All About the Brain

The brain requires three things to obtain optimal brain function: glucose, oxygen and stimulation.

Energy metabolism of neurons and glial cells (glucose to the brain)

The human brain is a highly metabolically active tissue that depends on a constant 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. Blood glucose levels must be maintained at all times to avoid hypoglycemia and to supply the brain with its preferential fuel. During the initial stages of fasting, blood glucose levels 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 is a required key enzyme in the gluconeogenic pathway. While glucose is the obligatory fuel, ketone bodies can also be used by the brain when glucose supply is inadequate, such as during prolonged fasting or starvation.

For glucose to produce energy for the brain to function at optimal levels, it must undergo oxidation.

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 used in reactions that completely metabolize glucose to carbon dioxide and water. Additionally, the nutritionally essential minerals magnesium, iron, and manganese are required for the complete metabolism of glucose; these micronutrients are used as cofactors, substrates, or components of enzymes in glycolysis and the citric acid cycle. Moreover, generation of cellular energy in the form of ATP by the electron transport chain requires the vitamins, riboflavin, and niacin; iron contained in iron-sulfur clusters; and the endogenously synthesized compound, coenzyme Q10 .

Cerebral blood supply (oxygen to the brain)

At rest, the brain receives approximately 15% of cardiac output. Proper cerebral blood supply is necessary to deliver oxygen, glucose and other macronutrients, and the required micronutrients for proper 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 results from impaired cerebral blood supply. [1]

Impairment of the heart’s ability to pump enough blood for all the body’s needs is known as congestive heart failure. In coronary artery disease, accumulation of atherosclerotic plaque in the coronary arteries may prevent parts of the heart muscle from getting adequate blood supply, ultimately resulting in cardiac damage and impaired pumping ability. Myocardial infarction (MI) may also damage the heart muscle, leading to heart failure. Any of the above conditions will result in decrease blood flow to the brain, which will decrease the glucose, oxygen and micronutrients delivered to the brain and compromise brain function.

The standard lipid profile (total cholesterol, triglycerides, LDL & HDL) in determining someone’s risk for cardiac dysfunction is inadequate. Advanced lipid testing is essential in any cardiac evaluation. (See Cardiovascular Health)

Other conditions that will decrease glucose, oxygen or micronutrients to the brain are:

• Anemia
• Hypertension
• Hypotension
• Poor lung function
• Diabetes
• Obesity
• Thyroid dysfunction
• Hypoglycemia
• Malabsorption
• Endothelial dysfunction (see Cardiovascular Health)
• Stress (inhibits blood flow to the brain)
• Sleep apnea
• Micronutrient deficiencies
• Blood viscosity
• Medications
• Carbon dioxide levels
• Hydrogen ion concentration
• Oxygen concentration
• Smoking
• Caffeine
• Sedentary lifestyle (lack of exercise)

There are numerous means of improving blood flow to brain. Obviously, the above conditions under an individual’s control should be corrected, i.e., avoid smoking, excess caffeine and living a sedentary lifestyle. Seek the assistance of a functional medicine specialist to assist in correcting any medical condition and discontinuing medication if it is possible. Regular exercise and proper nutrition are imperative. Garlic, cayenne, beet juice, ginger, coconut oil, turmeric, dark chocolate, massage and hydrotherapy have been demonstrated to improve blood flow.

The importance of adequate micronutrients for the heart to function efficient cannot be overstated. The importance of magnesium is illustrated in the articles cited below. Impaired heart function will decrease glucose, oxygen and micronutrients in the brain that are required for optimal brain health.

