Search

Traumatic brain injury (TBI) is a significant public health burden, and the development of advanced countermeasures to mitigate and prevent these injuries during automotive, sports, and military impact events requires an understanding of the intracranial mechanisms related to TBI. In this study, the efficacy of tissue-level injury metrics for predicting TBI was evaluated using finite element reconstructions from a comprehensive, multi-species TBI database. The database consisted of human volunteer tests, laboratory-reconstructed head impacts from sports, in vivo non-human primate (NHP) tests, and in vivo pig tests. Eight tissue-level metrics related to brain tissue strain, axonal strain, and strain-rate were evaluated using survival analysis for predicting mild and severe TBI risk. The correlation between TBI risk and most of the assessed metrics were statistically significant, but when injury data was analyzed by species, the best metric was often inconclusive and limited by the small datasets. When the human and animal datasets were combined, the injury analysis was able to delineate maximum axonal strain as the best predictor of injury for all species and TBI severities, with maximum principal strain as a suitable alternative metric. The current study is the first to provide evidence to support the assumption that brain strain response between human, pig, and NHP result in similar injury outcomes through a multi-species analysis. This assumption is the biomechanical foundation for translating animal brain injury findings to humans. The findings in the study provide fundamental guidelines for developing injury criteria that would contribute towards the innovation of more effective safety countermeasures.

Finite element models (FEMs) are used increasingly in the traumatic brain injury (TBI) field to provide an estimation of tissue responses and predict the probability of sustaining TBI after a biomechanical event. However, FEM studies have mainly focused on predicting the absence/presence of TBI rather than estimating the location of injury. In this study, we created a multi-scale FEM of the pig brain with embedded axonal tracts to estimate the sites of acute (≤6 h) traumatic axonal injury (TAI) after rapid head rotation. We examined three finite element (FE)-derived metrics related to the axonal bundle deformation and three FE-derived metrics based on brain tissue deformation for prediction of acute TAI location. Rapid head rotations were performed in pigs, and TAI neuropathological maps were generated and colocalized to the FEM. The distributions of the FEM-derived brain/axonal deformations spatially correlate with the locations of acute TAI. For each of the six metric candidates, we examined a matrix of different injury thresholds (th x ) and distance to actual TAI sites (d s ) to maximize the average of two optimization criteria. Three axonal deformation-related TAI candidates predicted the sites of acute TAI within 2.5 mm, but no brain tissue metric succeeded. The optimal range of thresholds for maximum axonal strain, maximum axonal strain rate, and maximum product of axonal strain and strain rate were 0.08-0.14, 40-90, and 2.0-7.5 s -1 , respectively. The upper bounds of these thresholds resulted in higher true-positive prediction rate. In summary, this study confirmed the hypothesis that the large axonal-bundle deformations occur on/close to the areas that sustained TAI.

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse ( n = 13) or focal ( n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics.

