Micromechanical analysis of brain’s diffuse axonal injury

Computational models are important tools which help researchers understand traumatic brain injury (TBI). A mechanistic multi-scale numerical approach is introduced to quantify diffuse axonal injury (DAI), the most important mechanism of TBI, induced by a mechanical insult at micro-scale regions of the white matter or voxels where fiber orientations are the same. Using the mechanical properties of a single axon with a viscoelastic constitutive relation and its functional failure in terms of electrophysiological impairment, a numerical 2D micro-level lattice method is implemented to directly analyze the percentage of injured axons in a voxel containing a bundle of axons all with the same orientation under biaxial stretches. Reference micro-injury maps are then developed with the input parameters based on the principal strain or stretch values and their direction with respect to axons, which provide the percentage of injured axons in the voxel of interest as the output. The methodology is independent of any statistical analyses of the accident data and medical reports to derive probabilistic injury risk curves for DAI. Avoiding a structurally detailed full finite element head model, this study proposes a micro-mechanical approach which considers the anatomical structure of neural axons in the white matter together with their mechanical properties using a numerical lattice method to analyze the brain’s diffuse axonal injury. This work has the potential to help develop safer prevention tools and more effective diagnosis methods for DAI.     

An axonal strain injury criterion for traumatic brain injury

Computational models are often used as tools to study traumatic brain injury. The fidelity of such models depends on the incorporation of an appropriate level of structural detail, the accurate representation of the material behavior, and the use of an appropriate measure of injury. In this study, an axonal strain injury criterion is used to estimate the probability of diffuse axonal injury (DAI), which accounts for a large percentage of deaths due to brain trauma and is characterized by damage to neural axons in the deep white matter regions of the brain. We present an analytical and computational model that treats the white matter as an anisotropic, hyperelastic material. Diffusion tensor imaging is used to incorporate the structural orientation of the neural axons into the model. It is shown that the degree of injury that is predicted in a computational model of DAI is highly dependent on the incorporation of the axonal orientation information and the inclusion of anisotropy into the constitutive model for white matter.     

Methodology to determine failure characteristics of planar soft tissues using a dynamic tensile test

Predicting the injury risk in automotive collisions requires accurate knowledge of human tissues, more particularly their mechanical properties under dynamic loadings. The present methodology aims to determine the failure characteristics of planar soft tissues such as skin, hollow organs and large vessel walls. This consists of a dynamic tensile test, which implies high-testing velocities close to those in automotive collisions. To proceed, I-shaped tissue samples are subjected to dynamic tensile tests using a customized tensile device based on the drop test principle. Data acquisition has especially been adapted to heterogeneous and soft biological tissues given that standard measurement systems (considered to be global) have been completed with a non-contact and full-field strain measurement (considered to be local). This local measurement technique, called the Image Correlation Method (ICM) provides an accurate strain analysis by revealing strain concentrations and avoids damaging the tissue. The methodology has first been applied to human forehead skin and can be further expanded to other planar soft tissues. The failure characteristics for the skin in terms of ultimate stress are 3 MPa +/- 1.5 MPa. The ultimate global longitudinal strains are equal to 9.5%+/-1.9% (Green-Lagrange strain), which contrasts with the ultimate local longitudinal strain values of 24.0%+/-5.3% (Green-Lagrange strain). This difference is a consequence of the tissue heterogeneity, clearly illustrated by the heterogeneous distribution of the local strain field. All data will assist in developing the tissue constitutive law that will be implemented in finite element models.     

Can sulci protect the brain from traumatic injury?

The influence of sulci in dynamic finite element simulations of the human head has been investigated. First, a detailed 3D FE model was constructed based on an MRI scan of a human head. A second model with a smoothed brain surface was created based on the same MRI scan as the first FE model. These models were validated against experimental data to confirm their human-like dynamic responses during impact. The validated FE models were subjected to several acceleration impulses and the maximum principle strain and strain rate in the brain were analyzed. The results suggested that the inclusion of sulci should be considered for future FE head models as it alters the strain and strain distribution in an FE model.     

