Many studies demonstrate the destructive effects of malnutrition and nutrient deficiencies on learning and cognition. Most studies examine specific periods of development (eg, prenatal, infancy and school age or aging) while neglecting the postinfancy period, in which a number of nutritional deficiencies including but not limited to choline, selenium, zinc, folate, vitamin B12 and iodine, have been shown to interfere with normal development and cognition (1).
The most commonly studied deficiencies in children are protein-energy malnutrition, including Kwashiorkor and marasmus, iron deficiency and essential fatty acids deficiency. The aim of this review is to examine the limited studies that have been performed on children of this age, and to offer a broader view of the relationships among nutrition, nutrients and cognition.
RELATIONSHIP OF NUTRITIONAL DEFICIENCY TO THE TIMING OF BRAIN DEVELOPMENT
Malnutrition, undernutrition, and nutrient imbalance may affect learning and memory by modifying or interfering with brain physiology or with brain structure. Two conditions of nutritional insults may prevail: temporary damage (which lasts only as long as the nutritional problem exists) includes short-term blockage in the bioavailability of nutrients essential for a specific action. For example, depletion of the bioavailability of tyrosine to the brain will halt the production of catecholamine neurotransmitters. However, if the nutritional insult occurs in a “critical period,” the damage will no longer be temporary but rather have long-term consequences. Many studies tend to concentrate on nutritional deficiencies during the early infancy period when many accelerated developmental events occur. It was recently concluded that while the brain undergoes rapid development during infancy, the maturation of the brain is not yet completed. Maturation of areas of the brain is not uniform, and different areas mature at different ages. It seems that the areas of the brain that mediate cognitive function mature last. There are several indicators for brain maturation, such as synaptogenesis, myelin formation and dendrite formation (2,3). Several techniques, such as the PET scan or magnetic resonance imaging (4), demonstrate brain development well into the preschool period, and the glucose utilization test shows a higher rate of brain glucose metabolism in the postinfancy period than during adulthood (5). The 2 brain areas that mediate most of the cognitive functions, the frontal and prefrontal cortex and the hippocampus, mature during postinfancy or later. Several investigations have correlated the appearance of different types of cognition and memory with the rate of maturation of specific brain areas (6). Some researchers estimate that the frontal cortex finally matures at age 10. Insults to the process of the synaptogenesis or to the rate of myelination induce severe delay in development and maturation of brain areas, which results in delayed cognitive development.
The sensory system matures before the cognitive system. Delay in maturity (eg, disturbance in the myelin formation process) in the visual or auditory system, severely impacts the cognitive system, where sensory-motor coordination is essential for normal cognitive development. Even a correction of the nutritional deficit may leave persistent long-term effects on the auditory system.
Protein energy malnutrition (PEM) is a state that mainly affects infants as a result of energy restriction and a protein- and amino acid–deficient diet. Although most children with PEM exhibit cognitive deficits, the magnitude of the disorder among postinfancy children is not known. This syndrome is a combination of the effects of undernutrition and a severe decrease in essential enzymes and neurotransmitters. Other known nutritional disorders may be confounded by a history of energy restriction.
Iodine may be responsible for mental retardation and can appear at any age, although it is most devastating when it occurs during infancy. The mechanism is clear: iodine is required for the formation of thyroxin, which is an essential nutrient for the brain.
Iron deficiency (ID) is the most prevalent nutritional disorder at all ages. There are many animal and human studies describing the effects of ID and its effects on dopamine and dopamine D2 receptors (7). Behaviorally, children with ID showed lethargy, irritability, apathy, fatigue, inability to concentrate, pica, inattention and a decreased IQ. Some theories relate ID to attention-deficit/hyperactivity disorder (ADHD). In animal studies, ID induces a delay in maturation of the frontal cortex, which may explain the cognitive deficits found in animal and human studies, and hippocampus, which may explain the spatial cognitive decline (7,8).
Recently the authors found that most of the neurological reflexes (galabella, palmer grasp, planter grasp, passive movement arm, passive leg movement, and Babinsky) were severely delayed in ID/low ferritin premature infants (9). The long-term effects of infancy ID has been studied in a group of rehabilitated children. At ages 9 to 10 (with normal values of hemoglobin, iron and ferritin) their IQ score was the same as non-ID infant children; however, their scores on subset tests that required spatial cognition were significantly lower. In addition, in auditory tests they exhibited statistical but not clinical delay in processing auditory signals (10). One of the mechanisms that may explain these results is the interference of ID in the normal rate of myelination. In addition, ID may slow down the development and maturation of brain neurotransmitters. In contrast to infantile ID, which is hard to treat and has a long-term effect, ID that occurs later in life is much easier to treat. Despite discussions of ID-impaired learning or memory or motivation and concentration, the ultimate resulting condition is decreased cognitive function (11,12). In our study with rehabilitated ID children we did not find any decrease in motivation or concentration, but we did find a tendency toward lower IQ scores.
Nutritionally induced ID modifies other body systems in addition to the brain and its biochemistry. Modifications of the endocrine system (an increased insulin sensitivity and a decreased thyroxin level) were reported. Several aspects of the 2-way relationship between ID and cell-mediated immunity have been described. On the one hand, interleukin-1 (IL-1) induces ID; on the other hand, our results showed that among ID rats the level of IL-1 (proinflammatory) is increased and the level of IL-2 (anti-inflammatory) is decreased (7). An increased level of IL-1 and a decreased level of thyroxin leads to deficits in the learning process and cognition. In addition, the effects of ID on the immune system can explain the finding that the rate of children with ID who are sick with infectious diseases is much higher than that for non-ID children.
