TY - JOUR
AU - Schneider, Nora
AB - Abstract Executive functions refer to a set of higher-order cognitive processes involved in the control and organization of information to serve goal-directed behaviors. Skills in executive functioning are developed throughout childhood and adolescence and have been shown to be predictive of academic achievement. The coordination of these complex processes is critically dependent on brain maturation and connectivity, including key neurodevelopmental processes like myelination and synaptogenesis. Among other factors, research highlights the influential effect of nutrition and diet on these neurodevelopmental processes, which may impact executive function performance in healthy and deficient populations. This review considers the research to date on the role of key nutrients that have been identified for executive function development and their underlying neurophysiological processes in school-aged children. brain development, cognitive function, myelination, nutrition, synaptogenesis INTRODUCTION The ability to coordinate one’s thoughts and actions is associated with the development of executive function (EF), an umbrella term referring to top-down neurocognitive processes responsible for purposeful and goal-directed behavior.1 EFs are comprised of 3 core, interrelated functions.2 The first of these, inhibitory control, refers to the ability to control one’s attention, behavior, thoughts, and emotions to override a strong internal predisposition and instead do what is more appropriate.3 The second core EF, working memory (WM), involves holding information in mind and mentally working with it. The third core EF is called cognitive flexibility, which involves switching between two different concepts, thinking about multiple concepts, and having the ability to change perspective.3 From these core components, many higher-order processes can be built, including goal selection, reasoning, problem solving, planning, sustained attention, and self-regulation.3,4 These executive processes are essential for almost every aspect of life, as they play an important role in many aspects of a child’s behavior, cognitive functioning, emotional control, and social skills.3 The developmental importance of these skills in school-aged children is further realized from evidence demonstrating EFs to be predictive of academic achievement.5–7 The maturation of specific cognitive functions parallels the maturation of the brain’s structure and function.8 The protracted development of EFs, which begins in early childhood and continues through adolescence,4,9 is suggested to be due to the protracted development of the frontal networks, which are an important contributor to the neural basis of EFs. The development of EFs and their underlying brain processes is influenced by a variety of biological and environmental factors,10 with nutrition being one of the most readily modifiable factors in children.11 Consequently, a child’s dietary intake of key nutrients throughout childhood has an important role in providing the best environment for EF development. Maternal and early life nutrition can have effects on EF outcomes in later life,12,13 as the rapidly developing brain is particularly vulnerable to nutrient insufficiency.14 During this time, deficiencies in certain nutrients can have long-lasting effects due to sensitive periods in brain development.15 Less is currently known, however, about the effect of nutrient intake during the school years on EF. Accordingly, the aim of the current review is to summarize existing evidence on key nutrients identified as contributing towards EF development in early to late childhood, considering: neurophysiological maturation processes that are important for EF development; key nutrients that have been identified as important for the maturation of these processes; and nutritional studies investigating behavioral changes in EF and school-aged children. NEUROPHYSIOLOGICAL PROCESSES ASSOCIATED WITH EF DEVELOPMENT The frontal lobe is heavily involved in the control and coordination of “higher order” executive functions such as planning, developing strategies, problem solving, focusing attention, and in the inhibition of prepotent responses.16,17 The ongoing maturation of the frontal areas in school-age children is reflected in the brain areas recruited during EF tasks and in functional activation differences when compared with adult patterns.18,19 This protracted development is suggested to be due to the delayed maturation of higher-order association areas such as the prefrontal cortex (PFC) and lateral temporal cortices.20 The importance of the frontal lobe for EF development also derives from rich connections with almost all other parts of the brain.17 EFs recruit several brain regions and circuits and therefore depend on the integrity of not just frontal lobe connections, but also their structural and functional connectivity with other brain regions. Important related brain maturational processes across childhood include myelination, synaptogenesis, and synaptic pruning. Myelination Myelination refers to the formation of a myelin sheath that surrounds neuronal axons; this process acts to speed up neuronal action potential propagation, enabling efficient and rapid transmission of cell signaling.8 Myelination is critical for EF development in young children, as processing speed increases the amount of information that can be mentally manipulated, and the complexity of such manipulation.21 Its importance is highlighted in studies linking the neural architecture that forms bundles of myelinated nerve fibers, known as white matter microstructure, to children’s executive and applied abilities, including task-switching,22 spatial WM,23 inhibition,24 reading ability,25 and arithmetic skills.26 Furthermore, developmental changes in processing speed have been shown to mediate improvements in WM, which in turn contribute towards level of intelligence.27 By means of diffusion tensor imaging (DTI), structural brain connectivity can be associated with behavioral performance and cognitive development. Namely, the emergence of specific cognitive skills and the myelination of brain regions and networks subserving those functions have been found to coincide.25,28,29 For example, a correlation between the maturation of white matter and improvements in WM in 8–18-year-olds has been demonstrated.25 Furthermore, frontostriatal connectivity, which is that between the PFC and striatum, has been shown to not only increase with age, but also to be correlated with inhibitory task performance in participants aged 7–31.30 This latter study suggests that enhanced connectivity in frontostriatal fiber tracts contributes to children’s developing capacity for cognitive control, and moreover that variability in myelination and the regularity of frontostriatal connections may contribute to individual differences in individuals of the same age. Synaptogenesis and synaptic pruning Synaptogenesis and synaptic pruning are defining processes during brain maturation. Synaptogenesis refers to the formation of new synapses, a process that occurs throughout childhood before slowing across adolescence.31 Synaptic density peaks in the early years of life; thus, when compared with an adult brain, the immature brain has a greater number of neural connections.32 The fine-tuning of neuronal networks occurs via the process of synaptic pruning, which refers to the elimination of synapses that are not functionally appropriate.9 This process is suggested to involve adjustment of the excitatory/inhibitory balance of individual neurons and within networks of neurons, with inhibitory neurons having a critical role in the PFC for mediating information flow through local networks.33,34 Previous work has identified five periods of rapid growth in the frontal lobes, with the first growth spurt ranging from birth to 5 years of age and the last spanning through adolescence into early adulthood.35 Each growth spurt is linked with significant gains in EF skills and performance, with attentional control being one of the first to develop and executive control developing in latter stages.4 As these growth spurts occur across childhood and adolescence, the childhood period may provide a developmental window in which appropriate nutrition can foster EF development. NUTRIENTS FOR EF DEVELOPMENT AND EF-RELATED NEURAL PROCESSES IN CHILDREN Nutrients provide the building blocks for the brain to create and maintain crucial connections important for EF development.36 The importance of early life nutrition, particularly during the first 2 years, is well established37; the importance of nutrition beyond early childhood, however, is not as clearly communicated, despite ample knowledge of the continuing development of particular brain regions being available. The frontal lobe is one of the slowest areas to myelinate, beginning at approximately 6 months and continuing throughout childhood, adolescence, and adulthood.16 Knowledge of this protracted development is based on several postmortem morphometric and in vivo imaging studies, which suggest that brain maturation develops posteriorly to anteriorly.11 The frontal lobe undergoes a rapid phase of development during childhood, making children highly sensitive to positive and negative experiences.4 This period of vulnerability may present a prime opportunity to foster EF development via the provision of critical nutrients across childhood. In the next section of this review, the role of key nutrients identified as required for the underlying neurophysiological processes of EF is considered, namely myelination and synaptogenesis, and existing clinical evidence supporting the relation between EF and the intake of the identified key nutrients is reviewed. To identify nutrients related to EF development, a search of the literature was performed on PubMed and Web of Science for articles investigating executive function and nutrition in school-aged children published between 1990 and 2019. Search terms included “child” OR “children” AND “nutrient” OR “micronutrient*” OR “macronutrient*” “vitamin” OR “mineral” OR “lipid*” OR “fatty acids” AND “executive function” OR “cognitive function” OR “higher cognitive functioning” OR “cognitive control” OR “inhibit” OR “working memory” OR “cognitive flexibility” OR “mental flexibility” OR “attention” OR “goal directed” and combinations thereof. Studies were eligible for this review if they were in English and considered nutritional associations with EF benefits (observational studies) or nutritional interventions targeted at EF changes (interventional studies). Studies were excluded if they: assessed general cognitive functioning (eg, intelligence), were based on preclinical investigations, or focused on disease conditions or premature birth. Full texts were reviewed and agreed upon for inclusion by 2 members of the study team, and reference lists of key studies were examined to identify any further relevant articles. Table 112,38–65 provides a summary of the identified studies investigating nutrients and executive function in school-aged children. Table 1 Summary of studies investigating nutrients and executive function in school-aged children Author (year) . Sample size, age, health status . Study design, country . Methods . Executive function measuresa . Reported findings . Iron Algarín et al (2013)38 n = 132 6–18 months/ 10 years IDA (n = 69) vs non-IDA (n = 63) Longitudinal, Chile Follow-up study from early childhood to 10 years in children with and without IDA. Cognitive tasks administered. Blood analysis excluded three 10-year-olds with current IDA Go/No-Go task IDA in early childhood was associated with slower reaction times and poorer inhibitory control 8 to 9 years after iron therapy Lukowski et al (2010)12 n = 132 1–2 years/19 years IDA (n = 33) vs non-IDA (n = 81) Longitudinal, Costa Rica Follow-up study from early childhood to 19 