A concussion is a minor traumatic brain injury (TBI) that affects the function and structure of the brain. The functional abnormalities cause symptoms such as memory and attention impairment, headache, and alteration of mental status. After a concussion, there are tissue changes within the brain due to the direct trauma as well as from cerebral blood flow changes which can lead to secondary ischemic injury. There are three main types of concussions. These include focal (brain injury is located where the brain was hit), linear (brain injury when there is no direct contact such as in whiplash), and the most severe, rotational (results from a sudden head twist that temporarily separates the brain stem and spinal cord).

A focal concussion is the most common in which there is a sudden direct blow or bump to the head. There are a few common physical, mental, and emotional symptoms an individual may display following a concussion, including confusion, clumsiness, slurred speech, nausea, headache, sensitivity to light/noise, concentration difficulties, and memory loss. The level at which these symptoms occur is based on how severe the concussion is. Concussions are graded as mild, moderate, or severe. In a mild concussion, symptoms last for less than 15 minutes and there is no loss of consciousness. In a moderate concussion, there is no loss of consciousness but symptoms last longer than 15 minutes. In a severe concussion, there is a loss of consciousness. Secondary injuries that appear several hours or days after the trauma are critical to monitor as these secondary tissue damages are frequently the origin of significant long-term effects, including brain damage, cognitive deficits, and behavioral/emotional changes.

During a concussion, the brain, which is made of soft tissue, is moved rapidly back and forth causing the brain to bounce inside the skull, stretching and damaging the delicate cells and structures inside of the brain. Secondary injuries which are activated in the brain due to the concussion, cause a production of harmful chemicals like free radicals, inflammation, impaired transport of molecules within nerve cells, and imbalances of key ions needed for nerve function.² Different parts of the brain can move at different speeds, which produces shearing forces that can stretch and tear nerve tissue. This mechanical insult initiates a complex cascade of metabolic events that leads to neuronal homeostatic imbalances.¹ In a healthy brain, the brain cells maintain a balance of salts and electrolytes inside and outside of the cell with the consumption of energy. When the brain becomes damaged such as in a concussion, the membrane of the cell leaks in potassium while sodium leaks out. This causes the cell to utilize more energy than normal and the effect is the brain cells deplete its energy and do not work properly in that particular region.3 Brain trauma also causes a release of toxic excitatory neurotransmitters such as glutamate which results in further brain cell injury and dysfunction.³ Blood flow to the site of injury is also reduced, which hinders the delivery of oxygen and nutrients needed for recovery.²

Lipid metabolism is of particular importance for the CNS, as it has a high concentration of lipids, second only to adipose tissue. Altered lipid metabolism is also believed to be a key event which contributes to CNS injury. There are eight types of lipids, one being phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol. Phospholipids are important components of all mammalian cells and have a variety of biological functions including formation of lipid bilayers of cell membranes; function as an energy reservoir (for example, triglycerides); and serve as precursors for various second messengers, such as arachidonic acid (ArAc), docosahexaenoic acid (DHA), ceramide, 1,2-diacylglycerol (DAG), phosphatidic acid and lyso-phosphatidic acid.

'Oxidative stress' occurs with increased levels of free radicals or reactive oxygen species (ROS) when blood flow is reduced and cells don’t have enough capacity to detoxify them due to a TBI. ROS then cause oxidative damage to nucleic acids, proteins, carbohydrates and lipids. ROS can attack the unsaturated fatty acids (PUFAs) in the phospholipids and cause lipid peroxidation which is very damaging to the cell membrane as well as the entire cell structure. Such deregulated lipid metabolism is believed to be associated with not only TBI but also in many neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, schizophrenia, bipolar disorders, epilepsy, and stroke.

Microglia, which have a variety of functions in the brain, become rapidly active in response to a TBI. Early microglial activation is beneficial as it may contribute to the restoration of homeostasis in the brain. Unfortunately, if they remain chronically activated, microglia display a classically activated phenotype and release pro-inflammatory molecules and reactive oxygen species, resulting in further tissue damage and potentially neurodegeneration.5 This chronic inflammation can lead to scar tissue formation within certain brain structures.

