Nutrition and the developing brain: nutrient priorities and

measurement13
Michael K Georgieff

KEY WORDS
onate, fetus

Nutrition, brain, development, assessment, ne-

GENERAL PRINCIPLES OF NUTRIENT EFFECTS ON

THE DEVELOPING BRAIN

Nutrients and growth factors regulate brain development during fetal and early postnatal life. The developing brain between
24 and 42 wk of gestation is particularly vulnerable to nutritional
insults because of the rapid trajectory of several neurologic processes, including synapse formation and myelination (for more
extensive reviews, see references 15). Conversely, the young
brain is remarkably plastic and therefore more amenable to repair
after nutrient repletion. On balance, the brains vulnerability to
nutritional insults likely outweighs its plasticity, which explains
why early nutritional insults result in brain dysfunction not only
while the nutrient is in deficit, but also after repletion.

614S

All nutrients are important for neuronal cell growth and

development, but some appear to have greater effects during
the late fetal and neonatal time periods. These include protein,
iron, zinc, selenium, iodine, folate, vitamin A, choline, and
long-chain polyunsaturated fatty acids (13). The effect of
nutrient deficiency or supplementation on the developing
brain is a function of the brains requirement for a nutrient in
specific metabolic pathways and structural components. The
effects are regionally distributed within the brain on the basis
of which areas are rapidly developing at any given time (4).
During late fetal and early neonatal life, regions such as the
hippocampus, the visual and auditory cortices, and the striatum are undergoing rapid development characterized by the
morphogenesis and synaptogenesis that make them functional
(5, 6). The hippocampus that subserves recognition memory
behavior is one of the earliest areas to show cortical-cortical
connectivity and functionality. Furthermore, brain-wide processes such as myelination accelerate during late fetal and
early neonatal life and are vulnerable to deficits of nutrients
that support them. A nutrient that promotes normal brain
development at one time may be toxic at another point in
development. Similarly, a nutrient that promotes normal brain
development at one concentration may be toxic at another.
Several nutrients, including iron, are regulated within a relatively narrow range, where either an excess or a deficiency
induces abnormal brain development. Others have wider
ranges of tolerance.
Nutrients are necessary not only for neurons but also for supporting glial cells. For any given region, early nutritional insults
have a greater effect on cell proliferation, thereby affecting cell
number (7, 8). Later nutritional insults affect differentiation,
including size, complexity, and in the case of neurons, synaptogenesis and dendritic arborization. Microarray analysis of
genomic transcripts from various brain regions in the developing
rat shows an important breakpoint at approximately postnatal
day 7, before which proliferation genes are predominantly expressed (8). After this time point, genes that control differentiation are preferentially expressed. Postnatal day 7 in the rat brain
is roughly equivalent to a late-gestation human fetal brain.
1

From the Department of Pediatrics and Child Development, University

of Minnesota School of Medicine, Minneapolis, MN.
2
Presented at the conference Maternal Nutrition and Optimal Infant
Feeding Practices, held in Houston, TX, February 2324, 2006.
3
Address reprint requests to MK Georgieff, MMC 39, D-136 Mayo Building, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail:
georg001@umn.edu.

Am J Clin Nutr 2007;85(suppl):614S20S. Printed in USA. 2007 American Society for Nutrition

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ABSTRACT
Nutrients and growth factors regulate brain development during fetal
and early postnatal life. The rapidly developing brain is more vulnerable to nutrient insufficiency yet also demonstrates its greatest
degree of plasticity. Certain nutrients have greater effects on brain
development than do others. These include protein, energy, certain
fats, iron, zinc, copper, iodine, selenium, vitamin A, choline, and
folate. The effect of any nutrient deficiency or overabundance on
brain development will be governed by the principle of timing, dose,
and duration. The ability to detect the specific effects of nutrient
deficiencies is dependent on knowing which area of the brain is
preferentially affected and on having neurologic assessments that
tap into the functions of those specific areas. As examples, proteinenergy malnutrition causes both global deficits, which are testable
by general developmental testing, and area-specific effects on the
hippocampus and the cortex. Iron deficiency alters myelination,
monoamine neurotransmitter synthesis, and hippocampal energy
metabolism in the neonatal period. Assessments of these effects
could include tests for speed of processing (myelination), changes in
motor and affect (monoamines), and recognition memory (hippocampus). Zinc deficiency alters autonomic nervous system regulation and hippocampal and cerebellar development. Long-chain
polyunsaturated fatty acids are important for synaptogenesis, membrane function, and, potentially, myelination. Overall, circuitspecific behavioral and neuroimaging tests are being developed for
use in progressively younger infants to more accurately assess the
effect of nutrient deficits both while the subject is deficient and after
recovery from the deficiency.
Am J Clin Nutr 2007;85(suppl):
614S20S.

