Traumatic Brain Injury (TBI) and Concussion: Time for Brain Food

IMG_0008

Traumatic Brain Injury (TBI) and Concussion: Time for Brain Food

Presented July 7, 2017 in Snowbird, Utah at the 2017 Neurotrauma Conference. Abstract Published July issue of Journal of Neurotrauma.

Introduction: Given combat casualties, sports-related injuries, and motor vehicle accidents, traumatic brain injury (TBI) is the leading cause of death under age 44. TBI deficits linger in concentration, depression, sleep-wake cycle, behavior and motor skills. Basic science has long instructed that omega-3 fatty acids, specifically docosahexaenoic acid (DHA), improve cell membrane fluidity and signaling. B-complex vitamins provide nerve myelin substrate and neurotransmitter cofactors. The presence of all 20 amino acids is critical to cell membrane and neurotransmitter protein production.

Hypothesis: This systematic review hypothesizes that given ample substrates of DHA, B-complex vitamins, and elemental amino acids, the brain will promote tissue restoration.

Methods: A literature search of the PUBMED database identified current research using the keywords “omega-3-fatty acid”, “B-complex vitamin”, “elemental amino acids” with “TBI”, and “MTHFR C667T”.

Findings: DHA deficiency in the population may be as high as 80%. DHA having more double bonds than vegetable oil, provides greater brain tissue strength. Researchers have found that DHA increases cognitive ability, motor function, membrane fluidity, cell signaling, and is neural protective. DHA enhances neuronal growth, transmission speed, dendritic formation, and synaptic maintenance. The American Society for Parenteral and Enteral Nutrition now suggests fish oil for trauma patients. Studies have found B- complex vitamin deficiencies in spinal cord injury patients. B-complex vitamins improve sensorimotor skills, cognitive function, memory, vision, and DNA methylation. Folate’s role in DNA methylation may be reduced by genetic polymorphisms. Amino acids mediate cell damage, are neuro-protective, and decrease hippocampal deficits. Amino acids demonstrate increased cerebral blood flow and DNA methylation.

Conclusion: DHA, B-complex vitamins and elemental amino acids show evidence of improving TBI prognosis. These nutrients are a safe, effective manner to apply basic science to rebuild brain tissue and improve patient outlook.

Keywords: TBI, concussion, neuroprotective, DHA, B-complex, amino acids, MTHFR C677T

Page 1 of 34

 

Traumatic brain injury(TBI) causes approximately 52,000 deaths, 220 hospitalizations, and 85,000 permanent cases of debilitation each year in the U.S. “Approximately 15-20% of U.S. Soldiers in Iraq and Afghanistan experience TBI while deployed, making TBI one of the most common injuries among military personnel (Warden D, 2006).” “It is estimated that 1.6 – 3.8 million sports-related TBIs occur in the US annually (Hasadri et al., 2013).” In 2010, the economic cost of TBI was estimated at $76.5 Billion (Humphreys et al., 2013). Concussion or mild TBI (mTBI) has seen a 4.2 fold case increase since 1998 (Barrett et.al, 2014). Symptoms of mTBI include loss of consciousness, headache, mental fogginess, light sensitivity, and sleep disturbances for typically 7-10 days post injury. These symptoms may persist for months or longer. (Barrett et.al. 2014). “TBI is one of the most disabling injuries causing motor and sensory deficits, and leading to severe cognitive, emotional, and psychosocial impairment, crippling vital areas of higher functioning (Hasadri et al., 2013).” “Long term health disorders associated with TBI include post-traumatic stress disorder (PTSD), neurodegenerative diseases (Alzheimer’s disease and Parkinsonism), neurocognitive deficits, psychosocial health problems (e.g. Binge drinking, major depression, impairment of social functioning and ability to work, suicide), epilepsy, pain, and other alterations in personality or behavior (Omalu et al, 2006) (Guskiewicz KM, 2007)(Omalu BI, 2010).” The societal impact is staggering given brain injury’s excessive financial cost, short term disabilities, and long term propensity to cause mental disease. While there is no cure for TBI, the following scenario has lead to the exploration of a potential effective therapy.

