Traumatic Brain Injury and Forgetting

Accidents Can be Serious
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Take care to wear a helmet. [3] (2014)

Traumatic Brain Injury (TBI) is caused by physical trauma to the head or neck and can lead to disruptions in memory, learning, cognitive abilities, sleep, and mood. Many brain areas may be damaged in TBI, commonly the frontal cortex and the temporal lobes. In the immediate or primary stage of injury, cells and blood vessels are ripped or contorted. During secondary injury, which takes place in the weeks and months following impact, the brain shows diffuse inflammation and neurotoxin release as well as breakage of the blood brain barrier. Axons of cells throughout the brain may detach from cell bodies. Within cells, mitochondria function defectively, and there are inappropriate amounts of glutamate release and cation entry [1]. Individuals with more severe TBI may show high concentrations of amyloid-beta plaques and neurofibrillary tangles, factors associated with dementia [2]. All of these changes can cause forgetting if they damage memory structures such as the hippocampus, where memories are formed, and the cortex, in which memories are consolidated. Memory loss can be temporary, or in other cases, can manifest as anterograde or retrograde amnesia. Current treatments for TBI in humans are mostly rehabilitation services. Recently, much research is looking at potential drugs and compounds that can treat the pathology that follows injury.

Pathological Factors

Inflammation, Bleeding, and Neurotoxins

Damage to the brain causes the diffuse release of many different agents related to inflammation, bleeding, and neurotoxins. These factors can often feed onto and exacerbate one another.

Inflammation refers to the brain’s reparative response to injury, and is carried out by astrocytes and microglia. Astrocytes have been seen to become more active, with more bulging cell bodies and processes, after mild TBI [4]. It has been suggested that inflammation can contribute to later accumulation of proteins implicated in dementia, which will be described further in the section about neurofibrillary tangles and amyloid-beta plaques.

Bleeding generally occurs because blood vessels have broken in the primary stage of injury, and blood disrupts nearby glia and neurons [5]. If blood leaks into the ventricles, it can spread farther and more easily, making dangerous symptoms much more likely, and perhaps even leading to death. Bleeding can lead to the release of other agents, such as oxyhemoglobin and thrombin, the latter of which is activated almost immediately after injury [6] [5]. Thrombin is a factor that contributes to blood clotting, and whose role it is to prevent blood from spreading, and acts directly at receptors called PARs [6]. Thrombin is known to activate neurotoxins such as Src Family Kinases and glutamate (a neurotoxin if it is in excess) downstream [5] [6].

Common neurotoxins are neurotransmitters, which become toxic when they are inappropriately highly active [7]. Excitatory amino acids such as glutamate may excite cells at inappropriate levels and times [7]. Src Family Kinases are a prominent family of neurotoxins released after TBI [5]. In an animal model of TBI where the brains of rats were rapped with fluid, Src Family Kinases were seen to increase. Src Family Kinases activate a Rho-kinase pathway, and inappropriately changes the activity of NMDA receptors, both of which can lead to cell death [5].

Neurons can be affected
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White matter = axons and cell processes
David Cofer [8] (2002)

White Matter Reduction

White matter, or the axons of neurons and glia, is frequently damaged in TBI. Axons may be ripped off in primary injury, but are more likely to disintegrate and be shuffled off in the months of secondary injury that follow. It was shown in a rat model of mild TBI that animals with brain injury had decreased volume in the corpus callosum 6 months after injury [4]. For rats with repetitive mild TBI, reduction in white matter continued, although to a lesser extent, even 12 months after injury. White matter reduction inhibits communication among brain cells, and is linked to lowered higher executive functioning, slower speeds of processing, and memory and attention problems [9] [4].

Intracellular Changes

One prominent change within cells following injury is that cells allow an increased amount of Na+ to flow into them [10]. More Na+ inside the cell encourages water to diffuse in, which then causes the cell to grow in size and possibly degenerate. The increase in fluid also can leak into and destroy endothelial junctions that form the blood brain barrier. It has been shown that Nav1.3 channels are upregulated in rats two hours and 24 hours following lateral percussion to the brain, so these channels are likely greatly responsible for the inappropriate Na+ levels. This also indicates that Na+ regulation is an important part of the pathology of TBI.

