Types of traumatic brain injury
TBI remains a major cause of disability among individuals under 40 years of age, contributing to 30.5% of all injury-related deaths in the USA alone (Langlois et al.).  Of the 1.7 million people sustaining TBI in the USA alone, 275,000 required hospitalization with 52,000 resulting in death (Faul et al.).  Because of the heterogeneous nature of causes leading to head injuries, TBIs have been generally classified into two broad categories. The first encompasses open-head brain injuries that are accompanied by skull fractures and disruption of the meninges. In this case, physical damage directly to the brain from a contusion (bruising) or laceration (tearing) together with varying degrees of hemorrhaging outside and inside the brain may occur. A second major category includes closed-head brain injuries without penetration of the skull or meninges. In this second category, bleeding is less severe and may be restricted to the meningeal layers and the perivascular spaces of the parenchyma. TBIs from this latter category are the most common, as they have a wide range of causes, from head bumps, concussions, shaking, to acceleration/impact injuries such as those resulting from falls in the elderly population or those incurred during sports or car accidents. The diversity of TBI causes and their ensuing heterogeneous injuries led to the development of the Glasgow Coma Scale in 1974 (Teasdale and Jennet),  which allowed accurate reading of the conscious state of the patient. More recently, the Neurological Outcome Scale for Traumatic Brain Injury (NOS-TBI) is thought to provide a more accurate assessment for the treatment and rehabilitation of TBI patients (Wilde et al.; McCauley et al.). ,, Because of the extensive TBI research literature accumulated in the last two decades, this review first summarizes information on the most common types of injury and then focuses on events related to the second category of injuries (i.e., closed-head injuries).
Because of the TBI diversity mentioned above, finding a suitable TBI experimental animal model to replicate some of the neurological issues encountered in the clinics has been problematic. Generally, three TBI models have been widely used and considered as validated:
- Lateral fluid percussion,
- Controlled cortical impact, and
- Impact acceleration model. In the lateral percussion model, after trepanation of the skull, a pressurized pulse of saline solution is delivered against the surface of the dura mater (McIntosh et al. Morales et al.). ,
While data from this model are applicable only to certain open-skull (i.e., penetrating) injuries, it would not be useful to study effects from the more commonly occurring closed head injuries seen in the clinics. In the controlled cortical impact model (Dixon et al.),  a force-controlled piston impacts directly the surface of the brain, which also makes the model an open-head injury type. Apart from having the limitations of the first model, injury sites with this model usually exhibit substantial tissue necrosis and extravasation of blood (i.e. hemorrhages), which are much less severe in closed-head models. Finally, the impact acceleration model (Foda and Marmarou, Marmarou et al.) , derived from an earlier weight drop model, uses a known weight dropped onto the surface of the skull from selected heights. The utilization of a steel “helmet” and underbody foam pad ensures integrity of the skull and consistency in the delivery of impact, thus mirroring the acceleration-deceleration phenomena associated with closed-head injuries as seen in many TBI patients (Foda and Marmarou, Rafols et al.). , In addition, this model reliably yields both robust diffuse axonal injury (DAI) and alterations in the brain microcirculation, both of these pathologies commonly seen in patients who have sustained closed-head injuries (Rafols et al.). 
Pathologies and Related Pathophysiologies in Traumatic Brain Injury
Regardless of whether a TBI is of the closed-head or open-skull variety, all TBIs lead to three major pathologies:
- Structural damage to neurons, neuronprocesses (e.g., dendrites, axon), glial cells, and cellular components of blood vessels,
- Inflammation and metabolic alteration such as edema, and
- Sustained vasospasm and loss of the local autoregulation of the microcirculation.
The sustained vasospasm and diminished flow of blood through the microcirculation brings about a state of hypoperfusion of the brain parenchyma that can last from hours to days after the traumatic event (Bouma and Muizelaar, Morales et al., Coles et al., Inoue et al., Oertel et al.). ,,,, Under prolonged hypoxia, brain cells and synaptic circuits are compromised, which may impact on lasting behavioral deficits and neurological outcome. Other pathologies such as petechial (e.g., perivascular) bleeding and formation of microthrombi or capillary plugs have been observed in several trauma models. An important distinction related to the development of the injury would be whether these pathologies develop immediately after initial trauma or over time, which results in the recognition of the “primary injuries” and “secondary injuries.” Thus, a “primary injury” is the result of mechanical force applied to the brain tissue, which acutely produces direct injury to neurons, neuronal processes, glia cells, and blood vessels. However, while such injury usually brings about the pathologies mentioned above, some of their associated pathophysiologies and deleterious effects may not develop immediately but over the course of time, which may lead to accruement of primary tissue damage, thus resulting in the “secondary injury.” As the time window between primary and secondary injuries can be in the order of weeks to months (and sometimes years), much research today is designed to develop therapeutic interventions to prevent the development of secondary injuries. An example of primary and secondary injuries may relate to events associated with a focal contusion to the brain. Thus, at the side of impact, the primary injury would primarily consist of an area that would include rapidly dying nerve cells, glia cells, and vascular cells, together with varying degrees of hemorrhaging, the extent of this injury being proportional to the severity of the impact. However, in the course of time, a secondary injury affecting areas close or distant to the primary one would ensue, in this case its extent determined by the severity of the primary injury.
