ALS disrupts sleep, but an insomnia medication may help

Clinicians and researchers once thought that the deadly neurodegenerative disease amyotrophic lateral sclerosis (ALS) was very selective, in that it killed motor neurons in the brain and spinal cord but left other neurons untouched. “This is completely wrong,” said Luc Dupuis, a neuroscientist at the University of Strasbourg. “The rest of the brain is actually affected earlier.”

Many people with ALS start to experience weight loss up to 15 years before their motor symptoms manifest, and in 2023 Dupuis tied this change to the loss of certain neurons in the hypothalamus, which regulates both essential sensations like hunger and functions like sleep (1). Dupuis grew curious if changes in the hypothalamus might be responsible for the poor sleep quality that researchers have observed in ALS (2).

In a recent Science Translational Medicine study, Dupuis and his team showed that people with a recent ALS diagnosis as well as younger, seemingly asymptomatic people who carried mutations that cause familial ALS had altered sleep cycles (3). Administering sleep hormone therapeutics to mice with ALS-like symptoms helped to normalize the animals’ sleep, suggesting that these medications could alter disease progression or at least improve quality of life for people with ALS.

You want to turn ALS into a disease that people can live with.”
-Shyuan Ngo, University of Queensland

As people with ALS lose the neurons that control their diaphragm, they struggle to breathe, and shallow breathing can cause them to wake up frequently in the night. “But this is secondary,” said Dupuis. “The question we wanted to ask was whether there could be sleep problems long before the disease.”

That’s why he and his team chose to study people with ALS who had yet to experience respiratory symptoms and asymptomatic younger relatives of patients who had ALS caused by inheritable genetic mutations. The scientists measured the brain activity of sleeping participants via electroencephalography (EEG). Even though they did not have any complaints about their sleep, the researchers found that both groups spent more of their sleep cycle in a state of wakefulness and less time in deep sleep. These changes even occurred in younger relatives in their forties, who were likely 20 years away from manifesting symptoms.

“It’s a really good first step,” said Shyuan Ngo, a neuroscientist at the University of Queensland who was not involved in the study. She hopes that Dupuis’ team will track the study participants over time to see if and how sleep alterations relate to the onset and severity of symptoms.

In the meantime, Dupuis wanted to explore whether interventions that target sleep could be worth pursuing for people with ALS. To do so, he turned to mouse models of the disease. First, his team used EEG and found that mice with three different mutations that cause ALS-like symptoms experienced increased wakefulness and less time in deep sleep, like humans.

To find out whether these sleep disturbances could be treated, Dupuis and his team gave two of their mouse models melanin-concentrating hormone (MCH), which promotes sleep and releases from the hypothalamic neurons that Dupuis had previously found depleted in people with ALS.

Purple neurons in a spinal cord section against a black background. — Dupuis took spinal cord sections from mice with ALS-like symptoms and stained them for motor neurons. A mouse treated with MCH (left) retained more motor neurons than an untreated mouse (right).
Credit: Matei Bolborea/Luc Dupuis

The results were mixed. Both groups of mice experienced less wakefulness and spent more time dreaming, but only one spent more time in deep sleep. In fact, MCH exacerbated the deep sleep deficit for the second group of mice.

Nevertheless, the mutation in the second group of mice causes such rapid loss of motor neurons and paralysis that Dupuis and his team were able to check how early MCH treatment affected late-stage disease outcomes for those animals. Although the mice did not survive longer than their untreated counterparts, they retained more of the neurons in their lower spinal cord later into the course of their disease.

Part of the issue may have been that Dupuis’ team delivered MCH continuously. “It did not respect at all the circadian rhythm,” he said. Consequently, the mice were always a bit drowsy, not well-rested.

Dupuis’ team then gave all three groups of mice the insomnia medication suvorexant, which inhibits the wakefulness hormone orexin, at dawn when the nocturnal rodents naturally become sleepy. Although he had never observed a loss of orexin-releasing neurons in people with ALS, he figured that a drop in MCH levels might coincide with a rise in orexin levels because of the two hormones’ antagonistic relationship. “It’s a tug-of-war between MCH and orexin neurons to regulate sleep,” said Dupuis.

Sure enough, suvorexant normalized the sleep cycle in each mouse model of ALS. Now that Dupuis and his team have evidence of the medication’s immediate impact, they want to see what happens if they give it to the animals over longer periods of time. Dupuis wants to move quickly to see if this pill, which the FDA has already approved for insomnia, could help people with ALS.

Both Dupuis and Ngo consider ALS to be less of a clearly defined disease and more of a syndrome with environmental and genetic causes that vary from person to person. Ngo said that even though there is not currently evidence that poor sleep plays a causal role in the disease or its progression, better sleep quality would improve quality of life for everyone, including people with ALS.

“You want to turn ALS into a disease that people can live with,” said Ngo.

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