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Amino Acid Therapy for TBI and Concussion: A literature review

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.

Fish Oil (DHA – omega 3) Therapy for TBI and Concussion: A Literature Review

Fish Oil and Concussion: A Case Study and Review

Case Study: A 14 y/o female, club soccer player suffered concussion. She continued to play through two full-length soccer games. In the days following, she suffered headaches and bright flashes of light in both visual fields. Loud sounds exacerbated the pain. She experienced complete exhaustion, lack of concentration, and difficulty sleeping. Sports activities caused headaches. She missed school due to the chronic pain, causing her grades to drop. As months passed, she discontinued sports and “lost hope in life”. Having been diagnosed with concussion, she visited multiple physicians who initiated various therapies without resolve. To avoid social exclusion, she did not discuss the pain publicly. The following year, she began taking 500mg fish oil supplements of docosahexanoic acid (DHA). Over the next month, the headaches were alleviated, allowing her to return to previous school and sports activities.

Discussion: Concussion and traumatic brain injury(TBI) cause approximately 52,000 deaths, 220 hospitalizations, and 85,000 permanent cases of debilitation each year in the U.S.. Concussion has seen a 4.2 fold increase in cases since 1998 (Barrett et.al, 2014). Symptoms include loss of consciousness, headache, a fogginess, light sensitivity and sleep disturbances for typically 7-10 days after injury. Symptoms may persist for months or longer. (Barrett EC, et.al. 2014). Laboratory rodent experiments show that nerve axonal injury is a progressive event which leads to the swelling and disconnect of the axon membrane in hours to days following TBI. The injury causes a lack of transport and communication across axonal membranes, ultimately leading to cell death (Mills JD, et.al., 2011). The societal impact of concussion is staggering given it’s excessive financial cost and ability to cause long term mental disease.

Fish oil contains omega-3 fatty acids such as docoashexanoic acid (DHA) and eicosapentanoic acid (EPA). This paper explores the current literature evaluating docosahexanoic acid (DHA) as a potential therapy for TBI. Omega-3 fatty acids, most significantly DHA, comprise 60% of brain tissue (Crawford, et al, 1993). An improved understanding of the omega-3 fatty acid nutritional requirements such as DHA, has improved concussion outlooks (Mills JD, et.al., 2011). DHA is essential for maintaining membrane fluidity, thereby affecting the speed of neuronal transmission. Previous laboratory rodent studies have demonstrated the neurological benefits of DHA. More recently, military studies have shown the neurologic benefits of DHA in humans. When

brain tissue is damaged, supplying adequate levels of docosahexanoic acid can be a protective and restorative mechanism for neuronal tissue (Hasadri L, et.al., 2013).

Rodent Neuroprotective DHA findings:

Rodent studies significantly advanced brain trauma therapy in 2006, when a single intravenous dose of DHA was found to reduce inflammatory markers and improve neuron survival (King VR, 2006). In 2008, Drs. Wan-Ling Chung, Jen-Jui Chen, and Hui-Min Su of the Department of Physiology, National Taiwan University College of Medicine in Taipei 100, Taiwan sought to determine whether reference and working memory could be enhanced with DHA supplementation in male rats previously DHA deficient. They fed pups divided into four groups either a normal diet, an eicosapentanoic acid (EPA) supplemented diet, a DHA supplemented diet, or an omega-3 deficient diet. At 140 days after birth, they assessed memory in the rats, through use of a Morris Maze. The rats found the location of the submerged platform in a working memory test and remembered the location of the platform in a reference memory test. The DHA deficient rats showed a significantly poorer memories which were partially improved with DHA supplementation. Rats receiving supplementation throughout brain development and adulthood resulted in a significant enhancement of both memories (Chung, 2008). The hippocampus showed a greater accumulation of DHA.

In evaluation of this study based upon the Quality Criteria Checklist for Primary Research in Non-Human Subjects, this study does not discuss the number of rats in study. The rat selection appears to be free of bias having been obtained from Charles River Laboratories in Taiwan. The criteria appear to have been applied evenly with relevant characteristics being described and analyzed through tissue samples in the lab. Controls were used. Data and statistical analysis appear to be valid, but study groups are not elaborated upon. Interventions were described in detail as to diets and the outcomes clearly defined. Observations and measurements appear to be based on standard, valid, and reliable data. At some points, there appears to be confusion on which type of memory is being measured. They had two goals in determining whether supplementation could revive memory in previously deficient rats and if recovery was brain region specific. They received positive results with both hypotheses. The importance of this study, in the eventual development of DHA as a therapy, is that improvements in rodent neurocognitive abilities are established.

In 2011, two researchers, Dr. Julian Bailes and Dr. J.D. Mills from West Virginia University School of Medicine in Morgantown, West Virginia found that DHA supplementation significantly ameliorated secondary mechanisms of injury and reduced the number of damaged axons in 40 Sprague-Dewey male rats. They randomly selected four groups of 10 rats. One group served as a sham concussion group. A second group received a concussion but no fish oil. The third group received 6mg/kg/day of DHA and a fourth group, 24 mg/kg/day of DHA. DHA was neuroprotective in both the 6mg/kg/day and 24 mg/kg/day populations when administered for 30 days post concussion. The neurons were labeled for damage. The 6mg/kg/day and 24 mg/day groups showed 6.2 +/- 11.4 and 7.7 +/- 14.4 neurons labeled for damage, respectively. This labeling nearly matched the control sham concussion group (Mills, 2011).

In analyzing the results from Bailes and Mills, according to study criteria on the Qualify Criteria Checklist for Primary Research of Non-Human Subjects, the selection of study subjects were not free from bias in that only males rats were used. The study groups appear to be comparable in that random, concurrent controls were utilized given the sham injured, injured supplemented, 6mg/kg/day, and 24 mg/kg/day study groups. Protocol and context were described in detail. The intensity, duration, and treatment were sufficient to produce a meaningful effect and the data appeared to be free from bias and similarly assessed. Key outcomes and nutrition related data were well described and measured with several different markers. Data was based upon reliable procedures/testing and the level of precision was p < 0.05. Measurements were conducted consistently among the groups and the study reported a 96% reduction of axonal injury after DHA supplementation of only 6 mg/kg/day. While researchers may increase the size of this cohort to improve additional studies, the degree of positive results are impressive.

