REVIEW ARTICLE

published: 26 March 2013

HUMAN NEUROSCIENCE doi: 10.3389/fnhum.2013.00097

The role of nutrition in children’s neurocognitive

development, from pregnancy through childhood
Anett Nyaradi 1,2*, Jianghong Li 1,3,4 , Siobhan Hickling 1,2 , Jonathan Foster 1,5,6,7 and Wendy H. Oddy 1
1
Centre for Child Health Research, Telethon Institute for Child Health Research, The University of Western Australia, Perth, WA, Australia
2
School of Population Health, The University of Western Australia, Perth, WA, Australia
3
Centre for Population Health Research, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
4
Social Science Research Center, Berlin, Germany
5
School of Psychology and Speech Pathology, Curtin University, Perth, WA, Australia
6
Neurosciences Unit, Health Department of Western Australia, Perth, WA, Australia
7
School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, Australia

Edited by: This review examines the current evidence for a possible connection between nutritional
Andrew Scholey, Swinburne intake (including micronutrients and whole diet) and neurocognitive development in
University, Australia
childhood. Earlier studies which have investigated the association between nutrition and
Reviewed by:
cognitive development have focused on individual micronutrients, including omega-3 fatty
Sebastian J. Lipina, Unidad de
Neurobiología Aplicada, Argentina acids, vitamin B12, folic acid, choline, iron, iodine, and zinc, and single aspects of diet.
Leigh Gibson, University of The research evidence from observational studies suggests that micronutrients may
Roehampton, UK play an important role in the cognitive development of children. However, the results of
*Correspondence: intervention trials utilizing single micronutrients are inconclusive. More generally, there is
Anett Nyaradi, Telethon Institute
evidence that malnutrition can impair cognitive development, whilst breastfeeding appears
for Child Health Research, The
University of Western Australia, 100 to be beneficial for cognition. Eating breakfast is also beneficial for cognition. In contrast,
Roberts Road, Subiaco, PO Box 855, there is currently inconclusive evidence regarding the association between obesity and
West Perth, WA 6008, Australia. cognition. Since individuals consume combinations of foods, more recently researchers
e-mail: [email protected]
have become interested in the cognitive impact of diet as a composite measure. Only
a few studies to date have investigated the associations between dietary patterns and
cognitive development. In future research, more well designed intervention trials are
needed, with special consideration given to the interactive effects of nutrients.

Keywords: nutrition, cognitive development, children, micronutrients, diet quality

INTRODUCTION systems in the brain (Bhatnagar and Taneja, 2001; Lozoff and
Cognition represents a complex set of higher mental functions Georgieff, 2006; Zeisel, 2009; De Souza et al., 2011; Zimmermann,
subserved by the brain, and includes attention, memory, thinking, 2011). Brain development is faster in the early years of life com-
learning, and perception (Bhatnagar and Taneja, 2001). Cognitive pared to the rest of the body (Benton, 2010a), which may make it
development in pre-schoolers is predictive of later school achieve- more vulnerable to dietary deficiencies.
ment (Tramontana et al., 1988; Clark et al., 2010; Engle, 2010). In this literature review, we assess the current research evidence
As Ross and Mirowsky (1999) state: “Schooling builds human for a link between nutritional intake in pregnancy and childhood
capital - skills, abilities, and resources—which ultimately shapes and children’s cognitive development. We first discuss individual
health and well-being.” Indeed, more education has been linked micronutrients and single aspects of diet, which represents earlier
to better jobs, higher income, higher socio-economic status, bet- research in this area. We next consider the more encompassing
ter health care access and housing, better lifestyle, nutrition, and aspects of diet, which have emerged as researchers became more
physical activity (Florence et al., 2008), which are all well-known interested in diet as a comprehensive measurement. The most
health determinants. Education increases an individual’s sense recent research trend in this area suggests a broader analysis of the
of personal control and self-esteem; these factors have also been role of nutrition in neurocognitive development, which we offer
shown to influence better health behavior (Ross and Mirowsky, here in comparison to previous reviews (Black, 2003b; Bellisle,
1999; Logi Kristjánsson et al., 2010). Academic achievement is 2004; Stevenson, 2006; Georgieff, 2007; Benton, 2010a).
important for future personal health, and is therefore a significant
concern for public health. BRAIN DEVELOPMENT IN HUMANS
Cognitive development is influenced by many factors, includ- The understanding of the functional and structural development
ing nutrition. There is an increasing body of literature that of the human brain has emerged from a range of methodolo-
suggests a connection between improved nutrition and optimal gies (including clinical lesion and experimental animal studies)
brain function. Nutrients provide building blocks that play a criti- and lately as a result of greatly improved neuroimaging meth-
cal role in cell proliferation, DNA synthesis, neurotransmitter and ods, in particular Positron Emission Tomography and Magnetic
hormone metabolism, and are important constituents of enzyme Resonance Imaging (MRI) (Levitt, 2003; Uddin et al., 2010).

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 1

Nyaradi et al. Nutrition and children’s cognitive development

Brain development is a temporally extended and complex pro- can have a direct effect on gene expression (Levi and Sanderson,
cess, with different parts and functions of the brain developing at 2004; Rosales et al., 2009; Attig et al., 2010; Lillycrop and Burdge,
different times (Grossman et al., 2003). By 5 weeks after concep- 2011; Jiménez-Chillarón et al., 2012). One of the first and best
tion in humans, the anterior-posterior and dorsal-ventral axes of known human studies in the rapidly growing field of “Nutritional
the neural tube have already developed (Levitt, 2003). The cor- Epigenomics” relates to the Dutch Hunger Winter during the
tical plate (which is the forerunner of the cerebral cortex) and 1940’s in which the offspring of mothers exposed to famine dur-
some inter-neuronal connections form from 8 to 16 weeks of ing pregnancy had an increased risk of cardiovascular, kidney,
gestation (Kostović et al., 2002; Levitt, 2003). From 24 weeks of lung, and metabolic disorders and reduced cognitive functions
gestation until the perinatal period, the neurons in the corti- (Roseboom et al., 2006; De Rooij et al., 2010). More specifi-
cal plate die and are replaced by more mature cortical neurons. cally, evidence has been obtained of hypo- and hyper-methylated
During this time, significant refinement in neural connections DNA segments from the blood cells of the affected individuals
take place (Levitt, 2003). From 34 weeks post-conception until (Heijmans et al., 2008).
2 years of age, peak synapse development, and significant brain Evidence suggests that the timing of nutritional deficien-
growth occurs (Huttenlocher and Dabholkar, 1997; Levitt, 2003). cies can significantly affect brain development. For example,
By preschool age, synaptic density has reached the adult level. The it is well known that folic acid deficiency between 21 and 28
myelination of some parts of the brain (particularly those that days after conception (when the neural tube closes) predis-
control higher cognitive functions, such as the frontal lobes) con- poses the foetus to a congenital malformation, called a neural
tinues well into adolescence, whilst myelination occurs earlier in tube defect. Hence, this is a critical period, because during that
other parts of the brain that coordinate more primary functions time an irreversible change in the brain structure and func-
(Toga et al., 2006). Although the gray matter (which contains the tion occurs if there is inadequate folic acid present (Blencowe
bodies of nerve cells) reaches asymptote by the age of 7–11 in et al., 2010). A critical period is a specific period within a
different regions of the brain, it is thought that the growth of sensitive timeframe (Knudsen, 2004). A sensitive period tends
the white matter (which represents axonal nerve tracts) continues to reflect a broader timeframe; during such a developmen-
beyond 20 years of age. Studies have shown that the maturation tal period the brain is more sensitive to specific interventions.
of specific brain areas during childhood is associated with devel- However, skills and abilities can still be acquired outside this
opment of specific cognitive functions such as language, reading, time period, albeit with less proficiency (Knudsen, 2004). An
and memory (Nagy et al., 2004; Deutsch et al., 2005; Giedd et al., example is that deaf children who receive cochlear implants
2010). The development of the frontal lobes, which are believed to within a sensitive period for brain development (i.e., before
control higher cognitive functions (including planning, sequenc- the age of 3–5 years) show better language development than
ing and self-regulation), appears to occur in growth spurts during those who receive a cochlear implant after this period (Penhune,
the first 2 years of life, and then again between 7 and 9 years of 2011).
age and also around 15 years of age (Thatcher, 1991; Bryan et al., Since rapid brain growth occurs during the first 2 years of life
2004). The development of some subcortical structures includ- (and by the age of 2 the brain reaches 80% of its adult weight), this
ing the basal ganglia, amygdala, and hippocampus (which are period of life may be particularly sensitive to deficiencies in diet
also centrally involved in some mediating higher cognitive func- (Bryan et al., 2004; Lenroot and Giedd, 2006). Adolescence is also
tions, including memory, executive functions, and emotion) also a significant and sensitive developmental period, with research
continues until late adolescence. In addition, a meta-analysis has indicating that structural reorganization, brain and cognitive
confirmed a connection between the size of the hippocampus and maturation and—in particular—major developments in the pre-
memory performance during brain development in children and frontal cortex take place during puberty (Luna and Sweeney,
young adults (Van Petten, 2004). Overall, the research evidence 2001; Sisk, 2004; Peper et al., 2009; Asato et al., 2010; Blakemore
suggests that cognitive development is strongly connected with et al., 2010).
micro and macro-anatomical changes which take place through-
out childhood (Levitt, 2003; Herlenius and Lagercrantz, 2004; DIETARY INFLUENCES ON COGNITIVE DEVELOPMENT
Ghosh et al., 2010). MICRONUTRIENTS AND COGNITIVE DEVELOPMENT
Individual brain development follows a genetic program Omega-3 fatty acids
which is influenced by environmental factors including nutri- In recent years, there has been an increasing interest in the
tion (Bryan et al., 2004; Toga et al., 2006; Giedd et al., 2010). effect of essential fatty acids, particularly long chain polyunsat-
Environmental influences may modify gene expression through urated fatty acids (LCPUFA), on cognitive brain development.
epigenetic mechanisms, whereby gene function is altered through Of the human brain’s dry weight 60% is comprised of lipids, of
the processes of DNA methylation, histone modification and the which 20% are docosahexaenoic acid (DHA; which is an omega-
modulating effect of non-coding RNAs, without the alteration 3 fatty acid) and arachidonic acid (AA; an omega-6 fatty acid).
of the gene sequence per se. These epigenetic factors can cause These represent the two core fatty acids found in gray matter
long lasting or even heritable changes in biological programs (Benton, 2010b; De Souza et al., 2011). Furthermore, the sup-
(Levi and Sanderson, 2004; Rosales et al., 2009; Murgatroyd and ply of LCPUFAs from food, especially the omega-3 fatty acids,
Spengler, 2011; Lillycrop and Burdge, 2012). It has been shown including DHA and eicosapentaenoic acid (EPA), is frequently
in animal and more recently in human studies that nutrition is inadequate for children as well as for adults (Schuchardt et al.,
one of the most salient environmental factors, and that nutrition 2010).

