The Vulnerable Premature Brain(1)

Rapid Neural Development in Third Trimester Heightens Brain Risks

by Brenda Patoine

May 24, 2010


The genesis and wiring of the human brain during fetal development is one of the most remarkable feats in all of biology. Within the first six weeks post-conception, the basic template for the brain and spinal cord is laid out. Over the next few months, a dynamic, carefully choreographed process unfolds as some 100 billion neurons and countless other brain cells are born. The cells differentiate and migrate to begin to form the complex synaptic connections that will ultimately orchestrate every aspect of human physiology, cognition, and behavior for the life of the individual.

Given the immense complexity of the task, it’s amazing how often everything goes right. The vast majority of babies are born with a perfectly normal brain primed for sensing, learning, and fine-tuning neural connections. Brain development doesn’t end at birth, of course; the prefrontal cortex, for example, will not be fully mature until as late as the third decade of life. Yet the gross structure of the brain and nervous system, including virtually all of the cells and a rough scaffolding of the synapses connecting them, is in place at birth. That is, if everything goes right.

Clearly, not everything does in every pregnancy. There is a textbook list of things that can go wrong that may have subtle, moderate, or wholly devastating effects on the fetal brain. Among them: missing or malfunctioning genes, congenital impairments due to faulty sperm or eggs, metabolic defects, environmental toxins like lead or pesticides, maternal infections or medical conditions (e.g., hypertension, diabetes, epilepsy, depression), certain medications, malnutrition, stress, poor prenatal care, and “lifestyle” choices such as smoking or illicit drug or alcohol use.

Premature Births on the Rise

Premature birth is the most common pregnancy complication that can seriously compromise the newborn brain’s viability and normal development. Babies born preterm—medically defined as three weeks or more before the normal 40-week gestational period—face a range of potential neurological disruptions, from subtle motor deficits that can be mostly overcome with therapy to severe mental disabilities. The earlier the birth, the greater the risk that these disruptions will produce devastating and potentially life-long cognitive, behavioral, and socialization deficits.

“There has been a trend to save ‘at risk’ infants at earlier and earlier ages”, says Mary Beth Hatten, Ph.D., a developmental neurobiologist at Rockefeller University and member of the Dana Alliance for Brain Initiatives. “We’re only now beginning to understand all the problems that premature infants have. Many face substantive developmental deficits, only some of which babies can ‘grow out of.’”

According to the March of Dimes, more than 543,000 babies are born prematurely in the U.S. annually; worldwide, the number is 13 million. The rate of preterm births has been rising consistently worldwide.  In 2006, 12.8 percent of live births in the U.S. were premature, an increase of 20 percent since 1990 (the rate declined slightly in 2007 and 2008).[i] The reasons behind the 16-year increase are not entirely clear. Advances in obstetric medicine likely play a role, as the rate of stillbirths has declined in parallel with the rise in preterm births. In addition, preterm cesarean delivery has become far more common, as have babies conceived with assistive reproductive technology, which is associated with multiple births as well as prematurity.

About 63,000 preemies born yearly in the U.S. are classified as “very low birth weight,” a group at high risk for significant cognitive disturbances as well as cerebral palsy, a condition marked by severe motor deficits. But while cerebral palsy may be the most well-known neurological consequence of premature birth, it is not the most common. According to Joseph Volpe, M.D., a neonatal neurologist at Harvard Medical School-Children’s Hospital, “the principal neurological syndrome in the large majority of premature infants involves cognitive deficits without major motor deficits.”[ii] This fact is largely underappreciated even among medical doctors and researchers, he suggests.

From Organogenesis to Pattern Formation

Human fetal brain development occurs in three broad stages, explains Dana Alliance Member Verne Caviness, M.D., D.Phil., a child neurologist at Harvard-Massachusetts General Hospital. It starts within hours of conception with organogenesis—the gross formation of the CNS—then proceeds to a stage marked by vast proliferation of neurons and glial cells, and finally to a period of “pattern formation,” defined by neuronal migration and axonal outgrowth to form the framework of cell layers and intercellular connections.

The third trimester of pregnancy—the “premature period”—is marked by great activity and complex events in the fetal brain, largely involving neuronal maturation and wiring. The weight of the brain roughly triples during the last 13 weeks of gestation, from an average of about 100 grams at the end of the second trimester to about 300 grams at full term, Caviness says. (The adult brain averages about 1,500 grams.) This rapid development translates to heightened vulnerability to damage from both the internal (e.g., ischemia, inflammation, free-radical attack) and external (e.g., hormones, drugs, poor nutrition, etc.) environments. “Any very actively developing event is highly vulnerable to insults,” says Volpe.

