Brain Quality Control Selectively Eliminates Neurons with Abnormal Variants in Development
By analyzing genomic data from neurons, scientists from Harvard Medical School (HMS), Boston Children’s Hospital, and their collaborators have gained insights into a critical quality-control mechanism that takes place in the developing fetal brain.
During development, the human brain generates an excess of neurons, most of which are eliminated around when the baby is born. According to a study published this week in Nature, scientists report that neurons with multiple copy number variants, including DNA duplications or deletions, are widespread in the developing brain. However they are selectively eliminated shortly before or after birth likely because the genomic alterations disrupt their ability to form synapses.
Full details are provided in a paper titled “Perinatal elimination of genetically aberrant human cortical neuron.” The findings reported there are significant because copy number variants can impact brain function and may contribute to neuropsychiatric conditions, including autism, schizophrenia, epilepsy, and intellectual disability. A better understanding of the pruning process in the developing brain could improve how autism and other disorders in which neural development goes awry are treated.
As Diane Shao, MD, PhD, HMS instructor of neurology at Boston Children’s and a co-first author on the study noted, “If that quality control system can be disrupted, that could be part of what goes wrong in neurodevelopmental disorders like autism. Understanding the mechanism could eventually point us toward what to look for, and maybe what to protect.”
One of the first steps in the study was exploring the prevalence of copy number variants in developing human brains. To do that, the scientists designed single-cell whole genome sequencing approaches that allowed them to lightly sequence the genomes of single neurons. They used this method to sequence over 1,500 neurons from 16 individuals. They then validated the results with deeper sequencing of over 800 neurons from 12 individuals. They then used various computational methods to identify copy number variants in each sequenced genome. With their approach, it was possible to see the genomic changes “one neuron at a time, map where in the genome they occur, and compare how common they are from before birth to old age,” explained Peter Park, PhD, co-senior author on the paper and professor of biomedical informatics at HMS.
The data showed that an average of nearly 26 percent of neurons in the prenatal cortex had widespread copy number variants, but this rapidly decreased to an average of 6.2 percent after birth. Specifically, “neurons with widespread CNVs were mainly eliminated perinatally, timed roughly parallel to periods of programmed cell death, whereas neurons with smaller CNV burdens declined slowly in frequency with postnatal age,” the scientists wrote.
“We were totally unprepared for how common these were in early development,” said Christopher Walsh, MD, PhD, a co-senior author on the paper and professor of pediatrics and neurology at Boston Children’s Hospital. “But it makes sense in the context of what we know about the formation of excess neurons and in the context of the IVF literature.”
Next, the team explored the pathways through which the abnormal neurons are eliminated. By sequencing and analyzing DNA and RNA from over 44,000 individual cells, they found that neurons with widespread copy number variants also had abnormal expression of the genes involved in the creation and maintenance of neural synapses. It suggests that unlike healthy brain cells, these abnormal neurons fail to make critical connections during fetal development which causes them to die off.
“This competition for synapses has been described for years, but without the benefit of a genomic understanding,” Walsh noted. We didn’t realize that this struggle for survival—this Darwinian competition—was nature’s quality control mechanism in the brain.”
As part of the study, the team also confirmed some earlier findings that flawed neurons continue to be eliminated throughout adulthood, albeit at a much slower rate. Currently, they are looking into whether this neural elimination process is different in developing brains of people with autism and other neurodevelopmental disorders. They are also exploring whether this process plays a role in development of adult-onset neurodegenerative disorders like Alzheimer’s disease.
The post Brain Quality Control Selectively Eliminates Neurons with Abnormal Variants in Development appeared first on GEN – Genetic Engineering and Biotechnology News.
What Are Night Terrors?
Growing up, my little brother experienced a phenomenon known as night terrors, though my parents, at first, weren’t sure what to call them. Extreme nightmares? Sleeping meltdowns? A born ’fraidy-cat, I would have guessed he had been possessed by a demon.
He would go to bed and fall asleep. But not long after, he would sit bolt upright, eyes wide open, and let out a blood-curdling scream. Sometimes it lasted only a minute before he closed his eyes and lay back down again. Other times, he would scream and cry for 10 or 15 minutes. For my parents and me, it felt like an eternity.
“Looking at his eyes and his face, you knew he wasn’t awake,” my mom told me recently. But it was disturbing because it also felt hard to believe that he was asleep.
In the morning, my brother would have no memory of what had happened — of sitting up, of screaming or being soothed, or even of being afraid. We remembered, though. So, when my mom discovered the term for these episodes, she felt it was a more fitting description for the parent’s experience than that of the child. “It throws you into a night terror,” she said.
What are night terrors?
Night terrors are technically called “sleep terrors” because they can happen anytime a child is sleeping, not just at night. They’re a kind of sleep-wake disorder, specifically a parasomnia, or abnormal sleep behavior. Like another common parasomnia, sleepwalking, they typically happen within the first three hours of falling asleep.
Night terrors are characterized by behavior that suggests extreme terror and panic. This is because the child’s brain engages a fear response, even as the child remains mostly, if not completely, unaware of it.
