NUTRITIONAL INFLUENCES ON HUMAN NEUROCOGNITIVE FUNCTIONING Topic Editors Michael Smith and Andrew Scholey HUMAN NEUROSCIENCE Frontiers in Human Neuroscience November 2014 | Nutritional influences on human neurocognitive functioning | 1 ABOUT FRONTIERS Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. FRONTIERS JOURNAL SERIES The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. 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Cover image provided by Ibbl sarl, Lausanne CH ISSN 1664-8714 ISBN 978-2-88919-336-3 DOI 10.3389/978-2-88919-336-3 Frontiers in Human Neuroscience | Nutritional influences on human neurocognitive functioning | 2 Topic Editors: Michael Smith, Northumbria University, United Kingdom Andrew Scholey, Swinburne University, Australia ‘You are what you eat’. It’s a saying that we’ve all heard time and time again. The notion that good nutrition is essential for adequate growth and sound physical wellbeing is very well established. Further, in recent years, there has been an overwhelming increase in research dedicated to better understanding how nutritional factors influence cognition and behaviour. For example, several studies have suggested that higher foetal exposure to omega-3 fatty acids and B vitamins such as folate promotes neurodevelopment. B vitamins may also play a role in neurocognitive functioning in later life, with some suggestion that lower vitamin B levels are associated with increased risk of dementia (although randomised controlled trials investigating B vitamin supplementation as a cognitive enhancer in the elderly have provided inconclusive evidence as to the benefits of such therapy for dementia). In fact, the nutritional underpinnings of Alzheimer’s disease and other disorders of cognitive ageing is becoming a much researched topic. In addition, consumption of several other foods has been found to convey more acute cognitively enhancing effects. For example, ingestion of carbohydrates (e.g. glucose), caffeine, resveratrol and several ‘nutraceutical’ herbal extracts has been associated with short-term improvements in cognitive performance. Beyond specific micronutrients and macronutrients, the current literature seems to support anecdotal evidence that consumption of a balanced breakfast is crucial to various measures of school performance, including attention in the classroom. What is clear from this emerging literature is that the relationship between nutritional status and neurocognitive functioning at various stages of the lifespan is complex. An aim of this Research Topic is to bring together some recent empirical findings, reviews and commentaries of the literature to date and opinion pieces relating to future directions for this burgeoning field. NUTRITIONAL INFLUENCES ON HUMAN NEUROCOGNITIVE FUNCTIONING November 2014 Frontiers in Human Neuroscience | Nutritional influences on human neurocognitive functioning | 3 Table of Contents 05 Nutritional Influences on Human Neurocognitive Functioning Michael A. Smith and Andrew B. Scholey 07 The Role of Nutrition in Children's Neurocognitive Development, From Pregnancy Through Childhood Anett Nyaradi, Jianghong Li, Siobhan Hickling, Jonathan Foster and Wendy H. Oddy 23 Nutrition as an Important Mediator of the Impact of Background Variables on Outcome in Middle Childhood Patricia Kitsao-Wekulo, Penny Holding, H. Gerry Taylor, Amina Abubakar, Jane Kvalsvig and Kevin Connolly 34 Perinatal Iron Deficiency and Neurocognitive Development Emily C. Radlowski and Rodney W. Johnson 45 Does Docosahexaenoic Acid Supplementation in Term Infants Enhance Neurocognitive Functioning in Infancy? Alexandra E. Heaton, Suzanne J. Meldrum, Jonathan K. Foster, Susan L. Prescott and Karen Simmer 57 Gluten- and Casein-Free Dietary Intervention for Autism Spectrum Conditions Paul Whiteley, Paul Shattock, Ann-Mari Knivsberg, Anders Seim, Karl L. Reichelt, Lynda Todd, Kevin Carr and Malcolm Hooper 65 Subjective Thirst Moderates Changes in Speed of Responding Associated With Water Consumption Caroline J. Edmonds, Rosanna Crombie and Mark R. Gardner 73 Habitual Fat intake Predicts Memory Function in Younger Women E. Leigh Gibson, Suzanne Barr and Yvonne M. Jeanes 85 The Effects of Breakfast on Behavior and Academic Performance in Children and Adolescents Katie Adolphus, Clare L. Lawton and Louise Dye 113 The Effect of Breakfast Cereal Consumption on Adolescents' Cognitive Performance