Nutrition and the developing brain: nutrient priorities andmeasurement13

Michael K GeorgieffABSTRACTNutrients and growth factors regulate brain development during fetaland early postnatal life. The rapidly developing brain is more vul-nerable to nutrient insufficiency yet also demonstrates its greatestdegree of plasticity. Certain nutrients have greater effects on braindevelopment than do others. These include protein, energy, certainfats, iron, zinc, copper, iodine, selenium, vitamin A, choline, andfolate. The effect of any nutrient deficiency or overabundance onbrain development will be governed by the principle of timing, dose,and duration. The ability to detect the specific effects of nutrientdeficiencies is dependent on knowing which area of the brain ispreferentially affected and on having neurologic assessments thattap into the functions of those specific areas. As examples, protein-energy malnutrition causes both global deficits, which are testableby general developmental testing, and area-specific effects on thehippocampus and the cortex. Iron deficiency alters myelination,monoamine neurotransmitter synthesis, and hippocampal energymetabolism in the neonatal period. Assessments of these effectscould include tests for speed of processing (myelination), changes inmotor and affect (monoamines), and recognition memory (hip-pocampus). Zinc deficiency alters autonomic nervous system regu-lation and hippocampal and cerebellar development. Long-chainpolyunsaturated fatty acids are important for synaptogenesis, mem-brane function, and, potentially, myelination. Overall, circuit-specific behavioral and neuroimaging tests are being developed foruse in progressively younger infants to more accurately assess theeffect of nutrient deficits both while the subject is deficient and afterrecovery from the deficiency. Am J Clin Nutr 2007;85(suppl):614S20S.

KEY WORDS Nutrition, brain, development, assessment, ne-onate, fetus

GENERAL PRINCIPLES OF NUTRIENT EFFECTS ONTHE DEVELOPING BRAIN

Nutrients and growth factors regulate brain development dur-ing fetal and early postnatal life. The developing brain between24 and 42 wk of gestation is particularly vulnerable to nutritionalinsults because of the rapid trajectory of several neurologic pro-cesses, including synapse formation and myelination (for moreextensive reviews, see references 15). Conversely, the youngbrain is remarkably plastic and therefore more amenable to repairafter nutrient repletion. On balance, the brains vulnerability tonutritional insults likely outweighs its plasticity, which explainswhy early nutritional insults result in brain dysfunction not onlywhile the nutrient is in deficit, but also after repletion.

All nutrients are important for neuronal cell growth anddevelopment, but some appear to have greater effects duringthe late fetal and neonatal time periods. These include protein,iron, zinc, selenium, iodine, folate, vitamin A, choline, andlong-chain polyunsaturated fatty acids (13). The effect ofnutrient deficiency or supplementation on the developingbrain is a function of the brains requirement for a nutrient inspecific metabolic pathways and structural components. Theeffects are regionally distributed within the brain on the basisof which areas are rapidly developing at any given time (4).During late fetal and early neonatal life, regions such as thehippocampus, the visual and auditory cortices, and the stria-tum are undergoing rapid development characterized by themorphogenesis and synaptogenesis that make them functional(5, 6). The hippocampus that subserves recognition memorybehavior is one of the earliest areas to show cortical-corticalconnectivity and functionality. Furthermore, brain-wide pro-cesses such as myelination accelerate during late fetal andearly neonatal life and are vulnerable to deficits of nutrientsthat support them. A nutrient that promotes normal braindevelopment at one time may be toxic at another point indevelopment. Similarly, a nutrient that promotes normal braindevelopment at one concentration may be toxic at another.Several nutrients, including iron, are regulated within a rela-tively narrow range, where either an excess or a deficiencyinduces abnormal brain development. Others have widerranges of tolerance.

