Ohio State University TBI Identification Method (OSU TBI-ID), a reliable and valid structured interview designed to elicit lifetime history of TBI. We also assessed relationships between TBI and psychiatric illnesses. Identifying prevalence and effects of TBI on mental health is critical to providing personalized, higher-quality care for psychiatric patients in community settings. Methods: Patients receiving mental health care at the IUSM Psychiatry Residency Clinic in Vincennes, Indiana were asked to participate in a research study assessing history of head or neck injuries. Patients attended their regularly scheduled appointments with resident physicians, and 2–5-minute TBI screenings were conducted during or immediately after their appointment. Following the interview, patient charts were reviewed for documentation of prior TBI and all current psychiatric diagnoses. Results: Prevalence of TBI was reported at 62.3% among patients receiving psychiatric care. 87 total TBI events were recorded, including repetitive TBI events, after 77 patient interviews. The most common cause of acute TBI was vehicular accident. The most common cause of repetitive TBI was sports injury. Of the 87 TBIs, only 5 TBI events were recorded in patient charts. History of TBI was more likely in patients with PTSD as well as substance use disorders, and this was especially evident in patients with repetitive TBI. Conclusion and Potential Impact: This study shows that TBI is quite common among psychiatric patients and is vastly under-reported in patient charts. Increasing clinician awareness of TBI history in their patients is critical to providing high-quality care, and the OSU TBI-ID provides an efficient way to screen patients for TBI.

Primary and secondary brain injury may occur with severe traumatic brain injury. Secondary traumatic brain injury results in a more severe effect compared to primary traumatic brain injury. Therefore, prevention of secondary traumatic brain injury is necessary to obtain maximum therapeutic results and accurate determination of prognosis and better quality of life. This study aimed to determine accurate and noninvasive prognostic factors in patients with severe traumatic brain injury. It was a cohort study on 16 subjects. Intracranial pressure was monitored within the first 24 hours after traumatic brain injury. Examination of Brain-Derived Neurotrophic Factor (BDNF) and S100B protein were conducted four times. The severity of outcome was evaluated using Glasgow Outcome Scale (GOS) three months after traumatic brain injury. Intracranial pressure measurement performed 24 hours after traumatic brain injury, low S100B protein (<2μg/L) 120 hours after injury and increased BDNF (>6.16pg/ml) 48 hours after injury indicate good prognosis and were shown to be significant predictors (p<0.05) for determining the quality of GOS. The conclusion is patient with a moderate increase in intracranial pressure Intracranial pressure S100B protein, being inexpensive and non-invasive, can substitute BDNF and intracranial pressure measurements as a tool for determining prognosis 120 hours following traumatic brain injury.

In addition to immediate brain damage, traumatic brain injury (TBI) initiates a cascade of pathophysiological events producing secondary injury. The biochemical and cellular mechanisms that comprise secondary injury are not entirely understood. Herein, we report a substantial deregulation of cerebral sphingolipid metabolism in a mouse model of TBI. Sphingolipid profile analysis demonstrated increases in sphingomyelin species and sphingosine concurrently with up-regulation of intermediates of de novo sphingolipid biosynthesis in the brain. Investigation of intracellular sites of sphingosine accumulation revealed an elevation of sphingosine in mitochondria due to the activation of neutral ceramidase (NCDase) and the reduced activity of sphingosine kinase 2 (SphK2). The lack of change in gene expression suggested that post-translational mechanisms are responsible for the shift in the activities of both enzymes. Immunoprecipitation studies revealed that SphK2 is complexed with NCDase and cytochrome oxidase (COX) subunit 1 in mitochondria and that brain injury hindered SphK2 association with the complex. Functional studies showed that sphingosine accumulation resulted in a decreased activity of COX, a rate-limiting enzyme of the mitochondrial electron transport chain. Knocking down NCDase reduced sphingosine accumulation in mitochondria and preserved COX activity after the brain injury. Also, NCDase knockdown improved brain function recovery and lessened brain contusion volume after trauma. These studies highlight a novel mechanism of secondary TBI involving a disturbance of sphingolipid-metabolizing enzymes in mitochondria and suggest a critical role for mitochondrial sphingosine in promoting brain injury after trauma.