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 2

Nyaradi et al. Nutrition and children’s cognitive development

Essential fatty acids play a central functional role in brain mercury concentration (which has been shown to alter neu-
tissue. They are not only the basic components of neuronal mem- rodevelopment adversely), research in American schoolchildren
branes, but they modulate membrane fluidity and volume and (Project Viva, a prospective pre-birth cohort study) demonstrated
thereby influence receptor and enzyme activities in addition to that higher maternal fish intake was still positively associated with
affecting ion channels. Essential fatty acids are also precursors for improved language scores on the Peabody Picture Vocabulary
active mediators that play a key role in inflammation and immune Test (PPVT), after adjustment for many potential confounders
reaction. They promote neuronal and dendritic spine growth and and covariates (Oken et al., 2008a). The Danish National Birth
synaptic membrane synthesis, and hence influence signal pro- Cohort study investigated the developmental milestones of 25,446
cessing, and neural transmission. In addition, essential fatty acids six- and 18-month old children on a developmental scale created
regulate gene expression in the brain (McCann and Ames, 2005; by the researchers, and found that higher maternal fish intake
Eilander et al., 2007; Innis, 2007; Cetina, 2008; Wurtman, 2008; was beneficial for cognitive development even after adjusting for
Ramakrishnan et al., 2009; Ryan et al., 2010; Schuchardt et al., breastfeeding and many sociodemographic factors (Oken et al.,
2010; De Souza et al., 2011). Therefore, the existing literature 2008b). Two other studies of Inuit children in Arctic Quebec,
strongly suggests that essential fatty acids are critical for brain Canada, showed that higher umbilical cord DHA concentration
development and function. was associated with: (1) improved infant cognitive development,
It has been suggested that the fast growth of the human cere- measured on the Fagan Test of Infant Intelligence at 6 months,
bral cortex during the last two million years was strongly related (2) on the Bayley Scales of Infant Development test used at 11
to the balanced dietary intake of LCPUFAs (Broadhurst et al., months (Jacobson et al., 2008), and (3) better memory perfor-
1998), specifically with an equal ratio of omega-6 and omega-3 mance of school children on both the Digit Span Forward subtest
fatty acids in the diet (Simopoulos, 1999). Evidence proposes of the WISC-IV and the California Verbal Learning Test-Children
that the modern Homo sapiens, whose brain developed signifi- Version (Boucher et al., 2011). These results were independent of
cantly relative to its ancestors, lived near rivers and oceans, where mercury contamination in seafood. Both studies adjusted for a
seafood and fish were abundant (Crawford et al., 1999). The rise wide range of socioeconomic and demographic factors. However,
in intellectual and brain development in Homo Sapiens also coin- these investigations used smaller samples, specifically 109 infants
cided with tool making and language development (Crawford (Jacobson et al., 2008) and 154 schoolchildren (Boucher et al.,
et al., 1999; Broadhurst et al., 2002). During the last 150 years, 2011), compared to the previously described studies. In conclu-
it is believed that the balance of omega-6 to omega-3 fatty acids sion, the positive association between maternal fish intake and
has shifted in favor of omega-6 fatty acids in the diet, resulting in cognitive development is supported by evidence from the studies
a ratio of 20–25:1 and a dietary deficiency in omega-3 fatty acids cited above.
(Simopoulos, 1999). A diet that is deficient in omega-3 fatty acids However, intervention studies of LCPUFA supplementation
may have health and developmental implications (Simopoulos, during pregnancy have produced conflicting results so far. Some
2008). studies have reported positive associations between DHA sup-
A number of epidemiological studies have shown a positive plementation and cognitive developmental parameters (Helland
association between maternal fish intake (which is a rich source et al., 2003, 2008; Colombo et al., 2004; Judge et al., 2007; Dunstan
of omega-3 fatty acids) during pregnancy and cognitive devel- et al., 2008). A randomized placebo-controlled double- blind
opment in children (Daniels et al., 2004; Hibbeln et al., 2007; study undertaken by Helland et al. (2003) in Norway used a
Jacobson et al., 2008; Oken et al., 2008a,b; Boucher et al., 2011). design which supplemented women from 18 weeks of pregnancy
Data from the Avon Longitudinal Study of Parents and Children until 3 months postpartum with cod liver oil containing 1183 mg
(ALSPAC) in the UK regarding fish consumption and child cog- DHA. Children’s cognitive status was assessed at 6 and 9 months
nitive development were analyzed in two studies (Daniels et al., on the Fagan Test of Infant Intelligence (Helland et al., 2001),
2004; Hibbeln et al., 2007). The earlier study found evidence that and at 4 years of age by the Kaufman Assessment Battery for
higher maternal fish consumption was associated with higher lan- Children (K-ABC), specifically the Mental Processing Composite
guage and social skills (after appropriate adjustments) in 7421 comprising the Sequential Processing, Simultaneous Processing,
British children assessed at 15 months, using the MacArthur and Non-verbal Scales (which reflects children’s problem solv-
Communicative Development Inventory (MCDI), and at 18 ing and information processing skills; Helland et al., 2003). The
months using the Denver Developmental Screening test (Daniels results indicated that maternal DHA supplementation improved
et al., 2004). The later ALSPAC study demonstrated that those children’s mental processing skills at 4 years of age (Helland
children whose mothers consumed lower levels of seafood during et al., 2003), but not recognition memory at 6 and 9 months of
pregnancy had lower IQ, measured by the Wechsler Intelligence age (Helland et al., 2001). However, in a follow-up study con-
Scale for Children III (WISC-III) at the age of 8 (after adjusting ducted at the age of 7, there was no difference in overall IQ
for a wide range of relevant covariates). Lower maternal seafood between supplemented versus non-supplemented children, but
consumption was also linked to suboptimal behavior at age seven a positive correlation was observed between the concentration
(measured using the Child Behavior Checklist) and to lower lev- of α-linolenic acid (ALA) and DHA in maternal plasma phos-
els of social, fine motor and language development (measured pholipid and performance on the Sequential Processing scale
using the Denver Developmental Screening test) at six, 18, 30, (Helland et al., 2008). A possible explanation of these findings
and 42 months of age in the same study (Hibbeln et al., 2007). is that by 7 years of age cognitive development is influenced by
Although higher fish intake may result in higher erythrocyte many other intervening factors, and the test battery used in the

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 3

Nyaradi et al. Nutrition and children’s cognitive development

research may not have been sensitive enough to detect the associ- birth and did not find any difference on the Bayley Scales of Infant
ation between diet and cognition at this later age (Helland et al., and Toddler Development at the age of 18 months between inter-
2008). The results of a study reported by Judge et al. (2007) also vention (supplemented with 800 mg DHA) and control groups
supported the findings of the previous study, providing evidence (supplemented with vegetable oil capsules), after adjustment for
that maternal DHA supplementation results in better problem potential confounders. Given the size of this study, the Makrides
solving ability (speed of processing) in 9 month old infants on et al. (2010) investigation was certainly adequately powered to
the Infant Planning Test, but not on recognition memory eval- detect a statistically significant difference; yet, no such difference
uated using the Fagan Test of Infant Intelligence. These findings was observed.
may indicate that DHA is more important in the development of Some published studies have also considered supplementation
problem solving and processing ability than other cognitive func- in lactating mothers in order to examine the effect of increased
tions such as memory. Visual attention or look duration declines omega fats in breast milk on the cognitive development of chil-
during the first year of life, giving place to more complex mental dren. Reviews of these studies have concluded that there are indi-
processing (Frick et al., 1999; Colombo et al., 2004; Judge et al., cations that supplementing lactating mothers with fish oil may
2007). Colombo et al. (2004) reported an association between positively influence cognitive development in children (Eilander
maternal DHA supplementation and faster decline in visual atten- et al., 2007; Hoffman et al., 2009).
tion during infancy, and better resistance to distractibility during In conclusion, the current findings show inconsistencies in the
the second year of life. Researchers in Western Australia supple- efficacy of maternal supplementation with omega-3 fatty acid. In
mented a small sample of women (n = 98) from 20 weeks of seeking to account for the contrasting findings, it seems that the
gestation until delivery with high dose (2200 mg) DHA or olive following considerations may be relevant: the interventions were
oil and showed significant improvements in hand and eye coor- applied in different groups of women, using a wide range of DHA
dination in the supplemented group at 2½ years of age, after dosage, with different durations of supplementation, and the out-
adjusting for maternal age, maternal education, and breastfeed- comes were measured on different cognitive instruments and at
ing (Dunstan et al., 2008). These researchers also demonstrated different ages. The more consistent results obtained in epidemio-
better performance in other elements of cognitive development logical studies (compared with supplementation trials using only
(locomotor, social, speech and hearing performance, and practi- omega-3 fatty acid) may be explained by the possibility that fish is
cal reasoning), evaluated using the Griffiths Mental Development a whole food, and it contains other nutrients important to cogni-
Scales, and on language development, evaluated using the PPVT tive development. Furthermore, by eating fish rather than taking
(Dunstan et al., 2008). However, these latter differences were not fish supplements, other possibly unhealthy or potentially inflam-
statistically significant, perhaps due to the relatively small sample matory foods may also be displaced—i.e., red meat and processed
size in the study. meats. Epidemiological studies may also be better powered but
Contrary to expectations, some studies did not find a rela- they may also potentially have less control for confounding.
tionship between LCPUFA supplementation during pregnancy Postnatal studies have considered the effect of omega-3
and cognitive development in children (Tofail, 2006; Makrides fatty acid supplementations on term and preterm infants.
et al., 2010; Campoy et al., 2011). One of these studies was Epidemiological studies and supplementation trials have also
conducted in a developing country, Bangladesh, where a high pro- been undertaken in older children in relation to cognitive devel-
portion of mothers suffer from undernutrition, and possibly from opment. The DHA component is believed to be one of the main
multiple micronutrient deficiencies important for brain develop- reasons why breast milk may improve the cognitive performance
ment. The pregnant mothers in this study were randomized into of children. Humans are able endogenously to synthesize DHA
fish-oil or soy-oil supplemented groups, and their infants’ cog- from precursor α-linolenic acid. However, the conversion rate
nitive development was measured on the Bayley Scales of Infant varies according to genetically determined polymorphisms in two
Development at ten months of age. In this study, the mothers were genes, namely FADS1 and FADS2. Moreover, in infants the con-
only given supplements during the third trimester, which may not version to DHA seems to be very limited (Hoffman et al., 2009;
have represented a sufficient timeframe for supplement admin- Guesnet and Alessandri, 2011). Research consistently shows that
istration (Tofail, 2006). In a recent study conducted in Europe the blood levels of DHA in formula-fed infants are lower than
on 270 women from three countries, cognitive development was in breastfed infants, irrespective of the level of precursors in for-
measured on the K-ABC at 6½ years of age after 500 mg DHA mulas (Hoffman et al., 2009). Therefore, this topic has generated
prenatal supplementation. In this study, the co-authors did not a great deal of scientific interest, especially with respect to the
find significant differences in intelligence between the interven- results of clinical trials that have supplemented infant formulas
tion and control groups (Campoy et al., 2011). The explanation with LCPUFA and investigated the relationship with cognitive
offered was that the positive effect of prenatal supplementation development in either term or preterm infants.
may have been overshadowed by other important factors (not A Cochrane review undertaken by Simmer et al. (2008)
all of which it is possible to control for) including social stim- included 11 studies and concluded that there is currently not
ulation, other nutrients taken, diet as a whole, illnesses, and enough evidence to support the supplementation of infant for-
drugs prescribed by the age of 6–7 years (Helland et al., 2008). mulas with LCPUFA to benefit cognitive development in children
Makrides et al. (2010) conducted a well-designed multicenter born at term. Another review by McCann and Ames (2005) con-
double-blind randomized controlled trial in Australia on 2399 sidered animal as well as human supplementation studies. These
women between 2005 and 2009 from 21 weeks of gestation until authors found that, although animal studies provided convincing

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 4

Nyaradi et al. Nutrition and children’s cognitive development

evidence for DHA supplementation and improved cognitive per- in axon myelination that is important for impulse conduction
formance, these studies were undertaken under extreme dietary from cell to cell, and it also protects neurons from degeneration.
conditions in which (in most cases) animals were severely defi- Vitamin B12 may also alter the synthesis of different cytokines,
cient in essential fatty acids. By contrast, in formula and breastfed growth factors and oxidative energy metabolites such as lactic acid
infants the differences in brain DHA concentrations are small, (Dror and Allen, 2008).
such that the positive effects of LCPUFA on cognitive devel- In children, the association between vitamin B12 and cognitive
opment may be difficult to detect. Eilander et al. (2007) also development has been mainly observed in infants born of veg-
concluded that there is no evidence that formula supplementa- etarian/vegan mothers or mothers on a macrobiotic diet. These
tion in term infants is beneficial for cognitive development. On diets can result in vitamin B12 deficiency, as vitamin B12 is largely
the other hand, Hoffman et al. (2009) reviewed 20 studies and found in animal products. A pooled analysis that included 48
suggested that those trials which supplemented formula milk with case studies of infants with vitamin B12 deficiencies reported
a similar level of DHA to breast milk (i.e., to an average of 0.32%) a variety of abnormal clinical and radiological signs, including:
found beneficial outcomes. A major intake of DHA in the brain hypotonic muscles, involuntary muscle movements, apathy, cere-
happens in the last trimester of pregnancy; therefore, preterm bral atrophy, and demyelination of nerve cells (Dror and Allen,
infants are disadvantaged and have decreased brain concentra- 2008). After vitamin B12 treatment, a rapid improvement in neu-
tion of this vital LCPUFA. Eilander et al. (2007) indicated that rological symptoms is reported in deficient infants, but many of
supplementing formula milk with LCPUFA may be beneficial for these infants remained seriously delayed in cognitive and lan-
the cognitive development of preterm infants. However, a recent guage development in the longer term (Dror and Allen, 2008).
Cochrane review undertaken on preterm infants reported no The long-lasting effect of vitamin B12 deficiency is supported by
significant outcome of supplementation with LCPUFA on their the findings of Louwman et al. (2000). These researchers inves-
cognitive development (Schulzke et al., 2011). tigated the cognitive functioning of adolescents who consumed
Since brain development continues through childhood, there a macrobiotic diet until the age of 6 years, compared to chil-
have been much interest in the association between cognitive dren with an omnivorous diet. Those adolescents who consumed
development and omega-3 fat levels through diet and/or supple- a macrobiotic diet until 6 years of age had lower levels of fluid
mentation in children. Ryan et al. (2010) reviewed the available intelligence, spatial ability and short term memory (even with
epidemiological studies and supplementation trials to date and currently normal vitamin B12 status) than the control subjects.
concluded that, although the results were inconsistent, it appears Although vitamin B12 deficiency is not likely to occur in non-
that those studies that supplemented with higher doses and longer vegetarian people in western countries, Pepper and Black (2011)
durations of DHA achieved a favorable positive outcome in raised concern about the more frequent gastric bypass surgeries
cognitive development in childhood. in obese women and the increased incidence of coeliac disease
and inflammatory bowel diseases (such as Crohn’s and ulcera-
Vitamin B12, folic acid, and choline tive colitis). In these conditions, the absorption of vitamin B12
B12 and folate deficiency resulting in anaemia is rare around is substantially decreased in the intestine, thereby potentially
the world. However, it can occur in both developing and adversely affecting the development of future children born to
developed countries especially in older people, in those with these women.
absorption problems and in vegetarians (De Benoist, 2008). The association between maternal blood folate status and
Folate fortification of bread products has been made manda- cognitive development has been investigated in several studies
tory in Australia and in many other countries, which has (Tamura et al., 2005; Veena et al., 2010). Tamura et al. (2005)
reduced this deficiency significantly (Brown et al., 2011). In did not find any relationship between maternal blood folate sta-
recent years, there has been an increasing interest in the asso- tus (“low” vs. “normal”) during the second half of the pregnancy
ciation between vitamin B12, folic acid, choline metabolism, and cognitive development of their children at the age of 5–6
and cognitive development. Folate affects neural stem cell pro- years on different cognitive tests including Differential Ability
liferation and differentiation, decreases apoptosis, alters DNA Scales, Visual and Auditory Sequential Memory, Knox Cube, the
biosynthesis, and has an important role in homocysteine and Gross Motor Scale and the Grooved Pegboard. These researchers
S-adenosylmethionine biosynthesis (Zeisel, 2009; Zhang et al., conducted their study among African-American women of low
2009). It is believed that choline has similar roles in brain devel- socioeconomic status and their disadvantaged children. These
opment as folate (Meck and Williams, 2003; McCann et al., children nevertheless did not present with signs or symptoms of
2006; Zeisel, 2006a,b, 2009; Signore et al., 2008). Furthermore, any overt clinical deficiency (such as megaloblastic anaemia). On
folate, choline and vitamin B12 metabolism are interconnected the other hand, Veena et al. (2010) reported that higher maternal
at the homocysteine-methionine-S-adenosylmethionine pathway blood folate concentration—but not folate status (“low” vs. “nor-
(Zeisel, 2009). S-adenosylmethionine is one of the main methyl mal”, similar to the previous study)—was associated with better
donors in different metabolic methylation reactions, including cognitive performance on a wide range of tests (Atlantis, Word
DNA methylation. Therefore, choline and folate deficiency may Order, Pattern Reasoning, Verbal Fluency, Koh’s Block Design
result in DNA hypomethylation, thereby altering gene tran- and WISC-III) in 9–10-year-old Indian children. Interestingly,
scription (Zeisel, 2009). In addition, choline is a component of most of the women (96%) in this study manifested blood folate
phospholipids in cell membranes and a precursor for the neuro- levels within the normal range. However, the only positive associ-
transmitter acetylcholine (Zeisel, 2006b). Vitamin B12 has a role ation found between maternal vitamin B12 status and cognitive