A cartoon mitochondrion
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Damaged in TBI —> adverse effects on neuronal
function. National Science Foundation [11] (2014)

Other ions besides Na+ also are inappropriately allowed into cells following TBI, and cumulative flow of positive ions into cells can activate dangerous signalling pathways [7]. More positive ions within the cell often means more excitatory neurotransmitters and amino acids, such as glutamate. These excitatory transmitters are released from neurons and bind to receptors such as NMDARs on other neurons, inappropriately depolarizing and activating them [6]. This cascade of depolarization induces cells to release more of their calcium, and high calcium upsets the cell's membrane interactions and organelle sizes [7].

Mitochondria are one type of organelle that are significantly affected - through the above described pathway of intracellular changes, mitochondria become less efficient at reducing oxygen species. The mitochondria disfunction leads to a myriad of effects where the cell works overly hard to try to compensate for the lack of energy metabolism, or resorts to oxygen-independent glycolysis. All of these changes affect brain plasticity and energy use, and as such, can damage the function of brain structures and result in the various symptoms such as memory loss [7].

Neuronal Death

All of the above factors – inflammation, bleeding, neurotoxin release, structural damage to axons, and intracellular changes – can result in neuronal death [10] [7]. Toxin release, glutamate excess, and oxidative damage have been shown particularly to lead to apoptotic pathways in neurons, often via the p53 protein [12]. p53 levels are higher in animal models of TBI in both the hippocampus and the cortex. Intracellular changes cause p53 to survive longer in cells and thus lead to more apoptosis than is normal or healthy [12].

Neuronal death is more common and expected in moderate or severe types of TBI [7]. In the case of mild TBI, neuronal death is more often observed when there are more than one mild traumatic event to the brain [7]. Often, the neuronal cells in the hippocampus or in other structures important to memory are depleted [5]. Cell death in memory structures is the main cause for memory loss and the broader implications of this pathological factor will be explored in the section on memory loss symptoms.

Orexin Neuron Activity Decrease

Like other neurons, orexin neurons, which are important for maintaining a wakeful state, show decreased activity after TBI [13]. Deficient orexin neurons cause sleep deprivation and decreased wakefulness, and these symptoms themselves can heighten the symptom of decreased memory, because sleep is important for memory storage.

Neurofibrillary Tangles and Amyloid-beta Plaques

In some moderate and severe cases of TBI, there are significantly higher percentages of neurofibrillary tangles and amyloid-beta plaques in the brain than in people who have not had TBI [2]. These pathological factors are associated with Alzheimer's Disease, and indeed, TBI can lead to AD for some people. Amyloid-beta plaques are one of the factors that can lead to more neuronal death through the p53 pathway [12]. Usually, people with TBI who have dementia-like pathology are also the ones likely to see their general symptoms worsen over time [2].

Memory, Learning, and Attention Deficiencies

The most common symptom of traumatic brain injury is memory loss. The initial impact can often cause post-traumatic amnesia, an immediate loss of memory of the events of the accident that caused the injury. More serious forms of memory loss, such as anterograde amnesia, involve not being able to form new declarative memories, while memories from before the injury remain intact. Retrograde amnesia may also occur, and describes when memories from before the accident are lost. People often experience mixed forms of anterograde and retrograde amnesia as the trauma affects many brain structures. The severity of amnesia varies greatly among individuals and is often related to the severity of the injury [15]. The particular brain structures damaged in different types of TBI-induced forgetting will be detailed below.

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Circuit's neurons important for LTP.
Thomson Reuters [16] (1998)

Hippocampal and Related Structures’ Damage

It is well documented that damage to the hippocampus and related structures results in varying degrees of memory loss. The type of memory loss is usually difficulty in acquiring, that is, encoding and consolidating new memories, because the hippocampus is important for forming memories. Thus, damage to the hippocampus is most commonly associated with anterograde amnesia. However, it has been noted that hippocampal damage can cause some sorts of retrograde amnesia, likely because it remains strengthened to some extent even in long-term memories [15].

Analysis of animal models shows that TBI does damage the hippocampus - for example, CA2/CA3 neurons in the hippocampus are killed in TBI rat models [5]. Large amounts of hippocampal neuronal death are more characteristic of moderate and severe TBI, as analyses of brain texture in individuals with mild TBI do not show differences in the structures of the hippocampus, the amygdala, or the thalamus when compared to these structures in people without brain injury. The damage in mild TBI patients may not be significant enough to be picked up by current technology [14]. Similarly, CT and MRI scans do not show strong differences between the brains of mTBI patients and controls [14]. This is not to say that people with mild TBI always come away with preserved memory - people with mild TBI can experience long-lasting amnesic symptoms, especially those that affect their ability to form new memories (anterograde) [14].