Hypotension and hypoxemia worsen traumatic brain injury outcomes. Hyperoxic resuscitation is controversial. The authors proposed that hyperoxia would improve hemodynamics and neuronal survival by augmenting oxygen delivery despite increased oxidative stress and neuroinflammation in experimental combined controlled cortical impact plus hemorrhagic shock in mice. Adult C57BL6 mice received controlled cortical impact followed by 35 min of hemorrhagic shock (mean arterial pressure, 25-27 mmHg). The resuscitation phase consisted of lactated Ringer's boluses titrated to mean arterial pressure greater than 70 mmHg. Definitive care included returning shed blood. Either oxygen or room air was administered during the resuscitation phases. Brain tissue levels of oxidative stress and inflammatory markers were measured at 24 h and hippocampal neuronal survival was quantified at 7 days. Hyperoxia markedly increased brain tissue oxygen tension approximately four- to fivefold (n = 8) and reduced resuscitation fluid requirements approximately 15% (n = 53; both P < 0.05). Systemic and cerebral physiologic variables were not significantly affected by hyperoxia. Hippocampal neuron survival was approximately 40% greater with oxygen versus room air (n = 18, P = 0.03). However, ascorbate depletion doubled with oxygen versus room air (n = 11, P < 0.05). Brain tissue cytokines and chemokines were increased approximately 2- to 20-fold (n = 10) after combined controlled cortical impact injury plus hemorrhagic shock, whereas hyperoxia shifted cytokines toward a proinflammatory profile. Hyperoxic resuscitation of cortical impact plus hemorrhagic shock reduced fluid requirements and increased brain tissue oxygen tension and hippocampal neuronal survival but exacerbated ascorbate depletion and neuroinflammation. The benefits of enhanced oxygen delivery during resuscitation of traumatic brain injury may outweigh detrimental increases in oxidative stress and neuroinflammation.

Because of extensive use of motorcycles as the traffic vehicle in Taiwan, traumatic brain injuries (TBI) has been particularly prevalent not only in car or sports accidents but also in young individuals encountering motorcycle accidents. Traumatic brain injury (TBI) causes tissue damage by primary and secondary injuries to the neural tissue. Primary injury is due to initial mechanical trauma resulting in physical disruption of vessels, neurons and their axons. Secondary injury is due to a series of complex events at the subcellular level following the primary impact and causes the death of additional cells at the peripheral zone of the initial damage. Secondary injury is considered to be the main target of medical treatment. Docosahexaenoic acid, a principle omega-3 polyunsaturated fatty acids (PUFA) of fish oils or marine algae, is of particular interest as it is found in the cellular membranes of most human tissues and is converted to protectin D1 (PD1) or neuroprotectin D1 (NPD1) in neural tissue, which exhibits antiinflammatory and proresolving bioactions. It has been known for quite a while that omega-3 fatty acids including DHA and eicosapentaenoic acid (EPA) participate in cell functions. By minimizing activation of toxic pathways and to enhance activity of endogenous neuroprotective mechanisms, ω-3 polyunsaturated fatty acids (n-3 PUFAs such as DHA and EPA) show the ability in neuroprotection. In addition, collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of DHA and EPA (perhaps through their metabolite NPD1) may act in combination to contribute to their neuroprotective effect. In this review, we summarize the evidence available to date that indicates that ω-3 PUFAs are neuroprotective in brain injuries caused by trauma or ischemia.

The aim of this study was to discuss secondary traumatic brain injury, the mitochondria and the use of antioxidants as a treatment. One of the leading causes of death globally is traumatic brain injury, affecting individuals in all demographics. Traumatic brain injury is produced by an external blunt force or penetration resulting in alterations in brain function or pathology. Often, with a traumatic brain injury, secondary injury causes additional damage to the brain tissue that can have further impact on recovery and the quality of life. Secondary injury occurs when metabolic and physiologic processes alter after initial injury and includes increased release of toxic free radicals that cause damage to adjacent tissues and can eventually lead to neuronal necrosis. Although antioxidants in the tissues can reduce free radical damage, the magnitude of increased free radicals overwhelms the body's reduced defence mechanisms. Supplementing the body's natural supply of antioxidants, such as coenzyme Q10, can attenuate oxidative damage caused by reactive oxygen species. Discussion paper. Research literature published from 2011-2016 in PubMed, CINAHL and Cochrane. Prompt and accurate assessment of patients with traumatic brain injury by nurses is important to ensure optimal recovery and reduced lasting disability. Thus, it is imperative that nurses be knowledgeable about the secondary injury that occurs after a traumatic brain injury and aware of possible antioxidant treatments. The use of antioxidants has potential to reduce the magnitude of secondary injury in patients who experience a traumatic brain injury.

Abstracts from The 39^th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care

Abstracts fromThe 32^nd AnnualNational Neurotrauma SymposiumJune 29–July 2, 2014San Francisco, California