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 began missing school due to the chronic pain, causing her stellar grades to decline. This patient’s family traveled extensively the following year, paying for eight physician visits with no improvement in her condition. Despite their medical biochemistry coursework, none of these physicians offered a biochemistry based nutrient therapy that would replenish her injured brain tissue. As months passed, she discontinued sports and “lost hope in life”. To avoid social exclusion, she avoided public discussion of the pain. The following year, this patient learned about biochemical nutrients and began taking fish oil, B complex, and amino acids to rebuild brain tissue. Over the next month, her concussion symptoms diminished, allowing her to return to school and sports.

Results such as these, plus the fact there is no existing therapy for TBI, have prompted the research presented in this paper. This paper proposes that the brain macronutrients docosahexaenoic acid (DHA), B-complex vitamins, and amino acids, may be suited to replenish damaged brain tissue and lessen the impact of future injuries. Current literature is evaluated regarding the efficacy of utilizing these brain macronutrients to restore and fortify brain tissue, possibly minimizing future injuries. This paper is intended to bring heightened awareness to medical practitioners as to the importance of using these brain macronutrients in the treatment of TBI. To be sure these practitioners

Page 2 of 34

 

already have comprehensive training in biochemistry. Nevertheless, when medicine seeks restorative therapies, biochemistry is rarely applied. Albeit, the brain’s biochemical intricacies extend far beyond man’s comprehension. “The pathological sequelae of TBI are mediated by an interaction of acute and delayed molecular, cellular and physiological events that are both complex and multifaceted physiological complexity of brain (Flanagan et al. 2008).” “A successful TBI treatment may have to simultaneously attenuate many injury factors (Scrimgeour & Condlin, 2014).” Nutrients with their extensive functionality may indeed attenuate many complex factors, simultaneously. Providing rich macronutrient supplies would allow the brain to synergistically facilitate repair without second injury (IOM, 2011) and void of major contraindications/side effects. “The evidence supporting multiple dietary components to reduce TBI-associated neuroinflammation is strong” expectedly because “there may be considerable synergism between them”. “If used appropriately, there may not be a downside to using food agents for therapy (Scrimgeour & Condlin, 2014).” It is hoped that through the biochemical nutrient findings presented in this paper, medicine will better provide brain macronutrient substrates to synergistically and comprehensively revitalize pathways and repair brain tissue for the long term. If medicine will consider using macronutrient biochemistry such as omega-3 fatty acids, B-complex vitamins, and amino acids so diligently studied and taught, the long term therapeutic results may be astounding. It is in this hopeful vein that this paper considers fish oil, B complex vitamins and amino acid brain macronutrients as therapy for TBI.

Fish Oil (DHA/EPA) – Omega 3 fatty acids

The most important brain macronutrient is fish oil. Fish oil contains the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentanoic acid (EPA). “DHA is a primary structural component of the mammalian cortex, comprising 50% of neuronal membrane phospholipids (Hasadri et al., 2013)(Singh et al., 2005).” While Western diets provide copious amounts of vegetable oil, “the CDC now estimates that up to 80% of the United States population is omega-3 fatty acid deficient (Scrimgeour & Condlin, 2014).” Studies report that omega-3 fatty acid deficiency for a single generation can decrease DHA content by up to 40% whereas severe DHA depletion (up to 80%) can be achieved after two or more consecutive generations (DeMar et al, 2006). Desai confirms that after three generations, “over 70% DHA depletion was observed in the cerebellum” (Desai A, et al, 2014). This widespread, generational deficiency makes fish oil and specifically DHA, the most important brain macronutrient to fortify.

The Western diet has made adequate dietary consumption of DHA and fish oil more challenging. Historically, the vegetable oil to fish oil dietary consumption ratios were closer to 1-2:1 (Scrimgeour & Condlin, 2014). This ratio mirrors DHA to vegetable oil concentration in the brain. However, in current diets, vegetable oil to fish oil consumption can be as high as 50:1 (Lewis et al., 2013). This ratio is likely due to increased red meat and vegetable oil consumption, and decreased fish consumption. While free range animals produce DHA, once these animals are caged and grain fed, their meat and eggs no longer contain DHA. Research finds that omega-3 fatty acids

Page 3 of 34

 

such as DHA “must be obtained from the diet, and are highly enriched in algal oil, krill, and cold water fish (Kris-Etherton et al, 2000)(Raper NR et al, 1992)(Tur JA, et al., 2012).” Often alpha linolenic acid(ALA) food sources such as “nuts, soybean, canola, and flax seed oils” are considered to be fortification of DHA levels. Unfortunately, insignificant amounts of ALA are converted to DHA, making these foods poor sources of DHA (Simopoulos AP, 2011). It is best to consume DHA foods directly or fortify the biochemical nutrient. The best foods are fresh fish such as salmon, tuna, and trout. DHA can also be found in fish skin, free range meat, cage free eggs, fortified milk, and fish oil.