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 5

Nyaradi et al. Nutrition and children’s cognitive development

performance in these children was on verbal fluency, although seems to modulate some neurotransmitters including glutamate
almost half of the mothers (42.5%) manifested moderately low and gamma- aminobutyric acid (GABA) receptors (Bhatnagar
vitamin B12 level. It is possible that vitamin B12 affects some and Taneja, 2001; Levenson, 2006).
cognitive functions only if the person is severely deficient, as can Zinc supplementation has a positive effect on the immune sta-
be seen in vegetarian mothers and their children. Another rea- tus of infants and may prevent congenital malformations (Shah
son for the limited findings may be that the tests conducted were and Sachdev, 2006). However, the relationship between mater-
not sensitive enough to detect small changes in different func- nal zinc status and the child’s cognitive development has not
tions. Another research group in India showed that lower vitamin been fully investigated. In an observational study, low mater-
B12 levels during pregnancy impaired short term memory (Digit nal zinc intake in Egyptian mothers was associated with lower
Span Test) and sustained attention (Color Trail Test) in 9 years old levels of focused attention in newborns, measured with the
children after adjusting for covariates (Bhate, 2008) while non- Brazelton Neonatal Behavior Assessment Scale (Kirksey et al.,
verbal intelligence on Raven’s Cultured Progressive Matrices and 1994). Surprisingly, a placebo controlled randomized trial under-
visual perception on a Visual Recognition Test were unaffected in taken on poor Bangladeshi mothers found that 13 months
this study. old infants of zinc supplemented mothers scored less on the
Although there is no sufficient data about the requirements Bayley scales of infant development than infants born to moth-
of choline in humans, choline does not seem to be deficient ers who received a placebo (Hamadani et al., 2002). In trying
in the general population, with the exception of experimental to explain their findings, these researchers argued that zinc sup-
conditions (Commonwealth of Australia, 2006). Evidence from plementation alone may cause imbalances or even deficiencies
numerous animal studies indicates that dietary choline has an of other micronutrients that are important for brain develop-
important impact on the cognitive development of offspring ment, as micronutrients interact with one another (Hamadani
(Meck and Williams, 2003; McCann et al., 2006). Choline in ani- et al., 2002)—a point which we will return to later in this review.
mal models alters the development of the hippocampus, which Another double-blind randomized controlled trial of maternal
has a central role in memory and learning (Zeisel, 2006a). Like zinc supplementation among African-American mothers showed
folate, choline also has a role in the closure of the foetal neu- no difference in the cognitive development of 5 years old chil-
ral tube. A study among Californian mothers found an increased dren between the intervention and control groups, measured on
risk of neural tube defects of their children with lower maternal the Differential Ability Scales, Visual and Auditory Sequential
dietary choline intake, as identified from a food frequency ques- Memory, Knox Cube, Gross Motor Scale, and Grooved Pegboard
tionnaire (Shaw et al., 2004). There is only one study to date that (Tamura et al., 2003). In both studies, the mothers were sup-
has evaluated the impact of maternal blood choline (represented plemented only in the second half of their pregnancy. Overall,
across a wide range of concentrations) on intelligence (measured there are only a limited number of studies on this topic. Taken
on the Wechsler Preschool and Primary Scale of Intelligence- together, the findings do not consistently show a positive relation-
Revised) in 5 year old children. However, the authors did not find ship between maternal zinc status and cognitive development of
a significant correlation between the two (Signore et al., 2008). In children.
summary, the impact of vitamin B12, folate and choline on chil- Two articles that reviewed earlier observational and random-
dren’s cognitive development has not been adequately researched ized control trials in children on zinc and cognitive development
to date in humans. concluded that zinc deficiency can negatively influence cognitive
development. Conversely, more recent randomized control tri-
Zinc als from India (Taneja et al., 2005) and Bangladesh (Black et al.,
Zinc deficiency appears to be a major problem worldwide, affect- 2004), where malnutrition is common among children, did not
ing 40% of the global population (Maret and Sandstead, 2006). find that zinc supplementation alone affects infants’ cognitive
Recent research suggests that toddlers, adolescents, older peo- development on the Bayley Scales of Infant Development test.
ple and individuals with diabetes are possibly at a higher risk of Nevertheless, in the Bangladeshi trial, when zinc was combined
zinc deficiency in Australia (Gibson and Heath, 2011). Animal with iron supplementation, it showed an improvement in cogni-
studies have established a relationship between zinc and neu- tion (Black et al., 2004). Additional studies are therefore needed
rodevelopment (Shah and Sachdev, 2006; Summers et al., 2008; to examine the long term benefit of zinc on brain development.
Coyle et al., 2009). It is believed that zinc is a vital nutrient
for the brain, with important structural and functional roles Iron
(Bhatnagar and Taneja, 2001; Black, 2003a; Bryan et al., 2004; One of the most common nutritional deficiencies in both devel-
Shah and Sachdev, 2006; Georgieff, 2007). More specifically, zinc oping and developed countries is iron deficiency. In some parts
is a cofactor for more than 200 enzymes that regulate diverse of the world, such as in Sub-Saharan Africa and South-East
metabolic activities in the body including protein, DNA and RNA Asia, the prevalence is more than 40%. In developed countries—
synthesis. In addition, zinc plays a role in neurogenesis, mat- including Australia—it could be as high as 20%, particularly in
uration, and migration of neurons and in synapse formation pregnant women and in children (World Health Organization,
(Bhatnagar and Taneja, 2001; Black, 2003a; Bryan et al., 2004; 2008). Over the past decades, a considerable literature has been
Shah and Sachdev, 2006; Georgieff, 2007). Zinc is also found published on the association between iron status/anaemia and
in high concentrations in synaptic vesicles of hippocampal neu- cognitive development in children, as well as in animal models
rons (which are centrally involved in learning and memory), and (Grantham-McGregor and Ani, 2001). It is believed that iron is

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 6

Nyaradi et al. Nutrition and children’s cognitive development

involved with different enzyme systems in the brain, including: for anaemic and cognitive development. However, treating older
the cytochrome c oxidase enzyme system in energy production, children with iron deficiency increased IQ significantly. A more
tyrosine hydroxylase for dopamine receptor synthesis, delta-9- recent review and meta-analysis on children (aged 6 years and
desaturase for myelination, and fatty acid synthesis, and ribonu- older), adolescents and adults found that iron treatment increased
cleotide reductase for brain growth regulation (Deungria, 2000; IQ in anaemic individuals, but iron supplementation did not
Lozoff and Georgieff, 2006; Georgieff, 2007; Rioux et al., 2011). In improve IQ in non-anaemic children (Falkingham et al., 2010).
addition, iron appears to modify developmental processes in hip- In summary, there is a lack of epidemiological evidence or data
pocampal neurons by altering dendritic growth (Jorgenson et al., from well-designed intervention trials demonstrating the impact
2003; Lozoff and Georgieff, 2006). of maternal iron supplementation on the cognitive development
There are a limited number of studies that have examined of healthy children. There is evidence that older anaemic children
the connection between maternal iron status or maternal iron benefit from iron treatments. However, cognitive performance
supplementation and cognitive development. (In the below, treat- tests including the Bayley Scales of Infant Development and
ment refers to anaemic individuals, and supplementation to the Denver Developmental Screening Test may not be sensitive
non-anaemic children.) Tamura et al. (2002) found significantly enough to detect small changes in short-term supplementation
inferior performance in language skills, fine motor skills and or treatment in young children (Armstrong, 2002). Furthermore,
attention (and lower but not significant scores in every other test) if iron deficiency occurs in very early life, the damage may be irre-
in 5 years old children whose cord ferritin levels lay in the lowest versible, and it may not be possible to reverse this damage with
quartile. Cognitive performance in this study was measured on iron treatment (Beard, 2008).
the WISC-R, the Test for Auditory Comprehension of Language,
fine and gross-motor scales of the Peabody Developmental Iodine
Motor Scales and the Yale Children’s Inventory for attention and Iodine deficiency is a significant worldwide public health issue,
tractability. The mothers who took part in the study were of especially in children and during pregnancy (World Health
African-American descent and low socioeconomic status, and a Organization, 2004). In Australia, the majority of children and
high proportion of the children were born small-for-gestational- pregnant women are mildly deficient in iodine, with some groups
age. However, a randomized placebo controlled iron supplemen- reaching moderate to severe deficiency (Gallego, 2010). Iodine
tation trial in a representative sample of Australian pregnant deficiency in the soils in many countries has led to food forti-
women failed to find any difference between an iron supple- fication, most commonly the use of iodized salt (World Health
mented vs. placebo group in the IQ of children at 4 years of age on Organization, 2004). The relationship between iodine and cog-
the Stanford–Binet Intelligence Scale, despite maternal iron status nitive development is extensively researched. It is well known
having improved due to supplementation (Zhou et al., 2006). The today that severe iodine deficiency during pregnancy may cause
authors suggested that supplementing pregnant women who are “cretinism” in children (Forrest, 2004; Zimmermann, 2007, 2009,
generally well-nourished with iron may not confer any additional 2011; Melse-Boonstra and Jaiswal, 2010). The clinical manifes-
health benefits, while Tamura’s study was undertaken in disad- tation of cretinism depends on the severity of iodine deficiency;
vantaged mothers and small-for-gestational-age infants (Tamura the features may include mental retardation, speech and hear-
et al., 2002; Zhou et al., 2006). A recent trial in Canada by Rioux ing impairment, upper motor neuron and extrapyramidal lesions
et al. (2011) also found no evidence that better maternal iron (Delong et al., 1985). Iodine is necessary for the production of
and DHA status enhanced cognitive development in six months thyroid hormones in the body; 70–80% of it is found in the thy-
old infants, measured on the Brunet-Lezine Scale of Psychomotor roid gland (Melse-Boonstra and Jaiswal, 2010). Iodine deficiency
Development of Early Childhood and the Bayley Scales of Infant manifests in hypothyroidism, causing underproduction of thy-
Development. These researchers recruited a small sample size roid hormones including triiodothyronin (T3) and thyroxin (T4).
of mothers from a higher socioeconomic background and with Thyroid hormones play an important role in neurodevelopment
better feeding practices, consistent with the methodology and and numerous neurological processes including neuronal cell
findings of the Australian study cited above. differentiation, maturation and migration, myelination, neuro-
In children, the relationship between iron and cognitive devel- transmission, and synaptic plasticity (Zimmermann, 2009, 2011;
opment has been well researched. In addition, these investiga- Melse-Boonstra and Jaiswal, 2010). In addition, in animal mod-
tions have been reviewed many times during the last decade. els hypothyroidism alters neurogenesis and the development and
Grantham-McGregor and Ani (2001) reviewed a range of longitu- functions of synapses in the hippocampus (Desouza et al., 2005;
dinal studies and reported that anaemic infants had poorer cogni- Gong et al., 2010).
tive and school performance in the long term, and that short-term Qian et al. (Qian, 2005) conducted a meta-analysis on stud-
iron treatment trials in anaemic children did not show benefits ies from different locations in China where the soil is severely
in cognitive development. A Cochrane review based on seven iodine deficient, and found a 12.3 point decrease in the IQ of
randomized controlled trials reached a similar conclusion, i.e., those children whose mothers lived in iodine deficient areas com-
that short term iron treatment for anaemia in children less than pared to those living in iodine sufficient locations. The association
3 years old did not improve cognitive development (Logan et al., between mild-moderate maternal iodine deficiency and cognitive
2001). Sachdev et al. (2005) included 17 randomized controlled development is not as clear as it is when iodine deficiency is severe
trials in their meta-analysis, and did not find convincing evidence (Forrest, 2004; Zimmermann, 2007, 2009, 2011; Melse-Boonstra
of an association between iron supplementation and treatment and Jaiswal, 2010). In mild-moderate iodine deficiency, maternal

