Brain Health and Function

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

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Essential nutrient molecules involved in brain function

Choline and inositol are perhaps the most important chemicals in the brain. Choline is an essential water-soluble nutrient, usually grouped with the B vitamins. Phosphatidylcholine is a form of choline that is abundant in cell membranes as well as being a precursor to the most abundant neurotransmitter in the brain, acetylcholine. Often, phosphatidylcholine and phosphatidylserine are combined in nutrient supplements for improving brain function. Choline deficiencies are seen with poor diets and with fatty liver accumulations. Choline deficiency may also cause kidney dysfunction, infertility, hypertension and bone abnormalities. Choline deficiency is not uncommon. It is believed that choline deficiency is more likely with vegan diets, and persons that eat very few eggs, as well as with people who drink a lot of alcohol, and frequently exert themselves with endurance exercise. Recent research from NHANES, by Dr. Steven Zeisel, found that less than 10 percent of Americans had choline intakes at or above the recommended AI (Adequate intake). Healthy sources of choline include tofu, kidney bean, quinoa, amaranth, spinach, whole milk, chicken, cod fish, egg and beef liver. Soy lecithin is also a good source. Supplementation may be best achieved by taking alpha-GPC (L-alpha glycerylphosphorylcholine, or choline alfoscerate), which is combined with acetyl L-carnitine in the Health Concerns supplement CogniSpark. Alpha-GPC is well studied, easily crosses the blood brain barrier, and like phosphotidylcholine, is derived from lecithin. Choline deficiency, and specifically deficiency of phosphatidylcholine, is now the subject of study of poor gastrointestinal microbiotic colony and mechanisms of obesity as well. Dysfunctional gut biota is strongly linked to excess breakdown of physophatidylcholine into harmful excess of methylamines in circulation, contributing to fatty liver disease, low-grade endotoxemia, and poor regulation of nutrient energy harvest as well as energy regulation. Not only supplementation and dietary improvement, but attention to gastrointestinal health and probiotic therapy, and use of herbal acetylcholinesterase inhibitors when necessary, may be important in reestablishing the choline metabolism.

Phosphatidylserine is also a phospholipid component of cell membranes, and is essential to brain function. Studies have so far been limited and of poor quality, but some studies have shown that phosphatidylserine improves cognitive function in neurodegenerative disease. The FDA has reviewed these studies and found that the evidence is so far not conclusive, but that the evidence does show a preliminary and limited relationship to cognitive dysfunction and that more reliable studies need to be conducted. An FDA qualified health claim was granted stating that "Consumption of phosphatidylserine may reduce the risk of dementia and cognitive dysfunction in the elderly." Other proven benefits of phosphatidylserine include a speeding of recovery from exercise, prevention of muscle soreness, and improved well being. Pilot studies also indicate that phosphatidylserine may be beneficial in the treatment of ADHD. Almost all of the phosphatidylserine in supplements today is derived from soy.

Inositol may be used as a medicinal supplement in the forms of inositol, inositol hexacotinate (a Vitamin B3), and IP6 (inositol hexaphosphate). Each of these may be utilized in the treatment protocol for brain dysfunction and health maintenance. Inositol is essential to healthy neural cell membranes, and as a precursor to IP3 (inositol triphosphate), which is important in signal transduction in cells. Inositol hexacotinate is a flush-free form of niacin, which improves nitric oxide metabolism and vasodilation, and is a precursor to the key cell signaling molecules NAD and NADH. Niacin also plays a role in DNA repair and the production of steroid hormones. Niacin is an essential nutrient that is seen in deficiency disease (pellagra), and mild deficiency, causing slowed metabolism and intolerance to cold, and is common nutrient deficiency. IP6 is shown to inhibit excess angiogenesis, serves as a potent antioxidant, and may serve to chelate iron toxicity and uranium radiation toxicity. Inositol is also found in various herbs and foods, including European Mistletoe (Viscum album), Lonicera japonica (Jin yin hua), wheatgrass, lentil, sesame seed, and plantain.

