Changes to the viscoelastic properties of brain tissue after traumatic axonal injury

While it has been shown that repetitive mild brain injuries can cause cumulative damage to the brain, changes to the mechanical properties of brain tissue at large deformations were also noted in the literature. The goal of this study was to show that the viscoelastic properties of brain tissue significantly change after traumatic axonal injury (TAI). An impact acceleration model was used to create TAI in the rat brainstem which was quantified with an immunohistochemistry technique at the ponto-medullary junction (PmJ) and pyramidal decussation (PDx). The viscoelastic properties at these two points with and without preconditioning were characterized using an indentation technique combined with finite element analysis and a comparison was made between injured and uninjured specimens, which revealed statistically significant reduction in the instantaneous elastic force at PDx where the brain tissue sustained a significantly higher level of injury. The result of this study can be used to characterize a damage function for the brain tissue undergoing large deformation.     

Multi-scale mechanics of traumatic brain injury: predicting axonal strains from head loads

The length scales involved in the development of diffuse axonal injury typically range from the head level (i.e., mechanical loading) to the cellular level. The parts of the brain that are vulnerable to this type of injury are mainly the brainstem and the corpus callosum, which are regions with highly anisotropically oriented axons. Within these parts, discrete axonal injuries occur mainly where the axons have to deviate from their main course due to the presence of an inclusion. The aim of this study is to predict axonal strains as a result of a mechanical load at the macroscopic head level. For this, a multi-scale finite element approach is adopted, in which a macro-level head model and a micro-level critical volume element are coupled. The results show that the axonal strains cannot be trivially correlated to the tissue strain without taking into account the axonal orientations, which indicates that the heterogeneities at the cellular level play an important role in brain injury and reliable predictions thereof. In addition to the multi-scale approach, it is shown that a novel anisotropic equivalent strain measure can be used to assess these micro-scale effects from head-level simulations only.     

Compromised axonal functionality after neurodegeneration,concussion and/or traumatic brain injury

Axonal swellings are almost universal in neurodegenerative diseases of the central nervous system, including Alzheimer’s and Parkinson’s disease. Concussions and traumatic brain injuries can also produce cognitive and behavioral deficits by compromising neuronal morphology. Using a spike metric analysis, we characterize computationally the effects of such axonal varicosities on spike train propagation by comparing Poisson spike train classes before and after propagation through a prototypical axonal enlargement, or focused axonal swelling. Misclassification of spike train classes and low-pass filtering of firing rate activity increases with more pronounced axonal injury. We show that confusion matrices and a calculation of the loss of transmitted information provide a very practical way to characterize how injured neurons compromise the signal processing and faithful conductance of spike trains. The method demonstrates that (i) neural codes encoded with low firing rates are more robust to injury than those encoded with high firing rates, (ii) classification depends upon the length of the spike train used to encode information, and (iii) axonal injuries reduce the variance of spike trains within a given stimulus class. The work introduces a novel theoretical and computational framework to quantify the interplay between electrophysiological dynamics with focused axonal swellings generated by injury or other neurodegenerative processes. It further suggests how pharmacology and plasticity may play a role in recovery of neural computation. Ultimately, the work bridges vast experimental observations of in vitro morphological pathologies with post-traumatic cognitive and behavioral dysfunction.     

An analytical model of traumatic diffuse brain injury

Diffuse axonal injury (DAI) with prolonged coma has been produced in the primate using an impulsive, rotational acceleration of the head without impact. This pathophysiological entity has been studied subsequently from a biomechanics perspective using physical models of the skull-brain structure. Subjected to identical loading conditions as the primate, these physical models permit one to measure the deformation within the surrogate brain tissue as a function of the forces applied to the head. An analytical model designed to approximate these experiments has been developed in order to facilitate an analysis of the parameters influencing brain deformation. These three models together are directed toward the development of injury tolerance criteria based upon the shear strain magnitude experienced by the deep white matter of the brain. The analytical model geometry consists of a rigid, right-circular cylindrical shell filled with a Kelvin-Voigt viscoelastic material. Allowing no slip on the boundary, the shell is subjected to a sudden, distributed, axisymmetric, rotational load. A Fourier series representation of the load allows unrestricted load-time histories. The exact solution for the relative angular displacement (V) and the infinitesimal shear strain (epsilon) at any radial location in the viscoelastic material with respect to the shell was determined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modelling organelle transport after traumatic axonal injury

This paper is motivated by recent experimental research (Tang-Schomer et al. 2012) on the formation of periodic varicosities in axons after traumatic brain injury (TBI). TBI leads to the formation of undulated distortions in the axons due to their dynamic deformation. These distortions result in the breakage of some microtubules (MTs) near the peaks of undulations. The breakage is followed by catastrophic MT depolymerisation around the broken ends. Although after relaxation axons regain their straight geometry, the structure of the axon after TBI is characterised by the presence of periodic regions where the density of MTs has been decreased due to depolymerisation. We modelled organelle transport in an axon segment with such a damaged MT structure and investigated how this structure affects the distributions of organelle concentrations and fluxes. The modelling results suggest that organelles accumulate at the boundaries of the region where the density of MTs has been decreased by depolymerisation. According to the model, the presence of such damaged regions decreases the organelle flux by only about 12%. This provides evidence that axon degradation after TBI may be caused by organelle accumulation rather than by starvation due to insufficient organelle flux.     

