Editing Diffuse axonal injury (section)

==Characteristics==
Lesions typically are found in the [[white matter]] of brains injured by DAI; these lesions vary in size from about 1–15&nbsp;mm and are distributed in a characteristic pattern.<ref name="Wasserman"/> DAI most commonly affects white matter in areas including the [[brain stem]], the [[corpus callosum]], and the [[cerebral hemisphere]]s.

The [[lobes of the brain]] most likely to be injured are the frontal and temporal lobes.<ref name="boon">{{cite web |vauthors=Boon R, de Montfor GJ |year=2002 |url=http://home.iprimus.com.au/rboon/BrainInjury.htm |title=Brain injury |website=Learning Discoveries Psychological Services |access-date=17 January 2008 |url-status=dead |archive-url=https://web.archive.org/web/20060903021119/http://home.iprimus.com.au/rboon/BrainInjury.htm |archive-date=2006-09-03}}<!--♦♦♦sketchy web ref♦♦♦--></ref> Other common locations for DAI include the white matter in the [[cerebral cortex]], the superior [[cerebral peduncle]]s,<ref name="SmithGreenwald"/> [[basal ganglia]], [[thalamus]], and deep hemispheric nuclei.{{clarify|date=June 2022}}<ref name="singh">{{cite web |vauthors=Singh J, Stock A |date=September 25, 2006 |url=http://www.emedicine.com/ped/topic929.htm |title=Head Trauma |website=Emedicine.com |access-date=2008-01-17}}</ref> These areas may be more easily damaged because of the difference in density between them and the other regions of the brain.<ref name="singh"/>

===Histological characteristics===
DAI is characterized by axonal separation, in which the axon is torn at the site of stretch and the part [[Anatomical terms of location#Proximal and distal|distal]] to the tear degrades by a process known as [[Wallerian degeneration]]. While it was once thought that the main cause of axonal separation was tearing due to mechanical forces during the trauma event, it is now understood that axons are not typically torn upon impact; rather, secondary [[biochemical cascade]]s, which occur in response to the [[Primary and secondary brain injury|primary injury]] (which occurs as the result of mechanical forces at the moment of trauma) and take place hours to days after the initial injury, are largely responsible for the damage to axons.<ref name="Wolf">{{cite journal |vauthors=Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH |year=2001 |url=http://www.jneurosci.org/cgi/content/abstract/21/6/1923 |title=Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels |journal=Journal of Neuroscience |volume=21 |issue=6 |pages=1923–1930|doi=10.1523/JNEUROSCI.21-06-01923.2001 |pmid=11245677 |pmc=6762603 }}<!--♦♦♦primary♦♦♦--></ref><ref>{{cite journal | pmid = 15371512 | doi=10.1523/JNEUROSCI.1362-04.2004 | volume=24 | title=Vulnerability of central neurons to secondary insults after in vitro mechanical stretch | date=September 2004 | vauthors=Arundine M, Aarts M, Lau A, Tymianski M | journal=Journal of Neuroscience | issue=37 | pages=8106–23| pmc=6729801 }}</ref><ref name="Mouzon2012">{{cite journal | vauthors = Mouzon B, Chaytow H, Crynen G, Bachmeier C, Stewart J, Mullan M, Stewart W, Crawford F | title = Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes | journal = Journal of Neurotrauma | volume = 29 | issue = 18 | pages = 2761–2173 | date = December 2012 | pmid = 22900595 | doi = 10.1089/neu.2012.2498 | url = http://eprints.gla.ac.uk/72680/7/72680.pdf }}</ref>

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 [[proteolysis|proteolytic]] degradation of the [[cytoskeleton]].<ref name="Iwata">{{cite journal |vauthors=Iwata A, Stys PK, Wolf JA, Chen XH, Taylor AG, Meaney DF, Smith DH |year=2004 |url=http://www.jneurosci.org/cgi/content/abstract/24/19/4605 |title=Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors |journal=The Journal of Neuroscience |volume=24 |issue=19 |pages=4605–4613|doi=10.1523/JNEUROSCI.0515-03.2004 |pmid=15140932 |pmc=6729402 }}<!--♦♦♦primary♦♦♦--></ref> It also opens [[sodium channel]]s in the [[axolemma]], which causes [[voltage-gated calcium channel]]s to open and Ca<sup>2+</sup> to flow into the cell.<ref name="Iwata"/> The intracellular presence of Ca<sup>2+</sup> triggers several different pathways, including activating [[phospholipase]]s and [[proteolytic enzyme]]s damaging [[mitochondria]] and the cytoskeleton, and activating [[secondary messenger]]s, which can lead to separation of the axon and death of the cell.<ref name="Wolf"/>

