The baby is lying on her right side, knees tucked close to her chest, hands curled under her chin. A white crocheted cap keeps her head warm. Her eyes, squeezed tight, have opened only a few times on the world.

Selena is just four days old. Born on a Saturday spring morning, she and her twin sister, Trinity, arrived 14 weeks early. Both are on the precipice of life.

The doctors at this neonatal intensive care unit in London, Ont., are doing their best to keep the twin girls alive. A ventilator pushes air into their lungs. An incubator keeps the air surrounding them warm and moist to prevent hypothermia. The light is dim to protect their eyes.

But the most vulnerable part of their bodies is their brains.

Twenty-six weeks after conception, the brain is at a critical period of development. It is still producing more than 50,000 neurons every second. Those neurons are migrating outward, assembling the different regions that will allow Selena to walk, to talk, to remember her mother’s voice. And the spinal cord has only just connected to the cerebral cortex, the region of the brain responsible for higher thought processes, something that must happen for Selena to be aware of her surroundings.

Dr. Victor Han has been treating babies like Selena for more than 30 years. Every time the neonatologist walks into this intensive care unit and sees the 40 premature infants asleep in incubators he wonders the same thing: What is going on in their brains?

“They are lying there and we are caring for them,” he says moments after washing his hands and leaving the third-floor ward. “What we don’t know is their cognition, how their brains are developing. That is one of my biggest questions.”

It is also one of science’s biggest unknowns.

From studying animal brain development and looking at the brains of human cadavers, scientists have pieced together what an adult brain is supposed to look like. Reverse engineering and more animal studies have shown how a child’s brain grows into its adult state. Meanwhile, imaging technologies, including functional magnetic resonance imaging, have revealed which region of brain tissue gets activated during certain cognitive processes.

But the development of the human fetal brain has largely remained a mystery.

Scientists know about form — this connects here, so that fits in there. But they still know little about function — why does this connect here, and why does that fit there.

A range of research, particularly the creation of non-invasive imaging technologies, will soon allow scientists to peer inside a developing human brain. The goal is to understand how it develops from a sheet of cells to a 380-gram mass about the size of a squash ball in the span of nine months. And how that infant brain is primed to see, smell, taste, feel, hear and understand her world.

Along the way, scientists hope to soon find answers to two critical questions. When does a fetus become conscious? And how does the fetal environment influence the way a baby’s brain develops?

Answering the first question will satisfy our innate curiosity about how life begins. The second question, once parsed out, has the potential to change how society prevents disease.

The human brain begins to develop astonishingly quickly after conception.

Just 16 days after a sperm has buried its head into an egg, the beginning of the brain emerges in the form of the neural plate. This single layer of cells, which develops from the outer layer of the embryo called the ectoderm, will give rise to the entire nervous system.

About five days later, the neural plate buckles in the middle and the sheet of cells curves together to form a tube. Each end then closes so the neural tube resembles the cylindrical cardboard carrier used to mail posters.

After the tube has closed — one of the critical points of brain development — the single layer of cells begins to rapidly divide. The neural tube expands and, between the fourth and seventh weeks after conception, a series of five vesicles, or sacs, appear at the front end of the tube. These will become the major portions of the brain.

“This is all a lizard would have,” says Cindi Morshead, an expert in adult neural stem cells, as she leans over some paper to sketch how the five vesicles arise. “It would have no cortex.”

No outer layer that, in humans, is the seat of higher thought.

Morshead, a professor at the University of Toronto, is in the institution’s anatomy museum explaining how the fetal brain develops. The J.C.B. Grant Museum is where researchers and medical students come to study historical specimens — some many decades old — of human anatomy, from heart ventricles to the ligaments that snake through the
human hand.

This section of the lab houses specimens of fetal brains and of fetuses at different stages of development. Morshead pauses in front of a 10-and-a-half-week-old fetus floating in a jar. Despite its lizard-like brain, the fetus is beginning to look distinctly human. Just three
inches long, it has facial features, curving ribs and toes as slender as the teeth on a comb.

“That’s pretty nice, eh, for 10-and-a-half weeks,” says Morshead, peering at the specimen. “Look how fast it grows. Within a very short period of time this metamorphosis occurs.”

Scientists who study the brain, even those who have been at it for decades, remain in awe of the astounding pace of development. It is incredible: a newborn’s brain has 20 billion neurons and a trillion synaptic connections, and the fetal brain must create a profusion of
brain cells during intrauterine life — about 250,000 each minute — to meet those demands.

“It’s the most fascinating thing, ever,” says Morshead with a broad grin. “People should be thinking about how a baby’s brain develops all the time. You start with a single cell, and look what you get. It’s unbelievable.”

