Head Injury Model Research Articles

Science, Anaesthesia and animal studies: what is ‘evidence’?

Science, <i>Anaesthesia</i> and animal studies: what is ‘evidence’?

Mathematical models used in TBI

Event Abstract Back to Event Mathematical models used in TBI Svein Kleiven1* 1 KTH School of Technology and Health, Neuronic Engineering, Sweden In Sweden, head injuries causes about 78% of the deaths in motor vehicle accidents. The total annual rate of head injuries in Sweden over the last 14 years is also relatively constant. Thus, in spite of several national preventive strategies, there has not been an important impact on the total burden of head injury. Neurotrauma is the physical damage that results when the human skull and brain are suddenly subjected to intolerable levels of energy that is usually transmitted mechanically. Most of the research in the injury prevention area was initiated by the military aircraft industry in the sixties and seventies. Today the research is to a greater extent sponsored by the car manufacturing industry, partly as a result of the demands from the customers and the media. However, there is a long way to go before a complete understanding of the pathophysiological events following an accident is reached. This paper primarily focuses on summarizing current efforts, and to outline future strategies in human head injury modeling. Although the finite element (FE) modeling of the human head has been advancing over the past decades, it is still far from being able to explain all brain injury mechanisms and predict all types of impact injuries. However, using proper material characterization, correct boundary conditions and detailed geometric representation, a finite element model of the human head can provide us a powerful tool. A detailed and parameterized FE model of the adult human head is presented. It includes the scalp, skull, brain, meninges, cerebrospinal fluid (CSF), and eleven pairs of bridging veins. Separate representations of gray and white matter, and inclusion of the ventricles were also implemented. Non-linear and viscoelastic models are derived for the central nervous system (CNS) and meninges and the importance for injury prediction is outlined. The fluids were modelled using an Eulerian FE formulation, and constrains between fluids and solids were defined. Proposed injury measures for the CNS are also evaluated. Application of the FE head model to reconstructions of real head injury cases will also be discussed. Keywords: accident reconstruction, brain injury prevention, Finite Element Analysis, Traumatic Brain Injury Conference: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System, Stockholm, Sweden, 15 Sep - 16 Sep, 2010. Presentation Type: Presentation Topic: Traumatic Injuries in the Nervous System Citation: Kleiven S (2010). Mathematical models used in TBI. Front. Neurol. Conference Abstract: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System. doi: 10.3389/conf.fneur.2010.56.00012 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Sep 2010; Published Online: 21 Sep 2010. * Correspondence: Dr. Svein Kleiven, KTH School of Technology and Health, Neuronic Engineering, Huddinge, Sweden, sveink@kth.se Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Svein Kleiven Google Svein Kleiven Google Scholar Svein Kleiven PubMed Svein Kleiven Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Intracranial Pressure and Experimental Model of Diffuse Brain Injury in Rats

In this study, we present a simple closed head injury model as a two-stage experiment. The height of the weight drop enables gradation of head trauma severity. The head injury device consists of three parts and there are three adjustable parameters-weight (100-600 g), height of fall (5-100 cm) and elasticity of the springs. Thirty male Wistar rats underwent monitoring of intracranial pressure with and without induction of the head injury. The weight drop from 45 to 100 cm led to immediate seizure activity and early death of the experimental animals. Severe head injury was induced from 40 cm weight drop. There was 50% mortality and all surviving rats had behavioral deterioration. Intracranial pressure was 9.3 +/- 3.76 mmHg. Moderate head injury was induced from 35 cm, mortality decreased to 20-40%, only half of the animals showed behavioral pathology and intracranial pressure was 7.6 +/- 3.54 mmHg. Weight drop from 30 cm caused mild head injury without mortality and neurological deterioration. Intracranial pressure was slightly higher compared to sham group- 5.5 +/- 0.74 mmHg and 2.9 +/- 0.81 mmHg respectively. This model is an eligible tool to create graded brain injury with stepwise intracranial pressure elevation.