===Cytoskeleton disruption===
[[File:APP immunostaining in a mouse brain after traumatic brain injury.png|thumb| Immunoreactive axonal profiles are observed as either granular (B, G, H) or more elongated, fusiform (F) swellings in the [[corpus callosum]] and the [[brain stem]] (H) at 24h post [[traumatic brain injury]]. Example of APP immunoreactive neurons (arrow heads) observed in the [[Cerebral cortex|cortex]] underneath the impact site (E, G). No APP staining was observed in healthy control animals (D).<ref name="Mouzon2012"/>
]]

Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal [[cytoskeleton]] can be broken. 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.<ref name="Staal">{{cite journal | vauthors = Staal JA, Dickson TC, Chung RS, Vickers JC | year = 2007 | title = Cyclosporin-A treatment attenuates delayed cytoskeletal alterations and secondary axotomy following mild axonal stretch injury | journal = Developmental Neurobiology | volume = 67 | issue = 14| pages = 1831–1842 | pmid = 17702000 | doi = 10.1002/dneu.20552 | s2cid = 19415197 | url = https://figshare.com/articles/journal_contribution/22860839 }}</ref> When this swelling becomes large enough, it can tear the axon at the site of the cytoskeleton break, causing it to draw back toward the cell body and form a bulb.<ref name="Smith"/> This bulb is called a "retraction ball", the [[histology|histological]] hallmark of diffuse axonal injury.<ref name="Wasserman"/>

When the axon is torn, [[Wallerian degeneration]], in which the part of the axon distal to the break degrades, takes place within one to two days after injury.<ref name="Lopachin">{{cite journal | author = LoPachin RM, Lehning EJ | year = 1997 | title = Mechanism of calcium entry during axon injury and degeneration | journal = [[Toxicology and Applied Pharmacology]] | volume = 143 | issue = 2| pages = 233–244 | pmid = 9144441 | doi = 10.1006/taap.1997.8106 | bibcode = 1997ToxAP.143..233L }}</ref> The axolemma disintegrates,<ref name="Lopachin"/> myelin breaks down and begins to detach from the cell in an anterograde direction (from the body of the cell toward the end of the axon),<ref name="Cowie">{{cite web |vauthors=Cowie RJ, Stanton GB |year=2005 |url=http://www.med.howard.edu/anatomy/gas/wk12/Lect.%2037_Axoplasmic%20Flow,%20injury.htm |title=Axoplasmic transport and neuronal responses to injury |archive-url=https://web.archive.org/web/20051029215534/http://www.med.howard.edu/anatomy/gas/wk12/Lect.%2037_Axoplasmic%20Flow%2C%20injury.htm |archive-date=2005-10-29 |publisher=Howard University College of Medicine |access-date=2008-01-17}}<!--♦♦♦web♦♦♦--></ref> and nearby cells begin [[phagocytosis|phagocytic]] activity, engulfing the cellular debris.<ref>{{cite journal | vauthors = Hughes PM, Wells GM, Perry VH, Brown MC, Miller KM | year = 2002 | title = Comparison of matrix metalloproteinase expression during wallerian degeneration in the central and peripheral nervous systems | journal = Neuroscience | volume = 113 | issue = 2| pages = 273–287 | pmid = 12127085 | doi = 10.1016/s0306-4522(02)00183-5 | s2cid = 37213275 }}</ref>

