Tryptophan’s Affect on Depression: A Review Article

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The Amino Acid Tryptophan produces the Neurotransmitter Serotonin.  Does Supplementing Tryptophan produce additional Serotonin to Attenuate Depression and Mood Disorders?

Southern California stood on high alert as depressed weapons expert, Christopher Dorner, declared war on fellow police officers. For days, he traveled through populated cities ambushing law enforcement officers. When Dorner was finally located in the remote San Bernardino forest, gunfire erupted. One officer died at the scene and a second was gravely injured. Both officers were medivaced to our Emergency Department at Loma Linda University. Hundreds of other police officers held a vigil in the parking lot. The injured officer was rushed past me into surgery. He would not survive. The following day, Christopher Dorner, an honorably discharged Navy reservist and former Los Angeles Police officer, took his own life.

Depression, according to World Health Organization estimates, will be the second highest cause of death (Muszyndska, et al., 2015). The affect of depression in the U.S. alone cost $210 billion in 2010 (Reus et al, 2015). Society experiences the increasingly common display of these depressive disorders on nightly television in the form of violent outbreaks, suicides, and school shootings.

Thus far, the major treatment for depression has been anti-depressant drugs. Although, treatment resistance occurs in over 20% of cases (Reus et al, 2015) and 50% of the patients experiencing Major Depressive Disorder will have episodic recurrences and chronic disease (Reus et al, 2015). During the first month of anti-depressant therapy, there is often no improvement in the depressive condition. Suicidal tendencies and inflicting self harm are a major side effect (Reus et al, 2015). Anti-depressant drugs are often designed to recycle the neurotransmitter chemicals present in an individual (Reus et al, 2015), typically not providing additional nutrients to raise neurotransmitter levels and rebuild damaged pathways. As a result, individuals are likely to be dependent upon anti-depressant drugs for an extended period. Eventually, the drug may no longer work or the individual may become treatment resistant ( Reus et al, 2015).
II. Tryptophan, Serotonin and the Alteration of Human Mood

The eventual cure for treating depression and mood disorders may be to provide nutrient based therapies with the goal of rebuilding major components of the neurological pathway systems involved with depression. One neurological pathway critical to affecting mood disorders generates the neurotransmitter serotonin (Bravo et al, 2013). Rebuilding the serotonin pathway to improve depressive-like symptoms may involve supplying the brain with the amino acid precursor, tryptophan.
Tryptophan hydroxylase Dopa Decarboxylase

Tryptophan ————–> 5-Hydroxytryptophan ————> Serotonin
(5-HTP) (5-HT, 5 -Hydroxytryptamine)

Cofactors: Vitamin B3, B9, Iron and Calcium Zinc, Vitamin B6 and C, Magnesium

(Educational Research, 2012)
This pathway illustrates the chemicals involved with the production of the neurotransmitter serotonin from the amino acid tryptophan. Tryptophan is a protein that cannot be made by humans, and thus is essential in the diet (Yao et al., 2011; Sarris & Byrne 2011). This pathway shows how tryptophan in the presence of the enzyme tryptophan hydroxylase (TH) and cofactors, vitamin B3, B9, iron and calcium, produces 5-hydroxytryptophan (5-HTP) (ERB, 2012). 5-HTP is able to cross the blood brain barrier (Patrick &Ames, 2015) where it is absorbed by brain nuclei which convert 5-HTP to serotonin (HT-hydroxytryptamine) in the presence of the enzyme dopa decarboxylase, and cofactors: zinc, vitamin B6, vitamin C, and magnesium (ERB, 2012). Cognitive behavior, sleep and mood are regulated by the neurotransmitter serotonin in humans, and pathway disturbances have been shown to exhibit anxiety, depression and cognitive disorders in humans (Cubero et al.,2011; Mendelsohn et al., 2009; Markus et al.,2005).

The serotonin production pathway is enhanced with many tryptophan or serotonin containing natural products in diets around the world. The natural plants, herbs and fungi that enhance the serotonin system include: Chinese saffron, Siberian Ginseng, African Griffonia, St. John’s Wort grown in Europe-Asia- Africa, African Kanna, Kava Kava from the Western Pacific, and mushrooms (Muszynska et al., 2015). The United States was prevented from using tryptophan and 5-HTP supplements late in the 1990s when a Japanese company supplied a tainted batch of product. The tainted batch caused eosinophilia-myalgia syndrome (EMS) in 1500 individuals including some deaths (Hill, et al., 1993; Druker, 2001). As a result, the FDA kept supplemental tryptophan unavailable until 2005. The scientific experiments described below will explore the use of supplemental tryptophan for the relief of depression and mood disorders in humans.

Tryptophan’s Effect on Human Mood

In this first experimental study, Mohajeri’s team hypothesized that positive emotional stimuli could be enhanced and negative stimuli reduced through dietary tryptophan. The article is titled “Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women”. Fifty-nine healthy women, 45-65 years old were randomly selected (age stratified) to compare a tryptophan fortified drink with placebo (Mohajeri, et al., 2015). Subjects experiencing psychiatric, neurological gastrointestinal disorders, receiving pharmaceuticals, diabetic, or pregnant, were excluded.

Subjects were baseline tested with four personality questionnaires: Dutch Personality Inventory, Depression Anxiety and Stress Scale, Aggression Questionnaire, and Barratt Impulsiveness Scale (Mohajeri, et al, 2015). Sleep/mood diaries were kept by the women. A large battery of pre and post tests assessed mental and physical sensations. Each woman was given tryptophan rich drinks for 19 days (Mohajeri, et al., 2015).

The experimental findings were similar between the placebo and tryptophan fortified drink in neuroticism, anxiety, impulsivity, depression and aggression. Cognitive results evaluated with the Rotary Pursuit Task, Rapid Visual Information Processing Task, Verbal Recognition Memory Test, and Driver Hazard Perception Test were similar (Mohajeri, et al, 2015). Final treatment increased high energy ratings on the Mental and Physical Sensations Scale. The Affective Go/No-Go Task slowed the negative word response time of the tryptophan drink group. The Facial Emotional Expression Rating Task showed no treatment effect, however, the intensity of anger lessened and overall happiness/mood improved (Mohajeri, et al, 2015)

These findings further showed that in the Simple Reaction Time Task, shorter reaction times resulted with the tryptophan drink. The Match to Sample Visual Search Task demonstrated an overall faster reaction time for the tryptophan supplemented group in locating targets (Mohajeri, et al., 2015). Evening mood and quality of sleep was evaluated through the self reported diary, Leeds Sleep Evaluation Questionnaire, and Thayer’s energetic arousal. ANCOVA found sleep and evening moods improved with the tryptophan drink (Mohajeri, et al, 2015). Subjects awoke fewer times during the night and rated their happiness higher. Mohajeri’s experiment found that the effect of the protein drink reduced anger, increased happiness/mood, improved sleep habits, and resulted in shorter reaction times. These four criteria relate directly to the depression related criteria analyzed in NHANES, as well as relate to criteria analyzed in the Beck Depression Inventory and Hamilton Psychiatric Rating Scale (Su et al, 2008; Raimo et al, 2015).

Tryptophan’s Effect on Human Mood and Sleep

This next experimental study is entitled “Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans” by R. Bravo and co-researchers. The hypothesis was whether sleep and depression/anxiety could be improved through a tryptophan rich cereal. This experiment is based upon the brain utilizing tryptophan to produce serotonin to regulate depression and anxiety (Cubero et al, 2011; Mendelsohn et al., 2009; Markus et al, 2005). Serotonin is then absorbed by the pineal gland to produce melatonin which is able to regulate sleep cycles and circadium rhythms (Bubenik & Konturek, 2011). Circadium rhythm disorders have been found to be related to depression and anxiety (Most et. al, 2010), and tryptophan supplementation has been found to increase circulating levels of both serotonin and melatonin (Aparicio et al, 2007)(Paredes et al., 2007)(Sanchez et. al., 2008a,b).

This tryptophan cereal experiment was performed with 35 caucasian volunteers (ages 55-75). These were healthy volunteers who experienced difficulty sleeping. They were not alcohol, drug users or smokers (Bravo et al., 2015). Individuals slept in their own homes and were asked to eat cereal for breakfast and dinner. During the first week of the experiment, Blevit Plus 8 control cereals containing (75mg tryptophan in 100g cereal) were eaten (Bravo et al, 2015). The second week, the Blevit Plus 8 experimental cereal (200mg tryptophan in 100g cereal) was eaten. The third week subjects returned to their normal diets (Bravo et al, 2015).

To analyze results, Sleep Analysis 5v.5.48 software and wrist actimetry were utilized to measure numerous sleep variables including actual sleep time, sleep efficiency, and number of awakenings (Bravo et al, 2015). Pre-test/post-test urinalysis through DRG kits were performed to measure 6-sulfatoxymelatonin (aMT6s) and 5-hydroxyindoleacetic acid (5-HIAA) which are melatonin and serotonin metabolites, respectively. The Cayman kit measured total antioxidant capacity of the urine to quantify the anti-oxidant activity of tryptophan (Bravo et al, 2015). Baseline Beck Depression Inventory and State-Trai Anxiety Inventory (STAI) tests were completed to evaluate pre-test/post-test depression and anxiety levels.

Bravo and colleagues found that when comparing sleep results during the tryptophan cereal treatment week with the control and normal diet weeks that sleep habits improved during the treatment week. Increased urine serotonin and melatonin metabolite findings following the high tryptophan cereal diet were statistically significant, as was urine anti-oxidant levels (Bravo et al, 2015). Trait anxiety did not differ from controls, however state anxiety reduced slightly. The Beck’s Depression Test results decreased, demonstrating fewer depression-like symptoms following the tryptophan cereal treatment diet (Bravo et al, 2015). Bravo and colleagues found that mood was positively correlated with the tryptophan diet.

III. A Systems Approach to Rebuilding the Serotonin Pathway

The experimental studies discussed in the last section found that supplementary tryptophan improved mood/depression-like disorders. The review studies discussed below reach beyond evaluating tryptophan as a single nutrient. These researchers have reviewed the mechanisms of the serotonin production pathway system and have considered the roles of additional nutrients that regulate and affect serotonin production. The first review paper evaluates the impact of omega-3 fatty acids which build brain tissue and suppresses inflammation. Additionally, this paper analyzes vitamin D’s role in regulation of the tryptophan hydroxylase enzyme which converts tryptophan to serotonin. The second review paper evaluates the biomarkers of gastrointestinal disease, including inflammation, as related to the biomarkers of depression.

Tryptophan, Vitamin D, and Murine Omega-3 Fatty Acids

In this review article written by Dr. Rhonda Patrick and Dr. Bruce Ames of the Nutrition and Metabolism Research Center in Oakland, California entitled “Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior” a physiological systems approach is applied. The authors discuss how serotonin pathway regulation and receptor access play important roles in pathway function. They write that when the serotonin pathway and the influential mechanisms are not working properly, a plethora of psychiatric disorders may arise including depression (Patrick & Ames, 2015) and social disturbances (Way et al, 2007; Varnas et al, 2004; Sanfey et al, 2007). Additionally, serotonin transporter polymorphisms have been identified which increase the risk of these psychiatric disorders in genetically predisposed individuals (Blair et al, 1995; Greenberg et al, 2000; Retz et al, 2004, Nielsen et al, 1994; Lesch et al, 1996). These researchers evaluate the mechanisms of vitamin D, eicosapentanoic acid (EPA), and docosahexanoic acid (DHA) in serotonin production.

Vitamin D regulates the conversion of tryptophan into serotonin by binding vitamin D response elements (VDRE) and transcriptionally acting upon the enzyme trytophan hydroxylase 1(TH1) (Patrick & Ames, 2015). TH1 is the enzyme responsible for converting tryptophan into serotonin in brain tissue (Patrick & Ames, 2015). Vitamin D has been found to be deficient in up to 70% of adults (Ginde, et al, 2009; Bailey et al, 2012; Mansbach et al, 2009). Deleterious cognitive effects of a vitamin D deficiency have been found in mice with genetic polymorphisms in their TPH genes (Zhang et al, 2004; Groves et al, 2013). These authors support vitamin D supplementation to help reduce psychiatric disease (Patrick & Ames, 2015).

EPA has a role in both the regulation of serotonin secretion and the suppression of inflammation (Gunther et al, 2010; Schlicker et al, 1987; Portanova et al, 1996). EPA inhibits generation of prostaglandins which decrease the release of serotonin and promote inflammation. EPA resolves depression caused by inflammatory cytokines (Su et al, 2014). In patients with gene polymorphisms the inflammatory process is pronounced (Su et al, 2010). While no mechanism has been found to explain how inflammation causes depression, it is known that serotonin is not released when inflammation is present. Stress and inflammatory cytokines are found to convert tryptophan into kynurenine instead of serotonin (Kiank et al, 2010) leading to increased anxiety (Patrick & Ames, 2015). EPA assists serotonin in performing its role to enhance positive social behavior and regulate mood (Patrick & Ames, 2015). In the average adult, dietary surveys show that a deficiency of EPA exists (U.S. Department of Agriculture, 2014).

DHA is important in the construction of the serotonin receptor (Patrick & Ames, 2015). The long chained, double bonded, DHA builds a fluid neuronal membrane allowing for proper positioning of the serotonin and dopamine receptors (Heron et al, 1980; Paila et al, 2010; Heinrichs et al, 2010). The serotonin receptors depend upon this accessibility given that receptor chains pass through the cell membrane seven times (Wassal et al, 2009; Escriba et al, 2007). Neuronal transmission of serotonin has found to decrease when omega-3 fatty acids are low (Chalon et al, 2006; de laPresa Owens & Innis, 1999). When additional omega-3 fatty acids are provided to humans, an increase of the serotonin metabolite 5-Hydroxyindoacetic acid (HIAA) has been found in the urine (Hibbeln et al, 1998). These authors recommend 1 gram per day of DHA and 2 grams of more of EPA (Patrick & Ames, 2015).

Patrick and Ames also highlighted the effectiveness of giving patients tryptophan or 5-HTP supplements to stimulate positive behaviors (Hudson et al, 2007; Young et al, 2007; aan het Rot et al, 2006). They stress the importance of exercise which causes branched chained amino acids (BCAA) to be utilized by muscle tissue, thereby increasing the tryptophan to BCAA ratio. Elevating this ratio increases tryptophan transport across the blood-brain barrier. Vitamin B6 and iron are important cofactors in serotonin production (Patrick & Ames 2015). In conclusion, these authors promote additional studies on the efficacy of utilizing tryptophan/5-HTP, murine omega-3 fatty acids (EPA and DHA), vitamin D, exercise, vitamin B6 and iron to restore normal cognitive function and acceptable social behavior in humans (Patrick & Ames, 2015). They see applications of this simple therapy in our prison system, where rehabilitation of individuals who impulsively display violent behavior could be most beneficial to society.

Tryptophan, Gastrointestinal Disease, and Inflammation

This second review article by Dr. Marta Martin-Subero and colleagues from Spain and Australia is entitled “Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways”. This article is most current in addressing the systemic effects of gut inflammation given the recent attention given to leaky gut syndrome. Much of leaky gut syndrome can be attributed to the high consumption of wheat germ agglutinun lectins and gluten proteins (Falth-Magnusson et al., 1995) in the diet. Martin-Subero and colleagues sought to connect the inflammatory pathologies of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn’s Disease (CD) and depression.

In comparing depression with IBD, both have alternating remissions and inflammatory episodes that appear to concurrently exist (Martin-Subero et al, 2015). Patients with IBD have a 2-3x greater likelihood of having depression (Martin-Subero et al, 2015). One case-controlled study of 12,500 individuals, found that depression and anxiety preceded a UC diagnosis (Kurina, MMS (15)). Chronically, a damaged leaky gut may deliver intestinal lipopolysaccharide from gut bacterial capsules and wheat lectins/gliadins into the blood serum resulting in a systemic inflammatory response (Falth-Magnusson et al., 1995). This inflammation may attenuate the release of serotonin promoting depression and psychosomatic disorders (Martin-Subero et al, 2015).

Researchers found that there are several pathways utilized by both IBD and depression. Initially, the levels of interleukins, tumor necrosis factor alpha, and interferon are increased in both conditions while levels of immune suppressive cytokines are decreased (Martin-Subero et al, 2015). Acute phase proteins and C-reactive protein are both increased in depression and IBD. Second, increased levels of protein, DNA, and lipid damage are seen, as well as decreased levels of some anti-oxidants. Oxidative and nitrosative stress plus reactive oxygen and nitrogen species are increased, (Martin-Subero et al, 2015) possibly due to mitochondrial dysfunction. Lower zinc levels are found in both conditions. Third, similar levels of serum antiphospholipid antibodies have been found in CD, UC, and depressed individuals. Autoimmune disorders are common with IL-6 and Th-17 levels increased (Martin-Subero et al, 2015).