years in children with and without IDA. Cognitive tasks administered TMT, intra-/extra-dimensional shift, Stockings of Cambridge, spatial working memory, RVIP Children with IDA performed worse on the TMT part B, intra-/extra-dimensional shift, and Stockings of Cambridge planning task at 19 years of age Scott et al (2018)40 n = 140 12–16 years Deficient RCT, India Randomly assigned to receive either iron biofortified millet (86 ppm) or conventional pearl millet (21–52 ppm) for 6 months. Hb, ferritin, and TfR were measured, and body iron was calculated at baseline and after 4 and 6 months. Cognitive tasks administered pre- and post-intervention Go/No-go task and Attentional Network Task Treatment effects seen for by 4 months for ferritin, TfR, and body iron, and at 6 months for TfR, indicating the efficacy of intervention. The fortified group had greater improvement in inhibition and executive control Omega-3 polyunsaturated fatty acids Adjepong et al (2018)39 n = 307 2–6 years 70%, 85%, and 97% had normal scores for stunting, malnutrition, and wasting, respectively Cross-sectional, Ghana Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Positive associations with DCCS performance were observed for whole-blood DHA, total n-3 fatty acids, and dihomo-gamma-linolenic acid. Subjects with the highest levels of total omega-3 fatty acids and DHA were 3 to 4 times more likely to pass at least one condition of the DCCS compared with those with the lowest levels Jumbe et al (2016)41 n = 130 4–6 years 16–20% of sample had malaria Cross-sectional, Tanzania Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Subjects with sufficient levels of whole-blood EFAs were nearly 4 times more likely to successfully complete DCCS. Individually, neither DHA nor EPA was associated with executive function Kennedy et al (2009)48 n = 190 10–12 years Healthy RCT, UK Three groups: 0 mg, 400 mg, or 1000 mg DHA per day for 8 weeks. No blood measures taken to determine pre-and post-DHA blood content. Cognitive tasks administered pre- and post-intervention Numeric working memory DHA supplementation had no consistent or interpretable effect on working memory Montgomery et al (2013)50 n = 493 7–9 years Healthy Cross-sectional, UK Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Recall of digits forward, recall of digits backward, academic performance Lower DHA and EPA concentrations associated with poorer performance on recall of digits forward assessing working memory and reading performance Montgomery et al (2018)51 n = 376 7–9 years Healthy RCT, UK 600 mg/d DHA or placebo for 16 weeks. Fingerstick blood tests taken pre- and post-intervention to assess compliance. Cognitive tasks administered pre- and post-intervention Recall of digits forward, recall of digits backward DHA group had significantly higher blood DHA levels post-intervention compared with the placebo group. No consistent differences between DHA and placebo group on either recall task Portillo-Reyes et al (2014)54 n = 78 8–12 years Malnourished RCT, Mexico Two omega-3 capsules (60 mg of DHA and 90 mg of EPA) or placebo/day for 3 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Matrix reasoning, letter–number sequencing, Stroop color and word test, TMT-B, academic performance Positive effect of omega-3 supplementation on EF measures, including matrix reasoning, Stroop color and color–word tasks. letter–number sequencing and matrix reasoning improved in more than 70% of omega-3–supplemented subjects Ryan and Nelson (2008)55 n = 175 4–5 years Healthy RCT, USA 400 mg/d DHA or placebo for 4 months. Capillary whole-blood samples taken pre- and post-intervention to determine DHA, ARA, and EPA levels. Cognitive tasks administered pre- and post-intervention Day–night Stroop Test and adapted CPT Mean capillary whole-blood content of DHA increased by 300%, EPA content doubled, and ARA decreased by 9% in DHA supplementation group. No change in placebo group. No difference between groups found for measures of EF. Authors suggest measures could have been compromised by unexpected ceiling effects Sheppard and Cheatham (2013)57 n = 70 7–9 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Spatial working memory, spatial span, Stockings of Cambridge, intra-extra dimensional set shift The ratio of n-6 to n-3 fatty acids was a significant predictor of EF scores in general. N-6 and n-3 mean intake variables predicted planning Sheppard and Cheatham (2017)58 n = 78 7–12 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Stockings of Cambridge, Spatial Working Memory, Paired-associate learning, Electric Maze Task Dietary and plasma n–6 to n–3 ratio and n–3 predicted performance on spatial working memory and Stockings of Cambridge planning task in subjects aged 7 to 12 years Zinc Chiplonkar and Kawade (2014)44 n = 403 10–16 years High deficiency prevalence Cross-sectional, India Venous blood samples collected to determine zinc levels. Cognitive tasks administered RPM Higher plasma and erythrocyte zinc associated with better RPM performance Sandstead et al (1998)56 n = 740 6–9 years Deficient RCT, China 20 mg zinc (Z), 20 mg zinc + MN (ZM), or MN alone provided 6/day per week for 10 weeks. Hb, serum ferritin, plasma and hair zinc and whole blood were assessed pre- and post-intervention via venous blood sample. Cognitive tasks were administered pre- and post-intervention CPAS-R modified oddity learning task and modified CPT Plasma zinc concentrations increased following intervention in ZM and M groups, but not in the Z group. Hair zinc decreased after all treatments. Performance on both the modified oddity learning and CPT tasks improved in the ZM group more than with Z or MN alone Tupe and Chiplonkar (2009)59 n = 180 10–16 years Not stated RCT, India Three groups: 20 mg ayurvedic zinc tablet (16.6 mg elemental zinc, 0.74 mg iron); zinc-rich snacks; control group. Supplementation provided 6/day per week for 10 weeks. Venous blood sample collected to determine plasma zinc and iron Cognitive tasks were administered pre- and post-intervention RPM Plasma zinc increased in both zinc tablet and enriched diet groups, but not control. Both zinc groups increased the RPM task score, while the control remained unchanged Iodine Aboud et al (2017)42 n = 1,262 4–6 years Deficient RCT, Ethiopia Intervention group received 4–6 months’ more exposure to iodized salt (8–10 months total) in market compared with control (4 to 6 months total). Assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention Matrix reasoning UI levels increased post-intervention following iodine supplementation compared with placebo. No significant effects were observed between groups Amarra et al (2007)43 n = 65 6–10 years Deficient (n = 34) and non-deficient (n = 31). Cross-sectional, Philippines Performed dietary recalls and assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention RPM Variance in deficit and adequate RPM performance explained by dietary intakes that met >80% RDA for energy, protein, thiamine, and riboflavin, alongside the use of iodized salt, iodine status, and stunting Gordon et al (2009)45 n = 184 10–13 years Deficient RCT, New Zealand 150 μg iodine/day or a placebo for 28 weeks. UI, serum thyroglobulin, and TT4 were assessed pre- and post-intervention via urine and fingerstick blood sample. Cognitive tasks administered pre- and post-intervention Picture concepts, matrix reasoning, letter–number sequencing UI and thyroglobulin concentration improve in the iodine supplementation group but not the placebo group. Iodine supplementation improved performance on the picture concepts and matrix reasoning tasks Huda et al (1999)46 n = 340 8–10 years Hypothyroid (n = 170) vs euthyroid (n = 170) Cross-sectional, Bangladesh Both groups were matched for school, grade level, and region. Blood samples taken to assess T4 and TSH. Cognitive tasks administered Digit Span, Corsi Block, RPM, modified Stroop, academic performance No association found between hypothyroidism and EF measures, though academic performance as assessed via reading and spelling was worse in subjects with hypothyroidism Huda et al (2001)47 n = 305 8–10 years Deficient RCT, Bangladesh 400 mg of oral Lipiodol or a placebo for 4 months. Assessed UI levels, serum thyroxine, and TSH pre- and post-intervention via venous blood sampling. Cognitive tasks administered pre- and post-intervention Digit Span, Corsi Block, modified Stroop Iodine supplementation increased UI levels in intervention group, but levels remained below normal. No difference observed in serum thyroxine, TSH levels, or in any cognitive test. van den Briel et al (2000)60 n = 196 7–11 years Deficient RCT, Benin 540g I/L of iodized oil or placebo for 24 weeks. UI concentration, TSH, serum ferritin, thyroglobulin, and free thyroxine were assessed pre- and post-intervention via urine and blood samples. Cognitive tasks administered pre- and post-intervention RPM Following intervention, UI concentrations improved in both groups but still classified as deficient. Pronounced improvement on RPM in subjects showing an improvement in urinary iodine status Zimmermann et al (2006)61 n = 310 10–12 years Deficient RCT, Albania 400 mg/day of iodized oil or placebo for 24 weeks. Pre- and post- intervention, a morning urine sample and fingerstick blood sample was collected to asses UI, TSH and TT4 concentrations. Cognitive tasks administered pre- and post-intervention RPM Iodine and thyroid status improved in iodine supplementation group but not placebo group. RPM performance improved with iodine supplementation but not placebo Vitamin B12 and folate Louwman et al (2000)49 n = 72 10–16 years B12 deficient (n = 31) Cross-sectional, Netherlands Forty-eight subjects recruited previously raised on macrobiotic diets until 6 years, and 24 subjects raised on omnivorous diet. Blood sample taken to determine B12 deficiency via serum cobalamin and concentration. Cognitive tasks administered RPM Control subjects performed better on RPM than B12-deficient macrobiotic subjects. Significant association between RPM score and B12 deficiency. Effect more pronounced within subgroup of macrobiotic subjects Nguyen et al (2013)52 n = 5365 6–16 years Predominantly healthy Cross-sectional, USA Blood samples collected to determine serum folate and vitamin B12 concentration. Cognitive tasks administered Block design, WRAT-R Higher serum concentrations of folate were associated with higher block design scores and WRAT-R reading scores after adjusting for various covariates. No associations were observed for vitamin B12 Nilsson et al (2011)53 n = 386 15 years Not reported Cross-sectional, Sweden Assessed school achievement via the sum of 10 core subjects in final semester of 9 years compulsory schooling Academic performance With covariates controlled for, tertiles of folate intake were associated with academic performance Multiple micronutrient supplementation Penland et al (1999)62 n = 240 7.5 years Not reported RCT, Mexico/USA Four groups: MN mixture, 20 mg zinc + MN, 24 mg iron + MN or placebo. Administered 5/d per week for 10 weeks. No blood measures taken. Cognitive tasks were administered pre- and post-intervention CPAS-R reasoning task Reasoning, as indicated by a smaller number of trials needed to learn simple concepts, significantly improved following supplementation with zinc + MNs Petrova et al (2019)63 n = 119 8–14 years Not reported RCT, Spain Randomly allocated to receive 600 ml/day of either fortified (n = 60) or regular full milk control (n = 59) for 5 months. Blood samples taken to assess multiple biochemical measures. Cognitive tasks were administered pre- and post-intervention Digit span and letter–number sequencing MN-fortified group improved digit span performance assessing working memory. No biochemical measure was associated with EF task performance Wang et al (2017)65 n = 360 12–14 years MN deficiencies in both groups at baseline RCT, China Randomly allocated to receive 250 ml/day of either