In a study that followed nearly 90,000 female nurses for 28 years, women in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal myocardial infarction) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day). [2]

Higher magnesium intakes were associated with an 8%-11% reduction in stroke risk in meta-analyses in two studies, each including over 240,000 participants. [3, 4]

Additionally, a meta-analysis of 13 studies including more than 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium. [5]

Neurotransmitter synthesis

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

In addition to various amino acids, several B vitamins, including thiamin, riboflavin, niacin, vitamin B6, folate, and vitamin B12, are needed as cofactors for the synthesis of neurotransmitters. Moreover, vitamin C is required for synthesis of norepinephrine, and the mineral zinc is important for proper function of GABA, aspartate, and norepinephrine. Further, choline is a precursor for the neurotransmitter acetylcholine. [3]

It is obvious from the above that any evaluation of the brain must include an intracellular micronutrient and mineral analysis through SpectraCell to ensure there are adequate micronutrients and minerals present for the brain to function at an optimal level.

Neurotransmitters

There are two types of neurotransmitters:

Excitatory: epinephrine, norepinephrine, serotonin, dopamine and acetylcholine

Inhibitory: GABA (the only truly inhibitory neurotransmitter) *

Nerves communicate by discharging a small chemical messenger called a neurotransmitter. Look at Figure 1 below. The nerve transmitting the signal is called the presynaptic nerve and the one receiving the signal is the postsynaptic nerve. The steps are listed.

1. The amino acid tyrosine (hydroxy-phenylalanine) is present in all food products and can be synthesized from phenylalanine. It enters the neuron by active transport. Phenylalanine has to be transported in the brain to produce tyrosine (hydroxyl-phenylalanine) and that requires the proper amount of insulin.
2. In the cytoplasm of the dopaminergic neuron, tyrosine is converted into dihydroxyphenylalanine (DOPA) by the tyrosine hydroxylase enzyme. This enzyme is rate-limiting for the synthesis of all three catecholamines.
3. DOPA is converted to dopamine in the cytoplasm by the enzyme aromatic L-amino acid decarboxylase (DOPA-decarboxylase).
4. Dopamine is then actively transported into the storage vesicles by the vesicular transport mechanism.
5. In the dopaminergic neuron, dopamine remains unchanged in the storage vesicles and is ready for release by exocytosis.
6. Dopamine released into the synaptic cleft is actively transported back into the neuronal terminal. This process is called reuptake-1 and is the most important mechanism by which dopamine and other catecholamines are removed from the synaptic cleft. Some of the dopamine entering the neuronal terminal (about 50%) is transported into the vesicles for storage and release.
7. The remaining dopamine that enters the neuronal terminal is destroyed by a mitochondrial enzyme, monoamine oxidase (MAO).
8. Some of the dopamine that is released into the synaptic cleft (about 10%) is actively transported into the effector cells. This process is known as reuptake-2. Dopamine entering the effector cells is inactivated primarily by an enzyme, catechol-O-methyltransferase (COMT). Although MAO is also present in the effector cells, its role in the inactivation of dopamine is unclear.
9. The remaining dopamine in the synaptic cleft diffuses into the circulation and is destroyed in the liver by COMT and MAO. The end products of metabolism of catecholamine are organic acids and alcohols, which are excreted in urine.

Each of these steps requires enzymes and those enzymes require cofactors, which may be vitamins and or minerals. Deficiencies of any of these cofactors could impair production of dopamine. For the receptors to be activated efficiently, there must be adequate amount of progesterone and the active thyroid hormone, T3. Hormone imbalance or thyroid dysfunction will result in inadequate dopamine signaling. If too much dopamine is released in the synaptic cleft, the receptors on the post-synaptic neuron become desensitized, resulting in ineffective stimulation. Genetic mutations (SNIPs) may occur in the enzymes (COMT and MAO) that degrade dopamine, resulting in an adverse response.

The point of this discussion is to demonstrate that this is an extremely complex process. Some companies propose that the neurotransmitters can be brought back to balance by giving the individual amino acids and the associated nutrients involved in a given neurotransmitter pathway. It’s not that simple!

Look at serotonin signaling in Figure 2.

