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http://lpi.oregonstate.edu/infocenter/cognition.html

Micronutrients and Cognitive Function

Summary

The brain requires a constant supply of micronutrients forenergy metabolism of neurons and glial cells, neurotransmittersynthesis and action, nerve impulse propagation, and homocysteinemetabolism .(More Information)

Deficiencies in various micronutrients, especially the Bvitamins, have adverse effects on cognition. (More Information)

The developing brain may be particularly vulnerable todeficiencies in choline and essential fatty acids. (More Information) Due to conflicting studies, more research in needed to

determine whether micronutrient supplementation affects attention-related cognitive functions. (More Information)

Presently, there is little evidence that supplementation with B

vitamins, antioxidant vitamins, choline, or omega-3 fatty acids willimprove memory performance. (More Information)

More research is needed to determine whether m icronutrientsupplementation has any effects on executive functioning (i.e.,higher-order cognitive processes). (More Information)

Some, but not all, studies have reported that micronutrientsupplementation improves overall mood and psychological well-being .(More Information)

It is not yet clear whether supplementation with B vitamins,antioxidants, or omega-3 fatty acids protects against age-relatedcognitive decline. (More Information) Several methodological issues (e.g., tests used to assess

cognition, choice of study population, nature of the supplementation,study duration, etc.) may have contributed to the conflicting resultsobserved in intervention studies. (More Information)

Good nutritional status is important for proper brain development andmaintenance of normal cognitive function (1). Through unique biologicalfunctions, various micronutrients affect brain function. This article discusses

the roles of key micronutrients, including the B vitamins, antioxidant vitamins,and certain essential minerals, in cognitive function. When appropriate,research on the role of other compounds, such as essential fatty

acids and choline, is also presented. The cognitive effects of micronutrientdeficiencies are discussed, and the effects of micronutrient supplementationon the broad areas of attention, memory, executive functions, mood, as wellas age-related cognitive decline are covered.

Basic Needs for Cognitive Performance

Energy Metabolism of Neurons and Glial Cells

The human brain is a highly metabolically active tissue that depends on aconstant supply of glucose to meet its energy needs. In fact, the brain

accounts for approximately 25% of total body glucose utilization at rest,despite representing only 2% of adult body weight (2, 3). Blood glucose levelsmust be maintained at all times to avoid hypoglycemia and to supply the brain

with its preferential fuel. During the initial stages of fasting, blood glucoselevels are maintained through the breakdown of liver glycogen and then

through the process of gluconeogenesis the production of glucose from non-

carbohydrate precursors, such as amino acids. The B vitamin biotin isrequired for a key enzyme in the gluconeogenic pathway (4). While glucose isthe obligatory fuel, ketone bodies can also be used by the brain when glucosesupply is inadequate, such as during prolonged fasting or starvation.However, ketone bodies are acidic, and very high levels of these compoundsin the blood are toxic and may result in ketoacidosis (5). Thus, glucose is the

preferred and normal energy substrate of the brain.

Glucose oxidation in the brain requires certain micronutrients as cofactors. For instance, forms of several B vitamins, including thiamin, riboflavin, niacin, and pantothenic acid, as well as the compound lipoic acid, are utilized inreactions that completely metabolize glucose to carbon dioxide and wate r(3).

Additionally, the nutritionally essential minerals, magnesium, iron,

and manganese are required for the complete metabolism of glucose; thesemicronutrients are utilized as cofactors, substrates, or components ofenzymes in glycolysis and the citric acid cycle (6, 7). Moreover, generation of

cellular energy in the form of ATP by the electron transport chain requires thevitamins, riboflavin and niacin; iron contained in iron-sulfur clusters; andthe endogenously synthesized compound, coenzyme Q 10 (8).

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Cerebral Blood Supply

At rest, the brain receives approximately 15% of cardiac output (9).

Prope rcerebral blood supply is necessary to deliver oxygen, glucose andothe rmacronutrients, and the required micronutrients forproper cognitive function. Nutrition has a role in maintaining optimal blood

supply to the brain. For instance, insufficiency of several dietary components

increases the risk of developing stroke, a pathological condition that resultsfrom impaired cerebral blood supply; see the Disease Index for examples.