The neuronal tissue in the brain extends down the brainstem into the spinal cord.
Spinal cord injuries (SCI) have long caused debilitating injury to the sensory and motor neurons below the injury site. In 2013, researchers at Loma Linda University found that DHA protected and restored neurons, resulting in significant improvement in the motor

and sensory tract functions destroyed following spinal cord injury (Figueroa, 2013).
DHA supplemented for 8 weeks in female Sprague-Dawley rats mediated the chronic pain present with SCI. They found that our Western diet may be hindering recovery from SCI, and that chronic DHA deficiency is associated with dysfunction following SCI (Figueroa, 2013). These research studies report that dietary prophylaxis with DHA results in distinctive improvements of nerve function that may facilitate functional recovery after SCI (Figueroa J, et.al., 2013).

Human DHA Neuroprotective Findings:

In 1997, the U.S. Food and Drug Administration confirmed that fish oil at levels up to 3 g/day were generally recognized as safe in the Federal Registry. At the same time, the FDA determined that fish oil up to 4 g/day was safe for cardiovascular therapy (FDA, 1997). In 1998, depression rates were found to be 50 times higher in countries with little seafood consumption (Hibbeln, 1998).

By 2005, Daily Reference Intakes did not yet provide for an Recommended Daily Allowance for DHA. Fish oil in the quality of 2g/d were shown to reduce suicidal tendencies, depression, and the perception of stress (Hallahan B, et.al., 2007). In 2010, the U.S. Dietary Guidelines added increased seafood consumption to its recommendations.

In 2011, the Institute of Medicine (IOM) published an extensive report entitled “Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel” which reviewed current literature on DHA and TBI. They reported that 80 percent of the fatty acids consumed in the U.S. were omega-6 or linoleic acids at a rate of 17g/day, and that while DHA is synthesized from alpha linoleic acid, only low amounts are produced (IOM, 2011). In animal studies, DHA was shown to have anti- inflammatory and neuroprotective activities in the brain and retina (IOM, 2011). Human studies showed that TBI patients would benefit by an inflammation reduction within 60 minutes of infusion (IOM, 2011). The IOM recommendation requests that more animal studies and human clinical trials be conducted. The conclusions further state that while intravenous fish oil formulations are available in Europe they have not yet been approved by the FDA in the U.S. The IOM recommends the early phase of severe TBI be provided with continuous enteral feeding with a formula containing fish oil (IOM, 2011).

This review is most significant in that is was formulated by the Institute of Medicine. While this is not original research, it is based upon original research of many research efforts which have received a positive rating from the IOM in that research reviewed has addressed issues of inclusion/exclusion bias, generalizability, and data collection and analysis. It is disappointing that 5 years post IOM report, the American Medical Society has not recommended the use of fish oil for TBI and the FDA has not published a position on the safety and efficacy of fish oil and TBI updating their 1997 declaration. While there have been remarkable case studies published demonstrating the efficacy of fish oil in severe TBI incidents, TBI is generally not treated with fish oil in the U.S..

Given the IOM call for additional human studies, a markedly higher rate of suicide among individuals who have suffered TBI as compared with the normal population has been demonstrated (Nowrangi, 2014). Dr. Michael D. Lewis and Dr. Joseph R. Hibbein of the Uniformed Services University in Bethesda, Maryland sought to determine if deficiencies in DHA were associated with an increased risk of suicide among a large, random sample of military personnel (Lewis, 2011). In a retrospective study they assayed serum samples from 800 military personnel who had committed suicide with 800 controls randomly matched for age, collection date, sex, rank and year of incident with sera within 12 months of their matched case (Lewis, 2011). Samples were assayed for DHA composition by robotic direct methylation coupled with fast gas-liquid chromatography to account for possible degradation. Researchers found that there was no difference when comparing female controls with cases, however there was a 62% greater risk of suicide death among men with lower serum DHA levels (Lewis, 2011).

In evaluating this study by the Quality Research Checklist for Primary Research, this study was not free from bias in that more men committed suicide than women. Given the military’s high availability of data, inclusion criteria were specifically matched with controls. Criteria appeared to be applied equally. Health and demographics were carefully described. Subjects appear to be a representative sample of the relevant population. The population is some what unique in being all military. Study groups were remarkably comparable given the military’s high availability of data. This study was randomized with 800 cases and 800 controls. The distribution of disease status was similar across the study groups. Concurrent controls were utilized. This was a case control study and there was blind comparison. There were no interventions or therapeutic regimens. All procedures were compared in detail. An exposure factor may have been the age of the serum, but the military was careful to utilize cases and control serum with similar dates and ages to alleviate discrepancies. Outcomes were clearly defined, and measurements valid and reliable. State-of-the-art equipment and statistical analysis were available to the military. Their primary hypotheses of whether suicide would be related to lower DHA levels was confirmed.

In this military study, nutrition measures were appropriate to outcome. Observations and measurements were based upon standard, valid, and reliable data collection instruments/tests/procedures. Precision varied from p < 0.01 to p < 0.07 (Lewis, 2011). Other factors were accounted for and the measurements were not consistent across groups in that DHA levels did not vary among women. Overall, this study presents sufficient information to form a positive correlation between suicidal tendencies and low levels of DHA. This study does not show that DHA will prevent suicide, however in using 1600 subjects, randomized and blinded this is an important report. The psychological benefit of a diet including DHA is confirmed.

In 2013, the American Medical Society for Sports Medicine (AMSSM) published a position statement on concussions. The purpose of their statement was to provide physicians with a practice summary to manage sports concussions, and to identify the current level of information including knowledge gaps needing additional research. They expressed the need for competent physicians experienced with concussion management to provide care and issue return-to-play decisions. They defined concussion or mild TBI as a disturbance of brain function involving a complex pathophysiological process which is generally self-limited and considered a less severe brain injury (Harmon, 2013). Researchers estimated that 3.8 million concussions occur in the U.S. per year with half going unreported (Harmon, 2013). They expressed concern for repeat injuries prior to initial recovery, causing severe metabolic changes in brain tissue.

The AMSSM discussed diagnosis of concussion, evaluation, and management by a knowledgable healthcare provider. They indicated the sensitivity of baseline neurocognitive testing by health care professionals. However, the AMSSM states that most concussions can be managed without neurocognitive testing. Academic accommodations such as reduced workload and rest were recommended for students.