Interference with memory acquisition interferes with learning and cognitive abilities. Remembering in visual, auditory, and verbal tasks are impaired, even in many people with mild TBI [9]. Animal models also perform poorly on standard memory tasks such as the Barnes Maze test. After being in the maze and learning how to find a box in which they can escape, TBI rats took longer to find that box than non-injured rats [4].

Research has noted problems with all three of encoding, consolidation, and retrieval of hippocampal memory following TBI [15]. The connection between hippocampus to the frontal lobe is particularly responsible for the strength of episodic memory formation and is damaged in TBI to give way to anterograde amnesia [15]. It has been suggested that the key root of memory problems in people with TBI is impaired synaptic consolidation at the level of the hippocampus [17]. In a test of verbal learning, moderate and severe TBI patients were measured against control participants for how well they initially stored (encoded), learned (consolidated), and recalled what they learned after a long delay (retrieval). Shortly following injury, TBI patients performed worse than controls in all three levels of memory in the task. Encoding and retrieval went back to control levels after 6 months. However, slow rates of learning, or damaged consolidation, in TBI individuals persisted until the last testing date, a year after when they were injured.

Cortical Damage

The cortex can be damaged in TBI and is associated with retrograde amnesia, or forgetting memories that have already been formed. It is generally the neocortex that stores long-term memories, and is the area damaged that results in retrograde amnesia, although cortical areas surrounding the limbic system can also have the same effect [15]. Recent memories are more often lost than older ones, because older memories have had more time to be solidified in synaptic connections in the cortex.

One study points to the negative effects of cortical damage on forgetting recent memories. In it, animals were injured such that the cortex, but not the underlying hippocampus, was damaged. They verified this separation of damage by confirming that mitochondrial respiration was only decreased in the cortex, not in the hippocampus. Likewise, membrane potential was only compromised in the cortex. They performed a passive avoidance task, where animals had to learn to avoid an upper dark chamber in which foot shocks are given, and learn to move into a lower bright chamber where there are no shocks. TBI rats were slower to recall their learning and took longer on average to move to the bright chamber. This deficiency in TBI rats was seen up to 17 days after initial learning. Since learning deficits occurred only after there had been clear cortical damage, cortical damage in TBI is important to the symptom of forgetting [18]. It's important to remember that the interaction between hippocampus and cortex is important for late long term potentiation and memory consolidation, so damage to either of these structures in TBI has the potential to give rise to different types of memory loss.

Other Physical Symptoms

Sleep Disruption

Other symptoms of TBI include sleep disruption and problems with staying awake [13]. Animals with TBI show spend less overall time in a day cycle awake, and are less able to stand long bouts of forced wakefulness [13]. They also have more transitions from wakefulness to sleep or from sleep to wakefulness, so their sleep/wake stages are shortened and fragmented [13]. As is well documented in studies of memory, disruptions of sleep and the wake state can exacerbate memory loss.

Emotional Disturbance

Finally, TBI can cause emotional distress over the injury and its effects, as well as from damage to brain areas important for regulating emotion [9]. Brain changes can lead in some cases to difficulties with personal relationships as well as anxiety or depression [7].

Decreased Awareness of Symptoms and Time Disperception

Poor memory is also associated with poor awareness of memory deficits – in a group of individuals with TBI, those who had worse memory were least able to predict how they would score on memory activities [19]. Interestingly, people with moderate and severe TBI even showed less accurate estimations of short lengths of time. They also were less efficient at tracking a timed moving object according to its patterned movements [20].


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Mental Activity and Social Support.
The Trauma and Mental Health Report [21] (2014)


Rehabilitation is the most common treatment for TBI. In the time immediately after injury, medical support is given to ensure breathing and heart activity are alright. Shortly after, assessment of future rehabilitation steps takes place. Over the weeks, months, and years following injury, patients may receive weekly or daily therapies. If the TBI is very severe (i.e. the person was once in a coma or barely conscious for an extended amount of time), rehabilitation may require being in a home dedicated to their well-being [1].

People receive rehabilitation services for a number of different symptoms from various experts. Examples of these experts include psychiatrists and psychologists, physiotherapists, speech pathologists, and occupational therapists [1]. Rehabilitation is most effective when the team members for a patients are in communication with each other, and the time spent rehabilitating a patient is geared toward the specific symptoms of that patient. The aim of therapy is to alleviate the pain of the symptoms as much as possible and help patients live as functional and happy lives as they can [1].