Documented morphologic alterations to neurons, their processes, and to blood vessels include changes in the normal ultrastructure of the nerve cell body, dendrites, and the axon (Marmarou et al.; Rafols et al.; Kallakuri et al.). ,, Morphological alteration of the cytoskeleton in the dendrites and axon with accompanying loss of shape and orientation of the processes has been widely observed. The most prominent in concussive, closed-head type injuries is the occurrence of diffuse axonal injury (DAI). As early as 1956, diffuse degeneration in white matter bundles that lead to permanent incapacitation was found in human patients with closed-head injuries (Strich).  Subsequent TBI studies demonstrated a correlation of injury severity with white matter integrity (Arfanakis et al.; Gupta et al.; Inglese et al.; Benson et al.; Rafols et al.; Wang et al.; Marquez de la Plata et al.). ,,,,,, The pathophysiology leading to DAI has been reviewed by Povlishock (2006). Briefly shearing forces transmitted through the brain after impact is thought to cause permeability changes and increased membrane poration of axons in the long tracts of white matter. Signal transduction then would lead to elevated intracellular calcium, activation of cysteine proteases such as calpain, degradation of neurofilaments, and ultimate fragmentation of the axon (Povlishock and Karz; Buki and Povlishock). , Another cause for DAI may be a secondary effect from the state of hypoperfusion immediately after TBI (see below). Thus, under insufficient oxygen delivery and increased anaerobic glycolysis, lactic acidosis accumulates, which alters membrane permeability due to the formation of reactive oxygen species (ROS) species and lipid peroxidation of membrane unsaturated fatty acids. As a consequence of these cellular and molecular events, the ensuing anterograde (i.e., Wallerian) axonal degeneration would lead to destruction of axon terminal branches, synaptic loss, and disruption of neural circuits underlying cognitive, sensory, and motor impairments afflicting many TBI patients.
A second major pathology after TBI is the formation of edema, an acute event, which has been classified into cytotoxic and vasogenic types (Marmarou et al.).  Thus, vasogenic edema after TBI may occur from either mechanical (e.g., disruption of tight junctions) or metabolic alterations [e.g., failure of adenosine triphosphate (ATP)-dependent osmotic pumps] of the BBB, which allows for the osmotic gradient transfer of fluids and solutes across the microvascular wall, that is, between blood plasma and the extracellular compartment around blood vessels (DeWitt and Prough; Unterberg et al.). , In contrast, cytotoxic edema affecting primarily the volume of cells is the accumulation of fluid passing from the extracellular to intracellular compartments of nerve cells and AS due to a failure in membrane permeability (Stifel et al.; Chen and Swanson; Unterberg et al.). ,, Brain swelling from edema and failure of reabsortion of fluids into the circulation are the main reasons for the sharply elevated ICP found after trauma. Cytotoxic edema and increased ICP develop within minutes following TBI and if unresolved, can lead to herniation, pressure coning on brainstem respiratory and cardiovascular centers, and cessation of breathing and cardiovascular function, which become critical morbidity issues in the acute care of TBI patients. Paradoxically provided that severe edema is resolved, it usually does not lead to significant cognitive impairment.
The third major pathology after TBI has been the least investigated to date and relates to alterations in CBF and the microcirculation that are initiated within minutes following onset of the traumatic event. Thus, within the last 30 years, experimental and clinical data demonstrated fluctuations in CBF and altered autoregulation of the microcirculation after TBI. Specifically in closed-head injuries as well as after direct impact of the brain, a state of sustained hypoperfusion independent of brain swelling has been observed to last from hours to days following impact (Abu-Judeh et al., Petrov and Rafols, Steiner et al., McBeth et al., Rafols et al.). ,,,, Although this theme is further elaborated in the next section, it is sufficient it to say that prolonged, insufficient perfusion and reduction of vital metabolites to the brain are thought to impact not only on the structural integrity of neurons, glial cells, and microvessels but also on the integrity of the BBB already damaged in the primary injury. Other morphological changes of cerebral microvessels in the form of constricted capillaries and PCs as well as diffuse formation of microthrombi have been documented in several models of TBI (Hekmatpanah and Hekmatpanah, Foda and Marmarou, Dore-Duffy et al., Rafols et al.) ,,, and may exacerbate the local hypoperfusion discussed above. Taken together, it is reasonable to envision the interrelatedness of these pathologies and how their associated pathophysiologies might contribute to the development of the secondary injury where the hope for therapeutic intervention lies.