Concern was expressed for long term disease management and “neurological sequelae” (Harmon, 2013). Additional studies were requested to determine the long term effects of concussion. In preventing concussion, fair rules of play, helmets and legislative efforts were recommended (Harmon, 2013) In terms of future directions, the AMSSM requests further research in neurocognitive testing, assessment tools, improved imaging tools, and the identification of additional biological markers to provide new insight. (Harmon, 2013).

Given the publication of the IOM report of 2011 calling for the use of fish oil as treatment for acute TBI, the lack of AMSSM recommendations for research and clinical application of these therapeutics is disappointing. Instead of treating the condition, the AMSSM appears focused on improving diagnosis and imaging tools. Further, the AMSSM discounts neurocognitive testing. By 2013 baseline neurocognitive testing has become standard in many school and universities across the nation, whereby individual baseline test are compared with post concussion tests to determine return-to-play. These testing systems are managed by school and university athletic trainers, and have proved critical for concussion management. A more treatment oriented AMSSM report would have addressed the proficiency of the current level of neurocognitive testing and recommended additional usage. The purpose of this report was to identify knowledge gaps. Given the current evidence on DHA it seems important to present the current research findings, and to issue a call to the medical community for additional clinical testing. Hopefully, the grave risk of liability in the U.S. has not thwarted our ability to potentially ameliorate 96% of brain trauma.

In 2013, Dr. Linda Hasadri, et.al. of the Mayo Clinic’s Department of Laboratory Medicine and Pathology, Rochester, Minnesota published a review of TBI DHA studies in the Journal of Neurotrauma. Her team reported that TBI is a global health risk and that nutritional interventions, such DHA, may provide a unique opportunity to repair brain tissue (Hasadri, 2013). While there have not been results of clinical trials evaluating the treatment of TBI with omega-3 fatty acids published, both animal and human studies have provided positive results (Hasadri, 2013). Chronic head injury may result in long term neurological disease including Alzheimer’s, Parkinson’s Disease, Post Traumatic Stress Disease, neurocognitive deficits, depression, and an inability to function (Hasadri, 2013). To improve outcomes, omega-3 fatty acids, such as DHA, may be obtained from a diet heavy in cold water fish, algae and krill (Hasadri, 2013), free range meat, cage free eggs, and fortified infant formula.

The Hasadri teams describes DHA as the longest and most unsaturated fatty acid. DHA provides a tremendously flexible and versatile structure, playing a significant role in the function of the neural cell membrane, retina, and sodium potassium pump (Hasadri, 2013). Pro-apoptotic proteins are down regulated and anti-apoptotic proteins are up-regulated with therapy (Hasadri, 2013). Chronic deprivation of DHA leads to learning and memory deficits, and decreased function of cholinergic and dopamine pathways. Risks may exist in that DHA has an oxidation potential that could create a carcinogenic substance. A fishy odor and rancidity are possible. In addition, there is a high risk of exposure to mercury and environmental toxins, although the benefits currently outweigh the risks (Hasadri, 2013). The research team concludes that DHA restores cellular energetics, reduces oxidative stress and inflammation, repairs cellular damage, and mitigates the activation of apoptotic processes after TBI (Hasadri, 2013). They conclude that DHA may provide a unique, well tolerated, easy to administer opportunity to treat TBI (Hasadri, 2013). This is an elegant summary of current research which additionally discusses the opportunity to inexpensively and practically reduce the societal impact of TBI with fish oil.

In 2014, The U.S. Food and Drug Administration (FDA) published a consumer health information publication entitled “Can a Dietary Supplement Treat a Concussion? No!”. This short report was apparently issued as a warning to companies and individuals.
The FDA reports that there is no scientific evidence that any supplements are safe and effective for preventing, treating or healing concussion (FDA, 2014). They state that no supplements exist that might allow athletes to return-to-play sooner than they are ready. They address the important need for patients to receive care from medical professions, that repeat injuries have a cumulative effect, and there may be substantial long-term neurological impact of concussions (FDA, 2014). The FDA sent warnings to physicians and companies selling products containing DHA supplements advertised as being beneficial for concussions. The FDA is calling these claims false and threatening legal action against any physician or company selling nutrients for this purpose.

In analyzing this report issued August, 2014 by the Federal Drug Administration, one wonders why the FDA failed to educate the consumer about rodent and human studies of distinguished researchers over the past decade, and more importantly, human research studies from the Institute of Medicine in 2011 and the U.S. Military calling for additional research and the use of fish oil with acute TBI. Instead, the FDA choose to

keep the consumer uneducated. In addition, they are thwarting attempts by physicians to further research and development of the important therapeutic use of a fatty acid which the FDA declared safe 20 years ago. It seems that the appropriate leadership role of the FDA should include educating physicians and consumers on the current status of fish oil research and promoting additional research for the benefit of the public it serves.

It is estimated that the cost of development and approval of a new drug is approximately $2.6B (Tufts, 2014), a percentage of which are fees collected by FDA from pharmaceutical companies. In issuing this negative report, perhaps the FDA is attempting to halt inexpensive public solutions from developing, thus allowing time for pharmaceutical companies to test prescription fish oil products requiring FDA approval and bringing profits to the FDA. As consumers await the actions of government bureaucracy, 3.8M consumers suffer concussion annually (AMSSM, 2013). In the meantime, consumers’ lack of information will cause them to bear the psychological and physiological burden of concussions, the long term neurological sequelae, increased health care premiums, and ultimately, the increased cost of purchasing FDA approved, prescription fish oil.

In 2014, the Academy of Nutrition and Dietetics issued a position paper on “Dietary Fatty Acids for Healthy Adults” they noted that Registered Dietitians are “uniquely positioned” to conduct research into dietary recommendations on fatty acids. The paper discusses fatty acid classifications and the need for 20-35% of the diet to be comprised of a variety of fatty acids. They discuss the structural importance of the double bonds in the omega-3 polyunsaturated fatty acids, and present a table describing the intake allowances recommended by the various agencies. The paper discusses the sources of DHA as being from fatty fish, seafood, salmon, sardines, tuna, herring, trout, seal meat, and marine or algal sources (AND, 2014). Importantly they state that while DHA has not been labeled an essential oil, because of the potential conversion of alpha- linolenic acid (ALA) to DHA, less than 1% of ALA reliably converts to DHA (Davis, 2003)(Burdge, 2004). DHA modulates inflammation and is neuroprotective. Supplements are made from fish oils such as anchovy, salmon, cod liver, krill and squid oils (AND, 2014). Up to 3g/day was generally recognized as safe by the FDA in 1997. Vegetarian sources of algae are available and genetically engineered supplements are being developed. The Academy’s position states the mean daily intake of DHA was

80mg for men and 60mg for women (AND, 2014) far below the recommended research dosages. Multiple agencies, including the American Psychiatric Association, do recommend fish twice a week for an average 450 to 500 mg of EPA and DHA per day (AND, 2014), stating that lower levels of DHA have been observed in individuals with cognitive decline and Alzheimer’s Disease (AND, 2014). The Academy’s Evidence Analysis Library examined 14 studies, whereupon 6 of these studies showed DHA demonstrated a decreased risk of cognitive decline (AND, 2014).