A proposed tolerance criterion for diffuse axonal injury in man.

The head injury criterion (HIC) is currently the government-accepted head injury indicator. The HIC is not injury-specific, does not relate to injury severity, nor does it take into account variations in the brain mass or load direction. This report focuses on one type of inertial brain injury, diffuse axonal injury (DAI), and utilizes animal studies, physical model experiments, and analytical model simulations to determine the kinematics of DAI in the subhuman primate and to scale these results to man. A human injury tolerance for moderate to severe DAI, which includes the influences of rotational loads and brain mass, is proposed.     

White matter tract-oriented deformation predicts traumatic axonal brain injury and reveals rotational direction-specific vulnerabilities

A systematic correlation between finite element models (FEMs) and histopathology is needed to define deformation thresholds associated with traumatic brain injury (TBI). In this study, a FEM of a transected piglet brain was used to reverse engineer the range of optimal shear moduli for infant (5 days old, 553–658 Pa) and 4-week-old toddler piglet brain (692–811 Pa) from comparisons with measured in situ tissue strains. The more mature brain modulus was found to have significant strain and strain rate dependencies not observed with the infant brain. Age-appropriate FEMs were then used to simulate experimental TBI in infant (\(n=36\)) and preadolescent (\(n=17\)) piglets undergoing a range of rotational head loads. The experimental animals were evaluated for the presence of clinically significant traumatic axonal injury (TAI), which was then correlated with FEM-calculated measures of overall and white matter tract-oriented tissue deformations, and used to identify the metric with the highest sensitivity and specificity for detecting TAI. The best predictors of TAI were the tract-oriented strain (6–7 %), strain rate (38–40 s\(^{-1})\), and strain times strain rate (1.3–1.8 s\(^{-1})\) values exceeded by 90 % of the brain. These tract-oriented strain and strain rate thresholds for TAI were comparable to those found in isolated axonal stretch studies. Furthermore, we proposed that the higher degree of agreement between tissue distortion aligned with white matter tracts and TAI may be the underlying mechanism responsible for more severe TAI after horizontal and sagittal head rotations in our porcine model of nonimpact TAI than coronal plane rotations.     

A proposed injury threshold for mild traumatic brain injury

Traumatic brain injuries constitute a significant portion of injury resulting from automotive collisions, motorcycle crashes, and sports collisions. Brain injuries not only represent a serious trauma for those involved but also place an enormous burden on society, often exacting a heavy economical, social, and emotional price. Development of intervention strategies to prevent or minimize these injuries requires a complete understanding of injury mechanisms, response and tolerance level. In this study, an attempt is made to delineate actual injury causation and establish a meaningful injury criterion through the use of the actual field accident data. Twenty-four head-to-head field collisions that occurred in professional football games were duplicated using a validated finite element human head model. The injury predictors and injury levels were analyzed based on resulting brain tissue responses and were correlated with the site and occurrence of mild traumatic brain injury (MTBI). Predictions indicated that the shear stress around the brainstem region could be an injury predictor for concussion. Statistical analyses were performed to establish the new brain injury tolerance level.     

New mechanics of traumatic brain injury

The prediction and prevention of traumatic brain injury is a very important aspect of preventive medical science. This paper proposes a new coupled loading-rate hypothesis for the traumatic brain injury (TBI), which states that the main cause of the TBI is an external Euclidean jolt, or SE(3)-jolt, an impulsive loading that strikes the head in several coupled degrees-of-freedom simultaneously. To show this, based on the previously defined covariant force law, we formulate the coupled Newton–Euler dynamics of brain’s micro-motions within the cerebrospinal fluid and derive from it the coupled SE(3)-jolt dynamics. The SE(3)-jolt is a cause of the TBI in two forms of brain’s rapid discontinuous deformations: translational dislocations and rotational disclinations. Brain’s dislocations and disclinations, caused by the SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum brain model.

