Neuroimaging, a new tool for investigating the effects of early diet on cognitive and brain development.

Nutrition is crucial to the initial development of the central nervous system (CNS), and then to its maintenance, because both depend on dietary intake to supply the elements required to develop and fuel the system. Diet in early life is often seen in the context of "programming" where a stimulus occurring during a vulnerable period can have long-lasting or even lifetime effects on some aspect of the organism's structure or function. Nutrition was first shown to be a programming stimulus for growth, and then for cognitive behavior, in animal studies that were able to employ methods that allowed the demonstration of neural effects of early nutrition. Such research raised the question of whether nutrition could also programme cognition/brain structure in humans. Initial studies of cognitive effects were observational, usually conducted in developing countries where the presence of confounding factors made it difficult to interpret the role of nutrition in the cognitive deficits that were seen. Attributing causality to nutrition required randomized controlled trials (RCTs) and these, often in developed countries, started to appear around 30 years ago. Most demonstrated convincingly that early nutrition could affect subsequent cognition. Until the advent of neuroimaging techniques that allowed in vivo examination of the brain, however, we could determine very little about the neural effects of early diet in humans. The combination of well-designed trials with neuroimaging tools means that we are now able to pose and answer questions that would have seemed impossible only recently. This review discusses various neuroimaging methods that are suitable for use in nutrition studies, while pointing out some of the limitations that they may have. The existing literature is small, but examples of studies that have used these methods are presented. Finally, some considerations that have arisen from previous studies, as well as suggestions for future research, are discussed.

Brain imaging and human nutrition: which measures to use in intervention studies?

The present review describes brain imaging technologies that can be used to assess the effects of nutritional interventions in human subjects. Specifically, we summarise the biological relevance of their outcome measures, practical use and feasibility, and recommended use in short- and long-term nutritional studies. The brain imaging technologies described consist of MRI, including diffusion tensor imaging, magnetic resonance spectroscopy and functional MRI, as well as electroencephalography/magnetoencephalography, near-IR spectroscopy, positron emission tomography and single-photon emission computerised tomography. In nutritional interventions and across the lifespan, brain imaging can detect macro- and microstructural, functional, electrophysiological and metabolic changes linked to broader functional outcomes, such as cognition. Imaging markers can be considered as specific for one or several brain processes and as surrogate instrumental endpoints that may provide sensitive measures of short- and long-term effects. For the majority of imaging measures, little information is available regarding their correlation with functional endpoints in healthy subjects; therefore, imaging markers generally cannot replace clinical endpoints that reflect the overall capacity of the brain to behaviourally respond to specific situations and stimuli. The principal added value of brain imaging measures for human nutritional intervention studies is their ability to provide unique in vivo information on the working mechanism of an intervention in hypothesis-driven research. Selection of brain imaging techniques and target markers within a given technique should mainly depend on the hypothesis regarding the mechanism of action of the intervention, level (structural, metabolic or functional) and anticipated timescale of the intervention's effects, target population, availability and costs of the techniques.

10-year cognition in preterms after random assignment to fatty acid supplementation in infancy.

OBJECTIVE: To test the hypothesis that long-chain polyunsaturated fatty acid (LCPUFA) supplementation in infancy would improve cognition into later childhood (after 9 years) at both general and specific levels. METHODS: A comprehensive cognitive battery was completed by 107 formerly preterm infants (mean age: 128 months). As infants, they had been assigned randomly to receive LCPUFA-supplemented (N = 50) or control (N = 57) formula, between birth and 9 months; the docosahexaenoic acid level (DHA) in the supplemented formulas was 0.5%. In addition to randomized comparisons, we planned supplementary analyses to examine the effects of both gender and feeding group (those receiving some maternal breast milk versus those receiving none). RESULTS: There were no significant differences between randomized diet groups on any cognitive measure. There was significant interaction between gender and supplementation; girls only showed beneficial effects of LCPUFAs on literacy. Significant interaction also occurred between feeding group and supplementation; increases of 0.7 SD in verbal IQ, full-scale IQ, and memory scores were found for the LCPUFA group, but only for infants who received only formula and no maternal breast milk. CONCLUSIONS: The results of this post-9-year cognitive follow-up study in a randomized trial of LCPUFA-supplemented formula for preterm infants suggest no overall group effects but indicate that gender-specific and diet-specific effects may exist. The data provide some evidence that LCPUFAs are a key factor in the cognitive benefits of breast milk. Caution is advised in data interpretation because of the small groups used.