Traumatic brain injury (TBI) is one of the leading causes of death in children worldwide. Emerging evidence suggests that alterations in mitochondrial function are critical components of secondary injury cascade initiated by TBI that propogates neurodegeneration and limits neuroregeneration. Unfortunately, there is very little known about the cerebral mitochondrial bioenergetic response from the immature brain triggered by traumatic biomechanical forces. Therefore, the objective of this study was to perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a high-fidelity large animal model of focal controlled cortical impact injury (CCI) 24h post-injury. This novel approach is directed at analyzing dysfunction in electron transport, ADP phosphorylation and leak respiration to provide insight into potential mechanisms and possible interventions for mitochondrial dysfunction in the immature brain in focal TBI by delineating targets within the electron transport system (ETS). Development and application of these methodologies have several advantages, and adds to the interpretation of previously reported techniques, by having the added benefit that any toxins or neurometabolites present in the ex-vivo samples are not removed during the mitochondrial isolation process, and simulates the in situ tricarboxylic acid (TCA) cycle by maximizing key substrates for convergent flow of electrons through both complexes I and II. To investigate alterations in mitochondrial function after CCI, ipsilateral tissue near the focal impact site and tissue from the corresponding contralateral side were examined. Respiration per mg of tissue was also related to citrate synthase activity (CS) and calculated flux control ratios (FCR), as an attempt to control for variability in mitochondrial content. Our biochemical analysis of complex interdependent pathways of electron flow through the electron transport system, by most measures, reveals a bilateral decrease in complex I-driven respiration and an increase in complex II-driven respiration 24h after focal TBI. These alterations in convergent electron flow though both complex I and II-driven respiration resulted in significantly lower maximal coupled and uncoupled respiration in the ipsilateral tissue compared to the contralateral side, for all measures. Surprisingly, increases in complex II and complex IV activities were most pronounced in the contralateral side of the brain from the focal injury, and where oxidative phosphorylation was increased significantly compared to sham values. We conclude that 24h after focal TBI in the immature brain, there are significant alterations in cerebral mitochondrial bioenergetics, with pronounced increases in complex II and complex IV respiration in the contralateral hemisphere. These alterations in mitochondrial bioenergetics present multiple targets for therapeutic intervention to limit secondary brain injury and support recovery., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Clinicians are charged with the significant task of distinguishing between accidental and inflicted head trauma. Oftentimes this distinction is straightforward, but many times probabilities of injuries from accidental scenarios are unknown making the differential diagnosis difficult. For example, it is unknown whether intracranial hemorrhage (IH) can occur at a location other than a focal contact site following a low height fall. To create a foundation for predicting regional IH in infants, we sought to identify the biomechanical response and injury threshold best able to predict IH in 3-5 day old piglets. First, finite element (FE) model simulations of in situ animal studies were performed to ascertain the optimal representation of the pia-arachnoid complex, cerebrospinal fluid and cortical vasculature (PCC) for predicting brain strain and brain/skull displacement. Second, rapid head rotations resulting in various degrees of IH were simulated (n=24) to determine the biomechanical predictor and injury threshold most closely correlated with IH. FE models representing the PCC with either spring connectors or solid elements between the brain and skull resulted in peak brain strain and brain/skull displacement similar to measured values in situ. However, when predicting IH, the spring connector representation of the PCC had the best predictive capability for IH with a sensitivity of 80% and a specificity of 85% when ≥ 1% of all spring connectors had at least a peak strain of 0.31 mm/mm. These findings and reported methodology will be used in the development of a human infant FE model to simulate real-world falls and identify injury thresholds for predicting IH in infants., (Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to develop a more efficient fluorescent microsphere method to facilitate the rapid use of the histological technique and to enable its use in large tissue regions. Using fluorescent plate/slide imaging technology and automated detection and analysis software, we were able to rapidly image, detect, and count 3 separate microsphere colors in 200 microm thick tissue sections from piglet brain. In resting newborn piglets (n=6) on isoflurane anesthesia, we measured a median total cerebral blood flow (CBF) of 105 ml/min/100g (range 27-206 ml/min/100 g). Compared with other FM analysis methods, our method reduces the time required to determine blood flow, improves accuracy in lipid-rich tissues and large tissue regions and, unlike the radiolabeled microsphere method, can be combined with histological analysis., (Copyright 2010 Elsevier B.V. All rights reserved.)