While fish oil contains both DHA and EPA, DHA has been found to be more important for maintaining cell membrane structure. As compared with vegetable oil, the omega-3 fatty acid DHA contains double bonds every third carbon, while the omega-6 vegetable oil contains only one double bond every sixth carbon. The DHA double bonds provide more strength, likely contributing to cell membrane structures which better withstand concussion. Research finds that DHA is important for “structural components of cell membranes, modulating membrane fluidity, cell wall thickness, cell signaling, and mitochondrial function”. DHA is “readily retained in neuronal plasma membranes … influencing the phospholipid content of plasma membrane (Dyall SC et al, 2008)(Salem N, et al., 2001).” “Membrane DHA in the brain provides resilience against propagation of injury-induced cellular damage and facilitates adaptive responses for recovery (Desai et al., 2014).” In neuronal membranes, DHA promotes growth (Cao, et al, 2005)(Robson et al., 2010), and within the body has an anti-inflammatory action (Scrimgeour & Condlin, 2014). Substantial rodent and human research findings support the importance of the brain macronutrient DHA to effect healing of TBI.

Rodent DHA Neuroprotective Findings and Safety

Studies indicate that TBI is a progressive event which causes axonal nerve injury and leads to the swelling and disconnect of the axon membrane in hours to days post injury. Brain damage causes a lack of transport and communication across axonal membranes, ultimately leading to cell death (Mills JD, et.al., 2011). “Membrane degrades phospholipids (Homayoun, et.al, 2000) resulting in disturbances in cellular membrane functions and contribution to secondary neuronal injury ” (Horrocks & Farooqui, 2004). DHA is an integral component of axonal and cell membrane structures, necessary to facilitate repair following TBI.

The findings from several rodent studies demonstrate that DHA in the diet improves membrane structure to enhance cell function and provides neuroprotection. UCLA researchers demonstrate that DHA in the diet improved molecular substrates of plasticity affected with brain concussive injury. “Diet plays a critical role to build resistance against the effects of TBI. Proper exposure to omega-3 fatty acids during gestation and throughout maturation of the central nervous system (CNS) is crucial for building neural resilience” (Ying et al., 2012). UCLA also found that the “combination of dietary DHA and voluntary exercise … counteracted the effects of TBI on cognitive function, … synaptic plasticity, and plasma membrane homeostasis.” “Exercise

Page 4 of 34

 

normalizes DHA content in the brain” and when combined with DHA supplementation has a “strong therapeutic potential for reducing TBI’s deleterious effects on membrane homeostasis, synaptic plasticity and cognition (Wu, et al., 2013).” Agrawal’s team from UCLA similarly found that “consumption of an omega-3 diet during early life influences the capacity of the adult brain to resist the effects of TBI”, thus giving credibility to DHA’s role in energy homeostasis, plasticity, mitochondrial biogenesis and control of oxidative damage (Agrawal, et al., 2014).