Nutrients are necessary not only for neurons but also for sup-porting glial cells. For any given region, early nutritional insultshave a greater effect on cell proliferation, thereby affecting cellnumber (7, 8). Later nutritional insults affect differentiation,including size, complexity, and in the case of neurons, synapto-genesis and dendritic arborization. Microarray analysis ofgenomic transcripts from various brain regions in the developingrat shows an important breakpoint at approximately postnatalday 7, before which proliferation genes are predominantly ex-pressed (8). After this time point, genes that control differentia-tion are preferentially expressed. Postnatal day 7 in the rat brainis roughly equivalent to a late-gestation human fetal brain.

1 From the Department of Pediatrics and Child Development, Universityof Minnesota School of Medicine, Minneapolis, MN.

2 Presented at the conference Maternal Nutrition and Optimal InfantFeeding Practices, held in Houston, TX, February 2324, 2006.

3 Address reprint requests to MK Georgieff, MMC 39, D-136 Mayo Build-ing, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail:georg001@umn.edu.

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Nutrients can affect not only neuroanatomy, but also neuro-chemistry and neurophysiology. Neurochemical alterations in-clude changes in neurotransmitter synthesis, receptor synthesis,and neurotransmitter reuptake mechanisms (9, 10). Neurophys-iologic changes reflect changes in metabolism and signal prop-agation. The changes across all 3 venues ultimately result inaltered neuronal performance at the time that the nutrient statusis altered. Long-term changes in form and function can occur ifthe altered nutrient state changes the trajectory of brain devel-opment in a substantive anatomical or neurochemical way, be-yond the period where repair can occur.

BRAIN DEVELOPMENT BETWEEN 24 AND 44 WKAFTER CONCEPTION

The human brain undergoes remarkable structural and func-tional changes between 24 and 44 wk after conception, progress-ing at the beginning of the third trimester from a smooth bilobedstructure with few gyrations or sulcations to a complex one atterm that morphologically resembles the adult brain (11). Theincrease in complexity largely reflects cortical neuronal growth,differentiation, and synaptic connections. In particular, theauditory and visual cortices begin to develop rapidly, as doareas underlying receptive language and higher cognitivefunction (5). Myelination begins before term birth as well. Mostimportantly, experience-dependent synapse formation occurs be-fore birth and provides a neuronal basis for the fetus to learn. Thehippocampus, which is central to recognition memory processing,has established most of its connections from the entorhinal cortexand has begun to send projections through thalamic nuclear struc-tures to the developing frontal cortex (12). These structures andprocesses are worth considering because they (and the functionsthey serve) are the ones that will be vulnerable to nutritional insultsin this time period.

NUTRIENTS AND PERINATAL BRAIN CIRCUITRYAs mentioned above, all nutrients are important for brain de-

velopment, but some appear to have a particularly large effect ondeveloping brain circuits during the last trimester and early neo-natal period (Table 1). The importance of these nutrients hasbeen established primarily through nutrient deficit studies andthrough knowledge of their role in the specific biochemical path-ways that underlie neuronal and glial growth and function. Acomplete consideration of all nutrient effects on brain develop-ment is beyond the scope of this article, but the subject has beenreviewed elsewhere (14). Nevertheless, certain nutrients arecommonly deficient in preterm and growth-retarded infants, andtheir effects on the developing brain in animals and humans arepresented below.

Protein-energy malnutritionProtein-energy malnutrition in fetal and early neonatal animal

models reduces neuronal DNA and RNA content and alters thefatty acid profile (7, 13). Neuropathologically, this results inlower neuronal number, reduced protein synthesis, and hypomy-elination. Brain size is reduced through all of these mechanismsas the result of changes in structural proteins, growth factorconcentrations, and neurotransmitter production. Ultrastructuralchanges include reductions in synapse number and dendritic

arbor complexity (1419). The cortex and hippocampus appearto be particularly vulnerable to protein-energy malnutrition (20).

