Mild Traumatic Brain Injury and Degenerative Function Physiological Strategies to Improve and Preserve Brain Function

Overview

Free radicals are atoms or molecules that have an unpaired set of electrons in their outer shell. Electrons, like shoes, function best in pairs. Free radicals, with their unpaired electrons, are unstable and can damage adjacent cell membranes, proteins, fats, and DNA.

The primary source of free radicals in our bodies is metabolism, the making of ATP energy from oxygen and glucose. The electron transport proteins of the inner membrane of the mitochondria are not 100% efficient in creating ATP molecules, and therefore always produce a percentage of oxygen free radicals. These oxygen free radicals are usually called “reactive oxygen species” or just abbreviated “ROS”.

When oxygen free radicals cause biological damage, it is often termed “oxidative stress” or just “oxidation”.

Therefore, for this discussion:

Free Radicals = Oxygen Free Radicals = Reactive Oxygen Species
And
Oxidative Stress = Oxidation

Since the primary source of oxygen free radicals is oxygen, the tissues that utilize the most oxygen also make the greatest number of oxygen free radicals. Because the brain uses the most oxygen, it also makes the largest number of oxygen free radicals. Consequently, the brain is particularly prone to suffering from oxidative stress.

A database search of the National Library of Medicine of the United States of America using PubMed and the words “brain function AND free radicals” found 16,377 citations (August 13, 2012). This shows the significance of the relationship between free radicals and brain function.

Dr. David Perlmutter, MD, is a Board Certified Neurologist with a private practice in Naples, Florida. He has authored five books. In his 2004 book, The Better Brain Book, Dr. Perlmutter states (1):

“The same forces that are aging your body are aging your brain, only they hit your brain earlier and harder.”

“These culprits are at the core of virtually all brain problems, from mild memory issues to brain fog to severe Alzheimer’s disease. They are:

1) The proliferation in the brain of destructive chemicals called free radicals.

2) The decline in the ability of the brain cells to make energy.”

The brain is the most metabolically active organ of the body; it uses 20% of consumed oxygen to make the energy to fuel all of its activities.

“Energy is made in the specialized parts of the cell called the mitochondria.”

“There is a price to pay for making all this energy. Every time a cell makes energy—any cell, in any part of your body—it also produces toxic substances call free radicals.”

Free radicals are unstable, and bond with molecules in healthy cells, damaging tissues and organs, such as the heart, joints, skin, and the fats of one’s brain.

Over time, free radicals can destroy substantial amounts of the brain and nerve tissue through this process of oxidation.

“When the mitochondria of your brain cells are injured, they become less efficient, produce less energy, and increase free radical production.”

“Free radicals can inhibit the brain’s ability to produce neurotransmitters, which have a profound impact on memory, learning, mood, and even balance and hand-eye coordination.”

“Free radicals pose another potentially deadly problem for the brain—they promote inflammation.”

Inflammation is linked to nearly all chronic brain diseases, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and dementia.

••••

Keshav Singh, PhD, is a senior scientist and professor of genetics at the University of Alabama at Birmingham. In his 2006 book, Oxidative Stress, Disease and Cancer, Dr. Singh details seven factors that contribute to accumulation of reactive oxygen species in the brain (2). In this discussion, I will review three of the factors:

1) Low Antioxidant Defenses

2) Arachidonic Acid [Inflammation; Omega-6/Omega-3 Ratio]

3) Glutamate [Excitotoxins]

Low Antioxidant Defenses

Antioxidants are molecules that inhibit oxidative stress of other molecules. Antioxidants are biological electron donors; by donating an electron to a free radical, that free radical is no longer unstable and it will no longer pose a damaging threat to membranes, proteins, fats, DNA, etc. Therefore, antioxidants are good, and the more one has the better.

Our primary exogenous source of antioxidants is from consumption of fruits and vegetables in the diet. Sadly, a report from the United States Centers for Disease Control (CDC) in 2009 indicated that only 14% of US adults and 9.5% of US teenagers were consuming the minimum of 5 servings of fruits and vegetables per day (3). “CDC officials said the findings indicate a disheartening gap between how people should be eating and what they’re actually doing in an era of rampant obesity.”

Michael Pollan, PhD, is a professor at the University of California, Berkeley. In his 2008 book In Defense of Food, Dr. Pollan stresses that there is no substitute for healthy eating (4). He stresses that the healthy diet should consist primarily of plant based foods, in part because of their higher levels of antioxidants. Yet, as noted from the CDC assessment, the average US citizen diet is falling far short of optimal in this regard. Consequently, even Dr. Pollan makes these comments in his book:

“Many of the nutrition experts I consulted recommend taking a multivitamin, especially as you get older.”

