Nutrition and the Brain: Nutrient Nutrition and the Brain: Nutrient Priorities and MeasurementPriorities and Measurement

Michael K. Georgieff, M.D.Michael K. Georgieff, M.D.Professor of Pediatrics and Child DevelopmentProfessor of Pediatrics and Child Development

Director, Center for Neurobehavioral Director, Center for Neurobehavioral DevelopmentDevelopment

Head, Section of NeonatologyHead, Section of NeonatologyUniversity of MinnesotaUniversity of Minnesota

ObjectivesObjectives

Identify nutrients in the neonatal period that are particularly Identify nutrients in the neonatal period that are particularly important for brain developmentimportant for brain development

Understand which brain regions and processes are Understand which brain regions and processes are particularly vulnerable to fetal/neonatal malnutritionparticularly vulnerable to fetal/neonatal malnutrition

Understand the array of clinical tests that assess global Understand the array of clinical tests that assess global and specific brain functions in the neonate and young childand specific brain functions in the neonate and young child

For recent reviews of all topics in this talk see:For recent reviews of all topics in this talk see: Georgieff MK. Nutrition and the Developing Brain: Nutrient Priorities and Management. Am J Georgieff MK. Nutrition and the Developing Brain: Nutrient Priorities and Management. Am J

Clin Nutr, 85:614S-620S, 2007Clin Nutr, 85:614S-620S, 2007 Fugelstad A, Rao R, Georgieff MK. The Role of Nutrition in Cognitive Development. In Fugelstad A, Rao R, Georgieff MK. The Role of Nutrition in Cognitive Development. In

Handbook in Developmental Cognitive Neuroscience.Handbook in Developmental Cognitive Neuroscience. (2 (2ndnd Edition) Cambridge, MA: MIT Edition) Cambridge, MA: MIT Press, 2008; pp.623-641.Press, 2008; pp.623-641.

I have nothing to disclose and no I have nothing to disclose and no conflicts of interestconflicts of interest

OverviewOverview

Nutrient-Brain InteractionsNutrient-Brain Interactions Specific Nutrients (Protein, fats, Fe, Zn)Specific Nutrients (Protein, fats, Fe, Zn)

– RequirementsRequirements– StudiesStudies– Assessment of Nutrient StatusAssessment of Nutrient Status

» BrainBrain» Total BodyTotal Body

Assessment of the Premature BrainAssessment of the Premature Brain– Available toolsAvailable tools– Fit to NutrientsFit to Nutrients

Early Nutrition and Brain Development:Early Nutrition and Brain Development:General PrinciplesGeneral Principles

NutrientsNutrients and and Growth FactorsGrowth Factors regulate regulate brain development during prenatal and brain development during prenatal and postnatal lifepostnatal life

Rapidly growing brain Rapidly growing brain – more vulnerable to damage more vulnerable to damage – more amenable to repair more amenable to repair

following nutritional perturbationsfollowing nutritional perturbations

““Vulnerability outweighs Plasticity”Vulnerability outweighs Plasticity” (NIH, in 1994 RFA)(NIH, in 1994 RFA)

Early Nutrition and Brain Development:Early Nutrition and Brain Development:General PrinciplesGeneral Principles

Nutrient deficiencies may cause negative effects Nutrient deficiencies may cause negative effects or no effects (head sparing)or no effects (head sparing)

Nutrient overabundance/supplementation may Nutrient overabundance/supplementation may produce positive, negative or no effectsproduce positive, negative or no effects

What happens is based on…What happens is based on…Timing, Dose and DurationTiming, Dose and Duration

Kretchmer, Beard, Carlson Kretchmer, Beard, Carlson (AJCN, 1996)(AJCN, 1996)

Nutrients with Particularly Large Effects Nutrients with Particularly Large Effects on Early Brain Developmenton Early Brain Development

MacronutrientsMacronutrients– Protein-EnergyProtein-Energy– Specific fats (e.g. LC-PUFAs)Specific fats (e.g. LC-PUFAs)

MicronutrientsMicronutrients– IronIron– ZincZinc– CopperCopper– Selenium, Iodine (Thyroid) Selenium, Iodine (Thyroid)

Vitamins/Cofactors Vitamins/Cofactors – B vitamins (B6, B12)B vitamins (B6, B12)– Vitamin AVitamin A– Vitamin KVitamin K– FolateFolate– CholineCholine

Fundamental QuestionsFundamental Questions

If a nutrient affects the brain, does it affect behavior?If a nutrient affects the brain, does it affect behavior? How close is the linkage?How close is the linkage?