The Academy of Nutrition and Dietetics could be a controlling influence in the advancement of fatty acids as a major neurological and cardiovascular protectant by promoting research and dietary recommendations to dietitians to encompass this safe and effective food supplement in the scope of their practice. Thus far, only the American Psychiatric Association is willing to recommend 450mg to 500mg per day of DHA. The American Medical Society currently lacks the scope and educational background. However, once supplements become regulated, the pharmaceutical companies and physicians will control their benefits through less nutrient based drug compounds. Consumer will loose access to these nutrients and the cost of nutrient based drug compounds will skyrocket. The opportunity for dietitians to control fish oil and other supplements in nutrient form exists now. Consumers will reap the health benefits of pure biochemistry based nutrient supplements vs. pharmaceutical drug, non- nutrient interventions, and the scope of dietitians to heal through biochemistry will expand exponentially.

The military is seeing the benefits of fish oil to heal their traumatized soldiers. In the November 2014 issue of Military Medicine, Julian Bailes MD and Vimal Patel PhD report that “our knowledge of the pathophysiology of cerebral concussion has undertaken significant advances in the last decade.” Military have a higher risk of repetitive injury due to explosive devices, resulting in a “unprecedented rate of non- penetrating head injury” (Bailes and Patel, 2014). Mitigation or prevention can be accomplished through DHA improving the neuroprotective effect when high doses (40 mg/kg) are given (Bailes and Patel, 2014).

In this review, Bailes and Patel explain the more recently recognized damage caused by TBI including the build up of tau protein, neurofibrillary tangles, and the long term development of chronic traumatic encephalopathy (Bailes and Patel, 2014). They describe how the highly flexible, long chain DHA fatty acid creates thin phospholipids

which pack well within the cell membrane, creating a more permeable phospholipid more suitable to membrane proteins, transport, signaling, and enzymes. They re-iterate that DHA decreases b-amyloid plaque buildup, reduces neuronal apoptosis, and may act as a prophylactic against cerebral concussion (Bailes and Patel, 2014). They recognize that the U.S. FDA designated DHA as Generally Recognized as Safe in 1997 (FDA, 1997).

In concluding, Bailes and Patel discuss the availability of DHA from fatty fish or algae sources and the potential presence of mercury. They recognize that given the safety profile, general health benefits, purity, availability and affordability of DHA, both our athletes and military populations, with high exposure to repetitive brain impacts, are at risk without adequate DHA (Bailes and Patel, 2014).

Conclusion:

DHA has been demonstrated to have a role in TBI recovery. The current state of DHA literature is primarily based upon animal models although, the military has initiated human studies. There are several clinical trials of DHA for TBI in progress. DHA has a strong safety profile and is a promising therapy. Intake recommendations range from 250 mg/d to 500 mg/d while current dietary recommendations are less than half that at 90-120mg/d (Barrett, 2014). Rat studies have shown efficacy at a mean human intake of 387 mg/d of DHA (Barrett EC, 2014). Given these studies, timing would be excellent for AND, AMA, and FDA to evaluate adequate DHA intake levels and educate their professionals as to the benefits of DHA. Legal agencies might lessen the liability risk of

initiating TBI therapy. Organizational and legislative agencies entrusted with health care planning and protection might better serve the public by increasing awareness and availability of these beneficial findings. Our military, athletes, and scholars would benefit most from this information to protect their brain function, thereby decreasing the mental healthcare burden placed upon society in terms of excessive costs and loss of lives.

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Hibbeln JR: Fish consumption and major depression. Lancet 1998; 351(9110): 1213.

Huang WL, King VR, Curran OE, et al. (2007). A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain 130, 3004-3019.

Institute of Medicine, April 22, 2011. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

King VR, Huang WL, Dyall SC, Curran OE, Priestley JV, and Michael-TItus AT. (2006). Omega-3 faty acids improve recovery, whereas omega-6 fatty acids worsen outcome, after spinal cord injury in the adult rat. J Neuroscience 26, 4672-4680.

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Neurotransmitter Pathways affecting Concussion, TBI, Stress, Depression, Tremor, Stroke, and Anxiety

Neurotransmitter Brain Food: Rebuilding the Acetylcholine (Choline or Lecithin), Serotonin (5-HTP or tryptophan) and Dopamine (Tyrosine) Neurotransmitter Pathways.

A Case Study Attacks Stress, Anxiety, and Tremor with pathway amino acids, choline (lecithin) and co-factors.

A middle-aged female with a family history of anxiety and Parkinson’s Disease developed a tremor and mild pain in her left arm. She had a history of painful joint injuries and anxiety due to job-related stress. She obtained little exercise and used ibuprofen (Advil) therapy for the joint pain. At work she occasionally painted the interior of homes, often inhaling the fumes. She reported awakening in the morning with an upper body tremor and a cold left arm. Her fists would be tightened and her hands tingly. During the day, her extra-ocular muscles were painful and she had difficulty focusing. She experienced somewhat normal energy levels during the early part of each day and then fatigued. Athletic stress, work place stress, intense mental concentration, painting, an emotional event, sugar or deep-fried food ingestion stimulated the tremor and reduced her energy levels. At bedtime, upon turning off the lights, she experienced vertical gaze problems.

Her daily vitamins included vitamin B complex (100mg b.i.d. (twice daily)), vitamin C (500mg t.i.d. (three times daily)), amino acids (1500mg t.i.d), fish oil (1g), calcium citrate (600mg), calcium phosphate (600mg), iron (65mg), coenzyme Q10 (200mg), lysine (500mg), beta-carotene (10,000 IU), zinc (50mg), and a multi-vitamin.