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 7

Nyaradi et al. Nutrition and children’s cognitive development

thyroid stimulating hormone (TSH) and the thyroid hormone of mildly iodine deficient 10–13 years old children improved
T3 level are unaffected, such that hypothyroidism is not clini- matrix reasoning in both studies. In addition, fine motor skills
cally or even sub-clinically diagnosed. In such situations the level and visual problem solving were improved in the Albanian trial
of maternal T4 may not be sufficient for the appropriate neuro- (Zimmermann, 2006; Gordon et al., 2009). Relatively few stud-
logical development of the foetus (Melse-Boonstra and Jaiswal, ies have been conducted in very young children to support the
2010). significance of iodine in cognitive development (Melse-Boonstra
A number of observational studies from iodine sufficient or and Jaiswal, 2010).
mildly iodine deficient areas of USA, Russia, The Netherlands, In conclusion, the above literature suggests that iodine is
Italy and Spain have shown a significant association between important for the cognitive development of older children.
mild maternal thyroid deficiency and cognitive impairment in Furthermore, although iodine supplementation is critical for
children. The tests that were reviewed in these studies included severely iodine deficient pregnant women, there is no general con-
the WISC, Neonatal Behavioral Assessment Scale, Bayley Scale sensus about the effectiveness of iodine supplementation during
of Infant Development, McCarthy Scales of Children’s Abilities pregnancy in countries with mild iodine deficiency.
and the Gnome Mental Development Scale (Haddow et al., 1999;
Pop, 2001; Pop et al., 2003; Vermiglio et al., 2004; Riano Galan Multivitamin and mineral supplementation
et al., 2005; Kasatkina et al., 2006; Kooistra et al., 2006). By con- Although it is important to investigate nutrients individually,
trast, one study did not find any relationship between maternal T4 deficiencies of nutrients rarely occur in isolation, and an inade-
levels and cognitive development in children at 6 months (visual quate diet typically causes multiple micronutrient deficiencies. In
recognition memory) and 3 years of age (PPVT and Wide Range addition, nutrients interact with each other and do not work sep-
of Visual Motor Ability). However, this study included only a arately (Benton, 2010a). Thus, it is important to investigate the
very small number of women with abnormal thyroid function association between multiple mineral and vitamins supplementa-
(Oken et al., 2009). Berbel et al. (2009) carried out a trial in Spain tion or deficiencies and cognitive development.
that showed better gross and fine motor coordination and social- A recent systematic review of prenatal maternal micronutri-
ization (Brunet-Lezine Scale) in 18-month-old children whose ent supplementation and children’s cognitive and psychomotor
mothers were supplemented with iodine from early pregnancy, development considered 18 studies, including six multiple-
compared to those who took the supplement from late preg- micronutrient supplementation trials. This review found some
nancy. Velasco et al. (2009) also found that those infants whose evidence that multivitamin and mineral supplementation might
mothers took daily iodine supplements from the first trimester of positively influence certain aspects of brain development in
pregnancy exhibited better psychomotor development (measured children (Leung et al., 2011). The review included six trials
on the Bayley Scales of Infant Development), compared to those on multiple-micronutrient supplementations conducted in Peru,
whose mothers were not supplemented with groups evaluated rural Taiwan, Tanzania (on HIV infected mothers), and in rural
at different ages (5.5 and 12.4 months, respectively). Contrary China, Indonesia and Bangladesh, where mothers were poorly
to expectation, another study from Spain reported lower psy- nourished (Joos et al., 1983; Schmidt et al., 2004; McGrath
chomotor development (measured on the Bayley Scale of Infant et al., 2006; Tofail et al., 2008; Li et al., 2009; Caulfield et al.,
Development) in infants (especially in girls) born to mothers 2010). A very recent randomized controlled trial in Indonesia
with maternal multivitamin supplementation that contained high found that multiple micronutrient supplementation in under-
amounts of iodine (100–149 μg/day), when compared to those nourished pregnant mothers resulted in improved motor devel-
infants with lesser amounts of maternal iodine supplementation opment, visual attention and spatial ability in pre-schoolers
(<100 μg/day) (Murcia et al., 2011). It is possible that the opti- (Prado et al., 2012). All the above-mentioned trials are from low
mum dose of iodine for those mothers who are manifesting only income countries, it is currently unknown whether the cognitive
mild iodine deficiency is less; further research is needed to deter- development of children of well-nourished mothers from higher
mine the safe level of iodine intake for mildly deficient pregnant income countries would benefit from multiple-micronutrient
women. supplementation.
The vast number of studies on the iodine status and supple- More consistent results from trials supplementing children
mentation in children and its relationship to cognitive develop- with multiple-micronutrients have been shown. A meta-analysis
ment in mild-moderate iodine deficient areas of the world has investigated 20 randomized controlled trials published from
been reviewed several times. An earlier review and meta- analysis 1970 to 2008 in developed as well as developing countries, and
of 18 studies found a 13.5 point difference in IQ between iodine found that multiple-micronutrient supplementation may result
sufficient and iodine deficient children (Bleichrodt and Born, in higher fluid intelligence (Eilander et al., 2010). However, this
1994). Other reviews reported that most observational studies on increase was only marginal, and no association was observed
iodine deficient children found some degree of cognitive impair- with crystallized intelligence in children. The finding of this
ment (when compared to children from iodine sufficient areas), review (i.e., that fluid intelligence, but not crystallized intel-
and iodine supplementation trials in school age children have ligence, may be influenced by multiple-micronutrient supple-
provided some promising results with respect to improvement mentation) is consistent with conclusions drawn from other
of some cognitive processes (Zimmermann, 2007, 2011; Melse- studies (Benton, 2001, 2012). Fluid intelligence refers to rea-
Boonstra and Jaiswal, 2010). More recent iodine supplementation soning ability that reflects the individual’s current neurological
trials from Albania and New Zealand found that supplementation potential (indexed by measures such as speed of processing)

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 8

Nyaradi et al. Nutrition and children’s cognitive development

rather than their level of past attainment and acquired, crys- higher IQ (measured on the WISC) in adolescents but with
tallized knowledge (which is measured by abilities such as increased white matter volume, especially in boys (Isaacs et al.,
depth of vocabulary). Fluid ability is typically measured via 2010).
non-verbal cognitive tests, while crystallized intelligence is In summary, the debate concerning whether breastfeeding and
more usually measured by administering verbal cognitive tests cognitive development have a positive association appears to con-
(Eilander et al., 2010; Benton, 2012). tinue, but with more advanced neuroimaging technologies now
available, future research may offer greater insights. Nevertheless,
OVERALL DIET, FOOD, AND COGNITIVE PERFORMANCE as Gökçay (2010) pointed out, breast milk provides the best nutri-
Breastfeeding tional intake for infants, regardless of its putative association with
A considerable amount of literature has been published on the cognitive development.
possible connection between breastfeeding and cognitive devel-
opment. Many of these studies demonstrate significantly positive Malnutrition
associations between the two; however, the associations typi- The number of malnourished (undernourished) children con-
cally diminish or are no longer significant after controlling for tinues to rise in some regions, such as in Sub-Saharan Africa
confounders including maternal IQ, which is believed to be the (De Onis, 2000). Every year, 20 million newborns (15.5% of
strongest predictor of children’s intelligence (Rey, 2003; McCann all births) are low birth weight, most of them from devel-
and Ames, 2005; Michaelsen et al., 2009). Furthermore, it remains oping countries (United Nations Children’s Fund and World
unclear whether the remaining, diminished associations between Health Organization, 2004). The effect of malnutrition on brain
breastfeeding and child cognitive development are further con- structures has been extensively researched in animal models.
founded by factors that have not been controlled for (Michaelsen Malnutrition appears to alter cell numbers, cell migrations,
et al., 2009). A meta-analysis of 20 studies undertaken in the late myelinisation, synaptogenesis, hippocampal formation and neu-
1990’s found that breastfeeding in normal birth weight infants rotransmission in rats (Debassio et al., 1996; Mathangi and
increased IQ by 2.7 points and in low birth weight children by Namasivayam, 2001; Granados-Rojas et al., 2002; Alamy and
5.2 points, but only six of the studies controlled for maternal IQ Bengelloun, 2012). In a human study, researchers described fewer
(Anderson et al., 1999). Three critical reviews conducted in the numbers of neurons with shorter dendrites and abnormal den-
early 1990’s concluded that the evidence linking breastfeeding and dritic spines in individuals with malnutrition; however, this study
cognitive development has not yet been comprehensively demon- was carried out just on 13 severely undernourished infants, com-
strated (Drane and Logemann, 2000; Jain et al., 2002; Rey, 2003). pared to seven adequately fed babies (Benítez-Bribiesca et al.,
However, a more recent review by Michaelsen et al. (2009) con- 1999). Because of small sample size, this study cannot provide
cluded that the majority of studies found an association between definitive evidence of the effect of malnutrition on brain struc-
breastfeeding and cognitive development, even after adjusting for ture (although the fact that significant differences were observed
confounders, and the difference in IQ related to breastfeeding is even with a relatively small number of participants is poten-
around 2–5 points at any age. This finding is supported by a large tially revealing, in terms of statistical power considerations).
randomized control trial, where breastfeeding mothers were ran- Moreover, malnourished children have less energy and inter-
domized into a breastfeeding promotion intervention trial that est for learning that negatively influences cognitive development
resulted in a higher breastfeeding rate up to 12 months after birth (Engle, 2010).
(43.3 vs. 6.4%). Intelligence tests were conducted at age 6½ years Malnutrition can develop in utero, when the mother is mal-
on the children in both groups (i.e., intervention vs. control) and nourished (as often happens in low income countries). In Western
associations between longer exclusive breastfeeding and improved countries, restricted foetal growth is often the result of a medical
cognitive development were found (Kramer et al., 2008). As noted condition such as severe hypertension, or if the mother con-
earlier in this review, it has been suggested that one of the rea- sumes higher levels of alcohol (Henriksen and Clausen, 2002;
sons behind the advantage of breastfeeding over formula feeding Feldman et al., 2012; Mustafa et al., 2012). For example, in
concerns the concentration of LCPUFA in breast milk, especially uncontrolled severe hypertension during pregnancy the placen-
DHA (Michaelsen et al., 2009). tal blood flow is restricted and there are placental abnormalities,
More recently, some studies have directly examined the which may prevent the foetus from obtaining the required oxy-
effect of breastfeeding on brain development and structure. gen and nutrients for development (Henriksen and Clausen,
A study by Kafouri et al. (2012) reported that longer breast- 2002). It has been shown that intrauterine growth retardation
feeding duration is positively associated with cortical thick- (IUGR) or small-for-gestational age (SGA) at birth is asso-
ness in the parietal lobe in adolescents, and in the same ciated with cognitive developmental delays and a decrease of
study they also found an association between intelligence 4–8 points in IQ scores compared to infants with a birth
(measured on WISC) and longer breastfeeding after adjusting weight that is appropriate-for-gestational-age (AGA; Pallotto and
for relevant confounders, which included maternal education. Kilbride, 2006). Apart from IUGR, stunting can be caused by
Herba et al. (2012) used cranial ultrasound in 2 months old a nutritional deficit (such as protein-energy malnutrition) dur-
infants; those infants who were breastfed exclusively had larger ing the rapid growth of young children. Most often intrauterine
gangliothalamic diameter and head circumference, and smaller malnutrition is followed by poor postnatal nutrition, and the
ventricular volume compared to bottle fed babies. Furthermore, combined and persistent effect of malnutrition across both peri-
breastfeeding has been associated previously with not only ods results in seriously stunted growth (Dewey and Begum,