– For each nutrient?For each nutrient?– For each time period of development?For each time period of development?

Is the effectIs the effect– Transient (only during deficiency)=> acute dysfunctionTransient (only during deficiency)=> acute dysfunction– Long-term (beyond time of deficiency)=>altered Long-term (beyond time of deficiency)=>altered

developmental trajectorydevelopmental trajectory

What is happening in theWhat is happening in the brain during this time period? brain during this time period?

Fetus Late Infancy/Toddler Pubertal

ProteinProtein

Why the Brain Needs ProteinWhy the Brain Needs Protein

DNA, RNA synthesis and maintenanceDNA, RNA synthesis and maintenance Neurotransmitter production (synaptic Neurotransmitter production (synaptic

efficacy)efficacy) Growth factor synthesisGrowth factor synthesis Structural proteinsStructural proteins

– Neurite extension (axons, dendrites)Neurite extension (axons, dendrites)– Synapse formation (connectivity)Synapse formation (connectivity)

IUGR Outcomes: Human StudiesIUGR Outcomes: Human Studies(Reviewed in Fuglestad et al, 2008; Handbook of Developmental Cognitive Neuroscience; MIT Press)(Reviewed in Fuglestad et al, 2008; Handbook of Developmental Cognitive Neuroscience; MIT Press)

IUGR=>Poor developmental outcomeIUGR=>Poor developmental outcome–verbal outcomeverbal outcome–visual recognition memoryvisual recognition memory–6.8 point IQ deficit at 7 years (6.8 point IQ deficit at 7 years (Strauss & Dietz, 1998Strauss & Dietz, 1998))–dose response based on degree of IUGRdose response based on degree of IUGR–15% with mild neurodevelopmental 15% with mild neurodevelopmental

abnormalitiesabnormalities Compounded by postnatal growth failure Compounded by postnatal growth failure

(prenatal + postnatal malnutrition) ((prenatal + postnatal malnutrition) (Casey et al, 2006; Casey et al, 2006; Pylipow et al, 2009Pylipow et al, 2009))

Protein Status: Protein Status: Assessment in the NeonateAssessment in the Neonate

Brain ProteinBrain Protein– OFC (sensitive to severe malnutrition)OFC (sensitive to severe malnutrition)– MRI volumetrics (gray matter)MRI volumetrics (gray matter)

Total Body ProteinTotal Body ProteinLong-termLong-term

» Length; Linear Growth TrajectoryLength; Linear Growth Trajectory» Lean Body Mass (MAMC; DEXA; Air Plethysmography)Lean Body Mass (MAMC; DEXA; Air Plethysmography)» Serum Albumin; Serum CreatinineSerum Albumin; Serum Creatinine

Short-termShort-term» Serum BUNSerum BUN» Rapid Turnover Serum Proteins (Prealbumin)Rapid Turnover Serum Proteins (Prealbumin)» Amino Acid Profile (“aminogram”)Amino Acid Profile (“aminogram”)

Neuroimaging: VolumetricsNeuroimaging: Volumetrics

Cerebral Cortex(Protein)

Cerebral White Matter(Fat; Iron)

Caudate Putamen

PPsychiatryIIowaNNeuroimaging CConsortium

Subcortical NucleiThalamus

Courtesy of P. Nopoulos

FatsFats

Why the brain needs fatsWhy the brain needs fats

Cell membranesCell membranesSynapse formationSynapse formationMyelinMyelin

Long Chain Polyunsaturated Fatty AcidsLong Chain Polyunsaturated Fatty Acids

Neurobiological Effects of LC-PUFAsNeurobiological Effects of LC-PUFAs

LC-PUFA deficiencyLC-PUFA deficiency– Altered fatty acid profileAltered fatty acid profile– Abnormal behavior including visual speed of processingAbnormal behavior including visual speed of processing

Suspected effects on fetal and neonatal brain Suspected effects on fetal and neonatal brain – Myelin production Myelin production – Neuronal membrane fatty acid compositionNeuronal membrane fatty acid composition– SynaptogenesisSynaptogenesis