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NUTRITION AND THE DEVELOPING BRAIN

Nutrients can affect not only neuroanatomy, but also neurochemistry and neurophysiology. Neurochemical alterations include changes in neurotransmitter synthesis, receptor synthesis,
and neurotransmitter reuptake mechanisms (9, 10). Neurophysiologic changes reflect changes in metabolism and signal propagation. The changes across all 3 venues ultimately result in
altered neuronal performance at the time that the nutrient status
is altered. Long-term changes in form and function can occur if
the altered nutrient state changes the trajectory of brain development in a substantive anatomical or neurochemical way, beyond the period where repair can occur.

BRAIN DEVELOPMENT BETWEEN 24 AND 44 WK

AFTER CONCEPTION

NUTRIENTS AND PERINATAL BRAIN CIRCUITRY

As mentioned above, all nutrients are important for brain development, but some appear to have a particularly large effect on
developing brain circuits during the last trimester and early neonatal period (Table 1). The importance of these nutrients has
been established primarily through nutrient deficit studies and
through knowledge of their role in the specific biochemical pathways that underlie neuronal and glial growth and function. A
complete consideration of all nutrient effects on brain development is beyond the scope of this article, but the subject has been
reviewed elsewhere (1 4). Nevertheless, certain nutrients are
commonly deficient in preterm and growth-retarded infants, and
their effects on the developing brain in animals and humans are
presented below.
Protein-energy malnutrition
Protein-energy malnutrition in fetal and early neonatal animal
models reduces neuronal DNA and RNA content and alters the
fatty acid profile (7, 13). Neuropathologically, this results in
lower neuronal number, reduced protein synthesis, and hypomyelination. Brain size is reduced through all of these mechanisms
as the result of changes in structural proteins, growth factor
concentrations, and neurotransmitter production. Ultrastructural
changes include reductions in synapse number and dendritic

Nutrient

Brain requirement for the

nutrient

Protein-energy Cell proliferation, cell

differentiation
Synaptogenesis
Growth factor synthesis
Iron
Myelin
Monoamine synthesis
Neuronal and glial energy
metabolism
Zinc
DNA synthesis
Neurotransmitter release
Copper
Neurotransmitter synthesis,
neuronal and glial energy
metabolism, antioxidant
activity
LC-PUFAs
Synaptogenesis
Myelin
Choline
Neurotransmitter synthesis
DNA methylation
Myelin synthesis
1

Predominant brain circuitry

or process affected by
deficiency
Global
Cortex
Hippocampus
White matter
Striatal-frontal
Hippocampal-frontal
Autonomic nervous system
Hippocampus, cerebellum
Cerebellum

Eye
Cortex
Global
Hippocampus
White matter

LC-PUFAs, long-chain polyunsaturated fatty acids.