Head trauma is the leading cause of death and debilitating injury in children. Computational models are important tools used to understand head injury mechanisms but they must be validated with experimental data. In this communication we present in situ measurements of brain deformation during rapid, nonimpact head rotation in juvenile pigs of different ages. These data will be used to validate computational models identifying age-dependent thresholds of axonal injury. Fresh 5 days (n=3) and 4 weeks (n=2) old piglet heads were transected horizontally and secured in a container. The cut surface of each brain was marked and covered with a transparent, lubricated plate that allowed the brain to move freely in the plane of rotation. For each brain, a rapid (20-28 ms) 65 deg rotation was applied sequentially at 50 rad/s, 75 rad/s, and 75 rad/s. Each rotation was digitally captured at 2500 frames/s (480x320 pixels) and mark locations were tracked and used to compute strain using an in-house program in MATLAB. Peak values of principal strain (E(peak)) were significantly larger during deceleration than during acceleration of the head rotation (p<0.05), and doubled with a 50% increase in velocity. E(peak) was also significantly higher during the second 75 rad/s rotation than during the first 75 rad/s rotation (p<0.0001), suggesting structural alteration at 75 rad/s and the possibility that similar changes may have occurred at 50 rad/s. Analyzing only lower velocity (50 rad/s) rotations, E(peak) significantly increased with age (16.5% versus 12.4%, p<0.003), which was likely due to the larger brain mass and smaller viscoelastic modulus of the 4 weeks old pig brain compared with those of the 5 days old. Strain measurement error for the overall methodology was estimated to be 1%. Brain tissue strain during rapid, nonimpact head rotation in the juvenile pig varies significantly with age. The empirical data presented will be used to validate computational model predictions of brain motion under similar loading conditions and to assist in the development of age-specific thresholds for axonal injury. Future studies will examine the brain-skull displacement and will be used to validate brain-skull interactions in computational models.

We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R=0.89, p<0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.

Computer finite element model (FEM) simulations are often used as a substitute for human experimental head injury studies to enhance our understanding of injury mechanisms and develop prevention strategies. While numerous adult FEM of the head have been developed, there are relatively few pediatric FEM due to the paucity of material property data for children. Using radiological serial images of infants (<6 wks old) and recent published material property data of infant skull and suture, we developed a FEM of the infant head to study skull fracture from occipital impacts. Here we determined the relative importance of brain material properties and anatomical variations in infant suture and scalp tissue on principal stress (sigma(p)) estimates in the skull of the model using parametric simulations of occipital impacts from 0.3m falls onto concrete. Decreasing the brain stiffness of pediatric brain tissue by a factor of two to simulate the softer adult brain properties we reported previously did not affect sigma(p). Using adult brain stiffness reported by others (4 times higher than our pediatric values) increased sigma(p) in skull by 38%. Interestingly, the precision used to model compressibility of the brain (0.49-0.4999) significantly varied sigma(p) 30-77%, underscoring the influence of the brain properties in models of fracture in the highly deformable infant skullcase. Suture thickness, small anatomical variations in suture width and the exclusion of scalp did not affect sigma(p) of the skull; however, unusually large sutures (10 mm) in young infants significantly lowered sigma(p). Validation of this model against published infant cadaver drop studies found good agreement with the prediction of fracture for falls onto hard surfaces. More biomechanical data from impacts onto softer surfaces is needed before skull fracture predictions can be made in these scenarios. In summary, the pediatric FEM response is not sensitive to small variations in anatomy or brain modulus, large deviations will significantly influence principal stress estimates and the prediction of skull fracture.

Traumatic brain injury (TBI) is the most common cause of death in childhood, and the majority of fatal cases are due to motor vehicle accidents, falls, sport-related accidents, and child abuse. Rodents and particularly rats became a commonly used animal model of TBI in childhood as well as in adults, and different techniques are described in the literature to induce the brain injury. However, findings reported in the last decade regarding the increased stiffness of brain tissue in young animals, including rats, are not considered in experimental designs of TBI studies, and this may seriously bias the results when TBI effects are compared across different animal ages. In this study, we determined the strain and stress distributions in neonatal (post-natal-day [PND] 13-17) and mature (PND 43 and 90) rat brains during a closed head injury, using age-specific finite element (FE) models. The FE simulations indicated that for identical cortical displacements, the neonatal brain may be exposed to larger peak stress magnitudes compared with a mature brain due to stiffer tissue properties in the neonate, as well as larger strain magnitudes due to its smaller size. The brain volume subjected to a certain strain level was greater in the neonate brain compared with the adult models for all indentation depths greater than 1 mm. In conclusion, our present findings allow better design of closed head impact experiments which involve an age factor. Additionally, the larger peak stresses and larger strain volumetric exposures observed in the neonatal brain support the hypothesis that the smaller size and stiffer tissue of the infant brain makes it more susceptible to TBI.

