Cobbers on the Brain

Picture 1: Impact to the brain[1].  

Concussion or mild traumatic brain injury(mTBI) is something that is prevalent, especially within sports, and something quite a lot of people experience in their lifetime. Recently, there has been an increase in the interest in researching the biological bases of concussions, and with more advanced neuroimaging it allows to look at the pathophysiology post-injury.

Definition of concussion/mild TBI:

The hallmarks of concussion or mTBI can be defined by having impaired neurobiological signs and symptoms after having biomechanical force to the brain. Described as a neurometabolic cascade of events, these involve bioenergetic challenges, cytoskeletal and axonal alterations, impairments in neurotransmission, vulnerability to delayed cell death and chronic dysfunction. It was found in adult animals that the impaired metabollism that comes post-injury can last up from 7 to 10 days, and was additionally found to be associated with behavioral impairments in spatial learning[2].

Symptoms and signs of concussion: [3]

Artstract: Typical symptoms and signs of concussions illustrated.

The acute pathophysiology: 

There are a various acute neurometabolic changes that occur in the brain after a concussion and has been described as a neurometabolic cascade of events. This cascade involves bioenergetic challenges, axonal and cytoskeletal alternations, neurotransmission impairments, vulnerability to delayed cell death and chronic dysfunction[4].

As illustrated in Figure 1 an ionic flux and hyper acute indiscriminate glutamate release happens as a result of the biochemical injury. In an effort to restore the ionic and homeostasis, the membrane ionic pumps that are APR causing hyperglycolysis (overdrive). This created relative depilation of intracellular energy reserves, and also increases levels of ADP. The intra-axonal calcium flux can result in loss of structural integrity in axons and cause cytoskeletal damage as neurofilaments side-arms can be phosphorylated and collapse. Further the damages to the neurofilaments and additionally microtubules lead to axonal dysfunction and is potential for disconnection. Lastly, an alteration in glutamate, NMDA, receptor subunit composition and function can be found after a concussion, this alters neurotransmission. This alteration interferes with normal developmental plasticity, electrophysiology, and memory[5].

Figure 1: The acute cellular biological processes that occur after a concussion or a mTBI[6].

The various activations and infiltrations of the microglia was found to cause inflammatory changes in the brain. After a TBI there is an extensive upregulation of cytokine and inflammatory genes. While for cell death, mTBI generally show little cell death, but with the impact of repeated mTBI may cause functional impairments, and there may be longer-term structural changes[7].

As for the repeated concussive injuries since the intracellular redox state is altered in the concussed brain if it`s hit with another impact it puts additional stress on the damaged free radicals and shifted metabolic pathways. That can trigger impairments that are longer lasting and is why the brain is more vulnerable to repeated injury[8].

Age differences with susceptibility and severity:

The young brain concusses more easily than the adult brain and can often have worse prognosis for the outcomes after the injury[9]. mTBI has demonstrated damage to white matter and have been associated with cognitive impairments. The injury disturbs growth and development in the brain. It was found in 2017, that TBI is the leading cause of death and disability in children[10]. As for adults over the age of 65, they were found to be four times more likely to have a negative outcome from a mTBI[11]. Additionally, there might be a gender difference in susceptibility for concussion, where females are more susceptible than males.

BIBLIOGRAPHY

[1] What to do if someone is showing concussion symptoms. (2022, July 25). Livi. https://www.livi.co.uk/your-health/concussion-symptoms/

[2] Giza, C. C., & Hovda, D. A. (2014). The new neurometabolic cascade of concussion. Neurosurgery, 75 Suppl 4(0 4), S24–S33. https://doi.org/10.1227/NEU.0000000000000505

[3] Concussion; Symptoms and causes. Mayo Clinic. (2024, January 12). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/concussion/symptoms-causes/syc-20355594

[4] Giza, C. C., & Hovda, D. A. (2014). The new neurometabolic cascade of concussion. Neurosurgery, 75 Suppl 4(0 4), S24–S33. https://doi.org/10.1227/NEU.0000000000000505

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Tator C. H. (2013). Concussions and their consequences: current diagnosis, management and prevention. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, 185(11), 975–979. https://doi.org/10.1503/cmaj.120039

[10] Araki, T., Yokota, H., & Morita, A. (2017). Pediatric Traumatic Brain Injury: Characteristic Features, Diagnosis, and Management. Neurologia medico-chirurgica, 57(2), 82–93. https://doi.org/10.2176/nmc.ra.2016-0191

