Traumatic brain injury refers to instances in which the brain is considerably damaged because of some observable event, such as a car or sporting accident. Traumatic brain injury does not include damage that can be ascribed to events within the brain, such as strokes or infection. In addition, traumatic brain injury, or TBI, does not include brain defects that are acquired before birth.
Traumatic brain injuries emanate from two categories of events: impact and inertia. Impact refers to objects that collide with the head--and these objects may either penetrate or not penetrate the scull. Inertia refers to sudden acceleration or deceleration of the brain within the meninges, like whiplash--the main cause of tears to the axons, called diffuse axonal injury. In addition, TBI can be focal or diffuse. Focal injuries are confined to specific regions of the brain. Diffuse injuries are distributed across the brain. Most injuries, especially if severe, are both focal and diffuse.
Sometimes, the effects of TBI magnify over time. TBI at one time can increase the likelihood of many psychological problems, from Alzheimer's Disease and epilepsy to borderline personality disorder and depression, in the future.
TBI, in general, coincides with a broad spectrum of symptoms. Lishman (1998) classified these symptoms into 4 categories: cognitive impairment, personality changes, neurosis, and psychosis.
Cognitive impairment, although remarkably varied, often revolves around limitations in attention, memory, and executive control--which entails attempts to plan, initiate, and monitor complex behaviors, intended to achieve some goal.
These impairments may underpin changes in personality, a problem that corresponds to about 30% of TBI patients. Cognitive impairments, for example, may compromise social functioning, promote apathy, evoke impulsive behavior, undermine emotional regulation, and diminish self-awareness, all of which manifest as changes in personality. Sometimes, past traits, such as irritability, are exacerbated by impairments to executive control.
Cognitive impairment and personality changes may also manifest as mood disorders and neuroses--manifesting in about 40% of individuals. For example, impediments in the capacity of individuals to initiate actions mirror symptoms of depression. Similarly, the inability of people to feel they can achieve their goals can also elicit dejection and similar emotions. These emotional difficulties are especially likely when physical problems are pronounced, social support is limited, and individuals are young.
Physical impairments can include seizures, impaired senses, headaches, and motor difficulties. Sometimes, the causes of TBI, such as accidents, were also responsible for these other problems.
The initial impact or change in inertia can provoke a range of complications. Yet, about 40% of patients actually deteriorate in hospital. This deterioration can be ascribed to secondary brain injury--that is, constellations of processes that follow the initial trauma.
Secondary injury tends to proceed hours or even days after the initial trauma. Several sequences of processes can explain the effects of these secondary injuries. First, trauma increases the level of glutamate in the extracellular space--the space around the cells. Excessive glutamate can destroy brain cells.
In particular, the trauma itself can damage blood vessels in the brain. Consequently, blood flow and oxygen to the brain may be impeded. As oxygen supply diminishes, phosphate compounds, such as ATP, needed to energize many neural processes, diminish. For example, ion pumps, such as Na2+ pumps, do not operate as effectively. As the concentration of Na2+ inside the cell increases, and the membrane potential diminishes, other uptake carriers--structures that shift chemicals into the cell--are no longer as effective. In particular, the carrier that shifts glutamate, an excitatory neurotransmitter, into the cell does not operate as efficiently. An excessive amount of glutamate accumulates in the extracellular space.
Excessive glutamate will tend to destroy cells, usually by provoking an influx of Ca2+ ions. In particular, this glutamate binds to various receptors, especially NMDA receptors or sometimes AMPA receptors. These responses facilitate the influx of Ca2+ ions into the cell. This calcium then activates various proteases such as calpain-enzymes that break down protein-as well as other enzymes. These enzymes then destroy the constituents of cells, including the membranes, cytoskeleton, and DNA.
Furthermore, when the calcium ions are excessive, pores on the membrane of mitochondria--an organelle in cells that that supplies energy--tend to open. As these pores open, the mitochondria swells with various molecules. The electrochemical gradient of these mitochondria then diminishes. Consequently, these organelles cannot as readily produce ATP, the main source of energy to cells. The limited energy further impedes ion channels and, thus, precludes the uptake of glutamate, as well as other complications.