In a fourth coordination of concurrent biomarkers in depression and gastrointestinal disease, both conditions activate indoleamine 2,3-dixoygenase (IDO) which converts tryptophan to kynurenine, transcending down the TRYCAT (tryptophan catabolism) pathway such that serotonin cannot be produced (Reus et al, 2015). Increased TRYCAT levels in conjunction with lower plasma tryptophan levels contribute to neurotoxic processes and depression-like symptoms (Martin-Subero et al, 2015; Maes et al, 2011). These results, including the presence of a leaky gut, cytokine elevations, TRYCAT induction and oxidative/nitrosative stress (Martin-Subero et al, 2015) in both conditions lead these researchers to propose an association between depression and IBD (Martin-Subero et al, 2015). To provide further evidence that some association exists, they note that TNF-alpha antagonist and anti-depressant drugs improve both IBD and depression( Banovic et al, 2009; Raison et al, 2013; Goodhand et al, 2012; Martin-Subero et al, 2015).

IV. Conclusion

As depression becomes the second highest cause of death, society will continue to suffer from the acts of the psychologically disturbed. The neurotransmitter serotonin has been found to improve mood and depressive disorders. Anti-depressant drugs costing millions of dollars have helped with short term treatment, but are not replacing the nutrient deficiencies in these affected individuals. An inexpensive and long term solution might be to utilize the basic biochemistry and physiological sciences taught in our medical professions to design therapies that provide adequate levels of all nutrients involved in neurotransmitter pathway systems. Fortifying food with tryptophan in conjunction with necessary cofactors produces serotonin and improves psycho-social behaviors. Fortifying individuals with vitamin D activates the conversion of tryptophan to serotonin. Fortifying individuals with the murine fish oils, EPA and DHA, decreases inflammation and improves the accessibility of serotonin binding receptors on neurons. Treating the complete serotonin pathway system may well provide an inexpensive, scientifically based, long-term solution. These treatments may benefit society through the attenuation of the potentially aggressive behaviors caused by depression and mood disorders.

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Amino Acid Therapy for TBI and Concussion: A literature review

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Amino Acid Therapy for Traumatic Brain Injury: A Literature Review

Introduction: High school biology has long instructed on the importance of protein in construction of neurons, cell membrane, and neurotransmitters. College biochemistry students memorize the twenty amino acids, and their required presence for protein transcription. Yet, in healing traumatic brain injury (TBI), elemental amino acid therapy is rarely considered. TBI is our leading cause of death among the population under age 44 given combat casualties, sports-related injuries, and motor vehicle accidents. TBI brings lingering deficits in concentration, depression, sleep-wake cycle, behavior, and motor skills. In addition, are the long term sequelae of chronic traumatic encephalopathy, dementia, and Alzheimer’s disease. While enteral/parenteral nutrition formulas supply the eight essential amino acids, they fail to consider the TBI hyper- metabolic state requiring the increased efficiency of elemental amino acids for healing. The Institute of Medicine Report (IOM, 2011) found that when elemental nutrient substrate was provided, second injury did not occur. The hypothesis is that nutritional interventions of elemental amino acids will effect a more complete recovery from TBI, than essential amino acids alone.

Methods: Study design was to search PUBMED with the keywords “TBI” and “Amino Acid Therapy”. The goal was to review 10 articles. With limited human studies, rodent studies were included. Criteria reported: Study Title, Journal/Date, Brief Summary, Purpose, Population, Setting, Research Design, Framework, Methods, Intervention, Significant Results, Conclusions, Significant Findings, Limitations, and Implications.

Results: Of the 10 primary studies, cysteine alleviated behavioral/cognitive deficits, regulated cytokines, and reduced oxidative stress (including lipid peroxidation). Aspartate was found to improve motor deficits. Arginine reduced contusion size, maintained cerebral perfusion pressure, and reduced intracranial pressure. While higher glutamine levels have been associated with worse outcome, which one study confirmed, supplying glutamine and alanine did not elevate brain glutamine levels nor predict a worse outcome. In two studies, the University of Pennsylvania astutely combined amino acids using branched-chained amino acid (BCAA) therapy. Hippocampal behavioral deficits, cognitive impairment, abnormal EEG, and wakefulness were restored. Additionally, in 2 review articles: the IOM found efficacy with protein, omega-3, choline, B-complex vitamins, and other nutrients (IOM 2011) and the Army found efficacy with omega-3, vitamin, D, zinc, and glutamine (Scrimgeor, 2014).

Conclusion: Beneficial reports of individual amino acid therapy ameliorating behavioral and motor deficits continue to emerge in both human and rodent studies.  In addition to the important findings described above, there are four clinically relevant concepts that will be applicable to research going forward.  First, if damaged neurons are stimulated to complete an energy dependent process, they die.  This finding may underscore the concept of mental rest for brain trauma patients.  Second, while amino acids may resolve TBI induced deficit, discontinuing supplementation restores the deficit.  Third, supplying amino acids thought to have little blood-brain-barrier penetration are found to significantly improve TBI.  Finally, TBI patients were found to benefit from increased amounts of both essential and so-called non-essential amino acids.  This, in part, confirms the hypothesis that elemental amino acids improve TBI. Only the University of Pennsylvania has creatively combined elemental amino acids for TBI therapy. The results were substantially impressive, such that they applied for a patent!

 

 

Study Title (1)

N-Acetylcystene and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats

Journal and Date

Neurochemical Research, April 2014

Brief Summary

“Oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI).” “Using Sprague-Dawley rats, researchers demonstrated that N- acetylcysteine (NAC) and selenium (Se) showed protective affects on the TBI- induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.”

Purpose

To make a research contribution to therapies for untreated traumatic brain injury.

Sample Population

Thirty-Six, 4 month-old male Sprague-Dawley rats

Setting

Neuroscience Research Center Lab, Suleyman Demirel University, Isparta Turkey

Research Design

Randomly selected, controlled/treatment groups, prospective, experimental rats

Theory/Framework

Amino acids supplied to the traumatized brain alleviate oxidative stress.

Methods

Marmarou’s weight drop model was used to induce TBI in rats. “Rats were divided into four groups:” 1) control group – placebo, 2) TBI group, 3) TBI group treated with gastric lavage NAC (150mg/kg) at 1, 24, 48, 72h after TBI, 4) TBI group treated with Se (NaSe 1.5mg/kg) intraperitoneal at 1, 24, 48, 72h after TBI. Brain cortex homogenate and plasma erythrocytes used to measure lipid peroxidation (LP), GSH, protein, vitamin A, vitamin E, B-carotene, vitamin C, TAS/ TOS, and cytokine levels. SPSS and Mann-Whitney U test used for analysis.

Intervention

TBI with 150mg/kg NAC given to group 3 and 1.5mg/kg Se given to group 4.

Significant Results

“LP is a biomarker of oxidative stress.” “Results showed that LP in brain cortex (p<0.05), plasma (p < 0.05) and erythrocyte (p < 0.01) and TOS levels (p<0.001) in the brain cortex in TBI group were significantly higher than the control. Hence oxidative stress..was increased by TBI.” “Brain cortex vitamin A, B-carotene, vitamin C, vitamin E, TAS, GSH and plasma vitamin E, IL-4, and brain cortex/ plasma levels of GSH-Px decreased by TBI.”

Conclusions

“Administration of NAC and Se caused decrease in LP of the brain cortex (p<0.05), plasma (p<0.05), and erythrocytes (p<0.01) in the TBI + NAC and TBI + Se group were significantly lower than the TBI group, respectively.” “IL-1B levels decreased and GSH, vitamin E, and IL-4 values increased.”

Significant Findings

“Se modulated the balance of oxidant and antioxidant, pro- and anti-inflammatory cytokines in rates by down-regulating the levels of pro-inflammatory (IL-B) cytokine and upregulating the levels of anti-inflammatory (IL-4) cytokines.”

Limitations

Transferring mouse model TBI therapies to human TBI therapies

Implications for Practice

N-acetyl-cysteine and selenium may be viable therapies to help alleviate human suffering from TBI.

Study Title (2)

Efficacy, dosage and duration of action of branched chain amino acid therapy for traumatic brain injury

Journal and Date

Frontiers in Neurology, March 30, 2015

Brief Summary

“Traumatic Brain Injury (TBI) results in long-lasting cognitive impairments for which there is currently no accepted treatment.” “Previous studies identified a novel therapy consisting of branched chain amino acids (BCAA), which restored normal mouse hippocampal responses and ameliorated cognitive impairment following fluid percussion injury. However, the optimal BCAA dose and length of treatment needed to improve cognitive recovery is unknown.” Results from this study show that “alterations in hippocampal function” “are reversible with at least 5 days of BCAA treatment and that sustaining this effect can occur with continuous treatment.”

Purpose

To contribute BCAA dosage amounts to existing BCAA TBI therapies data.

Sample Population

C57Bl/J6 Jackson Laboratory mice, 5 to 7 weeks old, 20-25g, male.

Setting

Research laboratories in Oregon and Philadelphia with an ambient temperature of 23C and humidity of 25C, 12h light/12h dark cycle, 100lux. Free access to food/ water. Performed within NIH Lab Animal Guidelines.

Research Design

Randomly selected, controlled, fluid percussion injury prospective, experimental

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

C57BL/J6 mice sustained fluid percussion injury (FPI) with a 48 hour recovery. Mice were individually housed then treated with BCAA supplemented or unsupplemented water. Concurrent experiments were conducted to determine duration of BCAA action and effective BCAA concentration. Control consisted of untreated tap water. Following TBI recovery, animals were fear conditioned. Then, 24 hours later were observed for freezing in the conditioning box. A lower freezing percentage is indicative of impaired contextual memory.

Intervention

Anesthesia, craniectomy, FPI of 1.8-2.1 atm, sutures, either 50mM BCAA or 100mM BCAA or regular tap water for 2, 3, 4, 5, 10 days.

Significant Results

“Injured mice that received BCAA treatment showed a significantly greater freezing response on average compared to the untreated FPI mice when treatment was delivered for 5 or 10 consecutive days.”

Conclusions

“Data establish that BCAA therapy is required for at least five consecutive days at a dose of either 100mM in ad libitum drinking water or 0.26 g/kg via oral gavage, to restore normal fear conditioning. Furthermore, stopping BCAA therapy, after 5 days, results in a functional relapse to levels seen in untreated injured animals.”

Significant Findings

“These results suggest the persistence of a functional deficit after TBI, which ongoing BCAA supplementation can successfully treat.”

Limitations

If BCAA therapy is stopped, the neurological hippocampal deficit returns.

Implications for Practice

In this and an earlier research study performed by these researchers, BCAA therapy has been shown to reverse hippocampal cognitive impairment from TBI. This has implications for human TBI therapy with enteral BCAAs. The University of Pennsylvania has applied for a patent to use BCAA therapy for TBI.

Study Title (3)

Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L_arginine decreases contusion size but not behavioral deficits after traumatic brain injury

Journal and Date

Brain Research, July 27, 2011

Brief Summary

Therapeutic effects of AdGDNF and L_arginine post traumatic brain injury were examined. “AdGDNF and L_arginine were injected into cortex immediately post controlled cortical impact. Contusion size was decreased by the combination but not by each treatment alone. Behavioral recovery was not affected.”

Purpose

To contribute to the research database defining TBI therapies.

Sample Population

344 Male Fisher 225 – 300g rats from Charles River Labs

Setting

“Rats were housed within the DePaul University Animal Facility…on a 12:12h light and dark cycle, with food and water available ad libitum. The NIH Guide for Care and Use of Laboratory Animal and Institutional Guidelines were adhered.”

Research Design

Randomly selected/assigned, control/treatment groups, prospective rat study

Theory/Framework

Amino acids supplied to the traumatized brain will affect contusion size

Methods and Intervention

Rats were anesthetized and inflicted with a controlled cortical impact (CCI). Treatment and controls groups of CCI, CCI + saline, CCI + control green fluorescent protein (AdGFP) + saline, CCI + AdGDNF + L_arginine or saline, then Sham only, Sham + AdGDNF + saline and Sham + AdGDNF + L_arginine. AdGFP and AdGDNF viral vectors were injected immediately. Within 30 min. L_arginine or saline “was injected into femoral vein (150mg/kg in sterile 0.9% saline)”. “Behavioral measures of forelimb function were administered on day 0 (pre injury/injections)..then on days 2,4,7,10,14,21 and 28.” “Forelimb coordination.. examined using Foot Fault Test”. Ipsilateral limb use tabulated. Contusion size measured through staining. Staining to detect AdGDNF. GFP expression measured by fluorescent microscope. One-way ANOVA and Fisher’s protected LSD post-hoc test used on contusion volume and GDNF ELISA data. One-way ANOVA and Tukey-Kramer post-hoc test on behavioral data.

Significant Results

Foot Fault Test through Tukey-Kramer post-hoc analysis showed that “AdGDFNF and L_arginine did not affect deficits in or recovery of motor coordination”. “There were no significant differences between all of the injured rats, which indicate that AdGDNF, L_arginine, or the combination of the two did not lessen preferences for the uninjured forelimb.”

Conclusions

“Post-hoc analysis further revealed that rats treated with the combination of AdGDNF and L_arginine post-CCI had significantly smaller contusions than rats that received no treatment post-CCI (32% smaller), rats treated with L_arginine only post-CCI (44% smaller), or rats treated with AdGDNF only post-CCI (44% smaller; all comparisons = p < 0.05).”

Significant Findings

“If neurons are stimulated to complete energy dependent processes post TBI, such as secreting or utilizing a protein …. will result in their death.”

Limitations

AdGDNF and L_arginine do not provide substrate to improve behavioral deficits.

Implications for Practice

AdGDNF and L_arginine may protect humans. AdGNF is “neuroprotective in animal models of stroke, Parkinson’s disease..and spinal cord injury.”

Study Title (4)

N-methyl-D-aspartate preconditioning improves short-term motor deficits outcome after mild TBI in mice

Journal and Date

Journal of Neuroscience Research, May 1, 2010

Brief Summary

“TBI cellular damage may be mediated by the excitatory neurotransmitters, glutamate and aspartate, through N-methyl-D-aspartate (NMDA) receptors.” “Mice preconditioned with NMDA were protected against all motor deficits revealed by footprint test, but not those observed in rotarod tasks”. “Mice showed motor deficits after TBI”, but not cellular damage. Glutamatergic excitotoxicity contributes to trauma severity. NMDA may elicit a neuroprotective mechanism by improving motor behavioral deficits.”

Purpose

To affect motor deficits following TBI

Sample Population

Male CF-1 mice (2-3 months, 30-35g) – UNESC breeding colony

Setting

Six animals/cage with food/water “ad libitum, maintained on a 12-hr light/dark cycle” following NIH Health Guide and Brazilian Society of Neuro & Behavior.

Research Design

Randomly selected, controlled, experimental design using male mice

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

“Animals treated with NMDA (75mg/kg) or vehicle (saline,0.9% NaCl, w/v 24 hr before” diffuse TBI. Sensimotor evaluation 1.5hr, 6 hr, or 24hr after TBI. “Four groups (7-9 mice/group/time = 98 animals)”. “Footprint assessed motor coordination and gaiting”. Rotarod assessed balance. Cellular viability/DNA fragmentation evaluated at 24hr. Footprint and rotarod data analyzed with two- way ANOVA, Fisher’s LSD test for behavioral analysis, footprint by Student’s t- test for dependent variables, p < 0.05.

Intervention

“NMDA dissolved in saline solution, pH to 7.4 with NaOH 1mEq/mol. Animal injected intraperitoneally with a low, nonconvulsant dose of NMDA (75 mg/kg) or vehicle (saline, 0.9% NaCl, w/v) 24hr before cortical trauma injury induction.”

Significant Results

“Sensorimotor behavioral test revealed uncoordinated movements in traumatic mice compared with control mice.” “Preconditioning with NMDA prevented distortion of gait for all parameters of mice that showed deficits.” “Irregular stride length and hindlimb stride observed in mice at 1.5hr after TBI were prevented in preconditioned mice.” “Mice revealed loss of rhythm coordination” via step alternation after TBI “which was prevented by NMDA treatment”. “Animals preconditioned with NMDA and exposed to TBI did not display defects in any of the stride parameters analyzed.” “TBI mice evaluated 1.5hr after TBI were unable to stay on the rotarod,” independent of NMDA or SAL treatment.

Conclusions

“Data showed that neuroprotection evoked by low activiation of the glutamatergic system through NMDA preconditioning was effective against the sensorimotor deficits displayed by mice in a model of diffuse trauma.

Significant Findings

“Protective effect of NMDA … in sensorimotor deficits induced by TBI”

Limitations

NMDA is a receptor; no substrate provided to heal tissue

Implications

That motor deficits can be restored following TBI

Study Title (5)

Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury

Journal and Date

PLoS One, February 1, 2014

Brief Summary

“Using two different injury models: either weight drop in mice or fluid percussion injury in rates”, simulating either mild or moderate TBI, “early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with TBI.” Using Y maze for mice and Morris water maze for rats, NAC treatment provided “significant behavioral recovery after injury.”