Diffuse neuronal perikaryal amyloid precursor protein immunoreactivity in an ovine model of non-accidental head injury (the shaken baby syndrome)

Non-accidental head injury (“shaken baby syndrome”) is a major cause of death and disability in infants and young children, but it is uncertain whether shaking alone is sufficient to cause brain damage or an additional head impact is required. Accordingly, we used manual shaking in an ovine model in an attempt to answer this question since lambs have a relatively large gyrencephalic brain and weak neck muscles resembling a human infant. Neuronal perikaryal and axonal reactions were quantified 6 hours after shaking using amyloid precursor protein (APP) immunohistochemistry. Neuronal perikaryal APP was widely distributed in the brain and spinal cord, the first time such a diffuse neuronal stress response after shaking has been demonstrated, but axonal immunoreactivity was minimal and largely confined to the rostral cervical spinal cord at the site of maximal loading. No ischaemic-hypoxic damage was found in haematoxylin and eosin-stained sections.

Mouse closed head injury model induced by a weight-drop device

Traumatic brain injury represents the leading cause of death in young individuals. Various animal models have been developed to mimic human closed head injury (CHI). Widely used models induce head injury by lateral fluid percussion, a controlled cortical impact or impact acceleration. The presented model induces a CHI by a standardized weight-drop device inducing a focal blunt injury over an intact skull without pre-injury manipulations. The resulting impact triggers a profound neuroinflammatory response within the intrathecal compartment with high consistency and reproducibility, leading to neurological impairment and breakdown of the blood-brain barrier. In this protocol, we define standardized procedures for inducing CHI in mice and determine various severity grades of CHI through modulation of the weight falling height. In experienced hands, this CHI model can be carried out in as little as 30 s per animal, with additional time required for subsequent posttraumatic analysis and data collection.

Prediction of Outcome Utilizing Both Physiological and Biochemical Parameters in Severe Head Injury

Traumatic brain injury is a major socioeconomic burden, and the use of statistical models to predict outcomes after head injury can help to allocate limited health resources. Earlier prediction models analyzing admission data have been used to achieve prediction accuracies of up to 80%. Our aim was to design statistical models utilizing a combination of both physiological and biochemical variables obtained from multimodal monitoring in the neurocritical care setting as a complement to earlier models. We used decision tree and logistic regression analysis on variables including intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and pressure reactivity index (PRx), as well as multimodal monitoring parameters to assess brain tissue oxygenation (PbtO(2)), and microdialysis parameters to predict outcomes based on a dichotomized Glasgow Outcome Score. Further analysis was carried out on various subgroup combinations of physiological and biochemical parameters. The reliability of the head injury models was assessed using a 10-fold cross-validation technique. In addition, the confusion matrix was also used to assess the sensitivity, specificity, and the F-ratio. In all, 2,413 time series records were extracted from 26 patients treated at our neurocritical care unit over a 1-year period. Decision tree analysis was found to be superior to logistic regression analysis in predictive accuracy of outcome. The combined use of microdialysis variables and PbtO(2), in addition to ICP, MAP, and CPP was found have the best predictive accuracy. The use of physiological and biochemical variables based on a decision tree analysis model has shown to provide an improvement in predictive accuracy compared with other previous models. The potential application is for outcome prediction in the multivariate setting of advanced multimodality monitoring, and validates the use of multimodal monitoring in the neurocritical care setting to have a potential benefit in predicting outcomes of patients with severe head injury.

