Diffuse axonal injury (DAI) is one of the most common and devastating types of brain injury (Iwata et al., 2004), occurring in almost half of all cases of severe head trauma (Park and Hyun, 2004). It is a type of diffuse brain injury, meaning that damage occurs over a more widespread area than in focal brain injury. DAI, which refers to extensive lesions in white matter tracts, is one of the major causes of unconsciousness and persistent vegetative state after head trauma (Wasserman, 2004). Brain damage or brain injury is the destruction or degeneration of brain cells. ... Head injury is a trauma to the head, that may or may not include injury to the brain (see also brain injury). ... White matter is one of the two main solid components of the central nervous system. ... A persistent vegetative state (or PVS) is a condition of patients with severe brain damage in whom coma has progressed to a state of wakefulness without awareness. The term was introduced by two doctors in 1972 to describe a syndrome that seemed to have been made possible by medicines...

Though diffuse axonal injury seldom leads to death, the outcome is frequently coma with over 90% of patients with severe DAI never regaining consciousness (Wasserman, 2004). Those who do wake up often remain significantly impaired (Vinas and Pilistis, 2004). This article or section does not adequately cite its references or sources. ... In medicine, a coma (from the Greek koma, meaning deep sleep) is a profound state of unconsciousness. ...

Mechanism

Unlike brain trauma that occurs due to direct impact and deformation of the brain, DAI is the result of traumatic shearing forces that occur when the head is rapidly accelerated or decelerated, as may occur in auto accidents, falls, and assaults (reviewed in Wolf et al., 2001). It usually results from twisting or rotational forces (angular momentum), rather than forward and back impacts linear momentum (Sanders and McKenna, 2001; Wasserman, 2004; Shepherd, 2004). Car accidents are the most frequent causes of DAI, with sports accidents and child abuse also common causes (Smith and Greenwald, 2003). Traumatic brain injury (TBI), traumatic injuries to the brain, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. ... In animals the brain, or encephalon (Greek for in the head), is the control center of the central nervous system, responsible for thought. ... In medicine, a trauma patient has suffered serious and life-threatening physical injury resulting in secondary complications such as shock, respiratory failure and death. ... This gyroscope remains upright while spinning due to its angular momentum. ... In physics, momentum is a physical quantity related to the velocity and mass of an object. ...

The major cause of damage in DAI is the tearing of axons, the neural processes that allow one neuron to communicate with another. Tracts of axons, which appear white due to myelination, are referred to as white matter. Acceleration causes shearing injury, which refers to damage inflicted as tissue slides over other tissue. When the brain is accelerated, parts of differing densities and distances from the axis of rotation slide over one another, stretching axons that traverse junctions between areas of different density, especially gray-white matter junctions (Wasserman, 2004). Two thirds of DAI lesions occur in areas where grey and white matter meet (Wasserman, 2004). An axon, or nerve fiber, is a long slender projection of a nerve cell, or neuron, which conducts electrical impulses away from the neurons cell body or soma. ... Drawing by Santiago Ramón y Cajal of neurons in the pigeon cerebellum. ... Myelin is an electrically insulating phospholipid layer that surrounds the axons of many neurons. ... White matter is one of the two main solid components of the central nervous system. ... Grey matter is a major component of the central nervous system, consisting of nerve cell bodies and short nerve cell extensions/processes (axons and dendrites). ...

Characteristics

Patients typically have several focal white matter lesions of variable size (1-15 mm) in a characteristic distribution. Areas most vulnerable to injury are the frontal and temporal lobes (Boone and de Montfort, 2002). Other common locations for DAI include the white matter in the cerebral cortex, the corpus callosum, the superior cerebral peduncles, basal ganglia, thalamus, and deep hemispheric nuclei (Smith and Greenwald, 2003; Stock and Singer, 2004). These areas may be more easily damaged because the difference in density between them and the rest of the brain (Stock and Singer, 2004). Location of the cerebral cortex Slice of the cerebral cortex, ca. ... The corpus callosum is a structure of the mammalian brain in the longitudal fissure that connects the left and right cerebral hemispheres. ... The cerebral peduncle, by most classifications, is everything in the mesencephalon except the tectum. ... The basal ganglia are a group of nuclei in the brain interconnected with the cerebral cortex, thalamus and brainstem. ... To meet Wikipedias quality standards, this article or section may require cleanup. ...

Histological characteristics

DAI is characterized by axonal separation, in which the axon is torn at the site of stretch and the part distal to the tear degrades. While it was once thought that the main cause of axonal separation was tearing due to mechanical forces during the trauma, it is now understood that secondary biochemical cascades, which occur in response to the primary injury and take place hours to days after the initial injury, are largely responsible for the damage to axons (Wolf et al., 2001; Arundine et al., 2004). In zootomy, several terms are used to describe the location of organs and other structures in the body of bilateral animals. ... A Biochemical Cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. ...