Night terrors are not indicators of a psychological condition — a question parents often ask, says Shelby Harris, PsyD, a clinical psychologist and sleep expert. Along the same lines, night terrors are not traumatic for children, nor should they be interpreted as a sign of trauma.
Night terrors come on suddenly, most often out of nowhere — as in, without a trigger like a sudden noise or flipping on a light. In a typical attack, a child will open their eyes and scream or cry. Other behaviors may include:
- Sitting upright in bed or jumping out of bed
- Kicking or moving around the room
- Extreme agitation
- Rapid breathing and heart rate
- Sweating
- Flushed face or dilated pupils
- Confused or incoherent speech
Episodes usually last for one to five minutes, though they can extend for 20 minutes or more. In the vast majority of cases, children do not remember having had a night terror when they wake up.
How common are night terrors?
Night terrors typically occur in childhood, though some adults experience them. Children usually grow out of them as they age, and they become less common after puberty.
Estimates of prevalence vary widely, though, ranging from 1 percent to about 6.5 percent of children between the ages of 1 and 12. Some kids experience them only once or a few times; for others, night terrors happen frequently.
Why do night terrors happen?
Night terrors are a disorder of arousal: They happen when a child gets “stuck” between the deepest stage of sleep and waking.
When we sleep, we cycle through three stages of deep non-rapid eye movement (NREM) sleep and lighter rapid-eye movement (REM) sleep. Night terrors typically occur during the deepest NREM stage, 3NREM. A child partially wakes up, then gets stuck in transition, unable to wake up completely.
“I once had a mentor many years ago describe it as if you’re driving a manual, a stick-shift car, and you’re shifting between gears,” says Dr. Harris. “That’s what’s happening when you’re going between sleep stages.”
When a child is having a night terror, they’re “grinding the gears” between the deepest stage of NREM sleep and awakening, she explains. The grinding gears explanation also applies to sleepwalking, another disorder of arousal, says Dr. Harris. It’s just a different presentation of the same glitch.
Night terror or nightmare?
It’s 3 o’clock in the morning, and your child wakes up, upset. They run into your bedroom and tell you they had a bad dream about a monster that crawled in through the window and hid under their bed, demanding pizza. The timing, the story-like quality of the dream, and your child’s fear are good signs that this is a nightmare.
Night terrors happen during the deepest stage of sleep earlier in the night, while nightmares typically occur during lighter REM sleep at the end of the night.
Dr. Harris offers a good rule of thumb: “Who remembers it? And who is more freaked out by it? If you, the parent, were more freaked out and remember it, it was probably a sleep terror. If the kid remembers it more, then it was probably a nightmare.”
Risk factors for night terrors
Common risk factors include:
- Fever or illness
- Stress or anxiety
- Medical issues, like sleep apnea
Children with autism spectrum disorder tend to experience more sleep problems, including night terrors, than kids who don’t have autism.
Disorders of arousal can be hereditary, so if you have ever experienced them, your child is more likely to. Dr. Harris was a sleepwalker as a child, and her children experienced both sleepwalking and night terror episodes.
“When my kids would be with either set of grandparents when they were really little, they’d come home, and I always knew I was going to have a night of sleep terrors,” Dr. Harris says. “Because they had been staying up late, eating lots of sugar, and not getting enough sleep.”
Kids who are susceptible to night terrors may be more likely to have one if they’re overtired or thrown off their sleep schedule. Sleep deprivation is really the big thing, says Angela Breidenstine, PhD, a psychologist at the Child Mind Institute. “Anything that’s disrupting sleep that might be making a child overly tired can increase the likelihood of having a sleep terror.”
That’s why sleep hygiene — including a good, consistent bedtime routine — is the best defense against them.
Diagnosis and treatment
Night terrors don’t need to be officially diagnosed to be addressed or treated. But it never hurts to talk to your doctor about them, especially if your child is getting regular sleep or having them for the first time at an older age, says Dr. Harris.
Your child’s doctor may recommend tests for medical conditions, such as sleep apnea. In rare cases, they may recommend an overnight sleep study.
How to deal with night terrors
In general, experts stress the importance of trying not to intervene during an episode. To master the right hands-off approach for your child, consider a few dos and don’ts.
Do stay present and keep them safe
You don’t want them falling out of bed or running into things if they’re prone to moving around. As with sleepwalkers, it may behoove you to remove sharp objects from the room, close open windows, or move furniture they could trip over before they go to bed. But try not to hold or restrain them — it could be startling. Instead, says Dr. Harris, use a gentle touch to guide them back to the bed or to lie back down.
Don’t wake them up
“If you try to wake them up, that actually can prolong the event,” Dr. Harris explains. They are stuck between sleep and waking, so the goal is to help them back to sleep. It’s not dangerous to wake them, Dr. Breidenstine explains, “but it usually doesn’t work out well. It just makes it more confusing and agitating for them.”