Closed Head Injury in a Mouse Model Results in Molecular Changes Indicating Inflammatory Responses

Cerebral gene expression changes in response to traumatic brain injury will provide useful information in the search for future trauma treatment. In order to characterize the outcome of mild brain injury, we studied C57BL/6J mice in a weight-drop, closed head injury model. At various times post-injury, mRNA was isolated from neocortex and hippocampus and transcriptional alterations were studied using quantitative reverse transcriptase PCR and gene array analysis. At three days post-injury, the results showed unilateral injury responses, both in neocortex and hippocampus, with the main effect seen on the side of the skull hit by the dropping weight. Upregulated transcripts encoded products characterizing reactive astrocytes, phagocytes, microglia, and immune-reactive cells. Markers for oligodendrocytes and T-cells were not altered. Notably, strong differences in the responses among individual mice were seen (e.g., for the Gfap transcript expressed by reactive astrocytes and the chemokine Ccl3 transcript expressed by activated microglial cells). In conclusion, mild TBI chiefly activates transcripts leading to tissue signaling, inflammatory processes, and chemokine signaling, as in focal brain injury, suggesting putative targets for drug development.

Experimental brain damage from fluid pressures due to impact acceleration. 1. Design of experimental procedure.

The significance of the intracranial acceleration pressure pattern at impact to the intact skull in production of brain damage is discussed particularly as regards the contre-coup pressures. Sudden pressure changes within the cranial cavity of the rabbit were studied by means of a new impact acceleration model. The rabbit skull was connected with a cylinder. Impact acceleration was applied to the model with the skull contents serving as a "contre-coup end". Skull deformation was minimized by reinforcement of the skull vault. Acceleration, velocity and displacement of the system were recorded at various sites and could be predicted within wide ranges. Simultaneous recordings were also made of the pressure changes in the skull cavity and cylinder contents. By adjusting the acceleration course and by introducing a quantified air bubble 050, 100, 150 mm3) at the impact of the cylinder, it was possible to produce and vary an intracranial pressure pattern of "contre-coup type", including predictable subatmospheric transients. The mechanics of the intracranial pressure changes and displacements are discussed. The method seems to be suitable for studying the relations between brief negative-positive pressure variations (about 5 ms) of "contre-coup type" and pathological alterations similar to those reported in other head injury models and in human head trauma.

Influence of deployable hood systems on finite element modelled brain response for vulnerable road users

Using full-scale Polar II adult dummy tests as input, a free-flying angled head-to-hood component test method was developed, and tests were performed at two different impact configurations at a test speed of 40 km/h. Both linear and rotational head acceleration were measured and used to drive the Wayne State University Head Injury Model (WSUHIM). The dummy tests showed small pre-impact head accelerations (<1000 rad s−2) and neck moments (<35 Nm). In all dummy tests, the rotational acceleration reached the highest levels about the X-axis. For a small under-hood clearance and using three different head impact configurations (one dummy and two impactors), a strain level of 0.35 was experienced by 22-42% of the brain volume; for a large under-hood distance, a strain level of 0.35 was experienced by only 2-5% of the brain volume at some time during the event (approximately a ten-fold reduction).

Biodynamics model for operator head injury in stand-up lift trucks

Biodynamics and injury potential of operators in stand-up rider lift truck accidents have been investigated with a special focus on head injury. An anthropomorphic test device (ATD) model was used as an operator surrogate in computer simulations of off-the-dock (OTD) and tip-over (TO) accidents. The biomechanical model representing the ATD was developed based on rigid body segments, and then combined with a rigid body truck model in the accident simulations. The operator compartment of the truck model was enclosed with a rear door. The computed kinematics are in agreement with the results of previous experimental testing. A 2D finite element model of the head was created to compute head impact decelerations in the sagittal plane. Values of the head injury criterion for the TO cases were computed from the model and shown to compare favourably with experimental values. The results advance the state of knowledge concerning injury potential in TO and OTD accidents and simulation models for such accidents.

Experimental modeling of head injury

The modern data about the experimental modeling of head injury are quoted. The main types of models, their features and descriptions are given. The special attention has been devoted to the head injury modeling devices.

