Axonal Deformation Research Articles

Mechanical mechanism and indicator of diffuse axonal injury under blast-type acceleration

Diffuse axonal injury (DAI) caused by acceleration is one of the most prominent forms of blast-induced Traumatic Brain Injury. However, the mechanical mechanism and indicator of axonal deformation-induced injury under blast-type acceleration with high peak and short duration are unclear. This study constructed a multilayer head model that can reflect the response characteristics of translational and rotational acceleration (the peak time of which is within 0.5 ms). Based on von Mises stress, axonal strain and axonal strain rate indicators, the physical process of axonal injury is studied, and the vulnerable area under blast-type acceleration load is given. In the short term (within 1.75 ms), dominated by sagittal rotational acceleration peaks, the constraint of falx and tentorium rapidly imposes the inertial load on the brain tissue, resulting in a high-rate deformation of axons (axonal strain rate of which exceed 100 s−1). For a long term (after 1.75 ms), fixed-point rotation of the brain following the head causes excessive distortion of brain tissue (von Mises stress of which exceeds 15 kPa), resulting in a large axonal stretch strain where the main axonal orientation coincides with the principal strain direction. It is found that the axonal strain rate can better indicate the pathological axonal injury area and coincides with external inertial loading in the risk areas, which suggests that DAI under blast-type acceleration overload is mainly caused by the rapid axonal deformation instead of by the excessive axonal strain. The research in this paper helps understand and diagnose blast-induced DAI.

Integrated multi-omics analysis reveals the underlying molecular mechanism for developmental neurotoxicity of perfluorooctanesulfonic acid in zebrafish.

Limited studies on multi-omics have been conducted to comprehensively investigate the molecular mechanism underlying the developmental neurotoxicity of perfluorooctanesulfonic acid (PFOS). In this study, the locomotor behavior of zebrafish larvae was assessed under the exposure to 0.1-20μM PFOS based on its reported neurobehavioral effect. After the number of zebrafish larvae was optimized for proteomics and metabolomics studies, three kinds of omics (i.e., transcriptomics, proteomics, and metabolomics) were carried out with zebrafish larvae exposed to 0.1, 1, 5, and 10μM PFOS. More importantly, a data-driven integration of multi-omics was performed to elucidate the toxicity mechanism involved in developmental neurotoxicity. In a concentration-dependent manner, exposure to PFOS provoked hyperactivity and hypoactivity under light and dark conditions, respectively. Individual omics revealed that PFOS exposure caused perturbations in the pathways of neurological function, oxidative stress, and energy metabolism. Integrated omics implied that there were decisive pathways for axonal deformation, neuroinflammatory stimulation, and dysregulation of calcium ion signaling, which are more clearly specified for neurotoxicity. Overall, our findings broaden the molecular understanding of the developmental neurotoxicity of PFOS, for which multi-omics and integrated omics analyses are efficient for discovering the significant molecular pathways related to developmental neurotoxicity in zebrafish.

Localized Axolemma Deformations Suggest Mechanoporation as Axonal Injury Trigger.

Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage, understanding the nature of cellular level impairment is crucial. Experimental observations have so far led to the formulation of conflicting theories regarding the cellular primary injury mechanism. Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly as injury trigger. However, mechanoporation thresholds of generic membranes seem not to overlap with the axonal injury deformation range and microtubules appear too stiff and too weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the mechanism of primary axonal injury, bridging finite element and molecular dynamics simulations. Despite the necessary level of approximation, our models can accurately describe the mechanical behavior of the unmyelinated axon and its membrane. More importantly, they give access to quantities that would be inaccessible with an experimental approach. We show that in a typical injury scenario, the axonal cortex sustains deformations large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal deformation of 10–12% agree well with the thresholds proposed in the literature for axonal injury and, above all, allow us to provide quantitative evidences that do not exclude pore formation in the membrane as a result of trauma. Our findings bring to an increased knowledge of axonal injury mechanism that will have positive implications for the prevention and treatment of brain injuries.

Decoupled epineurial and axonal deformation in mouse median and ulnar nerves.