Do help them ride it out
And if you talk to them, be quiet, soothing, and brief. “You can say something like, ‘It’s bedtime. It’s time for sleep,’” while gently guiding them back to bed, says Dr. Harris. Remember, they are asleep. “They’re out of it. They have no understanding of what’s going on.”
Don’t take it personally if they pull away or reject attempts to be soothed
While frustrating, this is completely normal. Not being able to soothe your child as you normally do can make you feel helpless — one scientific paper describes night terrors as a “parental nightmare” — but keep in mind, night terrors call for comfort of a different kind.
What is anticipatory waking?
If your child is having frequent night terrors, a doctor will likely recommend working on their sleep hygiene, including going to bed on time and keeping a consistent schedule. But if the night terrors continue, they may suggest a prevention tactic called anticipatory waking — but it requires a good amount of preparation. You can start by keeping a sleep journal. Consider:
- What time did your child go to bed?
- What time did they fall asleep?
- What time did the night terror happen?
- How long did it last?
After a few weeks, you might notice — for example — that your child consistently has a sleep terror about two-and-a-half hours after they fall asleep. “Then you have a pattern where you can intervene,” says Dr. Breidenstine.
Anticipatory waking, sometimes called scheduled awakening, means waking the child about 10 to 20 minutes before they would usually have a night terror.
“Basically, it interrupts the time where their brain is normally hitting this shift from deep sleep to the next stage, where it’s having this difficulty that results in the sleep terror,” Dr. Breidenstine explains. “You’re proactively preventing that by waking them up before it happens, and then it kind of resets the sleep cycle.”
It’s not necessary to wake the child completely — nudging them just enough to see them shift position or hear them make a noise is fine, says Dr. Harris. “Usually after about two weeks of doing that, it tends to fix it for some people,” she says.
But given the difficulty of implementing this approach, anticipatory waking isn’t typically a first-line recommendation.
Calming siblings — and yourself
While kids have no memory of having had a night terror when they wake up in the morning, other family members certainly do. Night terrors can disrupt sleep for parents and siblings, and their intensity can make it hard to fall back asleep. Dr. Harris recommends deep breathing exercises to calm yourself, or other children, down.
Siblings might also be confused about night terror episodes. Be reassuring and take care to explain the behavior, says Dr. Breidenstine. You can try saying something like: “Part of his body woke up, but he’s still sleeping — that’s why he screams like that. But he’s not hurting. He probably won’t remember it tomorrow. You don’t need to try to wake him up or help him. He’s okay. It will pass.”
By the same token, avoid talking about episodes in a dramatic or frightening way in front of the child.
“If parents are talking a lot about it the next day and then telling the child how scary the episode was, that might make the child feel anxious,” says Dr. Breidenstine. If they ask about them, she recommends offering them a similar script: “When you’re sleeping, sometimes part of your brain wakes up before the rest of it. You might sit up and yell or make a sound, but you’re mostly asleep. It’s not dangerous. We’re making sure you’re okay until you’re sleeping quietly again.”
The post What Are Night Terrors? appeared first on Child Mind Institute.
Depression in autism spectrum disorder: a scoping review of pharmacologic, neuromodulation, and psychosocial interventions
Effectiveness of the Autism Pupil Screen (APS) Detect Pupillometer for Identifying Autism Spectrum Disorder (ASD) in Routine Healthcare
Interventions: Device: Autism Pupil Screen (APS) Detect PLR Assessment #1; Other: Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT/R-F); Other: Social Responsiveness Scale, Second Edition (SRS-2); Diagnostic Test: Autism Diagnostic Observation Schedule, Second Edition (ADOS-2); Other: Mullen Scales of Early Learning (MSEL); Other: Adaptive Behavior Assessment System, Third Edition (ABAS-3); Device: Autism Pupil Screen (APS) Detect PLR Assessment #2; Device: Autism Pupil Screen (APS) Detect Assessment #3; Procedure: Well-child check
Sponsors: Schweitzer Engineering Laboratories; Palouse Pediatrics; Pullman Regional Hospital; Washington State University; SEL Health Clinic
Recruiting
Evaluation of a Novel Quantum-Inspired Intervention (QII) for Children With Autism Spectrum Disorder: A Global Confirmatory Study
Interventions: Other: Quantum-Inspired Intervention (QII)
Sponsors: BlissBot, Inc
Not yet recruiting
Dance- and movement-based interventions for autism spectrum disorder: a systematic review and exploratory meta-analysis
Predicting behavioral escalation in students with autism using physiological and movement data
TRIal of PPF3 vs. PlaCEbo in the TReatment of Children and AdolescenTs With NeurOdeveloPmental DisorderS
Interventions: Drug: PPF3; Drug: Placebo
Sponsors: Holland Bloorview Kids Rehabilitation Hospital; Ontario Brain Institute (Funder); Purposeful
Recruiting
Adapting the Sensory Environment to Reduce Stress in Children With Autism During Dental Visits
Interventions: Behavioral: Sensory-Adapted Dental Environment
Sponsors: Jagiellonian University
Active, not recruiting