fortified (n = 177) or unfortified (n = 183) milk for 6 months. Blood samples used to assess MN status pre- and post-intervention. Cognitive tasks were administered pre- and post-intervention Academic performance MN-fortified group raised blood vitamin B2 and iron levels. MN-fortified group reported higher scores in several subjects that require the use of EF, including languages and mathematics Vazir et al (2006)64 n = 608 6–15 years 50% of subjects had MN deficiencies at baseline RCT, India Randomly allocated to receive a MN-fortified beverage (n = 321) or placebo (n = 287) for 14 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Knox cube imitation test, letter-cancellation test, and academic performance Knox cube imitation test scores improved following MN-fortified beverage Author (year) . Sample size, age, health status . Study design, country . Methods . Executive function measuresa . Reported findings . Iron Algarín et al (2013)38 n = 132 6–18 months/ 10 years IDA (n = 69) vs non-IDA (n = 63) Longitudinal, Chile Follow-up study from early childhood to 10 years in children with and without IDA. Cognitive tasks administered. Blood analysis excluded three 10-year-olds with current IDA Go/No-Go task IDA in early childhood was associated with slower reaction times and poorer inhibitory control 8 to 9 years after iron therapy Lukowski et al (2010)12 n = 132 1–2 years/19 years IDA (n = 33) vs non-IDA (n = 81) Longitudinal, Costa Rica Follow-up study from early childhood to 19 years in children with and without IDA. Cognitive tasks administered TMT, intra-/extra-dimensional shift, Stockings of Cambridge, spatial working memory, RVIP Children with IDA performed worse on the TMT part B, intra-/extra-dimensional shift, and Stockings of Cambridge planning task at 19 years of age Scott et al (2018)40 n = 140 12–16 years Deficient RCT, India Randomly assigned to receive either iron biofortified millet (86 ppm) or conventional pearl millet (21–52 ppm) for 6 months. Hb, ferritin, and TfR were measured, and body iron was calculated at baseline and after 4 and 6 months. Cognitive tasks administered pre- and post-intervention Go/No-go task and Attentional Network Task Treatment effects seen for by 4 months for ferritin, TfR, and body iron, and at 6 months for TfR, indicating the efficacy of intervention. The fortified group had greater improvement in inhibition and executive control Omega-3 polyunsaturated fatty acids Adjepong et al (2018)39 n = 307 2–6 years 70%, 85%, and 97% had normal scores for stunting, malnutrition, and wasting, respectively Cross-sectional, Ghana Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Positive associations with DCCS performance were observed for whole-blood DHA, total n-3 fatty acids, and dihomo-gamma-linolenic acid. Subjects with the highest levels of total omega-3 fatty acids and DHA were 3 to 4 times more likely to pass at least one condition of the DCCS compared with those with the lowest levels Jumbe et al (2016)41 n = 130 4–6 years 16–20% of sample had malaria Cross-sectional, Tanzania Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Subjects with sufficient levels of whole-blood EFAs were nearly 4 times more likely to successfully complete DCCS. Individually, neither DHA nor EPA was associated with executive function Kennedy et al (2009)48 n = 190 10–12 years Healthy RCT, UK Three groups: 0 mg, 400 mg, or 1000 mg DHA per day for 8 weeks. No blood measures taken to determine pre-and post-DHA blood content. Cognitive tasks administered pre- and post-intervention Numeric working memory DHA supplementation had no consistent or interpretable effect on working memory Montgomery et al (2013)50 n = 493 7–9 years Healthy Cross-sectional, UK Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Recall of digits forward, recall of digits backward, academic performance Lower DHA and EPA concentrations associated with poorer performance on recall of digits forward assessing working memory and reading performance Montgomery et al (2018)51 n = 376 7–9 years Healthy RCT, UK 600 mg/d DHA or placebo for 16 weeks. Fingerstick blood tests taken pre- and post-intervention to assess compliance. Cognitive tasks administered pre- and post-intervention Recall of digits forward, recall of digits backward DHA group had significantly higher blood DHA levels post-intervention compared with the placebo group. No consistent differences between DHA and placebo group on either recall task Portillo-Reyes et al (2014)54 n = 78 8–12 years Malnourished RCT, Mexico Two omega-3 capsules (60 mg of DHA and 90 mg of EPA) or placebo/day for 3 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Matrix reasoning, letter–number sequencing, Stroop color and word test, TMT-B, academic performance Positive effect of omega-3 supplementation on EF measures, including matrix reasoning, Stroop color and color–word tasks. letter–number sequencing and matrix reasoning improved in more than 70% of omega-3–supplemented subjects Ryan and Nelson (2008)55 n = 175 4–5 years Healthy RCT, USA 400 mg/d DHA or placebo for 4 months. Capillary whole-blood samples taken pre- and post-intervention to determine DHA, ARA, and EPA levels. Cognitive tasks administered pre- and post-intervention Day–night Stroop Test and adapted CPT Mean capillary whole-blood content of DHA increased by 300%, EPA content doubled, and ARA decreased by 9% in DHA supplementation group. No change in placebo group. No difference between groups found for measures of EF. Authors suggest measures could have been compromised by unexpected ceiling effects Sheppard and Cheatham (2013)57 n = 70 7–9 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Spatial working memory, spatial span, Stockings of Cambridge, intra-extra dimensional set shift The ratio of n-6 to n-3 fatty acids was a significant predictor of EF scores in general. N-6 and n-3 mean intake variables predicted planning Sheppard and Cheatham (2017)58 n = 78 7–12 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Stockings of Cambridge, Spatial Working Memory, Paired-associate learning, Electric Maze Task Dietary and plasma n–6 to n–3 ratio and n–3 predicted performance on spatial working memory and Stockings of Cambridge planning task in subjects aged 7 to 12 years Zinc Chiplonkar and Kawade (2014)44 n = 403 10–16 years High deficiency prevalence Cross-sectional, India Venous blood samples collected to determine zinc levels. Cognitive tasks administered RPM Higher plasma and erythrocyte zinc associated with better RPM performance Sandstead et al (1998)56 n = 740 6–9 years Deficient RCT, China 20 mg zinc (Z), 20 mg zinc + MN (ZM), or MN alone provided 6/day per week for 10 weeks. Hb, serum ferritin, plasma and hair zinc and whole blood were assessed pre- and post-intervention via venous blood sample. Cognitive tasks were administered pre- and post-intervention CPAS-R modified oddity learning task and modified CPT Plasma zinc concentrations increased following intervention in ZM and M groups, but not in the Z group. Hair zinc decreased after all treatments. Performance on both the modified oddity learning and CPT tasks improved in the ZM group more than with Z or MN alone Tupe and Chiplonkar (2009)59 n = 180 10–16 years Not stated RCT, India Three groups: 20 mg ayurvedic zinc tablet (16.6 mg elemental zinc, 0.74 mg iron); zinc-rich snacks; control group. Supplementation provided 6/day per week for 10 weeks. Venous blood sample collected to determine plasma zinc and iron Cognitive tasks were administered pre- and post-intervention RPM Plasma zinc increased in both zinc tablet and enriched diet groups, but not control. Both zinc groups increased the RPM task score, while the control remained unchanged Iodine Aboud et al (2017)42 n = 1,262 4–6 years Deficient RCT, Ethiopia Intervention group received 4–6 months’ more exposure to iodized salt (8–10 months total) in market compared with control (4 to 6 months total). Assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention Matrix reasoning UI levels increased post-intervention following iodine supplementation compared with placebo. No significant effects were observed between groups Amarra et al (2007)43 n = 65 6–10 years Deficient (n = 34) and non-deficient (n = 31). Cross-sectional, Philippines Performed dietary recalls and assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention RPM Variance in deficit and adequate RPM performance explained by dietary intakes that met >80% RDA for energy, protein, thiamine, and riboflavin, alongside the use of iodized salt, iodine status, and stunting Gordon et al (2009)45 n = 184 10–13 years Deficient RCT, New Zealand 150 μg iodine/day or a placebo for 28 weeks. UI, serum thyroglobulin, and TT4 were assessed pre- and post-intervention via urine and fingerstick blood sample. Cognitive tasks administered pre- and post-intervention Picture concepts, matrix reasoning, letter–number sequencing UI and thyroglobulin concentration improve in the iodine supplementation group but not the placebo group. Iodine supplementation improved performance on the picture concepts and matrix reasoning tasks Huda et al (1999)46 n = 340 8–10 years Hypothyroid (n = 170) vs euthyroid (n = 170) Cross-sectional, Bangladesh Both groups were matched for school, grade level, and region. Blood samples taken to assess T4 and TSH. Cognitive tasks administered Digit Span, Corsi Block, RPM, modified Stroop, academic performance No association found between hypothyroidism and EF measures, though academic performance as assessed via reading and spelling was worse in subjects with hypothyroidism Huda et al (2001)47 n = 305 8–10 years Deficient RCT, Bangladesh 400 mg of oral Lipiodol or a placebo for 4 months. Assessed UI levels, serum thyroxine, and TSH pre- and post-intervention via venous blood sampling. Cognitive tasks administered pre- and post-intervention Digit Span, Corsi Block, modified Stroop Iodine supplementation increased UI levels in intervention group, but levels remained below normal. No difference observed in serum thyroxine, TSH levels, or in any cognitive test. van den Briel et al (2000)60 n = 196 7–11 years Deficient RCT, Benin 540g I/L of iodized oil or placebo for 24 weeks. UI concentration, TSH, serum ferritin, thyroglobulin, and free thyroxine were assessed pre- and post-intervention via urine and blood samples. Cognitive tasks administered pre- and post-intervention RPM Following intervention, UI concentrations improved in both groups but still classified as deficient. Pronounced improvement on RPM in subjects showing an improvement in urinary iodine status Zimmermann et al (2006)61 n = 310 10–12 years Deficient RCT, Albania 400 mg/day of iodized oil or placebo for 24 weeks. Pre- and post- intervention, a morning urine sample and fingerstick blood sample was collected to asses UI, TSH and TT4 concentrations. Cognitive tasks administered pre- and post-intervention RPM Iodine and thyroid status improved in iodine supplementation group but not placebo group. RPM performance improved with iodine supplementation but not placebo Vitamin B12 and folate Louwman et al (2000)49 n = 72 10–16 years B12 deficient (n = 31) Cross-sectional, Netherlands Forty-eight subjects recruited previously raised on macrobiotic diets until 6 years, and 24 subjects raised on omnivorous diet. Blood sample taken to determine B12 deficiency via serum cobalamin and concentration. Cognitive tasks administered RPM Control subjects performed better on RPM than B12-deficient macrobiotic subjects. Significant association between RPM score and B12 deficiency. Effect more pronounced within subgroup of macrobiotic subjects Nguyen et al (2013)52 n = 5365 6–16 years Predominantly healthy Cross-sectional, USA Blood samples collected to determine serum folate and vitamin B12 concentration. Cognitive tasks administered Block design, WRAT-R Higher serum concentrations of folate were associated with higher block design scores and WRAT-R reading scores