The effect of intrauterine growth on verbal IQ scores in childhood: a study of monozygotic twins.

OBJECTIVE: Given the adverse neurobiological effects of suboptimal nutrition on the developing brain, it is of social and medical importance to determine if the global prevalence of poor intrauterine growth causes lasting cognitive deficits. We examined whether suboptimal intrauterine growth relates to impaired cognitive outcome by comparing birth weight and cognition in monozygotic twins and considered whether children within-pair differences in birth weight were related to within-pair differences in IQ scores. METHODS: A total of 71 monozygotic twin pairs (aged 7 years 11 months to 17 years 3 months) participated. The Wechsler Intelligence Scale for Children, Third Edition, was administered, and verbal IQ (VIQ) and performance IQ (PIQ) scores were calculated. Regression was used to relate within-pair differences in birth weight to within-pair differences in IQ scores. RESULTS: VIQ but not PIQ score was affected by prenatal growth restriction. The results suggest that the mean advantage for heavier twins relative to their lighter co-twins can be as much as half an SD in VIQ points. In pairs with minimal discordance, heavier twins had lower VIQ scores than their lighter co-twins. CONCLUSIONS: Our study results suggest that lower birth weight in monozygotic twins can also have a negative long-term impact on cognition both in infants who are small at birth and also those with birth weights across the spectrum. Studying monozygotic twins enabled us to examine the effect of reduced intrauterine growth on cognition independently of confounding factors, including parental IQ and education and infant gender, age, genetic characteristics, and gestation.

The 10-year follow-up of a randomised trial of long-chain polyunsaturated fatty acid supplementation in preterm infants: effects on growth and blood pressure.

OBJECTIVE: To test the hypothesis that consumption of infant formulas containing long-chain polyunsaturated fatty acids (LCPUFAs) by preterm infants would favourably influence growth, body composition and blood pressure (BP) at age 10 years. METHODS: This was a follow-up study of a preterm cohort (<35 weeks and birth weight <2000 g) randomly assigned to unsupplemented or LCPUFA-supplemented formulas to 9 months post term. The setting was a research clinic at Yorkhill Hospital for Sick Children, Glasgow, UK. A total of 107 children aged 9-11 years who participated in the original randomised controlled trial (45% follow-up) took part. Main outcome measures were: (1) anthropometry, (2) body composition and (3) BP. RESULTS: There were no differences in growth or BP between randomised groups for the whole cohort. However, girls who had received LCPUFA-supplemented formula were heavier (42.20 (SD 9.61) vs 36.94 (9.46) kg, p=0.05), had greater skin fold thicknesses (biceps 10.7 (3.3) vs 8.5 (3.6) mm, p=0.03; suprailiac 16.7 (8.2) vs 12.0 (7.5) mm, p=0.03) and higher BP (mean 82.2 (8.4) vs 78.1 (6.2) mm Hg, p=0.04: systolic 111.4 (10.1) vs 105.9 (9.0) mm Hg, p=0.04: diastolic 64.8 (8.4) vs 61.1 (5.4) mm Hg, p=0.05). Differences in weight SD score (0.85 (95% CI 0.13 to 1.58), p=0.02), Ln sum of skin fold thicknesses (0.27 (0.02 to 0.52), p=0.04) and BP (mean 4.6 mm Hg (0.43 to 8.84), p=0.03; systolic 6.1 (0.45 to 11.7), p=0.04) remained after adjustment for prerandomisation confounders. Differences in BP were not significant following adjustment for current weight. CONCLUSIONS: Girls born preterm and randomised to LCPUFA-supplemented formula showed increased weight, adiposity and BP at 9-11 years, which might have adverse consequences for later health. No effects were seen in boys. Long-term follow-up of other LCPUFA supplementation trials is required to further investigate this finding.