Purpose

To contribute research to TBI therapies for military personnel

Sample Population

Experiment 1: Male Sprague-Dawley rats between 300 – 400g Experiment 2: Male ICR mice 6-8 wks, 30-40g Sprague-Dawley

Setting

Housed and bred under a 12 hr light/dark cycle and provided with food/water ad libitum.” Guidelines: Instn. Animal Care, Case Western Reserve, NIH Guide Lab

Research Design

Randomly selected, experimental, control, mice fluid percussion injury model

Theory/Framework

Amino acids supplied to the traumatized brain expedite repair

Methods

Experiment 1: Fluid Percussion Injury Rats, 3 groups: Sham, TBI, TBI-NAC, force of injury 1.82 – 1.95atm. NAC 30min post injury, 50mg/kg ip then q. 24hr for 3 days. Cognitive assessment – Morris water maze- hidden platform, spatial learning and memory. Tested 4 trials per day over 4 days PID 10 13. Morris water maze – probe trail and visible platform.

Experiment 2: Weight Drop Mice, 4 groups: Sham-Vehicle, Sham-Drug (NAC + topiramate), TBI-Vehicle or TBI-Drug (NAC + topiramate). NAC (100mg/kg) + topiramate (30mg/kg) administered ip one hour post injury. Cognitive assessment – 7, 30 days after WD or sham with novel object recognition and the Y maze behavioral tests. SPSS Statistics, one-way or repeated-measures ANOVA and Fisher’s LSD post hoc test, p < 0.05.

Intervention

N-Acetyl-Cysteine in rats, and NAC + Topiramate in saline solution in mice

Significant Results

“Single dose of NAC ameliorates biochemical and histological endpoints” and “multiple doses ameliorate inflammatory sequelae in rat models.” “NAC has antioxidant glutathione (GSH) precursor and anti-inflammatory effects on cytokine cascades and phospholipid metabolism.” “Sulfhydryl group of cysteine serves as a proton donor for antioxidant activity of GSH, rare in foods.”

Conclusions

“The cellular bases of memory and regulation of motivation … may be improved via NAC.” “Despite poor penetration into the CNS, NAC can significantly elevate GSH levels in brain after oxidative stress and GSH deficiency.” “Improved clinical outcomes after early NAC treatment for blast TBI are consistent with the hypothesis that vascular effects of TBI facilitate delivery of NAC to affected sites.”

Significant Findings

“Paper documents the efficacy of NAC in reversing or preventing cognitive abnormalities in rodent models of mild to moderate TBI” this parallels a protocol with blast mTBI in a combat setting including early treatment” w/ NAC/topiramate

Limitations

Studies show this may translate to man in a battlefield blast-induced TBI setting.

Implications for Practice

Often therapies not thought to cross the BBB are tabled. This study shows that amino acids with supposedly limited BBB penetration do reach the brain and can improve outcome.

Study Title (6)

Prolonged continuous intravenous infusion of the dipeptide L-alanine-L- glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe TBI

Journal and Date

Critical Care 2014 18:R139

Brief Summary

“Low plasma glutamine levels are associated with worse clinical outcome” for severe TBI and “optimal glutamine dose to normalize plasma glutamine levels without increasing plasma and cerebral glutamate has not yet been defined”.

Purpose

To determine dosage of glutamine to correct hypoglutaminemia.

Sample Population

“Twelve patient in two separate studies who were comparable presenting with mixed lesions, predominantly consisting of contusion/hemispheric edema. Study 1, two female and four male patients suffering from severe TBI, median age 30 yrs, median BMI 21 kg/m2,” sedated median 13 days. “Study 2, two female and four male patients suffering from severe TBI, median age 28 yrs, median BMI 23 kg/m2,” sedated median 14 days. “Glasgow Outcome Score of 6 at 12 months.”

Setting

Surgical Intensive Care, University Hospital Zuerich, Zuerich, Switzerland

Research Design

Prospective, experimental, 12 TBI Patients anticipated to die within 48 hours

Theory/Framework

Amino acids dosages supplied to the traumatized brain to expedite repair

Methods

“Inclusion criteria: patients suffering from severe TBI reflected by abnormal neurologic status and pathologic neuroradiologic findings were considered eligible when requiring pharmacologic coma.” “Study 1 (n=6), arterial and jugular venous plasma samples drawn at 1,4,12, and 23 hours during the infusion period and after infusion period at 4,12 and 23 hours.” “Study 2 (n=6), plasma arterial and jugular venous samples drawn at predefined time points 1,4,12,24,36,48,60, 72, 84,96,108, and 120 hours, and [drawn] after infusion period at 4,12, 23 and 48 hours.” Indirect Calorimetry performed before and after infusion period.

Intervention

“Study 1: six patients were included to investigate the effects of 0.5g glutamine/kg/ d (Dipeptiven – L+alanine+L+glutamine: 82 mg/100 ml L_alanine and 134.6 mg/ 100ml L_glutamine) continuously infused for 24 hours followed by a 24 hours observation period. In Study 2, a total of six patients were included to investigate the effects of 0.5g glutamine/kg/d (Dipeptiven = :_alanine_L_glutamine; 82mg L_alanine, 134.6 mg L_glutamine) continuously infused for 5 days followed by a 48 hours observation period.” “Dunn’s multiple comparison test, ANOVA,p <0.05.

Significant Results

“Continuous L_alanine_L_glutamine infusion significantly increased plasma and cerebral glutamine and alanine levels (sustained) during the 5 day infusion phase. Plasma glutamate remained unchanged and cerebral glutamate was decreased without any signs of cerebral impairment.”

Conclusions

“High dose L_alanine_L_glutamine infusion (0.75 g/kg/d up to 5 days) increased plasma and brain glutamine and alanine levels. This was not associated with elevated glutamine or signs of potential glutamate-mediated cerebral injury.”

Significant Findings

“Urea and ammonia were significantly increased WNL w/o organ dysfunction.”

Limitations

Optimal dosage not yet determined. Condition improvement not measured.

Implications

Glutamate infusion can be given without deleterious effects to normalize levels.

Study Title (7)

Role of extracellular glutamate measured by cerebral micro dialysis in severe traumatic brain injury

Journal and Date

Journal of Neurosurgery, September 2010

Brief Summary

“High glutamate levels are present in a substantial number of patients, and patterns of glutamate level changes are predictive of patient outcome.”

Purpose

“The present study was to evaluate glutamate levels in TBI, analyzing the factors affecting them and determine their prognostic value.

Sample Population

“Inclusion criteria: a blunt mechanism of head trauma, a GCS score LE 8 on presentation or w/n 48 hrs injury. Exclusion criteria included a penetrating head injury, a presentation GCS score of 3, and fixed, dilated pupils.” 165 patients.

Setting

Ben Taub General Hospital (Level I trauma center) in Houston, Texas (200-2007). Baylor Institutional Review Board approved. NICU, standard protocol.

Research Design

Prospective study, TBI Level 1 165 patients inclusion/exclusion criteria

Theory/ Framework

Consider TBI glutamate levels as related to MABP (mean arterial blood pressure), ICP (intracranial pressure), PO2 or SjvO2 (Jugular venous O2 saturation).

Methods

CT scan, treatable mass to OR, ventriculostomy catheter to monitor ICP, brain tissue PO2 monitor and SjvO2 monitor inserted ICU. Patients intubated/sedated. Head of bed elevated 30 degrees. Pts kept euvolemic, isothermic, feeding 24 hrs post admission. Fluid replacement/vasopressors PRN. ICP > 20 mm Hg treated with ventricluar drainage of CSF, mannitol and mild hyperventilation (PaCO2: 30-35 mm Hg). Barbiturate coma induced and/or decompressive craniectomy as needed. MABP, ICP, brain tissue PO2, SjvO2 recorded every hour for first 120 hours. Chi- square, Wilcoxon rank-sum, Pearson/Spearman correlation. 2 tailed p <0.05,SPSS

Intervention

Fiberoptic catheter in dominant internal jugular vein (Doppler US), verified by radiograph to measure SjvO2. Miniaturized Clark electrode positioned in cortex, non-necrotic frontotemporal region to measure brain tissue PO2. PO2 levels < 10 mm Hg due to hypotension, high ICP, hypoxemia or anemia treated.

Significant Results

“Glutamate in first 24hrs < 10 umol/L in 31 pts. (18.8%), between 10 and 20 umol/L in 58 pts (35.1%), and > 20 umol/L in 76 pts (46.1%). Trend of higher mortality … with glutamate > 20umol/L, however…p= 0.08.” No correlation between early glutamate levels and” initial GCS score or initial ICP.

Conclusions

Two patterns: Pattern 1, glutamate levels normalized. Either “levels initially low and remained low” or “level initially high but decreased over time.” Pattern 2, “glutamate levels tended in to increase over time or remain abnormally elevated.”

Significant Findings

With normalizing glutamate levels (71% of patients) the mortality rate was 17.1%; “41.2% of survivors ultimately achieved a good functional outcome.” With “levels that increase over time or remained abnormally elevated (29% of patients), the mortality rate was 39.6%; 20.7% of survivors had a good functional outcome.”

Limitations

High glutamate levels due to amino acid metabolism necessary for healing. Amino acids may be supplemented to aid in healing irrespective of glutamate levels.

Implications

Glutamate levels can be used as an outcome prognostic value.

Study Title (8)

Dietary Therapy Mitigates Persistent Wake Deficits Caused by Mild TBI

Journal and Date

Science Translational Medicine, December 11, 2013

Brief Summary

Sleep disorders are reported in up to “72% of patients with TBI up to 3 years after injury.” Animal models can “rigorously describe sleep-wake patterns in the chronic setting.” The orexin system may sustain wakefulness. Dietary branched chained amino acids may “alleviate injury-induced deficits in wakefulness.”

Purpose

Amino acids therapies contribute to TBI neurobehavioral consequences.

Sample Population

5 to 7 week old, 20 – 25g, male C57BL/J6 mice from Jackson Labs

Setting

Insulated/soundproof room, 23C, humidity 25%, 12 hr light/dark, 100 lux, free access to food and water. NIH guide, Univ. of Penn. Animal Care Guidelines

Research Design

Randomly, selected, prospective, controlled study, blinded, experimental

Theory/Framework

Consider BCAA as affecting orexin sleep-wake system in TBI

Methods

Two groups of mice: TBI (surgery and fluid percussion (FPI)) and sham (surgery only). FPI mice were anesthetized, 20-ms pulse of saline delivered onto the dura. Pressure 1.4 and 2.1 atm. AccuScan infrared monitoring for 30 days to count beam breaks in 10-s segments to estimate sleep/wakefulness. EEG/EMG signals digitized with Grass Gamma. Subset of mice “(n=7 sham, n=6 TBI, n=6 TBI+BCAA)” “received either BCAA-supplemented water (100mMM) or untreated tap water (control), 3-5ml/day. Baseline recorded day 1, 2, and 5.

Intervention

After Sham or TBI, EEG/EMG recorded Wake, NREM and REM sleep cycles. Polygraphs for 2 hours on day 3 and 3 hours on day 4. Anti-orexin-antibodies coated lateral hypothalamus, visualized with fluorescence to identify orexin neurons. Student’s t-test, one-way ANOVA, Dunnetts post hoc test, p < 0.05.

Significant Results

“Time spent continuously active, was significantly shorter in TBI mice.” Decreased and shortened activity bouts was evident in brain-injured mice. “The total number of transitions between active/inactive bouts was significantly increased after TBI”. “TBI mice spent significantly less time in both the light and dark phases, and more time in NREM sleep.” TBI mice treated with BCAAs showed a partial reversal of changes in wake and NREM states. “Total number of wake-to-sleep transitions was significantly increased in TBI mice compared to sham mice, and BCAA intervention after TBI decreased number of transitions back to sham control levels.” “Wake spectra for TBI mice were significantly lower at the theta frequency range (8-9hz), compared to sham control mice.” “Theta power was restored by BCAA therapy for spectra in the NREM state.” “TBI mice had a shorter latency to sleep compared to sham mice, and this shorter latency was partially restored by BCAA intervention.” “Compared to the sham and TBI + BCAA groups, TBI mice had significantly fewer activated orexin neurons.”

Conclusions

BCAA therapy restores many aspects of wakefulness, including EEG and orexin.

Significant Findings

“Total orexin neuron numbers were not significantly different between groups, indicating that injury primarily affects physiology rather than gross cell loss.”

Limitations

Not a therapeutic human experiment, yet.

Implications

Amino acid therapies highly effective in mice. BCAA therapy patent applied for.

Study Title (9)

Vasopressin for cerebral perfusion pressure management in patients with severe TBI: Preliminary results of a randomized controlled trial

Journal and Date

Journal of Trauma and Acute Care Surgery

Brief Summary

“AfterTBI, catecholamines (CAs) may be needed to maintain adequate cerebral perfusion pressure (CPP), but there are no recommended alternative vasopressor therapies. This is an interim report of the first study to test the hypothesis that arginine vasopressin (AVP) is a safe and effective alternative to CAs for the management of CPP in patients with severe TBI.

Purpose

To contribute to the knowledge base on amino acid vasopressor TBI therapies.

Sample Population

“Since 2008, all TBI patients requiring ICP monitoring at this Level 1 trauma center have been eligible for a randomized trial to receive either CA or AVP if vasopressors were required to maintain CPP greater than 60 mm Hg.” Minors, pregnant women and incarcerated individuals were excluded.

Setting

University of Miami/Jackson Memorial Hospital, Ryder Trauma Center

Research Design

“Single-institution, prospective, open-label, randomized, controlled clinical trial.”

Theory/Framework

Considering use of arginine as an alternative vasopressor therapy

Methods

TBI patients randomized to CA (control) or AVP for CPP management but only receive vasopressors if medically indicated. Stabilized in resuscitation. Transferred to neurosurgery or Trauma ICU if polytrauma. Switching vasopressors allowed. Deaths IRB reviewed. GCS, SBP, DBP, MAP, HR, CPP, ICP, fluids and meds data.

Intervention

“Treatment protocols: if CPP > 60mmg Hg no vasopressors required. If CPP < 60 mm Hg, ICP was < 20 mm Hg, and systolic BP < 90 mm Hg, then resuscitation was performed with fluid/blood products.” If pt. resuscitated “with CPP < 60 mm Hg and/or ICP < 20 mm Hg, then vasopressors were initiated to raise CPP < 60 mm Hg and systolic BP > 90 mm Hg.” AVP dosage was 1.2 U/h, increased 4 U/h.

Significant Results

To date, 96 patients have been randomized. Demographics, vital signs, and lab values were similar. As treated, 60 required no vasopressors, were least severe, had best outcomes. 23 patients received CS (70% levophed, 22% dopamine, 9% phenylephrine) and 12 patients received AVP. The two vasopressor groups had worse Injury Severity Score (ISS) and fluid requirements on ICU Day 1 in the AVP versus the CA group (p < 0.05) before treatment.” “Adverse events were not increased with AVP versus CA. Trends favored AVP versus CA, but no differences were statistically significant.. and there was no difference in mortality rates.”

Conclusions

“Preliminary results suggest that AVP is a safe/effective alternative to CA for the management of CPP after TBI and support the continued investigation and use of AVP when vasopressors are required for CPP management in TBI patients.”

Significant Outcomes

“AVP is effective for patients in septic shock, refractory cardiac arrest, and animal hemorrhagic shock models, showing that AVP is effective in combination with fluid resuscitation.” This “study reports a novel off-label indication for AVP.”

Limitations

Multi trauma center study desirable. Not evaluating arginine as healing substrate

Implications

A human study showing efficacy of AVP as a vasopressor therapy in human TBI.

Study Title (10)

Open-Label Randomized Trial of the Safety and Efficacy of a Single Dose Conivaptan to Raise Serum Sodium in Patients with TBI

Journal and Date

Neurocritical Care, 2011

Brief Summary

This study evaluated the use of conivaptan in TBI patients who had normal sodium levels to determine efficacy and whether intervention could reduce ICP. The study found that no adverse events occurred and ICP was reduced within 4h.

Purpose

To determine whether this arginine-vasopressin receptor antagonist is safe in normonatremic patient with TBI and could reduce ICP with a single dose.

Sample Population

216 patient assessed for eligibility, 10 met inclusion criteria.

Setting

Harborview Medical Center, Level I trauma center, Seattle, Washington. “Study approved by Human Subject Division Review Board of University of Washington.”

Research Design

“Open-label, randomized, controlled trial enrolling 10 subjects within 24h of severe TBI to receive single 20mg dose of conivaptan (n=5) or usual care (n=5).”

Theory/Framework

An arginine-vasopressin receptor antagonist could reduce ICP in TBI.

Methods

Admission criteria included age GE 18, ICU admission, severe TBI as defined by GCS of LE 8, ICP monitoring required, supplemental sodium needed to “raise to 10 mEq/l higher than admission to reduce cerebral edema and/or ICP.” A number of exclusion criteria existed including polytrauma. “Patients randomized to receive conivaptan in addition to usual care (n=5) or usual care alone (n=5). End point if serum sodium above target goal range or any drug-related adverse events. Seconday end points, mean serum Na, Na load in first 48 hr, mean ICP values, change in ICP, CPP. Urine volume measured in 4 h intervals during first 48h.