Of particular relevance to the potential neurological sequelae of premature birth are the dynamic changes underway during the last trimester in the cerebral cortex and cerebellum, the two brain areas most important to cognitive processes. During this period, the cerebrum undergoes “striking changes in white matter,” Volpe says, highlighted by rapid axonal growth into the cortical layer from differentiating neurons in brain regions beneath the cortex. Precursor oligodendrocytes, the cells responsible for ensheathing neurons with myelin (the fatty substance that speeds neural transmission and gives white matter its color), are dynamically expanding in the cortex, and are particularly vulnerable to damage at this stage. Cerebral white matter damage is the most commonly recognized pathology of prematurity; periventricular leukomalacia, a condition marked by lesions in the white matter, occurs in about 50 percent of low birth weight infants.

While less appreciated, the involvement of a group of cells called GABAergic neurons is likely to be just as important relative to later cognitive dysfunction, Volpe postulates. These specialized nerve cells play central roles in inhibiting neural signals from other cells and thus are critical to a wide range of cognitive processes. They are the hallmark cell type that differentiates human brains from other mammals. While the conventional wisdom was that all cortical neurons were in place by the third trimester, Volpe has preliminary evidence that GABAergic cells are still expanding rapidly in the cortex during this period.  If proven, this could have important implications for cognitive deficits arising from cortical underdevelopment or damage in the premature brain.

“GABAergic input to the cortex is essential to determining the critical periods when regions of the cortex become specified by experience,” Volpe says. “If that GABA input is not there, cortical specification for functions such as vision, auditory perception, and cognition won’t happen.”

Meanwhile, the cerebellum is growing faster in the third trimester than any other brain region. Its surface area increases 30-fold in the last 16 weeks of pregnancy as granule cells on its outer layer proliferate wildly and cerebellar tissue folds in upon itself.  Granule cells are the primary cell type in the cerebellum and the most populous neuron in the brain, numbering roughly 45 billion, says Hatten. As with other rapidly developing events, proliferating granule cells on the surface of the cerebellum are vulnerable. One of the most prominent subtypes of medulloblastoma, the most common malignant brain tumor of childhood, involves these cells.

The New Thinking about Premature Brain Damage

It turns out that preterm brain damage is more complicated than discrete tissue loss due to a specific insult like an injury or a tumor. Neurological problems are increasingly recognized to be a factor of “trans-synaptic effects,” damage in one part of the brain that impacts functioning in another synaptically connected region.  Dana Alliance Member Martha Denckla, a scientist and developmental neurologist at Kennedy Krieger Institute and Johns Hopkins, calls it “brain-to-brain activation” and says it is a much underappreciated problem in preterm infants.

“Just as we know the developing brain needs activation from the outside—the well-understood concept of activity-dependent activation—there are relationships within the brain for which timing is very crucial,” she says. “If a certain piece of brain is not sufficiently developed to give its inputs to something it is supposed to be in circuit with that develops later, that’s going to impact how the brain matures.”

Volpe says this represents “the big change” in thinking about the premature brain. “In the past, we’ve thought of neurological deficits as being secondary to tissue loss from some sort of injury to the brain,” he says. “Now we think the problems relate only partially to tissue injury and perhaps more to these trans-synaptic and other trophic [growth-related] effects.” For example, the classic white matter lesions seen in the cerebrum lead to subsequent disturbances in interconnected regions in the basal ganglia and cerebellum, he says.

“In the past two to three years, we’ve learned to think about this as not just a ‘white matter problem’ but as a problem involving both white and grey matter,” Volpe says.

More Human Research Needed

These experts all agree that more human research is urgently needed on both the premature brain and the normal brain’s in utero development. “There are precious few studies on the development of the human fetal brain,” says Hatten. Most of what is known, Volpe says, is from studies in rodents and non-human primates, which may not always be relevant to the human condition.

“It’s amazing how little information is available based on actually studying the human brain,” he says.

Published May 2010


[i] Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Eng J Med 2010 February; 362(6):529-35.

[ii] Volpe JJ. Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important. J Child Neurol 2009 September; 24(9):1085-1104.