Infant Brain Enlargements Increase Autism, Sleep Problems Risk

Dea Garic, PhD, and Mark Shen, PhD, of the UNC School of Medicine’s Department of Psychiatry, discovered that infant brain enlargement due to an accumulation of excess cerebrospinal fluid have a 2.2 times greater probability of having autism later in life.

Cerebrospinal fluid (CSF) pumps through small fluid-filled channels surrounding blood arteries in the brain, known as perivascular spaces, all day and night to flush away neuroinflammation and other neurological waste. This critical process can be disrupted, resulting in neurological malfunction, cognitive decline, or developmental delays.

Dea Garic, PhD, and Mark Shen, PhD, of the UNC School of Medicine’s Department of Psychiatry, discovered for the first time that children with abnormally expanded perivascular spaces have a 2.2 times greater probability of developing autism than infants with the same genetic risk. Their study also found that increased perivascular gaps in infancy are linked to sleep disorders seven to ten years later.

“These findings suggest that perivascular spaces may serve as an early indicator of autism,” said Garic, an assistant professor of psychiatry and member of the Carolina Institute for Developmental Disabilities (CIDD).

The infants tested were at a higher risk of having autism because they had an older sibling with autism. They tracked these babies from 6 to 24 months of age, before they were diagnosed with autism. Their research, published in JAMA Network Open, discovered that 30% of newborns who later acquired autism had increased perivascular gaps at the age of 12 months. Nearly half of the infants diagnosed with autism had increased perivascular spaces by the age of 24 months.

Cerebrospinal Fluid and Sleep: What You Need to Know
There has been a renaissance of study on the critical activities of CSF in regulating brain health and development over the last ten years. Shen’s lab was the first to demonstrate that increased CSF volume was seen in infants with autism at 6 months of age. Excessive CSF volume at 6 months was connected to larger perivascular gaps at 24 months, according to the current study.

Every six hours, the brain expels a wave of CSF that runs through perivascular gaps, removing potentially damaging neuroinflammatory substances like amyloid beta from the brain. Because the majority of CSF circulation and clearance happens when we sleep, the CSF cleansing process is highly efficient.

Disrupted sleep, on the other hand, can impair CSF clearance from perivascular spaces, resulting in dilatation or enlargement, however this has only been explored in animal research or adult human studies. This is the first such study in children.

Based on previous research, Shen, the senior author of the JAMA Network Open publication, and Garic expected that CSF abnormalities in infancy would be associated with later sleep disorders. According to the current sleep study, children with increased perivascular spaces at two years of age had a greater prevalence of sleep disruptions at school age.

“Because autism is so strongly linked to sleep problems, we were in this unique position to examine CSF dynamics and sleep,” said Garic, the paper’s first author. “It was fascinating to see such a strong association separated by such a long period of time throughout childhood.” But it truly demonstrates how perivascular regions can have long-term impacts as well as immediate effects.”

New Clinical Relevance in Infancy

The study was conducted in collaboration with the Infant Brain Imaging Study (IBIS), a countrywide network of researchers studying brain development, autism, and other developmental problems. The network is made up of five universities, with the University of North Carolina-Chapel Hill serving as the hub.

Garic and Shen used IBIS MRIs to measure increased CSF volume and expanded perivascular gaps for their study. MRIs were collected from babies while they were sleeping naturally at six, twelve, and twenty-four months of age in order to track changes over time.

During this time, the infant brain develops rapidly. Previously, it was considered that measuring perivascular gaps was only therapeutically useful for disorders of aging in older persons, such as dementia. These findings suggest that these types of brain anomalies should be investigated and monitored in younger populations.

“Our findings were striking, given that neuroradiologists typically view enlarged perivascular spaces as a sign of neurodegeneration in adults, but this study reported it in toddlers,” Garic added. “This is an important aspect of brain development in the first years of life that should be monitored.”

Future Scope

Garic and Shen hypothesize that extra CSF volume is sluggish, or blocked, and is not flowing as efficiently through the brain as it should. The researchers want to utilize MRIs to assess CSF in a sleeping infant’s brain again, but this time they will focus on the physiology and speed of CSF movement throughout the brain.

The research team is also collaborating with other groups to determine the amount of perivascular spaces and the severity of behavioral effects. The researchers also intend to expand their investigation into neurogenetic abnormalities associated with autism, such as Fragile X syndrome and Down syndrome.

“Collectively our research has shown that CSF abnormalities in the first year of life could have downstream effects on a variety of outcomes, including later autism diagnosis, sleep problems, neuroinflammation, and possibly, other developmental disabilities,” she added.

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