Acetyl L-carnitine is also an essential nutrient in brain function. L-carnitine is a derivative of the amino acid lysine, and the L isomer is the biologically active form. It is not an essential nutrient, as the body may synthesize it from lysine and methionine, but does play an important role as a nutrient medicine. In many disease states, the demand for L-carnitine exceeds the body's ability to produce it, especially if there is a deficiency of lysine or methionine, of if the health of the intestines is a problem. L-carnitine is found in meats, but studies have indicated that a vegetatarian diet, although containing less L-carnitine, resulted in an adaptation and higher bioavailability of L-carnitine in the individual. Bioavailability of acetyl L-carnitine is found to be higher than simple L-carnitine when taken as a supplement, and it is shown in scientific studies to be beneficial to treat brain function and slow cognitive impairment, maintain nerve and blood circulation, and support testosterone aging. In animal studies, acetyl L-carnitine protected brain cell mitochondrial function, ameliorated excitotoxicity, and improved bioenergetic status in the hippocampus neurons when the animals were exposed to hypoxia. Studies also showed a benefit in the treatment of depression and melancholia associated with alcoholism. One benefit of taking the supplement SamE (a methionine) is to create better bioavailability of L-carnitine.

L-carnitine is an essential cofactor in the metabolism of lipids and production of cellular energy. This amino acid, especially the acetyl form, has an important role in the beta-oxidation of essential fatty acids and transport of long-chain fatty acids, such as the omega-3 DHA, across the inner membrane of the mitochondria in neurons. Taking acetyl L-carnitine with P5P and DHA in the form of krill oil may improve the effectiveness. Since the function of neurons requires much energy, and mitochondria are the creators of this energy in the cells, generating most of the cell's ATP, aiding mitochondrial health is very important to brain function. Mitochondria are also important to the neuron in a variety of ways, though, involved in cell signaling, programmed cell death (apoptosis), and the cycle of cell growth and differentiation. Problems with mitochondrial health and function lie at the heart of our study of health problems in aging, and mitochondrial dysfunction is strongly implicated in a number of diseases, including bipolar disorder, optic neuropathy, dementia, and epilepsy. While these mitochondrial disorders may be inherited, or the propensity inherited with a single allele, the majority of mitochondrial dysfunctions are caused by acquired mutations due to the adverse effects of drugs, infections, toxins, or other environmental causes.

R-lipoic acid has been well studied as well concerning brain health due to its proven antioxidant effects, aid to glutathione cell detoxification, and aid to mitochondrial health, and is considered a companion to acety L-carnitine in its effects, as well as an essential cofactor in lipid metabolism and blocking of excess production of advanced glycation endproducts (AGEs). The R isomer of alpha lipoic acid, or R-lipoic acid, is better utilized and is the form that our neuronal cells synthesize. There is considerable scientific study of R-lipoic acid as a potent medical treatment of a number of neurological disorders. Consumption of lipoic acid in the diet has not been shown to create significant increases in neural cell concentration, though, and a supplement is considered necessary to enact medical benefits. R-lipoic acid is considered an essential cofactor to a number of mitochondrial enzyme complexes related to energy production and the breakdown (catabolism) of amino acids. R-lipoic acid is also considered to be a potent antioxidant in the brain, and is essential in the regeneration of other antioxidants, such as Vitamins A and C. The metabolite created from R-lipoic acid in the neuron, DHLA, also is able to reduce oxidized CoQ10 to increase the antioxidant effects of this chemical. In animals stressed by aging or oxidative stress, R-lipoic acid was able to significantly increase glutathione synthesis, as well. Glutathione is the chief cellular detoxification pathway in our body. R-lipoic acid significantly affects insulin cell signalling in the brain as well, an important factor in cognitive health. While insulin does not regulate glucose utilization in the brain, it does play an important role in regulation of tissue growth and repair.

An article published in Nature (25 March, 2010) reviewing current scientific understanding of neural mechanisms of aging and cognitive decline stated that: "The major risk factor for neurodegeneration and cognitive decline is the aging of the brain. Conserved pathways and mechanisms that control organismal aging, such as the insulin/IGF signaling and mitochondrial function, can modulate pathology and cognitive decline." Both mitochondrial function and the insulin signaling pathway are vitally important, and R-lipoic acid addresses the health of both of these systems. To achieve the best effect, a combination of R-lipoic acid, acetyl L-carnitine, and CoQ10-H2 is recommended. Combining such therapy with acupuncture and herbal medicine enhances its effects.