These open pores not only curb the production of ATP but also increase the production of free radicals and other reactive oxygen species. In particular, when the pores open, several antioxidant molecules, such as glutathione, leave the mitochondria. Consequently, the concentration of reactive oxygen species--reactive oxygen molecules that tend to accumulate with stress--increases in the mitochondria. These reactive oxygen molecules can damage DNA, RNA, and proteins.
In addition to the release of antioxidant molecules, the pores enable cytochrome C to leave the mitochondria, ultimately culminating in a programmed variant of cell death called apoptosis. In particular, cytochrome C binds to apoptotic protease activating factor-1 in the cytoplasm to form apoptosomes. These apoptosomes bind to another protein in the cytoplasm, called caspase-9--and this enzyme degrades the mitochondrial membrane, eventually inciting phagocytes and related to cells to devour the cell.
Depression, bipolar disorder, anxiety, including panic disorder and phobias, and other psychological disorders are common after TBI, although the prevalence differs markedly across studies. Furthermore, these disorders may depend on neurological damage, pre-trauma personality, post-trauma support, and many other considerations.
Some evidence indicates that TBI may facilitate the progress of Alzheimer's disease. Interestingly, both TBI and Alzheimer's disease are associated with amyloid and tau protein deposits.
TBI can also increase the likelihood of epilepsy days, months, or even years in the future, especially if the trauma had penetrated the brain and provoked bleeding. Indeed, about 5% of epilepsy cases can be ascribed to TBI. Antiepileptic drugs may control, but cannot prevent, the seizures that follow TBI.
Several theories have been proposed to explain how TBI may provoke epilepsy. According to the iron hypothesis, excessive iron in the blood can increase the production of free radicals, and these free radicals can damage cells. Cells that inhibit excitation could be impaired. Ion channels that increase the concentration of GABA relative to glutamate may be damaged. Consistent with this premise, iron injected into the brains of rats increases the prevalence of free radicals.
Second, TBI can increase the release of glutamate, an excitatory neurotransmitter. For example, the trauma can damage blood vessels in the brain& oxygen supply to the brain may be limited. ATP, the key source of energy to the brain, is inadequate. Ion pumps, designed to shift ions across the membrane of neurons, do not operate as effectively. Consequently, Na2+ ions accumulate outside the cell. This change in membrane potential stifles the utility of uptake carriers that shift glutamate into the cell. Glutamate increases the likelihood that other neurons will be activated, sometimes culminating in epilepsy.
People with borderline personality disorder exhibit prominent impulsivity--especially in social settings--as well as unstable emotions and erratic perceptions of themselves and their relationships. They may show frenetic efforts to prevent rejection as well as self-harm.
TBI may increase the likelihood that people will develop, or at least manifest, TBI. For example, as Streeter et al. (1995) showed, 42% of war veterans diagnosed with borderline personality disorder, but only 4% of war veterans not diagnosed with borderline personality disorder, had experienced TBI. Indeed, according to Hibbard et al. (2000), about a third of people with TBI may be diagnosed with borderline personality disorder.
Injury to specific brain circuits may be especially likely to provoke borderline personality disorder. Damage to prefrontal circuits, such as the dorsolateral prefrontal area, can increase impulsivity, as the capacity to inhibit dominant tendencies deteriorates. This impulsivity is a key feature of borderline personality disorder (Van Reekum et al., 1996).
If injuries do not penetrate the skull, the orbitofrontal cortex, sometimes called the ventromedial prefrontal cortex, is often damaged, primarily because this region may collide with bony protrusions inside the skull. When this region is impaired, social judgment is impaired and irritability, or even aggression, become more likely (Tekin & Cummings, 2002). Outbursts are thus more common, and such behavior is a common symptom of borderline personality disorder.
