ReviewExperimental models of traumatic axonal injury
Introduction
Traumatic brain injury (TBI), a devastating and common problem in today’s society, is one of the most frequent causes of morbidity and mortality in both industrialized and developing countries.1 Diffuse axonal injury (DAI), a common and important pathological feature of TBI, was first described by Strich in 1956 and named by Adams in 1982.[2], [3] The term is applied to the widespread destruction of white matter tracts by TBI, which makes a major contribution to neurological dysfunction in TBI patients.4 Although coined as “diffuse”, the pattern of axonal injury in the white matter is more accurately described as “multifocal”, and the term “traumatic axonal injury” (TAI) has been suggested as being more appropriate for this type of TBI.[5], [6] Recently, the descriptor TAI has been applied to experimental studies that have attempted to elucidate the mechanisms of axonal injury after TBI.
TAI in patients with head injury is usually associated with poor outcome and often results in burdensome health-care costs, and a more complete understanding of TAI is required in order to develop more effective treatments. In response to this need, a growing number of animal models have been introduced and characterized since the late 1980s. Technological breakthroughs, including new methodologies in radiological examination, improved neurochemical and molecular technologies, and transgenic animals, now allow researchers to pursue in-depth studies of TAI. The available animal models, however, are not without drawbacks. In particular, the complexity of the in vivo condition may result in a limited accessibility to the tissue of interest and prevent real-time and spatial measurements of biological or mechanical parameters.7 Several in vitro experimental approaches have been developed to complement the utility of in vivo models. Focusing principally on animal models, the following sections address the different models of TAI with a view to guiding and improving future research endeavors in this field.
Section snippets
Experimental models of traumatic axonal injury
The experimental models of TAI generally include in vivo models, in vitro models, physical models, and mathematical models (Table 1).[6], [7], [8], [9] Because physical and mathematical models are principally intended for biomechanical analysis of TAI, their purpose is distinct from that of in vivo and in vitro models; these are therefore not discussed in the present review. Multiple approaches and markers have been used in these diverse models to detect and characterize TAI. These commonly
The requirements of ideal experimental model
Diverse experimental models have been employed extensively to investigate the causes of TAI, to replicate the sequence of events taking place in patients, and to test the efficacy of new therapies. To maximize the reliability and validity of data obtained in these different models, experimental models should meet the following criteria:
- (i)
TAI is the predominant pathological change taking place post-injury; other types of injury not associated with TAI are avoided.
- (ii)
The injury mechanism resembles, as
Conclusions
Since the late 1980s many investigators have attempted to develop models that can accurately replicate different aspects of TAI. Data from studies using in vivo models, complemented by in vitro, physical, and mathematical models, have contributed to our growing understanding of TAI. In vivo models cast light on injury-loading conditions and permit the exploration of pathological, physiological, and behavioral changes taking place in TBI. They also permit the evaluation of new therapeutic and
References (90)
Diffuse axonal injury in non-missile head injury
Injury
(1982)Changing concepts of diffuse axonal injury
J Clin Neurosci
(1998)- et al.
Neurobehavioral functional deficits following closed head injury in the neonatal pig
Exp Neurol
(2007) Animal models of head trauma
NeuroRx
(2005)- et al.
Experimental models of traumatic brain injury: do we really need to build a better mousetrap?
Neuroscience
(2005) - et al.
Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats
Neuroscience
(1998) - et al.
Monitoring weight drop velocity and foam stiffness as an aid to quality control of a rodent model of impact acceleration neurotrauma
J Neurosci Methods
(1996) - et al.
Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury rats
Brain Res
(2006) - et al.
Changes of mGluR4 and the effects of its specific agonist L-AP4 in a rodent model of diffuse brain injury
J Clin Neurosci
(2003) - et al.
Metabotropic glutamate receptor antagonists and agonists: potential neuroprotectors in diffuse brain injury
J Clin Neurosci
(2006)
The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats
Neurobiol Dis
Technical aspects of an impact acceleration traumatic brain injury rat model with potential suitability for both microdialysis and PtiO2 monitoring
J Neurosci Methods
Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model
Neuroscience
Current concepts: diffuse axonal injury-associated traumatic train injury
Arch Phys Med Rehabil
Time course of cellular pathology after controlled cortical impact injury
Exp Neurol
Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons
Exp Neurol
Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury
Exp Neurol
Screening for differentially expressed genes in the rat inner retina and optic nerve after optic nerve crush
Neurosci Lett
Duration of neuronal stretch correlates with functional loss
Otolaryngol Head Neck Surg
Mechanically-induced membrane poration causes axonal beading and localized cytoskeletal damage
Exp Neurol
Mechanism responsible for the formation of focal swellings on injured neuronal processes using a novel in vitro model of axonal injury
Forensic Sci Int
An in vitro model of traumatic brain injury utilising two-dimensional stretch of organotypic hippocampal slice cultures
J Neurosci Methods
Traumatic brain injury: can the consequences be stopped?
