ReviewExperimental models of traumatic brain injury: Do we really need to build a better mousetrap?
Section snippets
Closed TBI
The characteristics of TBI are associated with complex processes including, but not limited to, static and dynamic loading (Graham et al., 2002). Static loading occurs when gradual forces are applied to the head, usually through a slow process. This mechanism of TBI is quite uncommon in the clinical setting, but may occur when the head is exposed to a heavy weight (such as the head being trapped underneath a car). The more common type of mechanical input causing TBI, dynamic loading, is
Model requirements
We have defined the term “model” as “a simplified representation of a phenomenon” (Merriam-Webster, 2005). Any experimental model designed to reliably and validly reproduce the clinical sequelae of TBI should fulfill a number of criteria. These include an ability to precisely vary the severity of injury and the response must be quantifiable and reproducible between different investigators and laboratories (Teasdale et al 1999, Graham et al 2000a) and replicate the type(s) of severity and injury
Modeling human focal injuries
Focal abnormalities observed after human TBI are characterized by surface contusions (pia remains intact) and lacerations (pia is torn), which may or may not be accompanied by skull fracture or hematoma formation (Gennarelli 1993, Gennarelli 1994). This type of damage usually occurs in the direct vicinity of the mechanical impact to the head and involves the underlying cortical and, in the case of injury of higher severity, subcortical structures, leading to multi-focal injuries (Laurer et al.,
Modeling human diffuse injury
Diffuse injuries are believed to occur from the tissue distortion, or shear, caused by inertial forces present at the moment of injury (Gennarelli 1993, Pettus et al 1994, Maxwell et al 1997). These are most commonly separated into four main pathologies: traumatic axonal injury (TAI) diffuse hypoxic brain damage, diffuse brain swelling due to an increase in the cerebral blood volume or the water content of the brain tissue, and diffuse vascular injury, which seems to be the worst of the four,
Behavioral assessments
Both focal and diffuse axonal injury (DAI) have been shown to cause motor and/or cognitive deficits. To follow and describe injury-induced responses in the experimental setting, a variety of tests have been developed to determine both the reversible and persistent posttraumatic sequelae after experimental TBI in the laboratory. In order to reveal the pattern of acute and chronic neurological dysfunction after TBI, it has been crucial for experimental laboratories to implement behavioral
The weight drop model of TBI (Feeney, Shohami)
This pioneering model, considered by most to be the original TBI model, uses the gravitational forces of a free falling, guided weight to produce a focal brain injury (Fig. 1A) (Feeney et al 1981, Dail et al 1981). Most investigations using this model have been performed with head restraint before delivering the impact, in order to ensure reproducibility among different laboratories. The anesthetized rat (Feeney et al., 1981) or mouse (Chen et al., 1996), is attached to the impactor or bottom
The impact acceleration model (Marmarou)
To reproduce the TAI often associated with severe clinical TBI, a model of impact-acceleration was developed which uses a stainless steel protection plate to avoid skull fracture when animals are exposed to weight drop brain injury of high severity (Marmarou et al 1994, Sawauchi et al 2003, Sawauchi et al 2004). This plate is glued to the vertex of the skull after opening the scalp and distributes the loading widely over the skull, therefore minimizing the chance of fracture. To perform the
Lateral FP injury (McIntosh, Dietrich, Grady, Hovda)
In 1989, the midline FP brain injury model was modified by moving the craniotomy placement to attempt to generate a coup-contrecoup injury in a small animal model (Fig. 1D) (McIntosh, unpublished observations). Although this outcome was not realized, lateral FP brain injury remains one of the most commonly used and well-characterized experimental models of TBI, producing both focal and diffuse injury characteristics (Cortez et al 1989, Yaghmai and Povlishock 1992, Hicks et al 1996, Graham et al
Models of combined primary and secondary features (Statler, Kochanek)
Secondary episodes markedly exacerbate the primary, initial injury. Important factors include number, duration, and magnitude of secondary insults experienced as well as their temporal course, all of which play crucial roles in increasing TBI-induced damage and may exacerbate behavioral impairment.
Clinical TBI is frequently complicated by hypotensive and/or hypoxic episodes, which have been known to occur both acutely and even over prolonged intervals in severely head-injured patients (Marshall
Experimental modeling of coma
Posttraumatic coma, which has been linked to TAI, is commonly observed in severe clinical TBI and is an important factor affecting patient morbidity and mortality (Gennarelli, 1983; Chestnut et al., 2000). Most clinicians define coma as a state in which a patient is incapable of following commands, does not speak and does not open his/her eyes in response to the presentation of painful stimuli. The inability to interact cognitively with the environment is a critical part of the definition of
Models of repetitive, concussive brain injury (Laurer, Longhi)
Of the more than 1,000,000 people who sustain a TBI in the USA every year, a significant portion are sports related (1999) with an annual estimated incidence of 300,000 cases (Kelly and Rosenberg 1997, Sosin et al 1999). Concussion can be defined as a trauma-induced alteration in mental status that may or may not involve loss of consciousness (American Academy of Neurology, 1997). Further investigations into these numbers have shown that athletes with a single concussion appear more susceptible
Challenges of experimental models: do we need to build a better mousetrap?
In our opinion, no. One ultimate goal of experimental neurotrauma research is to enhance our knowledge of human TBI, with the potential for the development of alternate treatment strategies and novel pharmacological compounds. The current standard of care for TBI patients consists of the management of mass lesions followed by supportive and predominantly palliative measures. To date, all large, multicenter phase III clinical trials evaluating pharmaceutical compounds or efficacy of hypothermia
Conclusion
There have been a large number of clinical and experimental studies completed in the past 20 years in an attempt to improve outcome for TBI patients. Although this research has not led to a complete cure for TBI, the insight gained into its pathophysiology has been greatly increased. However, no single model has been entirely successful in producing the spectrum of changes observed after clinical TBI, so should we continue the search for a new and better model? We believe the answer is no.
References (272)
- et al.
Staining of amyloid precursor protein to study axonal damage in mild head injury
Lancet
(1994) - et al.
The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats
Neurobiol Dis
(2004) - et al.
Time course of cellular pathology after controlled cortical impact injury
Exp Neurol
(2003) - et al.
Experimental fluid percussion brain injuryVascular disruption and neuronal and glial alterations
Brain Res
(1989) - et al.
Responses to cortical injury. I. Methodology and local effects of contusions in the rat
Brain Res
(1981) - et al.
Motor and cognitive function evaluation following experimental traumatic brain injury
Neurosci Biobehav Rev
(2004) - et al.
Ischaemic brain damage in fatal non-missle head injuries
J Neurol Sci
(1978) - et al.
Cumulative effect of concussion
Lancet
(1975) - et al.
Magnesium sulphate improves neurologic outcome following severe closed head injury in rats
Neurosci Lett
(1997) The management of concussion in sports
Neurology
(1997)