She has a family member who has been on standard of care therapy for Parkinson’s Disease for the past 7 years but the disease has progressed. To alleviate her left arm tremor, she began ingesting choline and lecithin in increasing amounts, until the tremor subsided. During the first weeks of therapy, she experienced a mild frontal lobe headache, more significant on the right side. Stressful days would be followed by the upper body shiver and left arm tremor, the next morning upon awakening. Sugar ingestion stimulated the tremor within an hour. A stressful work situation stimulated the upper body tremor. She slept quite heavily during the first two months of choline and lecithin therapy. Attempts to reduce the choline and lecithin dosages re-established the tremor.

During the third month of therapy, heavy stress continued at work. She was anxious and had a negative outlook. To alleviate the sleepiness brought on by the choline/lecithin supplements, provide more energy, and support the dopamine pathway, she began taking tyrosine. To fortify the serotonin pathway and improve her mental outlook, she added 5-hydroxytryptophan (5-HTP). There were positive results the first day. With the tyrosine and 5-HTP, she was able to perform more of her normal daily activities. In time, with the combination of these supplements, the natural oils returned to her skin and menses became painless. She continued to decrease stress levels and overwork. She rested frequently.

The adrenal glands are responsible for producing many neurotransmitters. They are small walnut shaped glands resting on top of the kidneys which produce cortisone and neurotransmitters in response to stress. To help her adrenals, she began taking a bovine adrenal rebuilder, the amino acid methionine (controls the adrenals), minimal amounts of sugar, no high fructose corn syrup, no deep-fried foods nor alcohol.

At the beginning of the fourth month, she continued 95% tremor free. Her left arm continued to experience mild pain depending upon sugar and choline/lecithin levels. She experienced improvement in her daily energy level and her arm tremor and pain resolved almost completely. The left arm would experience some irritability after stressful days or skipped choline/lecithin supplements.

At 4 ½ months post tremor initiation, the subject was pricked with a garden thorn. It appeared that her blood had thinned. She had experienced no side effects of choline (nausea, vomiting, diarrhea, sweating, increased sweating, or salivation (Livestrong Website)) nor side effects of lecithin (rash, low blood pressure, diarrhea, vision problems, fainting or loss of appetite (Headquarters Website)). However, internet research showed that blood thinning may occur with choline/lecithin. She began using ibuprofen and aspirin sparingly. She decreased her dosage of lecithin, however, the tremor returned. She resumed the lecithin dosage and purchased a multi-vitamin containing vitamin K and increased green food consumption. (Vitamin K which is found in greens is important in the blood clotting process).

At five months post tremor her left arm was the same temperature as her right arm upon awakening. The fists and tingling findings were infrequent. The left arm continued to have some irritability after stressful events. Exposure to paint fumes initiated the tremor. Relief from tremors, extraocular fatigue, body twitches, and spontaneous crying was found with additional choline and lecithin. She experienced some daily facial flushing and left sided chest pain/pressure with exercise. Knowing methionine is stored in the heart, she reduced her daily methionine intake.

More research as to the benefits of choline, lecithin, methionine, and tyrosine to improve neurological health may be beneficial. Urine amino acid testing is available and would be important to utilize more frequently to determine amino acid levels pre and post amino acid or pharmaceutical therapy. Better availability of a urine amino acid neurotransmitter test that specifically provides tyrosine, tryptophan, choline and co-factor levels vital to support the three important neurotransmitter pathways would be beneficial. We expect that Wellness 2020 will bring these advancements. For a complete discussion of Wellness 2020 see the home page of http://www.wheatfreediseasefree.com.

Neurotransmitter Discussion:

Nerves are key to communication within the body. They tell a muscle to move or an organ to function. It takes two nerves, one from brain cortex to the spinal cord and a second from the spinal cord to the foot, to make the foot move. Nerves communicate through chemicals similar to a car battery. The nerve running from the brain to the spinal cord will pass a chemical called a neurotransmitter to the nerve running between the spinal cord and the foot to stimulate the receiving neuron. Neurotransmitters travel from the sending neuron to the receiving neuron through a gap (cleft) and they are frequently recycled back into the sending neuron to use again. The adrenal glands play a key role in producing neurotransmitters from amino acids and dietary protein.

Electricity traveling through a battery or a house is either turned on or off, making man’s design of current either excitatory or off. The Creator’s design is a bit more elaborate in that it involves both excitatory and inhibitory transmissions. Epinephrine, acetylcholine, and glutamate are mainly excitatory neurotransmitters while dopamine, norepinepinephrine, and GABA (gaba-amino-buteric-acid) are inhibitory.

On the Concussion Brain Food post at http://www.wheatfreediseasefree.com we discussed the importance of Omega-3 fatty acids (cell membrane formation), B-complex (nerve formation), and Amino Acids (protein/neurotransmitter formation) for healthy brain and nerve tissue. This Neurotransmitter paper examines the three main neurotransmitter production pathways: ACETYLCHOLINE, DOPAMINE, and SEROTONIN and the amino acids and vitamins required to keep these cells healthy and alive.

THREE NEUROTRANSMITTER PATHWAYS:

I. Production of ACETYLCHOLINE:

Phosphatidylcholine (Lecithin) —-> Glycerophosphatidylcholine —> Choline

Choline + Acetyl Coenzyme A —-> Acetylcholine

Acetylcholine functions as both an inhibitory and excitatory neurotransmitter controlling many of the body’s nerves including excitatory skeletal muscle contraction and inhibitory actions on the heart and brain. The body can convert phosphatidycholine (lecithin) to glycerophosphatidylcholine and then to choline. The body makes the acetylcholine neurotransmitter by adding acetyl coenzyme A to choline. Choline is used for cell communication and used to produce phosphatidylcholine and sphingomyelin which make cell membrane (Linus Pauling Institute). Choline contributes to the production of the myelin coating around nerves (Oshida K et al., 2003) and it supports the folate pathway to produce DNA (Institute of Food, Medicine, and Nutrition Board, 1998). The three neurotransmitter pathways described in this paper appear to depend upon each other’s viability. Acetylcholine, for example, has an important role in activating the Dopamine Pathway. Normal levels of the dopamine pathway neurotransmitters may not be produced without sufficient levels of acetylcholine to act as a stimulus (Patrick RL et al.,1971). Low choline and dopamine levels have been implicated in Parkinson’s Disease (Zurchovsky L, 2012).

