nutrient-dependent brain functions
synthesis of neurotransmitters
Many neurotransmitters require micronutrient cofactors in their synthesis. Iron and copper have roles in serotonin and dopamine synthesis.39 40 Folic acid and vitamin B12 are involved as cofactors in serotonin and norepinephrine synthesis.41 Thiamine serves as a coenzyme in acetylcholine, GABA, and glutamate synthesis.42 Vitamin B6 serves as a cofactor in the synthesis of the neurotransmitters dopamine, serotonin, norepinephrine, epinephrine, histamine, and GABA,43 and vitamin B6 deficiency has been shown to reduce brain production of serotonin and GABA.44
regulation of neurotransmission
Micronutrients play key roles in regulating neuronal transmission. Zinc is extensively involved in synaptic transmission,45 46 both excitatory and inhibitory.47 In certain brain regions, vesicular zinc is co-localized and co-released with glutamate, modulating the function of a number of channels, receptors, and transporters,48 49 including NMDA receptors.50 Magnesium and copper are important modulators of NMDA-receptor activity, which has been implicated in the pathogenesis of mood disorders.51 52
methylation
Hypomethylation has been reported as a major risk factor for schizophrenia and bipolar disorder.53 Hundreds of methylation reactions occur in the body, including during DNA, RNA, and neurotransmitter synthesis. The neuropsychiatric effects of folate and vitamin B12 deficiencies result from defective methylation processes.54 55 Folate is a precursor to S-adenosyl-L-methionine (SAMe), a methyl donor that has been shown to have antidepressant properties.56 Choline is also major source of methyl groups for methylation reactions,57 and has been reported to enhance symptoms of patients being treated with lithium.58
prevention of genetic damage
Deficiency of folic acid, niacin, vitamin B6, vitamin B12, vitamin C, vitamin E, iron, or zinc (one or more of which is seen in half the US population59) have been shown to mimic radiation in causing single- and double-strand DNA breaks, which could decrease enzyme affinity for nutrient cofactors.60 61 Folate deficiency of a magnitude seen in 10% of the US population breaks chromosomes by causing massive mis-incorporation of uracil into human DNA.59 In addition, various vitamin and mineral deficiencies have been shown to accelerate mitochondrial decay, leading to DNA damage.62
gene expression
Various micronutrients are involved in gene expression. Folate plays an essential role in methylation, which is involved in gene expression, transcription, chromatin structure, genomic repair and genomic stability.63 Vitamin A and vitamin E have been reported to have roles in gene expression as well.64 65 Vitamin D, zinc and calcium have been shown to be involved in brain-derived neurotrophic factor (BDNF) gene expression, an effect also seen in clinically effective antidepressants.66 67 68 69 TrkB, a BDNF-activated receptor, has been shown to be activated by zinc and copper.70 71
neurite outgrowth
Several micronutrients have been shown to be involved in neurite outgrowth, which is critical in optimizing neural networks. Vitamin A is a precursor to retinoic acid, which is extensively involved in neurite outgrowth and axonal elongation.72 73 Calcium plays critical roles in neurite outgrowth.74 75 76 Magnesium, selenium, and copper are also involved.77 78 79
conclusion
Recent clinical trials using non-lithium micronutrient interventions have shown beneficial effects on mood. Multi-micronutrient interventions appear to be particularly promising. Certain sub-populations may have increased requirements for micronutrients, which are extensively involved in an array of mood-related brain functions. Micronutrient inadequacy may impair one or more critical brain functions, resulting in psychiatric symptoms.
Micronutrient inadequacy impairs mood-related brain function, resulting in psychiatric symptoms. When patients in research samples have multiple micronutrient inadequacies (USDA data38), single-nutrient interventions may show only marginal effects; multiple-nutrient interventions, however, result in more complete, dramatic effects. The concept of multiple-micronutrient inadequacy may explain why clinical trials using single-nutrient interventions show only marginal effects. A broad-spectrum multi-ingredient treatment is required to test the hypothesis that micronutrient inadequacy impairs key brain functions and produces psychiatric symptoms.