after adjusting for various covariates. No associations were observed for vitamin B12 Nilsson et al (2011)53 n = 386 15 years Not reported Cross-sectional, Sweden Assessed school achievement via the sum of 10 core subjects in final semester of 9 years compulsory schooling Academic performance With covariates controlled for, tertiles of folate intake were associated with academic performance Multiple micronutrient supplementation Penland et al (1999)62 n = 240 7.5 years Not reported RCT, Mexico/USA Four groups: MN mixture, 20 mg zinc + MN, 24 mg iron + MN or placebo. Administered 5/d per week for 10 weeks. No blood measures taken. Cognitive tasks were administered pre- and post-intervention CPAS-R reasoning task Reasoning, as indicated by a smaller number of trials needed to learn simple concepts, significantly improved following supplementation with zinc + MNs Petrova et al (2019)63 n = 119 8–14 years Not reported RCT, Spain Randomly allocated to receive 600 ml/day of either fortified (n = 60) or regular full milk control (n = 59) for 5 months. Blood samples taken to assess multiple biochemical measures. Cognitive tasks were administered pre- and post-intervention Digit span and letter–number sequencing MN-fortified group improved digit span performance assessing working memory. No biochemical measure was associated with EF task performance Wang et al (2017)65 n = 360 12–14 years MN deficiencies in both groups at baseline RCT, China Randomly allocated to receive 250 ml/day of either fortified (n = 177) or unfortified (n = 183) milk for 6 months. Blood samples used to assess MN status pre- and post-intervention. Cognitive tasks were administered pre- and post-intervention Academic performance MN-fortified group raised blood vitamin B2 and iron levels. MN-fortified group reported higher scores in several subjects that require the use of EF, including languages and mathematics Vazir et al (2006)64 n = 608 6–15 years 50% of subjects had MN deficiencies at baseline RCT, India Randomly allocated to receive a MN-fortified beverage (n = 321) or placebo (n = 287) for 14 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Knox cube imitation test, letter-cancellation test, and academic performance Knox cube imitation test scores improved following MN-fortified beverage a  Other cognitive measures may have been assessed. Abbreviations: CPAS-R: cognition-psychomotor assessment system-revised; CPT: continuous performance task; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; HB: hemoglobin; IDA: iron deficiency anemia; MN: micronutrient; ppm: parts per million; RCT: randomized controlled trial; RDA: recommended dietary allowance; RPM: Raven’s Standard Progressive Matrices; RVIP: Rapid Visual Information Processing; TfR: transferrin receptor; TMT: trail making test; TSH: thyroid-stimulating hormone; TT4: total thyroxine concentrations; UI: urinary iodine; WRAT-R: Wide Range Achievement Test-Revised. Open in new tab Table 1 Summary of studies investigating nutrients and executive function in school-aged children Author (year) . Sample size, age, health status . Study design, country . Methods . Executive function measuresa . Reported findings . Iron Algarín et al (2013)38 n = 132 6–18 months/ 10 years IDA (n = 69) vs non-IDA (n = 63) Longitudinal, Chile Follow-up study from early childhood to 10 years in children with and without IDA. Cognitive tasks administered. Blood analysis excluded three 10-year-olds with current IDA Go/No-Go task IDA in early childhood was associated with slower reaction times and poorer inhibitory control 8 to 9 years after iron therapy Lukowski et al (2010)12 n = 132 1–2 years/19 years IDA (n = 33) vs non-IDA (n = 81) Longitudinal, Costa Rica Follow-up study from early childhood to 19 years in children with and without IDA. Cognitive tasks administered TMT, intra-/extra-dimensional shift, Stockings of Cambridge, spatial working memory, RVIP Children with IDA performed worse on the TMT part B, intra-/extra-dimensional shift, and Stockings of Cambridge planning task at 19 years of age Scott et al (2018)40 n = 140 12–16 years Deficient RCT, India Randomly assigned to receive either iron biofortified millet (86 ppm) or conventional pearl millet (21–52 ppm) for 6 months. Hb, ferritin, and TfR were measured, and body iron was calculated at baseline and after 4 and 6 months. Cognitive tasks administered pre- and post-intervention Go/No-go task and Attentional Network Task Treatment effects seen for by 4 months for ferritin, TfR, and body iron, and at 6 months for TfR, indicating the efficacy of intervention. The fortified group had greater improvement in inhibition and executive control Omega-3 polyunsaturated fatty acids Adjepong et al (2018)39 n = 307 2–6 years 70%, 85%, and 97% had normal scores for stunting, malnutrition, and wasting, respectively Cross-sectional, Ghana Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Positive associations with DCCS performance were observed for whole-blood DHA, total n-3 fatty acids, and dihomo-gamma-linolenic acid. Subjects with the highest levels of total omega-3 fatty acids and DHA were 3 to 4 times more likely to pass at least one condition of the DCCS compared with those with the lowest levels Jumbe et al (2016)41 n = 130 4–6 years 16–20% of sample had malaria Cross-sectional, Tanzania Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Subjects with sufficient levels of whole-blood EFAs were nearly 4 times more likely to successfully complete DCCS. Individually, neither DHA nor EPA was associated with executive function Kennedy et al (2009)48 n = 190 10–12 years Healthy RCT, UK Three groups: 0 mg, 400 mg, or 1000 mg DHA per day for 8 weeks. No blood measures taken to determine pre-and post-DHA blood content. Cognitive tasks administered pre- and post-intervention Numeric working memory DHA supplementation had no consistent or interpretable effect on working memory Montgomery et al (2013)50 n = 493 7–9 years Healthy Cross-sectional, UK Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Recall of digits forward, recall of digits backward, academic performance Lower DHA and EPA concentrations associated with poorer performance on recall of digits forward assessing working memory and reading performance Montgomery et al (2018)51 n = 376 7–9 years Healthy RCT, UK 600 mg/d DHA or placebo for 16 weeks. Fingerstick blood tests taken pre- and post-intervention to assess compliance. Cognitive tasks administered pre- and post-intervention Recall of digits forward, recall of digits backward DHA group had significantly higher blood DHA levels post-intervention compared with the placebo group. No consistent differences between DHA and placebo group on either recall task Portillo-Reyes et al (2014)54 n = 78 8–12 years Malnourished RCT, Mexico Two omega-3 capsules (60 mg of DHA and 90 mg of EPA) or placebo/day for 3 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Matrix reasoning, letter–number sequencing, Stroop color and word test, TMT-B, academic performance Positive effect of omega-3 supplementation on EF measures, including matrix reasoning, Stroop color and color–word tasks. letter–number sequencing and matrix reasoning improved in more than 70% of omega-3–supplemented subjects Ryan and Nelson (2008)55 n = 175 4–5 years Healthy RCT, USA 400 mg/d DHA or placebo for 4 months. Capillary whole-blood samples taken pre- and post-intervention to determine DHA, ARA, and EPA levels. Cognitive tasks administered pre- and post-intervention Day–night Stroop Test and adapted CPT Mean capillary whole-blood content of DHA increased by 300%, EPA content doubled, and ARA decreased by 9% in DHA supplementation group. No change in placebo group. No difference between groups found for measures of EF. Authors suggest measures could have been compromised by unexpected ceiling effects Sheppard and Cheatham (2013)57 n = 70 7–9 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Spatial working memory, spatial span, Stockings of Cambridge, intra-extra dimensional set shift The ratio of n-6 to n-3 fatty acids was a significant predictor of EF scores in general. N-6 and n-3 mean intake variables predicted planning Sheppard and Cheatham (2017)58 n = 78 7–12 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Stockings of Cambridge, Spatial Working Memory, Paired-associate learning, Electric Maze Task Dietary and plasma n–6 to n–3 ratio and n–3 predicted performance on spatial working memory and Stockings of Cambridge planning task in subjects aged 7 to 12 years Zinc Chiplonkar and Kawade (2014)44 n = 403 10–16 years High deficiency prevalence Cross-sectional, India Venous blood samples collected to determine zinc levels. Cognitive tasks administered RPM Higher plasma and erythrocyte zinc associated with better RPM performance Sandstead et al (1998)56 n = 740 6–9 years Deficient RCT, China 20 mg zinc (Z), 20 mg zinc + MN (ZM), or MN alone provided 6/day per week for 10 weeks. Hb, serum ferritin, plasma and hair zinc and whole blood were assessed pre- and post-intervention via venous blood sample. Cognitive tasks were administered pre- and post-intervention CPAS-R modified oddity learning task and modified CPT Plasma zinc concentrations increased following intervention in ZM and M groups, but not in the Z group. Hair zinc decreased after all treatments. Performance on both the modified oddity learning and CPT tasks improved in the ZM group more than with Z or MN alone Tupe and Chiplonkar (2009)59 n = 180 10–16 years Not stated RCT, India Three groups: 20 mg ayurvedic zinc tablet (16.6 mg elemental zinc, 0.74 mg iron); zinc-rich snacks; control group. Supplementation provided 6/day per week for 10 weeks. Venous blood sample collected to determine plasma zinc and iron Cognitive tasks were administered pre- and post-intervention RPM Plasma zinc increased in both zinc tablet and enriched diet groups, but not control. Both zinc groups increased the RPM task score, while the control remained unchanged Iodine Aboud et al (2017)42 n = 1,262 4–6 years Deficient RCT, Ethiopia Intervention group received 4–6 months’ more exposure to iodized salt (8–10 months total) in market compared with control (4 to 6 months total). Assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention Matrix reasoning UI levels increased post-intervention following iodine supplementation compared with placebo. No significant effects were observed between groups Amarra et al (2007)43 n = 65 6–10 years Deficient (n = 34) and non-deficient (n = 31). Cross-sectional, Philippines Performed dietary recalls and assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention RPM Variance in deficit and adequate RPM performance explained by dietary intakes that met >80% RDA for energy, protein, thiamine, and riboflavin, alongside the use of iodized salt, iodine status, and stunting Gordon et al (2009)45 n = 184 10–13 years Deficient RCT, New Zealand 150 μg iodine/day or a placebo for 28 weeks. UI, serum thyroglobulin, and TT4 were assessed pre- and post-intervention via urine and fingerstick blood sample. Cognitive tasks administered pre- and post-intervention Picture concepts, matrix reasoning, letter–number sequencing UI and thyroglobulin concentration improve in the iodine supplementation group but not the placebo group. Iodine supplementation improved performance on the picture concepts and matrix reasoning tasks Huda et al (1999)46 n = 340 8–10 years Hypothyroid (n = 170) vs euthyroid (n = 170) Cross-sectional, Bangladesh Both groups were matched for school, grade level, and region. Blood samples taken to assess T4 and TSH. Cognitive tasks administered Digit Span, Corsi Block, RPM, modified Stroop, academic performance No association found between hypothyroidism and EF measures, though academic performance as assessed via reading and spelling was worse in subjects with hypothyroidism Huda et al (2001)47 n = 305 8–10 years Deficient RCT, Bangladesh 400 mg of oral Lipiodol or a placebo for 4 