Hen Do Babies Develop Brains in the Womb

From autism to schizophrenia, many brain disorders have long been thought to arise from problems with the connections among nervus cells in the encephalon.¹ Billions of threadlike fibers crisscross the brain, forming labyrinthine networks that relay messages between different brain regions.² Scientists call this signaling spaghetti the "connectome,"¹ and it makes up a pattern of the trillions of neural connections in the brain.

Some researchers hypothesize that these connections encode essential aspects of personality, behavior, knowledge, and memory. As neuroscientist Sebastian Seung subtitled his 2012 book Connectome, our neural wiring makes us who we are.³

In the past decade, advances in a neuroimaging technique chosen functional magnetic resonance imaging (fMRI) have offered researchers an unprecedented look at how those connections grade before and shortly after birth. With these advances, they accept also begun to unlock some of the signatures of aberrant brain development.

fMRI is not perfect. The images generated past the applied science oftentimes must be manipulated to correct for distortion and to scale encephalon scans to a consistent, comparable template. Motility causes problems with data analysis and estimation—and babies and fetuses are notoriously wriggly unless comatose or sedated. Finally, technical issues potentially issue in artifacts that may not be recognized equally errors.^iv

Even so, fMRI has likewise provided a new level of access to the developing encephalon. In improver, agreement the origins of neurodevelopment—and where encephalon role goes awry—may provide new insights on the impact of environmental exposures.⁵ The findings could one day provide avenues for novel neuroprotective strategies.

The procedure that will ultimately give rising to the connectome begins about 25 days after conception, when the neural tube begins to class. By the terminate of the embryonic period (gestational week 10), the basics of the neural system are established. All the structures proceed to develop throughout the fetal period and early childhood. By 6 years of age, the brain has reached 90% of its adult volume. By age 25, it typically is fully developed. Image: © TheVisualMD/Science Source.

The Black Box of Brain Evolution

Human brain development starts soon after conception and continues into early machismo. The fetal brain begins to develop during the third week of gestation. Neural progenitor cells brainstorm to divide and differentiate into neurons and glia, the two cell types that form the basis of the nervous system.⁶

By the 9th week, the brain appears as a small, polish structure. Over the course of pregnancy, the structure of the brain will change as information technology grows and begins to class the characteristic folds that designate distinct encephalon regions. Changes in brain anatomy reflect dramatic changes at the cellular level. Neurons in the different brain regions begin producing the chemical signaling molecules that will enable communication betwixt nerve cells. The cobweb pathways that will get the brain's information superhighway are forming. The cells that will brand up the neocortex—the role of the encephalon that coordinates sight, sound, spatial reasoning, conscious thought, and language—begin to communicate.⁶

Although the foundation of a operation brain is assembled prenatally, brain function itself continues to develop subsequently birth, driven largely past sensory input. The number of neural connections explode in the offset years of life—a phenomenon sometimes referred to every bit a synaptic "big bang."⁷ After age two years, the number of neural connections decreases. In a procedure known equally synaptic pruning, the encephalon organizes its connectome to perform more efficiently, removing inefficient connections to maximize performance.

A large torso of brute and epidemiological research suggests that prenatal exposures to harmful environmental stimuli, such as maternal stress or toxic agents, may modify the developmental trajectory of the fetal brain.⁸ Yet, until recently, prenatal neurodevelopment was a blackness box.

"We don't know a lot about what happens in fetal life, because we oasis't had the tools to measure out brain development in fetal life," says Robert Wright, an environmental epidemiologist and pediatrician at the Icahn Schoolhouse of Medicine at Mount Sinai in New York. "It may fifty-fifty differ from [postnatal] development, as the sensory inputs are largely biochemical and passed from female parent to child, different the direct feel of sound, light, temperature, and motility that a child experiences."

The developing brain relies on environmental and endogenous stimuli such as these to help it determine which connections should exist pruned and which should not. "When a neuron fires after a proper signal, its synaptic connections are solidified," Wright explains. "If a neuron's synaptic connection is rarely fired, it regresses and is removed."

Toxic exposures can interfere with the brain'due south ability to distinguish important connections from unimportant ones, altering the development of the connectome. For instance, pb can cause neurons to fire spontaneously in the absence of a proper point, Wright says. "By inducing neuronal activity inappropriately, [lead] tin change the normal trajectory of synaptic formation and synaptic pruning that underlies the formation of the connectome," he explains. Ultimately, this blazon of interference can lead to the evolution of maladaptive brain signaling networks.

The connectome is shaped by internal and external stimuli throughout the grade of life. In the fetus and young kid, sure chemic exposures and situational factors (such every bit maternal stress and low socioeconomic status) are risk factors for neurodevelopmental problems. However, positive influences, such every bit parental engagement, may help to build resilience and mitigate whatever negative impacts. Epitome: © Daniel Atkin/Alamy Stock Photograph.