Global/local head models to analyse cerebral blood vessel rupture leading to ASDH and SAH

Blunt and rotational head impacts due to vehicular collisions, falls and contact sports cause relative motion between the brain and skull. This increases the normal and shear stresses in the (skull/brain) interface region consisting of cerebrospinal fluid (CSF) and subarachnoid space (SAS) trabeculae. The relative motion between the brain and skull can explain many types of traumatic brain injuries (TBI) including acute subdural hematomas (ASDH) and subarachnoid hemorrhage (SAH) which is caused by the rupture of bridging veins that transverse from the deep brain tissue to the superficial meningeal coverings. The complicated geometry of the SAS trabeculae makes it impossible to model all the details of the region. Investigators have compromised this layer with solid elements, which may lead to inaccurate results. In this paper, the failure of the cerebral blood vessels due to the head impacts have been investigated. This is accomplished through a global/local modelling approach. Two global models, namely a global solid model (GSM) of the skull/brain and a global fluid model (GFM) of the SAS/CSF, were constructed and were validated. The global models were subjected to two sets of impact loads (head injury criterion, HIC = 740 and 1044). The relative displacements between the brain and skull were determined from GSM. The CSF equivalent fluid pressure due to the impact loads were determined by the GFM. To locally study the mechanism of the injury, the relative displacement between the brain and skull along with the equivalent fluid pressure were implemented into a new local solid model (LSM). The strains of the cerebral blood vessels were determined from LSM. These values were compared with their relevant experimental ultimate strain values. The results showed an agreement with the experimental values indicating that the second impact (HIC = 1044) was strong enough to lead to severe injury. The global/local approach provides a reliable tool to study the cerebral blood vessel ruptures leading to ASDH and/or SAH.     

The sensitivity to inter-subject variability of the bridging vein entry angles for prediction of acute subdural hematoma

Acute subdural hematoma (ASDH) is one of the most frequent traumatic brain injuries (TBIs) with high mortality rate. Bridging vein (BV) ruptures is a major cause of ASDH. The KTH finite element head model includes bridging veins to predict acute subdural hematoma due to BV rupture. In this model, BVs were positioned according to Oka et al. (1985). The aim of the current study is to investigate whether the location and entry angles of these BVs could be modelled using data from a greater statistical sample, and what the impact of this improvement would be on the model’s predictive capability of BV rupture.From the CT angiogram data of 78 patients, the relative position of the bridging veins and their entry angles along the superior sagittal sinus was determined. The bridging veins were repositioned in the model accordingly. The performance of the model, w.r.t. BV rupture prediction potential was tested on simulations of full body cadaver head impact experiments. The experiments were simulated on the original version of the model and on three other versions which had updated BV positions according to mean, maximum and minimum entry angles.Even though the successful prediction rate between the models stayed the same, the location of the rupture site significantly improved for the model with the mean entry angles. Moreover, the models with maximum and minimum entry angles give an insight of how BV biovariability can influence ASDH.In order to further improve the successful prediction rate, more biofidelic data are needed both with respect to bridging vein material properties and geometry. Furthermore, more experimental data are needed in order to investigate the behaviour of FE head models in depth.     

Estimating axonal strain and failure following white matter stretch using contactin-associated protein as a fiduciary marker

Axonal injury occurs during trauma when tissue-scale loads are transferred to individual axons. Computational models are used to understand this transfer and predict the circumstances that cause injury. However, these findings are limited by a lack of validating experimental work examining the mechanics of axons in their in situ state. As a first step towards validation for dynamic stretch, we use contactin-associated protein (Caspr), expressed at the nodes of Ranvier, as a fiduciary marker of quasistatic axonal stretch. We measured changes in the distance between immunolabled Caspr pairs along axons as a function of tissue-level stretch in chick embryo spinal cords harvested from different developmental periods. We then identified and characterized broken axons and adapted a kinematic model published previously by our group (Singh et al., 2015) to estimate average strain thresholds for axon mechanical failure. The distance between Caspr pairs increased with stretch, though not as much as predicted by simple continuum mechanics. For equivalent tissue stretch, greater numbers of broken axons were found at later stages of development. In adapting our kinematic model to predict a breaking threshold strain, we found that breaking thresholds decrease with development stage. When thresholds were split and classified based on kinematic behavior, non-affine, uncoupled axons had higher strain thresholds than affine, coupled axons, corroborating thresholds predicted from in vitro and in vivo preparations. These results provide a valuable launching point for generating more accurate multi-scale models in primary central nervous system injury.     

