Current Nutrition Reports

https://doi.org/10.1007/s13668-019-0268-z

NUTRITION AND THE BRAIN (J NASSER, SECTION EDITOR)

Micronutrients and Brain Development

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Purpose of Review This review summarizes the most recent evidence regarding the effects of micronutrients on brain
development.
Recent Findings Emerging evidence indicates that nutrition in the early life can profoundly influence neurodevelopment, affect-
ing later life health outcomes, neurocognitive performances, and disease risks. Inadequate early life nutrition has been associated
with some neuropsychiatric disorders. Epigenetic mechanisms could play a crucial role, imprinting the genomes in early life
making the individual more susceptible to develop diseases later in life.
Summary Children adequately nourished are more likely to reach their developmental potential in cognitive, motor, and
socioemotional abilities, with positive societal repercussions. Data from further clinical trials are needed before more definitive
conclusions can be drawn regarding the efficacy of dietary interventions for improving neurocognitive and social outcomes and
preventing some neuropsychiatric illnesses. Nevertheless, it is reasonable to make recommendations to our patients to adopt
certain dietary habits to optimize early life nutritional status in order to avoid long-term adverse consequences. Strategies of
prevention should focus on ensuring more quality food to preconceptional, pregnant, lactating women and to children in their
early life, not only in those areas where malnutrition is common but also in developed countries.

Keywords First 1000 days . Brain development . Neurodevelopment . Micronutrients . Micronutrient deficiencies . Iron . Iodine .
Zinc . Epigenetics . Neurocognitive performances . Neuropsychiatric diseases

Introduction showed that nutrition plays a critical role: firstly, being respon-
sible of providing those substances required for the creation of
The period included between the conception and the first the early brain structure and, secondly, being responsible of
2 years of life, known as the “first 1000 days”, is fundamental supporting and preserving its healthy functioning [4]. In addi-
to influence long-term child health outcomes. Particularly, this tion, accumulating evidence suggests that diet influences gene
time period constitutes a golden opportunity to program nor- expression through epigenetic mechanisms. These epigenetic
mal brain development [1]. Neurodevelopment is a highly changes, especially if experienced during the early develop-
complex process. Although it is mostly genetic, ment, could be responsible for later life diseases [5–7]. Several
preprogrammed, and experience-independent, there are envi- preclinical and clinical studies have helped to elucidate the
ronmental factors that can profoundly influence early brain role and mechanism of individual macro- and micronutrients
development. Some of these factors are beyond our control, on brain development [4]. While almost all nutrients are re-
but nutrition is not [2, 3]. In the last decades many studies quired, a subset of nutrients plays a particularly significant
role in a variety of critical neurodevelopmental processes
across brain regions, supporting the high rate of brain metab-
This article is part of the Topical Collection on Nutrition and the Brain
olism during early life. These include macronutrients (e.g.,
protein, long-chain polyunsaturated fatty acids, and glucose)
* Davide Mattei
[email protected] and micronutrients (e.g., iron, iodine, zinc, and vitamins)
[8••]. Over time, evidence has demonstrated that, regardless
1
of the cause, impairments in the early life neurodevelopment
Department of Surgical Sciences, Dentistry, Gynecology and
Pediatrics, Pediatric Division, University of Verona, Verona, Italy have long-term consequences on health, with respect to edu-
2 cation, job potential, and adult mental health [9, 10].
Pennington Biomedical Research Center, Baton Rouge, LA 70808,
USA Considering the worldwide diffusion of early life malnutrition
 Curr Nutr Rep