Additional effects may include cell signalingAdditional effects may include cell signaling Unknown: how much deficiency gives behavioral effectsUnknown: how much deficiency gives behavioral effects

LC-PUFAs and Mental DevelopmentLC-PUFAs and Mental Development

Effect size: preterms > termsEffect size: preterms > terms Outcome studies are short term Outcome studies are short term

– Generally gross (MDI) and not generally predictive of later functionGenerally gross (MDI) and not generally predictive of later function Long term studies underway; early acceleration may Long term studies underway; early acceleration may

result inresult in– No long term advantage (most likely)No long term advantage (most likely)– Permanent advantagePermanent advantage

Conclusion- Studies are underpowered re: long-term Conclusion- Studies are underpowered re: long-term efficacyefficacy

Fat Status: AssessmentFat Status: Assessment Brain Fat (experimental)Brain Fat (experimental)

– MRI Volumetrics (white matter)MRI Volumetrics (white matter)– Magnetic Resonance SpectroscopyMagnetic Resonance Spectroscopy– Red Cell Membrane Fatty Acid ContentRed Cell Membrane Fatty Acid Content

» Best way to assess LC-PUFA status ( S Innis, Pediatric Research, 1995)Best way to assess LC-PUFA status ( S Innis, Pediatric Research, 1995) Body FatBody Fat

Long-termLong-term» Weight Gain; Body proportionality (W/L)Weight Gain; Body proportionality (W/L)» Skinfold thickness; Arm Fat AreaSkinfold thickness; Arm Fat Area» DEXA; Air PlethysmographyDEXA; Air Plethysmography

Short-termShort-term» Serum TriglycerideSerum Triglyceride

IronIron

Why does the Brain Need Iron?Why does the Brain Need Iron?

EnergyEnergy– Iron found in cytochromes that make ATPIron found in cytochromes that make ATP–Brain energy (ATP) utilization high in fetus and Brain energy (ATP) utilization high in fetus and

neonateneonate NeurotransmittersNeurotransmitters

– Iron needed to make dopamine, serotonin, Iron needed to make dopamine, serotonin, norepinephrinenorepinephrine

MyelinMyelin– Iron containing enzymes to make fatty acids in Iron containing enzymes to make fatty acids in

myelinmyelin

Iron: What Can Negatively Affect Iron: What Can Negatively Affect Neonatal Brain Iron Status?Neonatal Brain Iron Status?

Maternal AnemiaMaternal Anemia– Fetus with very iron deficient mother (Hgb<8.5)Fetus with very iron deficient mother (Hgb<8.5)– Common (>30%) in developing countries (Common (>30%) in developing countries (WHO reportWHO report))

Intrauterine Growth RestrictionIntrauterine Growth Restriction– Usually due to maternal hypertension (Usually due to maternal hypertension (Georgieff et al, 1995Georgieff et al, 1995))

Diabetes Mellitus in PregnancyDiabetes Mellitus in Pregnancy– Pre-existing or Gestational (Pre-existing or Gestational (Georgieff et al, 1990Georgieff et al, 1990))

Maternal Smoking in Pregnancy Maternal Smoking in Pregnancy PrematurityPrematurity

– [Reduced iron accretion + phlebotomy ]- [transfusion + [Reduced iron accretion + phlebotomy ]- [transfusion + intake]intake]

PerinatalPerinatal Iron Deficiency: Human Outcomes Iron Deficiency: Human Outcomes

Behavioral abnormalitiesBehavioral abnormalities–Poorer recognition memory in newborns Poorer recognition memory in newborns (Siddappa et al, 2004)(Siddappa et al, 2004)

–Poorer school age neurodevelopmentPoorer school age neurodevelopment (Tamura et al, J. Pediatr; (Tamura et al, J. Pediatr; 2002)2002)

– Impaired working memory at 3.5 years after iron Impaired working memory at 3.5 years after iron repletionrepletion ( (Riggins et al, Dev Neuropsych, 2009)Riggins et al, Dev Neuropsych, 2009)

–Abnormal neurologic reflexes in premies at 36 week Abnormal neurologic reflexes in premies at 36 week PCAPCA (Armady-Sivan, et al, J Perinatol, 2004).(Armady-Sivan, et al, J Perinatol, 2004).