Neurotransmitter Synthesis

A neurotransmitter is a chemical released from a nerve cell that transmits animpulse to another nerve cell or an effector cell, such as a muscle cell.Neurotransmitters have either excitatory or inhibitory effects; the type of effectis dependent on the receptor on the receiving cell (10). Neurotransmitters canbe broadly divided into two main classes: small amino acids (e.g., gammaaminobutyric acid [GABA], glutamate, aspartate, and glycine) and biogenicamines (e.g., dopamine, epinephrine, norepinephrine ,serotonin, histamine,

and acetylcholine) (11).

In addition to various amino acids, several B vitamins, including thiamin ,riboflavin, niacin, vitamin B 6, folate, and vitamin B 12 , areneeded as cofactorsf or the synthesis of neurotransmitters. Moreover, vitaminC is required for synthesis of norepinephrine (3), and the mineral zinc isimportant for proper function of GABA, aspartate, and norepinephrine (12). Further, choline is a precursor for the neurotransmitter acetylcholine (13).

Neurotransmitter Binding to Receptors

Neurotransmitters function by binding to receptors on the cell membrane of

the neuron releasing the neurotransmitter (i.e., presynaptic neuron) or toreceptors on the cell membrane of the receiving cell (i.e., the postsynapticneuron). Receptor binding can either mediate the opening of ion channels orcause metabolic changes within the cell (3, 14). Specifically, direct action onion channels results from neurotransmitter binding to receptor sites on themembrane of postsynaptic neurons. This binding causes the gate-like ionchannels to open, which allows ions to flow into the cell (10). Influx ofpositively charged ions into the postsynaptic neuron can have excitatory

effects by depolarizing the membrane; membrane depolarization can causea nerve impulse or action potential if a certain threshold is reached within theneuron. This is commonly referred to as neuronal firing. In contrast, influx o fnegatively charged ions can have inhibitory effects by hyperpolarizing themembrane and thus preventing neuronal firing (15). In addition to direct

effects on ion channels, neurotransmitters may bind to G-protein coupledreceptors, thereby eliciting cell-signaling effects that could result in metabolic

changes (e.g., alterations in activity of various enzymes) within a postsynapticcell (14).

Vitamins could possibly influence binding of neurotransmitters to postsynapticreceptors. For instance, an in vitro study showed that two forms of vitamin B 6, pyridoxal and pyridoxal phosphate, inhibited the binding of GABA topostsynaptic receptors (16). Also, a rat study associated vitamin B 6 deficiencyduring fetal development and lactation with changes in the number andbinding of dopamine receptors (17).

Nerve Impulse Propagation

The speed at which nerve impulses (action potentials) are propagated is

influenced by the myelination of the nerve (18). Myelination refers to theprocess in which nerves acquire a myelin sheath the insulating layer oftissue made up of lipids and proteins that surrounds nerve fibers. This sheathacts as a conduit in an electrical system, allowing rapid and efficienttransmission of nerve impulses (10).

Certain micronutrients can affect the propagation of nerve impulses. Inparticular, adequate intake of both folate and vitamin B 12 is important inmaintaining the integrity of the myelin sheath, and thiamin is needed formaintenance of the nerves membrane potential and for proper nerveconductance (3). Additionally, iron has an important role in the development ofoligodendrocytes, the cells in the brain that produce myelin (19).

Homocysteine Metabolism

Homocysteine is a sulfur-containing amino acid that is an intermediate inthe metabolism of another sulfur-containing amino acid, methionine. Elevatedhomocysteine levels in the blood (i.e., hyperhomocysteinemia) may be a riskfactor for cardiovascular diseases and could also be linked to dementia and

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Alzheimers disease (20, 21). The amount of homocysteine in the blood isregulated by at least three vitamins: folate, vitamin B 6, and vitaminB12 (see diagram ). Additionally, the nutrient choline is also involved in

homocysteine metabolism. The choline metabolite, betaine, can also providea methyl group for the conversion of homocysteine to methionine.