The Mayo Clinic reports that DHA is a highly neuroprotective and integral component for rebuilding brain cell membrane. It is the “longest unsaturated fatty acid found in biological membranes”. “The structure is tremendously flexible and …. versatile” requiring minimal energy for conformation changes (Stillwell & Wassall, 2003)(Stillwell et al., 2005). “DHA is capable of undergoing rapid interconversions… and is particularly enriched in membranes which require rapid vehicle formation and release, such as rod outer segments in the retina and neuronal synapses.” (Stillwell et al., 2005). The “omega-3 fatty acids are essential for maintaining membrane fluidity (Valentine & Valentine, 2004) which in turn impacts neuronal cell adhesion, axon guidance, synapse maintenance, dendritic formation, and the speed of neuronal transmission (Hering et al., 2003)(Innis SM, 2008).” Additionally, membrane Na+/K+ pump failure is a common finding in TBI. DHA may play a role in maintaining the Na+ K+ pump which accounts for 60% of the energy utilization in the brain (Turner et al, 2003). Omega 3 fatty acids were found in retinoid X receptors which affect neuronal growth and proliferation, differentiation of catecholaminergic neurons, and the hippocampus (Innis SM, 2007) (Lane & Bailey, 2005). Finally, omega 3 fatty acid deprivation played a role in “1) decreased body size of neurons in hippocampus, hypothalamus, and parietal cortex, 2) reduced complexity of dendritic arborization on cortical neurons and 3) significant deficits in spatial learning and memory (Ahmad et al., 2002)(Aid et al., 2003)(Chaion, 2006)(Innis et al., 2001)(Wainwright et al., 1998).”

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 et al., 2013). Spinal cord tissue contains biochemical components analogous to cerebral tissue. Spinal cord injuries (SCI) have long caused debilitating injury to the sensory and motor neurons below the injury site. DHA supplemented for 8 weeks in female Sprague-Dawley rats mediated the chronic pain present with SCI. Researchers found that our Western diet may be hindering recovery from SCI, and that chronic DHA deficiency is associated with dysfunction (Figueroa et al., 2013). Their findings support dietary prophylaxis with DHA given distinctive improvements in nerve function that may facilitate recovery (Figueroa et.al., 2013).

An NIH study confirms DHA’s role in motor function by evaluating mice with DHA depletion. Researchers found that vestibulo-motor functioning in terms of acute motor deficits and fine motor control are impeded in DHA deficient mice (Desai et al., 2014). Acute motor deficits as determined by the rotarod were decreased by 50%. In one report, “when DHA was given within an hour of spinal cord injury (SCI), neuromotor

Page 5 of 34

 

function was maintained but the effect was lost when treatment was delayed four hours”. Further, DHA decreases neuronal damage by decreasing post-ischemic inflammation, and is neuroprotective (Hong et al., 2003) (Mukherjee et al., 2004).

Schober and colleagues from the University of Utah reported that “dietary DHA, given before cortical concussion impact (CCI) and continued daily, improved long-term rat pup outcomes after CCI. Specifically, DHA improved cognitive function, tissue sparing, and diffusion tensor imaging (DTI) indices of white matter injury after CCI, associated with decreased edema and oxidative stress.” “DHA decreased axonal injury in rat pups after CCI.” “DHA also modulated the cytokine response in a manner suggesting anti- inflammatory and neuroprotective activity.” In terms of safety and dosage, Schober’s results show that “DHA is safe and neuroprotective after experimental TBI in rat pups (Schober et al., 2016).” Researchers caution that their “diffusion tensor imaging (DTI) results are not directly comparable to humans because rat brains have significantly less white matter than do human brains (Kraft et al., 2012) (Schober et al., 2016).” Given the human brain’s increased surface area through gyri and sulci, these researchers expect that DHA would have a more dramatic effect on human brains than found with rodent brains. The dosage of DHA used was comparable to the 1.5-2 g/d used in clinical trials for adults and adolescents (Schober et al., 2016).

Thus, multiple medical centers have found DHA to be neuroprotective in rodent studies. This fatty acid’s versatile structure enables enriched membrane lipids to improve interconversion, fluidity, synapsis, transmission speed, neuronal size, plasticity and dendritic arborization. DHA decreases inflammation, oxidative damage, DTI damage, edema, and improves outcomes. These improved outcomes are evident through enhanced motor and sensory function, cognitive function, learning, and memory. DHA doses comparable to 1.5-2g/d in humans were found to be safe and strengthen neuroresilience in rodents.

Human DHA Neuroprotective Findings, Safety, and Recommendations

These prominent DHA rodent study results reducing the effect of TBI have been slow to transfer to human studies and recommendations. In 1997, the U.S. Food and Drug Administration confirmed that fish oil consumption 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). Since brain trauma commonly results in depression, human DHA studies began by evaluating depression as related to fish oil consumption. In 1998, retrospective studies found that depression rates were 50 times higher in countries with little seafood consumption (Hibbeln et al.,1998). By 2005, Daily Reference Intakes for DHA were not yet established by the United States Department of Agriculture (USDA). However in 2007, fish oil in the quantity 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 “increase seafood consumption” to its recommendations.

