ORIGINAL ARTICLES

SHEARING OF NERVE FIBRES AS A CAUSE OF BRAIN DAMAGE DUE TO HEAD INJURY: A Pathological Study of Twenty Cases

The goal of this study was to design, fabricate, and characterize hydrogel lattice structures with consistent, controllable, anisotropic mechanical properties. Lattices, based on three unit-cell types (cubic, diamond, and vintile), were printed using stereolithography (SLA) of polyethylene glycol diacrylate (PEGDA). To create structural anisotropy in the lattices, unit cell design files were scaled by a factor of two in one direction in each layer and then printed. The mechanical properties of the scaled lattices were measured in shear and compression and compared to those of the unscaled lattices. Two apparent shear moduli of each lattice were measured by dynamic shear tests in two planes: (1) parallel and (2) perpendicular to the scaling direction, or cell symmetry axis. Three apparent Young's moduli of each lattice were measured by compression in three different directions: (1) the “build” direction or direction of added layers, (2) the scaling direction, and (3) the unscaled direction perpendicular to both scaling and build directions. For shear deformation in unscaled lattices, the apparent shear moduli were similar in the two perpendicular directions. In contrast, scaled lattices exhibit clear differences in apparent shear moduli. In compression of unscaled lattices, apparent Young's moduli were independent of direction in cubic and vintile lattices; in diamond lattices Young's moduli differed in the build direction, but were similar in the other two directions. Scaled lattices in compression exhibited additional differences in apparent Young's moduli in the scaled and unscaled directions. Notably, the effects of scaling on apparent modulus differed between each lattice type (cubic, diamond, or vintile) and deformation mode (shear or compression). Scaling of 3D-printed, hydrogel lattices may be harnessed to create tunable, structures of desired shape, stiffness, and mechanical anisotropy, in both shear and compression.

In recent years, traumatic brain injury (TBI) has increasingly been recognized as an ongoing disease process, rather than an acute event. In support of this, persistent cognitive impairments are observed in approximately 65% of individuals following moderate–severe TBI, with reports that cognitive dysfunction may also present long-term in a small subset of individuals following mild injury. Both mild and moderate–severe TBI are known to increase the risk of dementia development, although to different extents. Despite this, key questions remain with regards to the brain mechanisms that may link the occurrence of TBI with heightened risk for dementia emergence years, or even decades, after the precipitating injury. Traumatic axonal injury (TAI) may be a key driver of this relationship, triggering multiple molecular cascades known to be critical for the pathophysiology of dementia, including oxidative stress, heightened neuroinflammation and accumulation of toxic oligomers of amyloid beta and tau. As these processes occur chronically following injury, they may represent an extended window for therapeutic intervention. Hence, an understanding of the brain mechanisms that explain the relationship between TAI and dementia may be key for developing targeted therapeutics, as well as for earlier identification of risk profiles within individuals.

Deep brain stimulation paradigms might be used to treat memory disorders in patients with stroke or traumatic brain injury. However, proof of concept studies in animal models are needed before clinical translation. We propose here a comprehensive review of rodent models for Traumatic Brain Injury and Stroke. We systematically review the histological, behavioral and electrophysiological features of each model and identify those that are the most relevant for translational research.

In forensic investigations, it is important to detect traumatic axonal injuries (TAIs) to reveal head trauma that might otherwise remain occult. These lesions are subtle and frequently ambiguous on macroscopic evaluations. We present a case of TAI revealed by pre-autopsy postmortem magnetic resonance imaging (PMMR).

A man in his sixties was rendered unconscious in a motor vehicle accident. CT scans revealed traumatic mild subarachnoid hemorrhage. Two weeks after the accident he regained consciousness, but displayed an altered mental state. Seven weeks after the accident, he suddenly died in hospital. Postmortem computed tomography (PMCT) and PMMR were followed by a forensic autopsy.

PMMR showed low-intensity lesions in parasagittal white matter, deep white matter, and corpus callosum on three-dimensional gradient-echo T1-weighted imaging (3D-GRE T1WI). In some of these lesions, T2∗-weighted imaging also showed low-intensity foci suggesting hemorrhagic axonal injury. The lesions were difficult to find on PMCT and macroscopic evaluation, but were visible on antemortem MRI and confirmed as TAIs on histopathology.

From this case, it can be said that PMMR can detect subtle TAIs missed by PMCT and macroscopic evaluation. Hence, pre-autopsy PMMR scanning could be useful for identifying TAIs during forensic investigations.

The physical structure of neurons – dendrites converging on the soma, with an axon conveying activity to distant locations – is uniquely tied to their function. To perform their role, axons need to maintain structural precision in the soft, gelatinous environment of the central nervous system and the dynamic, flexible paths of nerves in the periphery. This requires close mechanical coupling between axons and the surrounding tissue, as well as an elastic, robust axoplasm resistant to pinching and flattening, and capable of sustaining transport despite physical distortion. These mechanical properties arise primarily from the properties of the internal cytoskeleton, coupled to the axonal membrane and the extracellular matrix. In particular, the two large constituents of the internal cytoskeleton, microtubules and neurofilaments, are braced against each other and flexibly interlinked by specialised proteins. Recent evidence suggests that the primary function of neurofilament sidearms is to structure the axoplasm into a linearly organised, elastic gel. This provides support and structure to the contents of axons in peripheral nerves subject to bending, protecting the relatively brittle microtubule bundles and maintaining them as transport conduits. Furthermore, a substantial proportion of axons are myelinated, and this thick jacket of membrane wrappings alters the form, function and internal composition of the axons to which it is applied. Together these structures determine the physical properties and integrity of neural tissue, both under conditions of normal movement, and in response to physical trauma. The effects of traumatic injury are directly dependent on the physical properties of neural tissue, especially axons, and because of axons’ extreme structural specialisation, post-traumatic effects are usually characterised by particular modes of axonal damage. The physical realities of axons in neural tissue are integral to both normal function and their response to injury, and require specific consideration in evaluating research models of neurotrauma.

TBI is one of the most common causes of hospital admission and a leading cause of death, it is therefore frequently encountered by pathologists in the coronial and medicolegal services. It is not a single entity but a heterogeneous group of pathologies which are caused by different mechanisms and have different survival outcomes and medicolegal implications. TBI is caused by physical contact or acceleration and deceleration mechanisms or a combination of these. It is classified into focal and diffuse damage; both of which should be correlated with the circumstances of death and clinical history before a conclusion can be made regarding their contribution to the cause of death. Focal damage in the brain such as intracranial haemorrhages and contusions can be easily recognised by naked eye examination, but they require detailed description of their anatomical distribution and extent. However the diffuse traumatic brain damage, particularly those related to axonal injury, requires histological and immunohistochemical (IHC) tests to be established.

The understanding of the medicolegal implications of focal and diffuse axonal injury has evolved in the last decade with the introduction of better IHC and neuro-radiological methods.