A micromechanical procedure for modelling the anisotropic mechanical properties of brain white matter

This paper proposes a micromechanics algorithm utilising the finite element method (FEM) for the analysis of heterogeneous matter. The characterisation procedure takes the material properties of the constituents, axons and extracellular matrix (ECM) as input data. The material properties of both the axons and the matrix are assumed to have linear viscoelastic behaviour with a perfect bonding between them. The results of the modelling have been validated with experimental data with material white input from brainstem by considering the morphology of brainstem in which most axons are oriented in longitudinal direction in the form of a uniaxial fibrous composite material. The method is then employed to examine the undulations of axons within different subregions of white matter and to study the impact due to axon/matrix volume fractions. For such purposes, different unit cells composed of wavy geometries and with various volume factions have been exposed to the six possible loading scenarios. The results will clearly demonstrate the undulation and axon volume fraction impacts. In this respect, undulation affects the material stiffness heavily in the axon longitudinal direction, whereas the axons' volume fraction has a much greater impact on the mechanical properties of the white matter in general. Also the results show that the created stresses and strains in the axons and matrix under loading will be impacted by undulation change. With increase in undulation the matrix suffers higher stresses when subjected to tension, whereas axons suffer higher stresses in shear. The axons always exhibit higher stresses whereas the matrix exhibits higher strains. The evaluated time-dependent local stress and strain concentrations within a repeating unit cell of the material model are indicative of the mechanical behaviour of the white tissue under different loading scenarios.     

Fluid–structure interaction simulation of the brain–skull interface for acute subdural haematoma prediction

Traumatic brain injury is a leading cause of disability and mortality. Finite element-based head models are promising tools for enhanced head injury prediction, mitigation and prevention. The reliability of such models depends heavily on adequate representation of the brain–skull interaction. Nevertheless, the brain–skull interface has been largely simplified in previous three-dimensional head models without accounting for the fluid behaviour of the cerebrospinal fluid (CSF) and its mechanical interaction with the brain and skull. In this study, the brain–skull interface in a previously developed head model is modified as a fluid–structure interaction (FSI) approach, in which the CSF is treated on a moving mesh using an arbitrary Lagrangian–Eulerian multi-material formulation and the brain on a deformable mesh using a Lagrangian formulation. The modified model is validated against brain–skull relative displacement and intracranial pressure responses and subsequently imposed to an experimentally determined loading known to cause acute subdural haematoma (ASDH). Compared to the original model, the modified model achieves an improved validation performance in terms of brain–skull relative motion and is able to predict the occurrence of ASDH more accurately, indicating the superiority of the FSI approach for brain–skull interface modelling. The introduction of the FSI approach to represent the fluid behaviour of the CSF and its interaction with the brain and skull is crucial for more accurate head injury predictions.

     

Overproduction, purification, and characterization of recombinant aspartate semialdehyde dehydrogenase from Arabidopsis thaliana.

In plant and microorganisms, aspartate semialdehyde dehydrogenase (ASDH) produces the branch point intermediate between the lysine and threonine/methionine pathways. In this study, we report the first cDNA cloning, purification, and characterization of a plant ASDH. The Arabidopsis thaliana ASDH is an homodimeric enzyme composed of subunits of 36 kDa. The plant enzyme exhibited a specific activity of 26 micromol NADPH oxidized min(-1) mg(-1) of protein with a K(M) value for NADPH of 92 microM. ASDH showed cooperative behavior for aspartyl phosphate with a K(0.5) value of 37 microM.     

Strain relief from the cerebral ventricles during head impact: experimental studies on natural protection of the brain

Physical models of the parasagittal human skull/brain have been tested to investigate whether the cerebral ventricles provide natural protection of the brain by relieving strain during head rotation. A sophisticated model included anatomical structures, and a semicircular model consisted of a cylinder divided into two semicircles. Silicone gel simulated the brain and was detached from the vessel by a layer of liquid paraffin simulating the cerebrospinal fluid. Both models were run with and without an elliptical inclusion filled with liquid paraffin simulating a cerebral ventricle. The 2D models were exposed to angular acceleration by a pendulum impact causing 7600 rad/s2 peak rotational acceleration with 6 ms pulse duration. After rotating 100 degrees, the models were decelerated during 30 ms. The trajectory of grid markers was analyzed from high-speed video (1000 frames/s). Rigid-body displacement, shear strain and principal strain were determined from the displacement of three-point sets inferior and superior to the ventricle. For the subventricular (inferior) region in the sophisticated model, approximately 40% lower peak strain values were obtained in the model with ventricle than in the one without. Subcortical displacement was reduced by 12%. Corresponding strain reduction in the subcortical (superior) region was approximately 40% following the acceleration and 25% following the deceleration. Similar but less pronounced effects were found for the semicircular model. The lateral ventricles play an important role as strain relievers and provide natural protection against brain injury.     

