Title: Nutritional factors in brain development
Key words: intra-uterine, intrauterine, brain development, foetal brain, primates, humans, rats, lacustrine, evolution, fatty acids, nutrients, fish, neurones, neuronal development, undernutrition, postnatal, myelin, essential fatty acids, EFA, deficiencies, docosahexaenoic acid, DHA, polyunsaturated fatty acid, PUFA, cerebral cortex, brain maturation, visual acuity, cognitive development, zinc, n-3 PUFA, antioxidant, microthrombosis, protein, micronutrient, iron, anaemia, iron deficiency, malnutrition, mental retardation, iodine, thyroxin, psychomotor, folic acid, pregnancy, neural tube defect, prophylactic, IQ, vitamin B6, B12, homocysteine, preeclampsia, prematurity, lipids, arachidonic acid, cerebellum, retina, photoreceptors, lactation, breast milk, monounsaturated,
Date: Oct 2006
Author: Morgan, G
Nutritional factors in brain development
Human intra-uterine development is characterised by a rapid growth of the foetal brain. At term, the brain accounts for some 16% of body weight and consumes around 70% of the body’s energy requirements (Crawford 1997). Some 70% of brain neurones have completed their division at term (Harbidge 2004). This rapid rate of growth is unmatched in other primates or non-primate mammals and places enormous metabolic demands on the developing foetus. This review will consider the multiple aspects of the nutritional burden imposed on the developing human brain.
Characteristics of human evolution
The large energy expenditure devoted to foetal brain development distinguishes man from other primates. Comparative data shows humans to be comparatively ‘undermuscled’ compared with other primates and to have a richer and more varied diet, with greater fat stores, supporting the demands posed by a rapidly enlarging brain (Leonard 2003). The palaeoontological evidence would appear to support the theory that the evolution of the human brain was closely connected with the adoption of a lacustrine lifestyle, based on fish consumption, during a critical window in man’s evolution (Broadhurst 1998, Crawford 1999). The adoption of a diet rich in fatty acids and nutrients essential for brain development also enabled the brain to be ‘fed’ during times of famine and would have had additional survival value.
The animal model
In spite of ontological and morphological differences between species rendering extrapolation of data from animal experiments on brain development to humans difficult to interpret, biochemical and structural similarities of neurones across species indicate that animal data throw light on normal human neuronal development and its dependency on nutritional factors. The human data is supportive of this data in many instances.
Experiments in rats have shown that undernutrition in foetal and early postnatal life leads to reduced DNA replication and synapse formation (Lewis 1975, Bedi 1980). Undernutrition in postnatal life is associated with impaired oligodendrocyte activity and impaired myelin production in the rat (Wiggins 1982). These changes have been shown to be due to essential fatty acid (EFA) deficiencies and to demonstrate only partial recovery on restitution of a normal diet (Wiggins 1982, Yeh 1988).
The long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA) is a structurally important EFA. It has been found in high concentrations in the cerebral cortex and photoreceptors of both animals (Neuringer 1986, Bazan 1990) and humans (Makrides 1994). DHA deprived monkeys have shown persistent changes in visual acuity (Bazan 1990). Learning experiments in rodents have shown both EFAs and iron to be necessary for normal brain maturation and cognitive development (Carrie 2000, Kwik-Uribe 2000). Zinc deficiency has been shown to be associated with similar problems in monkeys (Golub 1995). These defects were not wholly correctable on repletion (Golub 1995, Felt 1996). In chicks with encephalo-malacia induced by undernutrition, experiments (Budowski 1987) have supported the hypothesis that imbalanced EFA intake, with n-3 PUFA and antioxidant deficiency may, in humans, be related to cerebral intravascular inflammation, microthrombosis, impaired brain development and small-for-dates babies (Crawford 1993a, Dieter 1994).
Human undernutrition is widespread worldwide. This is particularly the case in the developing world where protein and micronutrient malnutrition is often compounded by poor maternal status, parasitic infection, infectious diseases and poor obstetric and medical care. The developing brain appears to be quite resistant to the effects of protein malnutrition (DeLong 1993). Micronutrient deficiencies, however, are relatively common and do impact on normal brain development.