===Calcium influx===
While sometimes only the cytoskeleton is disturbed, frequently disruption of the [[axolemma]] occurs as well, causing the influx of [[calcium|Ca<sup>2+</sup>]] ions into the cell and unleashing a variety of degradational processes.<ref name="Lopachin"/><ref name="Povlishock">{{cite book | author = Povlishock JT, Pettus EH | chapter = Traumatically Induced Axonal Damage: Evidence for Enduring Changes in Axolemmal Permeability with Associated Cytoskeletal Change | year = 1996 | title = Mechanisms of Secondary Brain Damage in Cerebral Ischemia and Trauma | journal = Acta Neurochirurgica. Supplement | volume = 66 | pages = 81–86 | doi = 10.1007/978-3-7091-9465-2_15 | pmid = 8780803 | isbn = 978-3-7091-9467-6 }}</ref> An increase in Ca<sup>2+</sup> and [[sodium|Na<sup>+</sup>]] levels and a drop in [[potassium|K<sup>+</sup>]] levels are found within the axon immediately after injury.<ref name="Wolf"/><ref name="Lopachin"/> Possible routes of Ca<sup>2+</sup> entry include [[sodium ion channel|sodium channel]]s, [[membrane pore|pore]]s formed in the membrane during stretch, and failure of [[ATP-dependent transporter]]s due to mechanical blockage or lack of available metabolic energy.<ref name="Wolf"/> High levels of intracellular Ca<sup>2+</sup>, the major cause of post-injury cell damage,<ref name="zhou">{{cite journal | vauthors = Zhou F, Xiang Z, Feng WX, Zhen LX | year = 2001 | title = Neuronal free Ca<sup>2+</sup> and BBB permeability and ultrastructure in head injury with secondary insult | journal = Journal of Clinical Neuroscience | volume = 8 | issue = 6| pages = 561–563 | pmid = 11683606 | doi = 10.1054/jocn.2001.0980 | s2cid = 43789581 }}</ref> destroy mitochondria,<ref name="Smith"/> and trigger [[phospholipase]]s and proteolytic enzymes that damage Na+ channels and degrade or alter the cytoskeleton and the [[axoplasm]].<ref name="Castillo">{{cite journal | author = Castillo MR, Babson JR | year = 1998 | title = Ca<sup>2+</sup>-dependent mechanisms of cell injury in cultured cortical neurons | journal = Neuroscience | volume = 86 | issue = 4| pages = 1133–1144 | pmid = 9697120 | doi = 10.1016/s0306-4522(98)00070-0 | s2cid = 54228571 }}</ref><ref name="Lopachin"/> Excess Ca<sup>2+</sup> can also lead to damage to the [[blood–brain barrier]] and swelling of the brain.<ref name="zhou"/>

One of the proteins activated by the presence of calcium in the cell is [[calpain]], a Ca<sup>2+</sup>-dependent non-[[lysosome|lysosomal]] [[protease]].<ref name="Castillo"/> About 15 minutes to half an hour after the onset of injury, a process called calpain-mediated spectrin proteolysis, or CMSP, begins to occur.<ref name="Büki">{{cite journal | vauthors = Büki A, Okonkwo DO, Wang KK, Povlishock JT | title = Cytochrome c release and caspase activation in traumatic axonal injury | journal = The Journal of Neuroscience | volume = 20 | issue = 8 | pages = 2825–34 | date = April 2000 | pmid = 10751434 | pmc = 6772193 | doi = 10.1523/JNEUROSCI.20-08-02825.2000 | department = primary }}</ref> Calpain breaks down a molecule called [[spectrin]], which holds the membrane onto the cytoskeleton, causing the formation of [[bleb (cell biology)|bleb]]s and the breakdown of the cytoskeleton and the membrane, and ultimately the death of the cell.<ref name="Castillo"/><ref name="Büki"/> Other molecules that can be degraded by calpains are [[microtubule]] subunits, [[microtubule-associated protein]]s, and [[neurofilament]]s.<ref name="Castillo"/>

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 "programmed cell death".<ref name="Büki"/>

[[Mitochondria]], [[dendrite]]s, and parts of the cytoskeleton damaged in the injury have a limited ability to heal and regenerate, a process which occurs over two or more weeks.<ref name="Corbo">{{cite journal | author = Corbo J, Tripathi P | year = 2004 | title = Delayed presentation of diffuse axonal injury: A case report | journal = Trauma | volume = 44 | issue = 1| pages = 57–60 | pmid = 15226709 | doi = 10.1016/j.annemergmed.2003.11.010 }}</ref> After the injury, [[astrocyte]]s can shrink, causing parts of the brain to atrophy.<ref name="Wasserman"/>