[11] Lele A. V. (2022). Traumatic Brain Injury in Different Age Groups. Journal of clinical medicine, 11(22), 6739. https://doi.org/10.3390/jcm11226739

Traumatic Brain Injuries

Concussions are brain injuries that happen when your head is hit and can affect the way the brain works. Symptoms include headaches, hypersensitivity, and problems with learning and sleep. Most concussions in kids happen while playing sports, but they can also happen in a car accident, a fight, or a fall. In the medical world, concussions are known as mild traumatic brain injuries (mTBIs) and while they may be labeled as “mild,” the effects are anything but, making it an important topic for the public to take seriously. Concussions are being looked at with increasing concern for long-term impairment caused by chronic altered neurotransmission, an energy crisis, and axonal dysfunction.

Figure 1. An interesting article titled “A Gray Matter” by the NCAA regarding concussions in athletes (2).

To understand the symptoms, let’s take a closer look at the neurochemical events that occur right after a concussion. Functionally, concussions cause ionic shifts, hypometabolism, and impaired neurotransmission. These changes cause a neurometabolic cascade, leading to acute responses and chronic dysfunction.

Figure 2. The neurometabolic cascade that occurs following a concussion highlights the simultaneous impact of ionic flux, the energy crisis, and axonal injury on neurotransmission (1).

Altered Neurotransmission

When the injury occurs, the membrane gets leaky, and too much calcium ions come into the cell which causes an imbalance. The neurotransmitter glutamate also gets released in excess, this triggers the cell to depolarize and diffuse a “spreading depression-like” state. The way ionic flux contributes to migraine symptoms of concussions is in the hyperacute release of glutamate which can lead to excitotoxicity. Changes in NMDA receptor activity and excitatory/inhibitory imbalances cause altered neurotransmission post-concussion.

In the immature brain, metabolic changes are short-term, but axonal vulnerability may last longer. TBIs to immature brains are more vulnerable to long-lasting deficits in learning and memory because of the loss of experience-dependent plasticity.

Energy Crisis

Simultaneously in an effort to restore the ionic imbalance and return to homeostasis, an energy crisis occurs as the ATP-driven sodium/potassium ion pump becomes overactive. This causes hyperglycolysis, which is when there is an increase in glucose levels to support reduced blood flow and brain function (or healing in the case of concussions), and depleted intracellular energy (ATP) reserves. This shortage of ATP causes hypometabolism.

Because there is an increase in calcium coming into the cell, the mitochondria takes up excess as a short-term solution. The amount of calcium being taken into the cell for extended periods leads to mitochondrial dysfunctions and problems with oxidative metabolism.

Energy Crisis and Vulnerability to a Second Injury

The risk of a second concussion is the greatest in the first 10 days postinjury because of the ongoing energy crisis trying to heal your brain. The timing of repeat injuries has significant consequences on symptomology and long-term impacts as well.

Figure 3. The Energy Crisis is why the brain is so vulnerable to a second TBI injury (3).

Axonal Dysfunction

The force of the concussion also results in damage to microstructural components of neurons, like the axons and dendrites. The biomechanical stretch of axons disrupts microtubules, and the calcium influx causes neurofilaments to collapse, compromising axonal integrity and impairing neurotransmission. Axonal dysfunction in mTBIs often results in damage to white matter tracts, which are bundles of axons that connect different brain regions. While mTBIs are considered “mild,” the cumulative effects of repeated axonal dysfunction can have long-term consequences, especially in immature brains.

The impaired cognitive functioning and slowed reaction times observed in individuals with concussions could be from slower conductance, damage to cerebral networks, or impaired neurotransmission. One aspect that needs to be studied further is whether damaged axons can recover fully and if neurons can survive after axonal disconnection. This issue is particularly problematic in cases of repeat mTBIs where insufficient time for recovery between injuries, immature myelination, or genetic vulnerabilities may increase the risk of long-term effects.

Figure 4. The different types of axonal injuries that are experienced post-concussion (4).

Chronic Dysfunction: A Lingering Impact

The occurrence of repeat mTBIs before your brain is fully recovered can cause long-lasting metabolic changes because chronic energy crises trigger protease activation and cell death, leading to brain atrophy. Altered protein degradation after mTBIs can lead to the accumulation of toxic proteins like tau. 

I Have a Concussion… What Now?