L-carnosine is yet another amino acid that is found to be important in the maintenance of brain health and function. With aging, our DNA shorten, and the communicating ends of DNA, or repeated telomeres, are found to have fewer protective repeats, and thus leave our DNA open to more damage and mutation. L-carnosine was found to be protective of these telomeres. Carnosine is the naturally occurring complex of two amino acids, L-histidine and beta-alanine, is a potent antioxidant in the brain, a buffering agent against acidity, and important in the clearing and prevention of advanced glycation endproducts (AGEs). L-carnosine is neuroprotective, countering neurotoxicity from beta-amyloid peptide accumulation and lipid peroxidation of neuronal membranes. At present, much scientific study of L-carnosine is underway to confirm the pathways of neuroprotection and cognitive benefits seen in some studies. The various amino acids and antioxidants may be found in formulas that help achieve improved clearance of advanced glycation endproducts (AGEs). For instance, Vitamin Research Products provides a formula that combines L-carnosine, histidine, arginine, N-acetyl cysteine, R-Lipoic acid, P5P, B12, folic acid, benfotiamine, and various herbal extracts to inhibit 6 pathways of AGE formation and help clear excess AGEs, not only preventing atherosclerotic plague, but benefitting the brain health and function, and potentially helping to clear plagues and sticky proteins (beta-amyloid ant tau proteins) in the brain as well.

The most important neurotransmitters in the brain, acetylcholine, serotonin, GABA, epinephrine/norepinephrine (adrenaline), and dopamine are all derived from a few amino acids, namely choline (more of a vitamin), tryptophan (5HTP), glutamate (L-glutamine), and tyrosine. For this reason, the amino acids L-glutamine and L-tyrosine are potentially very helpful to correct problems with brain function. The tryptophan precursor 5HTP is a more widely known nutrient medicine, and does exert more immediate effects for more patients. There is a very fluid relationship in the production of serotonin from 5HTP, though, with 5HTP involved in a number of conversions and pathways, creating melatonin as well, and a balance of these chemicals, and a bioavailability, insures that our homeostatic mechanisms create the right amount of serotonin, as well as melatonin, at any one moment. The Vitamin B6 metabolite P5P is involved in these conversions and is also an essential nutrient to maintain a balanced bioavailability. P5P is also a cofactor in the assimilation of amino acids, and may help one obtain more of the amino acid when taking pills. Another balancing act occurs with the tyrosine pathway, which creates dopamine, which may convert to norepinephrine and then to epinephrine in local tissues. Tyrosine is also converted to other important molecules in the brain as well, though, such as melanin and pyruvate, and is the building block of the thyroid hormones as well. Insufficiency of tyrosine may play a significant role in hypothyroidism and mood disorders, and in clinical studies, patients with mood disorders subjected to increased stress noted improvements in mood and cognitive function after taking L-tyrosine. Patients with normal stress parameters noted no immediate effects. Patients with a subclinical hypothyroidism, though, may find that L-tyrosine supplementation has a more profound effect on mood and cognitive function.

Lastly, B12, or methylcobalamin, may be an essential nutrient medicine in brain health and function as well. B12 is involved in a number of important pathways in the brain, and has been well studied as a medicinal adjunct in the treatment of a wide variety of disorders, including sleep disorders, mood disorders, peripheral neuropathies, cognitive decline, and glutamate neurotoxicity. In the metabolic pathways of choline, B12 serves as a cofactor, with betaine, in the conversion of homocysteine to methionine and SAMe, which helps to maintain cell membrane function and create DNA and RNA via methylation. The betaine in this pathway is derived from choline, and deficiency of B12 could add stress to the choline pathway in the creation of acetylcholine, the most abundant neurotransmitter in the brain. Homocysteine is also integral to the pathway that creates glutathione, our main cellular detoxifier and antioxidant. B12 deficiency, therefore, in this one metabolic pathway, has the potential to add to a number of important dysfunctions in the brain. In clinical use, patients with a deficiency will often report much improvement of a variety of symptoms after taking a high dose liquid sublingual B12 methylcobalamin supplement, or after receiving a B12 intramuscular injection. Since B12 assimilation in the stomach depends on a chemical called intrinsic factor, which is often poorly expressed in patients with a B12 deficiency, common B12 supplement in vitamin pills and multivitamins may not be effective. Since much of our B12 is produced by symbiotic intestinal bacteria when needed, maintenance of gastrointestinal health and use of probiotics may also be helpful.

How do we know which of these nutrient medicines may make a significant effect in an individual patient? We don't. The more clinical experience the physician has prescribing these nutrient medicines, though, the better they get at assessing each individual and making the best guess. Often, though, this may be a situation where supplements need to be tried for a period of time, and a number of these supplements combined. One patient may respond to one nutrient while another with a similar presentation may respond more to another. The good thing is that these nutrient medicines are inexpensive and good for the patient overall, with no side effects. The bad aspect is that for a number of months, the patient must take a number of pills every day. This inconvenience is overblown by most patients, though, for some reason, and often compliance with prescription is the main obstacle to improvement. Obviously, taking a number of pills for a few months is not that much of a burden, especially when the gains are sometimes dramatic and can have dramatic results in terms of prevention of future devastating neurological problems.