Impact of breast milk on intelligence quotient, brain size, and white matter development.

Although observational findings linking breast milk to higher scores on cognitive tests may be confounded by factors associated with mothers' choice to breastfeed, it has been suggested that one or more constituents of breast milk facilitate cognitive development, particularly in preterms. Because cognitive scores are related to head size, we hypothesized that breast milk mediates cognitive effects by affecting brain growth. We used detailed data from a randomized feeding trial to calculate percentage of expressed maternal breast milk (%EBM) in the infant diet of 50 adolescents. MRI scans were obtained (mean age=15 y 9 mo), allowing volumes of total brain (TBV) and white and gray matter (WMV, GMV) to be calculated. In the total group, %EBM correlated significantly with verbal intelligence quotient (VIQ); in boys, with all IQ scores, TBV and WMV. VIQ was, in turn, correlated with WMV and, in boys only, additionally with TBV. No significant relationships were seen in girls or with gray matter. These data support the hypothesis that breast milk promotes brain development, particularly white matter growth. The selective effect in males accords with animal and human evidence regarding gender effects of early diet. Our data have important neurobiological and public health implications and identify areas for future mechanistic study.

Aluminum exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up.

OBJECTIVE: Aluminum has known neurotoxicity and may impair short-term bone health. In a randomized trial, we showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions. Here, in the same cohort, we test the hypothesis that neonatal aluminum exposure also adversely affects long-term bone health, as indicated by reduced bone mass. METHODS: Bone area (BA) and bone mineral content (BMC) of lumbar spine, hip, and whole body were measured with dual radiograph absorptiometry in 13- to 15-year-olds who were born preterm and randomly assigned standard or aluminum-depleted parenteral nutrition solutions during the neonatal period. RESULTS: Fifty-nine children (32% of survivors) were followed. Those who were randomly assigned to standard parenteral nutrition solution had lower lumbar spine BMC, apparently explained by a concomitant decrease in bone size. In nonrandomized analyses, children who were exposed to neonatal aluminum intakes above the median (55 microg/kg) had lower hip BMC (by 7.6% [95% confidence interval: 0.12-13.8]; P = 0.02), [corrected] independent of bone (or body) size. CONCLUSIONS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence, potential risk factors for later osteoporosis and hip fracture. These findings need confirmation in larger, more detailed studies. Nevertheless, given our previous finding of adverse developmental outcome in these individuals and the sizeable number of contemporary infants who undergo intensive neonatal care and are still exposed to aluminum via parenteral feeding solutions, the potential adverse long-term consequences of early aluminum exposure now deserve renewed attention.

Early diet and general cognitive outcome at adolescence in children born at or below 30 weeks gestation.

OBJECTIVE: To test the hypothesis that effects of early diet on cognition observed at age 8 years persist in adolescents born preterm at < or = 30 weeks gestational age. STUDY DESIGN: A subgroup from a preterm infant cohort recruited for a randomized trial studying the effects of early dietary intervention was assessed at age 16 years. IQ scores were compared between those assigned a high-nutrient diet (n = 49) or standard-nutrient diet (n = 46) in infancy at both 8 and 16 years. RESULTS: At age 8 years, the high-nutrient group had higher mean Verbal IQ (VIQ; P = .03), Performance IQ (P = .01), and Full-Scale IQ (P = .02) scores compared with the standard-nutrient group; the VIQ difference persisted at adolescence (P = .02). This effect was accounted for principally by a significant difference in the mean Verbal Comprehension Index score (P < .008). CONCLUSIONS: A brief period of dietary intervention after preterm birth, principally between 26 and 34 weeks of gestation, affected IQ at age 16 years. A standard-nutrient diet was associated with lower VIQ, accounted for mainly by differences in verbal comprehension, which persisted after control of social factors.