Protein-energy malnutrition in humans between 24 and 44 wkpostconception can occur either in utero or ex utero. Fetalprotein-energy malnutrition results in intrauterine growth retar-dation and is usually due to maternal hypertension or severemalnutrition during pregnancy (21). Postnatal malnutrition iscommon in sick preterm infants who are fluid restricted or whodo not tolerate high rates of nutrient delivery. Severe or pro-longed intrauterine growth retardation results in poor prenatalhead growth associated with poorer developmental outcome (22,23). In the absence of overt microcephaly, infants with intrauter-ine growth retardation nevertheless have a 15% rate of mildneurodevelopmental abnormalities characterized by cognitive(rather than motor) disabilities (24). Verbal and visual recogni-tion memory systems appear particularly to be vulnerable, whichis consistent with structures that are rapidly developing in thistime period (25, 26).Iron

Iron is accreted rapidly by the fetus during the last trimesterand is necessary for basic neuronal processes such as myelina-tion, neurotransmitter production, and energy metabolism (9).The effect of iron deficiency on the developing brain has beenassessed largely in the rat model, where variations in the timingand severity of the deficiency have helped to elucidate the bio-chemical, structural, and behavioral effects. Biochemically, fetaland neonatal iron deficiency results in reduced oxidative metab-olism in the hippocampus and frontal cortex (27), elevated in-tracellular neuronal glutamate concentrations (10), reduced stri-atal dopamine concentrations (9), and altered fatty acid andmyelin profiles throughout the brain (28). Structurally, dendriticarbors are truncated in the hippocampus (29), and global andregional brain masses are reduced while the animals are irondeficient and after iron repletion (30). Behaviorally, rodents have

TABLE 1Important nutrients during late fetal and neonatal brain development1

NutrientBrain requirement for the

nutrient

Predominant brain circuitryor process affected by

deficiency

Protein-energy Cell proliferation, celldifferentiation

Global

Synaptogenesis CortexGrowth factor synthesis Hippocampus

Iron Myelin White matterMonoamine synthesis Striatal-frontalNeuronal and glial energy

metabolismHippocampal-frontal

Zinc DNA synthesis Autonomic nervous systemNeurotransmitter release Hippocampus, cerebellum

Copper Neurotransmitter synthesis,neuronal and glial energymetabolism, antioxidantactivity

Cerebellum

LC-PUFAs Synaptogenesis EyeMyelin Cortex

Choline Neurotransmitter synthesis GlobalDNA methylation HippocampusMyelin synthesis White matter

1 LC-PUFAs, long-chain polyunsaturated fatty acids.

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long-term deficits in trace recognition memory (31), proce-dural memory (32), and spatial navigation (33) that indicatestructural and functional abnormalities in the hippocampusand striatum.

Newborn human infants can have altered iron status as theresult of severe maternal iron deficiency anemia, intrauterinegrowth retardation due to maternal hypertension, increased fetaliron demand for erythropoiesis due to maternal diabetes mellitus,or lack of fetal iron accretion due to premature birth (3438). Farfewer studies have been conducted on the neurologic conse-quences of perinatal iron deficiency than on classic postnataldietary iron deficiency. Infants with cord ferritin concentrationsin the lowest quartile have poorer neurodevelopment at schoolage (39). Iron-deficient infants of diabetic mothers have im-paired auditory recognition memory processing at birth (40),whereas iron-deficient premature infants have a higher rate ofabnormal neurologic reflexes at 36 wk postconception (41).

ZincFetal and neonatal zinc biology has been assessed in rodent

and primate models. Zinc is a cofactor in enzymes that mediateprotein and nucleic acid biochemistry (42). Fetal zinc deficiencyresults in decreased brain DNA, RNA, and protein content (43).Importantly, insulin-like growth factor I and growth hormonereceptor gene expression are regulated by zinc (44). Neuronally,presynaptic boutons are dependent on adequate zinc for deliveryof neurotransmitters to the synaptic cleft (45). Structural studieshave shown truncated dendritic arbors and reduced regionalbrain mass in the cerebellum, limbic system, and cerebral cortex(45). Zinc-deficient rats have abnormal cortical electrophysiol-ogy (46). The orbitofrontal cortex appears to be particularlyvulnerable. Behaviorally, zinc-deficient rhesus monkeys havepoor short-term memory (47). These effects suggest that zinc isparticularly important for the medial temporal lobe, frontal lobe,and cerebellar development.

