Lateral Fluid Percussion: Model of Traumatic Brain Injury in Mice

Traumatic brain injury (TBI) research has attained renewed momentum due to the increasing awareness of head injuries, which result in morbidity and mortality. Based on the nature of primary injury following TBI, complex and heterogeneous secondary consequences result, which are followed by regenerative processes ^1,2. Primary injury can be induced by a direct contusion to the brain from skull fracture or from shearing and stretching of tissue causing displacement of brain due to movement ^3,4. The resulting hematomas and lacerations cause a vascular response ^3,5, and the morphological and functional damage of the white matter leads to diffuse axonal injury ^6-8. Additional secondary changes commonly seen in the brain are edema and increased intracranial pressure ⁹. Following TBI there are microscopic alterations in biochemical and physiological pathways involving the release of excitotoxic neurotransmitters, immune mediators and oxygen radicals ^10-12, which ultimately result in long-term neurological disabilities ^13,14. Thus choosing appropriate animal models of TBI that present similar cellular and molecular events in human and rodent TBI is critical for studying the mechanisms underlying injury and repair.Various experimental models of TBI have been developed to reproduce aspects of TBI observed in humans, among them three specific models are widely adapted for rodents: fluid percussion, cortical impact and weight drop/impact acceleration ¹. The fluid percussion device produces an injury through a craniectomy by applying a brief fluid pressure pulse on to the intact dura. The pulse is created by a pendulum striking the piston of a reservoir of fluid. The percussion produces brief displacement and deformation of neural tissue ^1,15. Conversely, cortical impact injury delivers mechanical energy to the intact dura via a rigid impactor under pneumatic pressure ^16,17. The weight drop/impact model is characterized by the fall of a rod with a specific mass on the closed skull ¹⁸. Among the TBI models, LFP is the most established and commonly used model to evaluate mixed focal and diffuse brain injury ¹⁹. It is reproducible and is standardized to allow for the manipulation of injury parameters. LFP recapitulates injuries observed in humans, thus rendering it clinically relevant, and allows for exploration of novel therapeutics for clinical translation ²⁰.We describe the detailed protocol to perform LFP procedure in mice. The injury inflicted is mild to moderate, with brain regions such as cortex, hippocampus and corpus callosum being most vulnerable. Hippocampal and motor learning tasks are explored following LFP.     

Controlled Cortical Impact Model for Traumatic Brain Injury

Every year over a million Americans suffer a traumatic brain injury (TBI). Combined with the incidence of TBIs worldwide, the physical, emotional, social, and economical effects are staggering. Therefore, further research into the effects of TBI and effective treatments is necessary. The controlled cortical impact (CCI) model induces traumatic brain injuries ranging from mild to severe. This method uses a rigid impactor to deliver mechanical energy to an intact dura exposed following a craniectomy. Impact is made under precise parameters at a set velocity to achieve a pre-determined deformation depth. Although other TBI models, such as weight drop and fluid percussion, exist, CCI is more accurate, easier to control, and most importantly, produces traumatic brain injuries similar to those seen in humans. However, no TBI model is currently able to reproduce pathological changes identical to those seen in human patients. The CCI model allows investigation into the short-term and long-term effects of TBI, such as neuronal death, memory deficits, and cerebral edema, as well as potential therapeutic treatments for TBI.     

Finite element modeling of human brain response to football helmet impacts

The football helmet is used to help mitigate the occurrence of impact-related traumatic (TBI) and minor traumatic brain injuries (mTBI) in the game of American football. While the current helmet design methodology may be adequate for reducing linear acceleration of the head and minimizing TBI, it however has had less effect in minimizing mTBI. The objectives of this study are (a) to develop and validate a coupled finite element (FE) model of a football helmet and the human body, and (b) to assess responses of different regions of the brain to two different impact conditions – frontal oblique and crown impact conditions. The FE helmet model was validated using experimental results of drop tests. Subsequently, the integrated helmet–human body FE model was used to assess the responses of different regions of the brain to impact loads. Strain-rate, strain, and stress measures in the corpus callosum, midbrain, and brain stem were assessed. Results show that maximum strain-rates of 27 and 19 s^?1 are observed in the brain-stem and mid-brain, respectively. This could potentially lead to axonal injuries and neuronal cell death during crown impact conditions. The developed experimental-numerical framework can be used in the study of other helmet-related impact conditions.     

