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

Effects of Stress on Learning and Memory Processes

Psychologically stressful events evoke a long-term impact on behavior through changes in hippocampal function. These changes in glutamatergic, GABAergic, and glucocorticoid hormone signaling lead to altered regulation of gene transcription. Specifically, these epigenetic changes moderate the ERK/MAPK signaling pathway and the induction of c-fos and egr-1 genes.

Without memory, we could not function as human beings. We need memories to understand our environment and make decisions based on past knowledge. The hippocampus is an important brain region for memory formation. It’s vital for the consolidation of contextual memories. During stressful events, there is an increase in the secretion of glucocorticoid hormones (i.e. cortisol) that enhances memory formation in the hippocampus. The hypothalamus’s dentate gyrus (DG) is another important brain region involved in memory formation. The glucocorticoid receptors (GRs) in the dentate gyrus were found to be involved in the consolidation of adaptive responses based on memories of initial experiences.

In stressful events, we often form strong memories, however not all stressful events incapacitate people and keep them from their daily lives. So, why does 10% of the population develop PTSD? When people cannot adapt and cope after stressful events, they can develop an anxiety disorder like post-traumatic stress disorder (PTSD).

Figure 1. How stress affects our regulation of cortisol and impacts memory formation (3).

A Signaling Pathway Involved in Learning and Memory Processes

Calcium activates the NMDA receptor and mediates the ERK-MAPK signaling pathway. The activated ERK pathway helps form the dual histone marks in the DG granule neurons. When GRs are activated, they act like scaffold proteins for the ERK pathway), pERK1/2 then phosphorylates MSK1/2 and Elk-1. MSK phosphorylates serine (S10) and Elk-1 acetylates lysine (K14) of histone (H3) molecules within the c-fos and egr1 gene promoters. These modifications make histones less positive which causes DNA to unwind from them, allowing transcription factors to bind. Histone modifications and chromatin opening are needed to provide transcription factors access to their DNA binding sites.

Figure 2. Psychological stress-activated signaling pathways in dentate gyrus granule neurons drive epigenetic modifications underlying the induction of gene transcription and the consolidation of behavioral responses and memory formation in the hippocampus (1).

Epigenetics

Epigenetics is the study of how your behaviors and environment can cause changes that affect the way your genes work. Epigenetic changes that occur as a result of stressful events cause an increase in dual histone marks (H3S10p-K14ac). These dual histone marks are hypothesized to open chromatin’s structure by unraveling the histones from DNA so that transcription factors can bind to previously silent genes and IEG promoters. Immediate-early genes (IEGs) are crucial for memory formation, like c-fos and egr-1.

Nothing in Anxiety Disorders like PTSD makes sense, except in the light of stress-driven increases in dual histone marks and IEGs.

GABAergic Tone

The GABAergic system, known for its role in regulating anxiety states, influences the responsiveness of granule neurons in the DG to psychological stress. High anxiety levels are associated with low GABA activity, which can lead to debilitating effects. Balancing excitatory and inhibitory inputs is crucial for maintaining healthy information flow in brain circuits.

Figure 3. An imbalance of excitatory and inhibitory neurotransmission can lead to anxiety (2).

How do Strong Memories of Stressful Events Turn into PTSD?

When a stressful event overwhelms a person’s coping mechanisms, it can lead to the formation of strong memories. Overactive signaling pathways involving NMDARs, GRs, ERK/MAPK, MSK, and Elk-1 contribute to heightened stress responses and the consolidation of these memories. Higher levels of anxiety can further strengthen these memories and increase the likelihood of maladaptive responses to future stressful events.

Stressful situations have a profound impact on memory formation, often resulting in strong memories that can lead to anxiety disorders like PTSD. Understanding the intricate mechanisms involved, from epigenetic changes to neurotransmitter dynamics, is crucial for developing targeted interventions and therapies to support individuals affected by these conditions.

Figure 4. PTSD vs Anxiety (4).

References

Addiction

Artstract. Art found online that I believe depicts the detrimental impact psychostimulant drug use has on our brains.