and Mood Margaret A. Defeyter and Riccardo Russo 123 Breakfast and Cognition: Sixteen Effects in Nine Populations, No Single Recipe Tanya Zilberter and Eugene Y. Zilberter 128 Effects of Individual Glucose Levels on the Neuronal Correlates of Emotions Veronika Schöpf, Florian Ph. S. Fischmeister, Christian Windischberger, Florian Gerstl, Michael Wolzt, Karl Æ. Karlsson and Ewald Moser November 2014 Frontiers in Human Neuroscience | Nutritional influences on human neurocognitive functioning | 4 136 The Application of Near Infrared Spectroscopy in Nutritional Intervention Studies Philippa A. Jackson and David O. Kennedy 142 Neuroimaging, a New Tool for Investigating the Effects of Early Diet on Cognitive and Brain Development Elizabeth B. Isaacs November 2014 EDITORIAL published: 27 May 2014 doi: 10.3389/fnhum.2014.00358 Nutritional influences on human neurocognitive functioning Michael A. Smith 1 * and Andrew B. Scholey 2 1 Department of Psychology, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, UK 2 Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, VIC, Australia *Correspondence: michael4.smith@northumbria.ac.uk Edited and reviewed by: Hauke R. Heekeren, Freie Universität Berlin, Germany Keywords: nutrition, diet, brain, neurocognitive functioning, neuroimaging The notion that good nutrition is essential for adequate growth and sound physical wellbeing is very well established. Further, in recent years, there has been an overwhelming increase in research dedicated to better understanding how nutritional fac- tors influence cognition and behavior (Riby et al., 2012). An aim of this Research Topic was to bring together Review, Opinion and Original Research articles reflecting the current science in this discipline. These include the effects of a range of foods and nutri- tional substrates on acute and chronic human neurocognitive functioning. The 13 accepted papers which form this Research Topic cover a diverse range of topics relating nutritional fac- tors to neurocognitive functioning and performance. The articles demonstrate that neurocognitive performance is influenced by nutritional factors ranging from the dietary level (e.g., whole diet and meal composition) through to effects of macronutri- ents (such as glucose and omega-3 fatty acids) and micronutrients (vitamins, iron) on neurocognitive performance. An objective of this research topic was to consider how vari- ous nutritional factors impact upon neurocognitive functioning at different stages of the lifespan. A number of the submis- sions focused on effects of nutrition in childhood, during which time nutrition plays an important role in growth and develop- ment, including via influences on constituents of the human central nervous system. A review by Nyaradi et al. (2013) con- sidered the role of nutrition from a very broad perspective on neurocognitive development from the prenatal period through to childhood. This suggested that while observational studies have supported an important role for several individual nutrients (such as omega-3 fatty acids, B vitamins, iron) in the neurocog- nitive development of children, intervention studies aimed at supplementing intake of these individual nutrients have demon- strated inconclusive benefits. The authors of this review also highlighted the beneficial neurocognitive effects of breastfeed- ing and regular breakfast consumption as well as the impairing neurocognitive effects of childhood malnutrition. Kitsao-Wekulo et al. (2013) aimed to extend current understanding of this link between childhood malnutrition and poor cognitive outcomes, by investigating nutritional status as a mediator of the relation- ship between several socio-demographic variables and cognitive function in a sample of predominantly rural-dwelling Kenyan children. Nutritional status was found to mediate the relation- ship between socio-demographic factors and (i) language, (ii) motor function, and (iii) executive functioning in this study. With respect to specific micronutrient deficiencies that translate to adverse neurocognitive outcomes, Radlowski and Johnson (2013) reviewed the literature relating to the most common global nutri- ent deficiency, namely iron deficiency. They report that maternal anemia during the perinatal period increases the risk of delayed neurocognitive development. A further nutrient for which intake is typically below recommended