Mom: “Hi Baby”

Stranger: “Hi Baby”

Event Related Potentials (ERPs) in NewbornsEvent Related Potentials (ERPs) in Newborns

Iron Sufficient Iron Deficient

Siddappa et al., 2004, Pediatr. Res.

Assessment of Iron StatusAssessment of Iron Status(For review, see JL Beard et (For review, see JL Beard et al, al, Lab Med, 38:103-108, 2007)

Brain IronBrain Iron– No direct measuresNo direct measures– Newborn Serum Ferritin < 35 mcg/L = brain iron deficiencyNewborn Serum Ferritin < 35 mcg/L = brain iron deficiency

Body IronBody Iron– Hemoglobin, MCVHemoglobin, MCV– Zn or free erythrocyte protoporphyrinZn or free erythrocyte protoporphyrin– Serum transferrin receptorSerum transferrin receptor– Serum ferritin (measures iron stores)Serum ferritin (measures iron stores)

Anemia is a Anemia is a LATELATE sign of ID. Brain is already affected! sign of ID. Brain is already affected!

Why the Brain Needs ZincWhy the Brain Needs Zinc

Interacts with DNA (zinc finger proteins)Interacts with DNA (zinc finger proteins) Needed for growth factor (IGF-1 and GH) synthesisNeeded for growth factor (IGF-1 and GH) synthesis Important for neurotransmitter releaseImportant for neurotransmitter release Autonomic nervous system developmentAutonomic nervous system development Development of hippocampus (learning and memory)Development of hippocampus (learning and memory)

Zinc Deficiency: Who is at Risk?Zinc Deficiency: Who is at Risk?

Offspring of Zn deficient mothersOffspring of Zn deficient mothers Protein malnourished infantsProtein malnourished infants Infants on prolonged TPN with inadequate Zn intakeInfants on prolonged TPN with inadequate Zn intake Short bowel/ malabsorption conditionsShort bowel/ malabsorption conditions

Zinc Deficiency: Human StudiesZinc Deficiency: Human Studies

Fetuses of zinc deficient mothers demonstrate:Fetuses of zinc deficient mothers demonstrate:–Decreased fetal movementDecreased fetal movement–Decreased heart rate variabilityDecreased heart rate variability–Altered autonomic nervous system stabilityAltered autonomic nervous system stability

Postnatally: Postnatally: –Poorer memoryPoorer memory

» Decreased preferential looking behavior behavior Decreased preferential looking behavior behavior » But, no difference on Bayley Mental Developmental IndexBut, no difference on Bayley Mental Developmental Index

Assessment of Zinc StatusAssessment of Zinc Status

Brain Zinc- Brain Zinc- – No direct assessmentNo direct assessment

Body StatusBody Status– Tricky! Since red cells contain Zn, serum may not reveal Tricky! Since red cells contain Zn, serum may not reveal

total body storestotal body stores– Most practical approach is serum zinc level (<70 mcg/dL)Most practical approach is serum zinc level (<70 mcg/dL)– Most accurate approach is serum or RBC metallothionein Most accurate approach is serum or RBC metallothionein

concentrationsconcentrations

Can we see nutrient effects on the Can we see nutrient effects on the brain?brain?

Sensitivity- yesSensitivity- yesSpecificity- not really!Specificity- not really!

Nutrients and Perinatal Brain CircuitryNutrients and Perinatal Brain CircuitryNutrientNutrient Brain Requirement for Brain Requirement for

NutrientNutrientCircuitry/Process Circuitry/Process

AffectedAffectedProtein-EnergyProtein-Energy Cell Proliferation Cell Proliferation

Cell DifferentiationCell DifferentiationSynaptogenesisSynaptogenesisGrowth FactorsGrowth Factors

GlobalGlobalCortexCortex

HippocampusHippocampus

IronIron MyelinMyelinDopamineDopamine

EnergyEnergy

White MatterWhite MatterStriatal-FrontalStriatal-Frontal

Hippocampal-FrontalHippocampal-FrontalZincZinc DNADNA

Neurotransmitter Neurotransmitter releaserelease

ANSANSHippocampusHippocampus

CerebellumCerebellumLC-PUFAsLC-PUFAs SynaptogenesisSynaptogenesis

MyelinMyelinEyeEye

Cortex?Cortex?

