Traumatic brain injury: Stress increase the likelihood of developing epilepsy

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For the over one million Canadians living with traumatic brain injury, the likelihood of developing epilepsy increases significantly because of their injury.

When faced with stress or anxiety, that likelihood increases even more dramatically.

While a clinically well-known phenomenon, exactly what is occurring in the brain to cause this relationship has always been unclear.

Now, Western researchers have demonstrated a key factor in this relationship is that an injured brain responds differently to stress hormones.

The team was able to show abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, they found a way to stop it from occurring.

In a publication for eNeuro, “CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury,” the research team used a rodent model of traumatic brain injury.

When the animals were subjected to a stressful and anxiety provoking situation, all developed epileptic seizures.

In controls with no injury, none developed seizure activity when a stressor was applied.

“We were able to see that the recordings of the electrical activity in the brains of these rats mirrored what we see in human seizure activity,” said Schulich School of Medicine & Dentistry professor Michael Poulter, lead researcher on the study. “We then were able to ask the question, ‘What is causing this to occur?'”

Poulter, a Robarts Research Institute scientist, and a team of researchers looked specifically a molecule called corticotrophin releasing factor – or CRF – which is secreted in the blood and neurons as part of our bodies’ natural stress response, which causes the body to make the stress hormone, cortisol.

CRF is also released within the brain where it modifies brain activity.


What is corticotrophin-releasing hormone?

Corticotrophin-releasing hormone is secreted by the paraventricular nucleus of the hypothalamus which, among other functions, releases hormones. 

Corticotrophin-releasing hormone has several important actions. 

Its main role in the body is as the central driver of the stress hormone system, known as the hypothalamic–pituitary–adrenal axis.

Corticotrophin-releasing hormone is given this name because it causes release of adrenocorticotropic hormone from the pituitary gland.

Adrenocorticotropic hormone in turn travels in the bloodstream to the adrenal glands, where it causes the secretion of the stress hormone cortisol.

Corticotrophin-releasing hormone also acts on many other areas within the brain where it suppresses appetite, increases anxiety, and improves memory and selective attention. Together, these effects co-ordinate behaviour to develop and fine tune the body’s response to a stressful experience.

Corticotrophin-releasing hormone is also produced throughout pregnancy in increasing amounts by the foetus and the placenta, with the effects of increasing cortisol.

Ultimately, it is the high levels of corticotrophin-releasing hormone that, along with other hormones, are thought to start labour.

Finally, in smaller quantities, corticotrophin-releasing hormone is also made by certain white blood cells, where it stimulates swelling or tenderness known as inflammation, particularly of the gut.

How is corticotrophin-releasing hormone controlled?

Corticotrophin-releasing hormone secretion is stimulated by nervous activity within the brain. 

It follows a natural 24 hour rhythm in non-stressed circumstances, where it is highest at around 8 a.m. and lowest overnight. 

However, corticotrophin-releasing hormone can also be increased above the normal daily levels by a stressful experience, infection or even exercise.

An increase in corticotrophin-releasing hormone leads to higher levels of the stress hormone cortisol which mobilises energy resources needed for dealing with the cause of the stress. 

High levels of stress hormones over a long period can have negative effects on the body.

Because of this, cortisol blocks the continued release of corticotrophin-releasing hormone and switches off the hypothalamus–pituitary–adrenal axis, which is known as a negative feedback loop.

Some effects of corticotrophin-releasing hormone in the brain can also be blocked by leptin, a hormone produced by fat tissue. 

This may be partly why corticotrophin-releasing hormone can control appetite.

What happens if I have too much corticotrophin-releasing hormone?

Abnormally high corticotrophin-releasing hormone levels are connected with a variety of diseases. 

Because it stimulates anxiety and suppresses appetite, too much corticotrophin-releasing hormone is suspected of causing nervous problems such as clinical depression, anxiety, sleep disturbances and anorexia nervosa.

In addition, high levels of corticotrophin-releasing hormone may also make certain inflammatory problems worse, including rheumatoid arthritis, psoriasis, ulcerative colitis and Crohn’s disease.

 Initially this might seem unexpected because raised levels of corticotrophin-releasing hormone in the brain can lead to increased glucocorticoids production, and glucocorticoids have an anti-inflammatory effect. However, research has revealed that when high levels of corticotrophin-releasing hormone occur in tissues outside the brain, they can actually have a powerful inflammatory action.

Increased corticotrophin-releasing hormone levels within the joints, skin or gut can therefore make these inflammatory conditions worse or even play a role in their development.

What happens if I have too little corticotrophin-releasing hormone?

Research has shown that people with Alzheimer’s disease have particularly low corticotrophin-releasing hormone levels.

Some scientists also suspect that a lack of corticotrophin-releasing hormone might cause chronic fatigue syndrome, sometimes called myalgic encephalomyelitis, where sufferers have problems with sleep, memory and concentration. 

However, further research is needed into both these topics before this can be confirmed.

During pregnancy, low corticotrophin-releasing hormone production by the foetus or the placenta can result in miscarriage.


What they found is that if they used drugs to block CRF activity they also changed the abnormal electrical signaling in the brain, and stopped the seizures from occurring.

“This was a really exciting finding.

If we can stop the abnormal brain activity, we are on the way to finding a treatment.

The hope is if someone has a brain injury, you could treat them pre-emptively with a drug that blocks CRF, you could then prevent the onset of the epilepsy down the road,” Poulter said.

The research team had previously shown that CRF is a key player in stress-induced epilepsy in non-brain injured models as well. In that study, they found that in a normal brain, CRF diminished the activity of a seizure-producing part of the brain, but in an epileptic model, it did the exact opposite—ramping up the seizure-producing activity instead.

More information: Chakravarthi Narla et al. CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury, eNeuro (2019). DOI: 10.1523/ENEURO.0334-18.2019

Provided by University of Western Ontario

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