Though the processes involved in secondary brain injury are still poorly understood, it is now accepted that stretching of axons during injury causes physical disruption to and proteolytic degradation of the cytoskeleton (Iwata et al., 2004). It also opens sodium channels in the axolemma, which causes voltage-gated calcium channels to open and Ca²⁺ to flow into the cell (Iwata et al., 2004). The intracellular presence of Ca²⁺ unleashes several different pathways, including activating phospholipases and proteolytic enzymes, damaging mitochondria and the cytoskeleton, and activating secondary messengers, which can lead to separation of the axon and death of the cell (Wolf et al., 2001). Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion. ... The eukaryotic cytoskeleton. ... Sodium channels are integral membrane proteins that exist in a cells plasma membrane and regulate the flow of sodium (Na+) ions into it. ... The axolemma is the membrane of a neurons axon. ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... Neuraminidase ribbon diagram An enzyme (in Greek en = in and zyme = blend) is a protein, or protein complex, that catalyzes a chemical reaction and also controls the 3D orientation of the catalyzed substrates. ... In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... A Second messenger system is a method of cellular signaling where the signalling molecule does not enter the cell, but rather utilizes a cascade of events that transduces the signal into a cellular change. ...

Cytoskeleton disruption

Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal cytoskeleton can be broken. It is thought that integrins connected to the extracellular matrix outside the cell and to the cytoskeleton within it can transmit forces from the matrix to the cytoskeleton and cause the latter to tear when the axon is stretched (Ochs et al., 1996). An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. ... In biology, extracellular matrix (ECM) is any material part of a tissue that is not part of any cell. ... The eukaryotic cytoskeleton. ...

Misalignment of cytoskeletal elements after stretch injury can lead to tearing of the axon and death of the neuron. Axonal transport continues up to the point of the break in the cytoskeleton, but no further, leading to a buildup of transport products and local swelling at that point (Oztas, 2003). When it becomes large enough, swelling can tear the axon at the site of the break in the cytoskeleton, causing it to draw back toward the cell body and form a bulb (Smith and Meaney, 2000). This bulb is called a retraction ball, the hallmark of diffuse axonal injury (Wasserman, 2004). Dynein, a motor protein responsible for retrograde axonal transport, carries vesicles and other cellular products toward the cell bodies of neurons. ...

When the axon is transected, Wallerian degeneration, in which the part of the axon distal to the break degrades, takes place within one to two days after injury (Lopachin and Lehning, 1997). The axolemma disintegrates (Lopachin and Lehning, 1997), myelin breaks down and begins to detach from cells in an anterograde direction (Cowie and Stanton, 2005), and nearby cells begin phagocytic activity, engulfing debris (Hughes et al., 2002). Wallerian degeneration is a form of degeneration occurring in nerve fibers as a result of their division; - so called from Dr. Waller, who published an account of it in 1850. ...

Calcium influx

While sometimes only the cytoskeleton is disturbed, frequently disruption of the axolemma occurs as well, causing the influx of Ca²⁺ into the cell and unleashing a variety of degrading processes (Povlishock and Pettus, 1996; Lopachin and Lehning, 1997). An increase in Ca²⁺ and Na⁺ levels and a drop in K⁺ levels is found within the axon directly after injury (Lopachin and Lehning, 1997; Wolf et al., 2001). Possible routes of Ca²⁺ entry include sodium channels, pores torn in the membrane during stretch, and failure of ATP-dependent transporters due to mechanical blockage or lack of energy (Wolf et al., 2001). High levels of intracellular Ca²⁺, the major cause of post-injury cell damage (Zhou et al., 2001), destroy mitochondria (Smith and Meaney, 2000), contribute to the generation of reactive oxygen species (Arundine et al., 2004) and trigger phospholipases and proteolytic enzymes that damage Na+ channels and degrade or alter the cytoskeleton and the axoplasm (Lopachin and Lehning, 1997; Castillo and Babson, 1998). Excess Ca²⁺ can also lead to damage to the blood brain barrier and swelling of the brain (Zhou et al., 2001). The axolemma is the membrane of a neurons axon. ... General Name, Symbol, Number calcium, Ca, 20 Chemical series alkaline earth metals Group, Period, Block 2, 4, s Appearance silvery white Standard atomic weight 40. ... General Name, Symbol, Number sodium, Na, 11 Chemical series alkali metals Group, Period, Block 1, 3, s Appearance silvery white Standard atomic weight 22. ... General Name, Symbol, Number potassium, K, 19 Chemical series alkali metals Group, Period, Block 1, 4, s Appearance silvery white Standard atomic weight 39. ... Sodium channels (also known as voltage-gated sodium channels) are integral membrane proteins that are localized in and conduct sodium ions (Na+) through a cells plasma membrane. ... Reactive oxygen species (ROS) include oxygen ions, free radicals and peroxides both inorganic and organic. ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Axoplasm is the cytoplasm of the axon of a neuron. ... The blood-brain barrier is a physical barrier between the blood vessels in the central nervous system, and the central nervous system itself. ...