Choline is an essential nutrient and it is water soluble, therefore must be replenished daily in the diet. Choline is found in foods such as eggs, fish, liver, milk, wheat germ, and quinoa and is available as a supplement as choline or lecithin. Since choline plus acetyl coenzyme A make acetylcholine, sufficient quantities of both must be present. Adequate intake levels of choline for healthy individuals are 425-550mg/day (Linus Pauling Institute).

Low choline levels have been found to correlate with anxiety, intelligence and worry (Coplan JD et al., 2012). Liver and muscle damage (Sha W et al., 2010) athlerosclerosis, neurological disorders (Ziesel SH, et al., 2009), infertility (Johnson AR et al., 2012), and growth impairment (De Simone R et al, 1993) are promoted with deficiencies. Those who do not eat enough whole eggs may be at risk (Hasler CM et al., 2000). Choline is in high demand during pregnancy and helps to prevent neural tube defects (Pitkin RM, 2007).

Choline, B9 (folate), B12 (pyridoxal phosphate), and methionine have key roles in the methyl donor system and cancer protection (Kadaveru K, 2012). Diets rich in choline may lower the risk for breast cancer (Xu X et al., 2009), promote REM sleep (Kushikata F, 2006), and memory (Zhang W et al., 2012). Choline has been used as a treatment for Alzheimer’s disease (Zhang W, 2012), and stroke (Gutierrez-Fernandez et al., 2012). Choline is being studied to help treat traumatic brain injury. Choline or lecithin can be useful in treating neurological disorders characterized by inadequate release of acetylcholine such as Tardive Dyskinesia (described as involuntary, repetitive facial or limb movements, Growdon JH,1978). A single meal containing lecithin increases concentrations of choline and acetylcholine in rat adrenals and brain tissue (Hirsch MJ, 1978) Perinatalcholine is neuroprotective for seizures, depression, and the effects of alcohol (Glenn MJ et al., 2012). Ninety percent of humans in a research study conducted had choline below adequate levels (Zeisel, 2009).

II. Production of SEROTONIN:

Tryptophan ——————> 5-Hydroxytryptophan (5-HTP)

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

The Tryptophan to 5-HTP conversion requires Vitamin B3, B9, Iron and Calcium, and is facilitated by the enzyme tryptophan hydroxylase

The 5-HTP to Serotonin conversion requires Zinc, Vitamin B6, Vitamin C, and Magnesium and is facilitated by the enzyme dopa decarboxylase

.(Enzymes and cofactors required to produce 5-HTP and 5-HT from the Understand and Cure Website.)

Tryptophan, an essential amino acid for humans, makes serotonin. It must be included in the diet, humans are unable to produce it. Tryptophan is found in eggs, spirulina, fish, poultry, nuts, seeds, organic soybeans, milk, and cheese.

To convert tryptophan into 5-HTP and produce serotonin (5-HT, 5-hydroxytryptamine) an enzyme called tryptophan hydroxylase(TPH) is required with the cofactors vitamin B3 (niacin), B6 (pyridoxal-5-phosphate), B9 (folate), vitamin C (ascorbic acid), magnesium, iron, and calcium. High fructose corn syrup may decrease absorption of trytophan from the gut (Ledochowski M, et al., 2001) thereby reducing the quantity of TPH enzyme and serotonin produced. The Parkinson’s medication carbidopa-levadopa (Drugs.Com Website) is known to interfere with tryptophan, thus TPH and serotonin production.

Ninety percent of serotonin is stored in the chromaffin cells of the intestines (Donnerer J, et al., 2006) where it regulates digestion and maintains stomach function. Additionally, the remainder of serotonin is found in platelets and the central nervous system where serotonin is produced in the raphe nuclei and pineal gland of the brain (Neurophysiology Website). Nerve axons from the raphe nuclei cover the entire length of the brainstem and extend to all parts of the brain including the cerebellum and spinal cord where serotonin influences memory, learning, behavior, mood (well-being, happiness), appetite, sleep and regulates insulin (Young SN, 2007).

When a sending neuron releases serotonin to stimulate a receiving neuron, the neurotransmitter travels out the sending neuron, across a gap or cleft to receptors on the receiving neuron. By design the neurotransmitter is quickly reabsorbed back into the sending neuron and recycled. A drug that modifies this normal physiology by keeping serotonin in this gap between the neurons longer is called a serotonin re-uptake inhibitor (SSRI). The result of a SSRI is to create the physiological impression that more serotonin is present thus continuing the stimulation of the receiving neuron. Many antidepressants, anti-anxiety drugs and post-traumatic stress drugs function in this manner. These drugs do not produce more serotonin to resolve a deficiency, but create the illusion that more is present.

Should the body be deficient or low on serotonin, only ingesting the proper foods or supplementing the diet with tryptophan or 5-HTP provides more serotonin to the brain and intestines. Studies have shown that a change in only 10% of the number of serotonin transporters will affect anxiety levels (Lesch KP, et al., 1996). Research shows that supplementing tryptophan or 5-HTP (available at nutritional stores) helps to maintain serotonin levels and aids with depression and anxiety (Murphy SE, et al., 2006). Providing adequate nutrients is important to maintaining healthy cells and production pathways.

III. Production of DOPAMINE, NOREPINEPHRINE, and EPINEPHRINE:

Phenylalanine ———> Tyrosine ————> DOPA ————> Dopamine

Dopamine ——————–> Norepinephrine ———————–> Epinephrine

The Phenylalanine to Tyrosine conversion requires Vitamin B9.

The Tyrosine to DOPA conversion requires Vitamin B9 and Iron.

The DOPA to Dopamine conversion requires Vitamin B3, Vitamin B6 and zinc.

The Dopamine to Norepinephrine conversion requires Vitamin C.

The Norepinephrine to Epinephrine conversion requires S-Adenylmathionine (SAMe)

This is a complicated pathway in that if sufficient amounts of the amino acid phenylalanine or tyrosine, vitamin B9 (folate), iron, vitamins B3 (niacin) + B6 (pyridoxal phosphate), zinc, vitamin C (ascorbic acid), and methionine (used to produce SAMe) are all present, then the three catecholamine neurotransmitters in this pathway (dopamine, norepinephrine and epinephrine (adrenaline)) are produced to keep the pathway cells strong. If production falls and pathway cells die off (apoptosis) Parkinson’s Disease or Altzheimer’s may develop.