in all its forms—undernutrition, micronutrient deficiencies, of growth in this period is the highest throughout the lifespan.
obesity, and diet-related noncommunicable diseases—and In general, the higher the rate of an organ’s growth, the greater
the related unacceptably high long-term economic and socie- is its risk to be damaged by insufficient supply of nutrients.
tal repercussions, policy makers should focus their attention This makes the developing brain greatly susceptible to dam-
on planning and making appropriate assessments and inter- ages [13]. The brain is a heterogeneous organ. It is comprised
ventions, in order to optimize nutrient supplies during the of distinct anatomical regions (hippocampus, cortex, and stri-
most vulnerable period of brain development. This review will atum) and processes (e.g., myelination, neurotransmitters),
focus on the importance of early life nutrition to ensure opti- each with unique developmental trajectories and a set of nu-
mal brain development, first by describing the important mile- trient requirements [13]. Many of these regions or processes
stones of neurodevelopment, overviewing the basic principles have developmental trajectories that begin and accelerate in
that regulate the nutrient-brain interactions, and then present- fetal life or shortly after birth. Furthermore, every region and
ing recent findings about the most common micronutrient de- every process have two crucial moments: the critical period
ficiencies (iron, zinc, and iodine) and the associated risk of and the sensitive period. The borders between the two periods
neuropsychiatric adverse consequences. are blurred. However, they can conceptually be defined as
follows: the former is an early life epoch where irreversible
Early Brain Development long-term consequences follow insults; the latter represents
broader epochs when the brain is more susceptible to environ-
Human brain development is a protracted process that begins mental factors, such as nutrient deficiencies, but the effect is
in the third gestational week with the differentiation of the not inevitably permanent [14, 15]. As such, there are a series
neural progenitor cells and extends at least through late ado- of nutrient- and tissue-specific critical periods throughout the
lescence, arguably throughout the lifespan [11]. By the end of development, and the effects that nutrient deficiencies have on
the embryonic period (eighth week post conception), the ru- the vulnerability of the brain are determined by two factors:
dimentary structures of the brain are established and the major the timing of the nutrient deficiency and the specific region’s
compartments of the central and peripheral nervous systems requirement for that nutrient at that time [16••]. Failure to
are defined [11]. After the external form is established, a com- construct a brain region during its critical period can lead to
plex series of processes begins. Between the second and permanent consequences, such as residual structural defects
fourth months of gestation, major proliferative events occur: [17], persistent neurochemical and electrophysiological ab-
progenitors of neurons and glia are produced and proliferate. normalities, and altered gene expression [18–20, 21•]. These
From approximately 5 months of gestation to early postnatal mechanisms potentially explain the biological bases of long-
life, there is glial multiplication [12]. As progenitors cells term effects of early life nutritional perturbations (Fig. 1).
proliferate and differentiate, they migrate from their sites of Thus, ensuring adequate nutrient intake is necessary to allow
origin to different brain areas where they need to make con- a time-coordinated brain development and to create an inte-
nections with other neurons. The peak time for this occurrence grated healthy working brain structure.
is from the third to fifth months of gestation [12]. Once the
cells have reached their target region of the brain, in order to Epigenetics
become integrated into neural networks, they have to develop
neural processes (dendritic and axonal ramifications) that al- The first epidemiological evidence of a link between
low them to communicate through synaptic contacts. These inadequate early nutrition and diseases emerged from
organizational events, which occur from approximately the cohort studies examining health status of offspring
fifth month of gestation to several years after birth, are crucial whose mothers were pregnant during periods of severe
to establish the awesome circuitry that identifies the human famine, such as the Dutch Hunger Winter. These studies
brain. The efficiency of information transmission in the path- demonstrated that individuals prenatally exposed to se-
ways is greatly enhanced by myelin which ensheathes the vere famine were more likely to have coronary heart
axons. The period of myelination in humans is long, being disease, atherogenic lipid profile, disturbed blood coag-
rapid and dramatic from the second trimester of pregnancy ulation, increased stress responsiveness, obesity, and
to the first 2 years of postnatal life and continuing into adult glucose intolerance during adulthood [7]. Among all
life [11]. the diseases, there was also an increased risk of neuro-
psychiatric diseases, such as schizophrenia and affective
Principles of Nutrient Effects on Brain Development disorders [22–24]. In the last few years, growing atten-
tion has been put on epigenetics. The emerging hypoth-
In the first 1000 days of life, the brain faces an extraordinary esis is that part of these adverse health consequences
growth, increasing its dimension, differentiating gradually in a could be mediated by epigenetic changes, induced by
highly specialized organ, and slowly losing plasticity. The rate early life environmental risk factors such as inadequate
Curr Nutr Rep

Fig. 1 Interactions between genes and environment shape human neurodevelopment, can create an altered brain structure and induce
development. Early life nutrition (prenatal and neonatal) represents a altered patterns of epigenetic markers, leading to brief- and long-term
fundamental environmental factor that can profoundly affect brain adverse health consequences with respect to cognitive, social,
development. Early life malnutrition, during critical periods of emotional, neurological, and psychiatric performances