Intervention

Open-label administration. Conivaptan single dose of 20mg, mixed with 100ml of 5% dextrose in water, and infused over 30 min. Sodium assessment q. 4h.

Significant Results

Statistical methods included Student’s t-test, chi-square, linear mixed effects models to compare ICP with serum sodium, 2 sided, sig of 0.05. STATA vers 11. While further studies are required, conivaptan appears to be safe and effective at lowering ICP. Previous ICP therapies including “mannitol and hypertonic saline solutions elevate the osmolarity with in the cerebral vasculature and increase fluid movement across the BBB and into the capillary system.”

Conclusions

“Data suggest that a single dose of conivaptan is safe in non-hyponatremic patients with severe TBI for .. the purpose of ICP control. Conivaptan caused an increase in serum sodium within 4 h of administration with a concomitant significant reduction in ICP without adverse effects.” “Achieves ICP control.”

Significant Findings

“The observation that conivaptan has significant effects on ICP associated with a steep change in sodium level is important.” This fall in ICP is within 3-5 h.

Limitations

Avoid Conivaptan “in the presence of hypovolemia” since associated with diuresis.

Implications

An arginine product is effective at controlling human ICP with a single dose.

References – Primary Articles:

1. Elkind JA, Lim MM, Johnson BN, Palmer CP, Putnam BJ, Kirschen MP, Cohen AS. Efficacy, dosage, and duration of action of branched chain amino Acid therapy for traumatic brain injury. Front Neurol. 2015 Mar 30;6:73. doi: 10.3389/fneur.2015.00073. eCollection 2015. PMID: 25870584 Free PMC Article

2. Senol N, Naziroglu M, Yuruker V. N-Acetylcysteine and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats. Neurochemical Research, 2014 Apr, 39:4, pp 685-692. doi: 10.1007/ S11064-014-1255-9. PMID: 24519543

3. Degeorge ML, Marlowe D, Werner E, Soderstrom KE, Stock M, Mueller A, Bohn MC, Kozlowski DA. Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L-arginine decreases contusion size but not behavioral deficits after traumatic brain injury. Brain Res. 2011 Jul 27;1403:45-56. doi: 10.1016/j.brainres. 2011.05.058. Epub 2011 Jun 2. PMID: 21672665 Free PMC Article

4. Costa T, Constantino LC, Mendonça BP, Pereira JG, Herculano B, Tasca CI, Boeck CR. J. N-methyl-D-aspartate preconditioning improves short-term motor deficits outcome after mild traumatic brain injury in mice. Neurosci Res. 2010 May 1;88(6): 1329-37. doi: 10.1002/jnr.22300. PMID: 19998488

5. Eakin K, Baratz-Goldstein R, Pick CG, Zindel O, Balaban CD, Hoffer ME, Lockwood M, Miller J, Hoffer BJ. Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One. 2014 Apr 16;9(4):e90617. doi: 10.1371/journal.pone.0090617. eCollection 2014. PMID: 24740427 Free PMC Article

6. Nägeli M, Fasshauer M, Sommerfeld J, Fendel A, Brandi G, Stover JF. Prolonged continuous intravenous infusion of the dipeptide L-alanine- L- glutamine significantly increases plasma glutamine and alanine without elevating brain glutamate in patients with severe traumatic brain injury. Crit Care. 2014 Jul 2;18(4):R139. doi: 10.1186/ cc13962. PMID: 24992948

7. Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J Neurosurg. 2010 Sep;113(3):564-70. doi: 10.3171/2009.12.JNS09689. PMID: 20113156 Free PMC Article

8. Lim MM1, Elkind J, Xiong G, Galante R, Zhu J, Zhang L, Lian J, Rodin J, Kuzma NN, Pack AI, Cohen AS. Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. Sci Transl Med. 2013 Dec 11;5(215):215ra173. doi: 10.1126/ scitranslmed.3007092. PMID: 24337480

9. Van Haren RM, Thorson CM, Ogilvie MP, Valle EJ, Guarch GA, Jouria JA, Busko AM, Harris LT, Bullock, MR, Jagid JR, Livingstone AS, Proctor KG. J Vasopressin for cerebral perfusion pressure management in patients with severe traumatic brain injury: preliminary results of a randomized controlled trial. Trauma Acute Care Surg. 2013 Dec; 75(6):1024-30; discussion 1030. doi: 10.1097/TA.0b013e3182a99d48. PMID: 2425667

10. Galton C1, Deem S, Yanez ND, Souter M, Chesnut R, Dagal A, Treggiari M. Open- label randomized trial of the safety and efficacy of a single dose conivaptan to raise serum sodium in patients with traumatic brain injury. Neurocrit Care. 2011 Jun;14(3): 354-60. doi: 10.1007/s12028-011-9525-8. PMID: 21409494

References – Review Articles:

11. Institute of Medicine, 2011. Nutritional and Traumatic Brain Injury: Improving Outcomes in Military Personnel. A shortened version of this IOM book can be found on the website nationalacademies.org.

12. Scrimgeour, AG, Condlin ML. Nutritional Treatment for Traumatic Brain Injury. Journal of Neurotrauma 31.11, Jun 1, 2014: 989-99.

 

Disclaimer: The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice. Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist. Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material. We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.

Concussion Brain Food High School Athlete Dietary Survey

 

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CONCUSSION (mild TBI)   BRAIN  FOOD  SURVEY

ABSTRACT

Background:  The Emergency Department is an opportune place to initiate treatment of traumatic brain injury (TBI). New nutrition oriented therapies are emerging in military operations to treat traumatic brain injury however, civilian medical centers have been less progressive in evaluating and adopting these therapies.

Purpose: In the civilian environment athletes are at high risk of mild traumatic brain injury (mTBI).  This study was designed to evaluate the dietary intake of nutrients important to brain function in the diets of athletic high school students.

Methods: A dietary survey was prepared to measure intake of foods containing omega-3 fatty acids, B-complex vitamins, amino acids (protein) and vitamin C which support brain tissue and neurotransmitter production. 71 students completed the survey.

Results: Athletic high school students report a diet averaging .67 g/day of omega-3 fatty acids. Given the recommended daily allowance (RDA) of .90 g/day for a 14-18 y/o sedentary female or male, this intake of omega-3 fatty acids appears inadequate.

Athletic high school students report a diet averaging a thiamin (B1) intake of .65 mg/day whereas the RDA for a sedentary 14-18 y/o and adult female is 1.0 mg/day and the RDA for a sedentary 14-18 y/o and adult male is 1.2 mg/day.  Thiamin (B1)  intake does not appear adequate for these athletes.

Riboflavin levels of 1.0 mg/day and 1.3 mg/day for sedentary females and males, respectively have been established.  Student athletes surveyed report  a diet averaging 1.56 mg/day.  These intake levels may be adequate for high school athletes.

Niacin levels of 14.0 mg/day and 16.0 mg/day for sedentary females and males, respectively have been established.  Student athletes surveyed were receiving an average daily intake of 14.21 mg/day.  These niacin intake levels may be adequate for the athletes.

Athletic high school students report a 3.43 mg/day intake of pantothenic acid (B5).  The RDA for sedentary females and males is 5.0 mg/day.  The athletes surveyed have an inadequate intake of pantothenic acid (B5).

Pyridoxal Phosphate (B6) levels of 1.2 mg/day and 1.3 mg/day have been established for sedentary females and males, respectively.  Our athletes average intake was 1.61 mg/day.  These pyridoxal phosphate levels may be adequate.

Athletic high school student intake of folate (B9) was an average of 313.02 mg/day. Established RDAs for sedentary females and males is 400 mg/day. The folate (B9) intake of the athletes surveyed is inadequate.

Cobalamin (B12) levels of 2.4 ug/day have been established. Surveyed athletes averaged 4.73ug/day.  Surveyed athlete’s intake appears more than adequate.

Athletic high school students report a diet averaging 57.5 g/day intake of protein which meets the RDA of a sedentary 14-18 y/o and adult female (46 g/day) and sedentary male (52 g/day).  However, an RDA for protein has been established requiring 67.5 g/day for an athletic adult female and 83.5 g/day for an athletic adult male. The current protein (amino acid) intake for the athletic high school student surveyed may not be adequate.  Additionally, a diet or supplement must contain all 20 amino acids concurrently for protein synthesis to occur. Protein synthesis stops when one amino acid is missing.

Conclusions:  Omega-3 intake in the student athletes surveyed appears inadequate.  The brain would manufacture brain tissue with omega-6 fatty acids, but without the additional double bonds present in the omega-3 fatty acids, the tissue would fall apart when concussed.

Thiamin (B1), pantothenic acid (B5), and folate (B9) intake does not appear adequate to meet sedentary high school student needs.  Without adequate thiamin, oxygen transport and the synthesis of myelin would diminish.  With a diet low in thiamin and pantothenic acid, acetylcholine neurotransmitter levels would fall.  DNA repair/synthesis and red blood cell production would be impaired given low folate levels.

Riboflavin (B2), niacin (B3), pyridoxal phosphate (B6) and cobalamin (B12) levels may be adequate in athletic high school students.  However, only 50-90% of B-complex vitamins are absorbed in the gastrointestinal system, thus actual availability levels may be less (Wardlaw & Smith, 2013)

The Food and Nutrition Board has established protein RDAs for sedentary individuals and specifically for athletes. The amino acid intake levels of the athletes surveyed do meet the sedentary RDA values, however intake does not meet the athletic RDA levels.  Interestingly the sedentary RDA protein levels have been increased by 50% for athletes.  However, increased RDA omega-3 and vitamin B-complex levels have not been established for athletes. Vitamin B complex provides the cofactors to metabolize amino acids.  Are sedentary levels of B complex and omega-3s sufficient in an athlete or could amino acid metabolites be trapped in athletes due to the lack of vitamin B co-factors?

Vitamin C  intake appears adequate to promote adrenal function and thus neurotransmitter production, although athletic RDAs have not been established.

If physical stress, mental stress, or brain injury requires additional omega-3 fatty acids, B-complex vitamins, and amino acids to promote healing, sufficient nutrients would not be available in the average diet of the athletes surveyed.

This survey is a patient dietary intake survey where the patients have been asked to recall intake over a typical week’s time.  Nutrient levels have been assigned from Nutrition Data given the food, multiplied by the quantity consumed, and computed for an average daily consumption. Thus, this survey provides an estimate of average daily brain food nutrient intake.  Laboratory measured patient blood/urine nutrient levels would be of greater accuracy and important to pursue in future research efforts.

Introduction to Brain Biochemistry and Nutrition:

Dr. James Watson of Watson and Crick, the scientists who discovered the DNA double helix, tells us that to eliminate disease we must return to Biochemistry.  We expect that the many dedicated researchers referenced below would agree.  They have found that in Traumatic Brain Injury, nutrition matters.  Adequate supplies of the major tissue nutrients are critical.

In looking at a section of brain tissue, the lighter tan colored structures are called “white matter.” White matter consists of nerve fiber tracts or pathways traveling in both directions to and from the brain through the brainstem down the spinal cord and extending out to organs, arms, and legs.  A nerve can be up to four feet long. White matter nerve tissue is composed of essential fatty acids called omega-3s such as DHA (docosahexanoic acid) and EPA (eicosapentanoic acid).  Most nerve tissue contains a myelin coating.  The resistance created by this coating allows for impulse transmission at approximately 100m/sec ( 245 mph)! Nerve and myelin formation require B-complex vitamins.  The darker structures on a brain section are called  “gray matter.”  These are decision-making nuclei made from proteins composed of amino acid building blocks.  Proteins and amino acids formulate all structures, most noticeable of which are neurotransmitters made in the adrenal glands with help from vitamin C.  Neurotransmitters are critical to brain function and communication throughout the body.

Methods:

Study Design: This survey listed common foods in each of the brain food nutrient categories of omega-3 fatty acids, B complex vitamins, proteins, and vitamin C, and questioned the students as to their weekly consumption of each food type.

Study Setting and Population:  A small high school athletics program participated in this survey.  The athletic trainer performs baseline, concussive, return to play neurocognitive testing of all athletes.  The school host a variety of high school sports, with the football and soccer programs producing 15-25 concussions per year ranging from mild to more severe.

Instrument Development and Data Collection: Surveys were distributed to high school students at their annual physical and athletics team sign up fair.  The surveys took approximately 5 minutes to complete and were turned in on site.

Measures and Statistical Analysis

We asked respondents to numerically estimate the number of times each food was consumed during a typical week.  Respondents were asked several other general questions about sports, homework hours and concussion history.

A numerical nutrient level was assessed for each food.  This value was multiplied by the number of times the food was consumed during the week and divided by the a 7 day week to determine an average nutrient consumption per food per day.

Results

This Brain Food Survey has been developed to measure an average athletic high school student’s intake of omega-3 fatty acids, B-complex vitamins, amino acids and vitamin C.  It is expected that at least nutrient levels in accordance with the Recommended Daily Allowances (RDAs) are required for a healthy brain capable of healing a concussion (mild TBI) injury.

According to our survey the athletic high school student’s average daily intake of omega-3 fatty acids is  .67 g/day. Given the recommended daily allowance (RDA) of .90 g/day for a 14-18 y/o sedentary female or male, this intake is not adequate.

Athletic high school student intake of thiamin (B1) is .65 mg/day whereas the RDA for a sedentary, female, 14-18 y/o and adult is 1.0 mg/day and the RDA for a sedentary, male, 14-18 y/o and adult is 1.2 mg/day.  Thiamin intake may not be adequate.

Riboflavin levels of 1.0 mg/day and 1.3 mg/day for sedentary females and males, respectively have been established.  Our student athletes were receiving an average of 1.56 mg/day.  Riboflavin consumption appears adequate.

Niacin levels of 14.0 mg/day and 16.0 mg/day for sedentary females and males, respectively have been established.  Our student athletes were receiving an average of 14.21 mg/day.  These intake levels may be adequate.

Athletic high school student intake of pantothenic acid (B5) was an average of 3.43 mg/day.  The RDA for sedentary females and males is 5.0 mg/day.  Our athletes have an inadequate intake or pantothenic acid.

Pyridoxal Phosphate (B6) levels of 1.2 mg/day and 1.3 mg/day have been established for sedentary females and males, respectively.  Our athletes average intake was 1.61 mg/day.  These levels may be adequate.

Athletic high school student intake of folate (B9) was an average of 313.02 mg/day and established RDAs for sedentary females and males is 400mg/day. Our athletes’ intake is inadequate.

Cobalamin (B12) RDA levels of 2.4 ug/day have been established. Our athletes averaged 4.73ug/day.  Our athlete’s intake appears sufficient. However, gastrointestinal disorders may decrease secretion of intrinsic factor thereby decreasing colalbumin absorption.

The athletic high school students’ riboflavin, niacin, pyridoxial, and cobalamin appear adequate given the sedentary RDAs available.  However, vitamin B complex nutrients are said to be absorbed at a rate of only 50-90% and the prevalence of wheat lectins/gluten and other GI disturbances, the actual intake of these nutrients may be reduced.

The athletic high school student intake of an average of 57.5 g/day of protein meets the RDA of a sedentary 14-18 y/o and sedentary adult female (46 g/day) and sedentary male (52 g/day).  However, RDAs for protein have been established for an athletic adult female who requires 67.5 g/day and athletic adult male who requires 83.5 g/day. Current protein intake of the athletes surveyed may not be adequate.  All 20 amino acids must be consumed concurrently in the diet to enable protein synthesis. Missing amino acids will cause protein synthesis to stop.

Athletic high school student intake of vitamin C, ascorbic acid, was an average of 122mg/day.  Sedentary high school female student’s RDA is 65mg/day and male’s 75 mg/day.  Sedentary female adult RDA is 75mg/day and male 90mg/day.  Vitamin C intake appears more than adequate.

Athletic high school student intake of omega-3-fatty acids, thiamin, pantothenic acid, folate and amino acids are inadequate to sustain general sedentary nutrition and these low nutrients levels would appear to strain the body during increased physical stress, academic or social mental stress, and be most profoundly apparent during the body’s attempt to heal concussion.

Discussion:

The human brain is about the size of a cauliflower head with the density of medium soft cheese and can be easily sectioned with a spatula. The brain stem protrudes from the posterior-inferior surface sending commands up and down pathways and through relay centers to the pinky-sized spinal cord. The brain and spinal cord are surrounded by clear cerebral spinal fluid (CSF) and membranes which provide a shock absorber-like environment internal to the bony cranium and vertebrae.

When the cushion environment is disrupted by an “external mechanical force such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile” (Maas AI, et al., 2008), a traumatic brain injury (TBI) results.  A mild TBI is referred to as a concussion.