Midline brain injury in the immature rat induces sustained cognitive deficits, bihemispheric axonal injury and neurodegeneration

Infants and children less than 4 years old suffer chronic cognitive deficits following mild, moderate or severe diffuse traumatic brain injury (TBI). It has been suggested that the underlying neuropathologic basis for behavioral deficits following severe TBI is acute brain swelling, subarachnoid hemorrhage and axonal injury. To better understand mechanisms of cognitive dysfunction in mild-moderate TBI, a closed head injury model of midline TBI in the immature rat was developed. Following an impact over the midline suture of the intact skull, 17-day-old rats exhibited short apnea times (3–15 s), did not require ventilatory support and suffered no mortality, suggestive of mild TBI. Compared to un-injured rats, brain-injured rats exhibited significant learning deficits over the first week post-injury ( p < 0.0005), and, significant learning ( p < 0.005) and memory deficits ( p < 0.05) in the third post-injury week. Between 6 and 72 h, blood–brain barrier breakdown, extensive traumatic axonal injury in the subcortical white matter and thalamus, and focal areas of neurodegeneration in the cortex and hippocampus were observed in both hemispheres of the injured brain. At 8 to 18 days post-injury, reactive astrocytosis in the cortex, axonal degeneration in the subcortical white matter tracts, and degeneration of neuronal cell bodies and processes in the thalamus of both hemispheres were observed; however, cortical volumes were not different between un-injured and injured rat brains. These data suggest that diffuse TBI in the immature rat can lead to ongoing degeneration of both cell soma and axonal compartments of neurons, which may contribute, in part, to the observed sustained cognitive deficits.

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

The immature brain in the first several years of childhood is very vulnerable to trauma. Traumatic brain injury (TBI) during this critical period often leads to neuropathological and cognitive impairment. Previous experimental studies in rodent models of infant TBI were mostly concentrated on neuronal degeneration, while axonal injury and its relationship to cell death have attracted much less attention. To address this, we developed a closed controlled head injury model in infant (P7) mice and characterized the temporospatial pattern of axonal degeneration and neuronal cell death in the brain following mild injury. Using amyloid precursor protein (APP) as marker of axonal injury we found that mild head trauma causes robust axonal degeneration in the cingulum/external capsule as early as 30 min post-impact. These levels of axonal injury persisted throughout a 24 h period, but significantly declined by 48 h. During the first 24 h injured axons underwent significant and rapid pathomorphological changes. Initial small axonal swellings evolved into larger spheroids and club-like swellings indicating the early disconnection of axons. Ultrastructural analysis revealed compaction of organelles, axolemmal and cytoskeletal defects. Axonal degeneration was followed by profound apoptotic cell death in the posterior cingulate and retrosplenial cortex and anterior thalamus which peaked between 16 and 24 h post-injury. At early stages post-injury no evidence of excitotoxic neuronal death at the impact site was found. At 48 h apoptotic cell death was reduced and paralleled with the reduction in the number of APP-labeled axonal profiles. Our data suggest that early degenerative response to injury in axons of the cingulum and external capsule may cause disconnection between cortical and thalamic neurons, and lead to their delayed apoptotic death.

Natural animal shaking: a model for non-accidental head injury in children?

Non-accidental head injury (NAHI) is a form of child abuse where a perpetrator may violently subject an infant to repeated acceleration-deceleration forces with or without head impact, producing injuries including retinal haemorrhages in most cases. Animal models have included laboratory shaking of mice and rats, but only a small fraction develop retinal haemorrhages presumably due to the small eyes, which would require unattainable force levels to mimic that sustained by the infant eye. Animal models are also problematic due to ethical issues raised by subjecting even anaesthetized animals to abusive injury. We investigated a naturally occurring event, where three animal victims were shaken by a canine. The eyes were harvested and examined histologically. The victims' eyes showed no haemorrhage or retinoschisis. Our model may not be a complete NAHI mimic. The discrepancies may ensue from anatomical and mechanical differences in the injury mechanism. Other models must be sought to further study this form of abusive eye injury.