or inappropriate nutrition. There is convincing evidence determining neuropsychological phenotypes could poten-
that early malnutrition has an impact on genomes with tially offer an opportunity for preventing or treating
long-term consequences on health outcomes. By DNA some mental illnesses [28]. Thus, more and better-
methylation, histone modifications, and noncoding designed studies need to be done, to deepen our knowl-
microRNA, epigenetics modulates the intensity and the edge about the relationship between nutrition, epige-
timing of gene expression throughout the entire life netics, and neurodevelopment.
course, potentially leading to later life behavioral con-
sequences and diseases [6]. Several animal studies have Further Research
demonstrated that prenatal exposure to stressing events
(including malnutrition) induces lasting epigenetic All these considerations offer the opportunity not only to fo-
changes in the brain, which have been linked to chang- cus on ensuring the child with adequate nutrition to promote
es in brain gene expression, stress reactivity, and behav- normal brain development but also to consider nutrition as a
ior [25]. On the contrary, in humans, it is very chal- powerful instrument to optimize cognitive, social, emotional
lenging to establish this epigenetic link, for different behavioral development and health outcomes. Yet, the litera-
reasons: (i) they are exposed to a mixture of environ- ture related to this vast topic is frequently contradictory due to
mental factors that can have confounding effects; (ii) several reasons: critical and sensitive periods are challenging
brain tissue is inaccessible in living humans. Although to define and often used interchangeably; timing dose duration
some studies showed epigenetics changes in of supplementation principle is not always clearly definable;
neurodevelopmental-related genes, it still remains un- assessment of connections with neurobehavioral tests and out-
clear if these alterations are the actual cause of the come measures is not always made with the finest tests at the
neurodevelopmental disorders [26, 27]. Many human correct assessment age. Studies often are extremely different
diseases are the result of an interaction between genetic from each other (e.g., in terms of age and population exam-
and environmental factors. Understanding the mecha- ined, duration and doses of supplementation, assessment tests,
nisms through which dietary affects epigenomes and general health status, and sociocultural habits), explaining
how the se e pigen etic changes are involved in why meta-analyses are not the best tool to assess nutrient-
 Curr Nutr Rep

brain relationships. In the attempt to increase statistical power Table 1 This table presents recommended dietary allowances (RDAs)
in bold type and adequate intakes (AIs) in italic type. An RDA is the
by enlarging the sample size, all the nutrient nuances are lost
average daily dietary intake level sufficient to meet the nutrient
and the type II error increases, inevitably leading to inconclu- requirements of nearly all (97–98%) healthy individuals in a group. It is
sive results [29•]. As a result, finding or excluding nutrient- calculated from an estimated average requirement (EAR). If sufficient
brain decisive connection remains still problematic [30••]. scientific evidence is not available to establish an EAR, and thus
calculate an RDA, an AI is usually developed. For healthy breastfed
Further studies should take into account these factors, aiming
infants, an AI is the mean intake. The AI for other life stages and
to reduce confounding variables in order to obtain definite gender groups is believed to cover the needs of all healthy individuals
indications. in the groups, but lack of data or uncertainty in the data prevents being
able to specify with confidence the percentage of individuals covered by
this intake
Nutrients That Influence Neurodevelopment