TBIs are the leading cause of death/disability worldwide  (Alves OL, et al., 2001) and the number one cause of coma (Farag E, et al., 2011).   One third of TBI fatalities are firearm accidents (75% suicide) and another third are motor vehicle accidents (Leon-Carrion J, et.al., 2005). A total of 1.5 million people experience head trauma each year in the U.S. resulting in an annual cost exceeding $5.6 billion.  While most head injuries are mild (Cassidy JD, et al., 2004), the death rate to TBI is estimated at 21% by 30 days post injury (Greenwood, et al, 2003). The greatest number of TBIs occur in the male 15-24 age group (Hardman JM, et al., 2002) (Mass AI, et al., 2008). Sport and recreational activities in the U.S. alone may cause between 1.6 – 3.8 million TBIs each year (CDCP, 2007).  In addition, the military has seen a significant increase in TBIs. Approximately, 10-20% of veterans returning from the Middle East have experienced a TBI. The Department of Defense is conducting research to reduce the serious problems associated with these injuries and has requested a report from the Institute of Medicine (2011).

Clinically, a mild TBI or concussion is defined as post-traumatic amnesia of less than one day and a loss of consciousness between 0 -30 minutes (DOD TBI Task Force).  Symptoms include “headache, vomiting, nausea, lack of motor coordination, dizziness, and difficulty balancing” (Kushner D, 1998) along with “lightheadedness, blurred vision or tired eyes, ringing in the ear, bad taste in the mouth, fatigue or lethargy, and changes in sleep patterns.  Cognitive and emotional symptoms include behavioral or mood changes, confusion, and trouble with memory, concentration, attention, or thinking” (NINDS, 2008). Social behavior or emotional problems may also occur. Damage to the left side of the brain may involve speech, reading and writing difficulties.  Damage to the back of the brain may involve vision, balance, and coordination problems.

Current diagnostic techniques include neurological exam and neuro-imaging studies such as CT (CAT scan) or MRI (Magnetic Resonance Imaging).  CT scans are quickly completed in an emergency department. They are less expensive and better at showing bleeds than MRI  however, brain CT delivers a 1-2 millisievert dose of radiation.   MRI, which utilizes a magnetic field,  (no radiation exposure), delivers more detail of the brain and brain stem, but it is more time consuming and costly.  A CT of a more serious TBI may show hemorrhage, skull fracture, contusions (bruising), fracture, and/or edema (swelling).  An MRI of a more serious TBI, might show a shifting of brain structures, contusion, and hematoma. When blood exerts pressure upon the brain surface it can impair brain function. Interestingly, when brain tissue is seriously injured,  it appears to be cracked open on MRI, much like the appearance of a sponge that is torn open every 1-2 inches. The tears create fluid inlets, perhaps designed to bring nutrient rich CSF to the damaged areas.

A mild TBI or concussion will often show little damage on CT or MRI neuro-imaging studies, thus the increasing use of imPACT or CNS Vital Signs neurocognitive testing.  These computerized tests  have been more effective at assessing mild concussive damage by evaluating general mental functioning. To date, many athletic programs have been using them to compare pre and post injury results to determine ‘return to play’. Since they measure brain function in terms of verbal and visual memory, processing speed, reaction time, attention span, and non-verbal problem solving capabilities, neurocognitive testing has been successfully utilized to identify emotional and cognitive deficits related to mild TBIs.

When the brain is damaged, it immediately begins self repair. Raw materials are sought from nutrients in the blood supply and from CSF to rebuild the initial injury site.  When nutrient supply is insufficient, surrounding brain tissue may be broken down to supply substrate for reconstruction.

Damage apparent in adjacent tissue, has been defined as Second Injury and may result in more serious injury than the initial TBI (Park E, et al., 2008). When death results weeks later, it is typically caused by secondary damage (Ghajar J, 2000). In the past, this Second Injury has been commonplace and no therapy has been available to stop progression (Park E, et al., 2008). However, recent military studies found that by immediately supplying sufficient amounts of protein to the injured patient, Secondary Injury is significantly reduced (Institute of Medicine, 2011).  Providing omega-3 essential fatty acids (DHA/EPA) before injury or immediately after injury also reduces TBI damage (Mills JD, et al., 2011) (Wu A, et al., 2007).

Brain injury brings immune cells and fluids to the injury site, resulting in inflammation, but with the brain enclosed in the cranium there is minimal space to accommodate swelling.  The resultant increase in intracranial pressure may occlude blood vessels responsible for bringing oxygen and nutrients to brain cells and lymph vessels responsible for removing waste products (Scalea TM, 2005). Increased pressure can force the brain to herniate into spaces where it does not belong.  This renders the tissue non-functional and eventually will cause death.  A variety of anti-inflammatory medications are often utilized to diminish swelling.

Mild TBIs physically appear to resolve in 3 weeks and patients tend to return to normal activities.  Some patients have “physical, cognitive, emotional and behavioral problems such as headaches, dizziness, difficulty concentrating, and depression” (Parik S et al., 2007). Movement disorders, seizures, and substance abuse may also develop (Arlinghaus KA, et al., 2005). Depending upon the severity of the injury, the number of repeat injuries and the presence of adequate nutrients before and after the injury, the prognosis ranges from complete recovery to permanent disability, neurological disease or death. “Permanent disability is thought to occur in 10% of mild TBIs, 66% of moderate injuries, and 100% of severe injuries” (Frey LC, 2003). In many situations, particularly athletics, a second concussion may occur before the first concussion has healed.  This is of particular concern as multiple TBIs may have a cumulative effect (Kwasnica C, et al., 2008).

The Composition of Brain Tissue:

Dr. James Watson, of Watson and Crick the scientists who discovered the DNA double helix, tells us that to eliminate disease we must return to biochemistry.

In examining a section of brain tissue, the lighter tan colored structures are called “white matter.” White matter consists of nerve fiber tracts or pathways traveling in both directions to and from the brain through the brainstem down the spinal cord and extending out to organs, arms, and legs.  A nerve can be up to four feet long. White matter nerve tissue is composed of essential fatty acids called omega-3s such as DHA (docosahexanoic acid) and EPA (eicosapentanoic acid).  Most nerve tissue contains a myelin coating.  The resistance created by this coating allows for impulse transmission at approximately 100m/sec ( 245 mph)! Nerve and myelin formation require B-complex vitamins.  The darker brown structures on a brain section are called  “gray matter.”  These are decision-making nuclei made from proteins composed of amino acid building blocksAmino acids require B-complex vitamins to metabolizeProteins and amino acids formulate all structures, most noticeable of which are neurotransmitters.  Neurotransmitters are critical to brain function and communication throughout the body.  These neurotransmitters are produced in the adrenal glands which depend heavily on vitamin C and the amino acid methionine.

Essential Fatty Acids (DHA and EPA):

40% of brain tissue is essential fatty acids (DHA and EPA).   While EPA provides important anti-inflammatory actions (Sears B, 2011) and is included in supplements, 97% of the brain’s essential fatty acids are the 22 carbon chain,  Docosahexanoic Acid.  DHA is found in foods such as walnuts, microalgae, microplants, cod, salmon, mackerel, sardines, hake, caviar, herring, oysters, organ meats (liver), grass fed and finished beef, and fish oil or algae supplementsFish receive DHA from ocean phytoplankton (microalgae or microplants).  Cattle produce ? make? DHA from grass.  However, as we increasingly draw our food from farm-raised fish and grain-raised cattle lacking grass to produce DHA, our dietary intake of DHA is being depleted, (Abel R, 2002).

Most humans consume an overabundance of vegetable oil and butters which contain no double bonds in the carbon chain.  DHA has six double bonds (22:6), one at every third carbon (omega-3 or n-3). In cell membrane, these double bonds allow the fatty acid to neutralize damaging free radicals.  In addition, DHA increases the fluidity properties of cell membrane which helps to protect the cell from trauma and cell death (apoptosis) (Eckert GP, et al., 2011). Proper cell communication and signaling is critical for brain function. Fifty percent of nerve cell plasma membrane is DHA (Collins C, et al., 2002) which is important in cell communication, neuronal survival, and growth.  DHA is found in three cell membrane phospholipids:  phosphytidylethnolamine, ethnolamine plasmalogens, and phosphatidylserine. Upon injury, these phospholipid pools are important reservoirs to reconstruct cell membrane (Chang CY, et al., 2009).  In the absence of dietary DHA, the brain will improvise and construct brain tissue from vegetable oil. However, under traumatic conditions  vegetable oil fed rat brain falls apart, (Eckert  GP, et al., 2011) (Abel R, 2002).

Researchers found that in rats that were subject to TBI and then received 40mg/kg/day pharmaceutical grade fish oil rich in DHA and EPA for 30 days post TBI had more healthy nerve cells.  Essential fatty  acids  were shown  to be neuroprotective by reducing  the  number of  injured nerve axons, decreasing the level of inflammation,  and reducing oxidative stress and cell death (Mills JD et al., 2011). DHA fed to rats immediately post TBI was found to counteract cognitive decay, maintain membrane signaling function, and support the potential of DHA supplementation to reduce the effects of TBI. (Wu A, et.al 2011).  In addition, essential fatty acids DHA and EPA given to rats 4 weeks prior to TBI was found to help maintain brain homeostasis and reduce oxidative damage due to TBI (Wu A, et al., 2007).

DHA and EPA have been found to improve the outcome of stroke studies of both rat and human models (Kong W, et.al) (Hagiwara H, et.al.), but few human studies have been conducted using DHA as prophylaxis for TBI.  In 2006, high doses of DHA and hyperbaric oxygen treatment were used by Dr. Julian Bailes to treat the sole survivor of the West Virginia mining disaster who suffered carbon monoxide poisoning. This patient now claims that his brain function is near normal.  Dr. Bailes and his colleagues have since published many research papers demonstrating the benefits of essential fatty acids and fish oil supplements.  In addition, “individual case reports using fish oil doses of 2-4 grams per day have been described, however sufficient human research is unavailable to recommend dosages”  (Maroon, JC and Bost J, 2011)

One new human case study was published in October 2012, when Peter Ghassemi convinced physicians to give his son Bobby, who was in a coma following a motor vehicle accident, omega-3 fish oil ( a similar dose to Randal McCloy).  Bobby  had a Glasgow Coma Score of 3 (scale 3 – 15), which Dr. Michael Lewis says that “a brick or piece of wood has a Glasgow Coma Score of 3. It’s dead.”  Peter Ghassemi, Bobby’s father, indicates that it was difficult to convince physicians to give their son fish oil.  They wanted to see 1000 case studies first, to prove its efficacy.  Eventually, physicians agreed.  Thanks to his father’s perseverance, Bobby has recovered today.  U.S. Army Colonel Lewis who recommended the therapy to Peter Ghassemi describes the therapy like this.  ”If you have a brick wall and it gets damaged, wouldn’t you want to use bricks to repair the wall?  And omega-3 fatty acids are literally the bricks of the cell wall of the brain.”  (CNN,2012).

Eicosapentanoic Acid (EPA 20:5n-3?) is another essential fatty acid.  EPA is important in the synthesis of PGE (explain) and controls the thromboxine and leukotrine levels.  EPA is important in the metabolism of DHA.  Essential fatty acids (EFA) are among the most crucial molecules that determine the brain’s integrity and ability to perform. EFA are involved in the synthesis and functions of brain neurotransmitters.  Neuronal membranes contain phospholipid pools that are the reservoirs for the synthesis of specific lipid messengers on neuronal stimulation or injury.   (PMID 20329590). DHA and EPA maybe obtained through diet or supplements.

The textbook “Contemporary Nutrition” written by  Gordon M. Wardlaw and Anne M. Smith in 2013 tells us that EPA and DHA are only slowly synthesized in the brain from alpha linoleic acid but can be found in “fatty fish such as salmon, tuna, sardines, anchovies, striped bass, catfish, herring, mackerel, trout or halibut “(listed highest to lowest omega-3 content) and in foods such as “canola and soybean oils, walnuts, flax seeds, mussels, crab and shrimp”.  The authors warn about high mercury levels in swordfish, shark, king mackerel, and albacore, and indicate that fish with low mercury levels include salmon, sardines, bluefish, herring and shrimp.  Eating fish twice each week is recommended.  Omega-3 fatty acids tend to act to reduce blood clotting and inflammation, while omega-6 foods tend to increase clotting and inflammation.  Vitamin K and calcium carbonate are also involved in the clotting process. “Fish oil capsules should be limited for individuals who have bleeding disorders, take anticoagulant medications, or anticipate surgery, because they may increase risk of uncontrollable bleeding and hemorrhagic stroke”.

Wardlaw and Smith recommend 1.6 grams per day of omega-3 fatty acids for men and 1.1 grams per day for women.  Elevated blood triglycerides are treated with 2 to 4 grams per day.  Omega 3 fatty acids have been found to reduce the inflammation of rheumatoid arthritis and help with behavioral disorders and cases of mild depression.  Freezing fish oil capsules helps to reduces the fishy after taste.  ”2 tablespoons of flax seed per day is typically recommended as an omega-3 fatty acid source”.  Approximately 3 walnuts (6 halves) yields approximately 1 gram of DHA.  Care should be taken to keep DHA sources refrigerated as they turn rancid easily.  For TBI patients on IV feeding it is important to investigate the quantity of DHA and EPA present in total parenteral nutrition.  One researcher takes approximately 1 gram of DHA/EPA through fish oil daily and on a daily basis regulates intake by the dryness/moistness of the skin.  In drier climates, she finds this daily intake amount must be doubled to maintain skin moisture. Mercury consumption in fish oil is a serious risk and mercury free alternatives should be explored.  Many manufacturers are now producing fish oil products which are molecularly distilled.

B Complex Vitamins:

B complex vitamins are important for nerve, DNA and neurotransmitter synthesis,  and for cell energy production and metabolism.  The majority of the information cited below regarding the effects of B complex vitamins on brain function has been obtained from animal studies. Vitamin B is a vitamin complex  of B-1-thiamine, B-2 riboflavin, B-3 niacin, B-5 pantothenic acid, B-6 pyridoxine, B-9 folate, B12-cobalamin.

Thiamine (B1) is required for oxygen to be transported in red blood cells (Combs GF Jr, et al., 2008), production of the neurotransmitter acetylcholine (Butterworth RF, et al., 2006), and synthesis of the myelin coating surrounding nerve cells (Butterworth RF, et al., 2006). High school female RDA  of thiamine is 1.0 mg/day and male 1.2 mg/day. Adult thiamine RDA is 1.1 – 1.2 mg/day, Daily Value 1.5 mg/day, and no upper limit has been set. Thiamin is water soluble and rapidly lost in urine. Alcohol consumption reduces thiamin levels (Wardlaw, et.al., 2013).

Riboflavin (B2) is a component in all flavoproteins and  red blood cells (erythrocytes) and has been know to reduce TBI lesions, edema, and improve TBI outcome (Hoane MR, et al., 2005). High school female riboflavin RDA 1.0 mg/day, male 1.3 mg/day.  Adult riboflavin RDA is 1.1 – 1.3 mg/day, Daily Value 1.7 mg/day, no upper limit set.  Alcohol consumption reduces riboflavin levels (Wardlaw, et.al., 2013)

Niacin (B3) is involved in DNA repair, cholesterol, and energy production. It helps produce neurotransmitters in the adrenal gland.  Niacin reduces TBI lesion size and improves sensory, motor, cognitive, and behavioral recovery (Voner Haar C, 2011).  High school female niacin RDA 14 mg/day, male 16 mg/day.  Adult niacin RDA is 14 – 16 mg/day, Daily Value is 20 mg/day, upper limit is 35mg/day of nicotinic acid form. Alcohol consumption reduces niacin levels (Wardlaw, et.al., 2013)

Pantothenic Acid (B5) is  involved with neurotransmitter acetylcholine production involved in signal transduction and enzyme control.  High school female and male 5 mg/day.  Adult Adequate Intake is 5 mg/day, Daily Value is 10 mg, no upper limit set (Wardlaw, et. al, 2013).

Pyridoxal Phosphate (B6) controls all amino acid metabolism  (Sahley BJ, 2002), red blood  cell and  antibody formation (Sahley BJ, 2002). This vitamin is also involved with dopamine and GABA neurotransmitter production, and with the production of phospholipids for the myelin sheath.  High school RDA pyridoxal phosphate female 1.2 mg/day, male 1.3 mg/day.  Adult RDA is 1.3 – 1.7 mg/day, Daily Value is 2 mg, Upper Level is 100 mg/day based upon nerve damage.  Studies have shown that 2 – 6 grams/day of B-6 for 2 or more months can lead to irreversible nerve damage.  Symptoms of toxicity include walking difficulties and hand and foot numbness (Wardlaw, et. al, 2013).

Folate  (B9) is required to synthesize, repair, and methylate DNA, provides neuroprotection in TBI (Naim MY, et al., 2010), is important in rapid cell division and growth and the production of healthy red blood cells which prevents anemia. Folate forms cell membrane phospholipids and receptors (Karakula H, et al.,2009) (Surtees R, 1998), prevents nerve damage and neural tube defects during development and is required for myelin regeneration (van Rensburg SJ, et al., 2006) (Guettat L, et al., 1997). High school RDA female and male 400 mcg/day.Adult RDA and Daily Value is 400 mcg/day,  pregnant women 600mcg/day  (important to prevent neural tube defects), Upper Level is 1 mg/day.  Alcoholism and poor absorption reduces folate levels (Wardlaw, et.al., 2013).  This alcoholism – folate – neural tube defects is critically important to women expecting to conceive.