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 9

Nyaradi et al. Nutrition and children’s cognitive development

2011). Indeed, evidence from developing countries shows that (2012) did not find a similar association between increased
stunting in early childhood is associated with poorer cogni- body weight and cognitive performance as measured by the
tive development and academic performance in later child- Woodcock Johnson Revised Test of Achievement and the Memory
hood (Grantham-McGregor, 1995; Grantham-McGregor et al., for Digit Span test. Bisset et al. (2012) examined weight status
2007). A recent review concluded that even mild but persis- trajectories in 4–7-year-old children; overweight was not asso-
tent malnutrition in early life (i.e., during the first 2 years ciated with cognitive outcomes as measured on the Kaufman’s
of life) negatively influences reasoning, visuospatial functions, Assessment Battery for Children. The inconsistent findings in
IQ, language development, attention, learning, and academic humans between obesity and cognitive development may be
achievement, while supplementation with food can improve the result of the complexity of factors underlying these out-
cognitive performance (Laus, 2011). In an interesting study, comes (Li et al., 2008). Moreover, associations between obesity
researchers randomly assigned 425 preterm infants to a “stan- and cognition that have been reported may be mediated by
dard nutrient” group (who received either breast milk or sociodemographic factors that include discrimination and iso-
standard formula) and “high nutrient” group (who received lation rather than through biological mechanisms (Palermo and
a higher protein-energy and micronutrient diet). The cogni- Dowd, 2012).
tive development of the children was then measured at 7½–8
years of age, and it was found that IQ (measured on the Breakfast
WISC) was higher in the high nutrient group, especially with The level of glucose metabolism in children’s brains increases
respect to verbal IQ in boys (Lucas et al., 1998). A sub- from birth until 4 years of age, reaching twice that of the adults’
group of these children (n = 76) was assessed again at 16 metabolic rate. This rate of glucose metabolism in children
years, and a persistent effect of the high nutrient diet on remains elevated until 9–10 years of age, before it declines to the
verbal IQ was demonstrated. At this stage, brain MRIs were adult level by late adolescence (Chugani, 1998). Therefore, regular
also undertaken and showed a larger volume of the caudate meals and continuous glucose supply (to provide the brain with
(which was correlated with higher verbal IQ), but only in males the required glucose for its high metabolism) is more important
(Isaacs et al., 2008, 2009). in children than in adults (Bellisle, 2004). Accordingly, children
Obesity is a special form of malnutrition (overnutrition, as are more prone to the adverse effect of overnight fasting, and
opposed to undernutrition which has been previously consid- breakfast is a very important meal to provide fuel to the brain in
ered here), because the diet is likely to have low nutrient- the morning (Bellisle, 2004). A systematic review concluded that
density in conjunction with a high fat and carbohydrate content having breakfast is beneficial for cognitive function and devel-
(Tanumihardjo et al., 2007). Obesity is of growing concern world- opment, especially in malnourished children. A lack of studies
wide, with the number of overweight and obese children dramat- conducted into the optimal breakfast including type, composi-
ically increasing over the past two decades. It was estimated in tion and portion size exists but (Hoyland, 2009) carbohydrate
2010 that 43 million children worldwide (including 35 million rich, low-glycaemic food for breakfast that provides a contin-
from developing countries) were overweight or obese, and this uous supply of glucose is known to facilitate better cognitive
number is expected to continue to grow to 60 million by 2020 performance (Bellisle, 2004; Ingwersen et al., 2007; Micha et al.,
(De Onis et al., 2010). 2011).
Animal studies suggest that there may be a biological link A recent study showed that the brain’s gray and white
between obesity and impaired cognitive performance that is matter volume differed in various parts of healthy children’s
related to insulin resistance and altered glucose metabolism brain, according to the type of breakfast they ate (Taki et al.,
(Jurdak et al., 2008). Furthermore, when rats were fed a high 2010). The researchers suggested that the difference may be
fat diet, it decreased neurogenesis in the hippocampus (Lindqvist due to the different glycemic index of the different break-
et al., 2006). In addition, a maternal high-fat diet in mice altered fast staple types. The authors also proposed that if dif-
the development of hippocampus in the foetus (Niculescu and ferent breakfast types affect gray and white matter volume
Lupu, 2009), which may mediated by a decrease in the level in the brain, they may in turn influence cognitive func-
of brain-derived neurotrophic factor (Molteni et al., 2002). A tion. Therefore, the type of breakfast children eat can poten-
recent literature review concluded that overweight and obesity tially have a long-term influence on cognitive development
may result in poorer academic performance (measured as lit- (Taki et al., 2010).
eracy, numeracy, and school grades; Burkhalter and Hillman,
2011), but only a few studies have researched a possible connec- Dietary pattern and diet quality
tion between obesity/overweight and cognitive performance. Li Since individuals consume combinations of foods (which may
et al. (2008) described an association in 8–16-year-old children contain other bioactive compounds that could act synergisti-
and adolescents between increased body mass index (BMI) and cally or antagonistically within or between food groups; Tangney
reduced cognitive performance, specifically visuospatial func- and Scarmeas, 2011), it is important to investigate diet as a
tioning as measured on the block-design test (a subtest of the broadly encompassing variable in association with cognitive out-
WISC), but not attention, working memory (digit-span subtest) comes. Furthermore, as Tangney and Scarmeas (2011) state,
and academic performance (Wide Range Achievement Test). This if research shows an association between diet (as comprehen-
association remained after adjusting for a range of covariates sively measured) and better health outcomes, it may be eas-
and potential obesity mediating factors. Palermo and Dowd ier to implement changes in terms of dietary interventions.

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 10

Nyaradi et al. Nutrition and children’s cognitive development

Some researchers have investigated the influences of overall CONCLUSION AND RECOMMENDATIONS FOR FUTURE
diet on neurocognitive development during childhood. Gale et al. RESEARCH
(2009) considered dietary patterns in infancy in relation to cogni- The majority of studies, which have investigated the association
tive development and found higher full-scale IQ (measured on between nutrition and cognitive development, have focused on
the Wechsler Preschool and Primary Scale of Intelligence test) individual micronutrients, including omega-3 fatty acids, vitamin
at 4 years of age in children who consumed higher amounts of B12, folic acid, zinc, iron, and iodine. The evidence is more con-
fruit, vegetables and food prepared at home during infancy (i.e., sistent from observational studies, which suggest these micronu-
between 6 and 12 months). The association remained significant trients play an important role in the cognitive development of
after adjusting for a wide range of factors, including socioeco- children. However, the results from intervention trials of single
nomic status, maternal IQ and education. A cross-sectional study nutrients are inconsistent and inconclusive, prompting the need
reported by Theodore et al. (2009) examined the association for better controlled and more adequately powered studies in the
between (i) the intake of specific food groups in 3½ years old future. It is plausible that children living in poor countries may
children and in the same children again at 7 years of age and encounter more multiple micronutrient deficiencies, as opposed
(ii) their cognitive development measuring on the Stanford–Binet to children living in rich countries who are reasonably well nour-
Intelligence Scale (at 3 years) and on the WISC-III (at 7 years). ished (and where a small deficiency in one nutrient may not result
These researchers found that a higher level of consumption of in measurable, long-term change in cognitive outcomes, due to
fish at 7 years of age and bread and cereals at 3½ years of age compensation over time). These are important considerations,
was associated with higher IQ scores, whereas those children at because nutrients do not act alone; rather, they have in some con-
the age of 3½ who consumed margarine every day scored signifi- texts synergistic and in other contexts antagonistic effects with
cantly lower on IQ. Northstone et al. (2011) reported that higher each other.
scores on the “health conscious” dietary pattern (which included Individuals consume combinations of food and poor over-
more salad, rice, pasta, and fruits) at 3 years of age were asso- all diet can cause multiple macro-and micronutrient deficiencies
ciated with higher IQ score on the WISC-III when these same and imbalances. If an overall healthy diet synergistically enhances
children were tested aged 8½ years, compared to those children on cognitive development in children, then public health interven-
the “processed” dietary pattern (with high fat and sugar content), tions should focus on the promotion of overall diet quality rather
after adjusting for a wide variety of potential confounders. In the than isolated micronutrients or dietary components consumed by
same study, Smithers et al. (2012) examined six different dietary children and adolescents.
patterns and found negative associations between (i) the “discre-
tionary pattern” (which contains biscuits, sweets, soft drinks, and ACKNOWLEDGMENTS
snacks) at 6, 15, and 24 months of age, and ready-prepared baby Dr. Anett Nyaradi is supported by an Australian Postgraduate
foods at 6 and 15 months of age and (ii) IQ scores at 8 years of Award and a Western Australian Pregnancy (Raine) Cohort
age (measured on the WISC). Smithers et al. (2012) also reported Scholarship. Associate Professor Jianghong Li is supported by a
positive associations between children’s IQ at age 8 years and Curtin University Research Fellowship. Dr. Siobhan Hickling is
“breastfeeding pattern” (measured at 6 months), “home-made an Assistant Professor at The University of Western Australia.
contemporary” (legumes, fruits, fruit juices, cheese, egg) at 15 and Associate Professor Jonathan Foster is supported by a Curtin
24 months, “home-made traditional” (vegetables, meat, sauces) University Senior Research Fellowship. Professor Wendy Oddy
at 6 months (but not at 15 and 24 months), and “ready-to-eat” is funded by a National Health and Medical Research Council
food pattern (biscuits, breads, cereals, yoghurt) at 24 months. Population Health Research Fellowship.

REFERENCES Asato, M. R., Terwilliger, R., Woo, with severe protein-calorie M., et al. (2009). Delayed neu-
Alamy, M., and Bengelloun, W. A. J., and Luna, B. (2010). White malnutrition. Pediatrics 104, e21. robehavioral development in
(2012). Malnutrition and brain matter development in adolescence: Benton, D. (2001). Micro-nutrient sup- children born to pregnant women
development: an analysis of the a DTI study. Cereb. Cortex 20, plementation and the intelligence with mild hypothyroxinemia dur-
effects of inadequate diet dur- 2122–2131. of children. Neurosci. Biobehav. Rev. ing the first month of gestation:
ing different stages of life in Attig, L., Gabory, A., and Junien, C. 25, 297–309. the importance of early iodine
rat. Neurosci. Biobehav. Rev. 36, (2010). Early nutrition and epige- Benton, D. (2010a). The influence of supplementation. Thyroid 19,
1463–1480. netic programming: chasing shad- dietary status on the cognitive per- 511–519.
Anderson, J. W., Johnstone, B. M., ows. Curr. Opin. Clin. Nutr. Metab. formance of children. Mol. Nutr. Bhate, V. (2008). Vitamin B-12 sta-
and Remley, D. T. (1999). Breast- Care 13, 284–293. Food Res. 54, 457–470. tus of pregnant Indian women and
feeding and cognitive development: Beard, J. L. (2008). Why iron deficiency Benton, D. (2010b). Neurodevelo- cognitive function in their 9-year-
a meta-analysis. Am. J. Clin. Nutr. is important in infant development. pment and neurodegeneration: are old children. Food Nutr. Bull. 29,
70, 525–535. J. Nutr. 138, 2534–2536. there critical stages for nutritional 249–254.
Armstrong, B. (2002). Review: iron Bellisle, F. (2004). Effects of diet on intervention? Nutr. Rev. 68, S6–S10. Bhatnagar, S., and Taneja, S. (2001).
treatment does not improve behaviour and cognition in chil- Benton, D. (2012). Vitamins and neural Zinc and cognitive development. Br.
psychomotor development and dren. Br. J. Nutr. 92, S227–S232. and cognitive developmental out- J. Nutr. 85, S139–S145.
cognitive function at 30 days Benítez-Bribiesca, L., De La comes in children. Proc. Nutr. Soc. Bisset, S., Fournier, M., Janosz, M., and
in children with iron deficiency Rosa-Alvarez, I., and Mansilla- 71, 14–26. Pagani, L. (2012). Predicting aca-
anaemia. Evid. Based. Ment. Health Olivares, A. (1999). Dendritic Berbel, P., Mestre, J. L., Santamaria, demic and cognitive outcomes from
5:17. doi: 10.1136/ebmh.5.1.17 spine pathology in infants A., Palazon, I., Franco, A., Graells, weight status trajectories during