arbor complexity (14 19). The cortex and hippocampus appear

to be particularly vulnerable to protein-energy malnutrition (20).
Protein-energy malnutrition in humans between 24 and 44 wk
postconception can occur either in utero or ex utero. Fetal
protein-energy malnutrition results in intrauterine growth retardation and is usually due to maternal hypertension or severe
malnutrition during pregnancy (21). Postnatal malnutrition is
common in sick preterm infants who are fluid restricted or who
do not tolerate high rates of nutrient delivery. Severe or prolonged intrauterine growth retardation results in poor prenatal
head growth associated with poorer developmental outcome (22,
23). In the absence of overt microcephaly, infants with intrauterine growth retardation nevertheless have a 15% rate of mild
neurodevelopmental abnormalities characterized by cognitive
(rather than motor) disabilities (24). Verbal and visual recognition memory systems appear particularly to be vulnerable, which
is consistent with structures that are rapidly developing in this
time period (25, 26).
Iron
Iron is accreted rapidly by the fetus during the last trimester
and is necessary for basic neuronal processes such as myelination, neurotransmitter production, and energy metabolism (9).
The effect of iron deficiency on the developing brain has been
assessed largely in the rat model, where variations in the timing
and severity of the deficiency have helped to elucidate the biochemical, structural, and behavioral effects. Biochemically, fetal
and neonatal iron deficiency results in reduced oxidative metabolism in the hippocampus and frontal cortex (27), elevated intracellular neuronal glutamate concentrations (10), reduced striatal dopamine concentrations (9), and altered fatty acid and
myelin profiles throughout the brain (28). Structurally, dendritic
arbors are truncated in the hippocampus (29), and global and
regional brain masses are reduced while the animals are iron
deficient and after iron repletion (30). Behaviorally, rodents have

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The human brain undergoes remarkable structural and functional changes between 24 and 44 wk after conception, progressing at the beginning of the third trimester from a smooth bilobed
structure with few gyrations or sulcations to a complex one at
term that morphologically resembles the adult brain (11). The
increase in complexity largely reflects cortical neuronal growth,
differentiation, and synaptic connections. In particular, the
auditory and visual cortices begin to develop rapidly, as do
areas underlying receptive language and higher cognitive
function (5). Myelination begins before term birth as well. Most
importantly, experience-dependent synapse formation occurs before birth and provides a neuronal basis for the fetus to learn. The
hippocampus, which is central to recognition memory processing,
has established most of its connections from the entorhinal cortex
and has begun to send projections through thalamic nuclear structures to the developing frontal cortex (12). These structures and
processes are worth considering because they (and the functions
they serve) are the ones that will be vulnerable to nutritional insults
in this time period.

TABLE 1
Important nutrients during late fetal and neonatal brain development1

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GEORGIEFF

long-term deficits in trace recognition memory (31), procedural memory (32), and spatial navigation (33) that indicate
structural and functional abnormalities in the hippocampus
and striatum.
Newborn human infants can have altered iron status as the
result of severe maternal iron deficiency anemia, intrauterine
growth retardation due to maternal hypertension, increased fetal
iron demand for erythropoiesis due to maternal diabetes mellitus,
or lack of fetal iron accretion due to premature birth (34 38). Far
fewer studies have been conducted on the neurologic consequences of perinatal iron deficiency than on classic postnatal
dietary iron deficiency. Infants with cord ferritin concentrations
in the lowest quartile have poorer neurodevelopment at school
age (39). Iron-deficient infants of diabetic mothers have impaired auditory recognition memory processing at birth (40),
whereas iron-deficient premature infants have a higher rate of
abnormal neurologic reflexes at 36 wk postconception (41).
Zinc

Copper
Copper is an essential divalent cation for proteins involved in
brain-energy metabolism, dopamine metabolism, antioxidant
activity, and iron accretion in the fetal and neonatal brain (49
52). Although nutritional copper deficiency does not appear to be
a common clinical problem in the human fetus and neonate, the
neurodevelopmental effects in the developing rodent are striking, both while the animals are copper deficient as pups and after
copper repletion. In particular, the developing cerebellum appears to be particularly at risk in models of gestational copper
deficiency with long-term effects on motor function, balance,
and coordination (53).
Long-chain polyunsaturated fatty acids
Extensive reviews of the effects of long-chain polyunsaturated
fatty acids on the developing brain have been published and will

Other nutrients
Additional nutrients that affect brain and behavior development include iodine and selenium, which mediate their effects
through thyroid hormone metabolism (59, 60); folate and choline, which mediate their effects through one-carbon metabolism, DNA methylation, and neurotransmitter synthesis (61 63);
and vitamins A and B-6. A review of their effects can be found in
reference 1.