The amino acid tryptophan is metabolized to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase, but this requires the iron and biopterin as a cofactor. To produce biopterin require 5- methyltetrahydrofolate (5-MTHF). Mutations in the c677T or A1298C gene will impair production of biopterin. To convert 5-hydroxytryptophan to serotonin requires active B6 (pyridoxal-5-phosphate) as indicated by the arrows above, and both of these nutrients are depleted by estrogen therapy. Again, it’s very complicated, but if a healthcare professional is trying to determine why someone has low serotonin level, this knowledge is essential. Low serotonin is not a Prozac deficiency!

Look at Figure 3. For the receptors to be activated on the post-synaptic nerve requires estrogen for females and testosterone for men. Balanced hormone therapy is essential for females and males to produce optimal serotonin signaling. As demonstrated at the bottom of Figure 3, excess serotonin in the post-synaptic neuron will cause the receptors to down-regulate or refuse entry.

All the mechanisms noted above are impaired if someone can’t actively transport tryptophan from the serum to the brain. Insulin is essential in this process. Look at Figure 4.

It starts with proper protein consumption. The digestive system breaks down the protein into branch-chain amino acids (BCAA), leucine, isoleucine, and valine. The BCAA stimulates insulin to take the amino acids into the cell. Now tryptophan is at higher levels in the serum than the BCAA, which stimulates large neutral amino acids (LNNA) to transport tryptophan from the serum across the blood-brain barrier to produce serotonin in the brain. Again, it’s complex, but to understand why serotonin levels are not adequate, this knowledge is essential.

Now look at Figure 5. Abnormal insulin levels can lead to multiple metabolic problems that have a major effect on people’s lives. As indicated, insulin surges may lead to fatigue after meals and drowsiness.

Look at potential problems with reactive hypoglycemia in Figure 6.

Decreased serotonin production will lead to sugar cravings, which cause more insulin dysregulation (insulin resistance). In an attempt to maintain normal serum glucose levels, the adrenal glands will produce cortisol and norepinephrine. The sustained cortisol level will down-regulate insulin receptors and contribute to insulin resistance. Cortisol will stimulate glucose production in the liver (gluconeogenesis), which will raise blood sugar level and also leptin.

Leptin is a fat cell hormone and signals the brain that adequate food is present. With excess leptin, the brain doesn’t receive the signal that the body is full, so people keep on eating — again, increasing insulin resistance. Leptin and cortisol will block the conversion of T4 to T3, which will create a tissue hypothyroid condition. Low T3 will decrease cellular mitochondria (by 40%), which metabolizes glucose, contributing to further insulin resistance.

The common link between cancer, Alzheimer’s, heart disease and depression is excess insulin, not glucose. Alzheimer’s is often referred to as Type 3 diabetes and is increased by 70% by insulin resistance. The excess cortisol will cause central body weight gain, anxiety, poor sleep and immune suppression. If these conditions continue, cortisol will become depleted. Low cortisol may cause, fatigue, inflammation and allergies, low libido, fatigue/lethargy, and aging. Cortisol is also required to convert norepinephrine to epinephrine. Low cortisol will result in elevated norepinephrine and low epinephrine. Elevated norepinephrine has been associated with stress and anxiety, hyperactivity, and increased blood pressure. The purpose of this discussion is to try to impart the dangers of insulin dysregulation on the quality and length of life.

The common link between cancer, Alzheimer’s, heart disease and depression is excess insulin, not glucose. Alzheimer’s is often referred to as Type 3 diabetes and is increased by 70% by insulin resistance. The excess cortisol will cause central body weight gain, anxiety, poor sleep and immune suppression. If these conditions continue, cortisol will become depleted. Low cortisol may cause, fatigue, inflammation and allergies, low libido, fatigue/lethargy, and aging. Cortisol is also required to convert norepinephrine to epinephrine. Low cortisol will result in elevated norepinephrine and low epinephrine. Elevated norepinephrine has been associated with stress and anxiety, hyperactivity, and increased blood pressure. The purpose of this discussion is to try to impart the dangers of insulin dysregulation on the quality and length of life.