Phenylalanine is found in fish, beef, chicken, milk, cheese, eggs, and nuts (www.livestrong.com/article/317897-list-of-foods-that-contain-phenylalanine/).

Tyrosine is found in beef, pork, turkey, duck, fish, egg whites, cheese, milk, and soy milk (www.livestrong.com/article/81485-foods-Ityrosine/).

Methionine is essential amino acid required in the diet. It is found in popcorn, grass fed meat, brown rice, organic oranges, and yogurt. SAMe (s-adenylsylmethionine) is made from methionine. It’s production is influenced by the neurotransmitter acetylcholine produced in the Acetylcholine Pathway described above. Methionine is also found in wheat and can be a deficiency in a wheat free diet. Methionine controls the adrenal glands which are the first responders under stress conditions. Stress may deplete methionine stores. Methionine chelates metals and neutralizes harmful chemicals. Painters and those exposed to chemicals may require additional methionine to neutralize these chemicals. Methionine is critical for donating a methyl group (-CH3) to norepinephrine to produce epinephrine in the Dopamine Pathway giving the body energy. Adrenals that are subjected to low levels of methionine may be a contributing factor to Adrenal Insufficiency, Tremor, and Parkinson’s Disease.

Vitamin B3, Vitamin B6, Vitamin B9. B-complex vitamins are water soluble and must be ingested daily.

Foods highest in Vitamin B3 (niacin) can be found at http://www.healthaliciousness.com/articles/foods-high-in-niacin-vitamin-B3.php.

Foods highest in Vitamin B6 (pyridoxal phosphate) can be found at http://www.healthaliciousness.com/articles/foods-high-in-vitamin-B6.php.

Foods highest in Vitamin B9 (folate) are found at

http://www.healthaliciousness.com/articles/foods-high-in-folate-vitamin-B9.php.

Vitamin C is water soluble and must be ingested daily. Vitamin C food sources are listed at http://www.healthaliciousness.com/articles/vitamin-C.php. Vitamin C is the major vitamin keeping the adrenal organs healthy.

Zinc is an important mineral. There is an informative web site listing zinc foods at http://www.healthaliciousness.com/articles/zinc.php.

Iron food sources are listed at http://www.healthaliciousness.com/articles/food-sources-of-iron.php.

Dopamine is quickly degraded and excreted in the urine. While there is some re-uptake, dopamine must be continually replenished. Dopamine is produced in the adrenals, gastrointestinal tract, neurons, and brain generating either excitatory or inhibitory nerve impulses. It has important roles in reward and punishment brain activity, increased heart rate and blood pressure, sleep, mood, attention, working memory, learning, problem-solving, social behavior, cognition, voluntary movement, pain, and motivation.

Dopamine deficiency causes decline in memory, attention, problem-solving and sociability. Insufficient dopamine biosynthesis in the dopaminergic neurons can cause Parkinson’s Disease (Grace AA, 1984). Stress increases the depletion of dopamine stores (Furuyashiki T, 2012). Dopamine plays a role in pain processing (Viisanen H, et al., 2012 ),

Norepinephrine (noradrenaline) can be produced from tyrosine or phenylalanine in the presence of vitamin B9 (folate), iron, vitamin B3 (thiamine), vitamin B6 (pyridoxal phosphate), and zinc. Norepinephrine is a neurotransmitter produced in the adrenal glands which helps control the body’s sympathetic system. This system is responsible for the “fight or flight response” to danger (Guyton A, 2006). Norepinephrine is a stress hormone (Tanaka M, et al., 2000). Its release increases heart rate, releases glucose from tissue, increases blood flow to skeletal muscle and brain oxygen levels.

Norepinephrine is important to prevent fainting (syncope) by preventing a drop in heart rate to maintain blood pressure. Neurons project throughout the brain and spinal cord.

Norepinephrine has a role in behavior, motivation, attention, focus, decision making, learning, motor output, response to performance error, negative feedback, monetary loss, cost benefit evaluation, task difficulty and the decision making process (Devauges V, et al., 1990) (Lutzenberger, W, et al., 1987) (Usher M, et al., 1999) (Eisenberger M, et al., 2003)(Falkenstein M, et al., 1991)(Genring WJ, et al., 1993) (Neurophysiologica 35), (Nieuwenhuis, S, et al., 2003). It has different actions upon different cell types. Low levels of this neurotransmitter have a role in depression along with serotonin.

Norepinephrine is reabsorbed and degraded within seconds. It works as an anti-inflammatory agent in brain tissue, suppressing cytokines. In Alzheimer’s Disease the norepinephrine producing cells may be affected (Szot P, et al., 2012).

Epinephrine (adrenaline) is an important component of the sympathetic fight or flight system. Production of epinephrine occurs in the adrenals from phenylalanine and tyrosine. It acts on most all body tissues. Epinephrine increases blood glucose and fatty acid levels which provide energy for cells (Sabyasachi S, 2007). Plasma levels of epinephrine may increase 10-fold during exercise and perhaps by 50-fold during stress requiring an ample supply of tyrosine (Raymondos, K, 2008) (Baselt, 2000). Epinephrine is released during times of “physical threat, excitement, noise, bright lights, and high temperatures” (Nelson L, 2004). Stress causes the sympathetic nervous system to stimulate adrenocorticotrophic hormone (ACTH) which stimulates epinephrine release (by activating tyrosine hydroxylase and dopamine-B-hydroxylase). It also stimulates cortisone production by the adrenals.

One study found that catecholamines (neurotransmitters derived from tyrosine in the dopamine pathway) in rat adrenals took …FOUR DAYS … yes, FOUR DAYS … to recover their original levels after being chemically depleted, and the regeneration of these neurotransmitters required acetylcholine (Patrick RL, et al., 1970). A human taking a heavy examination may require several days to restore normal neurotransmitter levels, yet universities schedule mid-term and final exams on consequentive days allowing no time for neurotransmitter restoration. When human adrenals are stressed they may take a significant amount of time and resources to regenerate neurotransmitters and cortisol.

Tyrosine, vitamin B-complex, vitamin C, zinc, iron, and methionine or SAMe can be purchased at a health food store to supplement the diet and maintain a healthy dopamine pathway.

