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The human brain develops at breathtaking speed. It grows from 10,000 cells at the fourth week of gestation to 10 billion at the 24th—a rate that far outstrips other organs—and within the first days, months, and years of life forges complex connections and establishes patterns that persist for a lifetime.
“Concerns about early experience go back to Plato,” says Thomas R. Insel, director of the National Institute for Mental Health and a member of the Dana Alliance for Brain Initiatives. “Now we have the possibility of creating tools that get us closer to mechanisms, and help us understand individual variations [in the course and pace of development], and how poverty, nutrition, and experience—good and bad—affect development in the first few years of life.”
Insel introduced the Fifth Annual Aspen Brain Forum, in New York City, a wide-ranging, three-day discussion of the developing brain hosted by the New York Academy of Sciences.
“From the NIMH perspective, studying brain development is a real public health mandate. Neurodevelopmental disorders include not just autism and ADHD, but schizophrenia, depression, eating disorders, and PTSD,” he said. Three-fourths of adults with mental disorders say they began before age 25, and half by age 14.
The complexity of early development demands an integrated cross-disciplinary approach that explores both how biology affects behavior, and how behavior affects biology. “We have to understand development at multiple levels: from neurons to neighborhoods,” Insel said. Genetics and epigenetics, cell biology, brain regions and systems, societies—“the challenge is to create a convergent science that brings it all together.”
The study of nutrition in brain development has deployed just such a “layered interdisciplinary approach,” said Michael K. Georgieff, of the University of Minnesota, at a symposium at the Brain Forum. “There’s a huge amount of metabolism in the brain throughout prenatal and postnatal life—it accounts for 60% of the body’s total oxygen consumption in the newborn period—and nutrients support that metabolism.”
Studies of nutrition and deficiency illustrate the importance of “critical periods,” Georgieff said. “Any positive or negative effect is based on two things: timing and dose and duration.” Brain regions and processes have diverse developmental trajectories and may be vulnerable to particular nutrient deficiencies at different times. Supplementation after such periods may fail to redress lasting consequences.
“Timing is also important for cross-talk between developing systems,” he said. “A deficiency may affect only one system, but if that disconnects it from another system, it can [impair] how they work together. This may underlie some of the disordered thinking in adulthood we see following early nutritional deficiencies.”
Iron in the Brain
While the full spectrum of macro- and micronutrients are vital for proper brain development, speakers at the symposium focused on the most common single nutrient deficiency in the world: iron.
The study of iron deficiency offered a vivid example of the “convergent science” that Insel called for. Betsy Lozoff, of the University of Michigan, surveyed findings of a “multidisciplinary, multi-institution, multilayered, multidomain” project investigating the consequences of iron deficiency early in development and the mechanisms behind them.
The NIH-funded project, for which Lozoff was principal investigator, included a human infant study, two studies with monkeys, and one with rodents. “We tried for integration across species in our conceptual model, design, outcome measures and statistics,” she said. The project engaged scientists of diverse disciplines who probed the neurochemistry, neuroanatomy, and neurometabolic aspects of iron deficiency, as well as behavioral effects on language, sensory, motor, and affective-social areas.
One important finding from the first five-year phase of the project was that, in both human infants and monkeys, iron deficiency without anemia negatively affects neurodevelopment. “This is a hugely clinically important issue for pediatricians, because we only screen for anemia,” she said.
Another was the critical importance of sufficient iron during gestation. “It meant that things previously attributed to postnatal deficiency may well have been due to prenatal deficiency,” she said. In animal studies, treatment with supplementary iron at a period that would correspond to human late infancy “didn’t correct deficits,” she said. “This is when we would be treating in pediatrics.” Later studies focusing on the fetal-neonatal period found that “iron treatment at a time that corresponded to human birth failed to prevent long-term deficits.”
The implications for practice and policy are potentially enormous, she said.
“It’s an example of how preclinical models linked to human studies provided biological proof and deepened understanding of iron deficiency on the brain level: an approach relevant for other nutrients and other early insults,” Lozoff said.
Georgieff reported animal research that probed the neurobiology of iron deficiency in the prenatal period, and its links to long-term neurodevelopmental alterations. “One thing deficiency does is suppress critical synaptic plasticity and morphogenesis genes: despite repletion in the newborn period, structural changes in the hippocampus continue across the lifespan and affect behavior.”
Brain-derived neurotrophic factor (BDNF) declines during acute iron deficiency prenatally and in early life, but suppression of BDNF and expression of its receptor persist in the adult, which may have lasting negative effects on the ability to process and retain new information. Post-synaptic density protein, important for memory formation, is chronically suppressed. Structurally, hippocampal dendrites remain highly disorganized, also suggesting compromised learning and memory capacity.
Mechanisms behind the lasting impact of iron deficiency are unclear, but may include epigenetic modification. Enzymes that influence methylation of plasticity genes like BDNF4 contain iron, and “the patterning of gene regulation carries implications across the lifespan,” Georgieff said.
To explore critical periods for iron nutrition, Georgieff and his team used a transgenic rat, altering a gene essential for iron transport so it could be disabled in the hippocampus and then restored. If the gene was restored at the time of rapid dendritogenesis, hippocampal architecture resembled wild-type rats’; if restored outside that putative critical period, the same fractured dendrites were seen as in untreated animals.
Functional testing mirrored the effect: if iron transport was reinstated during the critical period, rats learned a maze task as well as control animals. If not, they failed to learn.
Georgieff also described research suggesting a way to mitigate the effects of deficiency without supplemental iron. Formerly iron deficient animals failed to show a novelty preference, an indication of normal memory and cognition, in adulthood. But prenatal supplementation with the nutrient choline significantly improved this response.
The salutary effect of choline may reflect increased acetycholine-associated neurostimulation during critical periods, or epigenetic modification, he said. In any case, these findings show “how basic biological exploration” might suggest “potential workarounds where iron supplementation is difficult.”
An Integrated View
Interactions between nutrition and other early influences should not be overlooked, emphasized Maureen M. Black, of the University of Maryland. She described how stunting—reduced linear size early in life, a common consequence of poor nutrition in certain countries—has been linked in longitudinal studies to poor school performance and reduced cognitive development years later.
Beside biological effects of chronic undernutrition on brain development, environmental context may come into play. “Small rat pups receive different kinds of caregiving from their mothers; they elicit less stimulation,” Black said. Human parent-child relationships may be similarly altered, and more generally, “small children may be regarded as younger and less competent, and less able to interact with peers and their environment.”
Black described a study in which children were given a multi-micronutrient supplement in a large network of preschool centers in India. Anemia rates declined across the board, and certain cognitive measures improved, particularly in low-quality preschools. “Nutrition is a critical component of brain development, along with responsive caregiving and early learning,” she said. “Investigators who ignore the context may miss the impact of nutritional intervention.”