CIRCUIT-SPECIFIC ASSESSMENT OF NUTRIENT

EFFECTS ON THE DEVELOPING BRAIN

Ideally, specific nutrient deficiencies would result in a recognizable, characteristic spectrum of neuroanatomical, neurochemical,
and neurophysiologic dysfunction in perinatal humans. Each nutrient would thus have a signature neurodevelopmental effect. Unfortunately, limitations exist that preclude the use of this concept to
generate accurate developmental outcome predictions for preterm
infants, based on neurologic assessment in the newborn period.
Preterm and term infants have limited behavioral expression of the
higher-function cortical activities that are the basis for behaviors
later assessed as intelligence. For example, they are preverbal,
which distinctly limits intellectual reasoning. Furthermore, ongoing
illness can depress brain activity and behavior. Finally, later
catch-up brain growth and the capacity for repair make predictive
assessments difficult.
Nevertheless, neurobehavioral assessments can be performed in infants at or near term that can give insight into
structure and function. Brain size can be estimated either by
occipitofrontal head circumference (assuming no hydrocephalus), computerized axial tomography (CAT), or magnetic
resonance imaging (MRI) scans. Moreover, regional brain
volumes or track size can be measured by structural MRI and
diffusion tensor imaging (DTI) (64, 65). Objective metrics of
brain electrical function can be obtained by electroencephalogram (EEG), auditory brainstem evoked response (ABR), or
event-related potentials (ERPs) (66). The advantage of ERPs
is that activity in response to cognitive stimuli and events,
such as auditory recognition memory, can be assessed (66,
67). Functioning of the hypothalamic-pituitary-adrenal axis
and the autonomic nervous system in response to stressors can
also be measured at this age (68). Finally, limited information
can be obtained from neurologic examination of the infant,
including assessment of neurologic reflexes (41).
Although these measurements are not specifically designed to
assess nutritional effects in the perinatal period, they can be used

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Fetal and neonatal zinc biology has been assessed in rodent

and primate models. Zinc is a cofactor in enzymes that mediate
protein and nucleic acid biochemistry (42). Fetal zinc deficiency
results in decreased brain DNA, RNA, and protein content (43).
Importantly, insulin-like growth factor I and growth hormone
receptor gene expression are regulated by zinc (44). Neuronally,
presynaptic boutons are dependent on adequate zinc for delivery
of neurotransmitters to the synaptic cleft (45). Structural studies
have shown truncated dendritic arbors and reduced regional
brain mass in the cerebellum, limbic system, and cerebral cortex
(45). Zinc-deficient rats have abnormal cortical electrophysiology (46). The orbitofrontal cortex appears to be particularly
vulnerable. Behaviorally, zinc-deficient rhesus monkeys have
poor short-term memory (47). These effects suggest that zinc is
particularly important for the medial temporal lobe, frontal lobe,
and cerebellar development.
Fetuses of zinc-deficient mothers show decreased fetal movement and heart rate variability, which is suggestive of altered
autonomic nervous system stability (48). Although intelligence
quotient does not seem to be affected, infants born to zincdeficient mothers have decreased preferential looking behavior,
which is indicative of altered hippocampal function.

not be reviewed here (3, 54, 55). Nevertheless, it is important to

note that these fats, particularly docosahexaenoic acid (DHA),
are potent neurobiological agents that affect neuronal membrane
structure, synaptogenesis, and myelination. Studies in preterm humans indicate important benefits for retinal and cognitive development, as indexed by improved electroretinogram activity, visual
acuity, and short-term global developmental outcome after DHA
supplementation of preterm infant formula (56, 57). The effects in
term infants are far less convincing and are substantially underpowered to draw any conclusions (58). DHA supplementation trials
should be considered formula repletion of deficit state studies,
because the fetus normally receives adequate DHA transplacentally,
and breastfed neonates receive DHA in human milk.

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NUTRITION AND THE DEVELOPING BRAIN

TABLE 2
The repertoire of neurodevelopmental assessments that can be used in
infants between 36 and 44 wk after conception and the relation to specific
nutritional deficits1
Assessment

Brain region or process

Risk nutrients

Neurologic examination

Whole brain
Whole brain, nervous system
Myelination
Whole brain, nervous system

EEG maturity

Cortex

Stimulated heart rate,

blood pressure,
salivary cortisol
responses

Autonomic nervous system

Protein-energy
Protein-energy
Iron
Protein-energy
Copper
Protein-energy
(LC-PUFAs)
Zinc (Proteinenergy)