Rest and let your brain heal!

ARTstract created by Kate Loidolt on canvas depicting the pressure of returning to sports after a concussion.

References

What is a mild traumatic brain injury and how do they happen?

Mild traumatic brain injuries (TBIs) are also referred to as concussions. They occur due to not only a bump or blow to the head, but also jolting the head too quickly. Essentially, the hit and movement of the head moves the brain too quickly. This causes chemical changes and stretching and damaging to brain cells. These are very serious injuries that may result in various symptoms [1]. Common symptoms of a concussion often mirror that of migraines including headaches, dizziness, nausea, and more. However, depending on the extent of the injury, it may result in cognitive and behavioral alterations [2].

What events take place in the brain after a mild TBI?

An article by Giza and Hovda discusses the fundamental neurometabolic cascade post-concussion (2014). The authors explain that the injury first begins with a potassium efflux, meaning it is leaving the cell, and sodium and calcium influx where these molecules flood into the cell. This triggers channels (voltage and ligand gated) to open and defuse through the rest of the cell. In an attempt to return to homeostasis, ATP membrane ionic pumps begin to work harder, and intracellular calcium is released, which furthers the energy crisis occurring in the cell because ATP is being utilized too much alongside mitochondrial dysfunction.

More specifically, intra-axonal calcium that is released to return the cell to homeostasis causes damage to neurofilaments and microtubules. This causes axonal dysfunction or even disconnection as these are two structures that are critical for structure and transportation within the axon. Each of these occurrences within the cell change ligand-gated excitatory and inhibitory neurotransmission, specifically for glutamate and GABA. Ultimately, downstream signaling and influx development is impacted causing vulnerability to comorbidities like anxiety disorders [2].

Common comorbidities

While neurological and psychiatric comorbidities are most commonly thought of due to the bodily region of the injury, others such as cardiovascular, endocrine, and respiratory can commonly occur as well. This makes sense because the brain is the control center for the rest of the body. Excitatory and inhibitory neurotransmission not only tells your body how to feel but also how to act. However, psychiatric comorbidities are among the most prevalent. Figure 1 displays the top 10 comorbidities seen in individuals as stated from a study by Sudhakar et al. (2023). The authors of this study explain how comorbidities are most likely to occur five years after the TBI has occurred with younger individuals (<50 years of age) being at increased risk for them [3].

Figure 1. Top 10 comorbidities with concussions [3].

Long term comorbidities and disorders

After repeated exposure to TBIs or more severe head injuries, long term neurological disorders may occur due to permanent damage in the brain such as cell death. Examples of these may include Chronic Traumatic Encephalopathy (CTE) which occurs after repeated head injuries which lead to a buildup of tau proteins, causing cognitive and behavioral changes. Another is Post-Concussion Syndrome (PCS) where the symptoms of the concussion last for an extended period of time. Interestingly, because of the connection of tau proteins, plaques, and cell death, risk for neurodegenerative diseases is also possible as the accumulation of brain damage may contribute to diseases such as Alzheimer’s. However, this proposition has yet to be studied further [4].

Tying it all together

Overall, mild TBIs are serious injuries that must be taken seriously. The neurometabolic cascade that occurs after them pose irregularities in excitatory and inhibitory neurotransmission that may contribute to different forms of comorbidities depending on where the brain is injured. This, as shown in figure 2, all comes together as the overall concussion symptoms that the individual faces. These comorbidities consist of psychiatric disorders such as depression and anxiety, cardiovascular comorbidities like hypertension, musculoskeletal, and more. Furthermore, even after the individual returns to normal activities, comorbidities may occur both short term and long term.

Figure 2. Conditions leading to overall concussion symptoms.

Fig.2. artstract created by M. Olson

Resources

[1] Mild TBI and Concussion | Concussion | Traumatic Brain Injury | CDC Injury Center. (2022, November 14). https://www.cdc.gov/traumaticbraininjury/concussion/index.html

[2] Giza, C. C., & Hovda, D. A. (2014). The New Neurometabolic Cascade of Concussion. Neurosurgery, 75(0 4), S24–S33. https://doi.org/10.1227/NEU.0000000000000505

[3] Sudhakar, S. K., Sridhar, S., Char, S., Pandya, K., & Mehta, K. (2023). Prevalence of comorbidities post mild traumatic brain injuries: A traumatic brain injury model systems study. Frontiers in Human Neuroscience, 17. https://doi.org/10.3389/fnhum.2023.1158483

[4] Madwire. (2023, September 21). Understanding the Link Between Concussions and Neurological Disorders. Atlanta Neuroscience Institute. https://atlneuroinstitute.org/blog/understanding-the-link-between-concussions-and-neurological-disorders/

Picture 1: Stress and the Brain[1]

Most people face stressful situations often in their days, and we move on and go about our days. But what happens when we endure a psychologically stressful, traumatic event, how does that impact us and how does it impact our brain?