Worldwide, iron deficiency continues to remain a major health issue. The WHO estimates that 25% of all children may be affected (De Maeyer 1985). It has been rated as an independent risk factor for mental retardation (Hurtado 1999). Although it has been argued from animal experiments (Kwik-Uribe 2000) that a ‘therapeutic window’ exists for correcting iron deficiency-induced cognitive damage in early life, a review of the iron repletion literature in infants less than 2 years old was not able to draw any firm conclusions owing to the poor methodology of the studies (Grantham-McGregor 1999). In older children, a review of 18 studies showed correlations between iron deficiency and poor cognitive performance and school performance (Lansdown 1995). Confounding factors in these cross-sectional studies rendered the attribution of causality difficult. A more closely controlled American study, however, did show early iron deficiency to be an independent risk factor for the later development of cognitive impairment (Lozoff 2000). Given the part played by iron in fatty acid and neurotransmitter metabolism, a putative role in brain development has been posited. Better controlled studies in early life are indicated to help resolve many of the issues raised by these studies.
Iodine deficiency remains a global problem with up to 30% of the world’s population being affected (WHO 1994). The association between maternal iodine deficiency, cretinism, and impaired mental development in childhood has been well documented through supplementation programmes (Pharoah 1971, Thilly 1980). Maternal blood thyroxin levels have been correlated with cognitive ability at age 14-15 (Connolly 1989). In one study, low-normal maternal thyroxin levels were found to be associated with poor psychomotor development in the first 10 months of life (Pop 1999). A meta-analysis of 19 worldwide studies showed an average decrement of 13.5 IQ points associated with iodine deficiency (Bleichrodt 1994).
Folic acid deficiency remains prevalent amongst women of childbearing age and during pregnancy (Cikot 2001). Its association, along with vitamin B6 and vitamin B12 deficiency, with neural tubal defects and maldevelopment of the nervous system has been well documented through its effect on elevating homocysteine levels (Lumley 2001). Trials of prophylactic folic acid supplementation have shown reductions in rates of these malformations (MRC 1991). Elevated homocysteine levels have been shown to be both toxic to neurones and vascular endothelium during foetal development (Rosenquist 2001). Associations with preeclampsia, low birth weight, prematurity and miscarriage testify to its damaging effect on both neural and somatic development.
Essential fatty acids
Lipids account for 60% of the weight of the brain. Phospholipids play important structural roles in nerve cell membranes and myelin sheaths. Arachidonic acid and DHA, the primary EFAs present in brain phospholipids, are key nutrients in brain development. They are found in high concentration in the cortex, cerebellum and retinal photoreceptors (Makrides 1994). Low levels in intrauterine life lead to poor neural development and low birth weight (Crawford 1993b). Relative long-chain n-3 PUFA deficiency in intrauterine life has been linked to inflammatory changes in the placental and cerebral blood vessels leading to microthromboses, foetal malnutrition, low birth weight and impaired brain development (Crawford 1993a). During lactation, breast milk continues to supply vital arachidonic acid and DHA. Breast fed infants have been shown to have higher DHA levels in the brain (Farquharson 1992), improved retinal function (Uauy 1990), and improved cognitive function at 9 years compared with bottle fed infants (Lucas 1992).
Recently, DHA has also been linked to a range of leukodystrophic disorders such as Refsum and Zellwegers syndrome, associated with cytosolic peroxisome function (Suzuki 2001, Martinez 2001). At birth long-chain saturated and monounsaturated fatty acids become increasingly important in the formation of myelin sheaths and are well provided for by breast milk (Crawford 1997).
Nutritional factors in brain development are multifactorial and interdependent. Vitamins, minerals, essential fatty acids, antioxidants, and other nutritional factors are all likely to play a role in undernutrition in early life. Doyle (Doyle 1990) has indicated that maternal deficiencies in magnesium and the B vitamins, both relatively common, may be particularly important in foetal development. Zinc may also be shown in the future to be important in foetal brain development. These nutrients all have close associations with essential fatty acid and neurotransmitter metabolism. Vascular and neurological health and development are closely linked to these nutritional factors and may explain the associations that have been drawn between placental failure, low birth weight and subsequent cardiovascular disease in adult life (Barker 1993, Crawford 1993a). Good maternal nutrition will help to reduce these risk factors during intrauterine life.
Postnatally, breast feeding and a diet rich in essential fatty acids and essential micronutrients will help to foster the further maturation of the brain and nervous system.
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