Circuit Specific Assessment of Nutrient Circuit Specific Assessment of Nutrient Effects on the Premature BrainEffects on the Premature Brain

Limitations to Neurologic Assessment & Limitations to Neurologic Assessment & Developmental Prediction in the PrematureDevelopmental Prediction in the Premature

Limited cortical expressionLimited cortical expression=> poor direct prediction of later functioning=> poor direct prediction of later functioning

Ongoing illness confound Ongoing illness confound => “not at their best”=> “not at their best”

Later plasticity/catch-up Later plasticity/catch-up => “it is not as bad as it might seem”=> “it is not as bad as it might seem”

Pre D/C Assessment at 36 weeks Pre D/C Assessment at 36 weeks PCA: What is in the Repertoire?PCA: What is in the Repertoire?

Head Circumference (OFC)Head Circumference (OFC) Neurologic ExamNeurologic Exam Electrophysiology (EEG)Electrophysiology (EEG)

– EEG maturityEEG maturity– HR, BP response to stressor-ANS stabilityHR, BP response to stressor-ANS stability– ABR/ERG latency- speed of processing ABR/ERG latency- speed of processing (Birch et al, 1992)(Birch et al, 1992)

– ERP (functional EEG)- recognition memoryERP (functional EEG)- recognition memory (deRegnier et al, 2000) (deRegnier et al, 2000)

NeuroimagingNeuroimaging– Cranial UltrasoundCranial Ultrasound– Structural MRI + Regional Volumetrics Structural MRI + Regional Volumetrics (Peterson et al, 2001)(Peterson et al, 2001)– Diffusion Tensor Imaging to assess myelinated tracts Diffusion Tensor Imaging to assess myelinated tracts (Huppi et al, 2005)(Huppi et al, 2005)

Assessments and At Risk NutrientsAssessments and At Risk Nutrients What can you diagnose with what you can measure?What can you diagnose with what you can measure?

ASSESSMENTASSESSMENT BRAIN AREABRAIN AREA RISK NUTRIENT(S)RISK NUTRIENT(S)

OFCOFC GlobalGlobal Protein-energyProtein-energy

ReflexesReflexes GlobalGlobalMyelinationMyelination

IronIron?Protein-energy?Protein-energy

Neurologic ExamNeurologic Exam GlobalGlobal Protein-energyProtein-energy

EEG maturityEEG maturity CortexCortex Protein-energy Protein-energy ?LC-PUFA?LC-PUFA

Stimulated HR, BP, Stimulated HR, BP, salivary cortisol salivary cortisol

response response

Autonomic Nervous Autonomic Nervous SystemSystem

ZincZinc

Assessments and At Risk NutrientsAssessments and At Risk Nutrients What can you diagnose with what you can measure?What can you diagnose with what you can measure?

ASSESSMENTASSESSMENT BRAIN AREABRAIN AREA RISK NUTRIENT(S)RISK NUTRIENT(S)

ABR/ERGABR/ERG Myelination; Myelination; synaptic efficacysynaptic efficacy

(processing speed)(processing speed)

IronIronLC-PUFALC-PUFA

Auditory Event Auditory Event Related PotentialsRelated Potentials

Hippocampus Hippocampus (recognition memory)(recognition memory)

ProteinProteinIronIronZincZinc

MRIMRI Global & Regional Global & Regional VolumetricsVolumetrics

ProteinProteinFatFat

MR-Diffusion Tensor MR-Diffusion Tensor ImagingImaging

Myelin & Tract Myelin & Tract IntegrityIntegrity

FatFatIronIron

MR-Spectroscopy MR-Spectroscopy NeurochemistryNeurochemistry IronIron

Functional Assessments in Year 1: Functional Assessments in Year 1: Beyond the BayleyBeyond the Bayley

The 12 month Bayley is a general assessment with poor The 12 month Bayley is a general assessment with poor predictive capacity for year 7 IQpredictive capacity for year 7 IQ