The effect of early human diet on caudate volumes and IQ.

Early nutrition in animals affects both behavior and brain structure. In humans, randomized trials show that early nutrition affects later cognition, notably in males. We hypothesized that early nutrition also influences brain structure, measurable using magnetic resonance imaging. Prior research suggested that the caudate nucleus may be especially vulnerable to early environment and that its size relates to IQ. To test the hypothesis that the caudate nucleus could be a neural substrate for cognitive effects of early nutrition, we compared two groups of adolescents, assigned a Standard- or High-nutrient diet in the postnatal weeks after preterm birth. Groups had similar birth status and neonatal course. Scans and IQ data were obtained from 76 adolescents and volumes of several subcortical structures were calculated. The High-nutrient group had significantly larger caudate volumes and higher Verbal IQ (VIQ). Caudate volumes correlated significantly with VIQ in the Standard-nutrient group only. Caudate volume was influenced by early nutrition and related selectively to VIQ in males, but not in females. Our findings may partly explain the effects of early diet on cognition and the predominant effects in males. They are among the first to show that human brain structure can be influenced by early nutrition.

Cortical anomalies associated with visuospatial processing deficits.

Children born preterm provide a fruitful population for studying structure-function relationships because they often have specific functional deficits in the context of normal neurological status. We selected a group of preterm adolescents with deficits in judgment of line orientation. Despite their very low birth weight, all were neurologically normal with no consistent abnormalities on conventional magnetic resonance imaging. However, voxel-based morphometric analysis of their magnetic resonance imaging scans showed areas of decreased gray matter and increased white matter most prominently in right ventral extrastriate cortex, close to an area previously implicated in the line orientation task. We suggest that these anomalies of cortical architecture relate to impaired performance on the line orientation task.

Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants.

OBJECTIVE: We tested the hypothesis that balanced addition of long-chain polyunsaturated fatty acid (LCPUFA) to preterm formula during the first weeks of life would confer long-term neurodevelopmental advantage in a double-blind, randomized, controlled trial of preterm formula with and without preformed LCPUFA. METHODS: The participants were 195 formula-fed preterm infants (birth weight <1750 g, gestation <37 weeks) from 2 UK neonatal units and 88 breast milk-fed infants. Main outcome measures were Bayley Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at 18 months and Knobloch, Passamanick and Sherrard's Developmental Screening Inventory at 9 months' corrected age. Safety outcome measures were anthropometry at 9 and 18 months, tolerance, infection, necrotizing enterocolitis, and death. RESULTS: There were no significant differences in developmental scores between randomized groups, although infants who were fed LCPUFA-supplemented formula showed a nonsignificant 2.6-point (0.25 standard deviation) advantage in MDI and PDI at 18 months, with a greater (nonsignificant) advantage (MDI: 4.5 points; PDI: 5.8 points) in infants below 30 weeks' gestation. LCPUFA-supplemented infants were shorter than control infants at 18 months (difference in length standard deviation score: 0.44; 95% confidence interval: 0.08-0.8). No other significant short- or long-term differences in safety outcomes were observed. Breastfed infants had significantly higher developmental scores at 9 and 18 months than both formula groups and were significantly heavier and longer at 18 months than LCPUFA-supplemented but not control infants. CONCLUSIONS: With the dose, duration, and preparation of LCPUFA used, efficacy was not demonstrated, although an advantage in later neurodevelopment cannot be excluded by global tests of development up to 18 months, particularly in infants below 30 weeks' gestation. The surprising effect of LCPUFA-supplemented formula on growth 18 months beyond the intervention period needs to be confirmed in other studies using similar supplementation strategies. Additional follow-up of this cohort is critical at an age when more specific tests of cognitive function are possible.