A multi-mode shock tube for investigation of blast-induced traumatic brain injury

Blast-induced mild traumatic brain injury (bTBI) has become increasingly common in recent military conflicts. The mechanisms by which non-impact blast exposure results in bTBI are incompletely understood. Current small animal bTBI models predominantly utilize compressed air-driven membrane rupture as their blast wave source, while large animal models use chemical explosives. The pressure-time signature of each blast mode is unique, making it difficult to evaluate the contributions of the different components of the blast wave to bTBI when using a single blast source. We utilized a multi-mode shock tube, the McMillan blast device, capable of utilizing compressed air- and compressed helium-driven membrane rupture, and the explosives oxyhydrogen and cyclotrimethylenetrinitramine (RDX, the primary component of C-4 plastic explosives) as the driving source. At similar maximal blast overpressures, the positive pressure phase of compressed air-driven blasts was longer, and the positive impulse was greater, than those observed for shockwaves produced by other driving sources. Helium-driven shockwaves more closely resembled RDX blasts, but by displacing air created a hypoxic environment within the shock tube. Pressure-time traces from oxyhydrogen-driven shockwaves were very similar those produced by RDX, although they resulted in elevated carbon monoxide levels due to combustion of the polyethylene bag used to contain the gases within the shock tube prior to detonation. Rats exposed to compressed air-driven blasts had more pronounced vascular damage than those exposed to oxyhydrogen-driven blasts of the same peak overpressure, indicating that differences in blast wave characteristics other than peak overpressure may influence the extent of bTBI. Use of this multi-mode shock tube in small animal models will enable comparison of the extent of brain injury with the pressure-time signature produced using each blast mode, facilitating evaluation of the blast wave components contributing to bTBI.     

An open air research study of blast-induced traumatic brain injury to goats

Purpose: We once reported blast-induced traumatic brain injury (bTBI) in confined space. Here, bTBI was studied again on goats in the open air using 3.0 kg trinitrotoluene. Methods: The goats were placed at 2, 4, 6 and 8 m far from explosion center. Trinitrotoluene (TNT) was used as the source of the blast wave and the pressure at each distance was recorded. The systemic physiology, electroencephalogram, serum level of S-100beta, and neuron specific enolase (NSE) were determined pre and post the exposure. Neuroanatomy and neuropathology were observed 4 h after the exposure. Results: Simple blast waveforms were recorded with parameters of 702.8 kPa-0.442 ms, 148.4 kPa- 2.503 ms, 73.9 kPa-3.233 ms, and 41.9 kPa-5.898 ms at 2, 4, 6 and 8 m respectively. Encephalic blast overpressure was on the first time recorded in the literature by us at 104.2 kPa-0.60 ms at 2 m, where mortality and burn rate were 44% and 44%. Gross examination showed that bTBI was mainly manifested as congestive expansion of blood vessels and subarachnoid hemorrhage, which had a total incidence of 25% and 19% in 36 goats. Microscopical observation found that the main pathohistological changes were enlarged perivascular space (21/36, 58%), small hemorrhages (9/36, 25%), vascular dilatation and congestion (8/36, 22%), and less subarachnoid hemorrhage (2/36, 6%). After explosion, serum levels of S-100b and NSE were elevated, and EEG changed into slow frequency with declined amplitude. The results indicated that severity and incidence of bTBI is related to the intensity of blast overpressure. Conclusion: Blast wave can pass through the skull to directly injure brain tissue.     

Cell-free DNA as a marker for prediction of brain damage in traumatic brain injury in rats