A Study on the Finite Element Model for Head Injury in Facial Collision Accident

In order to predict and evaluate injury mechanism and biomechanical response of the facial impact on head injury in a crash accident. With the combined modern medical imaging technologies, namely computed tomography (CT) and magnetic resonance imaging (MRI), both geometric and finite element (FE) models for human head-neck with detailed cranio-facial structure were developed. The cadaveric head impact tests were conducted to validate the headneck finite element model. The intracranial pressure, skull dynamic response and skull-brain relative displacement of the whole head-neck model were compared with experimental data. Nine typical cases of facial traffic accidents were simulated, with the individual stress wave propagation paths to the intracranial contents through the facial and cranial skeleton being discussed thoroughly. Intracranial pressure, von Mises stress and shear stress distribution were achieved. It is proved that facial structure dissipates a large amount of impact energy to protect the brain in its most natural way. The propagation path and distribution of stress wave in the skull and brain determine the mechanism of brain impact injury, which provides a theoretic basis for the diagnosis, treatment and protection of craniocerebral injury caused by facial impact.     

Technique and preliminary findings for in vivo quantification of brain motion during injurious head impacts

Computational models of the human brain are widely used in the evaluation and development of helmets and other protective equipment. These models are often attempted to be validated using cadaver tissue displacements despite studies showing neural tissue degrades quickly after death. Addressing this limitation, this study aimed to develop a technique for quantifying living brain motion in vivo using a closed head impact animal model of traumatic brain injury (TBI) called CHIMERA. We implanted radiopaque markers within the brain of three adult ferrets and resealed the skull while the animals were anesthetized. We affixed additional markers to the skull to track skull kinematics. The CHIMERA device delivered controlled, repeatable head impacts to the head of the animals while the impacts were fluoroscopically stereo-visualized. We observed that 1.5 mm stainless steel fiducials (∼8 times the density of the brain) migrated from their implanted positions while neutral density targets remained in their implanted position post-impact. Brain motion relative to the skull was quantified in neutral density target tests and showed increasing relative motion at higher head impact severities. We observed the motion of the brain lagged behind that of the skull, similar to previous studies. This technique can be used to obtain a comprehensive dataset of in vivo brain motion to validate computational models reflecting the mechanical properties of the living brain. The technique would also allow the mechanical response of in vivo brain tissue to be compared to cadaveric preparations for investigating the fidelity of current human computational brain models.     

Towards reducing impact-induced brain injury: lessons from a computational study of army and football helmet pads

We use computational simulations to compare the impact response of different football and U.S. Army helmet pad materials. We conduct experiments to characterise the material response of different helmet pads. We simulate experimental helmet impact tests performed by the U.S. Army to validate our methods. We then simulate a cylindrical impactor striking different pads. The acceleration history of the impactor is used to calculate the head injury criterion for each pad. We conduct sensitivity studies exploring the effects of pad composition, geometry and material stiffness. We find that (1) the football pad materials do not outperform the currently used military pad material in militarily relevant impact scenarios; (2) optimal material properties for a pad depend on impact energy and (3) thicker pads perform better at all velocities. Although we considered only the isolated response of pad materials, not entire helmet systems, our analysis suggests that by using larger helmet shells with correspondingly thicker pads, impact-induced traumatic brain injury may be reduced.     