months. Assessed UI levels, serum thyroxine, and TSH pre- and post-intervention via venous blood sampling. Cognitive tasks administered pre- and post-intervention Digit Span, Corsi Block, modified Stroop Iodine supplementation increased UI levels in intervention group, but levels remained below normal. No difference observed in serum thyroxine, TSH levels, or in any cognitive test. van den Briel et al (2000)60 n = 196 7–11 years Deficient RCT, Benin 540g I/L of iodized oil or placebo for 24 weeks. UI concentration, TSH, serum ferritin, thyroglobulin, and free thyroxine were assessed pre- and post-intervention via urine and blood samples. Cognitive tasks administered pre- and post-intervention RPM Following intervention, UI concentrations improved in both groups but still classified as deficient. Pronounced improvement on RPM in subjects showing an improvement in urinary iodine status Zimmermann et al (2006)61 n = 310 10–12 years Deficient RCT, Albania 400 mg/day of iodized oil or placebo for 24 weeks. Pre- and post- intervention, a morning urine sample and fingerstick blood sample was collected to asses UI, TSH and TT4 concentrations. Cognitive tasks administered pre- and post-intervention RPM Iodine and thyroid status improved in iodine supplementation group but not placebo group. RPM performance improved with iodine supplementation but not placebo Vitamin B12 and folate Louwman et al (2000)49 n = 72 10–16 years B12 deficient (n = 31) Cross-sectional, Netherlands Forty-eight subjects recruited previously raised on macrobiotic diets until 6 years, and 24 subjects raised on omnivorous diet. Blood sample taken to determine B12 deficiency via serum cobalamin and concentration. Cognitive tasks administered RPM Control subjects performed better on RPM than B12-deficient macrobiotic subjects. Significant association between RPM score and B12 deficiency. Effect more pronounced within subgroup of macrobiotic subjects Nguyen et al (2013)52 n = 5365 6–16 years Predominantly healthy Cross-sectional, USA Blood samples collected to determine serum folate and vitamin B12 concentration. Cognitive tasks administered Block design, WRAT-R Higher serum concentrations of folate were associated with higher block design scores and WRAT-R reading scores after adjusting for various covariates. No associations were observed for vitamin B12 Nilsson et al (2011)53 n = 386 15 years Not reported Cross-sectional, Sweden Assessed school achievement via the sum of 10 core subjects in final semester of 9 years compulsory schooling Academic performance With covariates controlled for, tertiles of folate intake were associated with academic performance Multiple micronutrient supplementation Penland et al (1999)62 n = 240 7.5 years Not reported RCT, Mexico/USA Four groups: MN mixture, 20 mg zinc + MN, 24 mg iron + MN or placebo. Administered 5/d per week for 10 weeks. No blood measures taken. Cognitive tasks were administered pre- and post-intervention CPAS-R reasoning task Reasoning, as indicated by a smaller number of trials needed to learn simple concepts, significantly improved following supplementation with zinc + MNs Petrova et al (2019)63 n = 119 8–14 years Not reported RCT, Spain Randomly allocated to receive 600 ml/day of either fortified (n = 60) or regular full milk control (n = 59) for 5 months. Blood samples taken to assess multiple biochemical measures. Cognitive tasks were administered pre- and post-intervention Digit span and letter–number sequencing MN-fortified group improved digit span performance assessing working memory. No biochemical measure was associated with EF task performance Wang et al (2017)65 n = 360 12–14 years MN deficiencies in both groups at baseline RCT, China Randomly allocated to receive 250 ml/day of either fortified (n = 177) or unfortified (n = 183) milk for 6 months. Blood samples used to assess MN status pre- and post-intervention. Cognitive tasks were administered pre- and post-intervention Academic performance MN-fortified group raised blood vitamin B2 and iron levels. MN-fortified group reported higher scores in several subjects that require the use of EF, including languages and mathematics Vazir et al (2006)64 n = 608 6–15 years 50% of subjects had MN deficiencies at baseline RCT, India Randomly allocated to receive a MN-fortified beverage (n = 321) or placebo (n = 287) for 14 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Knox cube imitation test, letter-cancellation test, and academic performance Knox cube imitation test scores improved following MN-fortified beverage Author (year) . Sample size, age, health status . Study design, country . Methods . Executive function measuresa . Reported findings . Iron Algarín et al (2013)38 n = 132 6–18 months/ 10 years IDA (n = 69) vs non-IDA (n = 63) Longitudinal, Chile Follow-up study from early childhood to 10 years in children with and without IDA. Cognitive tasks administered. Blood analysis excluded three 10-year-olds with current IDA Go/No-Go task IDA in early childhood was associated with slower reaction times and poorer inhibitory control 8 to 9 years after iron therapy Lukowski et al (2010)12 n = 132 1–2 years/19 years IDA (n = 33) vs non-IDA (n = 81) Longitudinal, Costa Rica Follow-up study from early childhood to 19 years in children with and without IDA. Cognitive tasks administered TMT, intra-/extra-dimensional shift, Stockings of Cambridge, spatial working memory, RVIP Children with IDA performed worse on the TMT part B, intra-/extra-dimensional shift, and Stockings of Cambridge planning task at 19 years of age Scott et al (2018)40 n = 140 12–16 years Deficient RCT, India Randomly assigned to receive either iron biofortified millet (86 ppm) or conventional pearl millet (21–52 ppm) for 6 months. Hb, ferritin, and TfR were measured, and body iron was calculated at baseline and after 4 and 6 months. Cognitive tasks administered pre- and post-intervention Go/No-go task and Attentional Network Task Treatment effects seen for by 4 months for ferritin, TfR, and body iron, and at 6 months for TfR, indicating the efficacy of intervention. The fortified group had greater improvement in inhibition and executive control Omega-3 polyunsaturated fatty acids Adjepong et al (2018)39 n = 307 2–6 years 70%, 85%, and 97% had normal scores for stunting, malnutrition, and wasting, respectively Cross-sectional, Ghana Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Positive associations with DCCS performance were observed for whole-blood DHA, total n-3 fatty acids, and dihomo-gamma-linolenic acid. Subjects with the highest levels of total omega-3 fatty acids and DHA were 3 to 4 times more likely to pass at least one condition of the DCCS compared with those with the lowest levels Jumbe et al (2016)41 n = 130 4–6 years 16–20% of sample had malaria Cross-sectional, Tanzania Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered DCCS Subjects with sufficient levels of whole-blood EFAs were nearly 4 times more likely to successfully complete DCCS. Individually, neither DHA nor EPA was associated with executive function Kennedy et al (2009)48 n = 190 10–12 years Healthy RCT, UK Three groups: 0 mg, 400 mg, or 1000 mg DHA per day for 8 weeks. No blood measures taken to determine pre-and post-DHA blood content. Cognitive tasks administered pre- and post-intervention Numeric working memory DHA supplementation had no consistent or interpretable effect on working memory Montgomery et al (2013)50 n = 493 7–9 years Healthy Cross-sectional, UK Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Recall of digits forward, recall of digits backward, academic performance Lower DHA and EPA concentrations associated with poorer performance on recall of digits forward assessing working memory and reading performance Montgomery et al (2018)51 n = 376 7–9 years Healthy RCT, UK 600 mg/d DHA or placebo for 16 weeks. Fingerstick blood tests taken pre- and post-intervention to assess compliance. Cognitive tasks administered pre- and post-intervention Recall of digits forward, recall of digits backward DHA group had significantly higher blood DHA levels post-intervention compared with the placebo group. No consistent differences between DHA and placebo group on either recall task Portillo-Reyes et al (2014)54 n = 78 8–12 years Malnourished RCT, Mexico Two omega-3 capsules (60 mg of DHA and 90 mg of EPA) or placebo/day for 3 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Matrix reasoning, letter–number sequencing, Stroop color and word test, TMT-B, academic performance Positive effect of omega-3 supplementation on EF measures, including matrix reasoning, Stroop color and color–word tasks. letter–number sequencing and matrix reasoning improved in more than 70% of omega-3–supplemented subjects Ryan and Nelson (2008)55 n = 175 4–5 years Healthy RCT, USA 400 mg/d DHA or placebo for 4 months. Capillary whole-blood samples taken pre- and post-intervention to determine DHA, ARA, and EPA levels. Cognitive tasks administered pre- and post-intervention Day–night Stroop Test and adapted CPT Mean capillary whole-blood content of DHA increased by 300%, EPA content doubled, and ARA decreased by 9% in DHA supplementation group. No change in placebo group. No difference between groups found for measures of EF. Authors suggest measures could have been compromised by unexpected ceiling effects Sheppard and Cheatham (2013)57 n = 70 7–9 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Spatial working memory, spatial span, Stockings of Cambridge, intra-extra dimensional set shift The ratio of n-6 to n-3 fatty acids was a significant predictor of EF scores in general. N-6 and n-3 mean intake variables predicted planning Sheppard and Cheatham (2017)58 n = 78 7–12 years Healthy Cross-sectional, USA Whole blood obtained via fingerstick sample for fatty acid quantification. Cognitive tasks administered Stockings of Cambridge, Spatial Working Memory, Paired-associate learning, Electric Maze Task Dietary and plasma n–6 to n–3 ratio and n–3 predicted performance on spatial working memory and Stockings of Cambridge planning task in subjects aged 7 to 12 years Zinc Chiplonkar and Kawade (2014)44 n = 403 10–16 years High deficiency prevalence Cross-sectional, India Venous blood samples collected to determine zinc levels. Cognitive tasks administered RPM Higher plasma and erythrocyte zinc associated with better RPM performance Sandstead et al (1998)56 n = 740 6–9 years Deficient RCT, China 20 mg zinc (Z), 20 mg zinc + MN (ZM), or MN alone provided 6/day per week for 10 weeks. Hb, serum ferritin, plasma and hair zinc and whole blood were assessed pre- and post-intervention via venous blood sample. Cognitive tasks were administered pre- and post-intervention CPAS-R modified oddity learning task and modified CPT Plasma zinc concentrations increased following intervention in ZM and M groups, but not in the Z group. Hair zinc decreased after all treatments. Performance on both the modified oddity learning and CPT tasks improved in the ZM group more than with Z or MN alone Tupe and Chiplonkar (2009)59 n = 180 10–16 years Not stated RCT, India Three groups: 20 mg ayurvedic zinc tablet (16.6 mg elemental zinc, 0.74 mg iron); zinc-rich snacks; control group. Supplementation provided 6/day per week for 10 weeks. Venous blood sample collected to determine plasma zinc and iron Cognitive tasks were administered pre- and post-intervention RPM Plasma zinc increased in both zinc tablet and enriched diet groups, but not control. Both zinc groups increased the RPM task score, while the control remained unchanged Iodine Aboud et al (2017)42 n = 1,262 4–6 years Deficient RCT, Ethiopia Intervention group received 4–6 months’ more exposure to iodized salt (8–10 months total) in market compared with control (4 to 6 months total). Assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention Matrix reasoning UI levels increased post-intervention following iodine supplementation compared with placebo. No