Shaping the Developing Brain: Spotlight on Nutrition and Brain Development

Journal Articles

Standardizing growth and nutritional status biomarkers

Bhutta ZA, Das JK, Rizvi A, et al. Lancet Nutrition Interventions Review Group; Maternal and Child Nutrition Study Group. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382(9890):452-77.

Frongillo EA, Tofail F, Hamadani JD, et al. Measures and indicators for assessing impact of interventions integrating nutrition, health, and early childhood development. Ann N Y Acad Sci. 2014;1308:68-88.

Frongillo EA Jr. Validation of measures of food insecurity and hunger. J Nutr. 1999;129(2S Suppl):506S-509S.

Lampl M, Johnson ML. Infant growth in length follows prolonged sleep and increased naps. Sleep. 2011;34(5):641-50.

Lampl M, Johnson ML, Frongillo EA Jr. Mixed distribution analysis identifies saltation and stasis growth. Ann Hum Biol. 2001;28(4):403-11.

Leroy JL, Ruel M, Habicht JP, Frongillo EA. Linear growth deficit continues to accumulate beyond the first 1000 days in low- and middle-income countries: global evidence from 51 national surveys. J Nutr. 2014;144(9):1460-6.

Onis M de, Garza C, Habicht JP. Time for a new growth reference. Pediatrics. 1997;100(8):E8.

Onis M de, Onyango A, Borghi E, et al. WHO Multicentre Growth Reference Study Group. Worldwide implementation of the WHO Child Growth Standards. Public Health Nutr. 2012;15(9):1603-10.

The most useful biomarkers for optimal childhood development

Aboud FE, Yousafzai AK. Global health and development in early childhood. Annu Rev Psychol. 2015;66:433-57.

Best C, Neufingerl N, Del Rosso JM, et al. Can multi-micronutrient food fortification improve the micronutrient status, growth, health, and cognition of schoolchildren? A systematic review. Nutr Rev. 2011;69(4):186-204.

Campbell F, Conti G, Heckman JJ, et al. Early childhood investments substantially boost adult health. Science. 2014;343(6178):1478-85.

Cooper WN, Khulan B, Owens S, et al. DNA methylation profiling at imprinted loci after periconceptional micronutrient supplementation in humans: results of a pilot randomized controlled trial. FASEB J. 2012;26(5):1782-90.

Eilander A, Gera T, Sachdev HS, et al. Multiple micronutrient supplementation for improving cognitive performance in children: systematic review of randomized controlled trials. Am J Clin Nutr. 2010;91(1):115-30.

Gertler P, Heckman J, Pinto R, et al. Labor market returns to an early childhood stimulation intervention in Jamaica. Science. 2014;344(6187):998-1001.

Levitsky DA, Barnes RH. Nutritional and environmental interactions in the behavioral development of the rat: long-term effects. Science. 1972;176(4030):68-71.

Prado EL, Dewey KG. Nutrition and brain development in early life. Nutr Rev. 2014;72(4):267-84.

Ramakrishnan U, Goldenberg T, Allen LH. Do multiple micronutrient interventions improve child health, growth, and development? J Nutr. 2011;141(11):2066-75.

Sachdev H, Gera T, Nestel P. Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutr. 2005;8(2):117-32.

Victora CG, de Onis M, Hallal PC, et al. Worldwide timing of growth faltering: revisiting implications for interventions. Pediatrics. 2010;125(3):e473-80.

Timing interventions to optimize brain development

Christian P, Murray-Kolb LE, Khatry SK, et al. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA. 2010;304(24):2716-23.

Fretham SJ, Carlson ES, Wobken J, et al. Temporal manipulation of transferrin-receptor-1-dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment. Hippocampus. 2012;22(8):1691-702.

Insel BJ, Schaefer CA, McKeague IW, et al. Maternal iron deficiency and the risk of schizophrenia in offspring. Arch Gen Psychiatry. 2008;65(10):1136-44.