Traumatic brain injury (TBI) in children results in a high number of emergency department visits and risk for long-term adverse effects. To estimate lifetime prevalence of TBI in a nationally representative sample of US children and describe the association between TBI and other childhood health conditions. Data were analyzed from the 2011-2012 National Survey of Children's Health, a cross-sectional telephone survey of US households with a response rate of 23%. Traumatic brain injury prevalence estimates were stratified by sociodemographic characteristics. The likelihood of reporting specific health conditions was compared between children with and without TBI. Age-adjusted prevalence estimates were computed for each state. Associations between TBI prevalence, insurance type, and parent rating of insurance adequacy were examined. Data analysis was conducted from February 1, 2016, through November 1, 2017. Lifetime estimate of TBI in children, associated childhood health conditions, and parent report of health insurance type and adequacy. The lifetime estimate of parent-reported TBI among children was 2.5% (95% CI, 2.3%-2.7%), representing over 1.8 million children nationally. Children with a lifetime history of TBI were more likely to have a variety of health conditions compared with those without a TBI history. Those with the highest prevalence included learning disorders (21.4%; 95% CI, 18.1%-25.2%); attention-deficit/hyperactivity disorder (20.5%; 95% CI, 17.4%-24.0%); speech/language problems (18.6%; 95% CI, 15.8%-21.7%); developmental delay (15.3%; 95% CI, 12.9%-18.1%); bone, joint, or muscle problems (14.2%; 95% CI, 11.6%-17.2%); and anxiety problems (13.2%; 95% CI, 11.0%-16.0%). States with a higher prevalence of childhood TBI were more likely to have a higher proportion of children with private health insurance and higher parent report of adequate insurance. Examples of states with higher prevalence of TBI and higher proportion of private insurance included Maine, Vermont, Pennsylvania, Washington, Montana, Wyoming North Dakota, South Dakota, and Colorado. A large number of US children have experienced a TBI during childhood. Higher TBI prevalence in states with greater levels of private insurance and insurance adequacy may suggest an underrecognition of TBI among children with less access to care. For more comprehensive monitoring, health care professionals should be aware of the increased risk of associated health conditions among children with TBI.

Objective To investigate the effect of long non-coding RNA F19 (lncRNA F19) on secondary brain injury following traumatic brain injury (TBI) in mice. Methods (1) A total of 96 C57BL/6J male wild-type mice were divided into sham group, sham+ control lentivirus group, sham+ F19 lentivirus group, TBI group, TBI+ control lentivirus group and TBI+ F19 lentivirus group according to the random number table. Each group consisted of two subgroups of 1 day and 3 days after TBI, with eight mice per subgroup. The expression and silence efficiency of lncRNA F19 were detected. (2) A total of 96 C57BL/6J male wild-type mice were divided into sham group, TBI+ control lentivirus group and TBI+ F19 lentivirus group according to the random number table. Each group consisted of two subgroups of 1 day and 3 days after TBI, with 16 mice per subgroup. The effect of lncRNA F19 on neuronal apoptosis after TBI was recorded. The mice TBI model was established using the controlled cortical damage method (CCI). The lncRNA F19 lentivirus or control lentivirus were administrated by intracerebroventricular injection 5 days before injury. The expressions of lncRNA F19(2-ΔΔct) were detected by real-time quantitative PCR (qRT-PCR) at 1 day and 3 days after injury. The Toll-like receptor 4 (TLR4), B lymphocyte tumor-2 (Bcl-2) and Bcl-2 related protein (Bax) expressions were detected by Western blot. The TUNEL was used to detect apoptosis around the traumatic lesions. Results From the first day after injury, both in the sham operation and TBI groups, the control lentivirus had no effect on the level of lncRAN F19 (P>0.05). One day after injury, compared with sham+ control lentivirus group, the levels of lncRNA F19 in sham+ F19 lentivirus group were significantly decreased (0.07±0.07∶0.93±0.17); compared with TBI+ control lentivirus group, levels of lncRNA F19 in TBI+ F19 lentivirus group were significantly decreased (2.91±1.18∶0.52±0.32) (P<0.05). There were significantly lower protein levels of TLR4 (0.51±0.13∶0.66±0.15), Bax (0.45±0.06∶0.67±0.16), lower TUNEL-positive neurons ratio [(23.55±6.85)%∶(31.58±7.52)%], but higher protein levels of Bcl-2 (0.76±0.16∶0.47±0.12) in TBI+ F19 lentivirus group compared with the TBI+ control lentivirus group (P<0.05). Three days after injury, compared with sham+ control lentivirus group, levels of lncRNA F19 in sham+ F19 lentivirus group were significantly decreased (0.11±0.09∶0.96±0.09); compared with TBI+ control lentivirus group, levels of lncRNA F19 in TBI+ F19 lentivirus group were significantly decreased (0.54±0.24∶3.39±0.90) (P<0.05). There were significantly lower protein levels of TLR4 (0.60±0.20)∶(0.85±0.09)], lower Bax (0.60 ± 0.12∶0.88±0.21), lower TUNEL-positive neurons ratio [(29.10±7.37)%∶(39.22±10.64)%], but higher protein levels of Bcl-2 (0.66±0.12∶0.35±0.16) in TBI+ F19 lentivirus group compared with the TBI+ control lentivirus group (P<0.05). Conclusion Inhibition of lncRNA F19 can significantly reduce the TLR4-induced neuronal apoptosis in cortex after TBI in mice and alleviate reduce the secondary brain injury. Key words: Brain injuries; Long non-coding RNAs; Toll-like receptor 4; Apoptosis