Consequences of Select Micronutrient Deficiencies

Thiamin

Thiamin (vitamin B1) deficiency, like deficiencies in several of the B vitamins,has negative cognitive effects. Adequate intake of thiamin is important forreactions in the brain that metabolize carbohydrates, lipids, and amino acids. For instance, phosphorylated forms of thiamin, including thiamin diphosphate

(TDP) and thiamin pyrophosphate (TPP), arerequired cofactors for enzymeso f glycolysis, the citric acid cycle, and thepentose phosphate pathway (22). Additionally, thiamin triphosphate (TTP)

may be involved in neuronalmembrane functions and nerve impulse (actionpotential) generation, but the exact biochemical role of TTP is still not well

understood (22, 23). Severe thiamin deficiency, which is rare in industrialized

nations, except in patients with chronic alcoholism, HIV-AIDS, orgastrointestinal conditions that impair vitamin absorption (23), results in thecondition called beriberi, of which there are many forms thatinvolve neurological symptoms. The dry and wet forms of beriberiinvolve peripheral neuropathy, whereas cerebral beriberi can lead to neuronalcell death and the clinical conditions of W ernicke's encephalopathy andKorsakoff's psychosis, especially in those who chronically abuse alcoho l(22,24). For more information about the various forms of thiamin deficiency, seethe separate article on Thiamin.

Niacin

The niacin (vitamin B3) coenzymes, NAD and NADP, are needed forsevera lredox and other reactions in the body (see the separate articleon Niacin) . Severe niacin deficiency, known as pellagra, has been historicallyassociated with poverty and consumption of a diet predominantly based oncorn, which is low in bioavailable niacin (25, 26). Today, the condition is

uncommon, but it can occur in cases of chronic alcoholism and in individualswith malabsorption syndromes (27). Among other symptoms, pellagra is

characterized b ydementia. Neurologic symptoms of pellagra includeheadache, fatigue, apathy, depression, ataxia, poor concentration, delusions,and hallucinations, which can lead to confusion, memory loss, psychosis, andeventual death (27).

Pantothenic Acid

Pantothenic acid (vitamin B5) is required as a component of coenzyme A(CoA), a coenzyme needed for the oxidative metabolism of glucose and fattyacids and for the biosynthesis of fatty acids, cholesterol, steroid hormones, the hormone melatonin, and the neurotransmitter acetylcholine. A form of thevitamin (4'-phosphopantetheine) is also required for the activity of acylcarrie rprotein, which is needed for the synthesis of fatty acids (28),

including phospholipids and sphingolipids. Phospholipids are importantstructural components of cell membranes, and the sphingolipid,sphingomyelin, is a component of the myelin sheath that enhances nerve

transmission (29). Naturally occurring pantothenic acid deficiency in humansis very rare and has been observed only in cases of severe malnutrition (30). Therefore, most information regarding the vitamin deficiency comes fromexperimentally induced states in laboratory animals. Such studies have foundthat select deficiency in pantothenic acid causes demyelination (destruction orloss of the myelin sheath) and peripheral nerve damage (13). In humans,

pantothenic acid deficiency has been induced experimentally by co-administering a pantothenic acid antagonist and a pantothenic acid-deficientdiet. Participants in this experiment complained of headache, fatigue,insomnia, intestinal disturbances, and numbness and tingling of their handsand fee t(31). In another study, participants who were f ed only a pantothenicacid-free diet did not develop clinical signs of deficiency, although someappeared listless and complained of fatigue (32).

Vitamin B 6

A form of vitamin B 6, pyridoxal 5'-phosphate (PLP), is a required coenzyme for

the biosynthesis of several neurotransmitters, including GABA, dopamine,norepinephrine, and serotonin (3). The vitamin has a number of otherbiological functions (see the separate article on Vitamin B 6). VitaminB6concentrations in the brain are about 100 times higher than levels in theblood; thus, it is not surprising that vitamin B 6 deficiencyhas neurologice ffects (13). Severe deficiency of vitamin B 6 is uncommon, but

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alcoholics are thought to be most at risk due to low dietary intakes andimpaired metabolism of the vitamin. In the early 1950s, seizures wereobserved in infants as a result of severe vitamin B 6 deficiency caused by anerror in the manufacture of infant formula. Additionally,abnormal electroencephalogram (EEG) patterns have been noted in some

studies of vitamin B 6 deficiency. Other neurologic symptoms noted in severevitamin B 6 deficiency include irritability, depression, and confusion (33).