levels in Western individuals is the omega-3 docosahexaenoic acid (DHA). Low dietary lev- els of this essential fatty acid are potentially problematic given (i) the involvement of this nutrient in mediating several critical brain functions, and (ii) DHA is derived from the diet alone. Similarly to the review of Nyaradi et al. (2013), Heaton et al. (2013) review concludes that dietary and plasma DHA levels in infancy appear to be associated with enhanced cognitive devel- opment, but that RCTs investigating infant DHA supplementa- tion have been inconclusive with respect to beneficial effects on cognitive development. However, these authors note substantial methodological issues with RCTs of infant DHA supplementa- tion studies, which could in part explain the equivocal findings (see also Meldrum et al., 2011). In a further review by Whiteley et al. (2013), it was argued that several dietary interventions have been effective in attenuating the neurocognitive and other adverse psychological outcomes in developmental disorders. The authors focused specifically on an intervention involving dietary elimi- nation of gluten (the major protein in wheat, barley and rye) and casein (found in mammalian dairy products), and reported that this gluten and casein free dietary intervention was effective in enhancing such functions as language, attention and motor control in individuals with autism spectrum disorders. Caroline Edmonds has conducted several studies investigating the influence of hydration status on cognitive functioning, with previous studies observing that access to water improves cognitive performance in children (Edmonds and Jeffes, 2009). In the paper included in this Research Topic, Edmonds et al. (2013) observed that beneficial effects of water consumption may be limited to individuals with relatively higher levels of subjective thirst, with thirsty individuals who were not provided with water exhibiting slower simple reaction times compared with (i) those who were administered water and (ii) those who were not administered water but reported lower levels of subjective thirst. In a further empirical study, Gibson et al. (2013) found that younger women with a higher dietary intake of saturated fat showed deficits in learning and memory. Three papers accepted into our Research Topic considered the role of breakfast, which has been argued by many nutritionists Frontiers in Human Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 358 | HUMAN NEUROSCIENCE 5 Smith and Scholey Nutritional influences on human neurocognitive functioning to be the “most important meal of the day,” in neurocogni- tive performance. A review by Adolphus et al. (2013) reported that (i) the quality and frequency of the habitual breakfast meal and (ii) engagement with school breakfast programmes in chil- dren and adolescents influences academic attainment. In addi- tion Defeyter and Russo (2013) investigated the acute effect of breakfast consumption (compared to fasting) in adolescent non- habitual breakfast consumers, and observed that breakfast con- sumption enhanced verbal memory (under conditions of greater cognitive load) and backwards counting performance. However, no effects were observed in a range of other cognitive domains. Conversely, Zilberter and Zilberter (2013) highlight the equivocal findings of previous studies investigating the relationship between breakfast consumption and neurocognitive performance. These authors report that several different breakfast effects which have been investigated previously (e.g., glycemic load of the break- fast meal, nutritional composition, breakfast vs. no breakfast) have yielded positive, negative, and null effects on neurocognitive performance across a range of different populations under inves- tigation. Thus it appears that more studies are needed to ascertain the specific benefits of breakfast on neurocognitive performance. Finally, in recent years neuroimaging studies have made a substantial contribution to our understanding of the neurocogni- tive mechanisms underpinning nutritional influences on human cognitive performance. Three papers within this Research Topic specifically discuss the role of neuroimaging in investigating the link between nutrition and cognitive functioning. With respect to carbohydrate intake and neurocognitive performance, it is well established that glucose ingestion enhances memory per- formance, but