OFC
Neurologic reflexes

ABR, ERG
Auditory ERP

HPA axis
Myelination
Synaptic efficacy
Hippocampal function

Global and regional volume

and structure

MR-DTI

Myelin and tract integrity

MR-proton
spectroscopy

Neurochemistry

1
Nutrients with unproven but likely effects based on animal models are
marked in parentheses. EEG; electroencephalogram; LC-PUFAs, long-chain
polyunsaturated fatty acids; HPA, hypothalamic-pituitary-adrenal; ABR, auditory brainstem evoked response; ERG, electroretinogram; ERP, event-related
potential; MRI, magnetic resonance imaging; DTI, diffusion tensor imaging;
OFC, occipitofrontal head circumference.

in such a manner (Table 2). It is important to note that many of

the nutrient deficits will affect similar regions and processes,
making it difficult to obtain a signature effect of any single

TABLE 3
Neurobehavioral and neuroimaging assessments that can be performed to evaluate the effects of neonatal nutrients on general brain development during
the first 6 y of postnatal life1
Neurologic domain

Risk nutrients for

domain

Global function

Protein-energy, iron,
zinc, LC-PUFAs

Myelination

Iron

Behavioral

Age of
reliability

Neuroimaging technique

Bayley Scales

1236 mo

OFC

Any age

WPPSI
Speed of
processing

4 y
4 mo

MR regional volumetrics
ABR, VEP

Newborn and 6 y
Any age

1236 mo

ERP
DTI
Regional MR

After term
Newborn and 6 y
Newborn and 6 y

Actigraph

Any age

LC-PUFAs
Motor function

Protein-energy
Iron
Copper

Bayley Scales
(PDI)
Activity
Coordination

Any age
Any age

Age of reliability

LC-PUFAs, long-chain polyunsaturated fatty acids; WPPSI, Wechsler Preschool and Primary Scale of Intelligence; MR, magnetic resonance; ABR,
auditory brainstem evoked response; VEP, visual evoked potential; ERP, event-related potential; DTI, diffusion tensor imaging; OFC, occipitofrontal head
circumference.

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MRI (structural)

Iron
LC-PUFAs
Iron (Zinc)
(Choline)
(Proteinenergy)
Protein-energy
(Iron) (Zinc)
(Copper)
Protein-energy
(Iron)
(Copper)
(Iron)

nutrient. The repertoire of assessments expands rapidly after the

neonatal period, particularly at 4 mo of age, when infant behavior
becomes more cortically dominant. By 4 6 mo of age adjusted
for prematurity, the recognition memory system can be assessed
behaviorally by the preferential looking task (69), and both the
explicit and implicit memory systems can be assessed electrophysiologically by using ERPs (70). Speed of processing,
which indexes myelination and synaptic efficacy, can be estimated from ABR and ERPs. Affect and distractiblility,
which at this age index striatal integrity and monoamine neurotransmitter function, can be assessed through direct observation and scoring (71). By the end of the first postnatal year,
more complex reasoning skills can be inferred from the subscales of the Bayley Scales of Infant Development (BSID) and
from specific testing of memory encoding, storage, and retrieval using elicited imitation (72, 73). The recent development of these region- and process-specific assessments for
at-risk newborns and young infants are welcome additions to
the repertoire that has depended on global assessments in the
past. The BSID administered at 12 mo corrected age remains
the most commonly used general assessment in many nutrient
outcome studies because it is widely available, requires little
special equipment, and is easily performed in multicenter
trials. Nevertheless, significant specific neurobehavioral
morbidities can be embedded with a normal Bayley-derived
Developmental Quotient, which can mask potentially important neurologic processing deficits.
More detailed and region-specific interrogation of the infants neurobehavioral repertoire can be conducted as postnatal age increases. The frontal lobes become more testable
by 5 y of age with use of the Cambridge Neuropsychological
Test automated battery (CANTAB), which assesses behaviors
such as strategy switching, executive function, planning,
and working memory (74). The integrity of these behaviors
may ultimately determine success in school performance (75).
By 6 y of age, children can be imaged by MRI scanning
without sedation. Functional MRI becomes a useful tool
for assessing attention, structure-function relations on