In particular, the orbitofrontal cortex seems to be needed to inhibit obsolete goals--that is, goals that could provoke indirect but consequential problems in the future. First, when this region is damaged, individuals tend to choose acts that can offer immediate rewards but future complications, such as compulsive gambling, drug use, and excessive swearing. Their social skills also tend to decline: They do not, for example, exhibit empathy. Second, they do not perform well on the faux pas test& that is, after watching someone articulate an awkward remark that could provoke offence, they cannot report why this comment was awkward. Third, reversal learning is impaired. For example, if told to press one button in response to a specific picture and another button in response to another picture, they cannot shift this behavior when they need to reverse these responses-even if incorrect responses are punished. Fourth, on the Iowa gambling task, they often choose cards that can generate pronounced negative consequences. In short, they do not seem to be sensitive to additional information that changes the valence or suitability of some act. Some of these tendencies may provoke impulsivity and thus exacerbate borderline personality disorder.
Yet, some research highlights differences between the impulsivity associated with borderline personality disorder and the impulsivity associated with TBI. Impulsivity associated with borderline personality disorder is more likely to be provoked by events in the environment, such as social cues (Gagnon et al., 2006b). Likewise, other features of borderline personality disorder diverge from related features of people with TBI. In borderline personality disorder, people are shift their perceptions of themselves dramatically. In TBI, people shift their perception of themselves after the injury but then gradually form a stable perception (Gagnon et al, 2006a). Instead, according to Hibbard et al. (2000), TBI may decrease the capacity of people to regulate negative behaviors or emotions and, therefore, increase the likelihood that pre-existing features of borderline personality disorder are amplified after the trauma.
PTSD can follow mild, moderate, or severe cases of TBI (Bryant, 2011). The likelihood of PTSD within 7.5 years of TBI has been estimated to approximate 14% (van Reekum et al., 2000). The likelihood of PTSD within 6 months after severe TBI may be as high as 27% (Bryant, Marosszeky, Crooks, & Gurka, 2000).
Several brain regions may underpin this association between TBI and PTSD. For example, the hippocampus is susceptible to injury and often damaged in TBI (Bigler & Maxwell, 2011), partly because of the synaptic plasticity of hippocampal cells. The hippocampus is vital to the regulation of fear and anxiety. Consequently, consistent with past studies, this region may often be damaged in people who exhibit PTSD (Dolan et al., 2012;; Fotuhi & Do, 2010).
In addition, TBI often damages regions in the prefrontal cortex that underpin working memory. When these regions are damaged, individuals cannot as readily inhibit dominant tendencies or transform information effectively--capabilities that are needed to diminish fear reactions (Bryant, 2011). Thus, fear reactions may be more pronounced, often culminating in PTSD.
TBI can increase the likelihood of generalized anxiety disorder specifically or anxiety in general. Meta-analyses by Van Reekum, Cohen, and Wong (2000) as well as Hiott and Labbate (2002) indicate that about 10% of TBI patients will develop generalized anxiety disorder, about twice the levels observed in the general population.
The likelihood that TBI translates to generalized anxiety disorder depends on which regions of the brain have been impaired. For example, as Jorge, Robinson, Starkstein, and Arndt (1993) showed, lesions in the right hemisphere in particular often coincided with generalized anxiety disorder. More specifically, Grafman, Vance, Weingartner, Salazar, and Amin (1986), in a longitudinal study of over 1000 Vietnam veterans, showed that lesions in the right orbitofrontal cortex, a region that is often damaged in accidents, was associated with generalized anxiety disorder.
Nevertheless, more recent analysis has challenged the simplicity of these conclusions. Knutson et al. (2013), for example, showed that injury to the left rather than right hemisphere, especially in cortical and limbic regions, was associated with generalized anxiety disorder. These limbic regions include the hippocampus, fusiform grey-matter regions, amygdala, insula, and para-hippocampus, all associated with emotional regulation and recognition. Indeed, according to Knutson et al. (2013), when recognition is impaired, settings may not seem as familiar, potentially exacerbating anxiety and similar emotions.