Developing the Tools to Written report the Brain in Utero

Most of what scientists know about fetal brain development comes from looking at animal brains or analyzing human postmortem samples.⁵ This inquiry has provided insights on the development of brain structure but offers few clues nearly how functional systems go organized.

The earliest investigations of homo fetal encephalon function engagement dorsum to the 1950s. When researchers placed electrodes on a pregnant woman's abdomen and on the walls of her neck during labor, they could detect electrical impulses that signaled fetal encephalon activity.^v Researchers began to notice that certain patterns of electrical activeness were associated with neurological abnormalities.⁹

In the 1990s, scientists began experimenting with fMRI to map the connections in unlike regions in the brain.^v fMRI detects changes in brain activeness associated with changes in blood catamenia. During fMRI, the patient typically performs a job—looking at pictures of faces or finger borer, for instance—while the machine scans his or her brain. Researchers wait for areas of the brain that calorie-free up during the task.

By that point, neuroscientists knew there was much more happening functionally than could be probed with a stimulus or task, but it was unclear how to all-time examine these functions. Then, in 1995, then–graduate student Bharat Biswal made a fortuitous observation: The encephalon produces signals all the time, fifty-fifty when it is not engaged in a chore.^ten Manipulating fMRI to measure out these resting-country signals immune scientists for the first time to investigate brain activity without the subject needing to then much as tap a finger.

Resting-state fMRI offered a more nuanced look at the highways and interstates connecting dissimilar brain regions. These connections course the basis of how different regions of the brain communicate with each other. Whereas investigators previously were limited to studying function inside a particular brain region, they could now begin to inquire big-motion-picture show, network-level questions near brain function.^vii

In the search for answers about how and when brain networks form, researchers turned to preterm infants.^xi Nearly x% of all babies worldwide are born preterm, meaning earlier the end of the 37th week of pregnancy.¹² Compared with term babies, these children are more likely to develop autism spectrum disorders, attention deficit/hyperactivity disorder, emotional disorders, and neurological abnormalities.¹³ Preterm infants also are more likely to have cognitive difficulties and trouble in schoolhouse later on.¹³ A growing body of research suggests that these cognitive impairments may be caused by disruptions in the way the brain is wired before or presently after nativity.⁵

Christopher Smyser, a pediatric neurologist at Washington University in St. Louis, Missouri, used fMRI images of preterm infant brains to report prenatal development of the connectome. In 2010, he showed that babies born as early as 26 weeks possessed immature forms of many of the functional brain networks seen in adults.¹⁴

These first studies past Smyser and others showed that the encephalon'south communication channels were present before term birth, albeit in an immature state. Preterm babies offered researchers the opportunity to study the development of neural patterns that unremarkably takes place inside the womb. Nonetheless, researchers constitute it hard to know if the patterns they were seeing in these infants reflected the normal development of brain communication networks. What did functional connectivity await like in a salubrious term pregnancy?

Imaging the Fetal Encephalon

Job-based fMRI had always been a poor option for studying children too immature to follow instructions. In utero, it was even less viable. "You could never know what a fetus was upwardly to, whether it was performing a task or at residue," says Veronika Schöpf, a professor of neuroimaging at the Academy of Graz in Austria.

In 2010, Schöpf began using resting-state fMRI to written report the brains of fetuses. She ultimately scanned the brains of more than 100 fetuses in their mothers' wombs.¹⁵ It was a tricky chore—too much movement on the part of the fetus could mistiness the picture. In the end, Schöpf had collected functional images of 16 healthy fetuses spanning the 20th to 36th weeks of gestation. Her study was the starting time to show that resting-state networks were present—and could exist detected—in a fetus.

At the time of this study, the chronology for the emergence of the encephalon's functional networks was withal unknown. Even so, in a 2014 follow-up study of 32 healthy fetuses, Schöpf et al. showed how the connectome adult over the 2nd half of pregnancy as short- and long-range connections between dissimilar brain regions begin to form.¹⁶ They found that development of those network connections peaks between well-nigh 27 and 30 weeks.

In 2012, Veronika Schöpf et al. captured functional images of fetal brains at gestational weeks 20–36 (the numbers in the figure above indicate gestational week). The squad was the offset to bear witness that resting-land networks can be detected in utero. This imaging was a major advance over the apply of task-based fMRI because, equally Schöpf put information technology, "Y'all could never know what a fetus was up to, whether information technology was performing a job or at rest." Image: Schöpf et al. (2012).⁵

Around the aforementioned fourth dimension, Moriah Thomason, a pediatric neuroscientist at New York Academy School of Medicine, published the first study to demonstrate age-related changes in fetal brain networks. In a cohort of significant Detroit women, she constitute differences in functional connectivity amid 25 healthy fetuses in the second versus the third trimester.¹⁷ She also institute show of synchronized action between mirror regions in the ii hemispheres of the brain. The study showed that this pattern of coordinated activity became stronger with each passing calendar week of pregnancy.