Clinical and biomechanical evidence indicates that mechanisms and pathology of head injury in infants and young children may be different from those in adults. Biomechanical computer-based modeling, which can be used to provide insight into the thresholds for traumatic tissue injury, requires data on material properties of the brain, skull, and sutures that are specific for the pediatric population. In this study, brain material properties were determined for rats at postnatal days (PND) 13, 17, 43, and 90, and skull/suture composite (braincase) properties were determined at PND 13, 17, and 43. Controlled 1 mm indentation of a force probe into the brain was used to measure naive, non-preconditioned (NPC) and preconditioned (PC) instantaneous (G(i)) and long-term (G( infinity )) shear moduli of brain tissue both in situ and in vitro. Brains at 13 and 17 PND exhibited statistically indistinguishable shear moduli, as did brains at 43 and 90 PND. However, the immature (average of 13 and 17 PND) rat brain (G(i) = 3336 Pa NPC, 1754 Pa PC; G( infinity )= 786 Pa NPC, 626 Pa PC) was significantly stiffer (p < 0.05) than the mature (average of 43 and 90 PND) brains (G(i) = 1721 Pa NPC, 1232 Pa PC; G( infinity ) = 508 Pa NPC, 398 Pa PC). A "reverse engineering" finite element model approach, which simulated the indentation of the force probe into the intact braincase, was used to estimate the effective elastic moduli of the braincase. Although the skull of older rats was significantly thicker than that of the younger rats, there was no significant age-dependent change in the effective elastic modulus of the braincase (average value = 6.3 MPa). Thus, the increase in structural rigidity of the braincase with age (up to 43 PND) was due to an increase in skull thickness rather than stiffening of the tissue. These observations of a stiffer brain and more compliant braincase in the immature rat compared with the adult rat will aid in the development of age-specific experimental models and in computational head injury simulations. Specifically, these results will assist in the selection of forces to induce comparable mechanical stresses, strains and consequent injury profiles in brain tissues of immature and adult animals.

Abstract: Computational models of the head can be used to simulate events associated with traumatic brain injury and to design protective equipment and environments. Accurate material property descriptions of biological tissues are crucial to the development of computational models that mimic human responses. Recent finite element models of adult head injury assign distinct homogeneous properties to white and gray matter regions within the brain, based on limited regional data. However, white matter is usually considered homogeneous, despite recent reports of significant mechanical property differences between corpus callosum and corona radiata. In this study, we extend our investigation of homogeneity to gray matter by measuring stiffness of cerebral cortex and comparing it to thalamus from our previous work. Using a parallel plate shear-testing device, we performed a sequence of stress relaxation tests at 2.5%, 5%, 10%, 20%, 30%, 40%, and then 50% strain. Force and displacement were measured and used to determine the stiffness in two different porcine cortical gray matter regions. While no significant difference was found between the two cortical regions, cortical gray matter was significantly less stiff than previously reported values of porcine thalamic gray matter (p<0.01) and human cortical gray matter (p<0.001). These data indicate that while intraregional gray matter may be considered homogenous, there exists heterogeneity between differing regions of the brain. The assumption of gray matter homogeneity should be carefully considered in future finite element models of the head. [Copyright &y& Elsevier]