Peripheral nerves accommodate mechanical loads during joint movement. Hypothesized protective features include increased nerve compliance near joints and axonal undulation. How axons perceive nerve deformation is poorly understood. We tested whether nerves increase local axonal undulation in regions of high epineurial strain to protect nerve fibers from strain-induced damage. Regional epineurial strain was measured near the elbow in median and ulnar nerves of mice expressing axonal fluorescence before and after decompression. Regional axonal tortuosity was quantified under confocal microscopy. Nerves showed higher epineurial strain just distal to the medial epicondyle; these differences were eliminated after decompression. Axonal tortuosity also varied regionally; however, unlike in the epineurium, it was greater in proximal regions. In this study we have proposed a neuromechanical model whereby axons can unravel along their entire length due to looser mechanical coupling to the peri/epineurium. Our findings have major implications for understanding nerve biomechanics and dysfunction. Muscle Nerve 59:619-619, 2019.

Do blast induced skull flexures result in axonal deformation?

Subject-specific computer models (male and female) of the human head were used to investigate the possible axonal deformation resulting from the primary phase blast-induced skull flexures. The corresponding axonal tractography was explicitly incorporated into these finite element models using a recently developed technique based on the embedded finite element method. These models were subjected to extensive verification against experimental studies which examined their pressure and displacement response under a wide range of loading conditions. Once verified, a parametric study was developed to investigate the axonal deformation for a wide range of loading overpressures and directions as well as varying cerebrospinal fluid (CSF) material models. This study focuses on early times during a blast event, just as the shock transverses the skull (< 5 milliseconds). Corresponding boundary conditions were applied to eliminate the rotation effects and the resulting axonal deformation. A total of 138 simulations were developed– 128 simulations for studying the different loading scenarios and 10 simulations for studying the effects of CSF material model variance–leading to a total of 10,702 simulation core hours. Extreme strains and strain rates along each of the fiber tracts in each of these scenarios were documented and presented here. The results suggest that the blast-induced skull flexures result in strain rates as high as 150–378 s-1. These high-strain rates of the axonal fiber tracts, caused by flexural displacement of the skull, could lead to a rate dependent micro-structural axonal damage, as pointed by other researchers.

Strain-Rate Dependency of Axonal Tolerance for Uniaxial Stretching.

This study aims to clarify the relation between axonal deformation and the onset of axonal injury. Firstly, to examine the influence of strain rate on the threshold for axonal injury, cultured neurons were subjected to 12 types of stretching (strains were 0.10, 0.15, and 0.20 and strain rates were 10, 30, 50, and 70 s-1). The formation of axonal swellings and bulbs increased significantly at strain rates of 50 and 30 s-1 with strains of 0.15 and 0.20, respectively, even though those formations did not depend on strain rates in cultures exposed to a strain of 0.10. Then, to examine the influence of the strain along an axon on axonal injury, swellings were measured at every axonal angle in the stretching direction. The axons that were parallel to stretching direction were injured the most. Finally, we proposed an experimental model that subjected an axon to more accurate strain. This model observed the process of axonal injury formation by detecting the same neuron before and after stretching. These results suggest that the strain-rate dependency of axonal tolerance is induced by a higher magnitude of loading strain and an experiment focusing on axonal strain is required for obtaining more detailed injury criteria for an axon.

Tissue loading and microstructure regulate the deformation of embedded nerve fibres: predictions from single-scale and multiscale simulations

Excessive deformation of nerve fibres (axons) in the spinal facet capsular ligaments (FCLs) can be a cause of pain. The axons are embedded in the fibrous extracellular matrix (ECM) of FCLs, so understanding how local fibre organization and micromechanics modulate their mechanical behaviour is essential. We constructed a computational discrete-fibre model of an axon embedded in a collagen fibre network attached to the axon by distinct fibre-axon connections. This model was used to relate the axonal deformation to the fibre alignment and collagen volume concentration of the surrounding network during transverse, axial and shear deformations. Our results showed that fibre alignment affects axonal deformation only during transverse and axial loading, but higher collagen volume concentration results in larger overall axonal strains for all loading cases. Furthermore, axial loading leads to the largest stretch of axonal microtubules and induces the largest forces on axon's surface in most cases. Comparison between this model and a multiscale continuum model for a representative case showed that although both models predicted similar averaged axonal strains, strain was more heterogeneous in the discrete-fibre model.