Fetuses of zinc-deficient mothers show decreased fetal move-ment and heart rate variability, which is suggestive of alteredautonomic nervous system stability (48). Although intelligencequotient does not seem to be affected, infants born to zinc-deficient mothers have decreased preferential looking behavior,which is indicative of altered hippocampal function.

CopperCopper is an essential divalent cation for proteins involved in

brain-energy metabolism, dopamine metabolism, antioxidantactivity, and iron accretion in the fetal and neonatal brain (4952). Although nutritional copper deficiency does not appear to bea common clinical problem in the human fetus and neonate, theneurodevelopmental effects in the developing rodent are strik-ing, both while the animals are copper deficient as pups and aftercopper repletion. In particular, the developing cerebellum ap-pears to be particularly at risk in models of gestational copperdeficiency with long-term effects on motor function, balance,and coordination (53).

Long-chain polyunsaturated fatty acidsExtensive reviews of the effects of long-chain polyunsaturated

fatty acids on the developing brain have been published and will

not be reviewed here (3, 54, 55). Nevertheless, it is important tonote that these fats, particularly docosahexaenoic acid (DHA),are potent neurobiological agents that affect neuronal membranestructure, synaptogenesis, and myelination. Studies in preterm hu-mans indicate important benefits for retinal and cognitive develop-ment, as indexed by improved electroretinogram activity, visualacuity, and short-term global developmental outcome after DHAsupplementation of preterm infant formula (56, 57). The effects interm infants are far less convincing and are substantially underpow-ered to draw any conclusions (58). DHA supplementation trialsshould be considered formula repletion of deficit state studies,because thefetusnormallyreceivesadequateDHAtransplacentally,and breastfed neonates receive DHA in human milk.

Other nutrientsAdditional nutrients that affect brain and behavior develop-

ment include iodine and selenium, which mediate their effectsthrough thyroid hormone metabolism (59, 60); folate and cho-line, which mediate their effects through one-carbon metabo-lism, DNA methylation, and neurotransmitter synthesis (6163);and vitamins A and B-6. A review of their effects can be found inreference 1.

CIRCUIT-SPECIFIC ASSESSMENT OF NUTRIENTEFFECTS ON THE DEVELOPING BRAIN

Ideally, specific nutrient deficiencies would result in a recogniz-able, characteristic spectrum of neuroanatomical, neurochemical,and neurophysiologic dysfunction in perinatal humans. Each nutri-ent would thus have a signature neurodevelopmental effect. Un-fortunately, limitations exist that preclude the use of this concept togenerate accurate developmental outcome predictions for preterminfants, based on neurologic assessment in the newborn period.Preterm and term infants have limited behavioral expression of thehigher-function cortical activities that are the basis for behaviorslater assessed as intelligence. For example, they are preverbal,which distinctly limits intellectual reasoning. Furthermore, ongoingillness can depress brain activity and behavior. Finally, latercatch-up brain growth and the capacity for repair make predictiveassessments difficult.

Nevertheless, neurobehavioral assessments can be per-formed in infants at or near term that can give insight intostructure and function. Brain size can be estimated either byoccipitofrontal head circumference (assuming no hydroceph-alus), computerized axial tomography (CAT), or magneticresonance imaging (MRI) scans. Moreover, regional brainvolumes or track size can be measured by structural MRI anddiffusion tensor imaging (DTI) (64, 65). Objective metrics ofbrain electrical function can be obtained by electroencepha-logram (EEG), auditory brainstem evoked response (ABR), orevent-related potentials (ERPs) (66). The advantage of ERPsis 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 axisand the autonomic nervous system in response to stressors canalso be measured at this age (68). Finally, limited informationcan be obtained from neurologic examination of the infant,including assessment of neurologic reflexes (41).