When you are exposed to long-term and chronic stress, this can lead to behavioral changes and changes in epigenetic regulation for gene transcription. When we are in traumatic or psychologically stressful situations we tend to form stronger memories, as it might be our bodies natural defense mechanism towards the event. However, creating stronger memories can also lead to the development of anxiety disorders like post-traumatic stress disorder (PTSD). PTSD is a disorder that can have serious comprimieses for the person’s quality of life over a long period of time, even lifelong. PTSD can develop as a result of damage and/or dysfunction of the dentate gyrus (DG) and other parts of the hippocampus[2]. About 10-20% of people who experience a traumatic event develops a stress-related disorders[3], such as PTSD.

Memory formation

We form memories because it allows us to interact in our environment, and to have the ability to build representations, understand and adapt to changes in the environment. In support of stronger memories being formed during stressful events, in hippocampus based behavioral models it was found that when we are exposed to a stressful event the stress-indices glucocorticoid hormones enhance the memory consolidation. The enhanced memory consolidation happens at the DG cellular level. Inputs from the hypothalamus and amygdala results in excitability of dentate neurons which can translate to an enhanced likelihood of NMDAR mediated activation of dentate granule neurons. This further leads to the activation of signaling, epigenetic, and changes within gene transcription that are all required for consolidation of memory[4]. Additionally, an important hormone is glucocorticoids, which are needed for memories associated with stressful challenges to be acquisitioned and consolidated.

What happens in the brain when a person is exposed to psychological stress?

When someone experiences psychological stress that activates the GR and NMDAR-ERK-MAPK pathways. GRs bind to intracellular receptors, and affects gene expression. The interaction of ERK1/2 and GR facilitates PERK1/2 to phosphorylate MSL1/2 and Elk-1. A result of this is the phosphorylation and acetylation of the histone dual mark H3S10p-K14ac, which allows genre transcriptions of the immediate early genes (IEGs), c-fos and erg1. These IEGs require the formation of H3S10p-K14ac in order to open up for transcription binding and the induction of gene transcription. This initiation of gene transcription is important for consolidation of memory formation with a traumatic or psychologically stressful event[5]. Figure 1, shows the signaling patway after exposure to psychological stress. So when a person is exposed to prolonged or psychological stressors there is an increased stimulation. And a factors that play a major role in modulating the effects of anxiety is GABA, which effects the responsiveness of dentate neurons to stressful events. GABA can be essential to prevent anxiety.

[6]

Figure 1: the psychological stress-activated signaling pathway that happens in the dentate gyrus, which modifies gene transcription, and consolidates memory formation and behavioral responses. 

Animal Models

The findings relating the pathways has been supported by animal models that study forced swimming induced behavioral immobility. The forced swimming test, rats or mice are put in a container that is filled with water and which they cannot stand in, testing how long the behavior of struggling and climbing movements appear, before an immobile or floating posture happens. Their immobility response is related to the NMDA-MEK-ERK-ELK/MSK pathway, and the phosphorylation. Alongside with GRs which in the DG are important for the consolidation of the behavioral response from the mice or rats.

Environmental factors

There has been suggestions that people who are more anxious are more likely or have an increased risk for developing PTSD after encountering a traumatic event[7]. Generally, feelings of anxiety are caused by environmental factors, and in relation to epigenetics, it shows how our behavior and environment cause changes in how the brain works. Which can be seen in the animal models and the study for forced swimming as this posed as an environmental challenge for the mice and rats. So, it might pose a question or suggestion that there might be genetic factors or implications that makes certain people more susceptible or vulnerable to develop PTSD? This topic would be interesting for further research.

Bibliography

[1] https://edrcsv.org/mercury-news-pandemic-stress-prematurely-aged-teens-brains-stanford-study-finds/

[2][3][4][5][6][7] Reul, J. M. H. M. (January 2014) Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. Front Psychiatry, volume 5. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2014.00005/full