– Easily performed; widely available; used in nutritional trials (e.g. LC-PUFA)Easily performed; widely available; used in nutritional trials (e.g. LC-PUFA) Specific, significant neuromorbidities can be embedded Specific, significant neuromorbidities can be embedded

within a normal Bayley derived DQwithin a normal Bayley derived DQ Specific nutritionally at-risk brain functions that can be Specific nutritionally at-risk brain functions that can be

assessed in year 1:assessed in year 1:– Recognition memory (Hippocampus): Preferential Looking (Fagan); Visual Recognition memory (Hippocampus): Preferential Looking (Fagan); Visual

ERPs, Elicited ImitationERPs, Elicited Imitation– Speed of Processing (Myelin; synaptic efficacy): ABR; ERPsSpeed of Processing (Myelin; synaptic efficacy): ABR; ERPs– Affect; Distractability (striatum; monoamine): Direct scoringAffect; Distractability (striatum; monoamine): Direct scoring– Procedural Memory (striatum): Visual priming studies Procedural Memory (striatum): Visual priming studies

Summary Summary Nutrients and the BrainNutrients and the Brain

Malnutrition can have global or circuit specific Malnutrition can have global or circuit specific effects on the developing braineffects on the developing brain

Effects are based on timing and magnitude of Effects are based on timing and magnitude of nutrient deficit + the brain’s need for the nutrientnutrient deficit + the brain’s need for the nutrient

Some nutrients have “signature” effects on the Some nutrients have “signature” effects on the brainbrain

Summary Summary Assessing Nutritional Effects on BrainAssessing Nutritional Effects on Brain

Key Point: Match nutrient with specific developing brain region Key Point: Match nutrient with specific developing brain region that is dependent on the nutrientthat is dependent on the nutrient

Use specific brain assessments that are sensitive to the nutrient Use specific brain assessments that are sensitive to the nutrient deficiencydeficiency

Testing of specific brain areas can be done at a very young age, Testing of specific brain areas can be done at a very young age, but becomes more reliable as the child ages but becomes more reliable as the child ages

And, remember, nutrition is the one thing in And, remember, nutrition is the one thing in the NICU you can do something about!the NICU you can do something about!

Enhancement Therapies for the Central Enhancement Therapies for the Central Nervous SystemNervous System

If some is good, is more better?If some is good, is more better?

Candidates for “Brain Enhancement”Candidates for “Brain Enhancement”

CholineCholine OligosaccharidesOligosaccharides Neurotrophic factors (growth factors)Neurotrophic factors (growth factors)– Brain Derived Neurotrophic FactorBrain Derived Neurotrophic Factor

Docosohexaenoic acid (an LC-PUFA)Docosohexaenoic acid (an LC-PUFA)– As supplementation rather than repletion of As supplementation rather than repletion of

deficit (current formulas)deficit (current formulas)

CholineCholine

Role of Choline in the BrainRole of Choline in the Brain

Essential nutrient for humansEssential nutrient for humans Substrate for neurotransmitter (acetylcholine)Substrate for neurotransmitter (acetylcholine) Likely has epigenetic effect (methyl donor)Likely has epigenetic effect (methyl donor) Promotes larger neuronal size, more dendritic Promotes larger neuronal size, more dendritic

arborization and greater neuronal signalingarborization and greater neuronal signaling–Especially in hippocampus (learning and Especially in hippocampus (learning and

memory)memory)

Effects of Maternal Choline SupplementationEffects of Maternal Choline Supplementation

Only studies are in animalsOnly studies are in animals Supplementation of choline sufficient rat dams results Supplementation of choline sufficient rat dams results

inin– More advanced hippocampal structural maturationMore advanced hippocampal structural maturation– Better performance than controls on memory functionBetter performance than controls on memory function

Rare example for “if some is good, more is better”Rare example for “if some is good, more is better” Human studies have started Human studies have started

(For recent reviews, see supplemental issue of Brain Research, October 2008)(For recent reviews, see supplemental issue of Brain Research, October 2008)

Does “Enhancement” Last? Caveats!Does “Enhancement” Last? Caveats!