Biotin

Biotin (vitamin B7) is required as a cofactor for carboxylase enzymes that areimportant in the metabolism of fatty acids and amino acids. Overt biotindeficiency is quite rare but has been documented in patients on prolongedintravenous feeding (parenteral nutrition) without biotin supplementation; inindividuals consuming high amounts of raw egg white that contains avidin,which binds biotin and prevents its absorption; and in those with hereditarydisorder, biotinidase deficiency (34). In adults, neurologic symptoms of biotindeficiency include depression, lethargy, hallucinations, and numbness andtingling of the extremities (35).

Vitamin B 12

Vitamin B 12 deficiency, which affects 10-15% of adults over the age of 60, isfrequently associated with neurological problems. Compared to youngeri

ndividuals, this vitamin deficiency is more common in older adults because ofthe higher prevalence of food-bound vitamin B 12 malabsorption (atrophicgastritis) and the higher incidence of the autoimmune condition, perniciousanemia (39). Hematological changes, including elevated blood levelsofhomocysteine and methylmalonic acid, are diagnostic of vitaminB12 deficiency; however, approximately 25% of cases include neurologicalsymptoms as the only clinical indicator of vitamin B 12 deficiency (40, 41). Suchneurologic symptoms of vitamin B 12 deficiency include numbness and tinglingof the extremities, especially the legs; difficulty walking; concentrationproblems; memory loss; disorientation; and dementia that may or may not beaccompanied by mood changes (41). In some cases, the dementia and otherneurologic symptoms caused by vitamin B 12 deficiency can be reversed byvitamin treatment (42), but reversibility seems to be dependent upon theduration of the associated neurologic complications (41). While thebiochemical mechanisms underlying the neurological effects of vitamin

B12deficiency are not understood, the vitamin deficiency is k nown to damagethe myelin sheath covering cranial, spinal, and peripheral nerves (42, 43).

Vitamin C

Vitamin C accumulates in the central nervous system, with neurons of thebrain having especially high levels (44). In addition to its well-

known antioxidant functions, vitamin C has a number of non-antioxidantfunctions. For instance, the vitamin is required for enzymatic reactionthat synthesizest he neurotransmitter norepinephrine from dopamine. Another

non-antioxidant action of vitamin C in the brain is in the reduction of metal(e.g. ,iron, copper) ions (44). Further, vitamin C may also be able toregenerate vitamin E (45), an important lipid-soluble antioxidant. Vitamin C

deficiency causes oxidative damage to macromolecules (lipids, proteins) inthe brain (13). Severe vitamin C deficiency, called scurvy, is a potentially fataldisease. However, in scurvy, vitamin C is retained by the brainfor neuronal function, and eventual death from the disease is more likely dueto lack of vitamin C fo rcollagen synthesis (44). Collagen is an importantstructural component of blood vessels, tendons, ligaments, and bone.

Vitamin D

The vitamin D receptor is expressed in brain tissue (46), and vitamin D isknown to be important for normal brain development and function (47).

Accordingly, vitamin D deficiency may impair cognitive abilities. Vitamin Ddeficiency is a major problem worldwide, with an estimated one billion peoplehaving insufficient or deficient levels of circulating 25-hydroxyvitamin D (48).

Aging is associated with a reduced capacity to synthesize vitamin D in theskin upon sun exposure (49). Thus, older adults may be more vulnerable tovitamin D deficiency and any untoward effects on cognition. Some studies in

older adults have either linked lower 25-h ydroxyvitamin D levels withmeasures of poor cognitive performance (50-53) or higher 25-hydroxyvitaminD levels with measures of better cognitive performance (54, 55). However, a

recent systematic review of five observational studies concluded that theassociation between 25-hydroxyvitamin D concentrations and cognitiveperformance is not yet clear (56). More research, especially from randomized

controlled trials, is needed to determine whether vitamin D deficiency hasadverse effects on cognition.