Kennedy BC, Dimova JG, Siddappa AJ, et al. Prenatal choline supplementation ameliorates the long-term neurobehavioral effects of fetal-neonatal iron deficiency in rats. J Nutr. 2014;144(11):1858-65.

Kretchmer N, Beard JL, Carlson S. The role of nutrition in the development of normal cognition. Am J Clin Nutr. 1996;63(6):997S-1001S.

Lozoff B, Jimenez E, Hagen J, et al. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics. 2000;105(4):E51.

Lukowski AF, Koss M, Burden MJ, et al. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Nutr Neurosci. 2010;13(2):54-70.

Pongcharoen T, Ramakrishnan U, DiGirolamo AM, et al. Influence of prenatal and postnatal growth on intellectual functioning in school-aged children. Arch Pediatr Adolesc Med. 2012;166(5):411-6.

Riggins T, Miller NC, Bauer PJ, et al. Consequences of low neonatal iron status due to maternal diabetes mellitus on explicit memory performance in childhood. Dev Neuropsychol. 2009;34(6):762-79.

Schmidt RJ, Tancredi DJ, Krakowiak P, et al. Maternal intake of supplemental iron and risk of autism spectrum disorder. Am J Epidemiol. 2014;180(9):890-900.

Thompson RA, Nelson CA. Developmental science and the media. Early brain development. Am Psychol. 2001;56(1):5-15.

Tran PV, Carlson ES, Fretham SJ, Georgieff MK. Early-life iron deficiency anemia alters neurotrophic factor expression and hippocampal neuron differentiation in male rats. J Nutr. 2008;138(12):2495-501.

Tran PV, Fretham SJ, Carlson ES, Georgieff MK. Long-term reduction of hippocampal brain-derived neurotrophic factor activity after fetal-neonatal iron deficiency in adult rats. Pediatr Res. 2009;65(5):493-8.

Wachs TD, Georgieff M, Cusick S, McEwen BS. Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research. Ann N Y Acad Sci. 2014;1308:89-106.

A paradigm for interdisciplinary approaches to nutritional neuroscience

Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr. 2011;141(4):740S-746S.

Lozoff B. Iron deficiency and child development. Food Nutr Bull. 2007;28(4 Suppl):S560-71.

Lozoff B. Perinatal iron deficiency and the developing brain. Pediatr Res. 2000;48(2):137-9.

Lozoff B, Beard J, Connor J, et al. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev. 2006;64(5 Pt 2):S34-43; discussion S72-91.

Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006;13(3):158-65.

Walker SP, Wachs TD, Gardner JM, et al. International Child Development Steering Group. Child development: risk factors for adverse outcomes in developing countries. Lancet. 2007;369(9556):145-57.

Websites

American Academy of Pediatrics. International and U.S. Growth Charts.

UNICEF Data: Monitoring the Situation of Children and Women
Surveys and statistics on child and maternal health around the world.

Sponsors

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The Nathaniel Wharton Fund

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Highlights

Growth is used as a health measure worldwide, but there is a need to develop internationally applicable measures for other aspects of child development.

Stunting afflicts 24% of children under 5 years old worldwide and has stark long-term effects neurologically, cognitively, and economically.

Standardizing nutritional status biomarkers

Physical growth in children is perhaps the most common health measure used worldwide. Growth is easy to measure repeatedly and is equivalent across contexts; it is also a marker for environmental deprivation and for cognition and other aspects of development. Edward A. Frongillo of the University of South Carolina discussed the need to standardize biomarkers for nutrition and other aspects of early childhood development and to develop the tools to assess them.

Current growth standards for children emerged from a 1995 World Health Organization plan to replace old references, which were based on primarily bottle-fed infants in the U.S. and thus did not apply to healthy breast-fed infants. The new standards describe how children grow under optimal conditions and were designed by sampling from six countries. Since the implementation of the new standards in 2006, policy makers' interest in nutrition has grown dramatically, and wealthy countries are considering large-scale investments to eliminate stunting caused by nutritional deprivation.