“It’s probably a good idea, and certainly can’t hurt, to take a multivitamin-and-mineral pill.”

The point is that a healthy plant-based diet will supply the consumer with a rich array of antioxidants, protecting the brain from free radical damage. Supplementing with a quality multiple vitamin-mineral pill could possibly enhance the free radical scavenging of a healthy diet, assisting in the protection and preservation of brain function. Such supplementation has already been shown to be associated with the longer length of telomeres, an important measure of biological longevity (the 2009 Nobel Prize in medicine/physiology) (5).

Arachidonic Acid [Inflammation; Omega-6/Omega-3 Ratio]
Omega-3 Fatty Acids

On January 2, 2006, in Upshur County, West Virginia, USA, there was an explosion in the Sago Coal Mine. The blast trapped 13 miners for nearly two days; only one miner survived. It was one of the worst mining disasters in the United States.

The lone survivor was Randal L. McCloy, Jr., age 26. He was found unconscious and suffering from carbon monoxide poisoning, a collapsed lung, brain hemorrhaging, edema, muscle injury, faulty liver and heart function, and almost no brain electrical activity. His initial prognosis for recovery was grim, expecting permanent damage to his brain. However, McCloy recovered almost fully.

The story of Ronald McCloy’s miraculous recovery is well reviewed in the magazine Men’s Health in 2007 in an article titled THE GOVERNMENT’S BIG FISH STORY (6). A portion of the Men’s Health Article follows:

When Randal McCloy was rushed to West Virginia University Ruby Memorial Hospital’s intensive-care unit, he was practically dead. The 27-year-old coal miner had spent 41 hours buried 2 1/2 miles underground after an explosion in the Sago, West Virginia mine where he’d been working. His 12 oxygen-starved colleagues had all perished.

“As far as we know, he survived the longest exposure to carbon monoxide poisoning,” says Julian Bailes, M.D., the neurosurgeon assigned to the case. McCloy was in a coma and in deep shock, his heart barely beating, one of his lungs collapsed, his liver and both kidneys shut down. Even if he somehow managed to pull through, doctors predicted McCloy would be severely brain damaged, since the carbon monoxide had stripped the protective myelin sheath from most of his brain’s neurons. “It’s very difficult to come back from a brain injury,” says Dr. Bailes. “There’s no drug that can help that.”

Dr. Bailes ordered a daily dose of 15,000 milligrams (mg) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) for the miner. In layman’s terms? Fish Oil.

Several weeks passed. Then, unexpectedly, McCloy emerged from his coma. This in itself was amazing, but he wasn’t done. In the weeks that followed, he stunned even the most optimistic experts by recovering his memory and gradually regaining his ability to walk, talk, and see, a turnaround that many in the medical field called miraculous.

Dr. Bailes states: “The omega-3s helped rebuild the damaged gray and white matter of his brain,” says Dr. Bailes, who now takes his own medicine, swallowing a fish-oil supplement each morning. On his orders, McCloy, still recuperating at home, continues to take fish oil daily. “I would say he should be on it for a lifetime,” says Dr. Bailes. “But then, I think everybody should.”

••••

Dr. Artemis P. Simopoulos, MD, is a physician and geneticist working in Washington DC. As of this writing (August 13, 2012), a search of the National Library of Medicine using her name and the word “omega-3” in the PubMed search engine located 50 citations. One particularly relevant reference was published late last year in the journal Molecular Neurobiology and titled (7):

Evolutionary Aspects of Diet:
The Omega-6/Omega-3 Ratio and the Brain

In this article Dr. Simopoulos notes that human beings evolved on a diet that had a ratio of omega-6 to omega-3 fatty acids (FA) of about 1/1. Yet, today, Western diets have a ratio of 10/1 to 20–25/1, indicating that Western diets are deficient in omega-3 FA compared with the diet on which humans evolved and their genetic patterns were established.

Dr. Simopoulos notes that docosahexaenoic acid (DHA) omega-3 is essential for the normal functional development of the brain. DHA accounts for 40% of the membrane phospholipid FA in the brain. Both eicosapentaenoic acid (EPA) and DHA omega-3s have an effect on brain membrane receptor function and even neurotransmitter generation and metabolism. The balance of omega-6 and omega-3 FA is important for brain homeostasis and normal brain function throughout the life cycle.

The change of omega-6/omega-3 ratio in the food supply of Western societies has occurred over the last 150 years. During evolution, omega-3 fatty acids were found in all foods consumed: meat, wild plants, eggs, fish, nuts, and berries. Today in Western societies the omega-6/omega-3 ratio is very high due to the high intake of soybean oil, corn oil, sunflower, safflower, and linseed oil.