Decompressive craniectomy causes a significant strain increase in axonal fiber tracts

Decompressive craniectomy (DC) allows for the expansion of a swollen brain outside the skull and has the potential to reduce intracranial pressure. However, the stretching of axons may contribute to an unfavorable outcome in patients treated with DC. In this study, we present a method for quantifying and visualizing axonal fiber deformation during both the pre-craniectomy and post-craniectomy periods to provide more insight into the mechanical effects of this treatment on axonal fibers. The deformation of the brain tissue in the form of a Lagrangian finite strain tensor for the entire brain was obtained by a non-linear image registration method based on the CT scanning data sets of the patient. Axonal fiber tracts were extracted from diffusion-weighted images. Based on the calculated brain tissue strain tensor and the observed axonal fiber tracts, the deformation of axonal fiber tracts in the form of a first principal strain, axonal strain and axonal shear strain were quantified. The greatest axonal fiber displacement was predominantly located in the treated region of the craniectomy, accompanied by a large axonal deformation close to the skull edge of the craniectomy. The distortion (stretching or shearing) of axonal fibers in the treated area of the craniectomy may influence the axonal fibers in such a way that neurochemical events are disrupted. A quantitative model may clarify some of the potential problems with this treatment.

Numerical study of axonal outgrowth in grooved nerve conduits

Nerve conduits with grooved inner texture, working as a topographical guidance cue, have been experimentally proved to play a significant role in axonal alignment. How grooved conduits guide axonal outgrowth is of particular interest for studying nerve regeneration. A viscoelastic model of axonal outgrowth in a conduit with a defined grooved geometry characterized by its width in the circumferential direction and its height in the radial direction is developed in this work. In this model, the axon is considered as an elastic beam and the axonal deformation and motion, including stretching, bending and torsion, are described using a Cosserat rod theory. The friction between axon and substrate is also considered in this model as well as the tip outgrowth. It is found that the directional outgrowth of the axon can be significantly improved by the grooved texture: when the groove width decreases or the groove height increases, the axonal elongation in the longitudinal direction of the conduit can be increased, which is in good agreement with experimental observations. This work is the first numerical model to study the effect of the substrate geometry on axonal outgrowth.

A tissue-level anisotropic criterion for brain injury based on microstructural axonal deformation

Different length scales from micrometers to several decimeters play an important role in diffuse axonal injury. The kinematics at the head level result in local impairments at the cellular level. Finite element methods can be used for predicting brain injury caused by a mechanical loading of the head. Because of its oriented microstructure, the sensitivity of brain tissue to a mechanical load can be expected to be orientation dependent. However, the criteria for injury that are currently used at the tissue level in finite element head models are isotropic and therefore do not consider this orientation dependence, which might inhibit a reliable assessment of injury. In this study, an anisotropic brain injury criterion is developed that is able to describe the effects of the oriented microstructure based on micromechanical simulations. The effects of both the main axonal direction and of local deviations from this direction are accounted for. With the anisotropic criterion for brain injury, computational head models will be able to account for aspects of diffuse axonal injury at the cellular level and can therefore more reliably predict injury.

Computation of axonal elongation in head trauma finite element simulation

In the case of head trauma, elongation of axons is thought to result in brain damage and to lead to Diffuse Axonal Injuries (DAI). Mechanical parameters have been previously proposed as DAI metric. Typically, brain injury parameters are expressed in terms of pressure, shearing stresses or invariants of the strain tensor. Addressing axonal deformation within the brain during head impact can improve our understanding of DAI mechanisms. A new technique based on directional measurements of water diffusion in soft tissue using Magnetic Resonance Imaging (MRI), called Diffusion Tensor Imaging (DTI), provides information on axonal orientation within the brain. The present study aims at coupling axonal orientation from a 12-patient-based DTI 3D picture, called “DTI atlas”, with the Strasbourg University Finite Element Head Model (SUFEHM). This information is then integrated in head trauma simulation by computing axonal elongation for each finite element of the brain model in a post-processing of classical simulation results. Axonal elongation was selected as computation endpoint for its strong potential as a parameter for DAI prediction and location. After detailing the coupling technique between DTI atlas and the head FE model, two head trauma cases presenting different DAI injury levels are reconstructed and analyzed with the developed methodology as an illustration of axonal elongation computation. Results show that anisotropic brain structures can be realistically implemented into an existing finite element model of the brain. The feasibility of integrating axon fiber direction information within a dedicated post-processor is also established in the context of the computation of axonal elongation. The accuracy obtained when estimating level and location of the computed axonal elongation indicates that coupling classical isotropic finite element simulation with axonal structural anisotropy is an efficient strategy. Using this method, tensile elongation of the axons can be directly invoked as a mechanism for Diffuse Axonal Injury.

Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors.

We demonstrated previously that dynamic stretch injury of cultured axons induces structural changes and Ca2+ influx modulated by tetrodotoxin (TTX)-sensitive voltage-gated sodium channels (NaChs). In the present study, we evaluated potential damage to the NaCh alpha-subunit, which can cause noninactivation of NaChs. In addition, we explored the effects of pre-injury and post-injury treatment with TTX and protease inhibition on proteolysis of the NaCh alpha-subunit and intra-axonal calcium levels ([Ca2+]i) over 60 min after trauma. After stretch injury, we found that [Ca2+]i continued to increase in untreated axons for at least 60 min. We also observed that the III-IV intra-axonal loop of the NaCh alpha-subunit was proteolyzed between 5 and 20 min after trauma. Pre-injury treatment of the axons with TTX completely abolished the posttraumatic increase in [Ca2+]i and proteolysis of the NaCh alpha-subunit. In addition, both pre-injury and post-injury inhibition of protease activity attenuated long-term increases in [Ca2+]i as well as mitigating degradation of the NaCh alpha-subunit. These results suggest a unique "feed-forward" deleterious process initiated by mechanical trauma of axons. Na+ influx through NaChs resulting from axonal deformation triggers initial increases in [Ca2+]i and subsequent proteolysis of the NaCh-subunit. In turn, degradation of the alpha-subunit promotes persistent elevations in [Ca2+]i, fueling additional pathologic changes. These observations may have important implications for developing therapeutic strategies for axonal trauma.

Modification of the cortical impact model to produce axonal injury in the rat cerebral cortex.

Diffuse axonal injury (DAI) is a form of brain injury that is characterized by morphologic changes to axons throughout the brain and brainstem. Previous biomechanical studies have shown that primary axonal dysfunction, ranging from minor electrophysiologic disturbances to immediate axotomy, can be related to the rate and level of axonal deformation. Some existing rodent head injury models display varying degrees of axonal injury in the forebrain and brainstem, but the extent of axonal damage in the forebrain has been limited to the contused hemisphere. This study examined whether opening the dura mater over the contralateral hemisphere could direct mechanical deformation across the sagittal midline and produce levels of strain sufficient to cause a more widespread, bilateral forebrain axonal injury following cortical impact. Intracranial deformation patterns produced by this modified cortical impact technique were examined using surrogate skull-brain models. Modeling results revealed that the presence of a contralateral craniotomy significantly reduced surrogate tissue herniation through the foramen magnum, allowed surrogate tissue movement across the sagittal midline, and resulted in an appreciable increase in the shear strain in the contralateral cortex during the impact. To evaluate the injury pattern produced using this novel technique, rat brains were subjected to rigid indentor impact injury of their left somatosensory motor cortex (1.5 mm indentation, 4.5-4.9 m/sec velocity, and 22 msec dwell time) and examined after a 2-7 day survival period. Neurofilament immunohistochemistry revealed numerous axonal retraction balls in the subcortical white matter and overlying deep cortical layers in the right hemisphere beneath the contralateral craniotomy. Retraction balls were not seen at these positions in normals, sham controls, or animals that received cortical impact without contralateral craniotomy and dural opening. The results from these physical modeling and animal experiments indicate that opening of the contralateral dura mater permits translation of sufficient mechanical deformation across the midline to produce a more widespread pattern of axonal injury in the forebrain, a pattern that is distinct from those produced by existing fluid percussion and cortical impact techniques.