Page 6 of 34

 

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 among other brain nutrients, reviewed current literature on DHA. The commission 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, however these fatty acids do not convert well to DHA in the body. The IOM reported human studies showing that DHA could reduce inflammation in TBI within 60 minutes of infusion (IOM, 2011). The IOM noted 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 recommended that patients in the early phase of severe TBI be provided with continuous enteral feeding formulas containing fish oil (IOM, 2011). Appreciably, this IOM report recommended that more DHA animal studies and human clinical trials be conducted for TBI.

Additionally in 2011, Dr. Michael D. Lewis and Dr. Joseph R. Hibbein of the Uniformed Services University in Bethesda, Maryland sought to compare suicide rates with DHA levels. A markedly higher risk of suicide is often associated with individuals who have suffered TBI (Nowrangi et al., 2014). In a retrospective, large random study, researchers assayed serum samples from 800 military personnel who had committed suicide (Lewis et al., 2011). Subjects were randomly matched with 800 controls for age, collection date, sex, rank and year of incident with sera within 12 months of their matched case (Lewis et al., 2011). Samples from both subjects and controls 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 a 62% greater risk of suicide death among men with lower serum DHA levels (Lewis et al., 2011).

In 2014, the Academy of Nutrition and Dietetics (AND) issued a position paper on “Dietary Fatty Acids for Healthy Adults”. The Academy’s Evidence Analysis Library examined 14 studies, whereupon 6 studies showed that DHA ingestion demonstrated a decreased risk of cognitive decline (AND, 2014). In this position paper, the Academy discusses the need for 20-35% of the diet to be comprised of a variety of fatty acids, stating the mean daily intake of DHA was only 80mg for men and 60mg for women (AND, 2014) far below the recommended research dosages. DHA’s double bond structure, inflammation modulation, and neuroprotective properties are discussed. The AND paper also notes that DHA is found in fatty fish, seafood, salmon, sardines, tuna, herring, trout, seal meat, and marine or algal sources (AND, 2014). Most importantly, AND writes that DHA should be considered essential, because less than 1% of alpha- linolenic acid (ALA) reliably converts to DHA (Davis, 2003)(Burdge, 2004). If fish is not consumed, biochemical nutrients can be purchased. Nutrients are made from fish oils such as anchovy, salmon, cod liver, krill and squid oils (AND, 2014). Additionally, vegetarian sources of algae are available and genetically engineered nutrients are being developed. Multiple agencies were cited in this AND position paper, including the American Psychiatric Association (APA), which stated that lower levels of DHA have been observed in individuals with cognitive decline and Alzheimer’s Disease (AND, 2014). The APA recommends fish twice a week for an average 450 to 500 mg of EPA and DHA per day (AND, 2014).

Page 7 of 34

 

Per the 2014 National Institutes of Health (NIH) review paper, “The American Heart Association has … established intakes of 1.0 g of EPA and DHA from fish or fish oils for patients with cardiovascular disease, and supplements of 2-4g for subjects with high blood triglycerides (Harris et al., 2008). Most clinical studies of DHA have used a dose of 2-6 g/d, and no consistent adverse events have been observed in humans consuming from less than 1.0 up to 7.5 g/day of DHA (Lien EL, 2009).” Additionally the NIH reports that “multiple clinical trials have shown that high-dose fish oil consumption is safe, even in patients receiving other agents that may increase the risk of bleeding, such as aspirin and warfarin (Maresta et al., 2002)(Filion et al., 2010)(Marik et al., 2009).” “Doses up to 6g/d do not have deleterious effects on platelet aggregation or other clotting parameters in normal persons, and fish oil does not augment aspirin- induced inhibition of blood clotting (Lien EL, 2009).” “Platelet function is … inhibited by DHA consumption in persons with type 2 diabetes … but may be beneficial to these persons (Woodman et al., 2003).” “It may be prudent to discontinue high-dose supplementation in the setting of a patient with TBI who presents with polytrauma (e.g an acute bleeding illness or at high risk for hemorrhagic stroke) or, as is frequently recommended with aspirin, warfarin, and clopidogrel, before planned invasive procedures with the highest risk of bleeding complications (Kris-Etherton et al., 2003) (Bays, 2007)(Caio et al., 2005)(Covington, 2004).” It is important for consumers to become aware of the efficacy of fish oil for TBI, its high availability, and low cost.