One of the proteins activated by the presence of calcium in the cell is calpain, a Ca²⁺-dependent non-lysosomal protease (Castillo and Babson, 1998). About 15 minutes to half an hour after the onset of injury, a process called calpain-mediated spectrin proteolysis, or CMSP, begins to occur (Büki et al., 2000). Calpain breaks down a molecule called spectrin, which holds the membrane onto the cytoskeleton, causing the formation of blebs and the breakdown of the cytoskeleton and the membrane, and ultimately the death of the cell (Castillo and Babson, 1998; Büki et al., 2000). Other molecules that can be degraded by calpains are microtubule subunits, microtubule-associated proteins, and neurofilaments (Castillo and Babson, 1998). A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Calpain is calcium-dependent, non-lysosomal proteolytic enzyme found in the brain (Castillo and Babson, 1998). ... Organelles. ... Proteases (proteinases, peptidases, or proteolytic enzymes) are enzymes that break peptide bonds between amino acids of proteins. ... Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure (Huh et al. ... A bleb is a large blister filled with serous fluid. ... Microtubules are one of the components of the cytoskeleton. ... In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. ... Intermediate filaments are one component of the cytoskeleton - important structural components of living cells. ...

Generally occurring one to six hours into the process of post-stretch injury, the presence of calcium in the cell initiates the caspase cascade, a process in cell injury that usually leads to apoptosis, or "cell suicide" (Büki et al., 2000). Caspases are a group of cysteine proteases, enzymes with a crucial cysteine residue that can cleave other proteins after an aspartic acid residue, a specificity which is unusual among proteases. ... A cell undergoing apoptosis. ...

Mitochondria, dendrites, and parts of the cytoskeleton damaged in the injury have a limited ability to heal and regenerate, a process which occurs over 2 or more weeks (Corbo and Tripathi, 2004; Wasserman, 2004). After the injury, astrocytes can shrink, causing parts of the brain to atrophy (Wasserman, 2004). In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... Dendrites (from Greek dendron, “tree”) are the branched projections of a neuron that act to conduct the electrical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project. ... The eukaryotic cytoskeleton. ... Astrocytes, also known as astroglia, are characteristic star-shaped glial cells in the brain. ...

Diagnosis and treatment

DAI is difficult to detect since it does not show up well on CT scans or with other macroscopic imaging techniques, though it shows up microscopically (Wasserman, 2004). Axonal damage in DAI is largely a result of secondary biochemical cascades, and has a delayed onset, so a person with DAI who initially appears well may deteriorate later. Thus injury is frequently more severe than is realized, and medical professionals must suspect DAI in any patients whose CT scans appear normal but who have symptoms like unconsciousness (Wasserman, 2004). CAT apparatus in a hospital Computed axial tomography (CAT), computer-assisted tomography, computed tomography, CT, or body section roentgenography is the process of using digital processing to generate a three-dimensional image of the internals of an object from a large series of two-dimensional X-ray images taken around... A Biochemical Cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. ...

MRI is more sensitive: 30% of head injured patients with normal head CT scans have signs of DAI on MRI (Corbo and Tripathi, 2004). But MRI may also miss DAI, because it identifies the injury using signs of edema, which may not be present (Corbo and Tripathi, 2004). The mri are a fictional alien species in the Faded Sun Trilogy of C.J. Cherryh. ... Edema (American English) or oedema (British English), formerly known as dropsy or hydropsy, is swelling of any organ or tissue due to accumulation of excess lymph fluid, without an increase of the number of cells in the affected tissue. ...

DAI is classified in grades based on severity of the injury. In Grade I, widespread axonal damage is present but no focal abnormalities are seen. In Grade II, damage found in Grade I is present in addition to focal abnormalities, especially in the corpus callosum. Grade III damage encompasses both Grades I and II in addition to rostral brain stem injury and often tears in the tissue (Bigler, 2000). Mostly enveloped by the cerebrum and cerebellum (blue), the visible part of brainstem is shown in black. ...

DAI currently lacks a specific treatment beyond what is done for any type of head injury, including stabilizing the patient and trying to limit increases in intracranial pressure (ICP). Intracranial pressure, (ICP), is the pressure exerted by the cranium on the brain tissue, cerebrospinal fluid (CSF), and the brains circulating blood volume. ...

Future treatments

The fact that a single stimulus, the stretching of axons, leads to harm to the cell by the activation of multiple degradative pathways introduces possibilities for treating head injury shortly after the event and preventing a large part of the damage from occurring.

Since chemicals used to block proteolytic enzymes and Na⁺ and Ca²⁺ channels have prevented damage due to the influx of Ca²⁺, new drugs could be invented to mitigate damage using these chemicals. In addition, since damage occurs as a cascade, with one element of the process activating the next, a single drug that inhibits one part of a cascade could thereby block all of the products downstream from it (Arundine et al., 2004).

See also

• Brain injury
• Axoplasmic transport

Brain damage or brain injury is the destruction or degeneration of brain cells. ... Axoplasmic transport, also called axonal transport, is responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other cell parts to and from a neurons cell body through the cytoplasm of its axon, which is called axoplasm. ...

External links

• TBI Resource Guide Traumatic Brain Injury Resource Guide
• Emedicine.com: Diffuse Axonal Injury (DAI). An article on Diffuse Axonal Injury by Jeffrey R Wasserman, giving a generalized overview of Diffuse Axonal Injury (DAI), its pathophysiology and other relevant information.

References

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