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 11

Nyaradi et al. Nutrition and children’s cognitive development

childhood. Int. J. Obes. (Lond.). 37, physical activity, nutrition, and obe- De Onis, M. (2000). Is malnutrition Cognitive assessment of children at
154–159. sity to cognition and scholastic declining? An analysis of changes age 2½ years after maternal fish
Black, M. M. (2003a). The evidence performance across the human lifes- in levels of child malnutrition since oil supplementation in pregnancy:
linking zinc deficiency with chil- pan. Adv. Nutr. 2, 201S–206S. 1980. Bull. World Health Organ. 78, a randomised controlled trial. Arch.
dren’s cognitive and motor func- Campoy, C., Escolano-Margarit, M. 1222. Dis. Child Fetal. Neonatal. Ed. 93,
tioning. J. Nutr. 133, 1473S–1476S. V., Ramos, R., Parrilla-Roure, M., De Onis, M., Blössner, M., and Borghi, F45–F50.
Black, M. M. (2003b). Micronutrient Csábi, G., Beyer, J., et al. (2011). E. (2010). Global prevalence and Eilander, A., Gera, T., Sachdev, H.
deficiencies and cognitive function- Effects of prenatal fish-oil and 5- trends of overweight and obesity S., Transler, C., Knaap, H. V. D.,
ing. J. Nutr. 133, 3927S–3931S. methyltetrahydrofolate supplemen- among preschool children. Am. J. Kok, F. J., et al. (2010). Multiple
Black, M. M., Baqui, A. H., Zaman, K., tation on cognitive development of Clin. Nutr. 92, 1257–1264. micronutrient supplementation for
Ake Persson, L., El Arifeen, S., Le, children at 6.5 y of age. Am. J. Clin. De Rooij, S. R., Wouters, H., Yonker, improving cognitive performance
K., et al. (2004). Iron and zinc sup- Nutr. 94, 1880S–1888S. J. E., Painter, R. C., and Roseboom, in children: systematic review of
plementation promote motor devel- Caulfield, L. E., Putnick, D. L., Zavaleta, T. J. (2010). Prenatal undernutrition randomized controlled trials. Am. J.
opment and exploratory behavior N., Lazarte, F., Albornoz, C., Chen, and cognitive function in late adult- Clin. Nutr. 91, 115–130.
among Bangladeshi infants. Am. J. P., et al. (2010). Maternal gesta- hood. Proc. Natl. Acad. Sci. U.S.A. Eilander, A., Hundscheid, D. C.,
Clin. Nutr. 80, 903–910. tional zinc supplementation does 107, 16881–16886. Osendarp, S. J., Transler, C., and
Blakemore, S.-J., Burnett, S., and Dahl, not influence multiple aspects of De Souza, A. S., Fernandes, F. S., and Zock, P. L. (2007). Effects of n-3
R. E. (2010). The role of puberty child development at 54 mo of Do Carmo, M. G. (2011). Effects long chain polyunsaturated fatty
in the developing adolescent brain. age in Peru. Am. J. Clin. Nutr. 92, of maternal malnutrition and post- acid supplementation on visual and
Hum. Brain Mapp. 31, 926–933. 130–136. natal nutritional rehabilitation on cognitive development throughout
Bleichrodt, N., and Born, M. (1994). Cetina, I. (2008). Long-chain omega-3 brain fatty acids, learning, and childhood: a review of human stud-
“A metaanalysis of research on fatty acid supply in pregnancy and memory. Nutr. Rev. 69, 132–144. ies. Prostaglandins Leukot. Essent.
iodine and its relationship to cogni- lactation. Curr. Opin. Clin. Nutr. Debassio, W. A., Kemper, T. L., Tonkiss, Fatty Acids 76, 189–203.
tive development,” in The Damaged Metab. Care 11, 297–302. J., and Galler, J. R. (1996). Effect Engle, P. L. (2010). INCAP studies of
Brain of Iodine Deficiency, ed J. B. Chugani, T. (1998). A critical period of of prenatal protein deprivation on malnutrition and cognitive behav-
Stanbury (New York, NY: Cognizant brain development: studies of cere- postnatal granule cell generation ior. Food Nutr. Bull. 31, 83–94.
Communication), 195–200. bral glucose utilization with PET. in the hippocampal dentate gyrus. Falkingham, M., Abdelhamid, A.,
Blencowe, H., Cousens, S., Modell, Prev. Med. 27, 184–188. Brain Res. Bull. 41, 379–383. Curtis, P., Fairweather-Tait, S., Dye,
B., and Lawn, J. (2010). Folic Clark, C. A., Pritchard, V. E., and Delong, G. R., Stanbury, J. B., L., and Hooper, L. (2010). The
acid to reduce neonatal mortality Woodward, L. J. (2010). Preschool and Fierro-Benitez, R. (1985). effects of oral iron supplementation
from neural tube disorders. Int. J. executive functioning abilities pre- Neurological signs in congen- on cognition in older children and
Epidemiol. 39, i110–i121. dict early mathematics achieve- ital iodine-deficiency disorder adults: a systematic review and
Boucher, O., Burden, M. J., Muckle, ment. Dev. Psychol. 46, 1176–1191. (endemic cretinism). Dev. Med. meta-analysis. Nutr. J. 9:4. doi:
G., Saint-Amour, D., Ayotte, Colombo, J., Kannass, K. N., Jill Child Neurol. 27, 317–324. 10.1186/1475-2891-9-4
P., Dewailly, E., et al. (2011). Shaddy, D., Kundurthi, S., Desouza, L. A., Ladiwala, U., Daniel, S. Feldman, H. S., Jones, K. L., Lindsay,
Neurophysiologic and neurobehav- Maikranz, J. M., Anderson, C. M., Agashe, S., Vaidya, R. A., and S., Slymen, D., Klonoff-Cohen,
ioral evidence of beneficial effects of J., et al. (2004). Maternal DHA Vaidya, V. A. (2005). Thyroid hor- H., Kao, K., et al. (2012). Prenatal
prenatal omega-3 fatty acid intake and the development of attention mone regulates hippocampal neu- alcohol exposure patterns and
on memory function at school age. in infancy and toddlerhood. Child rogenesis in the adult rat brain. Mol. alcohol-related birth defects and
Am. J. Clin. Nutr. 93, 1025–1037. Dev. 75, 1254–1267. Cell. Neurosci. 29, 414–426. growth deficiencies: a prospective
Broadhurst, C. L., Cunnane, S. C., Commonwealth of Australia. (2006). Deungria, M. (2000). Perinatal iron study. Alcohol. Clin. Exp. Res. 36,
and Crawford, M. A. (1998). Rift Nutrient reference values for deficiency decreases cytochrome c 670–676.
Valley lake fish and shellfish pro- Australia and New Zealand. oxidase (CytOx) activity in selected Florence, M. D., Asbridge, M., and
vided brain-specific nutrition for Canberra, ACT. regions of neonatal rat brain. Veugelers, P. J. (2008). Diet quality
early Homo. Br. J. Nutr. 79, 3–21. Coyle, P., Tran, N., Fung, J. N. T., Pediatr. Res. 48, 169–176. and academic performance. J. Sch.
Broadhurst, C. L., Wang, Y., Crawford, Summers, B. L., and Rofe, A. Deutsch, G. K., Dougherty, R. F., Health 78, 209–215.
M. A., Cunnane, S. C., Parkington, M. (2009). Maternal dietary zinc Bammer, R., Siok, W. T., Gabrieli, Forrest, D. (2004). The develop-
J. E., and Schmidt, W. F. (2002). supplementation prevents aberrant J. D. E., and Wandell, B. (2005). ing brain and maternal thyroid
Brain-specific lipids from marine, behaviour in an object recognition Children’s reading performance is hormone: finding the links.
lacustrine, or terrestrial food task in mice offspring exposed to correlated with white matter struc- Endocrinology 145, 4034–4036.
resources: potential impact on LPS in early pregnancy. Behav. Brain ture measured by diffusion tensor Frick, J. E., Colombo, J., and Saxon, T. F.
early African Homo sapiens. Comp. Res. 197, 210–218. imaging. Cortex 41, 354–363. (1999). Individual and developmen-
Biochem. Physiol. B Biochem. Mol. Crawford, M., Bloom, M., Broadhurst, Dewey, K. G., and Begum, K. (2011). tal differences in disengagement of
Bio. 131, 653–673. C., Schmidt, W., Cunnane, S., Galli, Long-term consequences of stunt- fixation in early infancy. Child Dev.
Brown, R. D., Langshaw, M. R., Uhr, C., et al. (1999). Evidence for ing in early life. Matern. Child Nutr. 70, 537–548.
E. J., Gibson, J. N., and Joshua, D. the unique function of docosahex- 7, 5–18. Gale, C. R., Martyn, C. N., Marriott, L.
E. (2011). The impact of manda- aenoic acid during the evolution of Drane, D. L., and Logemann, J. A. D., Limond, J., Crozier, S., Inskip, H.
tory fortification of flour with folic the modern hominid brain. Lipids (2000). A critical evaluation of the M., et al. (2009). Dietary patterns
acid on the blood folate levels of an 34, S39–S47. evidence on the association between in infancy and cognitive and neu-
Australian population. Med. J. Aust. Daniels, J. L., Longnecker, M. P., type of infant feeding and cogni- ropsychological function in child-
194, 65–67. Rowland, A. S., and Golding, J. tive development. Paediatr. Perinat. hood. J. Child Psychol. Psychiatry 50,
Bryan, J., Osendarp, S., Hughes, D., (2004). Fish intake during preg- Epidemiol. 14, 349–356. 816–823.
Calvaresi, E., Baghurst, K., and Van nancy and early cognitive develop- Dror, D. K., and Allen, L. H. (2008). Gallego, G. (2010). Iodine deficiency
Klinken, J.-W. (2004). Nutrients ment of offspring. Epidemiology 15, Effect of vitamin B12 deficiency on in Australia: is iodine supplemen-
for cognitive development in 394–402. neurodevelopment in infants: cur- tation for pregnant and lactating
school-aged children. Nutr. Rev. 62, De Benoist, B. (2008). Conclusions of rent knowledge and possible mech- women warranted? Med. J. Aust.
295–306. a WHO Technical Consultation on anisms. Nutr. Rev. 66, 250–255. 192, 461–463.
Burkhalter, T. M., and Hillman, C. folate and vitamin B12 deficiencies. Dunstan, J. A., Simmer, K., Dixon, Georgieff, M. K. (2007). Nutrition
H. (2011). A narrative review of Food Nutr. Bull. 29, S238–S244. G., and Prescott, S. L. (2008). and the developing brain: nutrient

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 12

Nyaradi et al. Nutrition and children’s cognitive development

priorities and measurement. Am. J. psychopathology. J. Child Psychol. Hibbeln, J. R., Davis, J. M., Steer, C., The role of nutrition on epige-
Clin. Nutr. 85, 614S–620S. Psychiatry 44, 33–63. Emmett, P., Rogers, I., Williams, netic modifications and their impli-
Ghosh, S. S., Kakunoori, S., Guesnet, P., and Alessandri, J.- C., et al. (2007). Maternal seafood cations on health. Biochimie 94,
Augustinack, J., Nieto-Castanon, M. (2011). Docosahexaenoic consumption in pregnancy and 2242–2263.
A., Kovelman, I., Gaab, N., et al. acid (DHA) and the developing neurodevelopmental outcomes in Joos, S. K., Pollitt, E., Mueller, W. H.,
(2010). Evaluating the validity of central nervous system (CNS) - childhood (ALSPAC study): an and Albright, D. L. (1983). The
volume-based and surface-based Implications for dietary rec- observational cohort study. Lancet Bacon Chow Study: maternal nutri-
brain image registration for devel- ommendations. Biochimie 93, 369, 578–585. tional supplementation and infant
opmental cognitive neuroscience 7–12. Hoffman, D. R., Boettcher, J. A., and behavioral development. Child Dev.
studies in children 4 to 11 years of Haddow, J. E., Palomaki, G. E., Allan, Diersen-Schade, D. A. (2009). 54, 669–676.
age. Neuroimage 53, 85–93. W. C., Williams, J. R., Knight, G. J., Toward optimizing vision and Jorgenson, L. A., Wobken, J. D., and
Gibson, R., and Heath, A.-L. (2011). Gagnon, J., et al. (1999). Maternal cognition in term infants by dietary Georgieff, M. K. (2003). Perinatal
Population groups at risk of zinc thyroid deficiency during pregnancy docosahexaenoic and arachidonic iron deficiency alters apical den-
deficiency in Australia and New and subsequent neuropsychological acid supplementation: a review dritic growth in hippocampal CA1
Zealand. Nutr. Diet. 68, 97–108. development of the child. New Eng. of randomized controlled trials. pyramidal neurons. Dev. Neurosci.
Giedd, J., Stockman, M., Weddle, C., J. Med. 341, 549–555. Prostaglandins Leukot. Essent. Fatty 25, 412–420.
Liverpool, M., Alexander-Bloch, A., Hamadani, J. D., Fuchs, G. J., Osendarp, Acids 81, 151–158. Judge, M. P., Harel, O., and Lammi-
Wallace, G., et al. (2010). Anatomic S. J. M., Huda, S. N., and Grantham- Hoyland, A. (2009). A systematic Keefe, C. J. (2007). Maternal
magnetic resonance imaging of McGregor, S. M. (2002). Zinc sup- review of the effect of breakfast consumption of a docosahexaenoic
the developing child and adoles- plementation during pregnancy and on the cognitive performance of acid–containing functional food
cent brain and effects of genetic effects on mental development and children and adolescents. Nut. Res. during pregnancy: benefit for infant
variation. Neuropsychol. Rev. 20, behaviour of infants: a follow-up Rev. 22, 220–243. performance on problem-solving
349–361. study. Lancet 360, 290–294. Huttenlocher, P. R., and Dabholkar, but not on recognition memory
Gökçay, G. (2010). Breastfeeding and Heijmans, B. T., Tobi, E. W., Stein, A. A. S. (1997). Regional differences tasks at age 9 mo. Am. J. Clin. Nutr.
child cognitive development. Child. D., Putter, H., Blauw, G. J., Susser, E. in synaptogenesis in human cere- 85, 1572–1577.
Care. Health Dev. 36, 591. S., et al. (2008). Persistent epigenetic bral cortex. J. Comp. Neurol. 387, Jurdak, N., Lichtenstein, A. H., and
Gong, J., Dong, J., Wang, Y., Xu, H., differences associated with prena- 167–178. Kanarek, R. B. (2008). Diet-induced
Wei, W., Zhong, J., et al. (2010). tal exposure to famine in humans. Ingwersen, J., Defeyter, M. A., Kennedy, obesity and spatial cognition in
Developmental iodine deficiency Proc. Natl. Acad. Sci. U.S.A. 105, D. O., Wesnes, K. A., and Scholey, young male rats. Nutr. Neurosci. 11,
and hypothyroidism impair neu- 17046–17049. A. B. (2007). A low glycaemic index 48–54.
ral development, up-regulate Helland, I. B., Saugstad, O. D., Smith, breakfast cereal preferentially pre- Kafouri, S., Kramer, M., Leonard, G.,
caveolin-1 and down-regulate L., Saarem, K., Solvoll, K., Ganes, vents children’s cognitive perfor- Perron, M., Pike, B., Richer, L.,
synaptophysin in rat hippocampus. T., et al. (2001). Similar effects mance from declining throughout et al. (2012). Breastfeeding and
J. Neuroendocrinol. 22, 129–139. on infants of n-3 and n-6 fatty the morning. Appetite 49, 240–244. brain structure in adolescence. Int. J.
Gordon, R. C., Rose, M. C., Skeaff, acids supplementation to pregnant Innis, S. M. (2007). Dietary (n-3) Epidemiol. doi: 10.1093/ije/dys172.
S. A., Gray, A. R., Morgan, K. M., and lactating women. Pediatrics fatty acids and brain development. [Epub ahead of print].
and Ruffman, T. (2009). Iodine sup- 108, e82. J. Nutr. 137, 855–859. Kasatkina, É., Samsonova, L.,
plementation improves cognition Helland, I. B., Smith, L., Blomén, B., Isaacs, E. B., Fischl, B. R., Quinn, B. T., Ivakhnenko, V., Ibragimova,
in mildly iodine-deficient children. Saarem, K., Saugstad, O. D., and Chong, W. K., Gadian, D. G., and G., Ryabykh, A., Naumenko, L.,
Am. J. Clin. Nutr. 90, 1264–1271. Drevon, C. A. (2008). Effect of sup- Lucas, A. (2010). Impact of breast et al. (2006). Gestational hypothy-
Granados-Rojas, L., Larriva-Sahd, J., plementing pregnant and lactating milk on intelligence quotient, brain roxinemia and cognitive function in
Cintra, L., Gutiérrez-Ospina, G., mothers with n-3 very-long-chain size, and white matter development. offspring. Neurosci. Behav. Physiol.
Rondán, A., and DíAz-Cintra, S. fatty acids on children’s IQ and Pediatr. Res. 67, 357–362. 36, 619–624.
A. (2002). Prenatal protein malnu- body mass index at 7 years of age. Isaacs, E. B., Gadian, D. G., Sabatini, S., Kirksey, A., Wachs, T. D., Yunis,
trition decreases mossy fibers-CA3 Pediatrics 122, e472–e479. Chong, W. K., Quinn, B. T., Fischl, F., Srinath, U., Rahmanifar, A.,
thorny excrescences asymmetrical Helland, I. B., Smith, L., Saarem, K., B. R., et al. (2008). The effect of early McCabe, G. P., et al. (1994).
synapses in adult rats. Brain Res. Saugstad, O. D., and Drevon, C. human diet on caudate volumes and Relation of maternal zinc nutriture
933, 164–171. A. (2003). Maternal supplementa- IQ. Pediatr. Res. 63, 308–314. to pregnancy outcome and infant
Grantham-McGregor, S. (1995). A tion with very-long-chain n-3 fatty Isaacs, E. B., Morley, R., and Lucas, development in an Egyptian village.
review of studies of the effect acids during pregnancy and lacta- A. (2009). Early diet and general Am. J. Clin. Nutr. 60, 782–792.
of severe malnutrition on men- tion augments children’s IQ at 4 cognitive outcome at adolescence in Knudsen, E. I. (2004). Sensitive peri-
tal development. J. Nutr. 125, years of age. Pediatrics 111, e39–e44. children born at or below 30 weeks ods in the development of the brain
2233–2238. Henriksen, T., and Clausen, T. (2002). gestation. J. Pediatr. 155, 229–234. and behavior. J. Cogn. Neurosci. 16,
Grantham-McGregor, S., and Ani, C. The fetal origins hypothesis: placen- Jacobson, J. L., Jacobson, S. W., Muckle, 1412–1425.
(2001). A review of studies on the tal insufficiency and inheritance ver- G., Kaplan-Estrin, M., Ayotte, P., Kooistra, L., Crawford, S., Van Baar, A.
effect of iron deficiency on cognitive sus maternal malnutrition in well- and Dewailly, E. (2008). Beneficial L., Brouwers, E. P., and Pop, V. J.
development in children. J. Nutr. nourished populations. Acta Obstet. effects of a polyunsaturated fatty (2006). Neonatal effects of mater-
131, 649S–666S. Gynecol. Scand. 81, 112–114. acid on infant development: evi- nal hypothyroxinemia during early
Grantham-McGregor, S., Cheung, Herba, C. M., Roza, S., Govaert, P., dence from the Inuit of Arctic pregnancy. Pediatrics 117, 161–167.
Y. B., Cueto, S., Glewwe, P., Hofman, A., Jaddoe, V., Verhulst, Quebec. J. Pediatr. 152, 356–364, Kostović, I., Judaš, M., Radoš, M., and
Richter, L., and Strupp, B. (2007). F. C., et al. (2012). Breastfeeding e351. Hrabač, P. (2002). Laminar organi-
Developmental potential in the first and early brain development: the Jain, A., Concato, J., and Leventhal, zation of the human fetal cerebrum
5 years for children in developing Generation R study. Matern. Child J. M. (2002). How good is the revealed by histochemical markers
countries. Lancet 369, 60–70. Nutr. doi: 10.1111/mcn.12015. evidence linking breastfeeding and magnetic resonance imaging.
Grossman, A. W., Churchill, J. D., [Epub ahead of print]. and intelligence? Pediatrics 109, Cereb. Cortex 12, 536–544.
McKinney, B. C., Kodish, I. M., Otte, Herlenius, E., and Lagercrantz, H. 1044–1053. Kramer, M. S., Aboud, F., Mironova, E.,
S. L., and Greenough, W. T. (2003). (2004). Development of neuro- Jiménez-Chillarón, J. C., Díaz, R., Vanilovich, I., Platt, R. W., Matush,
Experience effects on brain devel- transmitter systems during critical Martínez, D., Pentinat, T., Ramón- L., et al. (2008). Breastfeeding and
opment: possible contributions to periods. Exp. Neurol. 190, 8–21. Krauel, M., Ribó, S., et al. (2012). child cognitive development:new