Omega-3’s can affect not only cognitive functions, but also mood and emotional states and may act as a mood stabilizer. Omega-3’s have beneficial effects in a number of neurological diseases. Dr. Simopoulous notes:

“DHA is found in high amounts in the membranes of brain and retina and is critical for proper neurogenesis, neurotransmitter metabolism, neuroprotection and vision. The consumption of high amounts of DHA has been associated with multiple health benefits including brain and retinal development, aging, memory formation, synaptic membrane function, photoreceptor biogenesis and function, and neuroprotection. DHA is essential for pre-natal brain development.”

“Clinical studies show that cognitive performance improves with omega-3’s.”

“Western diets are characterized by high omega-6 and low omega-3 fatty acid intake, whereas during the Paleolithic period when human’s genetic profile was established, there was a balance between omega-6 and omega-3 fatty acids. Therefore, humans today live in a nutritional environment that differs from that for which our genetic constitution was selected.”

“The balance of omega-6/omega-3 fatty acids is an important determinant in maintaining homeostasis, normal development, and mental health throughout the life cycle.”

“Cognitive performance improves with omega-3’s supplementation possibly due to increased hippocampal acetylcholine levels, the anti-inflammatory effects of omega-3’s, decreased risk of cardiovascular disease or increased neuroplasticity.”

“In humans, the brain is the most outstanding organ in biological development: it follows that the priority is brain growth and development, and in the brain the balance between omega-6 and omega-3 PUFA metabolites is close to 1:1. This ratio should be the target for human nutrition.”

“The ratio of omega-6/omega-3 fatty acids in the brain between 1:1 and 2:1 is in agreement with the data from the evolutionary aspects of diet and genetics.”

“A ratio of 1:1 to 2:1 omega-6/omega-3 fatty acids should be the target ratio for health.”

••••

A relevant addition to this discussion is the letter to the editor of the political magazine, Time, June 4, 2012. Steven Gaulin, PhD, Anthropology Professor, University of California, Santa Barbara, and William Lassek, MD, former Assistant Surgeon General of the United States wrote:

Parenting Debate

“Your recent cover article on attachment parenting has provoked much discussion about breast-feeding. Anthropological surveys across many cultures indicate that the mean age at which weaning in our species occurs is 2.5 to 3 years. The evolutionary explanation for this long nursing period is clear. Our unusually large brains require large amounts of omega-3 fats, and breast milk concentrates these fats from mothers’ bodily resources. Unfortunately, the omega-6-laden American diet, based on corn and soybean oil and animals fed on these crops, deprives infants and children of the omega-3 fats needed for healthy brain development. Thus early weaning and bad diets are delivering a one-two punch to American kids.”

••••

Brain function and health is dependent upon the ratio of membrane omega-6 to omega-3 fatty acids. This ratio is critically important throughout life, from infancy to the elderly. It has been shown that a simple yet accurate assessment of this ratio in the brain is to evaluate the ratio in red blood cells (9). This assessment is accomplished on our patients with a simple, inexpensive finger prick blood analysis. The analysis looks at the ratio of the omega-6 fatty acid Arachidonic Acid (AA) to the omega-3 fatty acid Eicosapentaenoic Acid (EPA), or the AA/EPA ratio. If the ratio is too high (excessive AA or low levels of EPA), we supplement the patient with a quality fish oil product and encourage a reduction of omega-6 fatty acids in the diet. We retest in about 4 months.

Studies supporting this approach to improve brain function and health are numerous. As examples, studies supporting omega-3 fatty acids in brain trauma management (10) and prevention of neurological degenerative diseases have been recently published (9, 11).

Excitotoxins

Excitotoxins are molecules that function as excitatory neurotransmitters, but when present in excess they can literally excite the neuron to death. The word excitotoxins is credited to physician and neuropathologist John Olney, MD, currently at the University of Washington. Beginning in the late 1960s, Dr. Olney began to publish warnings about dietary exposure to 2 excitotoxins that are found as food additives, specifically as taste enhancers: glutamate and aspartate. A representative article of his work is found in the journal Neurotoxicoloty in 1981, titled (12):

Excitatory neurotoxins as food additives: an evaluation of risk

Stuart A. Lipton, MD, PhD, is a neuroscientist. He is former Associate Professor of Neurology, Harvard Medical School, and currently he is at the Salk Institute for Biological Studies and the Scripps Research Institute, La Jolla, California. Paul A. Rosenberg, MD, PhD, is also a neuroscientist and an Associate Professor of Neurology, Harvard Medical School. In 1994, Drs. Lipton and Rosenberg published an article in the New England Journal of Medicine suggesting that all brain neurologic disorders have a common pathway: excitotoxicity (13). Their article is titled:

Excitatory amino acids as a final common pathway for neurologic disorders

Consistent with Dr. Olney, Drs. Lipton and Rosenberg indicate that the 2 most prevalent excitotoxins are the amino acids glutamate and aspartate.