All this starts with insulin dysregulation, which can be prevented by proper nutrition and lifestyle choices.

Look at the effect hormones have on the various neurotransmitters.

Hormone Effects on Neurotransmitters

Each of these hormones must be evaluated when a healthcare professional is determining the overall health of the brain.

Now look at the effect neurotransmitters have on hormones.

Neurotransmitter Effects on Hormones

Brain and Sex Hormones

The brain is important target for Estrogen and Progesterone effects

Learning, memory, emotion, motivation and motor control

Brain development and plasticity [8]

Symptoms of Impaired Serotonin Activity

Loss of pleasure in hobbies and interests

Feelings of inner rage and anger

Feelings of depression

Difficulty in finding joy from life

Depression when it is cloudy or there is lack of sunlight

Loss of enthusiasm for favorite activities

Not enjoying favorite foods

Not enjoying friendships and relationships

Unable to fall into deep restful sleep *

Symptoms of Poor Dopamine Activity

Inability to self-motivate

Inability to start and finish tasks

Feeling of worthlessness

Feeling of hopelessness

Loss of temper for minor reasons

Inability to handle stress

Anger and aggression while under stress

Desire to isolate oneself from others

Unexplained lack of concern for family and friends*

Symptoms of Impaired Acetylcholine Activity

Loss of visual and photographic memory

Loss of verbal memory

Memory lapse

Diminished comprehension

Difficulty calculating numbers

Difficulty recognizing objects and faces

Slowness of mental responsiveness

Difficulty with directions and spatial orientation*

Symptoms Associated with GABA Imbalance

Feelings of anxiousness or panic for no reason

Feelings of dread

Feelings of inner tension and inner excitability

Feelings of being overwhelmed for no reason

Restless mind

Hard to turn your mind off when you want to relax

Disorganized attention

Worrying about things you have never thought about before. *

I would encourage everyone to read the above book! It is excellent!

*Why Isn’t My Brain Working by Datis Kharrazian, DHSc, DC, MS

High Norepinephrine

Aggression

Anxiety

Irritability

Muscle Tension

Low Norepinephrine

Depression

ADHD

Fatigue

Lack of Alertness

Memory Issues [9]

High Epinephrine

Aggression

Anxiety

Insomnia

Acute Stress

Fear

Low Epinephrine

Weight Gain

Attention Deficit

Lack of Concentration

Adrenal Fatigue [9]

It has been my clinical experience that the best laboratory for urinary testing for neurotransmitters is Sanesco International Inc. But the evaluation is not complete until it includes intracellular micronutrient testing (SpectraCell), complete hormone evaluation (estrogen, progesterone, testosterone, DHEA), cortisol, thyroid, and insulin metabolism, homocysteine, cardiovascular evaluation, and advanced lipid profile. Remember, the brain needs three things to function efficiently: glucose, oxygen and stimulation. If any one of these three factors are impaired, the brain will not function properly.

Recommended Supplements to Support Brain Health:

References

1. http://lpi.oregonstate.edu/mic/micronutrients-health/cognitive-function#brain-needs
2. J Am Heart Assoc. 2013;2(2):e000114
3. http://lpi.oregonstate.edu/mic/micronutrients-health/cognitive-function#brain-needs
4. Am J Clin Nutr. 2012;95(2):362-366
5. Nutr Metab Cardiovasc Dis. 2013;23(3):169-176)
6. PLoS One. 2013; 8(3):e57720.
7. Barth, C. et al, Neurosci. 2016: 9:37
8. Information courtesy of Sanesco International Inc.
9. http://dunwoodylabs.com/index.php/profiles/neurotransmitter-profile

*Why Isn’t My Brain Working by Datis Kharrazian, DHSc, DC, MS