CMAJ
Diffuse degeneration of the cerebral white matter in severe dementia following head injury
J Neurol Neurosurg Psychiatry
Axonal damage in traumatic brain injury
Neuroscientist
Traumatic axonal injury: practical issues for diagnosis in medicolegal cases
Neuropathol Appl Neurobiol
In vitro central nervous system models of mechanically induced trauma: a review
J Neurotrauma
Finite-element models of the human head
Med Biol Eng Comput
Biomechanical analysis of experimental diffuse axonal injury
J Neurotrauma
Serum biochemical markers for post-concussion syndrome in patients with mild traumatic brain injury
J Neurotrauma
Handbook of neurochemistry and molecular neurobiology: brain and spinal cord trauma
Diffuse axonal injury and traumatic coma in the primate
Ann Neurol
An analytical model of traumatic diffuse brain injury
J Biomech Eng
Diffuse axonal injury
J Neurosurg
Distribution of forebrain diffuse axonal injury following inertial closed head injury in miniature swine
Exp Neurol
Traumatic axonal injury after closed head injury in the neonatal pig
J Neurotrauma
Impact mechanics and axonal injury in a sheep model
J Neurotrauma
A new model for diffuse brain injury by rotational acceleration: I model, gross appearance, and astrocytosis
J Neurotrauma
Diffuse axonal injury due to lateral head rotation in a rat model
J Neurosurg
Calcium overloading in traumatic axonal injury by lateral head rotation: a morphological evidence in rat model
J Clin Neurosci
Large animal models of traumatic injury to the immature brain
Dev Neurosci
Possible axonal regrowth in late recovery from the minimally conscious state
J Clin Invest
Multifocal white matter ultrastructural abnormalities in mild traumatic brain injury with cognitive disability: a voxel-wise analysis of diffusion tensor imaging
J Neurotrauma
Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats
Acta Neuropathol
Workshop on animal models of traumatic brain injury
J Neurotrauma
Cited by (46)
Numerical study on the mechanical response of brain under the impact loading based on elastic-viscoelastic model
2016, Applied Mathematics and ComputationCitation Excerpt :It can help us understand the damage mechanism of brain injury, and reduce brain injury. There are the three ways to study the bio-mechanics of brain impact injury, such as experimental methods [7–9], theoretical models [10–13], and numerical simulations [14–16]. Biomechanists always construct a particular system, and get the physical and geometric properties.
A behavioral and histological comparison of fluid percussion injury and controlled cortical impact injury to the rat sensorimotor cortex
2015, Behavioural Brain ResearchCitation Excerpt :This leads to axonal swelling, rapid deformations and a loss of connectivity [10]. The FPI device delivers a fluid pulse to the intact dural surface, creating a diffuse load to the brain [11,12]. This model is beneficial in that different graded levels of injury can be administered, it can be used in several species of animals, and it leads to cavitation as well as axonal injury.
Torsional Behavior of Axonal Microtubule Bundles
2015, Biophysical JournalCitation Excerpt :Rotational acceleration of the brain is a major cause of TBI (1,21), and is suggested as the principal mechanical force responsible for DAI in animal models (22–24). Investigating the mechanical effect of torsion on neuronal axons due to this rotational acceleration would improve contemporary understanding of the underlying mechanism of DAI, which could enhance the effectiveness of future protective devices (25,26). It is believed that axonal swelling is initiated due to breaking of MTs, eventually leading to axonal degeneration (27).
Experimental models in traumatic brain injury: from animal models to in vitro assays
2019, Medicina IntensivaRole of integrin and its potential as a novel postmortem biomarker in traumatic axonal injury
2023, International Journal of Legal MedicineCerebral blood flow regulation is not acutely altered after a typical number of headers in women footballers
2022, Frontiers in Neurology