The Importance of Hormonal Balance and Function in the Central Nervous System

The growing importance of the field of Neurohormonal Immunology shows that the importance of hormonal effects in the brain have been downplayed due to a desire to find allopathic treatment targets rather than a more holistic restoration and modulation. It has been clear for many decades that the cell receptors for neurotransmitters are affected by hormones and immune cytokines, and that the hormone receptors are likewise affected by neurotransmitters. We can effectively call most neurotransmitters neurohormones, and of course we have long known of the importance of the central neurohormonal regulator, the hypothalamic-pituitary complex. While standard medicine has tried to separate the hypothalamus and pituitary into distinct neurological and hormonal endocrine centers, this is impossible, as the hypothalamus produces important hormones, such as oxytocin, and the pituitary is affected by neurotransmitters. These two small nuclei in the brain at the base of the brain stem are so intimately joined that it is difficult to actually separate them, and the strong relationship to the adrenal axis also shows that the nervous system and the hormonal system are joined. Adrenal catecholamines such as adrenaline, also call norepinephrine, are clearly both neurotransmitters and hormones, and the adrenal gland, or the tip of the kidneys, is clearly a neurohormonal organ. 

There is no doubt of the link between hormonal imbalances and the nervous system, most clearly evident in premenstrual syndromes, menstrual dysphoria syndromes, and perimenopausal syndromes, where hormonal imbalances produce strong symptoms of mood change and lability, as well as strong effects on the autonomic nervous system. These studied effects are not relegated to women either, as many studies have shown that male hormonal imbalances and pathologies have strongly affected the nervous system. We need to finally admit that neurohormonal concerns are integral to brain health and function, and explore ways to restore hormonal balance. Synthetic hormones have been dramatically effective, but intrinsically come with problems in a realm dominated by hormonal endocrine feedback regulation. When replacing hormones with synthetic drugs we inhibit the normal feedback regulation, or supplant it. By using bioidentical phytohormones at low dosage to stimulate natural endogenous production of hormones that are deficient in the whole mix of synergistic hormones, we are able to restore neurohormonal homeostasis, rather than just replace it. If possible, this would result in healthier outcomes. 

The study of neurohormonal effects show that variance in neurotransmitter receptor function and types of receptor expression are controlled by a cascade of chemicals at the receptors, and also that the function and expression of these neurotransmitter receptors are tied to groups of receptors, not isolated to specific receptors. For instance, receptors delegated as dopamine, GABA, benzodiazepine, and glutamate NMDA are shown to interact strongly to achieve specific effects, and that the types of receptors and the whole array of neurohormonal chemicals around them account for the differences in specific receptor functions in different parts of the brain. It has been given for many decades that specific neurotransmitters have predominantly stimulatory effects in one area of the brain, and predominantly inhibitory effects in another, and the long-standing assumption that the genetic codes in these different cells account for these opposite effects has long been supplanted by understanding that it is the holistic biochemical environment that is most important in this regard, and in fact controls the genetic expression. A stubborn insistence on a binary attitude and adherence to outdated theories is not helping us to achieve better results in treating the brain and central nervous system. 

While this more complex and holistic perspective on brain health is daunting, it does point to the importance of integrating more treatment protocols and individualizing treatment, rather than a narrow one-size-fits-all approach. We cannot continue to insist on prescribing the same variations of the same few types of psyche drugs to fix all problems. Complementary and Integrative Medicine and Traditional Chinese Medicine obviously (CIM/TCM) has much to offer, and each individual can utilize this integrative care as little or as much as they deem fit, as a preventive measure, or as treatment for specific disease mechanisms, or more complex syndromes of dysfunction.

The most effective antioxidants for the brain and CNS

Oxidative stress and the decreased ability to clear free radical oxidants from the brain, brainstem, and spinal cord have long been linked to neurodegenerative states. The affect on mitochondrial function with accumulation of reactive oxygen species (ROS) within the neural cells has been the area of greatest focus. The glutathione metabolism is the primary tool of brain cells to clear intracellular ROS, and a number of nutrient and herbal strategies have been found to increase the glutathione capacity. R-lipoic acid is perhaps the most studied in this regard, but an array of nutrients, herbal chemicals, and even acupuncture has been shown to increase glutathione capacity. N-acetyl cysteine, selenium, zinc monomethionine, P5P, B12 and 5MTHF have all been found to be useful to promote improved glutathione metabolism (read the article on glutathione on this website). Of these, methylselenocysteine, and active form of selenium, is perhaps the most promising in regards to neurodegeneration and brain function and health. Methylseleocysteine is a naturally occurring seleno-amino acid found in aged garlic, and many studies over decades have touted this compound and its ability to enhance glutathione antioxidant capacity. It is also an essential nutrient aid to the thyroid hormone metabolism, along with L-tyrosine, the building blocks of the thryoid protein hormones. 