Drs. Lipton and Rosenberg lists of neurologic conditions associated with glutamate and aspartate excitotoxicity include:

Acute insults: stroke, hypoglycemia, trauma, and epilepsy

Chronic neurodegenerative states: Huntington’s disease, the acquired immunodeficiency syndrome (AIDS) dementia complex, amyotrophic lateral sclerosis, and Alzheimer’s disease.

The primary glutamate/aspartate neuron receptor is the N-methyl-D-aspartate (NMDA) receptor. When the NMDA-receptor is activated there is an influx of calcium into the neuron, causing overstimulation, excessive free radical production, and neuronal injury/death. Drs. Lipton and Rosenberg state:

“The paradox of excitotoxicity is how or why the mammalian brain evolved with such extraordinary vulnerability to its own excitatory neurotransmitters.”

“The ambient concentrations of glutamate are close to those that can destroy neurons, and it is important that the extracellular glutamate concentration and compartmentalization be exquisitely controlled to prevent excitotoxicity.”

A number of contemporary physicians are writing books in an effort to warn the public about the dangers of consumption of excess dietary glutamate and aspartate, including:

1997
Excitotoxins, The Taste That Kills by Russell Blaylock, MD (University of Mississippi neurosurgeon), Health Press.

1999
In Bad Taste, The MSG Symptom Complex, by George Schwartz, MD, Health Press.

2000
The Crazy Makers, How the Food Industry Is Destroying Our Brains and Harming Our Children, by Carol Simontacchi, Tarcher Putnam.

Food Allergies by William Walsh, MD (Mayo Brothers), Wiley.

2001
Fast Food Nation by Eric Schlosser, Houghton Mifflin.

These authors remind the reader that aspartate is half of the artificial sweetener aspartame. Glutamate is ubiquitous in packaged foods, often in the salt form MSG (monosodium glutamate). Glutamate in food is often hidden, using names like (from Blaylock, 1997):

HIDDEN SOURCES OF MSG

The glutamate manufacturers and the processed food industries are always on a quest to disguise MSG added to food. Below is a partial list of the most common names for disguised MSG.

Additives that always contain MSG:

Monosodium Glutamate
Hydrolyzed Vegetable Protein
Hydrolyzed Protein
Hydrolyzed Plant Protein
Plant Protein Extract
Sodium Caseinate
Calcium Caseinate
Yeast Extract
Textured Protein
Autolyzed Yeast
Hydrolyzed Oat Flour

Additives that frequently contain MSG:

Malt Extract
Malt Flavoring
Bouillon Stock
Broth Flavoring
Natural Flavoring
Natural Beef or Chicken Flavoring

Additives that may contain MSG or excitotoxins:

Carrageenan
Enzymes
Soy Protein Concentrate
Soy Protein Isolate
Whey Protein Concentrate

Ideally, these book’s authors recommend that the excitotoxins glutamate and aspartate be avoided in the diet. Additionally, excessive glutamate and aspartate are cleared from the extracellular space by ATP energy dependent uptake systems and moved into astrocytes. When cellular energy metabolism is impaired or fails because of ATP depletion, harmful extracellular accumulation of glutamate and aspartate occurs. Deprivation of oxygen and/or glucose decreases the production of ATP. This energy failure itself is not toxic to neurons. What makes it neurotoxic is the accumulation of glutamate/aspartate and activation of glutamate-receptor-dependent excitotoxic mechanisms. ATP production is reduced as a consequence of such mechanisms as smoking, anoxia, hypoglycemia, and insulin resistance.

Both neurons and astrocytes contain large quantities of glutamate that leak out of injured/traumatized cells. This may explain the increased incidence of Alzheimer’s Dementia and other neurodegenerative disorders in National Football Players and others with a history of repeated brain trauma.

Drs. Lipton and Rosenberg note that magnesium blocks the NMDA receptor, and this may be the basis for its anticonvulsant and neuroprotective effects. They sum up their article with:

“A wide variety of acute and chronic neurologic diseases may be mediated, at least in part, by a final common pathway of neuronal injury involving excessive stimulation of glutamate receptors.”

