Why Lack of Sleep Increases Seizure Risk?

On July 29, 2025, Amita Sehgal of the University of Pennsylvania published a significant paper in the journal Nature Communications, titled "Sleep drive, not total sleep amount, increases seizure risk."

This research reveals a crucial distinction in our understanding of sleep and neurological health. The findings suggest that sleep drive—which is the homeostatic pressure to sleep that builds up during wakefulness—is a more critical factor in seizure susceptibility than the simple metric of total sleep amount.

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Overview

Sleep deprivation has long been associated with an increased risk of seizures. Using a fruit fly model of epilepsy with automated video monitoring for spontaneous seizures, the authors discovered that the exacerbation of seizures only occurred when sleep restriction elevated homeostatic "sleep drive," and not simply due to a reduction in total sleep time.

Further experiments reinforced this distinction:

• Acute activation of pro-sleep neural circuits worsened seizures because it increased sleep drive without changing the actual amount of sleep.
• Following sleep loss, these pro-sleep neural circuits became overactive, which was correlated with an increase in whole-brain activity.
• Conversely, during sleep restriction, using optogenetics to inhibit these pro-sleep circuits and thereby reduce sleep drive offered protection against seizures.
• The study also identified a specific molecular mechanism, showing that the downregulation of 5HT1A serotonin receptors in sleep-promoting cells mediated the effect of sleep drive on seizures.

Ultimately, the findings suggest that while homeostatic sleep is essential for compensating for lost sleep, the corresponding increase in sleep drive comes at the cost of heightened seizure susceptibility. This research provides a crucial new perspective on the intricate relationship between sleep regulation and epilepsy.

Fig.1 This schematic depicts how the homeostatic sleep drive increases the risk of seizures.¹

Findings

Since the FDA approved fenfluramine for Dravet syndrome-related seizures in 2020, there has been widespread interest in using serotonin-based drugs to treat epilepsy. Fenfluramine improves seizure control by activating 5-HT1D and 5-HT2C receptors.

Research has shown that 5HT1A receptor agonists can suppress seizures triggered by drowsiness in fruit flies. The study even identified an FDA-approved drug, buspirone, as being effective in reducing these types of seizures.

However, broadly activating serotonergic neurons can actually make seizures worse. This suggests that any effort to increase serotonin levels must be highly specific to a particular 5HT receptor.

Even though there are more anti-epileptic drugs available than ever before, about a third of patients still don't respond well to treatment. This research suggests that focusing on new, non-traditional approaches could offer a solution. For example, improving sleep quality (like through a ketogenic diet) can help control seizures. Targeting the underlying mechanisms of how drowsiness affects epilepsy could provide new strategies for clinical management.

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Reference

1. Cuddapah, Vishnu Anand et al. "Sleep drive, not total sleep amount, increases seizure risk." Nature communications vol. 16,1 6967. 29 Jul. 2025, doi:10.1038/s41467-025-62311-x. Distributed under Open Access license CC BY 4.0, without modification.