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and early predictors of neurological outcomes are of great clinical importance. Cell free DNA (CFD), a biomarker used for the diagnosis and monitoring of several diseases, has been implicated as a possible prognostic indicator after TBI. The purpose of this study was to determine the pattern and timing of CFD levels after TBI, and whether a relationship exists between the level of CFD and brain edema and neurological outcomes. Thirty-nine Sprague-Dawley rats were randomly assigned to two groups: rats in group 1 (sham group) were anesthetized and had a scalp incision without TBI, and rats in group 2 were anesthetized and had a scalp incision with TBI, which was induced by using a weight drop model that causes diffuse brain injury. A neurological severity score (NSS) was assessed at 1, 24, and 48?h after TBI. CFD was measured via blood samples drawn at t=0 (baseline), 12, 24, 48, 72, and 120?h after TBI. At 48?h after TBI, brain edema was determined in a subgroup of 11 rats by calculating the difference between rats' wet and dry brain weight. The significance of comparisons between and within groups (CFD levels, brain water content, and NSS) were determined using the Kruskal-Wallis, Mann-Whitney and Student t test. The correlation between CFD levels and the NSS, as well as between CFD levels and the extent of brain edema, was calculated using the Spearman and Pearson tests, respectively. Compared with baseline levels, the CFD levels in rats subjected to TBI were significantly increased at 24 and 48 h after TBI (p<0.01 and p<0.05, respectively). A positive correlation was demonstrated between CFD levels 24?h following TBI and the extent of brain edema (r=0.63, p<0.05), as well as between CFD levels and the NSS (r=0.79, p<0.005). In this study, we demonstrated an increase in CFD levels after TBI, as well as a correlation between CFD levels and brain edema and NSS. CFD levels may provide a quick, reliable, and simple prognostic indicator of neurological outcome in animals after TBI. Its role in humans has not been clearly elucidated, but has potentially significant clinical implications.     

Mechanisms of primary blast-induced traumatic brain injury: insights from shock-wave research

Traumatic brain injury caused by explosive or blast events is traditionally divided into four phases: primary, secondary, tertiary, and quaternary blast injury. These phases of blast-induced traumatic brain injury (bTBI) are biomechanically distinct and can be modeled in both in vivo and in vitro systems. The primary bTBI injury phase represents the response of brain tissue to the initial blast wave. Among the four phases of bTBI, there is a remarkable paucity of information about the cause of primary bTBI. On the other hand, 30 years of research on the medical application of shockwaves (SW) has given us insight into the mechanisms of tissue and cellular damage in bTBI, including both air-mediated and underwater SW sources. From a basic physics perspective, the typical blast wave consists of a lead SW followed by supersonic flow. The resultant tissue injury includes several features observed in bTBI, such as hemorrhage, edema, pseudoaneurysm formation, vasoconstriction, and induction of apoptosis. These are well-described pathological findings within the SW literature. Acoustic impedance mismatch, penetration of tissue by shock/bubble interaction, geometry of the skull, shear stress, tensile stress, and subsequent cavitation formation, are all important factors in determining the extent of SW-induced tissue and cellular injury. Herein we describe the requirements for the adequate experimental set-up when investigating blast-induced tissue and cellular injury; review SW physics, research, and the importance of engineering validation (visualization/pressure measurement/numerical simulation); and, based upon our findings of SW-induced injury, discuss the potential underlying mechanisms of primary bTBI.     

MicroRNA let-7i is a promising serum biomarker for blast-induced traumatic brain injury

Blast-induced traumatic brain injury (TBI) is of significant concern in soldiers returning from the current conflicts in Iraq and Afghanistan. Incidents of TBI have increased significantly in the current conflicts compared to previous wars, and a majority of these injuries are caused by improvised explosive devices. Currently, no specific technique or biomarker is available for diagnosing TBI when no obvious clinical symptoms are present. Micro-RNAs are small RNA (~ 22nts) molecules that are expressed endogenously and play an important role in regulating gene expression. MicroRNAs have emerged as novel serum diagnostic biomarkers for various diseases. In this study, we studied the effect of blast overpressure injury on the microRNA signatures in the serum of rats. Rats were exposed to three serial 120-kPa blast overpressure exposures through a shockwave tube. Blood and cerebrospinal fluid were collected at various time points after injury, and microRNA modulation was analyzed using real-time PCR. Five microRNAs were significantly modulated in the serum samples of these animals at three time points post-injury. Further, we also found that the levels of microRNA let-7i are also elevated in cerebrospinal fluid post-blast wave exposure. The presence of microRNA in both serum and cerebrospinal fluid immediately after injury makes microRNA let-7i an ideal candidate for further studies of biomarkers in TBI.     

Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury

Previous studies from our laboratory indicate that traumatic brain injury (TBI) in humans results in proteolysis of neuronally-localized, intracellular microtubule associated protein (MAP)-tau to produce cleaved tau (C-tau). The present study evaluated the utility of C-tau to function as a biomarker of neuronal injury and as a biomarker for evaluating neuroprotectant drug efficacy in a controlled cortical impact model of rat TBI. Brain C-tau was determined in rats subjected to controlled cortical impact-induced mild, moderate or severe levels of TBI. A significant severity-dependent increase in C-tau levels was observed in the cortex and hippocampus (1.5-8-fold) of TBI rats compared to shams 72 h after impact. C-tau rat brain and serum time course was determined by measuring levels at 0.25, 6, 24, 48, 72 and 168 h after TBI. A significant time-dependent increase in C-tau levels was observed in ipsilateral cortex (5-16-fold) and hippocampus (2-40-fold) compared to sham animals. C-tau levels increased as early as 6 h after TBI with peak C-tau levels observed 168 h after injury. Elevated brain C-tau levels were associated with TBI-induced tissue loss, which was histologically determined. The effect of cyclosporin-A (CsA), previously demonstrated to be neuroprotective in rat TBI, on brain C-tau levels was examined. CsA (20 mg/kg i.p., 15 min and 24 h after TBI) significantly attenuated the TBI-induced increase in hippocampal C-tau levels observed in vehicle-treated animals confirming CsA's neuroprotectant effect. CsA treatment also lowered ipsilateral cortical C-tau levels, although it did not reach statistical significance. CsA's neuroprotectant effect was confirmed utilizing histologic measures of TBI-induced tissue loss. In addition, serum C-tau levels were significantly increased 6 h after TBI but not at later time points. These results suggest that C-tau is a reliable, quantitative biomarker for evaluating TBI-induced neuronal injury and a potential biomarker of neuroprotectant drug efficacy in the rat TBI model. Serum data suggests that C-tau levels are dependent both on a compromised blood-brain barrier as well as release of TBI biomarkers from the brain, which has implications for the study of human serum TBI biomarkers.     

Sex offending as a psychosocial sequela of traumatic brain injury

OBJECTIVE: To describe the nature and extent of sexual offending after traumatic brain injury (TBI). DESIGN: Retrospective file review. SETTING: A brain injury unit providing inpatient and outpatient rehabilitation services. PARTICIPANTS: A review of five years of admissions to the Brain Injury Rehabilitation Unit (N = 477) identified a sample of 29 males who committed 128 incidents of sex offending. MAIN OUTCOME MEASURES: A protocol to record data on demographic, injury, radiological, and psychosocial variables and offending behaviors. RESULTS: Of the total population of 445 clients with TBI, 6.5% (n = 29) were identified as having committed some form of sexual offense. Alcohol was a factor in only three (2.3%) of the incidents, and only two clients had a preinjury history of sexual offending. The most common offenses were the "touching" offenses, followed by exhibitionism and overt sexual aggression. Staff members were the most common targets of the offenses, followed by members of the general public, other people with TBI, and family members. CONCLUSIONS: Sex offending is a significant clinical problem among a small minority of men after TBI. The absence of alcohol and preinjury histories of sexual offending suggest that the brain injury and contingent sequelae were a significant etiological factor underlying the offenses. A number of implications for the clinical management of clients with sexually aberrant behaviors is identified and discussed.     

Extracellular N-acetyl-aspartate as a biochemical marker of the severity of neuronal damage following experimental acute traumatic brain injury