Recommended dietary allowances (RDA), in bold type, and adequate
During pregnancy, macro- and micronutrient requirements in- intake (AI), in italic type.
crease. Adequate nutritional diet is a key to avoid adverse
Age Iron (mg/d) Iodine (μg/d) Zinc (mg/d)
health consequences for the developing fetus. The 2014
Italian RDA, specifically, indicate an additional requirement Infant 0–6 months 0.27 70–110 2
of 69 kcal/d for the first trimester, 266 kcal/day for the second 6–12 months 11 70–130 3
trimester, and 496 kcal/day in the third trimester of pregnancy Toddler–Adolescent
(for a grand total of an additional 76,530 kcal). Very similar 1–3 years 8 100 5
amounts have been established by the EFSA (70 kcal/day in 4–6 years 11 100 6
the first trimester to 260 and 500 kcal/day in the second and 7–10 years 13 100 8
third trimesters, respectively), with an increase of about ♂ 11–14 years 10 130 12
500 kcal/day during the first 6 months of exclusive 15–17 years 13 130 12
breastfeeding [31]. A comprehensive review of macronutri- ♀ 11–14 years 18 130 9
ents requirements is beyond the scope of this article. The fol- 15–17 years 18 130 9
lowing sections will focus on the most common micronutrient Adult
deficiencies. In Table 1, the estimated average requirements
♂ > 18 years 10 150 12
for the most common micronutrients are listed [32, 33].
♀ 18–29 years 18 150 9
30–59 years 18 150 9
> 60 years 10 150 9
Iron
Pregnancy 27 200 11
Breastfeeding 11 200 12
Iron is an essential micronutrient involved in many biological
processes, including neurodevelopment. It is necessary for
normal anatomic brain development [34–36], myelination,
and neurotransmission [37]. Iron deficiency is the most com- the supplementation between the 12th and 36th months of life
mon micronutrient deficiency worldwide. Approximately 2 did not confer additional benefits on general neurointellectual
billion people around the world are estimated to suffer from functioning [42] nor cause a neurocognitive catch-up growth
this condition, roughly half of the preschool-aged children and in those children who were not supplemented during gestation
pregnant women [38]. While during adolescence this condi- [43]. A Vietnamese study demonstrated that preconception
tion is frequently reversible without consequences, early life supplementation with iron and folic acid, compared with ex-
iron deficiency can lead to long-lasting and potentially perma- clusively folic acid supplementation, improved linear growth
nent effects, resulting in later life neurocognitive and behav- and fine motor development at 2 years of age [44]. A Chinese
ioral disorders [39]. Many animal and human studies demon- study proved that infants who received iron supplementation
strated a crucial role of iron in brain development [37]. in infancy (between 6 weeks and 9 months) exhibited better
Overall, it is well accepted that prevention of iron deficiency gross motor scores at 9 months than children who did not
is preferable to treatment [40]. A set of randomized clinical receive iron [45]. In addition, infants born iron-deficient ex-
trials conducted in Nepal demonstrated the known positive hibited slower recognition of their mothers’ voice at 2 months
effect of prenatal iron to support hippocampal and striatum of age, as measured by event-related potentials, than children
development. School-aged children whose mothers were sup- born iron-sufficient. This is in line with the effect of iron
plemented with iron/folic acid during gestation and early neo- deficiency on hippocampal development [46]. Formerly,
natal life had better neurocognitive performances (working iron-deficient infants were demonstrated to have significant
memory, inhibitory control, and fine motor functioning) than slower reaction times and poorer inhibitory control 8 to 9 years
those born from not supplemented mothers [41]. Furthermore, after supplementation [47], as well as different patterns of
Curr Nutr Rep