Cellulase system of a free-living, mesophilic clostridium (strain C7).

The enzymatic activity responsible for crystalline cellulose degradation (Avicelase activity) by a mesophilic clostridium (strain C7) was present in culture supernatant fluid but was not detected in significant amounts in association with whole cells or in disrupted cells. Cells of the mesophilic clostridium lacked cellulosome clusters on their surface and did not adhere to cellulose fibers. The extracellular cellulase system of the mesophilic clostridium was fractionated by Sephracryl S-300 gel filtration, and the fractions were assayed for Avicelase and carboxymethylcellulase activities. The Avicelase activity coincided with an A280 peak that eluted in the 700,000-Mr region. Nondenaturing polyacrylamide gel electrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of the 700,000-Mr fractions showed that Avicelase was present as a multiprotein aggregate that lost the ability to hydrolyze crystalline cellulose when partially dissociated by sodium dodecyl sulfate treatment. Proteins resulting from the partial dissociation of the aggregate retained carboxymethylcellulase activity. An Avicelase-deficient mutant of strain C7 (strain LS), which was not capable of degrading crystalline cellulose, lacked the Avicelase-active 700,000-Mr peak. The results indicated that an extracellular 700,000-Mr multiprotein complex, consisting of at least 15 proteins, is utilized by the mesophilic clostridium for the hydrolysis of crystalline cellulose. At least six different endo-1,4-beta-glucanases may be part of the cellulase system of strain C7. Sephacryl S-300 column fractions, corresponding to an A280 peak in the 130,000-Mr region, contained carboxymethylcellulase-active proteins that may serve as precursors for the assembly of the Avicelase-active complex by the mesophilic clostridium.     

A Pectinase-deficient Ralstonia solanacearum Strain Induces Reduced and Delayed Structural Defences in Tomato Xylem

It has been suggested that oligogalacturonides (OGAs) released by bacterial pectinases can induce plant defence responses. To test this hypothesis, resistant tomato cultivar LS-89 and susceptible cultivar Ponderosa were inoculated with either wild-type Ralstonia solanacearum strain K60 or a pectinase-deficient triple mutant K60-509, which lacks endo-polygalacturonase PehA, exo-poly-alpha- d -galacturonosidase PehB, and pectin methylesterase Pme. K60 induced structural defence responses, including electron-dense materials (EDMs) in vessels and apposition layers (ALs) in parenchyma cells adjacent to xylem vessels colonized by bacteria in LS-89 stems. In contrast, LS-89 infected with K60-509 did not have any EDMs in vessels at 4 days after inoculation (DAI), and had them only rarely at 7 DAI. In LS-89 infected with K60-509, ALs were rarely observed in parenchyma cells adjacent to vessels at 4 DAI, and while they were present at 7 DAI, they were thinner than ALs induced by K60. The bacterial density in LS-89 stems infected with K60-509 was lower than in stems infected with K60 at 4 DAI, but the strains reached similar population sizes by 7 DAI, showing the pectinase-deficient mutant colonized resistant stems more slowly than did the wild-type strain. Vessels infected with K60-509 contained fewer EDMs at 7 DAI than were observed at either 4 or 7 DAI in vessels colonized by K60, although bacterial density in the xylem tissues containing K60-509 at 7 DAI was about the same as in the xylem tissues containing K60 at 4 DAI. Neither the wild-type strain nor the pectinase-deficient mutant induced these histopathological changes on susceptible cultivar Ponderosa. These results indicate that R. solanacearum pectinases play some role in eliciting histopathological changes in LS-89, likely by releasing OGAs that trigger plant structural defences.     