Opposing roles for reactive astrocytes following traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Current medical therapies exhibit limited efficacy in reducing neurological injury and the prognosis for patients remains poor. While most research is focused on the direct protection of neuronal cells, non-neuronal cells, such as astrocytes, may exert an active role in the pathogenesis of TBI. Astrocytes, the predominant cell type in the human brain, are traditionally associated with providing only structural support within the CNS. However, recent work suggests astrocytes may regulate brain homeostasis and limit brain injury. In contrast, reactive astrocytes may also contribute to increased neuroinflammation, the development of cerebral edema, and elevated intracranial pressure, suggesting possible roles in exacerbating secondary brain injury following neurotrauma. The multiple, opposing roles for astrocytes following neurotrauma may have important implications for the design of directed therapeutics to limit neurological injury. As such, a primary focus of this review is to summarize the emerging evidence suggesting reactive astrocytes influence the response of the brain to TBI.     

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy

Abstract

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker’s limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.     

Anisotropic finite element models for brain injury prediction: the sensitivity of axonal strain to white matter tract inter-subject variability

Computational models incorporating anisotropic features of brain tissue have become a valuable tool for studying the occurrence of traumatic brain injury. The tissue deformation in the direction of white matter tracts (axonal strain) was repeatedly shown to be an appropriate mechanical parameter to predict injury. However, when assessing the reliability of axonal strain to predict injury in a population, it is important to consider the predictor sensitivity to the biological inter-subject variability of the human brain. The present study investigated the axonal strain response of 485 white matter subject-specific anisotropic finite element models of the head subjected to the same loading conditions. It was observed that the biological variability affected the orientation of the preferential directions (coefficient of variation of 39.41% for the elevation angle—coefficient of variation of 29.31% for the azimuth angle) and the determination of the mechanical fiber alignment parameter in the model (gray matter volume 55.55–70.75%). The magnitude of the maximum axonal strain showed coefficients of variation of 11.91%. On the contrary, the localization of the maximum axonal strain was consistent: the peak of strain was typically located in a 2 cm³ volume of the brain. For a sport concussive event, the predictor was capable of discerning between non-injurious and concussed populations in several areas of the brain. It was concluded that, despite its sensitivity to biological variability, axonal strain is an appropriate mechanical parameter to predict traumatic brain injury.     

The gut reaction to traumatic brain injury

Traumatic brain injury (TBI) is a complex disorder that affects millions of people worldwide. The complexity of TBI partly stems from the fact that injuries to the brain instigate non-neurological injuries to other organs such as the intestine. Additionally, genetic variation is thought to play a large role in determining the nature and severity of non-neurological injuries. We recently reported that TBI in flies, as in humans, increases permeability of the intestinal epithelial barrier resulting in hyperglycemia and a higher risk of death. Furthermore, we demonstrated that genetic variation in flies is also pertinent to the complexity of non-neurological injuries following TBI. The goals of this review are to place our findings in the context of what is known about TBI-induced intestinal permeability from studies of TBI patients and rodent TBI models and to draw attention to how studies of the fly TBI model can provide unique insights that may facilitate diagnosis and treatment of TBI.     

Extracellular N-acetylaspartate depletion in traumatic brain injury

N-Acetylaspartate (NAA) is almost exclusively localized in neurons in the adult brain and is present in high concentration in the CNS. It can be measured by proton magnetic resonance spectroscopy and is seen as a marker of neuronal damage and death. NMR spectroscopy and animal models have shown NAA depletion to occur in various types of chronic and acute brain injury. We investigated 19 patients with traumatic brain injury (TBI). Microdialysis was utilized to recover NAA, lactate, pyruvate, glycerol and glutamate, at 12-h intervals. These markers were correlated with survival and a 6-month Glasgow Outcome Score. Eleven patients died and eight survived. A linear mixed model analysis showed a significant effect of outcome and of the interaction between time of injury and outcome on NAA levels (p = 0.009 and p = 0.004, respectively). Overall, extracellular NAA was 34% lower in non-survivors. A significant non-recoverable fall was observed in this group from day 4 onwards, with a concomitant rise in lactate-pyruvate ratio and glycerol. These results suggest that mitochondrial dysfunction is a significant contributor to poor outcome following TBI and propose extracellular NAA as a potential marker for monitoring interventions aimed at preserving mitochondrial function.     

Modulation of autophagy in traumatic brain injury

Traumatic brain injury (TBI) is defined as a traumatically induced structural injury or physiological disruption of brain function as a result of external forces, leading to adult disability and death. A growing body of evidence reveals that alterations in autophagy-related proteins exist extensively in both experimentally and clinically after TBI. Of note, the autophagy pathway plays an essential role in pathophysiological processes, such as oxidative stress, inflammatory response, and apoptosis, thus contributing to neurological properties of TBI. With this in mind, this review summarizes a comprehensive overview on the beneficial and detrimental effects of autophagy in pathophysiological conditions and how these activities are linked to the pathogenesis of TBI. Moreover, the relationship between oxidative stress, inflammation, apoptosis, and autophagy occur TBI. Ultimately, multiple compounds and various drugs targeting the autophagy pathway are well described in TBI. Therefore, autophagy flux represents a potential clinical therapeutic value for the treatment of TBI and its complications.