Computational neurotrauma—design, simulation, and analysis of controlled cortical impact model

The controlled cortical impact (CCI) model is widely used in many laboratories to study traumatic brain injury (TBI). Although external impact parameters during CCI tests could be clearly defined, little is known about the internal tissue-level mechanical responses of the rat brain. Furthermore, the external impact parameters tend to vary considerably among different labs making the comparison of research findings difficult if not impossible. In this study, a design of computer experiments was performed with typical external impact parameters commonly found in the literature. An anatomically detailed finite element (FE) rat brain model was used to simulate the CCI experiments to correlate external mechanical parameters (impact depth, impact velocity, impactor shape, impactor size, and craniotomy pattern) with rat brain internal responses, as predicted by the FE model. Systematic analysis of the results revealed that impact depth was the leading factor affecting the predicted brain internal responses. Interestingly, impactor shape ranked as the second most important factor, surpassing impactor diameter and velocity which were commonly reported in the literature as indicators of injury severity along with impact depth. The differences in whole brain response due to a unilateral or a bilateral craniotomy were small, but those of regional intracranial tissue stretches were large. The interaction effects of any two external parameters were not significant. This study demonstrates the potential of using numerical FE modeling to engineer better experimental TBI models in the future.     

Biomechanical analysis of fluid percussion model of brain injury

Fluid percussion injury (FPI) is a widely used experimental model for studying traumatic brain injury (TBI). However, little is known about how the brain mechanically responds to fluid impacts and how the mechanical pressures/strains of the brain correlate to subsequent brain damage for rodents during FPI. Hence, we developed a numerical approach to simulate FPI experiments on rats and characterize rat brain pressure/strain responses at a high resolution. A previous rat brain model was improved with a new hexahedral elements-based skull model and a new cerebrospinal fluid (CSF) layer. We validated the numerical model against experimentally measured pressures from FPI. Our results indicated that brain tissues under FPI experienced high pressures, which were slightly lower (10–20%) than input saline pressure. Interestingly, FPI was a mixed focus- and diffuse-type injury model with highest strains (12%) being concentrated in the ipsilateral cortex under the fluid-impact site and diffuse strains (5–10%) being spread to the entire brain, which was different from controlled cortical impact in which high strains decreased gradually away from the impact site.     

A modified human head model for the study of impact head injury

A recently published finite element (FE) head model is modified to consider the viscoelasticity of the meninges, the spongy and compact bone in the skull. The cerebrospinal fluid (CSF) is simulated explicitly as a hydrostatic fluid by using a surface-based fluid modelling method, which allows fluid and structure interaction. It is found that the modified model yields smoother pressure responses in a head impact simulation. The baseline model underestimated the peak von Mises stress in the brain by 15% and the peak principal stress in the skull by 33%. The increase in the maximum principal stress in the skull is mainly caused by the updation of the material's viscoelasticity, and the change in the maximum von Mises stress in the brain is mainly caused by the improvement of the CSF simulation. The study shows that the viscoelasticity of the head tissue should be considered, and that the CSF should be modelled as a fluid, when using FE analysis to study head injury due to impact.     

The influence of acceleration loading curve characteristics on traumatic brain injury

To prevent brain trauma, understanding the mechanism of injury is essential. Once the mechanism of brain injury has been identified, prevention technologies could then be developed to aid in their prevention. The incidence of brain injury is linked to how the kinematics of a brain injury event affects the internal structures of the brain. As a result it is essential that an attempt be made to describe how the characteristics of the linear and rotational acceleration influence specific traumatic brain injury lesions. As a result, the purpose of this study was to examine the influence of the characteristics of linear and rotational acceleration pulses and how they account for the variance in predicting the outcome of TBI lesions, namely contusion, subdural hematoma (SDH), subarachnoid hemorrhage (SAH), and epidural hematoma (EDH) using a principal components analysis (PCA). Monorail impacts were conducted which simulated falls which caused the TBI lesions. From these reconstructions, the characteristics of the linear and rotational acceleration were determined and used for a PCA analysis. The results indicated that peak resultant acceleration variables did not account for any of the variance in predicting TBI lesions. The majority of the variance was accounted for by duration of the resultant and component linear and rotational acceleration. In addition, the components of linear and rotational acceleration characteristics on the x, y, and z axes accounted for the majority of the remainder of the variance after duration.     