functional brain connectivity [48]. A 10-year follow-up involved directly and indirectly in essentially all key
Chilean study verified that mistimed or excessive iron might neurodevelopmental processes [60, 61]. Both neurons and gli-
lead to worse neurodevelopmental outcomes at 10 years [49]. al cells (astrocytes and oligodendrocytes) are greatly provided
In another trial conducted in Nepal, it was found that delayed with thyroid hormone receptors. A recent review from Velasco
cord clamping (≥ 180 s after delivery) reduces anemia at 8 and et al. masterfully enumerates trials, meta-analyses, and re-
12 months of age in a high-risk population, which may have views that demonstrate which brain areas are affected by io-
major positive effects on infants’ health and development dine deficiency and the cognitive and neurodevelopmental
[50]. Longitudinal cohort studies showed that infants who consequences [62••]. In the last two decades, increasing evi-
experienced iron deficiency were more likely to experience dence has proved that adverse neurological outcomes are
cognitive and socioemotional impairments throughout infan- linked not only to maternal hypothyroidism but also to a con-
cy, childhood, and adolescence, with slower perceptual speed, dition known as hypothyroxinemia [63]. This is defined as the
poorer understanding of quantitative concepts, poorer spatial presence of a free thyroxine value below the 2.5th percentile
memory [51], impaired language abilities [52], and worse rec- with a thyrotropin level within the reference range.
ognition memory [53]. Furthermore, at 25 years, a higher pro- Hypothyroxinemia is not related to rural-insufficient iodine
portion of the group with chronic iron deficiency did not com- intake areas; evidence has showed that it exists even in
plete secondary school, were single, and reported poorer men- iodine-sufficient regions [64–66]. The phenotypes related to
tal health and more negative emotions [54]. Moreover, in ret- iodine deficiency have evolved from goiter and severe mental
rospective population-based cohorts, an association was found disability to a new clinical spectrum of neuropsychological
between maternal iron deficiency and risk of schizophrenia disorders associated with maternal hypothyroxinemia. In bi-
spectrum disorders among offspring [55], as well as an asso- opsies performed in experimental rodents, gestational thyroid
ciation between low iron intake and increased risk of autism hormone deficiency was found to cause dendritic and axonal
spectrum disorders [56]. Collectively, these studies confirm growth limitation, neural abnormal location, synaptic function
the timing-dose-duration principles previously explained alteration, hystogenesis, and cerebral cortex cytoarchitecture
[30••]. In addition, they are consistent with the long-term con- alteration. As such hypothyroxinemia causes disrupted neo-
sequences of early iron deficiency on neurodevelopmental cortical layering [67, 68]. Cognitive deficits and poor psycho-
processes and on neuropsychiatric susceptibility to diseases. motor development in the progeny of mothers who were
Lastly, new insights have been provided into the mechanisms hypothyroxinemic during the first half of gestation have been
through which iron deficiency could affect neurocognitive shown [67]. In two observational studies conducted in the UK
performance. Among these, epigenetics seems to play a role. and Australia, it was found that children of mothers with UIC
In a study performed on pigs, even though the sample size was < 150 μg/g creatinine were more likely to score within the
relatively low, it was demonstrated that neonatal iron deficien- lowest quartile on verbal IQ, reading accuracy, and reading
cy led to altered hippocampal DNA methylation and gene comprehension at age 8–9 years [69] and had lower educa-
regulation, potentially leading to effects on neurodevelopment tional outcomes at age 9 years [65]. These findings were con-
mediated by increased hypoxia-induced angiogenesis and in- firmed in a population-based prospective cohort of earlier chil-
creased blood-brain barrier permeability [57]. Another study, dren, where a UIC below ~ 100 μg/L was associated with
conducted on mice, showed that chronic iron deficiency dur- lower infant language skills up to 18 months [70]. A prospec-
ing development alters the adult hippocampal transcriptomes tive study from the Netherlands reported that low maternal
and that restoring iron status during a known critical period of UIC during pregnancy (< 10th percentile) was associated with
hippocampal neurodevelopment incompletely normalized impaired executive function in children at age 4 years [71]. A
these changes [21•]. Further detailed studies need to be de- large Norwegian population-based prospective observational
signed to better understand the implication of such biological study concluded that a suboptimal maternal iodine intake (be-
process. low the estimated average requirement of 160 μg/day) during
pregnancy was associated with symptoms of child language
delay, behavior problems, and reduced fine motor skills at
Iodine 3 years of age. Surprisingly, no beneficial effect was associat-
ed with iodine supplementation during pregnancy [66]. A re-
Gestation involves significant changes in maternal thyroid cent RCT in India and Thailand found no benefit of iodine
function. Even though fetal thyroid starts to produce hor- supplementation on 5–6-years child cognition born to mothers
mones around the 18th–20th weeks of gestation, the major with mild-to-moderate deficiency; however, it should be ob-
supply of thyroxine remains the mother. Since the first epide- served that the Indian women recruited were actually iodine-
miological studies, the association between severe iodine de- sufficient and that both countries adhere to iodized salt pro-
ficiency in pregnant women and fetal neurological damage grams [72]. In the last years, some evidence emerged, though
has been demonstrated [58, 59]. Thyroidal hormones are not consistent, that offspring of mothers with abnormal serum
 Curr Nutr Rep