Hippocampal Cell Loss in Posttraumatic Human Epilepsy

Hippocampal Cell Loss in Posttraumatic Human Epilepsy. Swartz BE, Houser CR, Tomiyasu U, Walsh GO, DeSalles A, Rich JR, Delgado-Escueta A. Epilepsia 2006;47(8): 1373–1382. Purpose: We performed this study to determine whether significant head trauma in human adults can result in hippocampal cell loss, particularly in hilar (polymorph) and CA3 neurons, similar to that observed in animal models of traumatic brain injury. We examined the incidence of hippocampal pathology and its relation to temporal neocortical pathology, neuronal reorganization, and other variables. Methods: Twenty-one of 200 sequential temporal lobectomies had only trauma as a risk factor for epilepsy. Tissue specimens from temporal neocortex and hippocampus were stained with glial fibrillary acidic protein (GFAP) and hematoxylin and eosin (H&amp;E). Eleven hippocampal specimens had additional analysis of neuronal distributions by using cresyl violet and immunolabeling of a neuron-specific nuclear protein. Results: The median age at onset of trauma was 19 years, the median time between trauma and onset of seizures was 2 years, and the median epilepsy duration was 16 years. The length of the latent period was inversely related to the age at the time of trauma ( r = 0.75; Spearman). The neocortex showed gliosis in all specimens, with hemosiderosis ( n = 8) or heterotopias ( n = 6) in some, a distribution differing from chance ( p = 0.02; Fisher). Hippocampal neuronal loss was found in 94% of specimens, and all of these had cell loss in the polymorph (hilar) region of the dentate gyrus. Hilar cell loss ranged from mild, when cell loss was confined to the hilus, to severe, when cell loss extended into CA3 and CA1. Some degree of mossy fiber sprouting was found in the dentate gyrus of all 10 specimens in which it was evaluated. Granule cell dispersion ( n = 4) was seen only in specimens with moderate to severe neuronal loss. Conclusions: Neocortical pathology was universally present after trauma. Neuronal loss in the hilar region was the most consistent finding in the hippocampal formation, similar to that found in the fluid-percussion model of traumatic head injury. These findings support the idea that head trauma can induce hippocampal epilepsy in humans in the absence of other known risk factors.

Monday, December 3, 2007 Found in Translation – New Target for Therapies 9:00 a.m.‐11:30 a.m.

John W. Swann 1 ( 1 Pediatrics/Neuroscience, Baylor College of Medicine, Houston, TX ) Summary: Epilepsy research scientists and clinicians are collaborating in translating scientific discoveries into new therapies for the intractable epilepsies. Discoveries of clinical researchers are guiding the development of relevant animal models. Studies in these models are leading to the identification of what appear to be key molecular steps in the genesis of epilepsy. These molecular mechanisms provide new targets for the development of rationale therapies, which can be tested in these same models. As an example of the progress being made, this program will review the most recent studies of the consequences of prolonged febrile seizures in children. Potential targets for new therapies that have been discovered in models of febrile seizures, head injury, neonatal seizures and kindling will be discussed.

Altered cytokine expression and sustained hypothermia following traumatic brain injury in heat acclimated mice

Long-term exposure to moderate ambient heat (heat acclimation, HA, 30 days at 34 ± 1 °C) provides protection toward a variety of stressors including traumatic brain injury. As previous studies suggested an anti-inflammatory effect of HA and given the ability of augmented pre-injury anti-inflammatory cytokine expression to harbor neuroprotection and to attenuate early post-injury expression of pro-inflammatory mediators, we hypothesized that HA-induced neuroprotection may involve enhanced pre-injury expression of anti-inflammatory mediators or a reduction in post-injury TNF alpha (TNFα) expression. Since the attenuation of inflammatory-associated entities has also been linked to mild hypothermia, an established neuroprotective paradigm, the effect of HA on post-injury body temperature was also studied. HA mice and normothermic (NT) counterparts were examined using a closed head injury model. Cytokines were measured within the ipsilateral cortex. Pre-injury protein levels of anti-inflammatory interleukins 10 and 4 (IL-10, IL-4) were quantified by enzyme-linked immunosorbent assays (ELISA). mRNA and protein levels of TNFα were quantified during the initial 2 h post-injury using semi-quantitative and real-time polymerase chain reaction (sqRT-PCR and qRT-PCR) or ELISA, respectively. Rectal temperatures were measured. HA induced augmented pre-injury IL-10 expression and a post-injury reduction in TNFα mRNA levels, as well as altered expression dynamics of TNFα protein. TNFα protein levels decreased relative to the sham state in HA mice only. HA mice displayed sustained post-injury hypothermia, namely significantly lower body temperature at 4 h post-injury. Given the evidence on the neuroprotective nature of hypothermia and anti-inflammatory cytokines, we suggest that these changes may contribute to HA-induced neuroprotection.