significant effects were observed between groups Amarra et al (2007)43 n = 65 6–10 years Deficient (n = 34) and non-deficient (n = 31). Cross-sectional, Philippines Performed dietary recalls and assessed UI concentration via urine sample. Cognitive tasks administered pre- and post-intervention RPM Variance in deficit and adequate RPM performance explained by dietary intakes that met >80% RDA for energy, protein, thiamine, and riboflavin, alongside the use of iodized salt, iodine status, and stunting Gordon et al (2009)45 n = 184 10–13 years Deficient RCT, New Zealand 150 μg iodine/day or a placebo for 28 weeks. UI, serum thyroglobulin, and TT4 were assessed pre- and post-intervention via urine and fingerstick blood sample. Cognitive tasks administered pre- and post-intervention Picture concepts, matrix reasoning, letter–number sequencing UI and thyroglobulin concentration improve in the iodine supplementation group but not the placebo group. Iodine supplementation improved performance on the picture concepts and matrix reasoning tasks Huda et al (1999)46 n = 340 8–10 years Hypothyroid (n = 170) vs euthyroid (n = 170) Cross-sectional, Bangladesh Both groups were matched for school, grade level, and region. Blood samples taken to assess T4 and TSH. Cognitive tasks administered Digit Span, Corsi Block, RPM, modified Stroop, academic performance No association found between hypothyroidism and EF measures, though academic performance as assessed via reading and spelling was worse in subjects with hypothyroidism Huda et al (2001)47 n = 305 8–10 years Deficient RCT, Bangladesh 400 mg of oral Lipiodol or a placebo for 4 months. Assessed UI levels, serum thyroxine, and TSH pre- and post-intervention via venous blood sampling. Cognitive tasks administered pre- and post-intervention Digit Span, Corsi Block, modified Stroop Iodine supplementation increased UI levels in intervention group, but levels remained below normal. No difference observed in serum thyroxine, TSH levels, or in any cognitive test. van den Briel et al (2000)60 n = 196 7–11 years Deficient RCT, Benin 540g I/L of iodized oil or placebo for 24 weeks. UI concentration, TSH, serum ferritin, thyroglobulin, and free thyroxine were assessed pre- and post-intervention via urine and blood samples. Cognitive tasks administered pre- and post-intervention RPM Following intervention, UI concentrations improved in both groups but still classified as deficient. Pronounced improvement on RPM in subjects showing an improvement in urinary iodine status Zimmermann et al (2006)61 n = 310 10–12 years Deficient RCT, Albania 400 mg/day of iodized oil or placebo for 24 weeks. Pre- and post- intervention, a morning urine sample and fingerstick blood sample was collected to asses UI, TSH and TT4 concentrations. Cognitive tasks administered pre- and post-intervention RPM Iodine and thyroid status improved in iodine supplementation group but not placebo group. RPM performance improved with iodine supplementation but not placebo Vitamin B12 and folate Louwman et al (2000)49 n = 72 10–16 years B12 deficient (n = 31) Cross-sectional, Netherlands Forty-eight subjects recruited previously raised on macrobiotic diets until 6 years, and 24 subjects raised on omnivorous diet. Blood sample taken to determine B12 deficiency via serum cobalamin and concentration. Cognitive tasks administered RPM Control subjects performed better on RPM than B12-deficient macrobiotic subjects. Significant association between RPM score and B12 deficiency. Effect more pronounced within subgroup of macrobiotic subjects Nguyen et al (2013)52 n = 5365 6–16 years Predominantly healthy Cross-sectional, USA Blood samples collected to determine serum folate and vitamin B12 concentration. Cognitive tasks administered Block design, WRAT-R Higher serum concentrations of folate were associated with higher block design scores and WRAT-R reading scores after adjusting for various covariates. No associations were observed for vitamin B12 Nilsson et al (2011)53 n = 386 15 years Not reported Cross-sectional, Sweden Assessed school achievement via the sum of 10 core subjects in final semester of 9 years compulsory schooling Academic performance With covariates controlled for, tertiles of folate intake were associated with academic performance Multiple micronutrient supplementation Penland et al (1999)62 n = 240 7.5 years Not reported RCT, Mexico/USA Four groups: MN mixture, 20 mg zinc + MN, 24 mg iron + MN or placebo. Administered 5/d per week for 10 weeks. No blood measures taken. Cognitive tasks were administered pre- and post-intervention CPAS-R reasoning task Reasoning, as indicated by a smaller number of trials needed to learn simple concepts, significantly improved following supplementation with zinc + MNs Petrova et al (2019)63 n = 119 8–14 years Not reported RCT, Spain Randomly allocated to receive 600 ml/day of either fortified (n = 60) or regular full milk control (n = 59) for 5 months. Blood samples taken to assess multiple biochemical measures. Cognitive tasks were administered pre- and post-intervention Digit span and letter–number sequencing MN-fortified group improved digit span performance assessing working memory. No biochemical measure was associated with EF task performance Wang et al (2017)65 n = 360 12–14 years MN deficiencies in both groups at baseline RCT, China Randomly allocated to receive 250 ml/day of either fortified (n = 177) or unfortified (n = 183) milk for 6 months. Blood samples used to assess MN status pre- and post-intervention. Cognitive tasks were administered pre- and post-intervention Academic performance MN-fortified group raised blood vitamin B2 and iron levels. MN-fortified group reported higher scores in several subjects that require the use of EF, including languages and mathematics Vazir et al (2006)64 n = 608 6–15 years 50% of subjects had MN deficiencies at baseline RCT, India Randomly allocated to receive a MN-fortified beverage (n = 321) or placebo (n = 287) for 14 months. No blood measures taken. Cognitive tasks were administered pre- and post-intervention Knox cube imitation test, letter-cancellation test, and academic performance Knox cube imitation test scores improved following MN-fortified beverage a  Other cognitive measures may have been assessed. Abbreviations: CPAS-R: cognition-psychomotor assessment system-revised; CPT: continuous performance task; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; HB: hemoglobin; IDA: iron deficiency anemia; MN: micronutrient; ppm: parts per million; RCT: randomized controlled trial; RDA: recommended dietary allowance; RPM: Raven’s Standard Progressive Matrices; RVIP: Rapid Visual Information Processing; TfR: transferrin receptor; TMT: trail making test; TSH: thyroid-stimulating hormone; TT4: total thyroxine concentrations; UI: urinary iodine; WRAT-R: Wide Range Achievement Test-Revised. Open in new tab Iron Iron is a critical nutrient required for both myelination and synaptogenesis, in addition to other neurophysiological processes, including neurotransmitter synthesis, cell division, and oxidative metabolism.10,66 Studies using animal models have found early life iron deficiency (ID) alters the location and functioning of oligodendrocytes, the cells responsible for making myelin.67 Furthermore, they indicate that early iron-deficiency anemia (IDA) modifies the myelin protein profile via the decline of proteolipid protein and myelin basic protein, both of which are necessary for myelin formation.67 It has also been suggested that ID affects the dopaminergic pathway. Early work in animal models documents ID-induced alterations in dopaminergic neurotransmission and consequently dopamine-dependent behavior.68 Dopamine neurotransmission is known to play an essential role in mediating EFs,12,69,70 and thus alterations are likely to have a significant impact on EF development.70 The long-term effects caused from ID and IDA during infancy are apparent in later childhood, as demonstrated by longitudinal clinical studies. Algarín et al38 found 10-year-old children who had IDA in early childhood performed worse on an inhibitory control task compared with non-anemic children. A further study found specific effects of severe ID during early childhood on EF at 19 years of age, with individuals performing worse on frontostriatal-mediated EFs, including inhibitory control, set-shifting, and planning.12 The detrimental effect of ID during early childhood on EF during the school-aged period appears to be well established, especially when combined with the known effects of ID on brain development from a neuroscientific perspective. Indeed, there are fewer studies examining school-aged children, though a recent randomized controlled trial (RCT) addressed this by investigating the effect of iron-biofortified pearl millet on a variety of cognitive measures, including EF, in Indian school-going adolescents aged 12–16.40 Following a 6-month intervention, participants in a high iron fortification group, compared with a control, had greater improvements on tasks assessing inhibition (Go/No-Go tasks) and attentional networks, including executive control (Attentional Network Task) as well as simple reaction time and memory. Within the study population, one-third of the adolescents had IDA, half were iron-deficient, and a quarter had negative body iron. Understanding of the neurophysiological role of iron in EF and overall cognitive development from a brain structural perspective supports its necessity for EF development. Available evidence supports this, with studies finding positive associations and effects of iron on EF task performance. However, there are very few studies looking at iron supplementation in school-aged children, thus highlighting an area in need of further research before any clear conclusions can be drawn. Omega-3 polyunsaturated fatty acids Omega-3 polyunsaturated fatty acids (PUFAs) are essential dietary nutrients for brain development, as they play a central functioning role in brain tissue and affect many neurophysiological processes, including myelination, synaptogenesis, and neuronal membrane integrity.14,71 The brain has a high lipid content, and thus the proper functioning of the CNS is highly dependent on the maintenance of the neuronal membranes’ unique lipid composition.72,73 Docosahexaenoic acid (DHA) is the most abundant omega-3 fatty acid in the CNS and is present in 30% to 40% of the phospholipids in the gray matter of the cerebral cortex.74 DHA is a major component of cell membranes and mediates its molecular and cellular effects through the regulation of properties such as membrane fluidity, permeability, and viscosity in synaptic membranes as well as via the modulation of neurotransmission, gene expression, and enzyme activity, all processes that are closely associated with activation of signaling pathways that sustain synaptic function and neuronal survival.74 Of the studies investigating omega-3 PUFA supplementation and the developing brain, the majority look at supplementation in infants, with a systematic review concluding PUFA supplementation may significantly improve cognitive development at this age.75 A review highlights the findings that visual acuity, visual recognition, memory, and enhanced performance on measures estimating cognitive performance in early infancy are negatively impacted by PUFA deficiency in human preterm infants, and positively impacted by PUFA supplementation.76 Other studies have found positive developmental outcomes with PUFA-supplemented early-life formula. For example, Clandinin et al77 found feeding formulas with DHA and arachidonic acid (ARA) supplementation resulted in better developmental outcomes compared with non-supplemented formulas in preterm infants. Furthermore, early-life formula supplemented with ARA and DHA, as compared with non-supplemented formulas, improved problem-solving at 10-months of age, possibly reflecting enhanced development of the frontal