Individuals who have suffered repeated concussions and brain injuries, such as sports players, are at risk of developing chronic traumatic encephalopathy (CTE) which is a neurodegenerative disease that can cause progressive cognitive decline and behavioral and emotional problems several years after the injuries. Many retired American football players have been shown to suffer from CTE. Symptoms of CTE include memory loss, depression, anxiety, headaches, and sleep disturbances that often gets worse over time and can result in dementia. CTE has also led to player deaths.4 According to the Boston University CTE Center, CTE is found in athletes, military veterans, and others with a history of repetitive brain trauma.⁴

The pathophysiology of CTE is a result of damage to the axons due to repetitive traumatic injury and neurodegeneration of the affected brain tissues. The concept of immunoexcitotoxicity has been proposed as a possible mechanism for CTE. A cascade of events begins with an initial head trauma, which “primes” the microglia for subsequent injuries. When the homeostasis of the brain is disturbed, some of the microglia undergo changes to set them in a partially activated state. When these microglia become fully activated by continued head trauma, they release toxic levels of cytokines, chemokines, immune mediators, and excitotoxins like glutamate, aspartate, and quinolinic acid. These excitotoxins inhibit phosphatases, which results in hyperphosphorylated tau protein and eventually neurotubule dysfunction and deposition of neurofibrillary tangles (NFTs) in particular areas of the brain.⁹

Damaged blood vessels and vasculitis within the brain could also trigger brain inflammation and, eventually, the development of proteins such as Tau, which clump and slowly spread throughout the brain in CTE. ⁴

The microglia cell can also remain primed from insults to the brain from infections in the brain, environmental toxins, and latent viral infections in the brain such as cytomegalovirus and herpes simplex virus.¹⁰ A number of studies have linked the risk of Alzheimer’s disease (AD) to latent viral infections in the brain. For example, the herpes simplex virus is strongly linked to AD risk.10 It may be that those at greatest risk of CTE following repetitive trauma are those with a combination of such risk factors.

References:

1. Signoretti, S., Lazzarino, G., Tavazzi, B. and Vagnozzi, R. (2011), The Pathophysiology of Concussion. PM&R, 3: S359-S368. doi:10.1016/j.pmrj.2011.07.018
2. Menon, D. (2015, June 11). What Happens in the Brain During and After a Concussion? Retrieved from https://www.brainfacts.org/ask-an-expert/what-happens-in-the-brain-during-and-after-a-concussion
3. The science behind concussions. (n.d.). Retrieved from https://www.xlntbrain.com/concussions/science/
4. What is CTE? (2020, April 15). Retrieved from https://concussionfoundation.org/CTE-resources/what-is-CTE
5. Donat, C. K., Scott, G., Gentleman, S. M., & Sastre, M. (2017). Microglial Activation in Traumatic Brain Injury. Frontiers in aging neuroscience, 9, 208. https://doi.org/10.3389/fnagi.2017.00208
6. Adibhatla, R. M., & Hatcher, J. F. (2007). Role of Lipids in Brain Injury and Diseases. Future lipidology, 2(4), 403–422. https://doi.org/10.2217/17460875.2.4.403
7. Ma, Z. F., Zhang, H., Teh, S. S., Wang, C. W., Zhang, Y., Hayford, F., Wang, L., Ma, T., Dong, Z., Zhang, Y., & Zhu, Y. (2019). Goji Berries as a Potential Natural Antioxidant Medicine: An Insight into Their Molecular Mechanisms of Action. Oxidative medicine and cellular longevity, 2019, 2437397. https://doi.org/10.1155/2019/2437397
8. Ying Peng, Mengjun Hu, Qi Lu, Yan Tian, Wanying He, Liang Chen, Kexing Wang & Siyi Pan (2019) Flavonoids derived from Exocarpium Citri Grandis inhibit LPS-induced inflammatory response via suppressing MAPK and NF-κB signalling pathways, Food and Agricultural Immunology, 30:1, 564-580, DOI: 10.1080/09540105.2018.1550056
9. Blaylock RL, Maroon J. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—A unifying hypothesis. Surg Neurol Int 30-Jul-2011;2:107
10. Itzhaki R. F. (2014). Herpes simplex virus type 1 and Alzheimer's disease: increasing evidence for a major role of the virus. Frontiers in aging neuroscience, 6, 202. https://doi.org/10.3389

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