She turns to look at a specimen of a fetal brain on a nearby shelf. The brain — a label says it is between three and four months into development — is two inches long and shown in cross-section. It is smooth, with few of the deep folds seen in adult brains, a creamy yellow, and looks like an oversize pecan sitting in its shell.

During this period of development, neurons are constantly being generated in the middle of the brain. The neurons then migrate outward toward the surface and self organize into different brain structures. Once the neurons reach their specific position, they extend axons, nerve fibres that send electrical signals away from a neuron, and dendrites, nerve fibres that carry signals back to a neuron, to join with other neurons. This forms the complex neural circuitry that allows communication between cells.

In the last months of fetal life, even as thousands of neurons continue to be produced every second, the brain starts to prune back excess neurons, eliminating cells and connections that are weak or duplicate. This sculpting of neural pathways continues after birth.

One could write an entire book — some have — about fetal brain development. Yet the underlying mechanisms by which cells divide, become neurons, migrate to the surface of the brain and form neural pathways is still under intense investigation.

“You know, we don’t really know anything beyond how a brain develops,” Morshead says. “We understand the physical structure and we’re learning about development. But we don’t know much about function.”

More simply: We think we know how a brain is made, but we know very little about why it is made this particular way.

One hundred years ago, doctors described neural anatomy in terms of information travelling between brain regions along a single path, like phone lines connecting houses or trains travelling along tracks. Now, the common analogy is a series of mini computer circuits.

But the way our brain works surely is infinitely more complex. There are few comparisons in the manmade world, never mind in the universe, to the tangle of cells housed in our skull’s bony box that leads to memory, emotion and consciousness.

He has spent much of his career trying to understand the life of a newborn.

Neonatologist Dr. Hugo Lagercrantz, renowned for his research on infants, particularly those born prematurely, has recently tried to pinpoint when consciousness emerges in a fetus.

As someone who cares for preterm infants whose brains and bodies must continue developing — for as many as 15 weeks — outside the womb, it is an important topic. Especially since pinpointing the time when a fetus perceives its surroundings will inform doctors about when to initiate or withdraw medical care for infants born at or before the 23rd week of gestation.

“I have this question: how is it to be a baby?” says Lagercrantz from his office at the Karolinska Institute in Stockholm.

“If the (preterm) baby is conscious, we should treat the baby in the same way as any adult patient.”

Last year, Lagercrantz, a pediatrician and researcher at the Astrid Lindgren Children’s Hospital, co-authored a review article that outlined what is known about how consciousness emerges in fetal life. The paper, published in the journal Pediatric Research, has been well-received and well-debated by the research community.

Many fetal experts say it is too early to discuss the topic because scientists have yet to fully define consciousness in adults. That infants and fetuses cannot talk, share their emotions or describe their experiences is another obstacle to defining when they might become conscious during development.

Scientists are waiting for the advent of non-invasive imaging techniques, expected within the next decade, to help reveal the inner workings of the fetal brain — to show them what happens when, say, the fetus is exposed to music.

Currently, all researchers can do is use indirect evidence to identify the time when a fetus could understand its surroundings.

“One day we might have more understanding of what a fetus is experiencing,” says Vivette Glover, a professor of perinatal psychobiology at Imperial College London. “But the mixture of not being able to study what is going on in the fetal brain while it’s alive and
not fully understanding the neural basis of consciousness anyway makes it quite a lot of guessing.”

What is known is that consciousness cannot occur until the peripheral nervous system joins up with the cerebral cortex, the region of the brain responsible for memory, awareness and language. That connection between the sensory receptors — what allows us to sense the outside world — and the higher brain doesn’t fully occur until about the 26th to 28th weeks of gestation.

“The nerve cells in the spinal cord only start to reach the brain from about 16 weeks,” Glover says. “Then they penetrate higher up to the brain . . . at about 18 to 20 weeks, then make full connections at about 26 weeks.”

Pregnant women at their first ultrasound appointment — about 12 weeks after conception — will likely see their unborn baby swirl and bounce in the womb. But given the fetus’s minimal neural circuitry at that time, those movements are reflex actions — similar to those in an earthworm that moves away from your touch — rather than deliberate

Experts believe there are flashes of consciousness before the third trimester, which begins at the 26th week.

“Some people use the image of a dimmer switch,” Glover says. “It doesn’t come on suddenly and one day the fetus becomes conscious. It could be flickering on and off and then grows.”

In his review article, Lagercrantz highlights evidence that suggests when a fetus reaches consciousness. The findings include: a preterm infant can hear at 26 weeks and smell at 29 weeks, and has developed the ability to see by 32 weeks. A fetus will withdraw from pain at 19 weeks, and the neuronal connections needed for a fetus to understand that something hurts are in place by 28 weeks. And by 32 weeks after conception, a fetus has defined sleep states, including deep, REM sleep.