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Vitamin E

The alpha-tocopherol form of vitamin E is an important lipid-soluble antioxidant. In the brain and other tissues, alpha-tocopherol has a keyrole in preventing oxidant- induced lipid destruction and is therefore vital inmaintaining the integrity of cell membranes. Accordingly, vitamin E deficiencycauses lipid peroxidation in brain tissues (57). Severe vitamin E deficiency

results mainly in neurological symptoms, including impaired balance andcoordination (ataxia) , injury to the sensory nerves (peripheral neuropathy) ,muscle weakness ( myopathy) , and damage to the retina of the eye(pigmented retinopathy). For this reason, people who develop peripheralneuropathy, ataxia, or retinitis pigmentosa should be screened for vitamin Edeficiency (58). The developing nervous system appears to be especiallyvulnerable to vitamin E deficiency. For instance, children who have withsevere vitamin E deficiency from birth and are not treated with vitamin Erapidly develop neurological symptoms. In contrast, individuals who developmalabsorption of vitamin E in adulthood may not develop neurologicalsymptoms for ten to 20 years. It should be noted, however, that symptomaticvitamin E deficiency in healthy individuals who consume diets low in vitamin Ehas never been reported (58, 59).

Calcium

Calcium ions are important intracellular signals that regulate a number ofphysiological processes, including neuronal gene expression, neuronalsecretion of neurotransmitters into synapses, and synaptic plasticity( reviewedin 60) . Normal blood levels of calcium are maintained even when dietaryintake of calcium is inadequate because the skeleton provides a large reserveof the mineral. Thus, effects of dietary calcium inadequacy would primarilyresult in negative effects to bone health. Interestingly, changes in calciumhomeostasis in the brain may contribute to the cognitive decline associatedwith normal aging and possibly to the development of neurodegenerative

disorders (61, 62).

Iodine

Iodine is required for the synthesis of thyroid hormones that regulate anumber of physiological processes, including growth, development,metabolism, and reproduction (63, 64). In addition, thyroid hormones are

important for myelination of the central nervous system, which mostly occursbefore and shortly after birth (64, 65). Because iodine is critical for normaldevelopment of the brain, deficiency of this mineral during critical periods,such as during fetal development or during early childhood, can havedeleterious effects on cognition. The most extreme cognitive effect ofdevelopmental iodine deficiency is irreversible mental retardation; mildercognitive effects include various neurodevelopmental deficits, includingintellectual impairment (66, 67). For more information on iodine deficiency,which is now accepted as the most common cause of preventable braindamage in the world, see the separate article on Iodine.

Iron

Iron is an essential component of hundreds of proteins and enzymes involvedin various aspects of cellular metabolism, including those involved in oxygentransport and storage, electron transport and energy generation,and DNAsynthesis (see the separate article on Iron) . Iron is needed for properdevelopment of oligodendrocytes (the brain cells that produce myelin) (19), and the mineral is also a required cofactor for several enzymes thatsynthesize neurotransmitters (68). Accordingly, iron deficiency during variousstages of brain development has detrimental consequences. Pregnant womenare at increased risk of iron deficiency because iron requirements aresignificantly increased during pregnancy due to increased iron utilization bythe developing fetus and placenta and because of blood volumeexpansion (69). Maternal iron deficiency has serious consequences for thewoman and the fetus (70). Animal studies have shown that maternal irondeficiency results in decreased iron concentrations in the brain andpermanent changes in cognitive performance and behavior in theoffspring (71). In humans, iron deficiency during perinatal stages results inpersistent deficits in learning and memory (reviewed in 60) . Moreover, irondeficiency in later stages of development, such as during childhood, may beassociated with impaired cognitive development (see the separate article

on Iron) . While iron is essential for brain function, it is toxic to neurons at highconcentrations (60).

Magnesium

Magnesium is required for more than 300 metabolic reactions in the body,many being important for normal brain function (see the separate article

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on Magnesium) . Magnesium deficiency in healthy individuals who areconsuming a balanced diet is uncommon because the mineral is abundant inboth plant and animal foods and because the kidneys are able to limit urinaryexcretion of magnesium when intake is low. However, magnesium deficiencyhas been induced experimentally and results in neurologic and muscularsymptoms that include tremor, muscle spasms, and tetany (72). Infact, enzymes involved in neuromuscular activity (i.e., the ATPase enzymesthat transport of sodium, potassium, and calcium ions) are apparently mostsensitive to magnesium deficiency (69).