Environmental and Genetic Pressures on Brain Functions
download pdf
clinical trials
mechanism of nutrient action
nutrient & genetic factors in brain function
references
Many neurotransmitters require micronutrient cofactors in their synthesis. Iron and copper have roles in serotonin and dopamine synthesis.39 40 Folic acid and vitamin B12 are involved as cofactors in serotonin and norepinephrine synthesis.41 Thiamine serves as a coenzyme in acetylcholine, GABA, and glutamate synthesis.42 Vitamin B6 serves as a cofactor in the synthesis of the neurotransmitters dopamine, serotonin, norepinephrine, epinephrine, histamine, and GABA,43 and vitamin B6 deficiency has been shown to reduce brain production of serotonin and GABA.44
regulation of neurotransmission
Micronutrients play key roles in regulating neuronal transmission. Zinc is extensively involved in synaptic transmission,45 46 both excitatory and inhibitory.47 In certain brain regions, vesicular zinc is co-localized and co-released with glutamate, modulating the function of a number of channels, receptors, and transporters,48 49 including NMDA receptors.50 Magnesium and copper are important modulators of NMDA-receptor activity, which has been implicated in the pathogenesis of mood disorders.51 52
methylation
Hypomethylation has been reported as a major risk factor for schizophrenia and bipolar disorder.53 Hundreds of methylation reactions occur in the body, including during DNA, RNA, and neurotransmitter synthesis. The neuropsychiatric effects of folate and vitamin B12 deficiencies result from defective methylation processes.54 55 Folate is a precursor to S-adenosyl-L-methionine (SAMe), a methyl donor that has been shown to have antidepressant properties.56 Choline is also major source of methyl groups for methylation reactions,57 and has been reported to enhance symptoms of patients being treated with lithium.58
prevention of genetic damage
Deficiency of folic acid, niacin, vitamin B6, vitamin B12, vitamin C, vitamin E, iron, or zinc (one or more of which is seen in half the US population59) have been shown to mimic radiation in causing single- and double-strand DNA breaks, which could decrease enzyme affinity for nutrient cofactors.60 61 Folate deficiency of a magnitude seen in 10% of the US population breaks chromosomes by causing massive mis-incorporation of uracil into human DNA.59 In addition, various vitamin and mineral deficiencies have been shown to accelerate mitochondrial decay, leading to DNA damage.62
gene expression
Various micronutrients are involved in gene expression. Folate plays an essential role in methylation, which is involved in gene expression, transcription, chromatin structure, genomic repair and genomic stability.63 Vitamin A and vitamin E have been reported to have roles in gene expression as well.64 65 Vitamin D, zinc and calcium have been shown to be involved in brain-derived neurotrophic factor (BDNF) gene expression, an effect also seen in clinically effective antidepressants.66 67 68 69 TrkB, a BDNF-activated receptor, has been shown to be activated by zinc and copper.70 71
neurite outgrowth
Several micronutrients have been shown to be involved in neurite outgrowth, which is critical in optimizing neural networks. Vitamin A is a precursor to retinoic acid, which is extensively involved in neurite outgrowth and axonal elongation.72 73 Calcium plays critical roles in neurite outgrowth.74 75 76 Magnesium, selenium, and copper are also involved.77 78 79
conclusion
Recent clinical trials using non-lithium micronutrient interventions have shown beneficial effects on mood. Multi-micronutrient interventions appear to be particularly promising. Certain sub-populations may have increased requirements for micronutrients, which are extensively involved in an array of mood-related brain functions. Micronutrient inadequacy may impair one or more critical brain functions, resulting in psychiatric symptoms.
Micronutrient inadequacy impairs mood-related brain function, resulting in psychiatric symptoms. When patients in research samples have multiple micronutrient inadequacies (USDA data38), single-nutrient interventions may show only marginal effects; multiple-nutrient interventions, however, result in more complete, dramatic effects. The concept of multiple-micronutrient inadequacy may explain why clinical trials using single-nutrient interventions show only marginal effects. A broad-spectrum multi-ingredient treatment is required to test the hypothesis that micronutrient inadequacy impairs key brain functions and produces psychiatric symptoms.
Environmental and Genetic Pressures on Brain Functions
download pdf clinical trials
mechanism of nutrient action
nutrient & genetic factors in brain function
references