One of the most important antioxidants in the brain is melatonin, a neurohormone with a broad array of effects. While we may think that melatonin is just a sleep aid, much research has shown that it is integral to clearing of oxidant stress, diurnal regulation, regulation in the substantia nigra, regulation of skin pigmentation, detoxification, and now even in the maintenance of the Blood Brain Barrier protections of the brain. A 2016 study by experts at the Chiang Mai University School of Medicine, and Mahidol University, in Thailand, proved that melatonin regulates inflammatory mediation in a number of ways as well, and in a study of methamphetamine-induced toxicity, was integral to improving the integrity of Blood Brain Barrier, glial cells, vascular endothelium, as well as neurons (PMID: 27297493). Various antioxidants provide the chief medical protocols to reverse mitochondrial dysfunction as well, now recognized as integral to many pathologies and dysfunctions in the brain. Mitochondrial disease is recognized as causing or contributing to pediatric and neonatal pathology, seizure disorders, craniofacial dysostosis (bone development pathology), and dysmetabolic manifestations in the CNS. Since mitochondria are the main source of cellular energy, and have their own distinct genetic codes, we are finally realizing the importance of helping to maintain mitochondrial health, and CoQ10, and various antioxidants and herbal chemicals are proving safe and effective in this regard. Coenzyme Q10 is produced in the mitochondria of all cells in the body, and this CoQ10 metabolism has been found to be deficient in most cases of heart disease and neurodegenerative disorders such as Parkinsonism. Of course, just taking CoQ10 is not enough to restore the CoQ10 production, but as part of a more holistic treatment protocol would be very valuable. The standard practice of reading some hype about one particular nutrient or herbal chemical and then believing that this alone is all that may be necessary to fix a health problem is not sensible, but utilizing professional medical treatment knowledgeable in this regard to individually design intelligent holistic protocols is very intelligent. Studies in 2014, at the Institute of Neurology, in London, UK, showed that when incorporating CoQ10 into treatment of mitochondrial dysfunction that a persistent high dose may be necessary, and we now also have evidence that more bioavailable forms of CoQ10, such as CoQ10-H2 may be helpful. To see this study, just click here: http://www.ncbi.nlm.nih.gov/pu...

Besides oxidative stress, iron overload capacity has also been clearly correlated with cognitive decline in the elderly (see study cited below). The decreased ability to transport iron effectively in the blood is the main reason for the iron overload toxicity associated with aging. Iron accumulation is usually slow and worsens with aging. Like all heavy metal toxicities, chelation is important in clearing this neurotoxicity, but improving the blood cell quality, clearing chronic hepatitis, and avoiding excessive and unhealthy iron supplementation regimens when anemia is diagnosed, may be important. A natural low dose plant derived iron supplement, with assimilation cofactors, is recommended if iron deficient anemia is present. In fact, patients with anemia should be screened for excess iron, as this could be the cause of the anemia, not the problem. Inadequate diagnostic workup with anemia is now very common, and any microcytic anemia is routinely treated with iron. Standard medicine still insists that the great majority of cases of iron overload must be linked to a genetic hemochromatosis, despite the numerous studies showing the high prevalence of iron accumulation in patients with cognitive decline and aging. Screening is indicated, chelating therapy recommended, and artificial vitamin C supplement should be avoided, as this worsens the iron overload neurotoxicity. You may go to the article on this website entitled Iron Overload Toxicity and Chronic Disease

to learn more about this important health issue.

Oxidative stress and the need for antioxidant clearing increases substantially in the brain with aging. Not only the mitochondrial processes, but damage to DNA and genetic expression occur with advancing oxidative stress as well. Many studies of gene expression show an age-dependant upregulation of oxidative stress-response genes in humans, and it has been widely surmised that increased antioxidant therapy with aging is likely to preserve cognitive health significantly. A host of Chinese herbs exert significant antioxidant effects, including the ginsengs. As stated, flavonoids and terpenoids are the two most studied groups of herbal chemicals with significant antioxidant capacity, and a large number of Chinese herbs have these chemicals in them. Some noted herbs commonly used professionally to treat cognitive dysfunction and neurodegeneration include Siberian Ginseng, Withania somnifera (Ashwagandha), Bacopa monieri, and Schizandra berry.