Yet lesions to some of these regions, such as the amygdala, may not always provoke anxiety. According to Bannerman et al. (2004), mild damage to the amygdala might impair emotional regulation, exacerbating anxiety. In contrast, severe damage to the amygdala might impede the generation of negative emotions, alleviating anxiety. As Glascher and Adolphs (2003) highlight, the role of this brain region not only depends on the severity of injury but also whether the left or right side is damaged: the right hemisphere may generate the negative emotions whereas the left hemisphere may regulate these emotions to some extent.
Besides lesions to brain regions, damage to the axons, a frequent consequence of TBI, might also decrease the concentration of neurochemicals that prevent anxiety. Specifically, as Raible, Frey, Cruz Del Angel, Russek, and Brooks-Kayal (2012) showed, TBI tends to diminish the concentration or effects of GABA, at least in rats. The precise mechanism is unknown& arguably, a sequence of limited blood flow, impaired ion channels, disrupted reuptake of glutamate, and the consequence excess of Ca2+ in the cells may diminish the sensitivity of GABA receptors. This decrease in the effect of GABA tends to provoke anxiety. Indeed, drugs that offset this decrease tend to alleviate anxiety& likewise, when GABA is impeded in the anterior basolateral amygdala, anxiety is intensified.
Recent evidence indicates that TBI also increases the likelihood of multiple sclerosis over the next few years. This relationship persists after controlling income and geographic region (Kang & Lin, 2012). The precise mechanisms that underlie this association have not been clarified definitively. Arguably, compromises to the blood brain barrier could underpin this association.
Several mechanisms underpin the association between TBI and impairment of the blood brain barrier. In particular, when forces are applied to the head, some brain structures move faster than other brain structures. Consequently, axons and blood vessels tend to be twisted, like a shearing motion. The vessels are thus damaged as a consequence. Proteins and red blood cells thus seep into the tissue. The endothelial lining--the lining of blood and lymphatic vessels--is damaged. This sequence of events tends to activate coagulation, and clots tend to form. Blood flow thus decreases as a consequence.
This damage increases the likelihood that various substances, such as albumin, fibrinogen, and thrombin, can access the brain. Fibrinogen, after its conversion to fibrin, acts on microglia, causing the rearrangement of microglial cytoskeleton and increased phagocytosis.
TBI at one time also increases the likelihood of Alzheimer's Disease in the future (Fleminger, Oliver, Lovestone, Rabe-Hesketh, & Gloria, 2003). Several accounts could explain this association.
First, both TBI and Alzheimer's Disease could be ascribed to overlapping causes, such as risky behaviour. People who engage in risky activities are more likely to be victims of accidents and therefore, experience TBI (Olson-Madden et al., 2012). Likewise, people who engage in risky activities may be more likely to initiate behaviors that increase the likelihood of Alzheimer's Disease, such as smoking.
To illustrate, Cataldo, Prochaska, and Glantz (2010) systematically examined 43 studies, each of which examined the association between smoking and Alzheimer's Disease. In general, these studies showed that smoking does increase the likelihood of Alzheimer's Disease. These associations were especially pronounced in studies that were not affiliated with the tobacco industry. Smoking, in turn, is associated with sensation seeking (Banerjee & Greene, 2009). That is, people who seek thrilling, exciting, and risky activities are also more likely to smoke. Furthermore, this tendency to engage in thrilling or risky activities also increases the likelihood of TBI (for a review, see Olson-Madden et al., 2012).
TBI may also facilitate the formation of protein aggregates called beta amyloid, sometimes referred to as beta amyloid plaques (Roberts, et al., 1994). These insoluble plaques are observed in about 30% of patients with TBI and in all patients with Alzheimer's disease. Therefore, beta amyloid plaques may represent an underlying pathology that both disorders share (Roberts, et al., 1994).
These plaques are solidified amalgams of many strands of beta amyloid--a protein in the extracellular fluid. The plaques, together with neurofibrillary tangles, are the characteristic features of Alzheimers's Disease. Yet, the same plaques seem to appear in response to TBI. For example, these plaques are detected in brain tissue samples that are harvested a month or so after a TBI has occurred (Uryk, et al., 2007).
Nevertheless, the plaques observed after TBI differ from the plaques observed in Alzheimer's disease. In particular, in contrast to Alzheimer's disease, in which the plaques develop gradually over time, in TBI, the plaques can appear within a few hours (Roberts, et al., 1994).
Despite this complication, many studies indicate that TBI might elicit a series of processes that increase the accumulation of beta amyloid plaques. First, after acute brain injuries, the number of glial cells proliferates. Glial cells include astrocytes--cells in the brain that exchange chemical and nutrients to support the function of neurons--and oligodendrocytes--cells in the brain that generate myelin sheaths--as well as other cells. These glial cells, especially the astrocytes, increase the production of amyloid precursor protein, or APP, a precursor of beta amyloid that tends to reside in the membrane of neurons (Sivanandam & Thakur, 2010). This rise in APP might be a key factor in the formation of beta amyloid plaques and ultimately Alzheimer's Disease.
Second, TBI increases the release of caspase-3 (Chen, et al., 2004). Caspase-3 is an enzyme that degrades protein and is vital to the immune system. Inadequate levels of caspase-3 can impede the destruction of tumors. Yet, elevated levels of caspase-3 can increase the accumulation of beta amyloid. That is, this enzyme facilitates the conversation of APP to beta amyloid, potentially augmenting the likelihood of plaques and Alzheimer's Disease.
Third, TBI is likely to increase levels of Beta secretase. To illustrate, about half the cases of TBI correspond to impaired blood flow and, therefore, low oxygen levels in the brain (Frugier, Morganti Kossmann, Reilly & Mc Lean, 2010). These low oxygen levels, called hypoxia, increases the transcription and expression of a specific gene called BACE 1. This gene augments the release of Beta secretase (Zhang & Le, 2010). Beta secretase is a protein enzyme that spans from inside the cell to outside the cell. Like caspase-3, Beta secretase also facilitates the conversation of APP to beta amyloid and, therefore, may increase the likelihood of plaques.
Nevertheless, this association between TBI and Alzheimer's disease may not apply to every category of brain injury. For example, beta amyloid seems to be elevated in response to diffuse injuries--in which many regions of the brain are damaged--but not focal injuries (Marklund, et al., 2009). Therefore, perhaps diffuse axonal injury may be more likely than focal injuries to culminate in Alzheimer's disease.
These arguments assume that beta amyloid plaques are the primary cause of Alzheimer's disease. Indeed, many researchers have assumed that such plaques may evoke a series of complications that, ultimately, culminate in cell death. For example, Hardy and Allsop (1991) proposed the amyloid cascade hypothesis. According to this argument, the beta amyloid plaques themselves evoke a range of complications. They provoke inflammation, increase the formation of reactive oxygen and nitrogen species, disrupt the function of mitochondria, as well as incite other changes. These changes ultimately increase the likelihood that a neuron will die. According to this perspective, neurofibrillary tangles are merely a consequence, rather than a cause, of these beta amyloid plaques.
Yet, this theory has been challenged recently. Arriagada et al. (1992) showed the number of neurofibrillary tangles, and not the number of plaques, correlate highly with the duration and severity of Alzheimer's Disease. These findings imply the neurofibrillary tangles may be more central to the development of Alzheimer's Disease. Second, neurofibrillary tangles seem to precede the appearance of beta amyloid plaques in some circumstances (Sch?nheit, Zarski, & Ohm, 2004). Again, these findings challenge the notion that beta amyloid plaques may cause Alzheimer's Disease. Third, interventions that prevent or diminish beta amyloid plaques do not seem to alleviate Alzheimer's Disease. For example, vaccines that reduce beta amyloid plaques have not been successful in preventing or treating dementias (Holmes, 2008).