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 13

Nyaradi et al. Nutrition and children’s cognitive development

evidence from a large randomized deficiency anaemia. Cochrane E., and Fawzi, W. W. (2006). Northstone, K., Joinson, C., Emmett, P.,
trial. Arch. Gen. Psychiatry 65, Database Syst. Rev. CD001444. doi: Effect of maternal multivitamin Ness, A., and Paus, T. (2011). Are
578–584. 10.1002/14651858.CD001444 supplementation on the mental dietary patterns in childhood asso-
Laus, M. (2011). Early postnatal Logi Kristjánsson, Á., Dóra and psychomotor development of ciated with IQ at 8 years of age?
protein-calorie malnutrition and Sigfúsdóttir, I., and Allegrante, children who are born to HIV- A population-based cohort study.
cognition: a review of human and J. P. (2010). Health behavior and 1–infected mothers in Tanzania. J. Epidemiol. Comm. Health. 66,
animal studies. Int. J. Environ. Res. academic achievement among ado- Pediatrics 117, e216–e225. 624–628.
Public Health 8, 590–612. lescents: the relative contribution Meck, W. H., and Williams, C. L. Oken, E., Braverman, L. E., Platek,
Lenroot, R. K., and Giedd, J. N. (2006). of dietary habits, physical activity, (2003). Metabolic imprinting of D., Mitchell, M. L., Lee, S. L., and
Brain development in children body mass index, and self-esteem. choline by its availability during Pearce, E. N. (2009). Neonatal
and adolescents: insights from Health Educ. Behav. 37, 51–64. gestation: implications for memory thyroxine, maternal thyroid
anatomical magnetic resonance Louwman, M. W., Van Dusseldorp, M., and attentional processing across function, and child cognition.
imaging. Neurosci. Biobehav. Rev. Van De Vijver, F. J., Thomas, C. the lifespan. Neurosci. Biobehav. Rev. J. Clin. Endocrinol. Metab. 94,
30, 718–729. M., Schneede, J., Ueland, P. M., 27, 385–399. 497–503.
Leung, B., Wiens, K., and Kaplan, et al. (2000). Signs of impaired cog- Melse-Boonstra, A., and Jaiswal, Oken, E., Radesky, J. S., Wright, R. O.,
B. (2011). Does prenatal nitive function in adolescents with N. (2010). Iodine deficiency in Bellinger, D. C., Amarasiriwardena,
micronutrient supplementation marginal cobalamin status. Am. J. pregnancy, infancy and childhood C. J., Kleinman, K. P., et al. (2008a).
improve children’s mental develop- Clin. Nutr. 72, 762–769. and its consequences for brain Maternal fish intake during preg-
ment? A systematic review. BMC Lozoff, B., and Georgieff, M. K. (2006). development. Best Pract. Res. Clin. nancy, blood mercury levels, and
Pregnancy Childbirth 11:12. doi: Iron deficiency and brain develop- Endocrinol. Metab. 24, 29–38. child cognition at age 3 years in a
10.1186/1471-2393-11-12 ment. Semin. Pediatr. Neurol. 13, Micha, R., Rogers, P. J., and Nelson, US cohort. Am. J. Epidemiol. 167,
Levenson, C. W. (2006). Regulation 158–165. M. (2011). Glycaemic index and 1171–1181.
of the NMDA receptor: implica- Lucas, A., Morley, R., and Cole, T. J. glycaemic load of breakfast pre- Oken, E., Usterdal, M. L., Gillman, M.
tions for neuropsychological devel- (1998). Randomised trial of early dict cognitive function and mood W., Knudsen, V. K., Halldorsson,
opment. Nutr. Rev. 64, 428–432. diet in preterm babies and later in school children: a randomised T. I., Strøm, M., et al. (2008b).
Levi, R. S., and Sanderson, I. R. (2004). intelligence quotient. Br. Med. J. controlled trial. Br. J. Nutr. 106, Associations of maternal fish intake
Dietary regulation of gene expres- 317, 1481–1487. 1552–1561. during pregnancy and breastfeed-
sion. Curr. Opin. Gastroenterol. 20, Luna, B., and Sweeney, J. A. (2001). Michaelsen, K. F., Lauritzen, L., and ing duration with attainment of
139–142. Studies of brain and cognitive Mortensen, E. L. (2009). “Effects developmental milestones in early
Levitt, P. (2003). Structural and func- maturation through childhood and of breast-feeding on cognitive childhood: a study from the Danish
tional maturation of the developing adolescence: a strategy for testing function,” in Breast-feeding: early National Birth Cohort. Am. J. Clin.
primate brain. J. Pediatr. 143, 35–45. neurodevelopmental hypotheses. influences on later health, eds G. Nutr. 88, 789–796.
Li, Q., Yan, H., Zeng, L., Cheng, Y., Schizophr. Bull. 27, 443–455. Goldberg, A. Prentice, A. Prentice, Palermo, T. M., and Dowd, J. B. (2012).
Liang, W., Dang, S., et al. (2009). Makrides, M., Gibson, R. A., McPhee, S. Filteau, and K. Simondon Childhood obesity and human cap-
Effects of maternal multimicronu- A. J., Yelland, L., Quinlivan, J., Ryan, (Netherlands: Springer), 199–215. ital accumulation. Soc. Sci. Med. 75,
trient supplementation on the men- P., et al. (2010). Effect of DHA Molteni, R., Barnard, R. J., Ying, 1989–1998.
tal development of infants in rural Supplementation during pregnancy Z., Roberts, C. K., and Gómez- Pallotto, E. K., and Kilbride, H. W.
Western China: follow-up evalua- on maternal depression and neu- Pinilla, F. (2002). A high-fat, refined (2006). Perinatal outcome and later
tion of a double-blind, random- rodevelopment of young children. sugar diet reduces hippocampal implications of intrauterine growth
ized, controlled trial. Pediatrics 123, J. Am. Med. Assoc. 304, 1675–1683. brain-derived neurotrophic factor, restriction. Clin. Obstet. Gynecol. 49,
e685–e692. Maret, W., and Sandstead, H. H. neuronal plasticity, and learning. 257–269.
Li, Y., Dai, Q., Jackson, J. C., and Zhang, (2006). Zinc requirements and the Neuroscience 112, 803–814. Penhune, V. B. (2011). Sensitive peri-
J. (2008). Overweight is associated risks and benefits of zinc supple- Murcia, M., Rebagliato, M., Iñiguez, ods in human development: evi-
with decreased cognitive function- mentation. J. Trace Elem. Med. Biol. C., Lopez-Espinosa, M.-J., Estarlich, dence from musical training. Cortex
ing among school-age children and 20, 3–18. M., Plaza, B., et al. (2011). Effect 47, 1126–1137.
adolescents. Obesity 16, 1809–1815. Mathangi, D. C., and Namasivayam, of iodine supplementation during Peper, J. S., Brouwer, R. M., Schnack, H.
Lillycrop, K. A., and Burdge, G. C. A. (2001). Effect of chronic protein pregnancy on infant neurodevel- G., Van Baal, G. C., Van Leeuwen,
(2011). The Effect of nutrition restriction on motor co-ordination opment at 1 year of age. Am. J. M., Van Den Berg, S. M., et al.
during early life on the epige- and brain neurotransmitters in Epidemiol. 173, 804–812. (2009). Sex steroids and brain
netic regulation of transcription albino rats. Food Chem. Toxicol. 39, Murgatroyd, C., and Spengler, D. structure in pubertal boys and
and implications for human dis- 1039–1043. (2011). Epigenetics of early child girls. Psychoneuroendocrinology 34,
eases. J. Nutrigenet. Nutrigenomics 4, McCann, J. C., and Ames, B. N. development. Front. Psychiatry 2:16. 332–342.
248–260. (2005). Is docosahexaenoic acid, doi: 10.3389/fpsyt.2011.00016 Pepper, M. R., and Black, M. M. (2011).
Lillycrop, K. A., and Burdge, G. C. an n–3 long-chain polyunsaturated Mustafa, R., Ahmed, S., Gupta, A., and B12 in fetal development. Semin.
(2012). Epigenetic mechanisms fatty acid, required for develop- Venuto, R. C. (2012). A comprehen- Cell Dev. Biol. 22, 619–623.
linking early nutrition to long ment of normal brain function? An sive review of hypertension in preg- Pop, V. J. (2001). Low maternal free
term health. Best Pract. Res. Clin. overview of evidence from cogni- nancy. J. Pregnancy 2012:105918. thyroxine concentrations during
Endocrinol. Metab. 26, 667–676. tive and behavioral tests in humans doi: 10.1155/2012/105918 early pregnancy are associated with
Lindqvist, A., Mohapel, P., Bouter, and animals. Am. J. Clin. Nutr. 82, Nagy, Z., Westerberg, H., and impaired psychomotor develop-
B., Frielingsdorf, H., Pizzo, D., 281–295. Klingberg, T. (2004). Maturation of ment in infancy. Clin. Endocrinol.
Brundin, P., et al. (2006). High-fat McCann, J. C., Hudes, M., and Ames, B. white matter is associated with the 50, 149.
diet impairs hippocampal neuroge- N. (2006). An overview of evidence development of cognitive functions Pop, V. J., Brouwers, E. P., Vader,
nesis in male rats. Eur. J. Neurol. 13, for a causal relationship between during childhood. J. Cogn. Neurosci. H. L., Vulsma, T., Van Baar, A.
1385–1388. dietary availability of choline during 16, 1227–1233. L., and De Vijlder, J. J. (2003).
Logan, S., Martins, S., and Gilbert, R. development and cognitive function Niculescu, M. D., and Lupu, D. S. Maternal hypothyroxinaemia dur-
(2001). Iron therapy for improving in offspring. Neurosci. Biobehav. (2009). High fat diet-induced ing early pregnancy and subse-
psychomotor development and Rev. 30, 696–712. maternal obesity alters fetal hip- quent child development: a 3-year
cognitive function in children McGrath, N., Bellinger, D., Robins, pocampal development. Int. J. Dev. follow-up study. Clin. Endocrinol.
under the age of three with iron J., Msamanga, G. I., Tronick, Neurosci. 27, 627–633. 59, 282–288.

