Cracking autism’s sleep conundrum

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About 15 years ago, Ashura Buckley made an observation that intrigued her.
She was monitoring the overnight brain activity of children with autism or developmental delay using electroencephalography (EEG) and noticed that their brain wave patterns were strikingly different from those of their neurotypical peers.

Specifically, in their recordings, the patterns that mark different stages of sleep were often much harder to spot, says Buckley, a pediatric neurologist and sleep medicine specialist at the U.S. National Institute of Mental Health in Bethesda, Maryland. So much so that Buckley and her colleagues could sometimes guess who had a neurodevelopmental condition just by looking at the EEG.

Since then, Buckley has been working to decode the meaning of brain activity that occurs during sleep. In November, she launched a project to assess the genetics, sleep and behavior of neurotypical children and those who have been flagged for, diagnosed with or have an older sibling with a neurodevelopmental condition, such as autism.

The goal of the new study is to decipher whether electrophysiologic signatures can predict later behavioral issues, such as problems with communicating or socializing. Buckley and her colleagues plan to add data from the study to a freely available online repository.

And many other efforts now underway are taking aim at the complicated ties between sleep and autism — with good reason. Up to 86 percent of people on the spectrum have trouble sleeping, and sleep problems and autism overlap in myriad ways, research shows. Yet the relationship between the two, like the function of sleep itself, remains elusive. Sleep problems may contribute to or derive from autism traits — or both.

For years, disturbed sleep has been thought of as a side effect of autism, but mounting evidence suggests it may be a core feature, with shared underlying biology. By mining these connections, Richdale says, researchers could uncover clues about the roots of autism, discover markers that define subgroups of the condition or find new ways to help autistic people with intractable sleep problems.

One area in which the biology of autism and sleep problems coalesce is the regulation of sleep-wake cycles. The circadian clock governs sleep and other daily processes via the coordinated expression of ‘clock’ genes, and it is a major organizing system: “It’s basically involved in all aspects of brain function,” says Jonathan Lipton, assistant professor of neurology at Harvard University.

This 24-hour biological timer is also intimately connected to pathways involved in neurodevelopmental conditions, he says.

Alterations in several autism-linked genes affect the circadian clock.

What’s more, sleep deprivation exacerbates the gene-expression differences seen in the brains of SHANK3 versus wildtype mice, Peixoto’s team has found. Many of the differentially expressed genes are tied to the circadian clock.

For years, disturbed sleep has been thought of as a side effect of autism, but mounting evidence suggests it may be a core feature, with shared underlying biology.

Autistic children are more likely to have rare variations in genes linked to circadian rhythms and insomnia than are their unaffected siblings, according to a new study.

The findings support a genetic link between sleep, circadian rhythms and autism, says Thomas Jongens, associate professor of genetics at the University of Pennsylvania in Philadelphia, who was not involved in the study.

Most children with autism have trouble sleeping, which may exacerbate other challenges associated with the condition. Sleep problems hint at disruptions in the circadian clock, a cellular timer that keeps cells in sync with the day-night cycle.

Previous studies have highlighted a genetic basis for sleep disruption in autism: Mice missing BMAL1, a core circadian clock gene, have atypical social behaviors and motor difficulties, for example. And people with autism — even those who sleep well — are twice as likely as non-autistic people to carry alterations in genes that control the circadian clock.

But the new study took a “unique perspective” by focusing on copy number variants (CNVs) — deletions or duplications of large chunks of DNA — says Olivia Veatch, assistant professor of psychiatry and behavioral sciences at the University of Kansas in Kansas City, who was not involved in the work. That’s something that has not been done before, she adds.

The new work analyzed genetic data from 5,860 autistic children and 2,092 of their unaffected siblings from two genetic repositories, the Simons Simplex Collection (SSC) and MSSNG. (The SSC is funded by the Simons Foundation, Spectrum’s parent organization.) The study also included genetic information from 7,509 teenagers and adults from the general population.

Compared with their unaffected siblings and unrelated controls, the children with autism harbored more CNVs in 312 genes that govern the circadian cycle and in 1,053 genes associated with insomnia.

Yet only 39 percent of the autistic participants had one or more traits of insomnia, just below the 40 to 80 percent found in previous studies. Parent reports revealed no link between the CNVs and time spent sleeping. The findings were published 3 October in Translational Psychiatry.

“I was baffled they didn’t see an increase in sleep problems in the autism population, even if they had a CNV in a circadian or insomnia gene,” Jongens says.

One explanation is that the databases lack the detailed information required to identify sleep changes. The data were drawn from questionnaires that probed a single aspect of sleep — overall duration — and overlooked factors such as the amount of rapid-eye-movement (REM) sleep someone gets, or how many night awakenings she experiences.

“We don’t have the level of granularity that we would really want,” says study investigator Rackeb Tesfaye, a graduate student in Mayada Elsabbagh’s lab at McGill University in Montreal, Canada.

What’s also missing from the databases is any information about the approaches the participants’ families might have used to promote better sleep, such as melatonin supplements or avoiding screen time in the evening. Because the data come from “parents who are involved enough to go to a scientific study, they may be more proactive [than others] at dealing with their kid’s problems,” Jongens says.