Many children with congenital heart disease (CHD)—the most common major birth defect in the United States—sustain brain damage that often leads to problems with behavior, thinking, and learning. Now, for the first time, researchers have described how the lack of brain oxygen that results from heart malformations might stunt the brains of newborns, opening avenues to potential therapies that could be used even before babies are born.
The results are “incredibly exciting,” says Caitlin Rollins, a child neurologist at Boston Children’s Hospital. “This kind of study allows us to start understanding the cellular mechanisms” behind the brain damage, she says. In the future, she adds, “we might be able to alter the course of brain development” with drugs targeted at the cellular anomalies and delivered during pregnancy.
CHD reduces oxygen delivery to the brain at a time when the fetus most needs it. This lack of oxygen is thought to be a primary cause of the brain aberrations, which first become visible on MRI scans in the third trimester of pregnancy. (The heart anomalies themselves are commonly identified in the second trimester, on routine ultrasound scans.) Yet until now, scientists have been unclear about the underlying cellular process causing the brain problems.
So a research team led by scientists at Children’s National Health System in Washington, D.C., delivered subpar levels of oxygen to newborn piglets, whose course of brain development and whose highly evolved brain structure mirrors in many respects those of humans. When the piglets were 2 days old, the scientists injected fluorescently labeled cell trackers into a key brain area, the subventricular zone (SVZ). In newborn mammals, the SVZ is the biggest depot for the precursor cells that migrate to populate various brain regions, and differentiate into multiple cell types.
The next day, the team began depriving the piglets of oxygen—the air they breathed was 10.5% oxygen, rather than the 21% that is normal in the air we breathe. When the animals were 14 days old, the researchers killed them and examined their brains. The team did the same thing in a control group of piglets that were not deprived of oxygen, injecting fluorescent trackers in their brains and killing the animals to examine their brains at 14 days of age. In addition, the group examined the brains of nine human infants who died at between 0 and 36 days of age, four from CHD and five from other causes.
During normal brain development in the first weeks of life, precursor cells in the SVZ in the piglets give birth to neurons that migrate primarily to the prefrontal cortex, the team reports today in Science Translational Medicine. In humans, that’s the area directly behind the forehead that is the seat of higher thought. There, the cells differentiate into interneurons, an important subcategory of neurons that are called “inhibitory” because they tamp down firing by “excitatory” neurons. The balance between excitation and inhibition allows this executive area of the brain to function optimally: making judgments, synthesizing facts, and solving problems.
In the oxygen-deprived piglets, the generation of neurons from precursors in the SVZ was severely impaired, and the number of neurons and interneurons in the frontal cortex was also significantly reduced. The pigs’ brains were smaller and weighed less than those of their normal counterparts. They also had fewer folds in their surfaces, which are known to be vital for higher cognitive function.
The brains of the human babies with CHD that died in the first month of life also showed a depletion of neural precursor cells in the SVZ. Their brains weighed significantly less than those of their counterparts that did not have CHD, and their cortexes had less of the gray matter that processes information.
The authors could only infer from the autopsy samples that a similar migration of neurons from the SVZ to the prefrontal cortex had taken place in the human infants. But their inference is strongly supported by findings from autopsy samples of human infants who died in the first few months of life from a variety of causes, published in Science last fall.
The fact that infants’ brains are still developing in those early weeks of life offers a therapeutic window of opportunity, the scientists say. “It’s incredibly important that these cells continue to grow after birth,” says Richard Jonas, a cardiac surgeon at Children’s National and a senior author on the paper. “That can potentially help a child whose congenital heart problem is fixed early in life because it offers a cellular mechanism for their brain to then catch up and develop normally.”
Pediatric physicians and heart surgeons are the first to admit that these basic cellular findings don’t translate into an immediate therapy for these newborns. But they are nonetheless excited. “It’s a great paper,” says Steven Miller, a neonatal neurologist at the Hospital for Sick Children in Toronto, Canada. “This is a first step,” he says, because it provides a target for therapy: somehow stimulating the SVZ to start replenishing the pool of cells that give rise to the vulnerable, depleted interneurons in CHD.
The study has weaknesses—the piglets didn’t truly model human CHD because they did not have heart anomalies and therefore were not actually deprived of oxygen while fetuses—only after birth.
Arnold Kriegstein, a neuroscientist at the University of California, San Francisco, also argues that though the scientists found inhibitory interneurons strikingly depleted in the brains of the oxygen-deprived piglets, this alone cannot account for the dramatic shrinking of the animals’ overall brain size and the diminished number of cortical folds “The interneurons are part of the story but not the entire story of how the brain is affected by this kind of [lack of oxygen].”