Cobalamin (B12) is involved in blood formation, critical to DNA synthesis through folate regeneration, and important for the formation of cell membrane phospholipids and receptors (Karakula H, et al., 2009) (Surtees R, 1998). Cobalamin supplementation partially resolved cognitive deficits and myelin imaging abnormalities (Chatterjee A, et.al., 1996) (Jongen JC, et al., 2001) and improved cerebral and cognitive functions  (Bourre JM, 2006). This vitamin is required for myelin synthesis (Hall CA, 1990) (van Rensburg SJ, et al, 2006) (Guettat L, et al., 1997) and promotes nerve regeneration (Okada K, et al., 2010). High school RDA colbalamin female and male 2.4 mcg/day.  RDA is 2.4 mcg/day, Daily Value is 6 mcg/day, no Upper Limit set, stored in liver, 50% of dietary intake may be absorbed.  Nerve damage and anemia may result from insufficient intake.

There are 150mg time release (9-10 hours) capsules available for B complex.  All  B vitamins are water soluble and need to be replenished daily.  Vitamin B complex has an important  role  in  alleviating anxiety and lactic acid buildup.  Dietary supply may be inadequate under stress (Sahley BJ, 2002).

Vitamin B is a complex  of B-1-thiamine, B-2 riboflavin, B-3 niacin (niacinamide), B-6 pyridoxine, B12-cyanocobalamin, pantothenic acid, biotin, PABA, folic acid, choline and inositol.  All B vitamins are water soluble and they are not stored.  They must be supplied in sufficient amounts at all times.  This supply may be inadequate under stress. (Sahley p 94).

Vitamin B provides cofactors for reactions within the body particularly amino acid reactions.  B vitamin cofactors initiate the transfer of electrons, plus methyl, carbon, amino, carboxyl, acetyl, acyl,  and formyl groups.

The RDAs are Recommended Daily Allowances taken from the Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine, National Academics. The vitamin B complex nutrients surveyed above are absorbed at a rate of 50-90% (Wardlaw & Smith, 2013).  Due to the prevalence of gastrointestinal disorders present in the population, even the nutrients that appear to be consumed at adequate levels may not be sufficient.

Protein (Amino Acids):

Linear chains of amino acids form proteins. Proteins produce nuclei in the brain, DNA,  cell membrane, enzymes, and neurotransmitters. Twenty amino acids are commonly identified.  All must be present for protein synthesis.

Alanine is the precursor of neurotransmitter dopamine (Coxon KM, et al., 2005).

Arginine, through agmantine, is neuroprotective in trauma and ischemia models by significantly reducing  brain swelling volume and blood-brain barrier protection (Kim JH, et al., 2009).

Cysteine forms DNA double helix disulfide bonds.

Glutamate is important for calcium ion binding; may reduce blood glucose levels in the injured spinal cord reducing neurological impairment (Zhang TL, et al., 2010).

Glutathione is critical to relieve oxidative stress in cells.

Glycine is important in red blood cell formation (Shemin D, et al., 1946); gives amino acid structures flexibility.

Histidine is used throughout the brain, this amino acid improves TBI outcome (Faden AI, et al., 1993) (Krusong K, et al., 2011).

Lysine is important for connective tissue maintenance, and affects protein binding to phospholipid membranes (Blenis J, et al., 1993).

Methionine is the sole methyl donor in the central nervous system.  Methionine forms Glutathione, an important amino acid in reducing free radical-mediated traumatic injury (Gidday JM, et al., 1999).  Methionine increases S-adenylmethionine (SAMe) in CSF aiding in neurological disorder treatment (Chishty M, et al., 2002).

Phenylalanine produces chlorophenylalanine (CPA) which slowed the breakdown of the blood-brain barrier permeability, brain edema and blood flow and reduced the number of damaged and distorted nerve cells (Sharma HS, et al., 2000).

Proline maintains connective tissue (Bhattacharjee A, et al., 2005)

Serine acts as a neurotransmitter in the brain (Wolosker H, et al., 2008).

Taurine is a major component of brain tissue and muscle (Brosnan JT, 2006).

Threonine is a component of the serine/threonine kinase and is neuroprotective following traumatic brain injury (Erlich S, et al.,2007).

Tryptophan is a precursor to neurotransmitter serotonin (Savelieva KV, et al., 2008); a modulator of serotonin which alters plasticity-related signaling pathways and matrix degradation (Penedo LA, et al., 2009).

Tyrosine is a precursor of the neurotransmitter dopamine, norepinephrine, epinephrine.

Amino Acids essential amino acids are arginine, histidine, isoleucine, leucine, lysine, methionine, phyenylalanine, threonine, tryptophan, and valine.  These play a vital role in the brain’s function (Sahley p23).  Under prolonged stress or illness the body is unable to produce sufficient required non-essential amino acids  (Sahley p 22).   Amino acids are monomers polymerizing to produce proteins.  A multistep process requiring proteins as substrate and translation/transcription factors results in production of DNA and RNA.  Proteins also form neurotransmitters, enzymes and are components of cell membranes participating in cell signaling.

Trauma damages DNA and RNA, and depletes neurotransmitters.  Neurological dysfunction caused by traumatic brain injury results in profound changes in net synaptic efficacy, leading to impaired cognition.  The limbic hippocampus, a brain structure implicated in higher learning and memory, is often damaged in TBI.  Significant reductions are seen in the concentration of branched chain amino acids (BCAAs).  BCAAs  (leucine, isoleucine, alanine) are key amino acids involved in de novo glutamate synthesis.  Dietary consumption of BCAAs restored hippocampal BCAA concentrations to normal, reversed injury-induced shifts in net synaptic efficacy, and left to reinstatement of cognitive performance after concussive brain injury.   (Cole paper, Univ of Penn Dietary AA ameliorate cognitive impairment).

Under prolonged stress or illness the body is unable to produce sufficient non-essential amino acids (Sahley BJ, 2002).  Trauma has been found to damage DNA and RNA, and to deplete neurotransmitters.  Neurological dysfunction is caused by traumatic brain injury (Cole J, et al., 2010).

As amino acids are utilized for energy and substrate, they are oxidized to urea and carbon dioxide producing high levels of glutamate.  These high levels seen in the TBI patient can include oxidation of branched chained amino acids. Dietary consumption of Branched Chain Amino Acids (BCAAs) restored BCAA concentrations to normal, improved nerve cell communication, and reinstated cognitive performance after concussive brain injury (Cole J, et al., 2010). BCAAs and amino acid complex (protein) are available at nutrition stores.

The objective of this discussion has been to bring current research advancements to light given the realization that concussive TBIs cause damage and disease, such that this information may be further evaluated by the public, health care providers, and the medical research community.

A variety of single drugs have failed clinical trials to treat TBI, suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. (PMID 20824218) Recent preclinical studies suggest that neurorestorative strategies that promote neurogenesis, and synaptogenesis provide promising opportunities for treatment of TBI. (PMID 21155204).

The IOM committee’s report, Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.  April 20, 2011.  Given the complexity of TBI and the current gaps in scientific knowledge, the committee could identify only one promising solution that can immediately improve treatment efforts: early feeding. Feeding protocols should be standardized to ensure the delivery of adequate levels of energy and protein to patients with severe TBI, and hospital intensive care units should include these protocols in their critical care guidelines. Specifically, the protocols should require providing, within the first 24 hours, a level of nutrition that represents more than 50 percent of the injured person’s total energy expenditure and provides 1 to 1.5 grams of protein per kilogram of body weight. This nutrition level should be continued for two weeks. Such nutritional intervention is likely to limit the person’s inflammatory response, which typically is at its peak during the first two weeks after an injury, and thereby improve the ultimate health outcome. Research has shown that feeding the severely injured soon after an injury is known to help in reducing mortality. (IOM report)

Based on findings about the physiological actions of nutrients and their effectiveness and safety from studies on animals and humans, the following nutritional interventions were identified as holding the most promise for improving TBI outcomes: the provision of or treatment with choline, creatine, n-3 fatty acids, and zinc. DOD should prioritize research on these interventions. (IOM report).

Conclusion:

Athletic high school student intake of omega-3-fatty acids, thiamin, pantothenic acid, folate and amino acids are inadequate to sustain general sedentary nutrition and these low nutrients levels would appear to strain the body during increased physical stress, academic or social mental stress, and be most profoundly apparent during the body’s attempt to heal concussion.

Research to determine RDAs under physical stress, mental stress, athletics or injury would be important for neurological health now and in the future.  In addition, given our highly processed food, modified crops and farm raised fish and stockyard raised cattle, the average diet may not be providing nutrient levels anticipated.  There may also be interference in the diet caused by enhanced lectins and gluten found in grains attacking our immune systems.  The impact of these food modifications will be important to continue to assess.

To date our typical brain injury therapy has been anti-inflammatories.  Awareness of the basic nutrients required for a healthy brain are not generally well known to the medical, dietary, or public. Education as to the roles of these nutrients is critical to bring about a healthier populace. The brain injury brought on by concussion, disease, mental and physical stress may well be eliminated or repaired should adequate nutrients be provided to enable the amazing brain to make the necessary repairs.

Traumatic Brain Injury References:

Alves OL, Bullock R (2001). “Excitotoxic damage in traumatic brain injury”. In Clark RSB, Kochanek P. Brain injury. Boston: Kluwer Academic Publishers. p. 1. ISBN 0-7923-7532-7. Retrieved 2008-11-28.

Arlinghaus KA, Shoaib AM, Price TRP (2005). “Neuropsychiatric assessment”. In Silver JM, McAllister TW, Yudofsky SC. Textbook Of Traumatic Brain Injury. Washington, DC: American Psychiatric Association. pp. 63–65. ISBN 1-58562-105-6.

Center for Disease Control and Prevention, National Center for Injury Prevention and Control. “Traumatic brain injury” (http://www.cdc.gov/ncipc/factsheets/tbi.htm) 2007.

Cassidy JD, Carroll LJ, Peloso PM, Borg J, von Holst H, Holm L et al. (2004). “Incidence, risk factors and prevention of mild traumatic brain injury: Results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury”. Journal of Rehabilitation Medicine 36 (Supplement 43): 28–60. DOI:10.1080/16501960410023732. PMID 15083870.

Carlson K, Kehle S, Meis L, Greer N, MacDonald R, Rutks I, Wilt TJ, “The Assessment and Treatment of Individuals with History of Traumatic Brain Injury and Post-Traumatic Stress Disorder: A Systematic Review of the Evidence [Internet].” Washington (DC), Department of Veterans Affairs (US); 2009 Aug, VA Evidence-based Synthesis Program Reports

Department of Defense and Department of Veterans Affairs (2008). “Traumatic Brain Injury Task Force”. http://www.cdc.gov/nchs/data/icd9/Sep08TBI.pdf.

Farag E, Manno EM, Kurz A. (2011) “Use of hypothermia for traumatic brain injury: point of view” Minerva Anesthesiol. 2011 Mar;77(3):366-70. Epub 2011 Feb 1. PMID: 21283076

Frey LC (2003). “Epidemiology of posttraumatic epilepsy: A critical review”. Epilepsia 44 (Supplement 10): 11–17. DOI:10.1046/j.1528-1157.44.s10.4.x. PMID 14511389.

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Ghajar J (September 2000). “Traumatic brain injury”. Lancet 356 (9233): 923–29. DOI:10.1016/S0140-6736(00)02689-1. PMID 11036909.

Greenwald BD, Burnett DM, Miller MA (March 2003). “Congenital and acquired brain injury. 1. Brain injury: epidemiology and pathophysiology”. Archives of Physical Medicine and Rehabilitation 84 (3 Suppl 1): S3–7. DOI:10.1053/apmr.2003.50052. PMID 12708551.

Hardman JM, Manoukian A (2002). “Pathology of head trauma”. Neuroimaging Clinics of North America 12 (2): 175–87, vii. DOI:10.1016/S1052-5149(02)00009-6. PMID 12391630. “TBI is highest in young adults aged 15 to 24 years and higher in men than women in all age groups.”

Kushner D (1998). “Mild traumatic brain injury: Toward understanding manifestations and treatment”. Archives of Internal Medicine 158 (15): 1617–24. DOI:10.1001/archinte.158.15.1617. PMID 9701095.

Kwasnica C, Brown AW, Elovic EP, Kothari S, Flanagan SR (March 2008). “Congenital and acquired brain injury. 3. Spectrum of the acquired brain injury population”. Archives of Physical Medicine and Rehabilitation 89 (3 Suppl 1): S15–20. DOI:10.1016/j.apmr.2007.12.006. PMID 18295644.

León-Carrión J, Domínguez-Morales Mdel R, Barroso y Martín JM, Murillo-Cabezas F (2005). “Epidemiology of traumatic brain injury and subarachnoid hemorrhage”. Pituitary 8 (3–4): 197–202. DOI:10.1007/s11102-006-6041-5. PMID 16508717.

Maas AI, Stocchetti N, Bullock R (August 2008). “Moderate and severe traumatic brain injury in adults”. Lancet Neurology 7 (8): 728–41. DOI:10.1016/S1474-4422(08)70164-9. PMID 18635021.

“NINDS Traumatic Brain Injury Information Page”. National Institute of Neurological Disorders and Stroke. 2008-09-15. Retrieved 2008-10-27.

Parikh S, Koch M, Narayan RK (2007). “Traumatic brain injury”. International Anesthesiology Clinics 45 (3): 119–35. DOI:10.1097/AIA.0b013e318078cfe7. PMID 17622833.

Park E, Bell JD, Baker AJ (April 2008). “Traumatic brain injury: Can the consequences be stopped?”. Canadian Medical Association Journal 178 (9): 1163–70. DOI:10.1503/cmaj.080282. PMC 2292762. PMID 18427091.

Salomone JP, Frame SB (2004). “Prehospital care”. In Moore EJ, Feliciano DV, Mattox KL. Trauma. New York: McGraw-Hill, Medical Pub. Division. pp. 117–8. ISBN 0-07-137069-2. Retrieved 2008-08-15.

Scalea TM (2005). “Does it matter how head injured patients are resuscitated?”. In Valadka AB, Andrews BT. Neurotrauma: Evidence-based Answers to Common Questions. Thieme. pp. 3–4. ISBN 3-13-130781-1.

Essential Fatty Acids References:

Abel R,  “The DHA Story, How Nature’s Super Nutrient Can Save Your Life”.  2002, ISBN 1-59120-001-6, (2002).

Adams C, Brantner V (2006). “Estimating the cost of new drug development: is it really 802 million dollars?”. Health Aff (Millwood) 25 (2): 420–8. DOI:10.1377/hlthaff.25.2.420. PMID 16522582.

Eckert GP, Chang S, Eckmann J, Copanaki E, Hagl S, Hener U, Müller WE, Kögel D, “Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing”.  Biochim Biophys Acta. 2011 Jan;1808(1):236-43. Epub 2010 Oct 29. PMID 21036142

Livestrong.com: http://www.livestrong.com/article/430423-how-many-omega-fish-oil-pills-should-you-take-a-day/

Mills JD,  Hadley K, Bailes JE, “Dietary Supplementation with the Omega-3 fatty acid Docosahexaenoic Acid in Traumatic Brain Injury”. Neurosurgery, 2011 Feb;68(2):474-81

Journal of Health Economics 2010 Study,  http://onlinelibrary.wiley.com/doi/10.1002/hec.1454/abstract

Sears, B (2011). “The fallacy of using DHA alone for brain trauma.” http://www.prweb.com/releases/concussion/brain_trauma/prweb4500964.htm

University of Maryland Medical System and University of Maryland Medical School:  Omega-3 fatty acids:  http://www.umm.edu/altmed/articles/omega-3-000316.htm

Vitamin B Complex References:

Bourre JM.  “Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 1: micronutrients”.  Nutr Health Aging. 2006 Sep-Oct;10(5):377-85. PMID: 17066209

Butterworth RF, Thiamin. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. Modern Nutrition in Health and Disease, 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006.

Chatterjee A, Yapundich R, Palmer CA, Marson DC, Mitchell GW. Neurology. “Leukoencephalopathy associated with cobalamin deficiency”, 1996 Mar;46(3):832-4. PMID: 8618695Acta Neurol Taiwan. 2009 Dec;18(4):231-41.

Chang CY, Ke DS, Chen JY, “Essential fatty acids and human brain”, Acta Neurol Taiwan. 2009 Dec;18(4):231-41.

Combs GF Jr., “The vitamins: Fundamental Aspects in Nutrition and Health. 3rd edition. Ithaca, NY: Elsevier Academic Press; 2000

Coxon KM, Chakauya E, Ottenhof HH et al. (August 2005). “Pantothenate biosynthesis in higher plants”. Biochemical Society Transactions 33 (Pt 4): 743–6. DOI:10.1042/BST0330743. PMID 16042590.