lobe.78 Conversely, there has been very little attention given towards the link between PUFAs and cognitive performance after infancy. Perhaps due to the small number of existing studies, there is currently limited empirical evidence for beneficial effects of essential fatty acids (EFAs) and PUFAs on the development of EF in school-aged children, with most evidence coming from observational studies. Kennedy et al48 performed a randomized placebo-controlled trial in ninety 10 to 12-year-old healthy children. In this study, children were provided with 400 mg or 100 mg DHA supplementation for 8 weeks and were assessed pre- and post-intervention on tests of psychomotor speed, WM, EF, and short-term memory. The results of the study found DHA supplementation to have no consistent or interpretable effect on any cognitive measure. Similar results were found in a randomized placebo-controlled trial (n = 175) when the effect of 400 mg/day DHA supplementation over 4 months was assessed on EF, sustained attention, and vocabulary in 4-year-old children.55 Though a positive association was found between blood levels of DHA and vocabulary scores, no differences were found for EF measures. A cross-sectional study50 conducted in 493 healthy 7–9-year-old children from the United Kingdom found, when controlling for socioeconomic status (SES) and sex, that lower DHA concentrations were associated with poorer reading ability and WM performance in addition to greater parent-rated behavioral problems. However, a confirmatory RCT follow-up trial51 administering 600 mg/day DHA or placebo for 16 weeks failed to show consistent differences in reading ability or WM between groups. Conversely, positive associations have been observed in more recent studies investigating fatty acids and EFs in school-aged children. A cross-sectional study (n = 130) found 4 to-6 year-old children who had sufficient whole-blood levels of EFAs were nearly 4 times more likely to successfully complete a dimensional change card sort (DCCS) task assessing EF compared with children with insufficient EFA levels.41 Support for this is provided in a recent study that similarly found an association between fatty acids, particularly omega-3 PUFAs, and EF.39 In this study, 307 Ghanaian children aged 2 to 6 years old attempted a DCCS task assessing EF and had dried blood spot samples taken for the analysis of fatty acid content. Positive associations with DCCS performance were observed for whole-blood DHA, total n-3 fatty acids, and dihomo-gamma-linolenic acid. Furthermore, children with the highest levels of total omega-3 fatty acids and DHA were 3 to 4 times more likely to pass at least one condition of the DCCS compared with those with the lowest levels. An RCT assessed EF in 8 to 12-year-old malnourished schoolchildren following supplementation with two omega-3 capsules containing 60 mg DHA and 90 mg EPA or a placebo each day for 3 months.54 Supplementation was found to significantly improve performance on 2 EF tasks: matrix reasoning and the Stroop task. Furthermore, when clinical improvement was assessed per subject, over 70% of the supplemented children improved on the letter–number sequencing task and matrix reasoning. In two separate cross-sectional studies, Sheppard and Cheatham57,58 investigated the effect of the omega-3 to omega-6 ratio, and omega-3 intake, on EF, due to the subserving brain area being particularly sensitive to imbalance. In both studies, dietary and plasma omega 3: omega-6 ratio and omega-3 intake both predicted EF performance in school-aged children. Moreover, in the most recent study,58 the omega-3: omega-6 ratio and omega-3 intake was found to predict EF performance differently in children aged 7–9 years and 10–12 years, indicating different optimal fatty acid balances across development. There is currently a disparity between the results of RCTs and cross-sectional studies when looking at omega-3 PUFA supplementation and EF performance. Only one of the identified RCTs for omega-3 PUFA supplementation reported a positive effect on EF task performance. Interestingly, however, all the cross-sectional studies reported positive associations. Combined with the evidence highlighting the important role of EFAs and PUFAs in the brain’s structural development,79 research is in support of a relationship between omega-3 fatty acids and EF in school-aged children. There is a clear need, however, for more RCTs in this area to delineate the role and effect of omega-3 PUFAs on EF in childhood. Furthermore, it is of importance for these studies to establish nutritional status to help understand and identify the effects in both healthy and malnourished populations, considering SES. Nutritional status and SES share a close relationship, both significantly contributing to cognitive development80; consequently, nutritional status and SES act not in an additive but in an interactive manner, making the understanding of one much clearer when considering the other. Zinc Zinc is essential for the function of many critical roles in the brain, including neurogenesis, neuronal migration, synaptogenesis, and neurotransmitter modulation, as well as playing an important role in gene expression, DNA transcription and translation, and protein synthesis.14,16,81,82 Zinc deficiency is one of the most widespread micronutrient deficiencies83 and constitutes a substantial disease load, especially in developing countries.84 Preclinical work has shown that severe deficiency, particularly during periods of rapid growth, such as gestation and adolescence, is associated with alterations in brain development, cognitive impairment, and a heightened response to stress.85,86 Furthermore, evidence suggests zinc deficiency may be associated with deficits in attention and motor development.82 Relatively few studies have examined the effect of zinc supplementation on EF in children. In a double-blind RCT, 740 6–9-year old children were provided with either 20 mg zinc supplementation, 20 mg zinc with micronutrients, or micronutrients without zinc for 6 days per week over 10 weeks.56 Cognitive assessments administered at baseline and following the 10-week intervention included a modified oddity learning task for the assessment of concept formation and abstract reasoning, as well as other cognitive domains, including visual perception, sustained attention, short-term memory, and fine motor skills. The results indicated that zinc-containing treatments were superior in tasks involving EF, short-term memory, perception, and fine motor skills. Interestingly, zinc supplementation combined with other micronutrients had the greatest effect on cognition, which may be suggestive of a synergistic effect. These observations are further supported in a later RCT,59 with similar results being reported for 10 to 16-year-old children. Participants were supplemented 6 times per week for 10 weeks with either a 20 mg ayurvedic zinc tablet (16.6 mg elemental zinc, 0.74 mg iron, and the remaining part being starch), or zinc-rich snacks, or they were placed in a control group. Cognitive assessments included an executive task of abstract reasoning in addition to visual memory, simple reaction time, and recognition reaction time. There was a higher impact of ayurvedic zinc supplementation than that of the zinc-enriched diet in improving cognitive performance, as seen in an increase in EF and memory and a decrease in simple reaction time and recognition reaction time. It is important to acknowledge in this study that, perhaps due to poor quality diet, plasma zinc status decreased in the control group over the intervention, which may have contributed to the effects seen. Nonetheless, this study demonstrates the importance of adequate zinc levels in school-aged children for the promotion of EF and cognitive function. Further research highlights the importance of zinc for EF in adolescent girls aged 10 to 16 years old. In a cross-sectional study,44 plasma and erythrocyte zinc were associated with better performance on the Ravens Progressive Matrices test, a non-verbal task typically used in educational settings assessing the ability to work out new concepts and abstract ideas. Furthermore, zinc levels were also associated with better visual memory as well as quicker simple and recognition reaction times. Though all children were assumed healthy, analysis revealed that many of the participants were deficient. Despite the exact mechanisms by which zinc contributes to EF development not yet being clear, research to date indicates zinc to be important for EF-dependent brain development, with deficiency potentially interfering with neurotransmission and subsequent neuropsychological behavior.81 When assessing the clinical evidence, RCTs and cross-sectional studies both show positive effects of zinc on EF task performance. Iodine Iodine is essential for the production of the thyroid hormones, thyroxine and triiodothyronine, both of which are crucial for the brain’s growth and development.87 Although the precise ways in which thyroid hormones impact brain functions are poorly understood, it is known that they affect processes such as myelination, synaptogenesis, synaptic plasticity, cell migration and differentiation, dendrite structure, and transcriptional regulation.88 The timing of iodine deficiency is particularly important during very early brain development in utero89 with deficiencies during this time being linked to later impairments in cognitive and motor function. Nonetheless, the involvement of iodine and thyroid hormones in the development of myelin and neurotransmitter synthesis, of which both continue across childhood and adolescence, is suggestive of its importance during this developmental period, though it is clear that any intervention with iodine will be more effective earlier in development, when there is greater plasticity.88 While the prenatal and early postnatal importance of iodine intake is well established, the potential benefits of iodine repletion during the school years remains unclear, with EF rarely being assessed. Most research on iodine deficiency has focused on IQ in childhood, with a clear consensus on the detrimental impact. For example, 2 meta-analyses90,91 indicated there to be a general loss of 12.5–13.5 IQ points in severely iodine-deficient populations compared with non-iodine-deficient groups. In a double-blind RCT, Zimmermann and colleagues61 found supplementation with 400 mg of iodized poppyseed oil for 24 weeks significantly improved abstract reasoning, as assessed by the Ravens Progressive Matrices test, alongside other cognitive domains in 10 to 12-year-old children, of which 87% were goitrous at baseline. Another RCT in 10 to 13-year-old mildly deficient children from New Zealand was later conducted.45 In this study, children were provided with 150 μg of iodine or a placebo for 28 weeks, with positive effects found for abstract reasoning in a Ravens Progressive Matrices test and picture concepts test. Van den Briel and colleagues60 found the largest improvements in tests of abstract reasoning in an RCT in 7 to 11-year-old school children in Benin who received iodized oil or a placebo across a 1-year intervention period. Importantly, however, only children showing an improvement in iodine status, rather than iodine status itself, determined mental performance. A cross-sectional study in Filipino school children found salt iodization, alongside adequate intakes of energy, protein, thiamin, and riboflavin, contributed to better mental performance as assessed by the Bender-Gestalt and Raven’s Progressive Matrices tests for psychomotor and cognitive function.43 Contrary to these studies, Huda and colleagues found no effect of iodized oil supplementation on cognition, including EF, or motor functions in a double-blind RCT in severely iodine-deficient 9-year-old children in Bangladesh.47 However, potential positive effects of iodine may have been undetected