Strategies to protect brain health and function as related to excitotoxicity include:

• Avoid excess dietary glutamate/aspartate (read food/drink labels)
• Do not smoke
• Consume high levels of antioxidant foods (fruits and vegetables)
• Possibly enhance dietary antioxidants with an antioxidant supplement
• Possibly supplement with magnesium
• Maintain aerobic fitness
• Avoid/manage blood glucose problems, especially insulin resistance (below)

Insulin Resistance

It is possible that the primary health problem in developed countries today is insulin resistance. As American science writer Gary Taubes notes in his 2008 book Good Calories, Bad Calories (14), insulin resistance creates a biological cascade that makes people overweight, a modern global epidemic.

But, it is important to recall that if one is insulin resistant, they also have a diminished capacity to get glucose out of the blood stream and into the neuron where it is converted into ATP energy. When brain ATP production is low, excessive glutamate and aspartate are not deactivated by pumping them into the astrocytes. Consequently there is increased excitotoxic brain injury and its associated pathology.

This thinking is the central theme of the 2011 book by neonatal physician Mary Newport, MD, titled Alzheimer’s Disease, What if There Was A Cure (15). Dr. Newport presents evidence and asserts that Alzheimer’s Disease is a type of diabetes in which the patient is actually suffering from brain neuron insulin resistance. Consequently, the patient’s brain is starved of adequate levels of ATP allowing excitotoxic damage to cascade.

Dr. Newport presents an academic discussion with numerous case studies suggesting that giving the brain compromised patient (disease, injury, etc.) alternative fuel to manufacture ATP will greatly improve the patient’s brain health and function. Because the patient is insulin resistant, this alternative fuel would have to be independent of the glucose/insulin relationship.

Dr. Newport’s review of the literature documents that such an alternative fuel source is medium chain saturated triglycerides. These fats are readily absorbed and transported to the liver where they are converted into ketones. These ketones readily cross the blood brain barrier, cross the neuronal membrane, and are quickly and efficiently converted to ATP in the mitochondria. All of this is done without the need of insulin, so if the patient is insulin resistant, the mechanism still works. The greater levels of ATP help to actively pump glutamate and aspartate into the astrocytes, improve the sodium pump function, improve the synthesis of neurotransmitters, etc. All of which enhances brain health and function.

Dr. Newport says a great source of medium chain saturated triglycerides is coconut oil (57-60%). She advocates and details how brain compromised people or people who want to optimize brain function can incorporate coconut oil into their daily regimes.

REFERENCES:

1. Perlmutter D; The Better Brain Book; Riverhead Books; 2004.
2. Singh K PhD, Oxidative Stress, Disease and Cancer, Imperial College Press, 2006.
3. Anderson L; US Diets Fall Short on Fruit, Vegetables; USA Today; September 30, 2009.
4. Pollan M; In Defense of Food; Penguin Press; 2008
5. Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H; Multivitamin use and telomere length in women; American Journal of Clinical Nutrition; Vol. 89, No. 6, 1857-1863, June 2009, pp. 1857-1863.
6. Erdely SR, Watkins D; THE GOVERNMENT’S BIG FISH STORY; Men’s Health; June 21, 2007.
7. Simopoulos AP; Evolutionary Aspects of Diet: The Omega-6/Omega-3 Ratio and the Brain; Molecular Neurobiology; October, 2011; Vol. 44; No. 2; pp. 203-15.
8. Gaulin SJC, Lassek WD; Parenting Debate (letter to the editor); Time, June 4, 2012.
9. S. Tan ZS, Harris WS, Beiser AS, Au R, Himali JJ, and 7 more; Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging; Neurology; February 28, 2012; 78; pp. 658–664.
10. Wu A, Ying Z, Gomez-Pinilla F; The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma; Journal of Neurotrauma; October 2011; Vol. 28; No. 10; pp. 2133-2122.
11. Gu Y, Schupf N, Cosentino SA, Luchsinger JA, Scarmeas N; Nutrient intake and plasma beta-amyloid; Neurology; June 5, 2012; Vol. 78; No. 23; pp. 1832-40.
12. Olney JW; Excitatory neurotoxins as food additives: an evaluation of risk; Neurotoxicology; 1981 Jan;2(1):163-92.
13. Lipton SA, Rosenberg PA; Excitatory amino acids as a final common pathway for neurologic disorders; The New England Journal of Medicine; March 3, 1994; Vol. 330; No. 9; pp. 613-622.
14. Taubes G, Good Calories, Bad Calories, Anchor Books, 2008;
15. Newport M; Alzheimer’s Disease, What if There Was A Cure; Basic Health, 2011.