Although these measurements are not specifically designed toassess nutritional effects in the perinatal period, they can be used

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in such a manner (Table 2). It is important to note that many ofthe nutrient deficits will affect similar regions and processes,making it difficult to obtain a signature effect of any single

nutrient. The repertoire of assessments expands rapidly after theneonatal period, particularly at 4 mo of age, when infant behaviorbecomes more cortically dominant. By 46 mo of age adjustedfor prematurity, the recognition memory system can be assessedbehaviorally by the preferential looking task (69), and both theexplicit and implicit memory systems can be assessed electro-physiologically by using ERPs (70). Speed of processing,which indexes myelination and synaptic efficacy, can be es-timated from ABR and ERPs. Affect and distractiblility,which at this age index striatal integrity and monoamine neu-rotransmitter function, can be assessed through direct obser-vation and scoring (71). By the end of the first postnatal year,more complex reasoning skills can be inferred from the sub-scales of the Bayley Scales of Infant Development (BSID) andfrom specific testing of memory encoding, storage, and re-trieval using elicited imitation (72, 73). The recent develop-ment of these region- and process-specific assessments forat-risk newborns and young infants are welcome additions tothe repertoire that has depended on global assessments in thepast. The BSID administered at 12 mo corrected age remainsthe most commonly used general assessment in many nutrientoutcome studies because it is widely available, requires littlespecial equipment, and is easily performed in multicentertrials. Nevertheless, significant specific neurobehavioralmorbidities can be embedded with a normal Bayley-derivedDevelopmental Quotient, which can mask potentially impor-tant neurologic processing deficits.

More detailed and region-specific interrogation of the in-fants neurobehavioral repertoire can be conducted as post-natal age increases. The frontal lobes become more testableby 5 y of age with use of the Cambridge NeuropsychologicalTest automated battery (CANTAB), which assesses behaviorssuch as strategy switching, executive function, planning,and working memory (74). The integrity of these behaviorsmay ultimately determine success in school performance (75).By 6 y of age, children can be imaged by MRI scanningwithout sedation. Functional MRI becomes a useful toolfor assessing attention, structure-function relations on

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

Neurologic domainRisk nutrients for

domain BehavioralAge of

reliability Neuroimaging technique Age of reliability

Global function Protein-energy, iron,zinc, LC-PUFAs

Bayley Scales 1236 mo OFC Any age

WPPSI 4 y MR regional volumetrics Newborn and6 yMyelination Iron Speed of

processing4 mo ABR, VEP Any age

LC-PUFAs ERP After termDTI Newborn and6 y

Motor function Protein-energy Bayley Scales(PDI)

1236 mo Regional MR Newborn and6 y

Iron Activity Any age Actigraph Any ageCopper Coordination Any age

1 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 headcircumference.

TABLE 2The repertoire of neurodevelopmental assessments that can be used ininfants between 36 and 44 wk after conception and the relation to specificnutritional deficits1

Assessment Brain region or process Risk nutrients

OFC Whole brain Protein-energyNeurologic reflexes Whole brain, nervous system Protein-energy

Myelination IronNeurologic examination Whole brain, nervous system Protein-energy

CopperEEG maturity Cortex Protein-energy

(LC-PUFAs)Stimulated heart rate,

blood pressure,salivary cortisolresponses

Autonomic nervous system Zinc (Protein-energy)

HPA axisABR, ERG Myelination Iron

Synaptic efficacy LC-PUFAsAuditory ERP Hippocampal function Iron (Zinc)

(Choline)(Protein-energy)

MRI (structural) Global and regional volumeand structure

Protein-energy(Iron) (Zinc)(Copper)

MR-DTI Myelin and tract integrity Protein-energy(Iron)(Copper)

MR-protonspectroscopy

Neurochemistry (Iron)

1 Nutrients with unproven but likely effects based on animal models aremarked in parentheses. EEG; electroencephalogram; LC-PUFAs, long-chainpolyunsaturated fatty acids; HPA, hypothalamic-pituitary-adrenal; ABR, audi-tory brainstem evoked response; ERG, electroretinogram; ERP, event-relatedpotential; MRI, magnetic resonance imaging; DTI, diffusion tensor imaging;OFC, occipitofrontal head circumference.