no such beneficial memory effect of glucose is typically observed for emotionally laden stimuli (Smith et al., 2011). Schopf et al. (2013) report that following glucose ingestion, the hypothalamus becomes inactive in response to emotional material, providing a mechanistic explanation for the previously observed behavioral observations. Further, Jackson and Kennedy (2013) discuss the ways in which near-infrared spectroscopy has proven useful in detecting changes in cerebral blood flow following ingestion of dietary constituents including caffeine, polyphenols and omega-3 fatty acids. A paper which reviewed the literature relating to neuroimaging studies that have investigated the mechanisms underpinning the influence of early diet on cog- nitive and brain development by Isaacs (2013) provides a sound overview of the work which has been conducted on this topic. In summary, it is clear that nutritional status, diet and the ingestion of a range of nutrients impacts upon neurocogni- tive development, function, and performance. The papers within this Research Topic consider a range of these effects. However, equivocal findings have emerged from many studies which have investigated the relationship between nutrition and cognition. Neuroimaging studies are informative with respect to the pre- cise mechanisms which mediate these effects, and future studies in this area will contribute greatly to our understanding of the relationship between nutrition, diet and human neurocognitive functioning. REFERENCES Adolphus, K., Lawton, C. L., and Dye, L. (2013). The effects of breakfast on behavior and academic performance in children and adolescents. Front. Hum. Neurosci. 7:425. doi: 10.3389/fnhum.2013. 00425 Defeyter, M. A., and Russo, R. (2013). The effect of breakfast cereal consumption on adolescents’ cognitive performance and mood. Front. Hum. Neurosci. 7:789. doi: 10.3389/fnhum.2013.00789 Edmonds, C. J., Crombie, R., and Gardner, M. R. (2013). Subjective thirst moder- ates changes in speed of responding associated with water consumption. Front. Hum. Neurosci. 7:363. doi: 10.3389/fnhum.2013.00363 Edmonds, C. J., and Jeffes, B. (2009). Does having a drink help you think? 6-7-Year-old children show improvements in cognitive performance from baseline to test after having a drink of water. Appetite 53, 469–472. doi: 10.1016/j.appet.2009.10.002 Gibson, E. L., Barr, S., and Jeanes, Y. M. (2013). Habitual fat intake pre- dicts memory function in younger women. Front. Hum. Neurosci. 7:838. doi: 10.3389/fnhum.2013.00838 Heaton, A. E., Meldrum, S. J., Foster, J. K., Prescott, S. L., and Simmer, K. (2013). Does docosahexaenoic acid supplementation in term infants enhance neurocognitive functioning in infancy? Front. Hum. Neurosci. 7:774. doi: 10.3389/fnhum.2013.00774 Isaacs, E. B. (2013). Neuroimaging, a new tool for investigating the effects of early diet on cognitive and brain development. Front. Hum. Neurosci. 7:445. doi: 10.3389/fnhum.2013.00445 Jackson, P. A., and Kennedy, D. O. (2013). The application of near infrared spec- troscopy in nutritional intervention studies. Front. Hum. Neurosci. 7:473. doi: 10.3389/fnhum.2013.00473 Kitsao-Wekulo, P., Holding, P., Taylor, H. G., Abubakar, A., Kvalsvig, J., and Connolly, K. (2013). Nutrition as an important mediator of the impact of back- ground variables on outcome in middle childhood. Front. Hum. Neurosci. 7:713. doi: 10.3389/fnhum.2013.00713 Meldrum, S. J., Smith, M. A., Prescott, S. L., Hird, K., and Simmer, K. (2011). Achieving definitive results in long-chain polyunsaturated fatty acid supple- mentation trials of term infants: factors for consideration. Nutr. Rev. 69, 205–214. doi: 10.1111/j.1753-4887.2011.00381.x Nyaradi, A., Li, J., Hickling, S., Foster, J., and Oddy, W. H. (2013). The role of nutrition in children’s neurocognitive development, from pregnancy through childhood. Front. Hum. Neurosci. 7:97. doi: 10.3389/fnhum.2013.00097 Radlowski, E. C., and Johnson, R. W. (2013). Perinatal iron deficiency and neurocognitive development. Front. Hum. Neurosci. 7:585. doi: 10.3389/fnhum.2013.00585 Riby, L. M., Smith, M. A., and Foster, J. K., (eds.). (2012). Nutrition and Mental Performance: A Lifespan Perspective . London: Palgrave MacMillan. Schopf, V., Fischmeister, F. P., Windischberger, C., Gerstl, F., Wolzt, M., Karlsson, K. A. E., et al. (2013). Effects of individual glucose levels on the neuronal correlates of emotions. Front. Hum. Neurosci. 