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GEORGIEFF

TABLE 4
Neurobehavioral and neuroimaging assessments that can be performed to evaluate the effects of neonatal nutrients on cognitive development during the
first 6 y of postnatal life1
Cognitive domain
Explicit-recognition
memory

Working memory

Implicit-procedural
memory

Risk nutrients
for domain

Age of
reliability

Neuroimaging technique

VPC

4 mo

ERP (auditory)

Newborn

DNMS
Elicited imitation

6 mo
12 mo

4 mo
Newborn and 6 y

Protein-energy

Elicited imitation

12 mo

ERP (visual)
MR volume
(hippocampus)
MR volume (prefrontal
cortex)

Iron

CANTAB

4 y

Iron

Priming

4 mo

fMRI
MR volume (striatum)

6 y
Newborn and 6 y

fMRI

Newborn and 6 y

Protein-energy,
iron, zinc

Behavioral
assessment

Age of reliability

Newborn and 6 y

VPC, Visual Paired Comparison (test); ERP, event-related potential; DNMS, Delay Non-Match to Sample (test); MR, magnetic resonance; CANTAB,
Cambridge Neuropsychological Test Automated Battery; fMRI, functional magnetic resonance imaging.

SUMMARY

Fetal and neonatal malnutrition can have global or circuitspecific effects on the developing brain. These effects are based
on the timing and magnitude of the nutrient deficit and on the
brains need for the particular nutrient at the time of the deficit.

It is important to recognize that nutritional effects on the developing brain include not only the provision of specific substrates,
but also the synthesis and activation of growth factors.
Although it would be attractive for each nutrient deficit to have
a signature effect on the brain that could be assessed behaviorally
or through neuroimaging, this is unlikely to occur with the currently available neuroimaging and behavioral techniques, in part
because common nutrient deficiencies in the neonate occur together and affect the same developing brain region. For example,
protein-energy, iron, and zinc malnutrition all affect the developing hippocampus. Ultimately, the attribution of short- and
long-term neurodevelopmental dysfunction to perinatal nutritional status will need to follow specific rules of developmental
neuroscience. The nutrient deficit must be present during the
developmental window when the brain requires that nutrient for
growth and function. Furthermore, the abnormal behavioral
function should be subserved by a brain region or process that is
affected by the nutrient. Usually, a multitier approach from human epidemiology to animal and cellular models will be necessary to provide reasonable scientific evidence of a cause-andeffect association.

TABLE 5
Neurobehavioral and neuroimaging assessments that can be performed to evaluate the effects of neonatal nutrients on affective development during the
first 6 y of postnatal life1
Affective domain

Risk nutrients
for domain

Attention

Iron, zinc

Reactivity (HPA/
ANS)

Iron, zinc

Social interaction

Iron, zinc

Behavioral assessment
Bayley Scales rating
CANTAB
Flanker task
Response to:
Restraint
Separation
Immunization
Spontaneous movement
Bayley Scales rating

Age of
reliability
12 mo
4 y
5 y
Newborn

Any age
12 mo

Neuroimaging technique

Age of reliability

MR volume (prefrontal cortex)

Newborn and 6 y

fMRI

6 y

Salivary cortisol
HR response
Vagal tone
fMRI

Any age
Any age
Any age
6 y

1
MR, magnetic resonance; CANTAB, Cambridge Neuropsychological Test Automated Battery; fMRI, functional magnetic resonance imaging; HPA/
ANS, hypothalamic pituitary adrenal/autonomic nervous system; HR, heart rate.

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working memory, and implicit memory tasks (76). The behavioral and neuroimaging assessments for general, cognitive, and affective neurobehavioral domains and the corresponding ages of utilization in this population between the
neonatal period and 6 y of age are summarized in Tables 3, 4
and 5.
Unfortunately, the longer the time period between the nutritional deficiency and the subsequent neurobehavioral assessment, the greater the risk that intervening confounding variables
such as postdischarge nutrition, illness, and home environment
will influence the outcome measure (77). Thus, there is a high
premium on further development of neurobehavioral assessments in close temporal proximity to the time of nutritional insult
in the neonatal period. Potential new methods that may be useful
include near infrared spectroscopy (NIRS) and magnetoencephalography (MEG) (78, 79).

NUTRITION AND THE DEVELOPING BRAIN

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