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 14

Nyaradi et al. Nutrition and children’s cognitive development

Prado, E. L., Alcock, K. J., Muadz, of mothers supplemented with vita- Taki, Y., Hashizume, H., Sassa, Y., a randomized trial from the
H., Ullman, M. T., and Shankar, min A in addition to iron dur- Takeuchi, H., Asano, M., Asano, K., Maternal and Infant Nutrition
A. H. (2012). Maternal multiple ing pregnancy. Br. J. Nutr. 91, et al. (2010). Breakfast staple types Interventions, Matlab (MINIMat)
micronutrient supplements and 279–285. affect brain gray matter volume study. Am. J. Clin. Nutr. 87,
child cognition: a randomized Schuchardt, J., Huss, M., Stauss- and cognitive function in healthy 704–711.
trial in Indonesia. Pediatrics 130, Grabo, M., and Hahn, A. (2010). children. PLoS ONE 5:e15213. doi: Toga, A. W., Thompson, P. M., and
e536–e546. Significance of long-chain polyun- 10.1371/journal.pone.0015213 Sowell, E. R. (2006). Mapping brain
Qian, M. (2005). The effects of iodine saturated fatty acids (PUFAs) for Tamura, T., Goldenberg, R. L., maturation. Trends Neurosci. 29,
on intelligence in children: a meta- the development and behaviour Chapman, V. R., Johnston, K. 148–159.
analysis of studies conducted in of children. Eur. J. Pediatr. 169, E., Ramey, S. L., and Nelson, K. G. Tramontana, M. G., Hooper, S. R., and
China. Asia Pac. J. Clin. Nutr. 14, 32. 149–164. (2005). Folate status of mothers Selzer, S. C. (1988). Research on the
Ramakrishnan, U., Imhoff-Kunsch, B., Schulzke, S. M., Patole, S. K., and during pregnancy and mental preschool prediction of later aca-
and Digirolamo, A. M. (2009). Role Simmer, K. (2011). Long-chain and psychomotor development of demic achievement: a review. Dev.
of docosahexaenoic acid in maternal polyunsaturated fatty acid their children at five years of age. Rev. 8, 89–146.
and child mental health. Am. J. Clin. supplementation in preterm Pediatrics 116, 703–708. Uddin, L. Q., Supekar, K., and
Nutr. 89, 958S–962S. infants. Cochrane Database Syst. Tamura, T., Goldenberg, R. L., Hou, J., Menon, V. (2010). Typical and
Rey, J. (2003). Breastfeeding and cogni- Rev. CD000375. doi: 10.1002/ Johnston, K. E., Cliver, S. P., Ramey, atypical development of func-
tive development. Acta Paediatr. 92, 14651858.CD000375.pub4 S. L., et al. (2002). Cord serum fer- tional human brain networks:
11–18. Shah, D., and Sachdev, H. P. S. (2006). ritin concentrations and mental and insights from resting-state fMRI.
Riano Galan, I., Sanchez Martinez, Zinc deficiency in pregnancy and psychomotor development of chil- Front. Syst. Neurosci. 4:21. doi:
P., Pilar Mosteiro Diaz, M., and fetal outcome. Nutr. Rev. 64, 15–30. dren at five years of age. Obstet. 10.3389/fnsys.2010.00021
Rivas Crespo, M. F. (2005). Psycho- Shaw, G. M., Carmichael, S. L., Yang, Gynecol. Survey 57, 493–494. United Nations Children’s Fund and
intellectual development of 3 W., Selvin, S., and Schaffer, D. Tamura, T., Goldenberg, R. L., Ramey, World Health Organization, (2004).
year-old children with early gesta- M. (2004). Periconceptional dietary S. L., Nelson, K. G., and Chapman, Low Birthweight: Country, Regional
tional iodine deficiency. J. Pediatr. intake of choline and betaine and V. R. (2003). Effect of zinc sup- and Global Estimates. New York, NY:
Endocrinol.Metab. 18(Suppl. 1), neural tube defects in offspring. Am. plementation of pregnant women UNICEF.
1265–1272. J. Epidemiol. 160, 102–109. on the mental and psychomotor Van Petten, C. (2004). Relationship
Rioux, F. M., Bélanger-Plourde, J., Signore, C., Ueland, P. M., Troendle, J., development of their children at 5 between hippocampal volume and
Leblanc, C. P., and Vigneau, F. and Mills, J. L. (2008). Choline con- y of age. Am. J. Clin. Nutr. 77, memory ability in healthy individ-
(2011). Relationship between centrations in human maternal and 1512–1516. uals across the lifespan: review and
maternal DHA and iron status and cord blood and intelligence at 5 y of Taneja, S., Bhandari, N., Bahl, R., meta-analysis. Neuropsychologia 42,
infants’ cognitive performance. age. Am. J. Clin. Nutr. 87, 896–902. and Bhan, M. K. (2005). Impact 1394–1413.
Can. J. Diet. Pract. Res. 72, 76. Simmer, K., Patole, S., and Rao, S. of zinc supplementation on mental Veena, S. R., Krishnaveni, G. V.,
Rosales, F., Reznick, J. S., and Zeisel, (2008). Long-chain polyunsatu- and psychomotor scores of children Srinivasan, K., Wills, A. K.,
S. (2009). Understanding the role of rated fatty acid supplementation aged 12 to 18 months: a random- Muthayya, S., Kurpad, A. V.,
nutrition in the brain and behav- in infants born at term. Cochrane ized, double-blind trial. J. Pediatr. et al. (2010). Higher maternal
ioral development of toddlers and Database Syst. Rev. CD000376. doi: 146, 506–511. plasma folate but not vitamin b-12
preschool children: identifying and 10.1002/14651858.CD000376.pub2 Tangney, C. C., and Scarmeas, N. concentrations during pregnancy
addressing methodological barriers. Simopoulos, A. P. (1999). Evolutionary (2011). The good, bad, and ugly?: are associated with better cognitive
Nutr. Neurosci. 12, 190–202. aspects of omega-3 fatty acids in the how blood nutrient concentrations function scores in 9- to 10- year-old
Roseboom, T., De Rooij, S., and Painter, food supply. Prostaglandins Leukot. may reflect cognitive performance. children in South India. J. Nutr.
R. (2006). The Dutch famine and Essen. Fatty Acids 60, 421–429. Neurology 78, 230–231. 140, 1014–1022.
its long-term consequences for Simopoulos, A. P. (2008). The impor- Tanumihardjo, S. A., Anderson, C., Velasco, I., Carreira, M., Santiago,
adult health. Early Hum. Dev. 82, tance of the omega-6/omega-3 fatty Kaufer-Horwitz, M., Bode, L., P., Muela, J. A., García-Fuentes,
485–491. acid ratio in cardiovascular disease Emenaker, N. J., Haqq, A. M., E., Sánchez-Muñoz, B., et al.
Ross, C. E., and Mirowsky, J. (1999). and other chronic diseases. Exp. et al. (2007). Poverty, obesity, and (2009). Effect of iodine prophylaxis
Refining the association between Biol. Med. 233, 674–688. malnutrition: an international per- during pregnancy on neurocog-
education and health: the effects of Sisk, C. (2004). The neural basis spective recognizing the paradox. nitive development of children
quantity, credential, and selectivity. of puberty and adolescence. Nat. J. Am. Diet. Assoc. 107, 1966–1972. during the first two years of life.
Demography 36, 445–460. Neurosci. 7, 1040. Thatcher, R. W. (1991). Maturation of J. Clin. Endocrinol. Metab. 94,
Ryan, A. S., Astwood, J. D., Gautier, Smithers, L. G., Golley, R. K., Mittinty, the human frontal lobes: physio- 3234–3241.
S., Kuratko, C. N., Nelson, E. B., M. N., Brazionis, L., Northstone, K., logical evidence for staging. Dev. Vermiglio, F., Lo Presti, V. P., Moleti,
and Salem, N. Jr. (2010). Effects of Emmett, P., et al. (2012). Dietary Neuropsychol. 7, 397–419. M., Sidoti, M., Tortorella, G.,
long-chain polyunsaturated fatty patterns at 6, 15 and 24 months Theodore, R. F., Thompson, J. M. D., Scaffidi, G., et al. (2004). Attention
acid supplementation on neurode- of age are associated with IQ at 8 Waldie, K. E., Wall, C., Becroft, deficit and hyperactivity disorders
velopment in childhood: a review years of age. Eur. J. Epidemiol. 27, D. M. O., Robinson, E., et al. in the offspring of mothers exposed
of human studies. Prostaglandins 525–535. (2009). Dietary patterns and intel- to mild-moderate iodine deficiency:
Leukot. Essent. Fatty Acids 82, Stevenson, J. (2006). Dietary influ- ligence in early and middle child- a possible novel iodine deficiency
305–314. ences on cognitive development and hood. Intelligence 37, 506–513. disorder in developed countries.
Sachdev, H., Gera, T., and Nestel, behaviour in children. Proc. Nutr. Tofail, F. (2006). Supplementation of J. Clin. Endocrinol. Metab. 89,
P. (2005). Effect of iron supple- Soc. 65, 361–365. fish-oil and soy-oil during preg- 6054–6060.
mentation on mental and motor Summers, B. L., Henry, C. M. A., Rofe, nancy and psychomotor develop- World Health Organization. (2004).
development in children: systematic A. M., and Coyle, P. (2008). Dietary ment of infants. J. Health Popul. Iodine Status Worldwide, WHO
review of randomised controlled tri- zinc supplementation during preg- Nutr. 24, 48–56. Global Database on Iodine
als. Public Health Nutr. 8, 117–132. nancy prevents spatial and object Tofail, F., Persson, L. Å., El Arifeen, S., Deficiency, Geneva.
Schmidt, M. K., Muslimatun, S., West, recognition memory impairments Hamadani, J. D., Mehrin, F., Ridout, World Health Organization. (2008).
C. E., Schultink, W., and Hautvast, J. caused by early prenatal ethanol D., et al. (2008). Effects of prenatal Worldwide Prevalence of Anaemia
G. (2004). Mental and psychomotor exposure. Behav. Brain Res. 186, food and micronutrient supple- 1993-2005: WHO Global Database
development in Indonesian infants 230–238. mentation on infant development: on Anaemia, Geneva.

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 15

Nyaradi et al. Nutrition and children’s cognitive development

Wurtman, R. J. (2008). Synapse for- phosphorylation and cell prolifera- iodine deficiency during pregnancy Received: 16 October 2012; accepted: 07
mation and cognitive brain devel- tion in fetal neural stem cells. Nutr. and childhood: a review. Thyroid March 2013; published online: 26 March
opment: effect of docosahexaenoic Neurosci. 12, 226–232. 17, 829–835. 2013.
acid and other dietary constituents. Zhou, S. J., Gibson, R. A., Crowther, Zimmermann, M. B. (2009). Iodine Citation: Nyaradi A, Li J, Hickling S,
Metabolism 57, S6–S10. C. A., Baghurst, P., and Makrides, deficiency in pregnancy and the Foster J and Oddy WH (2013) The role
Zeisel, S. (2006a). The fetal origins M. (2006). Effect of iron supple- effects of maternal iodine sup- of nutrition in children’s neurocognitive
of memory: the role of dietary mentation during pregnancy on the plementation on the offspring: development, from pregnancy through
choline in optimal brain develop- intelligence quotient and behavior a review. Am. J. Clin. Nutr. 89, childhood. Front. Hum. Neurosci. 7:97.
ment. J. Pediatr. 149, S131–S136. of children at 4 y of age: long- 668S–672S. doi: 10.3389/fnhum.2013.00097
Zeisel, S. H. (2006b). Choline: criti- term follow-up of a randomized Zimmermann, M. B. (2011). The role Copyright © 2013 Nyaradi, Li,
cal role during fetal development controlled trial. Am. J. Clin. Nutr. of iodine in human growth and Hickling, Foster and Oddy. This is an
and dietary requirements in adults. 83, 1112–1117. development. Semin. Cell Dev. Biol. open-access article distributed under
Annu. Rev. Nutr. 26, 229–250. Zimmermann, M. (2006). Iodine sup- 22, 645–652. the terms of the Creative Commons
Zeisel, S. H. (2009). Importance plementation improves cognition in Attribution License, which permits
of methyl donors during repro- iodine-deficient schoolchildren in Conflict of Interest Statement: The use, distribution and reproduc-
duction. Am. J. Clin. Nutr. 89, Albania: a randomized, controlled, authors declare that the research tion in other forums, provided the
673S–677S. double-blind study. Am. J. Clin. was conducted in the absence of any original authors and source are cred-
Zhang, X.-M., Huang, G.-W., Tian, Nutr. 83, 108–114. commercial or financial relationships ited and subject to any copyright
Z.-H., Ren, D.-L., and Wilson, J. Zimmermann, M. B. (2007). The that could be construed as a potential notices concerning any third-party
(2009). Folate stimulates ERK1/2 adverse effects of mild-to-moderate conflict of interest. graphics etc.

Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 16