We evaluated the acute changes in interstitial and whole brain N-acetyl-aspartate (NAA) measured by high-performance liquid chromatography in animal models of isolated traumatic brain injury (TBI) and TBI combined with secondary insult (hypotension-hypoxia [HH]). The Marmarou impact-acceleration model was used. Four groups were studied: (1) sham-operated control, (2) TBI alone (TBI 500 gm, 2 m), (3) TBI plus 30 min of hypoxia (PaO2, approximately 40 mm Hg) and hypotension (mean arterial blood pressure, approximately 40 mm Hg) (THH), and (4) HH alone. The baseline value for dialysate NAA (NAAd) in the rats was 8.17+/-1 microM. No significant difference between groups was found for this baseline value. The TBI group had a modest (100%) transient increase in NAAd after isolated TBI. The HH group had a transient (500%) increase in NAAd at 1 h, sustained for 2 h. In the THH group, there was a persistent increase in NAAd (800%) that peaked at 2.5 h. The whole brain NAA (NAAw) concentration in controls was 8.5+/-0.5 mmol/kg wet weight. There was no significant difference between TBI and controls; however, there was a significant decrease in NAAw in the THH and HH group compared to controls. Thus, in this animal model of TBI and TBI with secondary insult, we found that persistent, marked elevation in NAA is associated with TBI and secondary ischemic/hypoxic insult, but not with isolated TBI alone.     

Gender as a moderator of memory after traumatic brain injury in children

OBJECTIVE: To explore the possibility that gender has a moderating effect on memory after pediatric traumatic brain injury (TBI). DESIGN: Controlled group study. Gender effects between and within groups were evaluated by means of effect size comparisons and hierarchical regression analysis. SETTING: Regional rehabilitation center. PARTICIPANTS: Seventy children with TBI, selected from a 4-year series of consecutive referrals, and 70 demographically matched controls. MAIN OUTCOME MEASURES: Screening version of the Wide Range Assessment of Memory and Learning (WRAML-S) and the Wechsler Intelligence Scale for Children-Third Edition (WISC-III). RESULTS: Boys with TBI performed worse than girls with TBI, and worse than their counterparts in the control group, on the WRAML-S. There was no gender effect in the control group. Gender explained an additional 9% of the variance in WRAML-S performance over and above injury severity and age variables. However, gender differences were largely attenuated when speed of information processing, as assessed by the WISC-III, was used as a covariate. CONCLUSION: The effect of TBI on children's memory appears to be moderated by gender and may be mediated by speed of information processing.     

脑外伤后神经细胞功能障碍的机制

创伤性脑损伤后受损区的神经元细胞常可发生继发性损伤,其机制包括细胞凋亡、兴奋性氨基酸的作用、钙离子的作用等,并且在动物模型上都得到了证实。     

Stem cell transplantation as a therapeutic strategy for traumatic brain injury

Stem cell transplantation has enormous potential to be a viable therapeutic approach to replace the lost tissue/cells following traumatic brain injury (TBI). Several types of cell lines such as immortalized progenitors cells, embryonic rodent and human stem cells and bone marrow-derived cells have been successfully transplanted in experimental models of TBI, resulting in reduced neurobehavioral deficits and attenuation of histological damage. To date, it remains unclear whether stem cell are effective following transplantation into the injured brain via either cell replacement, trophic support, or manipulation of the local environment to stimulate endogenous neuroprotection/regeneration. This paper will review the most current and exciting pre-clinical data regarding the utility of cellular transplantation in experimental models of TBI. We believe that further work must continue to better understand the interaction between the host and the transplanted cells as well as the mechanisms regulating their differentiation into mature and functionally active neurons/glia.     

Participation as an outcome of traumatic brain injury rehabilitation

OBJECTIVES: Participation in meaningful life situations is an important aspect of functioning after traumatic brain injury (TBI). However, to date, few studies have included measures of social participation or community integration as outcome measures after TBI rehabilitation. This paper is a selective review of the literature that examines the effects of TBI rehabilitation on measures of participation or community integration. It also addresses the related questions of clinically significant improvements in community integration, variability in patterns of community functioning, and the relationship of participation and quality of life after TBI. DESIGN: Literature review. CONCLUSIONS: A small number of studies suggest that postacute TBI rehabilitation can produce improvements in participation and community integration. However, a considerable amount of variability in rehabilitation outcomes may be apparent. Analysis of clinically significant changes in individual's functioning suggests that rehabilitation may exert its benefits not only by facilitating improvements, but also by preventing declines in community functioning. Subjective well-being and quality of life have generally been ignored as TBI rehabilitation outcomes. There is considerable evidence that participation and subjective well-being represent distinct and dissociable outcomes after TBI, which may reflect the importance of patients' preferences and values in evaluating the effectiveness of rehabilitation.     