A mechanical characterization of the porcine atria at the healthy stage and after ventricular tachypacing

Atrial fibrillation (AF) is a cardiac arrhythmia that highly increases the risk of stroke and is associated with significant but still unexplored changes in the mechanical behavior of the tissue. Planar biaxial tests were performed on tissue specimens from pigs at the healthy stage and after ventricular tachypacing (VTP), a procedure applied to reproduce the relevant features of AF. The local arrangement of the fiber bundles in the tissue was investigated on specimens from rabbit atria by means of circularly polarized light. Based on this, mechanical data were fitted to two anisotropic constitutive relationships, including a four-parameter Fung-type model and a microstructurally-motivated model. Accounting for the fiber-induced anisotropy brought average R(2) = 0.807 for the microstructurally-motivated model and average R(2) = 0.949 for the Fung model. Validation of the fitted constitutive relationships was performed by means of FEM simulations coupled to FORTRAN routines. The performances of the two material models in predicting the second Piola-Kirchhoff stress were comparable, with average errors <3.1%. However, the Fung model outperformed the other in the prediction of the Green-Lagrange strain, with 9.2% maximum average error. To increase model generality, a proper averaging procedure accounting for nonlinearities was used to obtain average material parameters. In general, a stiffer behavior after VTP was noted.     

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.     

An integumental anatomy for the butterfly Glaucopsyche lygdamus (Lepidoptera:Lycaenidae):a morphological terminology and homology

An integumental anatomy for the lycaenid butterfly Glaucopsyche lygdamus is presented. Comparisons with other lepidopteran taxa are made to rectify the homology of parts and contrast anatomical divergences within the Lycaenidae. A general terminology based on Snodgrass is given, to replace many of the specialized and often synonymous terms restricted to the Lepidoptera. Many common anatomical svnonyms are also given. Several reinterpretations of the anatomy and homology of various integumental regions are discussed. A previously unreported cuticular anomaly on abdominal tergum 2 of male Polyommatinae (Downey's area) is described. The following new or newly combined terms are used:postgenal-occipital area, postgenal-occipital protuberance, dorsal temporal sulci, postantennal projections, pronotal projection, infraepisternal-basisternal plate, paracoxal-marginopleural sulci, dorsal epimeral sulci, ventral epimeral sulci, secondary coxal sulci, ventral subcostal-radial process, lateral secondary sclerite and Downey's area.     

Axonal Transport, Deposition, and Metabolic Turnover of Glycoproteins in the Rat Optic Pathway

Abstract: Following intraocular injection of [³H]fucose in the rat, radioactive glycoproteins are rapidly transported to the nerve terminals in at least two waves, one with a peak at 8 h and a second with a peak at about a week. The molecular weight distribution of radioactive peptides in ach transport wave as determined by gel electrophoresis in buffers containing sodium dodecyl sulfate is very similar. Most of the many glycopeptides in the first wave of rapid transport pass through the optic tract in unison (apparent half-life of about 15 h) and are preferentially destined for the nerve endings. However, two proteins of apparent M. W. 28,000 and 49,000 are preferentially retained in the axons. The remaining proteins, after reaching the nerve endings (superior colliculus), decay with apparent half-lives ranging from 17 to 34 h. During the second wave a large amount of the 28,000 and 49,000 M. W. peptides are again preferentially retained in the axons. The remaining proteins, on reaching the nerve endings, decay with apparent half-lives ranging from 5 to 9 days. Subcellular fractionation of the superior colliculus supports the hypothesis that the 49,000 and 28,000 M. W. peptides are the predominantly labeled glycoproteins present in myelinated axons (representing over 50% of the radioactive glycoproteins 7 days following injection), although they are probably also present in membranes of the nerve endings. A comparison with glycoprotein transport in other tracts (geniculocortical and nigrostriatal tracts) suggests that glycoprotein transport in these pathways has many similarities to glycoprotein transport in the retinal ganglion cells, and that the optic system is a good general model for axonal transport in the CNS.     

The peculiar properties of the falx and tentorium in brain injury biomechanics

The influence of the falx and tentorium on brain injury biomechanics during impact was studied with finite element (FE) analysis. Three detailed 3D FE head models were created based on the images of a healthy, normal size head. Two of the models contained the addition of falx and tentorium with material properties from previously published experiments. Impact loadings from a reconstructed concussive case in a sport accident were applied to the two players involved. The results suggested that the falx and tentorium could induce large strains to the surrounding brain tissues, especially to the corpus callosum and brainstem. The tentorium seemed to constrain the motion of the cerebellum while inducing large strain in the brainstem in both players involved in the accident (one player had mainly coronal head rotation and the other had both coronal and transversal rotations). Since changed strain levels were observed in the brainstem and corpus callosum, which are classical sites for diffuse axonal injuries (DAI), we confirmed the importance of using accurate material properties for falx and tentorium in a FE head model when studying traumatic brain injuries.