Pathophysiology of Traumatic Brain Injury
Primary traumatic brain injury insult triggers complex cellular and molecular processes leading to further neuronal dysfunction and death. The variety of processes involved contributes to the traumatic brain injury complexity but also create versatile therapeutic targets.  Multiple factors contribute to those pathophysiological mechanisms of secondary injury and their contribution to the severity of the secondary injury might vary.
Pathophysiology of Secondary Cerebral Damage after Traumatic Brain Injury
Three main areas of treatment: optimizing cerebral blood flow, the delivery of oxygen and the adequate supply of energy substrates. Bouzat at al. 2013
General pathophysiological features of TBI and mechanism following primary onset might include:
- Diffuse axonal injury
- Degradation of the cytoskeleton
- Cortical and subcortical neuronal injury/death
- Vascular-related changes (barrier breakdown, vasospasm, oedema)
- Glutamate Excitotoxicity
- Changes in Neurotransmitters
- Physiological Disturbances
- Free Radical Generation
- Disruption of Calcium Homeostasis
- Mitochondrial Disturbances
- Metabolic Disturbances
- Altered Brain Metabolism
- Altered Gene Expression
- Proinflammatory State
Those pathophysiological events impairing cell function impact movements, memory and learning ability as well as might cause damage to white matter structure.
The normal brain vascular autoregulation includes pressure and volume mechanism allowing continuous cerebral blood flow (CBF) and optimal oxygen supply. The main mechanism involved in maintaining consistent cerebral pressure in response to changing systemic arterial pressure are vasoconstriction and vasodilatation of brain vessels. Traumatic brain injury impairs or even abolish cerebrovascular autoregulation immediately after the trauma or over time. Multiple factors can initiate the vasodilation or vasoconstriction cascades, including; 
- systemic arterial pressure
- systemic blood volume
- blood viscosity
- oxygen level delivery
- hypo / hypercapnia
- pharmacologic agents 
The autoregulatory vasoconstriction is more averse than autoregulatory vasodilation and heads to greater brain tissue sensitivity to decreased cerebral perfusion pressure.
Vasodilation and vasoconstriction cascade in the cerebral blood volume and intracranial pressure regulation.  Following initial insult ischemia like stage of traumatic brain injury cascade of processes characterised by direct brain tissue damage and cerebral blood flow (CBF) regulation impairment as well as metabolism impairment are triggered. The cascade might result in oedema formation, increase of intracranial pressure (ICP), and decreased cerebral perfusion pressure (CPP).
Cerebral Perfusion Pressure
Cerebral perfusion pressure is a difference between systemic arterial pressure and intracranial pressure and in normal physiological status ranges approximately between 50 and 70 mmHg.
The following clinical mechanisms contribute to the dysregulation of normal mechanisms maintaining volume and pressure:
- depolarization and disturbance of ionic homeostasis
- neurotransmitter release (e.g., glutamate excitotoxicity)
- mitochondrial dysfunction
- neuronal apoptosis
- lipid degradation
- initiation of inflammatory and immune responses
The cerebral blood flow disruption can be also caused by mechanical displacement of brain structures, stretching and distorting brain vessels, arterial hypotension, vasospasm, changes in cerebral microvasculature.
Both hypoperfusion and hyperperfusion validation is related to relation between cerebral blood flow and cerebral metabolism and oxygen consumption. Therefore, decreased CBF with normal metabolic rate creates ischemic conditions.
Cerebral ischemia is a state of decreased blood supply of the brain (hypoperfusion) and leads primarily to metabolic stress and ionic perturbations.  Coexisting traumatic damage like structural injury of cell bodies, astrocytes and microglia, cerebral vascular and endothelial damage intensify the brain tissue damage. The factors involved in post-traumatic vasospasm and contributing to resultant ischemia include:
- Morphological damage due to mechanical displacement, i.e.: vessel distortion
- Depletion of nitric oxide and or cholinergic neurotransmitters
- Vascular smooth muscle depolarisation related to potassium channel reduced activity
- Potentiation of prostaglandin induced vasoconstriction
- Free radicals formation
TBI leads to focal or global cerebral ischemia frequently and its presence points towards poor clinical outcome like persistent vegetative state or death.
Mechanism responsible for oedema formation and intracranial pressure increase is hyperaemia. Due to reduced proximal cerebrovascular resistance and increased cerebral blood volume and vessel dilatation the impaired brain blood barrier cause excess of fluids to reside in vascular bed. This pathology is equally detrimental to brain tissue as ischemia causing increase in intracranial pressure. Oedema is a common result of TBI and can be vasogenic or cytotoxic and can cause ICP increase and secondary ischemia.
- Vasogenic brain oedema is caused by endothelial cells damage. The ion and protein flow through vascular wall to interstitial space causing increased volume in extracellular space.
- Cytotoxic oedema results from intracellular water accumulation related to increased cells membrane permeability.