7:212. doi: 10.3389/fnhum.2013.00212 Smith, M. A., Riby, L. M., Eekelen, J. A., and Foster, J. K. (2011). Glucose enhancement of human memory: a comprehensive research review of the glucose memory facilitation effect. Neurosci. Biobehav. Rev. 35, 770–783. doi: 10.1016/j.neubiorev.2010.09.008 Whiteley, P., Shattock, P., Knivsberg, A. M., Seim, A., Reichelt, K. L., Todd, L., et al. (2013). Gluten- and casein-free dietary intervention for autism spectrum conditions. Front. Hum. Neurosci. 6:344. doi: 10.3389/fnhum.2012.00344 Zilberter, T., and Zilberter, E. Y. (2013). Breakfast and cognition: sixteen effects in nine populations, no single recipe. Front. Hum. Neurosci. 7:631. doi: 10.3389/fnhum.2013.00631 Conflict of Interest Statement: Andrew Scholey has received research funding and consultancy from the health supplement industry. The authors declare that the manuscript was prepared in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received: 02 April 2014; accepted: 09 May 2014; published online: 27 May 2014. Citation: Smith MA and Scholey AB (2014) Nutritional influences on human neu- rocognitive functioning. Front. Hum. Neurosci. 8 :358. doi: 10.3389/fnhum.2014.00358 This article was submitted to the journal Frontiers in Human Neuroscience. Copyright © 2014 Smith and Scholey. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licen- sor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Human Neuroscience www.frontiersin.org May 2014 | Volume 8 | Article 358 | 6 REVIEW ARTICLE published: 26 March 2013 doi: 10.3389/fnhum.2013.00097 The role of nutrition in children’s neurocognitive development, from pregnancy through childhood Anett Nyaradi 1,2 *, Jianghong Li 1,3,4 , Siobhan Hickling 1,2 , Jonathan Foster 1,5,6,7 and Wendy H. Oddy 1 1 Centre for Child Health Research, Telethon Institute for Child Health Research, The University of Western Australia, Perth, WA, Australia 2 School of Population Health, The University of Western Australia, Perth, WA, Australia 3 Centre for Population Health Research, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia 4 Social Science Research Center, Berlin, Germany 5 School of Psychology and Speech Pathology, Curtin University, Perth, WA, Australia 6 Neurosciences Unit, Health Department of Western Australia, Perth, WA, Australia 7 School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, Australia Edited by: Andrew Scholey, Swinburne University, Australia Reviewed by: Sebastian J. Lipina, Unidad de Neurobiología Aplicada, Argentina Leigh Gibson, University of Roehampton, UK *Correspondence: Anett Nyaradi, Telethon Institute for Child Health Research, The University of Western Australia, 100 Roberts Road, Subiaco, PO Box 855, West Perth, WA 6008, Australia. e-mail: anyaradi@ichr.uwa.edu.au This review examines the current evidence for a possible connection between nutritional intake (including micronutrients and whole diet) and neurocognitive development in childhood. Earlier studies which have investigated the association between nutrition and cognitive development have focused on individual micronutrients, including omega-3 fatty acids, vitamin B12, folic acid, choline, iron, iodine, and zinc, and single aspects of diet. The research evidence from observational studies suggests that micronutrients may play an important role in the cognitive development of children. However, the results of intervention trials utilizing single micronutrients are inconclusive. More generally, there is evidence that malnutrition can impair cognitive development, whilst breastfeeding appears to be beneficial for cognition. Eating breakfast is also beneficial for cognition. In contrast, there is currently inconclusive evidence regarding the association between obesity and cognition. Since individuals consume combinations of foods, more recently researchers have become interested in the cognitive impact of diet as a composite measure. Only a few studies to date have investigated the associations between dietary patterns and cognitive development. In future research, more well designed intervention trials are needed, with special consideration given to the interactive effects of nutrients. Keywords: nutrition, cognitive development, children, micronutrients, diet quality INTRODUCTION Cognition represents a complex set of higher mental functions subserved by the brain, and includes