It is important to note another effect of ID, namely that the bioavailability of molecules in the brain is highly dependent on proper function of the blood-brain barrier (BBB). Although the neonate is born with an immature BBB, the BBB matures quickly to protect the developing brain. We found that the pattern of penetration of several compounds into the brain of ID rats is different from that of the control rats (13). It is interesting to note that the ID state does not damage the BBB but rather induces specific changes in the penetration rate. One of the compounds that is able to cross the BBB in ID rats is β-endorphin, which is unable to cross the BBB in normal rats. Here again, higher brain levels of β-endorphin are associated with poor learning and memory.
ESSENTIAL FATTY ACIDS DEFICIENCY
The activity of the brain is highly dependent on the integrity of the neuronal membrane (14,15). The neuronal membrane is composed mainly of proteins and lipids. The proteins in the membrane are relatively stable, whereas the lipids exhibit a fast turnover rate. Also, it should be remembered that the neuronal membrane, the myelin sheath, surrounds the membrane, and that the myelin is composed mainly of lipids.
The physical state of the neuronal membrane is critical for the neuronal functions. The ideal state is a gel state. There are known molecules that are able to change the physical state of the membrane, for example, alcohol fluidizes the membrane, whereas cholesterol hardens the membrane. The change in the physical state of the neuronal membrane modifies some of the membrane functions, including neuronal information along the axon and neuronal information in the synapse.
Essential fatty acids (EFA) are essential for the developing brain. It is outside the scope of this review to deal with the most important issue of EFA supplements to baby formulas. EFA are involved in most of the aspects of brain development and maintenance. They are major components of myelin and are able to induce myelination, determining the index of membrane fluidity. EFA are also involved in neurotransmitters and the production of peptides. In EFA deficiency (EFAD) states the membrane becomes much harder and cannot perform its functions.
Whereas the brain uses linoleic (n-6) and α-linolenic (n-3) acids for many functions, their derivatives (ie, the longer chains of polyunsaturated fatty acids [PUFA]) are also important. The same enzymes that are responsible for the elongation of the fatty acids act upon both families of PUFA and compete with each other. Numerous studies have confirmed that that the level of PUFA in the neuronal membrane is important, and recent studies have shown that the types of PUFA and the ratio between n-3 and n-6 PUFA are just as important. For example, the ratio between the total PUFA and cholesterol level in the membrane determines the membrane fluidity index. Not all ratios of PUFA are equally effective in decreasing the level of cholesterol in the membrane. The ratio of 1:4 (n-3:n-6) was found to be the most effective in decreasing the cholesterol level in the membrane (14).
The role of n-3 in various brain functions is facilitated greatly by diet-induced deficiency. Studies have shown that n-3-deficient rats exhibit poor learning and memory in a variety of tasks, including but not limited to Morris Water Maze performance and olfactory-based learning in addition to sensory deficits such as selected visual functions (16). In n-3 deficiency there is a significant decrease in the neuron size in the hippocampus, hypothalamus and cortex, the areas of the brain that mediate spatial and serial learning. In addition, n-3 deficiency induces a significant reduction in cerebral catecholamines, in glucose transport capacity and glucose utilization in the brain and in the rate of myelinization (17). Each of these variables can be responsible for learning deficits.
Clearly, the various fatty acids serve different roles in the nervous system and throughout the body's machinery. It has been suggested that the nervous system has an absolute molecular species requirement for proper function. Studies in our laboratory confirm this finding and even suggest an added qualifying requirement (eg, the need for a proper ratio between the EFAs. Many studies examined the effects of various fatty acids on learning and memory, but few examined the ratio between various PUFA. We tested a wide range of PUFA ratios and found that a mixture of linoleic (n-6) and α-linolenic acids (n-3) with a ratio of 4:1 was the most effective in improving learning performance (as assessed by the Morris Water Maze and passive avoidance), elevating pain threshold, improving sleep and improving thermoregulation. This ratio was also able to correct learning deficits induced by the neurotoxins AF64A and 5,7-dihydroxytryptamine and by 6-OH-DA (ie, reduction in brain dopamine level).
Our studies in animal models were not limited to an examination of memory disorders. The PUFA compound was effective in decreasing elevated cortisol levels in an experimental model of stress (18). The PUFA mixture was also found to improve the status of an experimental rat model of multiple sclerosis and a decrease in the frequency of seizures in pentetrazol-treated rats. Ongoing clinical trials with patients with refractory seizure, using a commercial fatty acid preparation, appear to confirm the success of seizure control that was observed in the animal data (14).
A question of major concern in pediatric neurology relates to the establishment of the degree of nutritional deficiencies that is able to induce behavioral disturbances, even in the preschool period. In a recent survey the authors found that a large percentage of children with ADHD are iron deficient, EFAD, and some are both. We were unable to establish that the nutritional deficiency was the unequivocal cause of the behavioral disturbances, or that because the children tend to be anorectic and consume large amounts of junk food, the nutritional deficiencies are the results of the behavioral disturbance. However, recent studies showed that ID induces changes in the index of membrane fluidity. In addition, children with EFAD exhibited the same auditory changes as children with ID, and changes in the BBB functions were found among EFAD rats.
The succinct message of this review is that the postinfancy or preschool period is not a quiet period in brain development. Although it is true that no critical developments were identified in the postinfancy or preschool periods, it is clear that the brain continues to develop and that any damage incurred during these periods may have long-term results. The critical brain areas that mediate reasoning (prefrontal cortex) (19) and spatial learning (hippocampus) (20) do not reach maturation in this period. Various types of learning such as sequential learning (21), spatial cognition (22) or inhibitory control (23) must wait until the brain area is ready to perform the task. Nutritional deficiencies will delay these performances for a long time (24,25).
The authors would like to thank the Rose K. Ginsburg Chair for Research into Alzheimer's Disease and the William Farber Center for Alzheimer Research for their support.
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