To explain these findings, some researchers argue that beta amyloid oligomers are more toxic than perhaps beta amyloid plaques. Beta amyloid oligomers are aggregates of merely a few beta amyloid proteins& beta amyloid plaques, in contrast, are aggregates of millions of beta-amyloid protein. (Lacor, et al., 2007). In particular these oligomers are assumed to bind to receptors and change the structure of synapses, ultimately impeding communication between neurons (Lacor, et al., 2007).
Some researchers instead assume that beta amyloid oligomers are a consequence of another defect (Mudher & Lovestone 2002)--the formation of neurofibrillary tangles, also called the hyper-phosphorylation of tau. Tau is a protein, central to the formation of microtubules inside cells. These microtubules facilitate the exchange of nutrients into the cell and waste products from the cell.
In Alzheimer's Disease, the microtubules disintegrate and tau proteins are released into the cell, sometimes binding with phosphate or PH4 molecules. This process is called the hyper-phosphorylation of tau. Clusters of hyperphosphorylized tau bind together, creating clumps called neurofibrillary tangles (Mudher & Lovestone 2002). Without the microtubules, the cells begin to disintegrate and many other processes, such as inflammation and the release of reactive oxygen species are provoked. The neurofibrillary tangles may also obstruct the movement of vesicles and, therefore, impede the release of neurotransmitters.
TBI can increase the likelihood these neurofibrillary tangles will form and microtubules will disintegrate. In particular, TBI damages the microtubules in axons. This possibility was substantiated by the finding that TBI increases the levels of tau by 1000 times in the cerebrospinal (Liliang, et al., 2010). Accordingly, this damage to the microtubules may facilitate the formation of neurofibrillary tangles--a possible cause of Alzheimer's Disease.
TBI also increases the production of glutamate, an excitatory neurotransmitter (Park, Bell & Baker, 2008). When the levels of glutamate are excessive, neurons tend to die in a process called apoptosis-in which the cell initiates a series of changes that ultimately culminates in its death. Apoptosis, as a consequence of elevated levels of glutamate, is also a key feature of Alzheimer's disease (Areosa Sastre, McShane, Sherriff, 2004). Accordingly, TBI may exacerbate the death of cells and thus expedite the progress of Alzheimer's disease.
Alternatively, both TBI and Alzheimer's disease may be related to overlapping genes, such as apolipoprotein E. Specifically, a particular allele of this gene, called epsilon 4, increases the risk of Alzheimer's disease. If this allele is present on both chromosomes, individuals are 15 times the average person to later experience Alzheimer's disease (Blennow, de Leon & Zetterberg, 2006). These alleles diminish the capacity of individuals to metabolize beta-amyloid, and either oligomers or plaques are more likely to form.
Likewise, this allele also impairs recovery after TBI. Cognitive functioning after TBI is likely to remain impaired in people with this allele, especially in younger individuals (Teasdale, Murray & Nicoll, 2005). Accordingly, this gene might merely increase the likelihood of both Alzheimer's disease and impair recovery in TBI.
Damage to prefrontal circuits and the medial temporal lobe are common in TBI and may underpin many of the psychological complications. In particular:
Some complications arise when clinicians assess the history of patients with TBI. First, TBI is often associated with problems in memory retrieval and self-awareness (McAllister, 2008). Consequently, clinicians will often need to interview other people, such as managers and family.
The historical assessment should be conducted as soon as possible& otherwise, people will often attribute idiosyncrasies of the person to the injury rather than pre-existing tendencies.
Typically, clinicians implement interventions that are intended to resolve depression and irritability. Yet, while treating patients with TBI, several complications need to be considered.
First, patients often exhibit stimulus boundedness, in which they are unduly sensitive to immediate changes in the environment. Likewise, they often are especially fond of their existing routines, especially if cognitive deficits are apparent (McAllister, 2008).
The results of some studies can be challenged. For example, many studies compare patients with TBI to health control individuals, without controlling past differences. These studies, therefore, may disregard the possibility that people with TBI differ from the general population even before the trauma. Furthermore, many studies do not report the magnitude of trauma& whether the results would apply to mild, moderate, or strong traumas cannot be ascertained therefore.
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Last Update: 7/21/2016