attention, memory, thinking, learning, and perception (Bhatnagar and Taneja, 2001). Cognitive development in pre-schoolers is predictive of later school achieve- ment (Tramontana et al., 1988; Clark et al., 2010; Engle, 2010). As Ross and Mirowsky (1999) state: “Schooling builds human capital - skills, abilities, and resources—which ultimately shapes health and well-being.” Indeed, more education has been linked to better jobs, higher income, higher socio-economic status, bet- ter health care access and housing, better lifestyle, nutrition, and physical activity (Florence et al., 2008), which are all well-known health determinants. Education increases an individual’s sense of personal control and self-esteem; these factors have also been shown to influence better health behavior (Ross and Mirowsky, 1999; Logi KristjÆnsson et al., 2010). Academic achievement is important for future personal health, and is therefore a significant concern for public health. Cognitive development is influenced by many factors, includ- ing nutrition. There is an increasing body of literature that suggests a connection between improved nutrition and optimal brain function. Nutrients provide building blocks that play a criti- cal role in cell proliferation, DNA synthesis, neurotransmitter and hormone metabolism, and are important constituents of enzyme systems in the brain (Bhatnagar and Taneja, 2001; Lozoff and Georgieff, 2006; Zeisel, 2009; De Souza et al., 2011; Zimmermann, 2011). Brain development is faster in the early years of life com- pared to the rest of the body (Benton, 2010a), which may make it more vulnerable to dietary deficiencies. In this literature review, we assess the current research evidence for a link between nutritional intake in pregnancy and childhood and children’s cognitive development. We first discuss individual micronutrients and single aspects of diet, which represents earlier research in this area. We next consider the more encompassing aspects of diet, which have emerged as researchers became more interested in diet as a comprehensive measurement. The most recent research trend in this area suggests a broader analysis of the role of nutrition in neurocognitive development, which we offer here in comparison to previous reviews (Black, 2003b; Bellisle, 2004; Stevenson, 2006; Georgieff, 2007; Benton, 2010a). BRAIN DEVELOPMENT IN HUMANS The understanding of the functional and structural development of the human brain has emerged from a range of methodolo- gies (including clinical lesion and experimental animal studies) and lately as a result of greatly improved neuroimaging meth- ods, in particular Positron Emission Tomography and Magnetic Resonance Imaging (MRI) (Levitt, 2003; Uddin et al., 2010). Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | HUMAN NEUROSCIENCE 7 Nyaradi et al. Nutrition and children’s cognitive development Brain development is a temporally extended and complex pro- cess, with different parts and functions of the brain developing at different times (Grossman et al., 2003). By 5 weeks after concep- tion in humans, the anterior-posterior and dorsal-ventral axes of the neural tube have already developed (Levitt, 2003). The cor- tical plate (which is the forerunner of the cerebral cortex) and some inter-neuronal connections form from 8 to 16 weeks of gestation (Kostovi ́ c et al., 2002; Levitt, 2003). From 24 weeks of gestation until the perinatal period, the neurons in the corti- cal plate die and are replaced by more mature cortical neurons. During this time, significant refinement in neural connections take place (Levitt, 2003). From 34 weeks post-conception until 2 years of age, peak synapse development, and significant brain growth occurs (Huttenlocher and Dabholkar, 1997; Levitt, 2003). By preschool age, synaptic density has reached the adult level. The myelination of some parts of the brain (particularly those that control higher cognitive functions, such as the frontal lobes) con- tinues well into adolescence, whilst myelination occurs earlier in other parts of the brain that coordinate more primary functions (Toga et al., 2006). Although the gray matter (which contains the bodies of nerve cells) reaches asymptote by the age of 7–11 in different regions of the brain, it is thought that the growth of the white matter (which represents axonal nerve tracts) continues beyond 20 years of age. Studies have shown