International growth chart for girls aged 0–5 years old showing severely stunted girl at 17 months. (Image courtesy of Edward A. Frongillo)

Because studies on stunting have concluded that deprivation affects growth between conception and age 2, policy efforts focus on this timeframe. However, Leroy, Frongillo, and colleagues recently reported that 30% of the growth deficit of children under 5 years old occurs after age 2, suggesting that attention should be paid to the 2- to 5-year-old age group in addition to the current focus on conception to age 2.

Frongillo said researchers should devise internationally applicable measures and indicators for aspects of development besides growth—such as cognitive and language skills and social and emotional development—particularly ones that are validated in low- and middle-income countries and scalable to large sample sizes.

The most useful biomarkers for optimal childhood development

Growth and micronutrient status are clear biomarkers of nutritional adequacy, explained Maureen M. Black of the University of Maryland School of Medicine. Although the number of children who are stunted because of nutritional deprivation is falling, according to UNICEF data the condition afflicts 25% of children under 5 years old worldwide—161 million children.

Stunting has stark long-term effects neurologically, cognitively, and economically. It has been linked with low IQ scores, poorer academic performance, early marriage, and less earning capacity, thus taking a toll not just on individuals but also on communities. Our knowledge about brain development suggests that early intervention to promote optimal brain functioning is most effective, but trials attempting to treat or prevent the effects of nutritional deprivation have shown inconsistent results.

Stunting interferes with normal brain development. (Image courtesy of Maureen M. Black)

These inconsistencies could result from children having multiple deficiencies, and it is often unclear how to intervene. Epigenetic changes at the time of conception could also be at play. Another key and often ignored factor in the efficacy of an intervention is the context in which it is delivered. For example, in a study in rural India, 6 months of micronutrient supplementation improved iron status and growth, but school performance and language development improved only for children in low-quality schools, not for those in high-quality schools. Interventions integrating nutrition with other aspects of child development, such as cognition and language skills, are likely to have the best chance for success.

Highlights

Properly timed nutritional interventions may reverse some deficits caused by iron deficiency that were previously thought to be permanent.

Results from a cross-species project of iron deficiency in humans, monkeys, and rats indicated that many long-term deficits previously attributed to iron deficiency in infancy may stem from prenatal iron deficiency—complicating prospects of iron treatment in deficient children.

Timing interventions to optimize brain development

Different brain regions and processes have different developmental trajectories, so timing is crucial in nutritional interventions. Michael K. Georgieff of the University of Minnesota demonstrated the importance of timing in an intervention previously thought to be ineffective. Fetal and neonatal iron deficiency suppresses synapse formation and plasticity in the hippocampus and has been strongly linked to long-term neurodevelopmental changes. Until recently, researchers thought certain effects of early-life iron deficiency were permanent and could not be ameliorated, but Georgieff's work suggests that properly timed interventions may be effective.

In a mouse model, his lab reversibly disabled iron uptake in fetal hippocampal neurons during late gestation. In adulthood, the mice had improperly formed hippocampal dendrites and performed poorly on the Morris water maze, a hippocampus-linked memory task. Hippocampal dendrite formation peaks at 3 weeks of age; restoring iron uptake before then led to restoration of both dendritic architecture and Morris maze performance. Restoring iron uptake later had no benefit to structure, behavior, or gene expression.