thyroid hormone concentrations during early pregnancy might domains assessed [81]. A DB-RCT was conducted on
present an increased risk of attentional problems, such as at- Peruvian infants aged 6–18 months in order to determine the
tention-deficit/hyperactivity disorder (ADHD). A Norwegian effects of prevention of zinc deficiency on cognitive and sen-
study found that a low iodine intake (< 200 g/L) was associ- sorimotor development during infancy. A set of assessments
ated with increased child ADHD symptom scores, but not measured the cognitive development (attention, memory, and
with ADHD diagnosis. Iodine supplementation did not reduce learning) and the developmental status, finding zinc to be
the risk [73]. Additionally, Román et al. [74] found a consis- supportive in sustaining normative neurodevelopment in the
tent association between severe, early gestation, maternal first 2 years of life [82]. Intriguingly, among individuals with
hypothyroxinemia and autistic symptoms in offspring. The autism spectrum disorders, the incidence rate of zinc deficien-
possibility of preventive interventions must be further cy in very young age has been reported to be significantly
investigated. increased compared with age-matched healthy control sub-
jects [83, 84]. In addition, two small case-control studies
showed a correlation between low levels of zinc and atten-
Zinc tion-deficit/hyperactivity disorder [85]. Further studies are
needed to clarify good interventions in terms of
Zinc is an essential trace mineral for all forms of life because neurocognitive outcomes.
of its universal role in keeping cells operating. Inadequate zinc
intake is common, especially in individuals and population
whose regular diets do not include readily bioavailable zinc Conclusions
sources or are overreliant on cereals (rich with zinc inhibitors)
[75]. Gestation and older infancy constitute periods of in- The studies reviewed here suggest that early life environment,
creased risk of zinc deficiency. Many preclinical studies dem- particularly the fetal and early postnatal environment, influ-
onstrated its key role in neurodevelopmental processes (such ences later life health outcomes and disease risks across mul-
as neurogenesis, neuronal migration, synaptic genesis, and tiple organ systems. Among all the environmental factors,
myelination) and modulation of intra- and intercellular signal- nutrition plays a fundamental role. From conception to ap-
ing (GABAergic neurons) [75, 76]. While it has been well proximately 3 years of age, the basis for lifespan brain func-
established that severe deficiencies cause serious brain struc- tions is established. Children adequately nourished are more
tural malformations [77], less is known about mild-to- likely to reach their developmental potential in cognitive, mo-
moderate deficiency affecting sensorimotor and cognitive de- tor, and socioemotional abilities, with positive societal reper-
velopment. An Indian DB-RCT showed that zinc supplemen- cussions. The restricted development of these skills during
tation till 3-month corrected age in preterm breastfed infants early life increases the risk for later neuropsychological prob-
significantly improves alertness and attention patterns; it de- lems, psychiatric illnesses, poor school achievement, early
creases signs of hyperexcitability and abnormal patellar and school dropout, low-skilled employment, and poor care of
bicipital reflexes [78]. Among 8–18-month infant adoptees future children, thus contributing to the intergenerational
coming from three global regions (post-Soviet states, transmission of poverty.
Ethiopia, and China), zinc deficiency was the second most Epigenetics seems to play a leading role, explaining, at
common micronutrient deficiency and was associated with least in part, how early life stimuli can have these long-term
compromised memory functioning [79]. In 2002, a study in- consequences. Despite recent advances in technologies, our
vestigated the effects of iron-folic acid and/or zinc supplemen- knowledge regarding nutritional epigenetics is still limited.
tation on the results of the Fagan Test of Infant Intelligence Further studies are needed to better understand the use of
and the A-not-B task of executive functioning among 367 nutrition for maintaining health and preventing diseases
Nepali infants living in Sarlahi District. Neither the combined through modifiable epigenetic mechanisms.
nor the individual micronutrient supplements improved the In order to draw more evidence-based, relevant, and ready-
performance five indicators of information processing [80]. to-use conclusions on nutrition, data collection and research
A recent double-blind trial conducted in Tanzania randomized must be conducted more regularly and more rigorously, with a
infants at 6 weeks of age to zinc, multivitamins, zinc and higher focus on national and regional idiosyncrasies.
multivitamins, or placebo. At approximately 15 months, a Disaggregation of data based on wealth, age, gender, disabil-
subsample of children underwent developmental assessment ities, and geography could lead to the establishment of more
using the cognitive, language (receptive and expressive), and specific standards for diagnosis, treatment, and prevention of
motor (fine and gross) scales of the Bayley Scales of Infant all forms of malnutrition. Being more aware of how nutritional
and Toddler Development Third Edition. Neither daily zinc status might vary within households even in the same region
nor multivitamin (vitamins B-complex, C, and E) supplemen- could support drawing policies to tackle long-term conse-
tation led to improvements in any of the developmental quences of early life malnutrition.
Curr Nutr Rep

Strategies of prevention should focus on ensuring more outcomes in developing countries. Lancet. 2007;369:145–57.
https://doi.org/10.1016/S0140-6736(07)60076-2.
quality food to preconceptional, pregnant, lactating women
11. Stiles J, Jernigan TL. The basics of brain development.
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Lastly, although it is premature to propose diet as therapy 12. Silbereis JC, Pochareddy S, Zhu Y, Li M, Sestan N. The cellular and
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for mental illnesses and more studies are needed to deepen our
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Conflict of Interest Davide Mattei and Angelo Pietrobelli declare that teristics and causal interpretations. Psychol Bull. 1989;105:179–97.
they have no conflict of interest. 15. Colombo J. The critical period concept: research, methodology, and
theoretical issues. Psychol Bull. 1982;91:260–75.
Human and Animal Rights and Informed Consent This article does not 16.•• Cusick SE, Georgieff MK. The role of nutrition in brain develop-
contain any studies with human or animal subjects performed by any of ment: the golden opportunity of the “first 1000 days”. J Pediatr.
the authors. 2016;175:16–21. https://doi.org/10.1016/j.jpeds.2016.05.013 This
is an excellent review about recent evidence on nutrition effects
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