“Parkinson’s Disease is associated with the depletion of tyrosine hydroxylase, dopamine, serotonin, and norepinephrine” and “administration of L-dopa may deplete L-tyrosine, L-tryptophan and 5-hydroxytryptophan (5-HTP), serotonin and sulfur amino acids (cysteine, methionine)” (Hinz M, et al., 2011). Researchers found that co-administration of L-dopa with 5-HTP, L-tyrosine, L-cysteine and cofactors enabled more effective treatment for Parkinson’s Disease by allowing optimal dosing of L-dopa for symptom relief without the barriers imposed by side effects and adverse reactions. (Hinz M et al., 2011)

THE CRITICAL ADRENALS:

We have discussed three important pathways for producing neurotransmitters. The organs most responsible for this job are the adrenals. The adrenals are critical to brain health. They are small, walnut shaped glands positioned on top of the kidneys. Back pain can be felt below the rib cage on either side when the adrenals are over-stressed. These organs produce neurotransmitters, sex hormones, and cortisol. Under athletic, academic, work-related, emotional, food-related, disease or inflammation-related stress conditions, the adrenals are the first to respond by producing high amounts of cortisol. The body tends to prioritize, so high cortisol production may come at the cost of reduced sex hormone and neurotransmitter production. We may see this in the triathlete with sporadic menses or the businessperson or student with high anxiety levels. The adrenals are prioritizing cortisol production to cope with the acute or chronic stress over the production of sex hormones and neurotransmitters

Upon the realization that these tiny organs are responsible for handling these vital functions, keeping the adrenals healthy becomes of critical importance. We have described the three neurotransmitter pathways to reinforce the importance of providing the proper amino acids and vitamins to the body to keep these pathways alive and well. Cells die off when adequate nutrients are not present. Vitamin C and the amino acid methionine are important for general adrenal function. Methionine is found in wheat, so wheat free diets may be deficient in methioinine. Glandular adrenal rebuilders are available at health food stores. Sugar, high fructose corn syrup, alcohol, and deep fried food consumption stress out the adrenals and make them work hard. There is an excellent book written by Dr. James Wilson, entitled “Adrenal Fatigue – The 21st Century Stress Syndrome”, (Smart Publications, 2001). A future http://www.wheatfreediseasefree.com post will discuss adrenal insufficiency, methionine and a wheat free diet. Restoring adrenal health and providing sufficient neurotransmitter substrate may be critical to restoring neurotransmitter supplies and eliminating disease. More research should be completed and better monitoring of neurotransmitter nutrient pathways through physician and home based testing would be helpful.

Street Drugs, Nicotine, Caffeine, and Neurotransmitters:

The street drug cocaine is a triple re-uptake inhibitor in that it blocks the re-uptake of serotonin, dopamine and norepinephrine (Fattore L, et al., 2009 ). Street drugs can increase dopamine levels 10 fold and temporarily cause psychosis (Williams). Amphetamines are similar in structure to dopamine. MDMA (ecstasy) releases serotonin, norepinephrine and dopamine and then inhibits their transport which increases concentrations within cell cytoplasm (Bogen IL, et al., 2003) (Fitzgerald JL, et al., 1990).

Amphetamines increase the concentrations of dopamine, serotonin and norepinephrine possibly by reversing the transport of dopamine and serotonin back into the gap or cleft between the neurons (Florin SM, 1994) (Jones S, et al., 1999). Dextromorphan, a cough suppressant, works as an SSRI (Schwartz AR, et al., 2008). LSD is a serotonin agonist in that it stimulates the serotonin receptor on the receiving neuron by mimicking serotonin (Titeler M, et al., 1988). Caffeine increases activity of serotonin, acetycholine, epinephrine, dopamine, and norepinephrine. Nicotine is thought to increase acetylcholine and dopamine levels. Street drugs, caffeine, and nicotine force the body to release stores of neurotransmitters and then keep the neurotransmitter in circulation by inhibiting the reuptake. Again, these drugs are not making more neurotransmitter but they are depleting current stores and tricking the body into thinking there is more chemical. The only way to enable the body to produce more neurotransmitters is to provide the proper nutrients through diet or supplements.

Analysis Unique to the Wheat Free Diet:

Many individuals damage their adrenals through alcohol, sugar, high fructose corn syrup, deep fried foods, low vitamin C and low nutrient intake causing depression, fatigue and eventually tremor. The case above is unique, because this patient eats a healthy diet with the exception of wheat which contains the amino acids methionine and lysine. Thus, her diet may be deficient in methionine. However, nutritiondata.com shows detailed analysis that if she consumes meat, ample methionine should be present. Unlike earlier times, most cattle and fish are no longer raised in the wild. Do they still contain adequate amino acids? If this subject typically eats meat, containing several grams of amino acids per day, why would 500mg – 1g of supplemental methionine improve her condition?

Additionally, methionine is responsible for chelating harmful chemicals such as those found in paint. She may require additional methionine to detoxify the fumes. This subject is highly stressed which would cause the adrenals to produce more cortisone. Regulation of the adrenal-pituitary-hypophyseal axis requires methionine. Perhaps a combination of low dietary intake plus a high methionine requirement resulted in damaging her adrenals and a reduction of neurotransmitter production.

Case Study References:

Livestrong website: http://www.livestrong.com/article/458050-choline-risks/

Headquarters Website: http://www.nutritionalsupplementshq.com/soy-lecithin-side-effects/

Acetylcholine References:

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Street Drugs, Nicotine, Caffeine, Alcohol and Neurotransmitters:

Jones S, Kauer JA (November 1999). “Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area”. J. Neurosci. 19 (22): 9780–7. PMID 10559387.

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Williams: http://www.williams.edu/imput/synapse/pages/IIIB5.htm

12-02-12

To request specific dosage data for this case study, please send an email to wheatfreediseasefree@gmail.com.

Photograph: Jordanelle Reservoir, Park City, Utah

A Special Thanks to Billie Jay Sahley PhD. and her books on amino acids including her book “The Anxiety Epidemic” for inspiring research with neurotransmitter pathways, substrates and cofactors.

Concussion Brain Food High School Athlete Dietary Survey

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.

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 blocks. Amino acids require B-complex vitamins to metabolize. Proteins 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 supplements. Fish 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):

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:

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:

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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:

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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

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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

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

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 B–complex 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:

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.

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

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).