that the maturation of specific brain areas during childhood is associated with devel- opment of specific cognitive functions such as language, reading, and memory (Nagy et al., 2004; Deutsch et al., 2005; Giedd et al., 2010). The development of the frontal lobes, which are believed to control higher cognitive functions (including planning, sequenc- ing and self-regulation), appears to occur in growth spurts during the first 2 years of life, and then again between 7 and 9 years of age and also around 15 years of age (Thatcher, 1991; Bryan et al., 2004). The development of some subcortical structures includ- ing the basal ganglia, amygdala, and hippocampus (which are also centrally involved in some mediating higher cognitive func- tions, including memory, executive functions, and emotion) also continues until late adolescence. In addition, a meta-analysis has confirmed a connection between the size of the hippocampus and memory performance during brain development in children and young adults (Van Petten, 2004). Overall, the research evidence suggests that cognitive development is strongly connected with micro and macro-anatomical changes which take place through- out childhood (Levitt, 2003; Herlenius and Lagercrantz, 2004; Ghosh et al., 2010). Individual brain development follows a genetic program which is influenced by environmental factors including nutri- tion (Bryan et al., 2004; Toga et al., 2006; Giedd et al., 2010). Environmental influences may modify gene expression through epigenetic mechanisms, whereby gene function is altered through the processes of DNA methylation, histone modification and the modulating effect of non-coding RNAs, without the alteration of the gene sequence per se . These epigenetic factors can cause long lasting or even heritable changes in biological programs (Levi and Sanderson, 2004; Rosales et al., 2009; Murgatroyd and Spengler, 2011; Lillycrop and Burdge, 2012). It has been shown in animal and more recently in human studies that nutrition is one of the most salient environmental factors, and that nutrition can have a direct effect on gene expression (Levi and Sanderson, 2004; Rosales et al., 2009; Attig et al., 2010; Lillycrop and Burdge, 2011; JimØnez-Chillarón et al., 2012). One of the first and best known human studies in the rapidly growing field of “Nutritional Epigenomics” relates to the Dutch Hunger Winter during the 1940’s in which the offspring of mothers exposed to famine dur- ing pregnancy had an increased risk of cardiovascular, kidney, lung, and metabolic disorders and reduced cognitive functions (Roseboom et al., 2006; De Rooij et al., 2010). More specifi- cally, evidence has been obtained of hypo- and hyper-methylated DNA segments from the blood cells of the affected individuals (Heijmans et al., 2008). Evidence suggests that the timing of nutritional deficien- cies can significantly affect brain development. For example, it is well known that folic acid deficiency between 21 and 28 days after conception (when the neural tube closes) predis- poses the foetus to a congenital malformation, called a neural tube defect. Hence, this is a critical period, because during that time an irreversible change in the brain structure and func- tion occurs if there is inadequate folic acid present (Blencowe et al., 2010). A critical period is a specific period within a sensitive timeframe (Knudsen, 2004). A sensitive period tends to reflect a broader timeframe; during such a developmen- tal period the brain is more sensitive to specific interventions. However, skills and abilities can still be acquired outside this time period, albeit with less proficiency (Knudsen, 2004). An example is that deaf children who receive cochlear implants within a sensitive period for brain development (i.e., before the age of 3–5 years) show better language development than those who receive a cochlear implant after this period (Penhune, 2011). Since rapid brain growth occurs during the first 2 years of life (and by the age of 2 the brain reaches 80% of its adult weight), this period of life may be particularly sensitive to deficiencies in diet (Bryan et al., 2004; Lenroot and Giedd, 2006). Adolescence is also a significant and sensitive developmental period, with research indicating that structural reorganization, brain and cognitive maturation and—in particular—major developments in the pre- frontal cortex take place during puberty (Luna and Sweeney, 2001; Sisk, 2004; Peper et al., 2009; Asato et al., 2010; Blakemore et al., 2010). DIETARY INFLUENCES ON COGNITIVE DEVELOPMENT MICRONUTRIENTS AND COGNITIVE DEVELOPMENT Omega-3 fatty acids In recent years, there has been an increasing interest in the effect of essential fatty acids, particularly long chain polyunsat- urated fatty acids (LCPUFA), on cognitive brain development. Of the human brain’s dry weight 60% is comprised of lipids, of which 20% are docosahexaenoic acid (DHA; which is an omega- 3 fatty acid) and arachidonic acid (AA; an omega-6 fatty acid). These represent the two core fatty acids found in gray matter (Benton, 2010b; De Souza et al., 2011). Furthermore, the sup- ply of LCPUFAs from food, especially the omega-3 fatty acids, including DHA and eicosapentaenoic acid (EPA), is frequently inadequate for children as well as for adults (Schuchardt et al., 2010). Frontiers in Human Neuroscience www.frontiersin.org March 2013 | Volume 7 | Article 97 | 8 Nyaradi et al. Nutrition and children’s cognitive development Essential fatty acids play a central functional role in brain tissue. They are not only the basic components of neuronal mem- branes, but they modulate membrane fluidity and volume and thereby influence receptor and enzyme activities in addition to affecting ion channels. Essential fatty acids are also precursors for active mediators that play a key role in inflammation and immune reaction. They promote neuronal and dendritic spine growth and synaptic membrane synthesis, and hence influence signal pro- cessing, and neural transmission. In addition, essential fatty acids regulate gene expression in the brain (McCann and Ames, 2005; Eilander et al., 2007; Innis, 2007; Cetina, 2008; Wurtman, 2008; Ramakrishnan et al., 2009; Ryan et al., 2010; Schuchardt et al., 2010; De Souza et al., 2011). Therefore, the existing literature strongly suggests that essential fatty acids are critical for brain development and function. It has been suggested that the fast growth of the human cere- bral cortex during the last two million years was strongly related to the balanced dietary intake of LCPUFAs (Broadhurst et al., 1998), specifically with an equal ratio of omega-6 and omega-3 fatty acids in the diet (Simopoulos, 1999). Evidence proposes that the modern Homo sapiens, whose brain developed signifi- cantly relative to its ancestors, lived near rivers and oceans, where seafood and fish were abundant (Crawford et al., 1999). The rise in intellectual and brain development in Homo Sapiens also coin- cided with tool making and language development (Crawford et al., 1999; Broadhurst et al., 2002). During the last 150 years, it is believed that the balance of omega-6 to omega-3 fatty acids has shifted in favor of omega-6 fatty acids in the diet, resulting in a ratio of 20–25:1 and a dietary deficiency in omega-3 fatty acids (Simopoulos, 1999). A diet that is deficient in omega-3 fatty acids may have health and developmental implications (Simopoulos, 2008). A number of epidemiological studies have shown a positive association between maternal fish intake (which is a rich source of omega-3 fatty acids) during pregnancy and cognitive devel- opment in children (Daniels et al., 2004; Hibbeln et al., 2007; Jacobson et al., 2008; Oken et al., 2008a,b; Boucher et al., 2011). Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK regarding fish consumption and child cog- nitive development were analyzed in two studies (Daniels et al., 2004; Hibbeln et al., 2007). The earlier study found evidence that higher maternal fish consumption was associated with higher lan- guage and social skills (after appropriate adjustments) in 7421 British children assessed at 15 months, using the MacArthur Communicative Development Inventory (MCDI), and at 18 months using the Denver Developmental Screening test (Daniels et al., 2004). The later ALSPAC study demonstrated that those children whose mothers consumed lower levels of seafood during pregnancy had lower IQ, measured by the Wechsler Intelligence Scale for Children III (WISC-III) at the age of 8 (after adjusting for a wide range of relevant covariates). Lower maternal seafood consumption was also linked to suboptimal behavior at age seven (measured using the Child Behavior Checklist) and to lower lev- els of social, fine motor and language development (measured using the Denver Developmental Screening