Modification of cerebral perfusion pressure and cerebral blood flow (CBF) are crucial components of the therapies designed to reduce secondary damage after traumatic brain injury (TBI). Previously we documented a robust decrease in CBF after rapid sagittal head rotation in our well-validated animal model of diffuse TBI. Mechanisms responsible for this immediate (<10 min) and sustained (∼24 h) reduction in CBF have not been explored. Because the carotid arteries are a major source of CBF, we hypothesized that blood flow through the carotid arteries (Q) and vessel diameter (D) would decrease after rapid nonimpact head rotation without cervical spine injury. Four-week-old (toddler) female piglets underwent rapid (<20 msec) sagittal head rotation without impact, previously shown to produce diffuse TBI with reductions in CBF. Ultrasonographic images of the bilateral carotid arteries were recorded at baseline (pre-injury), as well as immediately after head rotation and 15, 30, 45, and 60 min after injury. Diameter (D) and waveform velocity (V) were used to calculate blood flow (Q) through the carotid arteries using the equation Q=(0.25)πD2V. D, V, and Q were normalized to the pre-injury baseline values to obtain a relative change after injury in right and left carotid arteries. Three-way analysis of variance and post-hoc Tukey-Kramer analyses were used to assess statistical significance of injury, time, and side. The relative change in carotid artery diameter and flow was significantly decreased in injured animals in comparison with uninjured sham controls ( p<0.0001 and p=0.0093, respectively) and did not vary with side ( p>0.39). The average carotid blood velocity did not differ between sham and injured animals ( p=0.91). These data suggest that a reduction in global CBF after rapid sagittal head rotation may be partially mediated by a reduction in carotid artery flow, via vasoconstriction. [ABSTRACT FROM AUTHOR]

We have developed and implemented a noninvasive, objective neurofunctional assessment for evaluating the sustained effects of traumatic brain injury (TBI) in piglets with both diffuse and focal injury types. Derived from commercial actigraphy methods in humans, this assessment continuously monitors the day/night activity of piglets using close-fitting jackets equipped with tri-axial accelerometers to monitor movements of the thorax. Acceleration metrics were correlated ( N = 7 naïve piglets) with video images to define values associated with a range of activities, from recumbancy (rest) to running. Both focal ( N = 8) and diffuse brain injury ( N = 9) produced alterations in activity that were significant 4 days post-TBI. Compared to shams ( N = 6) who acclimated to the animal facility 4 days after an anesthesia experience by blurring the distinction between day and night activity, post-TBI time-matched animals had larger fractions of inactive periods during the daytime than nighttime, and larger fractions of active time in the night were spent in high activity (e.g., constant walking, intermittent running) than during the day. These persistent disturbances in rest and activity are similar to those observed in human adults and children post-TBI, establishing actigraphy as a translational metric, used in both humans and large animals, for assessment of injury severity, progressions, and intervention. [ABSTRACT FROM AUTHOR]

The objective of this study was to define the constitutive response of brainstem undergoing finite shear deformation. Brainstem was characterized as a transversely isotropic viscoelastic material and the material model was formulated for numerical implementation. Model parameters were fit to shear data obtained in porcine brainstem specimens undergoing finite shear deformation in three directions: parallel, perpendicular, and cross sectional to axonal fiber orientation and determined using a combined approach of finite element analysis (PEA) and a genetic algorithm (GA) optimizing method. The average initial shear modulus of brainstem matrix of 4-week old pigs was 12.7 Pa, and therefore the brainstem offers little resistance to large shear deformations in the parallel or perpendicular directions, due to the dominant contribution of the matrix in these directions. The fiber reinforcement stiffness was 121.2 Pa, indicating that brainstem is anisotropic and that axonal fibers have an important role in the cross-sectional direction. The first two leading relative shear relaxation moduli were 0.8973 and 0.0741, respectively, with corresponding characteristic times of 0.0047 and 1.4538 s, respectively implying rapid relaxation of shear stresses. The developed material model and parameter estimation technique are likely to find broad applications in neural and orthopaedic tissues. [ABSTRACT FROM AUTHOR]