Guettat L, Gille M, Delbecq J, Depré A, “Folic acid deficiency with leukoencephalopathy and chronic axonal neuropathy of sensory predominance”.  Rev Neurol (Paris). 1997 Jun;153(5):351-3. PMID: 9296172

Hall CA, “Function of Vitamin B12 in the central nervous system as revealed by congential defects”, Am J Hematol. 1990 Jun;34(2):121-7

Hoane MR, Wolyniak JG, Akstulewicz SL, “Administration of riboflavin improves behavioral outcome and reduces edema formation an glial fibrillary protein expression after traumatic brain injury”, J Neurotrauma, 2005 Oct 22;(10):1112-22

Jongen JC, Koehler PJ, Franke CL, “Subacute combined degeneration of the spinal cord: easy diagnosis, effective treatment”, Ned Tijdschr Geneeskd. 2001 Jun 30;145(26):1229-33. PMID: 11455686

Karakuła H, Opolska A, Kowal A, Domański M, Płotka A, Perzyński J, “Does diet affect our mood? The significance of folic acid and homocysteine”  Pol Merkur Lekarski. 2009 Feb;26(152):136-41.

Naim MY, Friess S, Smith C, Ralston J, Ryall K, Helfaer MA, Marguiles SS, “Folic acid enhances early functional recovery in a piglet model of pediatric head injury”, Dev Neurosci. 2010;32(5-6):466-79. Epub 2011 Jan 5. PMID: 21212637

Okada K, Tanaka H, Temporin K, Okamoto M, Kuroda Y, Moritomo H, Murase T, Yoshikawa H. “Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model.”, Exp Neurol. 2010 Apr;222(2):191-203. Epub 2010 Jan 4.

Surtees R, “Demyelination and inborn errors of the single carbon transfer pathway” Pediatr. 1998 Apr;157 Suppl 2:S118-21. PMID: 9587038

van Rensburg SJ, Kotze MJ, Hon D, Haug P, Kuyler J, Hendricks M, Botha J, Potocnik FC, Matsha T, Erasmus RT, “Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis”, Metab Brain Dis. 2006 Sep;21(2-3):121-37. Epub 2006 May 26. PMID: 16729250

Vonder Haar C, Anderson G, Hoane MR, “Continuous nicotinamide administration improves behavioral recovery and reduces lesion size following bilateral frontal controlled cortical impact injury.”, Behav Brain Res, 2011 Oct 31;224(2):311-7.  Epub 2011 Jun 17.

Protein (Amino Acids) References:

Bhattacharjee A, Bansal M (March 2005). “Collagen structure: the Madras triple helix and the current scenario”. IUBMB Life 57 (3): 161–72. DOI:10.1080/15216540500090710. PMID 16036578.

Blenis J, Resh MD (December 1993). “Subcellular localization specified by protein acylation and phosphorylation”. Current Opinion in Cell Biology 5 (6): 984–9. DOI:10.1016/0955-0674(93)90081-Z. PMID 8129952.

Brosnan JT, Brosnan ME (June 2006). “The sulfur-containing amino acids: an overview”. The Journal of Nutrition 136 (6 Suppl): 1636S–1640S. PMID 16702333.

Chishty M, Reichel A, Abbott NJ, Begley DJ. “S-adenosylmethionine is substrate for carrier mediated transport at the blood-brain barrier in vitro.” Brain Res. 2002 Jun 28;942(1-2):46-50. PMID: 12031851

Jeffrey T. Cole, Christina M. Mitala, Suhali Kundu, Ajay Verma, Jaclynn A. Elkind, Itzhak Nissim,and Akiva S. Cohena, “Dietary branched chain amino acids ameliorate injury-induced cognitive impairment”,.Proc Natl Acad Sci U S A. 2010 January 5; 107(1): 366–371. Published online 2009 December 29. doi: 10.1073/pnas.0910280107 PMCID: PMC2806733

Erlich S, Alexandrovich A, Shohami E, Pinkas-Kramarski R. “Rapamycin is a neuroprotective treatment for traumatic brain injury.” Neurobiol Dis. 2007 Apr;26(1):86-93. Epub 2007 Jan 31.  PMID: 17270455

Faden AI, Labroo VM, Cohen LA. “Imidazole-substituted analogues of TRH limit behavioral deficits after experimental brain trauma.” J Neurotrauma. 1993 Summer;10(2):101-8.  PMID: 8411214

Gidday JM, Beetsch JW, Park TS. “Endogenous glutathione protects cerebral endothelial cells from traumatic injury.”  J Neurotrauma. 1999 Jan;16(1):27-36. PMID: 9989464

Institute of Medicine committee report, Nutrition and Traumatic Brain Injury; Improving Acute and Subacute Health Outcomes in Military Personnel.  April 20, 2011.  http://www.nap.edu/openbook.php?record_id=13121&page=1

Kim JH, Lee YW, Park KA, Lee WT, Lee JE. “Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia”, J Cereb Blood Flow Metab. 2010 May;30(5):943-9. Epub 2009 Dec 23. PMID: 20029450

Krusong K, Ercan-Sencicek AG, Xu M, Ohtsu H, Anderson GM, State MW, Pittenger C. “High levels of histidine decarboxylase in the striatum of mice and rats.” Neurosci Lett. 2011 May 16;495(2):110-4. Epub 2011 Apr 1. PMID: 21440039

Penedo LA, Oliveira-Silva P, Gonzalez EM, Maciel R, Jurgilas PB, Melibeu Ada C, Campello-Costa P, Serfaty CA. “Nutritional tryptophan restriction impairs plasticity of retinotectal axons during the critical period.”Exp Neurol. 2009 May;217(1):108-15. Epub 2009 Feb 10. PMID: 19416666

Sahley BJ (2002), “The Anxiety Epidemic”, ISBN: 1-889391-23-9

Savelieva KV, Zhao S, Pogorelov VM et al. (2008). Bartolomucci, Alessandro. ed. “Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants”. PloS ONE 3 (10): e3301. Bibcode 2008PLoSO…3.3301S. DOI:10.1371/journal.pone.0003301. PMC 2565062. PMID 18923670.

Sharma HS, Winkler T, Stålberg E, Mohanty S, Westman J. “p-Chlorophenylalanine, an inhibitor of serotonin synthesis reduces blood-brain barrier permeability, cerebral blood flow, edema formation and cell injury following trauma to the rat brain.” Acta Neurochir Suppl. 2000;76:91-5.  PMID: 11450100

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Mt Kilamanjaro at sunrise as seen from Mt. Meru, Tanzania Africa.

Disclaimer: The ERB is a literature research team presenting the findings of other researchers. The ERB is not licensed medical nor dietary clinicians and will not give medical nor dietary advice. Any information presented on this website should not be substituted for the advice of a licensed physician or nutritionist. Users of this website accept the sole responsibility to conduct their own due diligence on topics presented and to consult licensed medical professionals to review their material. We make no warranties or representations on the information presented and should users utilize this research without consulting a professional, they assume all responsibility for their actions and the consequences.

Concussion (mild TBI) Brain Food: A Review of Fish Oil, B-Complex and Protein (Amino Acid) Therapies

Concussion (mild Traumatic Brain Injury) Brain Food Treatment Research Summary:  Research shows that fish oil supplements if supplied before or after brain trauma aid in protecting cell membrane from damage and death. The Institute of Medicine research report shows that by immediately providing sufficient protein to brain damaged victims, mortality rates and Second Injury (damage surrounding the initial injury) can be significantly reduced.  Protein builds DNA, cell structures, and neurotransmitters. Researchers have found that Bcomplex vitamins are critical to maintaining reactions involved in the production of red blood cells, cell membrane, the myelin coating surrounding nerves fibers, and neurotransmitter production, making B-complex vitamins vital for nerve communication and brain function.   This report reviews these findings to encourage further evaluation and testing.  Home laboratory testing to monitor these nutrient levels should be evaluated.

High School Soccer Player Concussion Case Study:

As he jumped into the air, the soccer player was struck on the back of the head (posterior parietal, right side). He fell to the ground and lost consciousness for 10 – 15 seconds.  Afterwards, he felt normal and returned to play for 40 minutes. The next morning, the back of his head was swollen.  He described the pain as a “bad migraine”. The subject was lethargic and bright lights made him nauseous.  He experienced no balance nor vision problems.  Quick movements intensified his headache. He did not attend school, as it was difficult to concentrate, read, write, or spell.  He had memory difficulties. Bright light caused dizziness and irritated his headache.  He experienced no improvement of his condition during the first two weeks.

The third week post concussion, the subject began taking Fish Oil (600mg DHA+EPA, twice daily), B-complex (100mg/twice daily) , and Amino Acids (750mg/twice daily).  Feeling better, he attempted to attend school, but found himself “fading out”. At his physician’s office, he was unable to memorize colors or spell simple words.  Swelling was identified on the right side of his parietal lobe and left side of his frontal lobe.  He returned to school several days later for a few hours. He was unable to complete homework.  The third week he attended school part-time and on the fourth week, he attended full time. He felt “fairly normal”, however, continued to have difficulties with bright lights and could not recall elementary school memories.  He discontinued the vitamins at the end of the fourth week.

One year later, the subject suffered a minor concussion as the front of his head (right frontal lobe) struck a goal post.  His pupils were dilated.  He could remember colors and spell however, he was dizzy in bright light.  He discontinued play, but did not consider this event as serious as the previous. He took the vitamins for a few days and felt better.  The following year, he again hit his head during soccer season and took the vitamins for a couple days.

Since most concussions improve about the third to fourth week, it is difficult to determine whether fish oil, b-complex, and amino acids shortened recovery time. The subject believes that the improvements began with the vitamins.  He states that upon taking the vitamins, he felt like returning to school. Additional research would be more valuable should baseline, post concussion, and post treatment neurocognitive testing be completed with control and test groups.

Concussion – mild Traumatic Brain Injury Discussion:

The human brain is about the size of a cauliflower head with the density of medium soft cheese and can be easily sectioned with a spatula. The brain stem protrudes from the posterior-inferior surface sending commands up and down pathways and through relay centers to the pinky-sized spinal cord. The brain and spinal cord are surrounded by clear cerebral spinal fluid (CSF) and membranes which provide a shock absorber-like environment internal to the bony cranium and vertebrae.

When the cushion environment is disrupted by an “external mechanical force such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile” (Maas AI, et al., 2008), a traumatic brain injury (TBI) results.  A mild TBI is referred to as a concussion.

TBIs are the leading cause of death/disability worldwide  (Alves OL, et al., 2001) and the number one cause of coma (Farag E, et al., 2011).   One third of TBI fatalities are firearm accidents (75% suicide) and another third are motor vehicle accidents (Leon-Carrion J, et.al., 2005). A total of 1.5 million people experience head trauma each year in the U.S. resulting in an annual cost exceeding $5.6 billion.  While most head injuries are mild (Cassidy JD, et al., 2004), the death rate to TBI is estimated at 21% by 30 days post injury (Greenwood, et al, 2003). The greatest number of TBIs occur in the male 15-24 age group (Hardman JM, et al., 2002) (Mass AI, et al., 2008). Sport and recreational activities in the U.S. alone may cause between 1.6 – 3.8 million TBIs each year (CDCP, 2007).  In addition, the military has seen a significant increase in TBIs. Approximately, 10-20% of veterans returning from the Middle East have experienced a TBI. The Department of Defense is conducting research to reduce the serious problems associated with these injuries and has requested a report from the Institute of Medicine (2011).

Clinically, a mild TBI or concussion is defined as post-traumatic amnesia of less than one day and a loss of consciousness between 0 -30 minutes (DOD TBI Task Force).  Symptoms include “headache, vomiting, nausea, lack of motor coordination, dizziness, and difficulty balancing” (Kushner D, 1998) along with “lightheadedness, blurred vision or tired eyes, ringing in the ear, bad taste in the mouth, fatigue or lethargy, and changes in sleep patterns.  Cognitive and emotional symptoms include behavioral or mood changes, confusion, and trouble with memory, concentration, attention, or thinking” (NINDS, 2008). Social behavior or emotional problems may also occur. Damage to the left side of the brain may involve speech, reading and writing difficulties.  Damage to the back of the brain may involve vision, balance, and coordination problems.

Current diagnostic techniques include neurological exam and neuro-imaging studies such as CT (CAT scan) or MRI (Magnetic Resonance Imaging).  CT scans are quickly completed in an emergency department. They are less expensive and better at showing bleeds than MRI  however, brain CT delivers a 1-2 millisievert dose of radiation.   MRI, which utilizes a magnetic field,  (no radiation exposure), delivers more detail of the brain and brain stem, but it is more time consuming and costly.  A CT of a more serious TBI may show hemorrhage, skull fracture, contusions (bruising), fracture, and/or edema (swelling).  An MRI of a more serious TBI, might show a shifting of brain structures, contusion, and hematoma. When blood exerts pressure upon the brain surface it can impair brain function. Interestingly, when brain tissue is seriously injured,  it appears to be cracked open on MRI, much like the appearance of a sponge that is torn open every 1-2 inches. The tears create fluid inlets, perhaps designed to bring nutrient rich CSF to the damaged areas.

A mild TBI or concussion will often show little damage on CT or MRI neuro-imaging studies, thus the increasing use of imPACT or CNS Vital Signs neurocognitive testing.  These computerized tests  have been more effective at assessing mild concussive damage by evaluating general mental functioning. To date, many athletic programs have been using them to compare pre and post injury results to determine ‘return to play’. Since they measure brain function in terms of verbal and visual memory, processing speed, reaction time, attention span, and non-verbal problem solving capabilities, neurocognitive testing has been successfully utilized to identify emotional and cognitive deficits related to mild TBIs.

When the brain is damaged, it immediately begins self repair. Raw materials are sought from nutrients in the blood supply and from CSF to rebuild the initial injury site.  When nutrient supply is insufficient, surrounding brain tissue may be broken down to supply substrate for reconstruction.

Damage apparent in adjacent tissue, has been defined as Second Injury and may result in more serious injury than the initial TBI (Park E, et al., 2008). When death results weeks later, it is typically caused by secondary damage (Ghajar J, 2000). In the past, this Second Injury has been commonplace and no therapy has been available to stop progression (Park E, et al., 2008). However, recent military studies found that by immediately supplying sufficient amounts of protein to the injured patient, Secondary Injury is significantly reduced (Institute of Medicine, 2011).  Providing omega-3 essential fatty acids (DHA/EPA) before injury or immediately after injury also reduces TBI damage (Mills JD, et al., 2011) (Wu A, et al., 2007).

Brain injury brings immune cells and fluids to the injury site, resulting in inflammation, but with the brain enclosed in the cranium there is minimal space to accommodate swelling.  The resultant increase in intracranial pressure may occlude blood vessels responsible for bringing oxygen and nutrients to brain cells and lymph vessels responsible for removing waste products (Scalea TM, 2005). Increased pressure can force the brain to herniate into spaces where it does not belong.  This renders the tissue non-functional and eventually will cause death.  A variety of anti-inflammatory medications are often utilized to diminish swelling.

Mild TBIs physically appear to resolve in 3 weeks and patients tend to return to normal activities.  Some patients have “physical, cognitive, emotional and behavioral problems such as headaches, dizziness, difficulty concentrating, and depression” (Parik S et al., 2007). Movement disorders, seizures, and substance abuse may also develop (Arlinghaus KA, et al., 2005). Depending upon the severity of the injury, the number of repeat injuries and the presence of adequate nutrients before and after the injury, the prognosis ranges from complete recovery to permanent disability, neurological disease or death. “Permanent disability is thought to occur in 10% of mild TBIs, 66% of moderate injuries, and 100% of severe injuries” (Frey LC, 2003). In many situations, particularly athletics, a second concussion may occur before the first concussion has healed.  This is of particular concern as multiple TBIs may have a cumulative effect (Kwasnica C, et al., 2008).

Brain Biochemistry:

As discussed in ‘The ERB Vision for Wellness‘ tab on this website, Dr. James Watson of Watson and Crick, the scientists who discovered the DNA double helix, tells us that to eliminate disease we must return to Biochemistry.  We expect that the many dedicated researchers referenced below would agree.  They have found that in Traumatic Brain Injury, nutrition matters.  Adequate supplies of the major tissue nutrients are critical.

In looking at a section of brain tissue, the lighter tan colored structures are called “white matter.” White matter consists of nerve fiber tracts or pathways traveling in both directions to and from the brain through the brainstem down the spinal cord and extending out to organs, arms, and legs.  A nerve can be up to four feet long. White matter nerve tissue is composed of essential fatty acids called omega-3s such as DHA (docosahexanoic acid) and EPA (eicosapentanoic acid).  Most nerve tissue contains a myelin coating.  The resistance created by this coating allows for impulse transmission at approximately 100m/sec ( 245 mph)! Nerve and myelin formation require B-complex vitamins.  The darker structures on a brain section are called  “gray matter.”  These are decision-making nuclei made from proteins composed of amino acid building blocks.  Proteins and amino acids formulate all structures, most noticeable of which are neurotransmitters.  Neurotransmitters are critical to brain function and communication throughout the body.