due to other limiting nutritional factors and a short follow-up period. In an earlier association study, the same authors similarly found no association between hypothyroidism and EF.46 Similar results were found in a separate RCT in preschool children, with no differences in cognitive outcomes, including abstract reasoning, being found between an iodized salt treatment group and a control group.42 Iodine deficiency is known to have detrimental effects on general cognitive performance due to its impact on neuronal development, structure, and function. Evidence regarding the effects of iodine supplementation during childhood, specifically on EF, is limited, and some studies suffer from methodological constraints. However, positive results in RCTs provide rationale for more well-controlled randomized studies to be done in this area to determine whether iodine repletion during childhood has beneficial effects on EFs that are critical to school performance. Vitamin B12 and folate Vitamin B12 and folate, also known as vitamin B9, are fundamentally important for brain development and are often considered together as they are metabolically associated with one another, suggesting that a deficiency in one may alter the metabolism of the other. Black92 considers the disruption of myelination as one mechanism by which vitamin B12 and folate deficiency could influence brain processes and subsequent behavior, with a second mechanism being inflammation. The importance of vitamin B12 for myelination is due to its role in the metabolism of the fatty acids needed to produce the myelin sheath; thus, deficiency can result in the degeneration of nerve fibers and irreversible brain damage.15 Vitamin B12 attracts particular attention, as only animal products offer significant quantities; consequently, deficiencies can be high among individuals and cultures that follow a meat-free diet, and particularly diets that abstain from all animal products, due to other sources of vitamin B12 being found in dairy products.15 In addition to having a role in myelination, B vitamins are also cofactors for enzymes that synthesize neurotransmitters, thus impacting cognitive function throughout childhood and adolescence.93 Although the majority of research has focused on the role of folate and vitamin B12 during gestation, there is some clinical evidence highlighting the important role of both these B-vitamins for cognitive performance in children.49,53 In a study conducted among children and adolescents in the Netherlands,49 cognitive assessments were performed by forty-eight 10 to 16-year-olds who had been raised on macrobiotic diets for the first 6 years of life, followed by lacto-vegetarian or omnivorous diets, and 24 adolescents raised on omnivorous diets. Many of the adolescents raised on a macrobiotic diet early in life had poor vitamin B12 status during adolescence, even if they had been following an omnivorous diet since the age of 6, illustrating the importance of early-life dietary vitamin B12 intake. The results demonstrated that adolescents with low vitamin B12 status performed significantly worse on an abstract reasoning task, as assessed by Raven’s Progressive Matrices test, compared with the control subjects, in addition to having poorer performances on assessments of further cognitive domains. The importance of both B12 and folate on tasks requiring complex cognitive skills is highlighted further in 2 cross-sectional studies. One examined the associations of serum folate and vitamin B12 with cognitive performance in 5365 children and adolescents aged 6–16 years old.52 Cognitive assessments included reading, math, block design, and digit span from the Wechsler Intelligence Scale for Children–Revised and the Wide Range Achievement Test–Revised. The percentage-deficient values for folate and vitamin B12 were 6.02 and 0.35%, respectively. Higher serum concentrations of folate were associated with higher reading and block design scores after adjusting for various covariates. Vitamin B12, however, was not associated with any of the test scores. In agreement with these results, a further study reported folate intake to have a positive association with cognitive performance.53 Specifically, this cross-sectional study looked at the association between dietary folate intake (as assessed via dietary assessment) in Swedish children aged 15 (n = 386) and academic performance taken from the sum of school grades in 10 core subjects. A positive link was found between folate intake and academic performance, independent of socioeconomic status and income of parents. Limitations of this study, however, include no measure of serum folate and no reporting of deficiency, both of which may have significantly affected the results. It is acknowledged that academic performance does not explicitly assess EF; however, there is a large body of evidence demonstrating the important and intertwined relationship between EF and academic performance.94 There are many correlational studies94–96 and predictive studies5–7,97–99 that show EFs are heavily involved in academic performance success. This is interpreted to mean that EFs are a key driver in the ability to learn, and thus it was considered appropriate to include these studies. Though evidence regarding B12 and folate status predominantly focuses on the gestational period, emerging evidence highlights the importance of these vitamins for EF and academic performance throughout child development and brings attention to the importance of getting these vitamins through the diet, which may be challenging for individuals following meat-free diets. Currently, however, there are very few cross-sectional studies, and no RCTs, examining the effect of folate and B12 on EF; thus, to gain a greater understanding and a more comprehensive view of the role of these B vitamins in EF development, more studies are needed before conclusions can be drawn. Multiple micronutrient supplementation While it is important to investigate individual nutrients and their influence on the developing brain, it is also important to take a holistic view and appreciate the complex interactions among nutrients and their dependency upon one another for normal functioning.36 Consequently, it is of interest to examine the interaction between multiple micronutrient supplementation and EF in school-aged children. Positive effects on an EF task were reported in 240 Mexican-American school children aged 7.5 years, following the supplementation of a micronutrient mix with zinc, as compared with one without or a placebo.62 Though some aspects of cognition were unaffected, reasoning, as indicated by a smaller number of trials needed to learn simple concepts, was significantly improved following supplementation 5 days per week for 10 weeks. In a recent RCT, 8 to 14-year-old children were randomly allocated into a fortified milk group with micronutrients and omega-3 PUFAs (n = 60) or a regular full milk control group (n = 59).63 Following a 5-month intervention, the intervention group improved WM performance. A similar study in China provided 12 to 14-year-old children with either micronutrient-fortified (n = 177) or unfortified (n = 183) milk for 6 months.65 Though the authors did not directly measure EF, children in the intervention group reported higher scores in several academic subjects that require the use of EF, including languages and mathematics, compared with children in the control group. Further support for the effects of multiple micronutrient supplementation on EF is provided in a double-blind, placebo-controlled, matched-pair, randomized study.64 A cohort of 6 to 15-year-old (n = 608) middle-income school children received a micronutrient-fortified beverage or placebo for 14 months and were assessed on attention, concentration, memory, and intelligence. Supplementation with the fortified beverage significantly improved sustained attention and concentration over the duration of the study, while intelligence quotient, memory, and academic performance were not affected. All the identified studies for multiple micronutrient intake and EF are RCTs, and all demonstrate a positive effect on performance, providing good reasoning to suggest that supplementation and/or fortification with multiple micronutrients, or a blend of micronutrients, can have positive effects on tasks requiring the use of EFs. Evidence surrounding EF in school-aged children is still limited, however, and as most studies are conducted in deficient populations, further research is required to gain a more holistic understanding of how micronutrient supplementation supports EF development. With many deficiencies rarely occurring in isolation, multiple micronutrient supplementation may prove to be an effective strategy in promoting EF development. CONCLUSION AND LIMITATIONS IN CURRENT RESEARCH EFs are critical for many of the skills children need to succeed at school and in later life. The prolonged development of EFs and the underlying brain structures in childhood may provide an opportunity for interventions targeting EF-related brain maturational processes in school-aged children. As one of the factors to influence EF and underlying brain developmental processes in children, nutrition may provide an effective way to promote EF. Research highlighting the neurophysiological role of iron, omega-3 PUFAs, zinc, iodine, vitamin B12, and folate in EF development, alongside emerging clinical evidence, suggests these to be involved in the development of the brain and emergent EFs. Indeed, research in nutrition has certain restrictions when involving vulnerable populations, such as children, which may explain the limited research in this area. However, to further develop current understanding behind the role of nutrition in EF development in both healthy and deficient populations, well-designed nutritional intervention studies are needed to provide stronger support and enable clearer conclusions to be drawn. A limitation of this review is that study quality assessment was not performed, though from analysis it is clear there is a particular need for randomized placebo-controlled trials. Furthermore, studies should assess blood markers pre- and post-intervention to enable efficacy of the supplementation period to be evaluated alongside the cognitive assessments, and studies should continue assessing nutrient status to provide a clear understanding of the population being assessed. Where possible, future studies should consider the combined assessment of the structural and functional connectivity underlying EFs alongside behavioral assessments. It is also recommended that studies take into consideration other environmental influencers, such as SES, when considering the impact of nutrition on EF, to facilitate a more in-depth understanding of the differences potentially observed. With the dawn of novel analysis methods of large datasets, new opportunities for knowledge generation regarding the interaction between nutrients and brain func arise. Acknowledgments Author contributions. All authors (S.C., E.G., and N.S.) contributed significantly to the conception, design, and interpretation of this research. S.C. and E.G. screened and selected the literature. S.C. evaluated the literature, drafted the initial manuscript, and revised the manuscript. All authors critically reviewed, read, and approved the final manuscript. Funding. No external funds supported this work. Declaration of interest. Authors are employees of Société des Produits Nestlé SA. References 1 Carlson SM. 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TI - Nutrients for executive function development and related brain connectivity in school-aged children
JF - Nutrition Reviews
DO - 10.1093/nutrit/nuaa134
DA - 2020-12-22
UR - https://www.deepdyve.com/lp/oxford-university-press/nutrients-for-executive-function-development-and-related-brain-0XzegLJKNF
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -