therapy – Brain Food … Brain Food

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.

References:
Bailes JE, Mills JD. (2010). Docosahexaenoic acid reduces traumatic axonal injury in a

rodent head injury model. J. Neurotrauma 27, 1617-1624.

Bailes JE, Patel V, (2014). The potential for DHA to mitigate mild traumatic brain injury. Mil Med 2014 Nov;179(11 Suppl):112-6. doi: 10.7205/MILMED-D-14-00139.

Barrett EC, McBurney MI, Ciappio ED. w-3 fatty acid supplementation as a potential therapeutic aid for the recovery from mild traumatic brain injury/concussion. Adv Nutr. 2014 May 14;5(3):268-77. doi: 10.3945/an.113.005280. Print 2014 May.

Burdge G. Alpha-linolenic acid metabolism in men and women: Nutritional and biological implications. Curr Opin Clin Nutr Metab Care. 2004;7(2):137-144.

Crawford MA. (1993). The role of essential fatty acids in neural development: Implications for perinatal nutrition. Am J Clin Nutr 57, 703S-09S; discussion 09S-10S.

Davis BC, Kris-Etherton PM. Achieving optimal essential fatty acid status in vegetarians: Current knowledge and practical implications. Am J Clin Nutr. 2003;78(3 suppl):640S-646S.
FDA Substances affirmed as generally recognized as safe: Menhaden oil. Final Rule: Federal Registry, 1997, 30751-30757.

Figueroa JD, Cordero K, Lian MS, De Leon M. Dietary omega-3 polyunsaturated fatty acids improve the neurolipidome and restore the DHA status while promoting functional recovery after experimental spinal cord injury. J Neurotrauma. 2013 May 15;30(10):853- 68. doi: 10.1089/neu.2013.2718.

Figueroa JD, Cordero K, Serrano-Illan M, Almeyda A, Baldeosingh K, Almaguel FG, De Leon M. Metabolomics uncovers dietary omega-3 fatty acid-dervied metabolites implicated in anti-nociceptive response after experimental spinal cord injury. Neuroscience 2013;255-1-18. doi: 10.1016/j.neuroscience.2013.09.012. Epub 2013 Sep 14.

Hallahan B, Hiebbeln JR, Davis JM, Garland MR: Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial. Br. J Psychiatry 2007; 190: 118-22.

Harmon KG, Drezner JA, Gammons M, Guskiewicz KM, Halstead M, Herring SA, Kutcher JS, Pana A, Putukian M, Roberts WO. (2013). American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med 2013 Jan; 47(1);15-26. doi: 10.1136/bjsports-2012-091941.

Hasadri L, Wang BH, Lee JV, Erdman JW, Liano DA, Barbey AK, Wszalek T, Sharrock MF, Wang HJ. Omega-3 fatty acids as a putative treatment for traumatic brain injury. J Neurotrauma. 2013 Jun 1;30(11):897-906.doi:10.1089/neu.2012.2672.Epub 2013 Jun 5.

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.

Lewis MD, Bailes J, (2011) Neuroprotection for the warrior: dietary supplementation with omega-3 fatty acids. Mil Med 2011 Oct; 176(10):1120-7.

Mills JD, Bailes, JE, Sedney CL, Hutchins H, and Sears B. (2011). Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model. J. Neurosurgery 114, 77-84.

Mills JD, Hadley K, and Bailes JE. (2011). Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury. Neurosurgery 68, 474-481; discussion 481.

Tufts Center for the Study of Drug Development, Tufts University; http://csdd.tufts.edu/new/complete_story/pr_tufts_csdd_2014_cost_study, 2014