Selenium

Selenium is required for glutathione peroxidases (GPx) importan tantioxidant enzymes in the brain and other t issues. GPx reducepotentially damaging reactive oxygen species (ROS), such as hydrogenperoxide and lipid hydroperoxides, to harmless products like water andalcohols by coupling their reduction with the oxidation of glutathione (seethe diagram in the separate article on selenium) (73, 74). Selenium deficiencyhas been associated with decreased GPx activity in the brain of laboratoryanimal s(75); thus, selenium deficiency may be linked to a reduced antioxidantcapacity in the brain.

Zinc

Zinc is present at high levels in the brain where it has catalytic, structural, andregulatory roles in cellular metabolism (see the separate article on Zinc) . Inthe brain, most of the zinc ion is tightly bound to proteins, but free zinc ispresent in synaptic vesicles and has a role in neurotransmission mediated byglutamate and GABA (76). Experimentally induced zinc deficiency in humanshas been shown to impair measures of mental and neurologic function (77). Deficiency of the mineral during critical periods of cognitive development canbe more devastating. For instance, zinc deficiency during fetal braindevelopment can cause congenital malformations, and zinc deficiency duringlater stages of brain development have been associated with deficits inattention, learning, memory, and neuropsychological behavior (13, 78, 79). Onthe other hand, cellular release of zinc in the brain canmediate neuronalapoptosis and may be pathologically associatedwith Alzheimers disease and amyotrophic lateral sclerosis (ALS) (80). Thus,intracellular zinc levels in the brain are homeostatically regulated.

Choline

Choline can be synthesized by the body in small amounts, but dietary intakeis needed to maintain health. Thus, choline is considered to be an essentialnutrient for humans (81). Choline and its metabolites have a number of vitalbiological functions (see the separate article on Choline) (82-84). With respectto cognitive function, choline is needed for myelination of nerves and is

a precursor for acetylcholine an important neurotransmitter involved inmuscle action, memory, and other functions. Choline is also used in thesynthesis of the phospholipids, phosphatidylcholine and sphingomyelin, whichare structural components of cell membranes and precursors for certain cell-signaling molecules. Studies in laboratory rats have shown that cholinedeficiency during the perinatal period results in persistent memory and othercognitive deficits (85).

Essential Fatty Acids

Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids (PUFA),meaning they contain more than one cis double bond (86). The essential fatty

acids include alpha-linolenic acid (ALA), an omega-3 fatty acid, and linoleicacid (LA), an omega-6 fatty acid. ALA and LA cannot be synthesized byhumans and thus must be obtained from the diet; dietary intakerecommendations set by the Institute of Medicine are for ALA and LA (see theseparate article on Essential Fatty Acids) (86). The long-chain omega-6 fattyacid, arachidonic acid (AA), can be synthesized from LA. Additionally, twolong-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), can be synthesized from ALA, but theirsynthesis may be insufficient under certain conditions, such as duringpregnancy and lactation (87, 88).

Excluding adipose tissue, tissue of the nervous system has the greatestconcentration of lipids in the human body (89). Lipids found in the humanbody include fatty acids, phospholipids, triglycerides, and cholesterol. Omega-3 and omega-6 PUFA are incorporated into phospholipids, where they notonly serve structural roles in cell membranes of the nervous system, but alsoaffect membrane fluidity, flexibility, permeability, as well as the activities ofmembrane-associated enzymes and receptors (13, 90). Through theseeffects, omega-3 and 6 PUFA play several important roles in vision andnervous system function. DHA is selectively incorporated

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into retinal and neuronal cell membranes (91, 92), suggesting it playsimportant roles in vision and nervous system function. The phospholipids ofthe brain's gray matter contain high proportions of DHA and AA, indicatingthey are important to central nervous system function (93). Brain DHA contentmay be particularly important, since animal studies have shown that depletionof DHA in the brain can result in learning deficits. It is not clear how DHAaffects brain function, but changes in DHA content of neuronal cellmembranes could alter the function of ion channels or membrane-associatedreceptors, as well as the availability of neurotransmitters (94).