Effect of glycyrrhizin on traumatic brain injury in rats and its mechanism

Objective： To investigate the neuropro- tective effects of glycyrrhizin （Gly） as well as its effect on expression of high-mobility group box 1 （HMGB1） in rats after traumatic brain injury （TBI）. Methods： Male Sprague-Dawley rats were randomly divided into three groups： sham group, TBI group, and TBI＋Gly group （n=36 per group）. Rat TBI model was made by using the modified Feeney＇s method. In TBI＋Gly group, Gly was administered intravenously at a dosage of l0 mg/kg 30 min after TBI. At 24 h after TBI, motor function and brain water content were evaluated. Meanwhile, HMGB 1/HMGB 1 receptors including toll-like receptor 4 （TLR4） and receptor for advanced glycation end products （RAGE）/nuclear fac- tor-κ B（NF- κ B） signaling pathway and inflammatory cytokines in the injured brain tissues were detected using quantitative real-time polymerase chain reaction, western blot, electrophoretic mobility shift assay and enzyme-linked immunosorbent assay. Furthermore, HMGB l, RAGE and TLR4 immunohistochemistry and apoptosis were analyzed. Results： Beam walking performance impairment and brain edema were significantly reduced in TBI＋Gly group compared with TBI group; meanwhile, the over-expressions of HMGB 1PHMGB 1 receptors （TLR4 and RAGE）/NF- κB DNA-binding activity and inflammatory cytokines were inhibited. The percentages of HMGB 1, RAGE and TLR4- positive cells and apoptotic cells were respectively 58.37%±5.06%, 54.15%±4.65%, 65.50%± 4.83%, 52.02%±4.63% in TBI group and 39.99%±4.99%, 34.87%±5.02%, 43.33%±4.54%, 37.84%±5.16% in TBI＋Gly group （all P〈0.01 compared with TBI group）. Conclusion： Gly can reduce secondary brain injury and improve outcomes in rat following TBI by down-regula- tion of HMGB 1/HMGB 1 receptors （TLR4 and RAGE）/NF- κB - mediated inflammatory responses in the injured rat brain.     

Hypertension in traumatic brain injury

The incidence and natural history of hypertension associated with traumatic brain injury were studied using a cohort of 80 patients discharged from a brain-injury rehabilitation centre. Although a significant incidence (15%) of hypertension is documented in traumatic brain-injured patients, the problem appears transient for most patients. Nonetheless, hypertension after brain injury merits treatment while it is an ongoing process for the anticipated few patients in whom it might persist.     

Bromocriptine in traumatic brain injury

The authors report the case of a 63-year-old patient with severe traumatic brain injury (TBI) associated with Parkinson's syndrome, whose performances were dramatically improved by bromocriptine therapy, with an improvement of the scores, not only on tests evaluating motor functions but also on tests evaluating the patient's cognitive functions. However, no improvement was observed with levodopa.     

Neuromonitoring in traumatic brain injury

Current approaches to monitoring in severe traumatic brain injury (TBI) include a wide array of modalities, providing insight into pressure parameters, oxygenation, perfusion, electrophysiology and metabolism of the brain. The intent of "multimodality monitoring" is to obtain a better understanding of what is going on within the brain of an individual patient in order to target treatment more appropriately. In this review we highlight the current status of neuromonitoring for TBI with a specific focus on how advanced analysis and integration of these parameters may be used to implement more personalized treatment approaches. In particular, combining information from different parameters and performing dynamic testing offers the potential to better understand the pathophysiological mechanisms active in the brain of a particular patient. Rather than persisting in a standardized "one size fits all" approach to therapy or continuing down the separate tracts of goal directed therapy, we suggest to think more in terms of "individualized therapeutic strategies" more focused on the specific requirements of each patient. Given the considerable data overload in multimodality monitoring and the complexity in interpretation of signals from multiple sources, specific attention needs to be directed to data processing and user-friendly displays. Intense collaboration and interaction between clinicians, basic researchers, IT-experts, nurses and industry will be required to further advance the fields towards more personalized approaches.