Essential Fatty Acids (DHA and EPA):

40% of brain tissue is essential fatty acids (DHA and EPA).   While EPA provides important anti-inflammatory actions (Sears B, 2011) and is included in supplements, 97% of the brain’s essential fatty acids are the 22 carbon chain,  Docosahexanoic Acid (DHA).  DHA is found in foods such as walnuts (ALA), microalgae, microplants, cod, salmon, mackerel, sardines, hake, caviar, herring, oysters, organ meats (liver), grass fed and finished beef, and fish oil or algae supplements.  Fish receive DHA from ocean phytoplankton (microalgae or microplants).  Cattle receive DHA from grass.  However, as we increasingly draw our food from farm-raised fish and grain-raised cattle, our dietary intake of DHA is being depleted, (Abel R, 2002).

Most humans consume an overabundance of vegetable oil and butters which contain no double bonds in their carbon chains.  DHA has six double bonds (22:6), one at every third carbon (omega-3 or n-3). In cell membrane, these double bonds allow the fatty acid to neutralize damaging free radicals.  In addition, the double bonds increase the fluidity properties of cell membrane which helps to protect the cell from trauma and cell death (apoptosis) (Eckert GP, et al., 2011). Proper cell communication and signaling is critical for brain function. Fifty percent of nerve cell plasma membrane is DHA (Collins C, et al., 2002) which is important in cell communication, neuronal survival, and growth.  DHA is found in three cell membrane phospholipids:  phosphytidylethnolamine, ethnolamine plasmalogens, and phosphatidylserine. Upon injury, these phospholipid pools are important reservoirs to reconstruct cell membrane (Chang CY, et al., 2009).  In the absence of dietary DHA, the brain will improvise and construct brain tissue from vegetable oil.  However, under traumatic conditions  vegetable oil fed rat brain falls apart, (Eckert  GP, et al., 2011) (Abel R, 2002).

Researchers found that in rats subject to TBI which then received 40mg/kg/day pharmaceutical grade fish oil rich in DHA and EPA for 30 days post TBI had more healthy nerve cells.  Essential fatty  acids  were shown  to be neuroprotective by reducing  the  number of  injured nerve axons, decreasing the level of inflammation,  and reducing oxidative stress and cell death (Mills JD et al., 2011). DHA fed to rats immediately post TBI was found to counteract cognitive decay, maintain membrane signaling function, and support the potential of DHA supplementation to reduce the effects of TBI. (Wu A, et.al 2011).  In addition, essential fatty acids DHA and EPA given to rats 4 weeks prior to TBI was found to help maintain brain homeostasis and reduce oxidative damage due to TBI (Wu A, et al., 2007). 

DHA and EPA have been found to improve the outcome of stroke studies of both rat and human models (Kong W, et.al) (Hagiwara H, et.al.).  Few human studies have been conducted using DHA as prophylaxis for TBI.  In 2006, 20 grams per day of omega-3 fish oil (CNN, 2012)  and hyperbaric oxygen treatment were used by Dr. Julian Bailes to treat the sole survivor of the West Virginia mining disaster, Randal McCloy, who suffered carbon monoxide poisoning. This patient now claims that his brain function is near normal.  Dr. Bailes and his colleagues have since published many research papers demonstrating the benefits of essential fatty acids and fish oil supplements.  In addition, “individual case reports using fish oil doses of 2-4 grams per day have been described, however sufficient human research is unavailable to recommend dosages”  (Maroon, JC and Bost J, 2011).

One new human case study was published in October 2012, when Peter Ghassemi convinced physicians to give his son Bobby, who was in a coma following a motor vehicle accident, omega-3 fish oil ( a similar dose to Randal McCloy).  Bobby  had a Glasgow Coma Score of 3 (scale 3 – 15), which Dr. Michael Lewis says that “a brick or piece of wood has a Glasgow Coma Score of 3. It’s dead.”  Peter Ghassemi, Bobby’s father, indicates that it was difficult to convince physicians to give their son fish oil.  They wanted to see 1000 case studies first, to prove its efficacy.  Eventually, physicians agreed.  Thanks to his father’s perserverance, Bobby has recovered today.  U.S. Army Colonel Lewis who recommended the therapy to Peter Ghassemi describes the therapy like this.  “If you have a brick wall and it gets damaged, wouldn’t you want to use bricks to repair the wall?  And omega-3 fatty acids are literally the bricks of the cell wall of the brain.”  (CNN,2012)

The textbook “Contemporary Nutrition” written by  Gordon M. Wardlaw and Anne M. Smith in 2013 tells us that EPA and DHA are slowly synthesized in the brain from alpha linoleic acid and can be found in “fatty fish such as salmon, tuna, sardines, anchovies, striped bass, catfish, herring, mackerel, trout or halibut “(listed highest to lowest omega-3 content) and in foods such as “canola and soybean oils, walnuts, flax seeds, mussels, crab and shrimp”.  The authors warn about high mercury levels in swordfish, shark, king mackerel, and albacore, and indicate that fish with low mercury levels include salmon, sardines, bluefish, herring and shrimp.  Eating fish twice each week is recommended.  Omega-3 fatty acids tend to act to reduce blood clotting and inflammation, while omega-6 foods tend to increase clotting and inflammation.  Vitamin K and calcium carbonate are also involved in the clotting process. “Fish oil capsules should be limited for individuals who have bleeding disorders, take anticoagulant medications, or anticipate surgery, because they may increase risk of uncontrollable bleeding and hemorrhagic stroke”.

Wardlaw and Smith recommend 1.6 grams per day of omega-3 fatty acids for men and 1.1 grams per day for women.  Elevated blood triglycerides are treated with 2 to 4 grams per day.  Omega 3 fatty acids have been found to reduce the inflammation of rheumatoid arthritis and help with behavioral disorders and cases of mild depression.  Freezing fish oil capsules helps to reduces the fishy after taste.  “2 tablespoons of flax seed per day is typically recommended as an omega-3 fatty acid source”.  Approximately 3 walnuts (6 halves) yields approximatley 1 gram of DHA.  Care should be taken to keep DHA sources refrigerated as they turn rancid easily.  For TBI patients on IV feeding it is important to investigate the quantity of DHA and EPA present in total parenteral nutrition.  One researcher takes approximately 1 gram of DHA/EPA through fish oil daily and regulates intake by the dryness/moistness of the skin.  In drier climates, she finds this daily intake amount must be doubled.  Mercury consumption in fish oil is a serious risk and mercury free alternatives should be explored.

More human studies are needed to establish the benefits/risks of DHA and EPA with TBI. Eventually these will come however, the bureaucracy is heavy, and the cost estimates of bringing a new drug to market varies from $500 million to $2 billion (Adams C, et al., 2006) (JHE, 2010). A bottle of fish oil, with a small profit margin, may not provide sufficient return on investment to entice investigation.  One subject with a fish oil allergy could mire the researching organization in million dollar legal proceedings for years to come. That said,  research studies are important for physicians to have as legal and medical support for their recommendations.  Given this climate, many individuals and their health care providers have taken on the responsibility to evaluate whether  fish oil supplements are a safe and worthwhile benefit or a risk addition to their diet.  By 2020, we expect clinicians and individual to measure and maintain their optimum DHA/EPA levels.

B Complex Vitamins:

Vitamin B is a vitamin complex  of B-1-thiamine, B-2 riboflavin, B-3 niacin, B-5 pantothenic acid, B-6 pyridoxine, B-9 folate, B12-cobalamin.  B complex vitamins are important for nerve, DNA and neurotransmitter synthesis,  and for cell energy production and metabolism.  The majority of the information cited below regarding the effects of B complex vitamins on brain function has been obtained from animal studies.

Thiamine (B1):

  • Required for red blood cells to carry oxygen (Combs GF Jr, et al., 2008)
  • Acetylcholine neurotransmitter production(Butterworth RF, et al., 2006)
  • Myelin synthesis in nerve cells (Butterworth RF, et al., 2006)
  • High school female RDA 1.0 mg/day, male 1.2 mg/day.
  • Adult RDA is 1.1 – 1.2 mg/day, Daily Value 1.5 mg/day, no upper limit set because water soluble and rapidly lost in urine, alcohol consumption reduces thiamin levels (Wardlaw, et.al., 2013)
Riboflavin (B2):
  • A component in all flavoproteins and  red blood cells (erythrocytes)
  • Reduced TBI lesions, edema, and improved outcome (Hoane MR, et al., 2005)
  • High school female RDA 1.0 mg/day, male 1.3 mg/day.
  • Adult RDA is 1.1 – 1.3 mg/day, Daily Value 1.7 mg/day, no upper limit set.  Alcohol consumption reduces riboflavin levels (Wardlaw, et.al., 2013)

Niacin (B3):

  • Involved in DNA repair, cholesterol, and energy production
  • Helps produce neurotransmitters in the adrenal gland
  • Reduces TBI lesion size and improves sensory, motor, cognitive, and behavioral recovery (Voner Haar C, 2011)
  • High school female RDA 14 mg/day, male 16 mg/day.
  • Adult RDA is 14 – 16 mg/day, Daily Value is 20 mg/day, upper limit is 35mg/day of nicotinic acid form. Alcohol consumption reduces niacin levels (Wardlaw, et.al., 2013)

Pantothenic Acid (B5)

  • Neurotransmitter acetylcholine production
  • Involved in signal transduction, and enzyme control
  • High school female and male 5 mg/day.
  • Adult Adequate Intake is 5 mg/day, Daily Value is 10 mg, no upper limit set (Wardlaw, et. al, 2013).

Pyridoxal Phosphate (B6):

  • Controls all amino acid metabolism  (Sahley BJ, 2002)
  • Red blood  cell and  antibody formation (Sahley BJ, 2002)
  • Dopamine and GABA neurotransmitter production
  • Nerve myelin sheath phospholipid production
  • High school RDA female 1.2 mg/day, male 1.3 mg/day.
  • Adult RDA is 1.3 – 1.7 mg/day, Daily Value is 2 mg, Upper Level is 100 mg/day based upon nerve damage.  Studies have shown that 2 – 6 grams/day of B-6 for 2 or more months can lead to irreversible nerve damage.  Symptoms of toxicity include walking difficulties and hand and foot numbness (Wardlaw, et. al, 2013)

Folate  (B9):

  • Required to synthesize, repair, and methylate DNA.
  • Provides neuroprotection in TBI (Naim MY, et al., 2010)
  • Important in rapid cell division and growth.
  • Production of healthy red blood cells and anemia prevention
  • Forms cell membrane phospholipids and receptors (Karakula H, et al.,2009) (Surtees R, 1998)
  • Prevents nerve damage and neural tube defects during development
  • Required for myelin regeneration (van Rensburg SJ, et al., 2006) (Guettat L, et al., 1997)
  • High school RDA female and male 400 mcg/day.
  • Adult RDA and Daily Value is 400 mcg/day,  pregnant women 600mcg/day  (important to prevent neural tube defects), Upper Level is 1 mg/day alcoholism and poor absorption reduces folate levels (Wardlaw, et.al., 2013)

Cobalamin (B12):

  •  Involved in blood formation.
  • Critical to DNA synthesis through folate regeneration
  • Formation of cell membrane phospholipids and receptors (Karakula H, et al., 2009) (Surtees R, 1998)
  • B12 supplementation partially resolved cognitive deficits and myelin imaging abnormalities (Chatterjee A, et.al., 1996) (Jongen JC, et al., 2001)
  • Improves cerebral and cognitive functions.  (Bourre JM, 2006)
  • Required for myelin synthesis (Hall CA, 1990) (van Rensburg SJ, et al, 2006) (Guettat L, et al., 1997)
  • Promotes nerve regeneration (Okada K, et al., 2010)
  • High school RDA female and male 2.4 mcg/day.
  • RDA is 2.4 mcg/day, Daily Value is 6 mcg/day, no Upper Limit set, stored in liver, 50% of dietary intake may be absorbed.  Nerve damage and anemia may result from insufficient intake.

There are 150mg time release (9-10 hours) capsules available for B complex.  All  B vitamins are water soluble and need to be replenished daily.  Vitamin B complex has an important  role  in  alleviating anxiety and lactic acid buildup.  Dietary supply may be inadequate under stress (Sahley BJ, 2002).

Protein (Amino Acids):

Linear chains of amino acids form proteins. Proteins produce nuclei in the brain, DNA,  cell membrane, enzymes, and neurotransmitters. Twenty amino acids are commonly identified.  All 20 amino acids need to present concurrently for protein synthesis to occur.  A problem may be that most foods do not provide all 20 amino acids concurrently as is provided by a 20 amino acid complex supplement.  More research needs to be completed on this topic.

Alanine – Precursor of neurotransmitter dopamine (Coxon KM, et al., 2005)

Arginine – Through agmantine, it is neuroprotective in trauma and ischemia models by significantly reducing  brain swelling volume and blood-brain barrier protection (Kim JH, et al., 2009)

Cysteine – Forms DNA double helix disulfide bonds

Glutamate – Important for calcium ion binding; may reduce blood glucose levels in the injured spinal cord reducing neurological impairment (Zhang TL, et al., 2010)

Glutathione – Critical to relieve oxidative stress in cells

Glycine – Important in red blood cell formation (Shemin D, et al., 1946); gives amino acid structures flexibility

Histidine – Used throughout the brain;  improves TBI outcome (Faden AI, et al., 1993) (Krusong K, et al., 2011)

Lysine – Important for connective tissue maintenance, and affects protein binding to phospholipid membranes (Blenis J, et al., 1993)

Methionine – The sole methyl donor in the central nervous system; increases S-adenylmethionine (SAMe) in CSF aiding in neurological disorder treatment (Chishty M, et al., 2002); forms Glutathione, important in reducing free radical-mediated traumatic injury  (Gidday JM, et al., 1999)

Phenylalanine – Produces chlorophenylalanine (CPA) which slowed the breakdown of the blood-brain barrier permeability, brain edema and blood flow; reduced the number of damaged and distorted nerve cells (Sharma HS, et al., 2000).

Proline – Maintains connective tissue (Bhattacharjee A, et al., 2005)

Serine – Acts as a neurotransmitter in the brain (Wolosker H, et al., 2008)

Taurine – Major component of brain tissue and muscle (Brosnan JT, 2006)

Threonine – A component of the serine/threonine kinase; neuroprotective following traumatic brain injury (Erlich S, et al.,2007)

Tryptophan – Precursor to neurotransmitter serotonin (Savelieva KV, et al., 2008); a modulator of serotonin which alters plasticity-related signaling pathways and matrix degradation (Penedo LA, et al., 2009)

Tyrosine – Precursor of the neurotransmitter dopamine, norepinephrine, epinephrine

Under prolonged stress or illness the body is unable to produce sufficient non-essential amino acids (Sahley BJ, 2002).  Trauma has been found to damage DNA and RNA, and to deplete neurotransmitters.  Neurological dysfunction is caused by traumatic brain injury (Cole J, et al., 2010

As amino acids are utilized for energy and substrate, they are oxidized to urea and carbon dioxide producing high levels of glutamate.  These high levels seen in the TBI patient can include oxidation of branched chained amino acids. Dietary consumption of Branched Chain Amino Acids (BCAAs) restored BCAA concentrations to normal, improved nerve cell communication, and reinstated cognitive performance after concussive brain injury (Cole J, et al., 2010). BCAAs and amino acid complex (protein) are available at nutrition stores.

The Institute of Medicine committee report of April 20, 2011 on Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel   found that supplying high levels of protein to the TBI patient within the first 24 hours severely reduced mortality.  This report calls for standardized protocols to require  a level of nutrition that represents more than 50 percent of the injured person’s total energy expenditure and provide 1 to 1.5 grams of protein per kilogram of body weight for two weeks. They expect this nutritional intervention limits the inflammatory response, thereby improving outcome.  Most importantly, in following this protein therapy, the detrimental secondary injury process was not apparent.

Protein needs of a sedentary adult are estimated at .8 grams/kilogram  or 56 grams/day for a 70-kilogram, 154lb man.  (Pounds/2.2 kilograms per pound * .8 grams/kilogram).   Protein needs of a football, power sport playing athlete are approximately 1.4 – 1.7 grams/kilogram for males and 1.1 – 1.5 grams/kilogram for females or 98-119 grams/day. Athletes in a strength training program can be recommended up to 2.0 grams of protein per kilogram per day, almost twice the RDA (Wardlaw, et. al., 2013).

The objective of this discussion has been to bring current research advancements to light given the realization that concussive TBIs cause damage and disease, such that this information may be further evaluated by the public, health care providers, and the medical research community.

Traumatic Brain Injury References:

Alves OL, Bullock R (2001). “Excitotoxic damage in traumatic brain injury”. In Clark RSB, Kochanek P. Brain injury. Boston: Kluwer Academic Publishers. p. 1. ISBN 0-7923-7532-7. Retrieved 2008-11-28.

Arlinghaus KA, Shoaib AM, Price TRP (2005). “Neuropsychiatric assessment”. In Silver JM, McAllister TW, Yudofsky SC. Textbook Of Traumatic Brain Injury. Washington, DC: American Psychiatric Association. pp. 63–65. ISBN 1-58562-105-6.

Center for Disease Control and Prevention, National Center for Injury Prevention and Control. “Traumatic brain injury” (http://www.cdc.gov/ncipc/factsheets/tbi.htm) 2007.

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