Potential Drug Therapies and Injections

Much research now is looking at how the pathology of TBI can be treated directly. Targeted therapies focus on different particular factors to inhibit. One such factor is thrombin, which as mentioned above, is a clotting factor that is released because of brain bleeding, but sets off a number of toxic cascades that can result in neuronal death [5]. Since thrombin works through a family of receptors called PARs, inhibiting these receptors has been of great interest to people looking to find direct treatments for TBI. PAR-1 antagonists effectively block thrombin levels in an animal model [6]. In mice, thrombin levels correlated positively with poor performance on a memory task where mice were shown objects, and then later were in a room with objects, one of which was new. Mice with proficient memory - those uninjured and not injected with thrombin - spent a great amount of time with the new object [6]. Mice with mild TBI or those injected with thrombin spent no more time with the new object than with the old objects, demonstrating poor memory. When a PAR-1 antagonist was injected, injured mice (mice with TBI, or mice with thrombin injection) performed as well as controls on the memory task [6].

PP2, an Src Family Kinase Inhibitor
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PP2 improves memory of TBI rats
Adapted from [5] (2014)

As mentioned in the section about pathology, rats damaged by TBI showed a decreased number of neurons in the CA2/CA3 region of the hippocampus. An Src Famiy Kinase Inhibitor, PP2, raised the number of surviving neurons in the CA2/CA3 area of the hippocampus. Function improved as well – injured rats with PP2 showed improved performance on memory tasks such as the Morris Water Maze The Morris Water Maze tests how quickly, after learning to find a platform in a pool, rats can locate that same platform [5].

In another study involving the Morris Water Maze and TBI rats, one group was injured cranially and then injected in their ventricles with antisense oligodeoxynucleotides (ODNs), which attack the mRNA of Nav1.3 channels. The other group was injured in the same way, but not treated with ODN. The ODN-treated TBI rats showed higher retention of neurons in the CA3 and hilus of the hippocampus and better performance on the Morris Water Maze memory task than non-ODN-treated TBI rats [10].

Another compound, phenoxybenzamine, has shown promising results in animal trials for ameliorating the memory loss and motor deficiency symptoms of TBI. Rats in the study were either injured or uninjured, and injured rats were either given phenoxybenzamine or the inert saline. They were then tested on memory tasks a day, 1 week, 2 weeks, 3 weeks, and 30 days after injury. They were tested on the foot fault test, in which locomotive disability is gauged by how often a rat slips while walking across a grid. Rats treated with phenoxybenzamine performed better on a foot fault test than their injured saline-injected counterparts starting at 2 weeks after injury. The animals were also examined for performance on the Morris Water Maze test. Phenoxybenzamine-treated injured rats learned the MWM task faster than non-treated injured rats did, and performed better in remembering their training (which shows spatial memory proficiency) as well. Phenoxybenzamine-treated rats learned and had as good spatial memory as non-injured controls [22].

PFT-α is yet another drug that could potentially improve symptoms of TBI. It acts against p53, the apoptosis-encouraging factor that's increased in TBI. PFT-α is a tetrahydrobenzothiazole and may block glutamate excitation, or the function, transcription, or movement of p53. In a model of TBI in rats, those that were injured and treated with PFT-α performed better on a visual memory test than injured rats not treated with PFT-α. PFT-α treated injured rats also did better than non-treated injured rats on a Y Maze task, in which they had to learn to find a food reward in two arms of a Y-shaped maze. In both tasks, TBI rats treated with PFT-α did as well as control rats who had not been injured or given PFT-α. Most tellingly on the physical side of the experiment, PFT-α decreased the ratio of degenerating neurons to overall number of mature neurons. That is to say, PFT-α maintains higher number of neurons. Indeed, in culture with glutamate or oxidative stress, PFT-α has this same neuron-maintaining effect [12].

The studies of drugs and injected compounds in animals is exciting, although the next challenge for the field will be trying to come up with ways to adapt these treatments for human use.

Potential of Nutrition

Diet may be a potential tool for ameliorating the symptoms and related symptoms of sleep deprivation. In mice, a diet of branched chain amino acid supplements were shown to increase activity of orexin neurons in TBI rats [13]. The supplements helped decrease the number of switches from wake to sleep and sleep to wake states [13]. The diet also brought up levels of theta frequency in theta sleep which had been deterred by TBI [13].

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