Many “enrichment” studies are actually “less deficit” Many “enrichment” studies are actually “less deficit” studiesstudies– LC-PUFALC-PUFA

Early environmental enrichment studies in at-risk Early environmental enrichment studies in at-risk humans (e.g. Head Start; IHDP) show wash-out over humans (e.g. Head Start; IHDP) show wash-out over timetime

Neurobehavioral Domain Assessments:Neurobehavioral Domain Assessments: General General

DOMAINDOMAIN RISK RISK NUTRIENTNUTRIENT

TESTTEST AgeAge NeuroimagingNeuroimaging AgeAge

GlobalGlobal Protein/Protein/EnergyFe, Zn, EnergyFe, Zn, LC-PUFALC-PUFA

OFCOFC 1-2.5 y1-2.5 y<2.5 y<2.5 y>2.5 y>2.5 y

MR-VolumetricsMR-Volumetrics NB &NB &>6 y>6 y

MyelinMyelin FeFeLC-PUFA?LC-PUFA?

Speed of Speed of ProcessingProcessing

4m4m ABR, VEPABR, VEPERPERPDTIDTI

NB->NB->NB->NB->NB & NB & >6y>6y

ANSANS ZincZinc PDI (Bayley)PDI (Bayley)Spontaneous Spontaneous activityactivityBimanual Bimanual CoordinationCoordination

1-2.5y1-2.5y Regional MR Volume Regional MR Volume (sensory-motor)(sensory-motor)

NB & NB & >6y>6y

Cognitive Domain AssessmentsCognitive Domain AssessmentsDomainDomain NutrientNutrient BehaviorBehavior AgeAge NeuroimagingNeuroimaging AgeAge

CognitionCognition-Recognition-Recognition

(HC)(HC)

Protein/EnergyProtein/EnergyFe, Fe, Zn, Zn,

VPCVPCElicited Elicited ImitationImitationDNMSDNMS

>4m>4m>12m>12m>6m>6m

ERP (auditory)ERP (auditory)ERP (visual)ERP (visual)ERP (cross-modal)ERP (cross-modal)HC VolumeHC Volume

NBNB4m4m8m8mNB/>6yNB/>6y

CognitionCognition-Working-Working

(PFC)(PFC)

FeFe Elicited Elicited ImitationImitation

CANTABCANTAB

>12m>12m

>4y>4y

MR PFC volumeMR PFC volume

fMRIfMRI

NB & NB & >6y>6y

>6y>6y

CognitionCognition-Procedural-Procedural

(striatum)(striatum)

FeFeIVH*IVH*

Implicit Implicit memory- memory- primingpriming

>4m>4m MR Caudate MR Caudate volumevolume

NB & NB & >6y>6y

Affective Domain AssessmentsAffective Domain AssessmentsDomainDomain NutrientNutrient BehaviorBehavior AgeAge NeuroimagingNeuroimaging AgeAge

AffectAffect-Attention-Attention

Fe, Fe, Zn Zn

Bayley ratingBayley ratingCANTABCANTABFlanker taskFlanker task

>12m>12m>5y>5y>5y>5y

MR Frontal volumeMR Frontal volume?Dopamine ?Dopamine challengechallenge

NB & NB & >6y>6y

AffectAffect-Reactivity-Reactivity

(HPA; ANS)(HPA; ANS)

Fe,Fe,ZnZn

RestraintRestraintSeparationSeparationImmunizationImmunization

NB->NB-> HR response; vagal HR response; vagal tonetone

NB->NB->

AffectAffect-Social -Social

InteractionInteraction

FeFe Spontaneous Spontaneous movement movement (actigraph)(actigraph)Bayley ratingBayley rating

NB->NB->

>12m>12m

NoneNone

Testing: Beyond Year 2Testing: Beyond Year 2

By age 5, frontal lobes become more testable By age 5, frontal lobes become more testable using CANTAB Neuropsych Batteryusing CANTAB Neuropsych Battery– Strategy switchingStrategy switching– Executive function; planningExecutive function; planning– Working memoryWorking memory

By age 6-8, children can be imaged without By age 6-8, children can be imaged without sedation allowing fMRIsedation allowing fMRI– Working memory (back4)Working memory (back4)– Attention (Flanker task)Attention (Flanker task)– Implicit memory (Priming tasks)Implicit memory (Priming tasks)

Mom: “Hi Baby”

Stranger: “Hi Baby”

Neonatal ERPs to Auditory Recognition TaskNeonatal ERPs to Auditory Recognition Task

Pz Cz FzControl

IDMPz Cz Fz

Newborn Data: Midline Leads

Mother’s Voice Stranger’s Voice

return to baselineNSW

deRegnier et al, 2000