In general, essential fatty acid deficiency (i.e., deficiency of both ALA and LA)has been observed only in patients with chronic fat malabsorption, cysticfibrosis, or those on parenteral nutrition without PUFA (86, 95) (see the articleon Essential Fatty Acids) . Clinical manifestations of essential fatty aciddeficiency primarily include skin effects (i.e., dermatitis), butnegative hematologic effects and impaired immunity have also been seen inhumans (96). Decreased physical growth in infants and children is alsoassociated with essential fatty acid deficiency. The developing brain may beespecially vulnerable to the effects of deficiencies in essential fatty acids (97). Since phospholipids of certain brain regions are enriched with DHA and AA,

omega-3 or omega-6 PUFA deficiency during brain development could havelasting effects on visual and cognitive function (13). For instance, studies inlaboratory rodents have found that dietary omega-3 PUFA deficiency impairedmeasures of cognitive performance through influencing the dopamineneurotransmitter system in the frontal cortex region of the brain (98). Omega-3 PUFA deficiency during fetal development has also been shown to haveuntoward effects on visual function (reviewed in 99, 100) .

Effects of Micronutrient Supplementation

Compared to the consequences of micronutrient deficiencies, considerablyless is known regarding the cognitive effects of micronutrient

supplementation. Many of the intervention trials conducted to date haveexamined whether supplementation with B vitamins might attenuate thecognitive decline associated with normal aging. Other trials have looked atwhether micronutrient supplementation improves specific measures ofcognitive performance, including attention, memory, and various executivefunctions. These and other cognitive functions are interrelated; for example,memory of new information is dependent on proper attention (101).

Additionally, cognitive performance can be affected by other factors, including

ones overall mood (101). A summary of randomized controlled trials(RCTs)o n these cognitive parameters is presented below.

Attention

Attention is the mental process of selectively concentrating on informationwhile excluding extraneous information. Proper attention is needed for higher-order cognitive abilities; thus, deficits in attention can profoundly affectlearning and behavior (102). While there are different types of attention (i.e.,selective, divided, sustained) (101), neuropsychological tests measureattention to either visual or auditory stimuli (102).

A few trials have assessed the effect of multivitamin/mineral supplementationon attention, with most being conducted in school-aged children. Yet, a 1-year placebo- controlled, double-blind trial that provided ten times therecommendation of nine vitamins was carried out in 127 healthy young adults(aged 17-27 years) (103). Compared to baseline measurements, the multiplevitamin supplementation was associated with improvements on twoassessments of attention in women but not in men; however, the differences

between the vitamin and placebo groups were not statistically different at anyof the measured timepoints (3 months, 6 or 9 months, and 12 months )(103). In a 14-month randomized, double-blind, placebo-controlled trial thatadministered a daily micronutrient- fortified beverage (details lacking) orplacebo to 608 children (aged 6-15 years) in India, micronutrientsupplementation was linked to improved scores on one measure of attentionand concentration (Knox Cube test) but not on another assessment (LetterCancellation test) (104). Another trial administered a micronutrient-fortified(vitamins A, B 6, B 12 , C, and folate and the minerals, iron and zinc) drink, adrink fortified with docosahexaenoic acid (DHA) and eicosapentaenoic acid(EPA), a drink fortified with the micronutrients and omega-3 fatty acids, orplacebo for six days a week for 12 months to 644 school-aged children in

Australia and Indonesia (105). This trial reported that the various treatments

had no effect on attention compared to placebo, despite some improvementsin nutrient status (105). Most recently, a randomized, double-blind, placebo-controlled trial in 81 children (8-14 years) residing in the UK found that use ofa daily multivitamin/mineral supplement, containing most vitamins as well asiron, copper, zinc, calcium, and magnesium, was associated with an increasein accuracy on one attention task (Arrows Flankers test) throughout the 12-week study (106). Thus, trials conducted to date are conflicting and more

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