Brain tissue analysis of impacts to American football helmets

Concussion in American football is a prevalent concern. Research has been conducted examining frequencies, location, and thresholds for concussion from impacts. Little work has been done examining how impact location may affect risk of concussive injury. The purpose of this research was to examine how impact site on the helmet and type of impact, affects the risk of concussive injury as quantified using finite element modelling of the human head and brain. A linear impactor was used to impact a helmeted Hybrid III headform in several locations and using centric and non-centric impact vectors. The resulting dynamic response was used as input for the Wayne State Brain Injury Model to determine the risk of concussive injury by utilizing maximum principal strain as the predictive variable. The results demonstrated that impacts that occur primarily to the side of the head resulted in higher magnitudes of strain in the grey and white matter, as well as the brain stem. Finally, commonly worn American football helmets were used in this research and significant risk of injury was incurred for all impacts. These results suggest that improvements in American football helmets are warranted, in particular for impacts to the side of the helmet.     

Proposing a Radial Basis Function and CSDM Indices to Predict the Traumatic Brain Injury Risk

BackgroundMany head injury indices and finite element (FE) head models have been proposed to predict traumatic brain injury (TBI). Although FE head models are suitable methods with high accuracy, they are computationally intensive. Head motion-based brain injury criteria are usually fast tools with lower accuracy. So, the objective of this study is to propose new criteria along with an artificial neural network model to predict TBI risks, which can be fast and accurate.MethodsFor this purpose, 250 FE head simulations have been carried out at 5 magnitudes and 50 rotational impact directions using the SIMon model. The effects of directions and magnitudes of rotational impacts were assessed for cumulative strain damage measure (CSDM) values. Next, statistical analysis and neural network were applied to predict CSDM values.ResultsThe results of the present research showed that the direction of rotation in the sagittal and frontal planes had a considerable effect on the CSDM values. Furthermore, new brain injury indices and a radial basis function neural network have been proposed to predict CSDM values which having high correlation coefficients with SIMon responses.ConclusionsThe results of this research demonstrated that rotational impact directions should be used to develop new head injury criteria being able to predict CSDM values. However, findings of present research proved that head motion-based brain injury criteria and RBF network can be used to predict FE head model responses with high speed and accuracy.     

创伤性脑损伤中神经炎症相关细胞的研究进展

创伤性脑损伤(traumatic brain injury, TBI), 亦称颅脑损伤或头部外伤, 专指由外伤引起的脑组织损害。然而,从轻度到重度的TBI,改善TBI患者预后的治疗方法都十分匮乏。神经炎症可引起脑外伤后急性继发性损伤,并与慢性神经退行性疾病有关,因此,系统了解参与TBI后神经炎性反应的细胞显得尤为重要。主要对TBI中参与炎症反应的细胞（如小胶质细胞、星形胶质细胞、少突细胞、中性粒细胞和淋巴细胞）的启动以及相互作用的最新研究进展进行了综述,以期为临床研究提供新的策略。     

Extensive degradation of myelin basic protein isoforms by calpain following traumatic brain injury

Axonal injury is one of the key features of traumatic brain injury (TBI), yet little is known about the integrity of the myelin sheath. We report that the 21.5 and 18.5-kDa myelin basic protein (MBP) isoforms degrade into N-terminal fragments (of 10 and 8 kDa) in the ipsilateral hippocampus and cortex between 2 h and 3 days after controlled cortical impact (in a rat model of TBI), but exhibit no degradation contralaterally. Using N-terminal microsequencing and mass spectrometry, we identified a novel in vivo MBP cleavage site between Phe114 and Lys115. A MBP C-terminal fragment-specific antibody was then raised and shown to specifically detect MBP fragments in affected brain regions following TBI. In vitro naive brain lysate and purified MBP digestion showed that MBP is sensitive to calpain, producing the characteristic MBP fragments observed in TBI. We hypothesize that TBI-mediated axonal injury causes secondary structural damage to the adjacent myelin membrane, instigating MBP degradation. This could initiate myelin sheath instability and demyelination, which might further promote axonal vulnerability.     