The hippocampus of control animals (A, C, and E) shows orderly dendritic connections (red arrows). In the absence of iron uptake in hippocampal neurons, dendritic connections become disordered (B, blue arrow). When iron is restored at postnatal day 21 (C), dendritic connections return to normal. But when iron uptake is restored later, at postnatal day 42 (D), there is no effect. The bar graphs (bottom) show corresponding performance on the Morris water maze, indicating a restoration in hippocampal memory. (Image courtesy of Michael K. Georgieff)

Next, Georgieff's team examined whether the negative brain effects of iron deficiency can be tempered or ameliorated with the nutrient choline, which improves electrophysiological, morphological, and functional deficits in early rodent brain development through neurotransmitter-mediated and epigenetic mechanisms. Giving choline to iron-deficient pregnant rats partially improved memory deficits in their offspring by adulthood. The intervention normalized the expression of a gene important in hippocampal function, potentially mediated by epigenetic mechanisms.

A paradigm for interdisciplinary approaches to nutritional neuroscience

According to the World Health Organization, iron is among the most common nutrient deficiencies. One quarter of the world's infants have an iron deficiency severe enough to cause anemia, but treating children with iron has not reversed cognitive, motor, and social-emotional alterations. To investigate why, Betsy Lozoff of the University of Michigan and a multi-institutional team of colleagues conducted a 10-year investigation of the effects of iron depletion on brain and behavior, as well as its timing, duration, and potential for intervention.

A 10-year study examined multiple elements of brain development and behavior that could be affected by iron deficiency. (Image courtesy of Betsy Lozoff)

The study assessed brain chemistry, structure, and anatomy, as well as cognitive, sensory-motor, and social domains in rats, monkeys, and humans. Iron deficiency negatively affected neurodevelopment even when not severe enough to cause anemia. In animal models, iron deficiency altered brain structure and function and genomic and proteomic profiles. These findings are clinically important, Lozoff told the audience, because pediatricians only screen for anemia. Giving iron at the equivalent of later infancy—when pediatricians would administer it—did not ameliorate deficits.

The research also pointed to the conclusion that long-term deficits previously attributed to iron deficiency in later infancy may have also stemmed from iron deficiency during gestation (prenatally). Iron supplementation beginning at birth in humans—or the equivalent developmental time in animal models—did not prevent deficits in later infancy. Furthermore, rapid neonatal repletion in the developing rat with an amount of iron equivalent to the high-end used in clinical pediatric care was as detrimental as the deficiency itself. Researchers should look for better ways to deliver iron to the developing brain, as well as adjunct therapies that can ameliorate the effects of iron deficiency, Lozoff concluded.

Discussion

The speakers emphasized that correcting anemia and blood measures of iron deficiency differs from correcting brain iron and the effects of deficiency on the developing central nervous system. Blood measures of iron deficiency readily respond to iron treatment, but it is still unclear how best to provide timely, adequate iron to the developing brain. The research summarized points to the critical importance of iron nutriture during gestation. However, despite recommendations for iron supplementation during pregnancy, many infants worldwide are born iron-depleted. Furthermore, the fetal brain may be iron-deficient in common clinical conditions when the mother may be iron-sufficient, such as diabetes during pregnancy or intrauterine growth restriction, which is often caused by hypertension.

The speakers also discussed areas of nutrition-related research still in their infancy, such as nutrigenomics and microbiome studies. For example, different gene variants might cause certain nutrients to be more effectively taken up than others. Research into how these mechanisms work needs to be completed and then tested in the field.

Speakers raised the need for better methods to study the effects of nutrition on human brain development. Current brain-based measures generally involve sophisticated technologies that are difficult to apply in the settings where nutrient deficiencies are most widespread. Furthermore, many of the most sensitive measures are not standardized. Classic neurological research is often based on a clear deficit, such as an inability to speak after a stroke, but nutrients have subtler effects that are harder to detect but may nonetheless affect function in daily life.

Which biomarkers of development are most appropriate for application as international standards?

What kinds of standardized child development measures would best translate research on brain development into science-based policies?

Which aspects of childhood development are most important when combining nutritional with other types of interventions?

To what extent can early-life nutritional deficiency be ameliorated by later supplementation in humans?

What is the optimal timing for iron supplementation?