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working memory, and implicit memory tasks (76). The be-havioral and neuroimaging assessments for general, cogni-tive, and affective neurobehavioral domains and the corre-sponding ages of utilization in this population between theneonatal period and 6 y of age are summarized in Tables 3, 4and 5.

Unfortunately, the longer the time period between the nutri-tional deficiency and the subsequent neurobehavioral assess-ment, the greater the risk that intervening confounding variablessuch as postdischarge nutrition, illness, and home environmentwill influence the outcome measure (77). Thus, there is a highpremium on further development of neurobehavioral assess-ments in close temporal proximity to the time of nutritional insultin the neonatal period. Potential new methods that may be usefulinclude near infrared spectroscopy (NIRS) and magnetoen-cephalography (MEG) (78, 79).

SUMMARYFetal and neonatal malnutrition can have global or circuit-

specific effects on the developing brain. These effects are basedon the timing and magnitude of the nutrient deficit and on thebrains need for the particular nutrient at the time of the deficit.

It is important to recognize that nutritional effects on the devel-oping 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 havea signature effect on the brain that could be assessed behaviorallyor through neuroimaging, this is unlikely to occur with the cur-rently available neuroimaging and behavioral techniques, in partbecause common nutrient deficiencies in the neonate occur to-gether and affect the same developing brain region. For example,protein-energy, iron, and zinc malnutrition all affect the devel-oping hippocampus. Ultimately, the attribution of short- andlong-term neurodevelopmental dysfunction to perinatal nutri-tional status will need to follow specific rules of developmentalneuroscience. The nutrient deficit must be present during thedevelopmental window when the brain requires that nutrient forgrowth and function. Furthermore, the abnormal behavioralfunction should be subserved by a brain region or process that isaffected by the nutrient. Usually, a multitier approach from hu-man epidemiology to animal and cellular models will be neces-sary to provide reasonable scientific evidence of a cause-and-effect association.

TABLE 4Neurobehavioral and neuroimaging assessments that can be performed to evaluate the effects of neonatal nutrients on cognitive development during thefirst 6 y of postnatal life1

Cognitive domainRisk nutrients

for domainBehavioralassessment

Age ofreliability Neuroimaging technique Age of reliability

Explicit-recognitionmemory

Protein-energy,iron, zinc

VPC 4 mo ERP (auditory) Newborn

DNMS 6 mo ERP (visual) 4 moElicited imitation 12 mo MR volume

(hippocampus)Newborn and6 y

Working memory Protein-energy Elicited imitation 12 mo MR volume (prefrontalcortex)

Newborn and6 y

Iron CANTAB 4 yfMRI 6 y

Implicit-proceduralmemory

Iron Priming 4 mo MR volume (striatum) Newborn and6 y

fMRI Newborn and6 y1 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.

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

Affective domainRisk nutrients

for domain Behavioral assessmentAge of

reliability Neuroimaging technique Age of reliability

Attention Iron, zinc Bayley Scales rating 12 mo MR volume (prefrontal cortex) Newborn and6 yCANTAB 4 yFlanker task 5 y fMRI 6 y

Reactivity (HPA/ANS)

Iron, zinc Response to: Newborn

Restraint Salivary cortisol Any ageSeparation HR response Any ageImmunization Vagal tone Any age

Social interaction Iron, zinc Spontaneous movement Any age fMRI 6 yBayley Scales rating 12 mo

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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