A modified human head model for the study of impact head injury

A recently published finite element (FE) head model is modified to consider the viscoelasticity of the meninges, the spongy and compact bone in the skull. The cerebrospinal fluid (CSF) is simulated explicitly as a hydrostatic fluid by using a surface-based fluid modelling method, which allows fluid and structure interaction. It is found that the modified model yields smoother pressure responses in a head impact simulation. The baseline model underestimated the peak von Mises stress in the brain by 15% and the peak principal stress in the skull by 33%. The increase in the maximum principal stress in the skull is mainly caused by the updation of the material's viscoelasticity, and the change in the maximum von Mises stress in the brain is mainly caused by the improvement of the CSF simulation. The study shows that the viscoelasticity of the head tissue should be considered, and that the CSF should be modelled as a fluid, when using FE analysis to study head injury due to impact.     

Finite element modelling of equestrian helmet impacts exposes the need to address rotational kinematics in future helmet designs

Jockey head injuries, especially concussions, are common in horse racing. Current helmets do help to reduce the severity and incidences of head injury, but the high concussion incidence rates suggest that there may be scope to improve the performance of equestrian helmets. Finite element simulations in ABAQUS/Explicit were used to model a realistic helmet model during standard helmeted rigid headform impacts and helmeted head model University College Dublin Brain Trauma Model (UCDBTM) impacts.

Current helmet standards for impact determine helmet performance based solely on linear acceleration. Brain injury-related values (stress and strain) from the UCDBTM showed that a performance improvement based on linear acceleration does not imply the same improvement in head injury-related brain tissue loads. It is recommended that angular kinematics be considered in future equestrian helmet standards, as angular acceleration was seen to correlate with stress and strain in the brain.     

重度创伤性脑损伤后肠黏膜屏障应激性变化的模型

目的建立一种观察重度创伤性脑损伤(TBI)后肠黏膜屏障(IMB)应激性变化的模型。方法选用雄性Wistar大鼠64只,随机分为两组。TBI组(32只):采用改良的Feeney自由落体撞击法,建立TBI模型;假手术对照组(32只):只开骨窗,不行落体致伤。两组大鼠分别按术后6、12、24和48h时相点分为4个亚组(每组均为8只),观察脑组织、肠黏膜组织病理以及扫描和透射电镜下肠黏膜超微结构的变化。结果光镜下TBI组肠黏膜上皮细胞受损,电镜下还可见细胞间紧密连接较对照组明显增宽。结论用改良的Feeney自由落体撞击法,建立的重度TBI大鼠模型肠黏膜上皮细胞受损,细胞间紧密连接增宽,提示其IMB的功能的确发生了应激性损害,说明这种用来观察重度TBI后IMB应激性变化的模型是成功的。     