Neuroprotection

The ability of pharmacological agents to limit secondary biochemical damage and cell death has been well established in numerous animal models of stroke, head injury, and spinal cord injury, yet the results of such neuroprotective treatment strategies in human injury have been disappointing. A number of conceptual and methodological issues have undoubtedly contributed to the difficulties in translating the experimental results to the clinic. Most recently, different experimental approaches and altered clinical trial methodologies have provided renewed, albeit cautious, optimism regarding future clinical trials of neuroprotective agents. Herein, we reviewed both the critical problems and potential solutions, emphasizing recent experimental and clinical work.

Diffuse alterations in synaptic protein expression following focal traumatic brain injury in the immature rat

The mechanisms responsible for cognitive decline after traumatic brain injury (TBI) in pediatric patients are poorly understood. The present study examined the potential role of synaptic alterations in this process by using an animal model of immature head injury to define the impact of TBI on expression of the synaptic protein, synaptophysin. After craniotomy, TBI was induced in postnatal day 17 (PND17) rats using controlled cortical impact delivered to the left hemisphere. NeuN, a neuronal marker, and synaptophysin expression were examined 1 day, 1 week, and 1 month after injury by immunohistochemistry and immunoblotting. There were significant decreases in both NeuN and synaptophysin after 1 day and 1 week but not 1 month after injury within the hippocampus and neocortex adjacent to the impact site compared to sham-injured controls. The decrease in synaptophysin and NeuN was also noted in the contralateral hippocampus by 1 day after injury and in the contralateral neocortex by 1 week, indicating that changes in protein expression were not solely localized to the injury site but occurred in more distant regions as well. In conclusion, the decrease and recovery in synaptophysin parallel the cognitive changes that occur after experimental TBI in the PND17 rat, which suggests that changes in this protein may contribute to cognitive declines after injury. The results also suggest that, in spite of the focal nature of the impact, diffuse alterations in protein expression can occur after immature TBI and may contribute to the subsequent cognitive dysfunction.

Vaccinia virus complement control protein significantly improves sensorimotor function recovery after severe head trauma

Vaccinia virus complement control protein (VCP) is an immunomodulator that inhibits both the classical and alternate pathways of the complement system, therefore preventing cell death and inflammation. VCP has previously been shown to be therapeutically effective in mild and moderate traumatic brain injury models. In this study the efficacy of VCP in a severe head injury model is investigated in Wistar rats. Training in a Morris Water Maze (MWM) commenced 2 days prior stereotaxic surgery. Rats were anesthetized before being subjected to a severe (2.7–3.0 atm) lateral fluid percussion injury (FPI) 3.0 mm lateral to the sagittal suture and 4.5 mm posterior to bregma. Ten microliters of VCP (1.7 μg/μl) was injected into the injury site immediately after FPI. Fourteen days post-FPI, rats were tested for spatial learning and memory using the Morris Water Maze, followed by a battery of sensorimotor tests. The latter tests showed statistically significant differences between saline-treated and VCP-treated rats in lateral left pulsion ( p = 0.001) and tactile placing ( p = 0.002) on the first 5 days of testing. In addition, significant differences in right lateral pulsion in the first 4 days ( p = 0.007) of testing was evident. The results suggest that in a severe head injury model, VCP at this dosage favorably influences sensorimotor outcome.