Psychostimulant Use Disorder

Psychostimulant Use Disorder (PUD) causes changes in the brain’s reward circuit and glutamatergic neurotransmission. Because amphetamine-like psychostimulants have a similar structure (phenylalkylamines) to the endogenous catecholamine neurotransmitters (norepinephrine, epinephrine, and dopamine), psychostimulants are theorized to alter catecholamine neurotransmission. These changes lead to dopamine-driven reinforcement and drug-seeking behaviors (1).

Nothing in PUD makes sense, except in the light of altered brain neuroplasticity.

Figure 1. Psychostimulant structure compared to catecholamine neurotransmitters (2).

Psychostimulants

Psychostimulants are drugs that increase (“stimulate”) the CNS. They bind to extracellular catecholamine receptors (i.e. DA) to promote the release of neurotransmitters (NTs). They can also suppress monoamine NT reuptake and oxidase metabolism, which leads to elevated levels of NTs in the synapse.

Glutamate

Glutamate is the primary excitatory neurotransmitter in the central nervous system. Modulating glutamate neurotransmission has emerged as a promising approach for treating cognitive deficits associated with substance use disorders (SUDs), including PUD. When glutamate is released from presynaptic neurons, it diffuses through the synapse and binds to various glutamate receptors including ionotropic (such as NMDA and AMPA) receptors that are fast-acting and crucial for brain plasticity as well as metabotropic receptors. Metabotropic glutamate receptors are categorized into three groups:

Group 1

• mGluR1 & mGluR5
• postsynaptic
• Gq-coupled.

Group 2

• mGluR2 & mGluR3
• presynaptic
• Gi-coupled.

Group 3

• mGluR4 & mGluR6 & mGluR7 & mGluR8
• presynaptic
• Gi-coupled.

Figure 2. Distribution of mGluRs in the Brain’s Reward Circuit (1).

Neurocircuitry of SUDs: The Brain’s Reward Circuit

The reward circuit involves intricate interactions between dopaminergic projections from the ventral tegmental area (VTA), glutamatergic and GABAergic neurotransmission, and brain regions like the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc).

Dopamine activity in the brain is modulated by the VTA brain region. In reward processing and drug-seeking behaviors, glutamatergic neurons from the mPFC stimulate the VTA’s dopaminergic neurons to release dopamine in the NAc (1).

Figure 3. VTA plays an important role in the brain’s reward circuit (3).

Neuroplasticity and Memory Formation in PUD:

Alterations in synaptic strength, dendritic morphology, and receptor expressions are found in neurons associated with the brain’s reward circuits. Long-term potentiation (LTP) and long-term depression (LTD) in glutamate synapses, particularly in the hippocampus and mesocorticolimbic pathways play a crucial role in the altered neuroplasticity that comes from drug abuse.

Group 1 mGluRs have been found to affect synaptic plasticity in reward circuit brain regions in PUD cases. They modulate short- and long-term synaptic plasticity, including LTD, through intracellular signaling pathways involving phospholipase C (PLC) that increase learning, memory, and LTP. mGluR1 is thought to be involved in the acquisition process while mGluR5 has a role in retaining and maintaining spatial memories. Because group 1 mGluRs are located on the postsynaptic neuron, antagonist drug treatments have been found to reduce drug-seeking behaviors by blocking the reward signal from being passed on (1).

Figure 4. Antagonist drug treatments have been found to reduce addiction when targeting Group 1 receptors because they inhibit mGluRs on the postsynaptic cell.

Group 2 mGluRs negatively regulate glutamate release and are necessary for inducing LTD in the reward circuit. Because group 2 mGluRs are located on the presynaptic neuron, agonist drug treatments have been found to reduce drug-seeking behaviors by stimulating auto receptors to decrease the number of neurotransmitters released in the synapse (1). Group 3 mGluR’s role in PUD synaptic plasticity needs to be studied further, particularly mGluR7 and 8 in regions like the NAc, VP (striatum), and the hypothalamus.

Figure 5. Agonist drug treatments have been found to reduce addiction when targeting Group 2 receptors because they stimulate the mGluR auto receptors that self-regulate by reducing NT release.

Questions to Think About…

• Does the altered brain chemistry from addiction ever go back to the way it was?
• Can we unlearn memory/ the motivated driver of addiction?

References