tBHQ和SFN在创伤性脑损伤小鼠中的疗效比较性分析

目的:探讨叔丁基对苯二酚(t BHQ)和莱菔硫烷(SFN)在患有创伤性脑损伤大鼠的疗效差异性。方法:80只健康成年的雄性SD大鼠分为假手术组、常规损伤组、t BHQ治疗组和SFN治疗组,使用电子颅脑损伤仪(e CCI)制备TBI模型。其中t BHQ治疗组在伤前24 h大鼠腹腔注射三次t BHQ(50 mg/kg),每8 h一次;SFN治疗组在伤后15 min给予腹腔注射SFN(5 mg/kg)。给药24 h后,采用m NSS方法评价各组大鼠神经功能缺损状况,利用干湿称量法计算脑含水量,Western blot和ELISA方法分别测定大鼠脑组织的NOX2和Nrf2的表达水平。结果:损伤发生后第24 h,t BHQ治疗组和SFN治疗组在m NSS评分((4.5±0.71)vs(9.2±0.79),(6.0±0.82)vs(9.2±0.79))、脑水肿(79.4%vs 85.6%,80.3%vs 85.6%)、NOX2和Nrf2(0.93 ng/m L vs 0.81 ng/m L,0.87 ng/m L vs 0.81 ng/m L)表达上与常规损伤组差异明显,而t BHQ治疗组和SFN治疗组间在m NSS评分((4.5±0.71)vs(6.0±0.82))、NOX2和Nrf2(0.93 ng/m L vs 0.87 ng/m L)表达上差异显著。结论:在大鼠TBI模型中,t BHQ和SFN均可以有效的降低机体自身的氧化应激作用,并改善神经功能,但t BHQ的疗效要好于SFN。     

Caspase 7: increased expression and activation after traumatic brain injury in rats

Caspases, a cysteine proteinase family, are required for the initiation and execution phases of apoptosis. It has been suggested that caspase 7, an apoptosis executioner implicated in cell death proteolysis, is redundant to the main executioner caspase 3 and it is generally believed that it is not present in the brain or present in only minute amounts with highly restricted activity. Here we report evidence that caspase 7 is up-regulated and activated after traumatic brain injury (TBI) in rats. TBI disrupts homeostasis resulting in pathological apoptotic activation. After controlled cortical impact TBI of adult male rats we observed, by semiquantitative real-time PCR, increased mRNA levels within the traumatized cortex and hippocampus peaking in the former about 5 days post-injury and in the latter within 6-24 h of trauma. The activation of caspase 7 protein after TBI, demonstrated by immunoblot by the increase of the active form of caspase 7 peaking 5 days post-injury in the cortex and hippocampus, was found to be up-regulated in both neurons and astrocytes by immunohistochemistry. These findings, the first to document the up-regulation of caspase 7 in the brain after acute brain injury in rats, suggest that caspase 7 activation could contribute to neuronal cell death on a scale not previously recognized.     

在大鼠创伤性脑损伤模型中神经干细胞移植对突触素表达的影响

目的探讨神经干细胞（NSCs）移植对创伤性脑损伤（TBI）模型大鼠感觉运动功能的恢复作用及其对损伤脑组织中突触素（SYP）表达的影响。方法体外培养大鼠胚胎皮质NSCs;采用Feeney法制备TBI模型,于造模后72h,移植组采用PKH26荧光示踪剂标记的NSCs直接移植于脑损伤区,对照组以等量生理盐水代替NSCs;分别于移植后不同时间点,采用Gridwalk和Latency试验检测TBI大鼠的感觉运动功能;荧光显微镜下计数移植细胞的存活数量;采用免疫印迹和RT-PCR技术检测脑损伤区及周围组织中SYP的表达。结果 NSCs移植大鼠前、后肢功能分别在移植后第2w和4w恢复至手术前水平,而直到第8w,对照组大鼠后肢功能和通过平板移动时间与NSCs移植组和基线比较仍有显著性差异（P〈0.05）。移植的NSCs随移植时间延长存活数量减少,移植后第4w和8w的存活数分别为6.3%±1.0%和4.1%±0.9%。在移植后的8w期间,移植组脑损伤区及周围组织中SYP的表达均明显高于对照组（P〈0.05）。结论移植的NSCs在TBI脑内能够存活,并明显改善了TBI大鼠对侧肢体的感觉运动功能;NSCs移植促进了脑损伤区及周围组织中SYP的表达,这可能是NSCs移植促进功能恢复的机理之一。