Schöpf's and Thomason's early on studies offered the showtime evidence about the timing of functional development in the fetal brain. They also demonstrated that resting-land fMRI may be a helpful tool in identifying and improve understanding critical windows of fetal neurodevelopment. With this groundwork laid, investigators now aim to elucidate the origins of neurological disease.

Disentangling the Pre- and Postnatal Environments

In studies of preterm infants conducted after nativity, researchers discover it hard to know whether developmental abnormalities ascend from the preterm birth itself (e.g., every bit a result of oxygen impecuniousness) and the stress of subsequent medical interventions, or if those abnormalities are the event of disease processes that started in the womb. Without that piece of the puzzle, it is incommunicable to establish whether preterm nativity is a symptom or a cause of developmental issues.

The same tin can be said for almost studies of early-life environmental exposures. "If you cannot disentangle the prenatal from the postnatal environment, yous cannot get at the genesis of disease," says Thomason.

Lead exposure is one example. Fetal exposure to lead has been associated with cerebral impairments in childhood.⁸ However, if lead was present in the female parent's environs during pregnancy, information technology'southward likely to exist present in the child's surroundings, too (provided the mother and child live together in the domicile where she resided while pregnant). Therefore, whether an adverse cognitive result is a result of something that happened either in fetal life or when the child was 1 or ii years sometime is hard to determine. "Establishing when the event started might be a clue to understanding if the critical window is fetal life or later in life," says Wright.

In the case of preterm births, researchers would ideally clarify the brains of preterm infants earlier birth, but it is often hard to identify which babies will be born early. Nevertheless, Thomason has managed to do just that past studying a subset of her cohort of significant Detroit women who went on to deliver prematurely. In 2017, Thomason presented the first direct evidence that infants built-in preterm may be wired differently before birth.¹⁸ The fMRI images generated during pregnancy suggested a deviation betwixt the brains of preterm versus term babies: An area on the left side of the brain that later forms a language-processing region had weaker connections to other brain regions in fetuses that would exist born preterm compared with fetuses carried to term.

Chiefly, the was small—simply 14 preterm and 18 term pregnancies—and the medical relevance of the findings is not nevertheless clear. Long-term studies are needed to determine whether differences detected in utero predict cognitive impairment subsequently in life, according to Thomason.

The oldest children in Thomason's Detroit cohort take at present reached school age. She is working to link patterns of early brain action to childhood behavioral outcomes, including speech, motor skills, and cognition. If maps of functional connectivity in the fetal brain turn out to predict wellness outcomes afterward in life, the findings will bring us closer to understanding the origins of neurodevelopmental problems.

Still, for Thomason, her enquiry is as much nigh finding the alterable conditions in an environment that could alter a child's developmental trajectory as it is most understanding the genesis of disease. During dwelling visits, she has nerveless information nearly each child's environment. "Fetal encephalon activity may predict a particular outcome, but what other environmental factors buffer or exacerbate prenatal risk factors?" she asks.

Ecology Wellness Connections

Other researchers agree that interim on environmental risk factors may be key to developing effective neurobehavioral interventions.⁴ For preterm infants, interventions could include changing the hospital environment, says Annemarie Stroustrup, a neonatologist at Mount Sinai Infirmary in New York.

"The neonatal intensive care unit [NICU] is non designed for environmental health safety," Stroustrup says. Preterm babies face a host of unfamiliar stressors in the NICU—from bright lights and loud sounds to stressful interventions and potentially toxic chemicals.^nineteen For example, plastic medical equipment may comprise hormone-disrupting chemicals, such as phthalates or phenols, and intravenous feeding solutions may contain high levels of neurotoxic metals, such as aluminum. Although such exposures may be largely or wholly tolerable for older patients, their toxicity is amplified in the preterm babe.²⁰

Some developmental abnormalities upshot from disease processes that started in the womb, but others may ascend from the very act of being born prematurely and the stress of subsequent medical interventions. Annemarie Stroustrup et al. are investigating whether the NICU surround contributes to the latter category. If it does, that'southward i negative influence that could be changed to a positive—or at least improved. Image: © Nenov/Getty Images.

Stroustrup leads a report designed to look at the developmental impacts of NICU exposures.¹¹ She plans to incorporate the use of neuroimaging to appraise neurodevelopment in premature infants under NICU intendance and then compare early on brain connectivity to measures of exposure and babyhood behavioral outcomes. "If it turns out that some morbidities are related to ecology exposures in the NICU, that information could exist used to improve the NICU environment," she says.

The encephalon is plastic, especially during childhood. That means it is able to organize its neural connections in response to its environs—including both positive and negative influences. Although toxic exposures can have a negative influence, other positive influences may assist to build resilience and mitigate the negative impacts, Wright says.

"It's a misconception that if you're exposed to a sure chemical, you're destined to get a damaged brain," he says. "Adverse outcomes are by no means destiny. Positive influences can remold the brain."

Lindsey Konkel is a New Jersey–based journalist who reports on scientific discipline, health, and the surround.

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