Cerebral Metabolic Dysfunction
Cerebral metabolic disfunction relates to oxygen and glucose depletion as well as reduced cerebral energy state at the period of posttraumatic hypermetabolic demand. Hypermetabolism is pathophysiological phenomenon following TBI and occurs as a result of transmembrane ionic influx leading to overexcitation and uncoupling with cerebral blood flow. The extend of primary injury is reflected by the extend of pathophysiological processes like mitochondrial disfunction related to decreased respiratory rates and ATP production, depletion of nicotinic co-enzyme pool, intramitochondrial accumulation of calcium ions leading to metabolic failure.  The overload of excitatory amino acid neurotransmitters results with overstimulation of ionotropic and metabotropic glutamate receptors with consecutive calcium, sodium and potassium ions flow triggering brain blood barrier breakdown and cellular compensatory ATPase activity increase resulting in aggravated metabolic demand. The cascade of those mismatched processes of overflow and metabolism creates excitotoxicity. TBI metabolic failure is also related to imbalance between oxygen supply and oxygen consumption and leads to hypoxia. The extend of the hypoxia and its duration determines the clinical outcome. Therefore, the measuring the brain oxygenation is one of the standard measurements along with ICP and CPP. The oxidative stress related to imbalance of free radicals and endogenous antioxidants availability can lead to immediate cell death or inflammatory processes or apoptosis.
Damage to blood vessel endothelium following TBI triggers neuroinflammation process with release of cytokines, free radicals, prostaglandins and complements mobilising active response from immune system to eliminate the damaged cells and format the scar tissue. Proinflammatory enzymes like interleukin-1, interleukin -6 intensify the activity within the first hours from initial insult. The leucocytosis increasing cell debris and phagocytosis response might enhance further inflammatory response and tissue destruction affecting undamaged tissue extending the injury and decomposing dead tissue.
Cell death and axonal injuries contribute to the extent of the TBI. Main death processes are known as necrosis and apoptosis. Apoptotic and necrotic neurons are present even in mild injuries and can be found in areas distant from the injury impact area. Degenerating oligodendrocytes and astrocytes are present in the white matter of primary injury area Categories of biochemical, cellular, and molecular mechanisms proposed to be involved in the evolution of secondary damage after ischemic or traumatic brain injury. Three major categories of secondary mechanisms include
- Ischemia, excitotoxicity, energy failure, and cell death cascades;
- Cerebral swelling; and
- Axonal Injury.
A fourth category, inflammation and regeneration, influences each of these cascades.
Necrosis (cell death) occurs after first few hours following an insult to brain tissue, mechanical or hypoxic, and is related to cell membrane damage and uncontrolled release of cell death products. The blood brain barrier become impaired and white matter injury usually increases. The resulting detritus is interpret as ‘antigen’ and triggers inflammatory process and scaring.
Apoptosis is naturally programmed cell death and affects undamaged neurons. The imbalance of pro and anti-apoptotic proteins triggers the death cell mechanism hours post primary insult. Apoptosis is triggered by cell surface receptors engagement, growth factor withdrawal and DNA damage.
Several groups of proteins and biochemical transitional pathways are involved in cell death mechanisms and their tracking might create new therapeutic opportunities limiting neurodegeneration and resulting disabilities especially with apoptosis providing the window of opportunity for therapy due to delayed nature.
Morphologically, axons with their long structure are at significant mechanical risk during the impact of external forces. Sheering or stretching of axons results in primary axotomy or when damage incomplete they trigger secondary axon degeneration. There are some localities of the brain with greater vulnerability with the junction of grey and white matter being the on of them. Myelination might provide some protective features and enhance recovery. The pathophysiological mechanisms involved in axonal damage also include swelling of intact axons and “retraction bulbs”. 
Cytoskeletal organization in growth cones versus retraction bulbs.  Blanquie & Bradke 2018
Axonal damage due to deafferentation interrupts established pathways and can cause focal and diffused injury immediately after or even after several years from the primary insult. Extend of deafferentation in mild to severe injuries and axonal damage impact ability of synaptic sprouting of undamaged axons. The more sever injury with extensive secondary damage the less possible axonal reconnection and function recovery.
Diffuse Axonal Injury (DAI)The primary insult of axonal injury leads to disconnection and/or neurons connections malfunction resulting in functional areas impairment. Mechanically disrupted axons present cytoskeletons malfunction resulting in proteolysis, swelling, and other microscopic and molecular changes to the neuronal structure.
Neurological presentation of DAI includes bilateral neurological examination deficits frequently affecting the frontal and temporal white matter, corpus callosum, and brainstem.
The Adams Diffuse Axonal Injury Classification:
A mild diffuse axonal injury with microscopic white matter changes in the cerebral cortex, corpus callosum, and brainstem
A moderate diffuse axonal injury with gross focal lesions in the corpus callosum
A severe diffuse axonal injury with finding as Grade 2 and additional focal lesions in the brainstem.
The DAI is severe form of brain injury and is usually diagnosed after a traumatic brain injury with GCS < 8 for more than six consecutive hours. DAI features in computed tomography (CT) present as small punctate haemorrhages to white matter. However, CT head has a low yield in detecting DAIs and magnetic resonance imaging (MRI), specifically Diffuse Tensor Imaging (DTI), is the imaging modality of choice for diagnosis of diffuse axonal injury.
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