Accumulated sleepiness, not sleep deprivation, worsens seizures: New discovery changes approach to epilepsy treatment

A study published in Nature Communications fundamentally changes our understanding of the relationship between sleep and epilepsy. An international team of researchers led by Amita Sehgal of the University of Pennsylvania showed that increased sleep pressure (sleepiness), rather than sleep reduction itself, increases seizure activity in organisms with an increased tendency to epilepsy.

Context: Why is this important?

Epileptic seizures often increase with sleep deprivation. This is well known both in clinical practice and in the scientific literature. However, why this happens has remained unclear. It was generally believed that it was due to a reduction in sleep time, which disrupts the balance of excitation and inhibition in the brain. But this study shifts the focus from sleep duration to “sleep drive” — the physiological need for sleep.

How was the study conducted?

The scientists used a fruit fly (Drosophila melanogaster) model of epilepsy with a parabss1 mutation that causes increased seizure activity. This is one of the most studied and reproducible models for studying epilepsy.

Approach:

• Researchers have induced sleep restriction in a variety of ways: caffeine, fasting, thermogenetic activation of neurons, and genetic mutations that increase activity.
• At the same time, they used a high-precision video system to record seizures in real time.
• The levels of seizures and the degree of physiological “sleep drive” (how much the body needs sleep) were compared.

Key finding:
Seizure activity increased only when sleep drive increased. When sleep was reduced without increasing sleepiness (as in some genetically modified flies), seizures did not increase.

What is sleep drive and how does it affect seizures?

Sleep drive is a biological pressure that has been building up in the body since the last time we slept. The longer we stay awake, the stronger the sleep drive becomes.

According to the authors' hypothesis, when sleep drive reaches a certain threshold:

• specialized neurons in the brain involved in sleep regulation are activated;
• These neurons increase the overall excitability of neural networks, including those involved in the formation of seizures;
• As a result, a state of increased risk of epileptic seizure occurs.

New Role for Serotonin and the 5-HT1A Receptor

The authors found that one of the key players in the formation of sleep drive is the serotonin receptor 5-HT1A. Its expression in sleep regulatory centers is critical for controlling the level of sleepiness.

What they did:

• Genetic editing was used to reduce the expression of the 5-HT1A receptor.
• This was found to reduce sleep drive and reduce seizure activity, even after sleep restriction.
• What's more, they tested buspirone, an FDA-approved drug that is a 5-HT1A partial agonist, and saw an anticonvulsant effect after sleep deprivation.

Medical significance of the discovery

1. Paradigm Shift:
   Previously, it was thought that seizure risk was linked to the amount of sleep. Now it appears that the quality of wakefulness and level of sleepiness play a key role.

2. New therapeutic avenue:
   If the results are confirmed in mammals, it might be possible to develop drugs that reduce sleep drive or block its effects, thereby preventing seizures.

3. Buspirone Potential:
   Drug previously used for anxiety may be repurposed to prevent nocturnal or sleep-deprivation-induced seizures in patients with epilepsy.

Conclusion

This study is one of the first to link the neurobiological mechanism of sleep and seizure activity at the level of specific neural circuits and receptors. It opens the way to the creation of fundamentally new approaches to the treatment and prevention of epilepsy, especially forms that are aggravated by sleep disturbance.