Last year, researchers from the Netherlands reported that 30- to 38-week-old fetuses have short-term memory, evident in the fact they habituate to a vibrating, honking device. When first exposed to the device (it was placed on the abdomens of pregnant mothers), the fetuses squirmed and their heart rate went up. Ten minutes later, the fetuses did not react to the noise. They also showed little reaction when exposed to the noise after four weeks had elapsed.

Studies like these and his own experiences in neonatal wards have convinced Lagercrantz that preterm infants can lay down memories, a sign of consciousness.

“I think they do have short term memory,” he says, “but very primitive. They are not thinking of what something costs or planning for the future.”

Two hours after

Selena and Trinity were born, Dr. Victor Han was bending over their incubators in the neonatal intensive care unit at London’s St. Joseph’s Hospital.

The twins, born 26-and-a-half weeks after conception, about 95 days too early, will likely leave hospital as healthy as babies born at term. Han and the team of health-care workers here know how to care for these fragile newborns. Every effort is made to replicate the environment of the mother’s womb, from the warm, moist air inside the isolates to the ward’s dim lighting.

But standing over Selena’s isolate, Han sighs: “All of these things are artificial. We cannot duplicate the womb. They are lying on a surface, not suspended in liquid. The air is dry, not wet. It’s light, not dark. It’s noisy, not silent.

“All of these things are changing the babies’ brains.”

Han, a Canada Research Chair in Maternal and Fetal Health, is referring to one of the hottest topics in the study of fetal development: how the fetal environment alters the development of a fetus and influences an individual’s long-term health as an adult.

The effect of a neonatal intensive care unit on an infant is perhaps one of the most extreme examples of this process, dubbed fetal programming.

“Brain development happens better inside the uterus,” says Dr. Carter Snead, head of the neurology division at the Hospital for Sick Children. He points to studies that have shown babies born prematurely or at a low birth weight are more likely to have learning difficulties in childhood than babies born at term.

“Even though they do develop the skills and circuitry, it’s much more efficient if they are still in utero.”

Brain growth and development are largely genetically determined. An
individual’s genome provides much of the blueprint for the placement of
neurons, the trajectory of axons and the number of synaptic connections.

But environment also has a profound effect. Indeed, it is the combination of genes and environment that make every individual unique.

“The scientific underpinnings for that thinking and that hypothesis are just beginning to emerge now,” says Snead. “All the data now is pointing to epigenetics as being the mechanism by which environment influences brain development.”

Epigenetics refers to any process that alters the gene activity in a strand of DNA without changing the genes themselves. Much like a software program that tells a computer how to work, epigenetic processes tell our DNA when, where and how to express each of the body’s 25,000 genes.

Epigenetic processes are a normal and necessary part of life. But if they go wrong or work ineffectively, there can be major health consequences.

It has long been understood that environment has a critical effect on how the fetal brain develops. That’s why mothers are warned away from alcohol and cigarettes.

But in the past decade, more and more research has shown that a great number of environmental factors outside the womb — everything from
what a mother eats for breakfast to her stress levels at work — can
influence fetal brain development.

Glover, of Imperial College London, was one of the first researchers to show fetal programming in humans. In one study, she found mothers who suffered unusually high stress in pregnancy had children whose IQ was generally about 10 points below average. Another study found mothers who reported being anxious during pregnancy had children who were at twice the risk of developing behavioural problems, such as attention deficit hyperactivity disorder. Yet another showed a mother’s stress hormones can affect the brain development of a fetus at just 17 weeks after conception, the first to show that a mother’s emotional state can affect development so early in pregnancy.

Since Glover’s work in the mid-2000s, dozens of other studies have shown links between the fetal environment and the baby’s long-term health and well-being.

“The phenomenon is pretty well established,” she says. “But we have loads more to do; we’re just beginning to understand the epigenetic mechanisms.

“This is a very important area of research because for a lot of outcomes that have been associated with prenatal stress — ADHD, conduct disorder, emotional problems, cognitive delay — once they are established, they are quite hard to do anything about. But if we
understand that we can prevent them by giving better emotional care to pregnant women, we could prevent them happening in the first place.”

Researchers around the world are trying to dig down to find the epigenetic mechanisms that control fetal brain development. They believe they’re the key to dozens of diseases, and that uncovering them will lead to new therapies and understanding of basic biology.

We are at the beginning of the journey, says Han, who, as a professor at the University of Western Ontario’s Schulich School of Medicine and Dentistry, is investigating how the interaction between genes and environment influence fetal development.

The way billions of neurons and trillions of connections come together in the highly organized tangle of the baby’s brain may never be fully understood. And even if we did understand it, it would remain a phenomenon to marvel at.

“That is the miracle,” says Han. “The majority of babies develop normally. And that normal birth is a true miracle, with everything in place and everything right.” (…)

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Source: Toronto Star –