The military, seeking to heal traumatized soldiers, has recognized the benefits of DHA in healing brain trauma. In the November 2014 issue of Military Medicine, Julian Bailes MD and Vimal Patel PhD report that “military members 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 to improve the neuroprotective effect when high doses (40 mg/kg) are given (Bailes and Patel, 2014). In this review article, Bailes and Patel explain that more recently, TBI damage has been found to include neurofibrillary tangles and the build up of tau protein. Long term, chronic traumatic encephalopathy may develop (Bailes and Patel, 2014). Researchers describe how the highly flexible, long chain DHA fatty acid creates thin phospholipids which pack well within the cell membrane, and create a more permeable phospholipid more suitable to membrane proteins, transport, signaling, and enzymes. They state that DHA decreases b-amyloid plaque buildup, reduces neuronal apoptosis, and may act as a prophylactic against cerebral concussion (Bailes and Patel, 2014). Bailes and Patel discuss the potential presence of mercury in fish. They recognize that given the safety profile, general health benefits, purity, availability and affordability of DHA, both athletes and military populations with high exposure to repetitive brain impacts are at risk unless they ingest adequate levels of DHA (Bailes and Patel, 2014).

A 2015 retrospective human study by Cedars-Sinai reviewed 240 TBI patients, and compared patients receiving immune enhancing nutrition (IEN) containing DHA with standard formula. Researchers found that while sepsis rates decreased and prealbumin levels were higher in IEN patients, the IEN patients spent more time in ICU and on the ventilator. IEN nutritional support was Pivot 1.5 containing 1.3 g/L DHA and 1500

Page 8 of 34

 

calories (Painter et al., 2015). Retrospectively, this low level of DHA did not reduce ICU stay. Neurological function testing was not conducted.

As of January 2016, the American Society for Parenteral and Enteral Nutrition (ASPEN) and the Society of Critical Care Medicine (SCCM) now recommend that “immune enhancing enteral formulations with omega-3 fatty acids should be used in critically ill surgical patients including trauma (McClave et al., 2009)(McClave et al., 2016).” Orally administered omega-3-fatty acids may take days to weeks to incorporate into cellular membranes … therefore IV administration … could be more suitable … following TBI (Hasadri et al., 2013).” Recently, Nestle’s Impact Peptide 1.5 enteral nutrition formula providing 4.9 g DHA/EPA per liter (Nestle, 2017) was specifically formulated for trauma patients, and SMOF lipid provides enteral nutrition with DHA and EPA omega-3s (SMOF, 2017).

In 2016, Schoeber reports DHA “has an excellent safety record in non-TBI pediatric studies that span the developmental spectrum between infancy and adolescence (Colombo et al, 2013)(Fleith et al., 2005)(Stonehouse et al., 2014). These “results complement those of Russell and colleagues (Russel et al., 2014) in showing that DHA is safe and neuroprotective after experimental TBI in rat pups.” Schoeber describes the NIH case study which reports a motor vehicle accident patient, with an initial GCS of 3, remaining on Nordic Natural Ultimate Omega delivering 9,756mg EPA and 5,756 DHA via PEG for over one year who experienced no side effects (Lewis et al., 2013), further demonstrating fish oil’s high safety profile.

In summary, “our knowledge of the pathophysiology of cerebral concussion has undertaken significant advances in the last decade (Bailes and Patel, 2014).” DHA has been established as the most important brain macronutrient given that it comprises approximately 30% of brain tissue. DHA’s double bonds provide additional strength to brain tissue which enhances cell membrane fluidity, signaling, neuronal growth, dendritic formation and synaptic maintenance. Improving these axonal and cell membrane properties results in cognitive and motor improvements. Following the recommendations of 2011 IOM report, ASPEN and SCCM now recommend fish oil for trauma patients. Nestle has produced Impact Peptide 1.5 with 4.9g of fish oil per liter, and SMOF lipid is now available with an w-3 profile as parenteral nutrition. One gram per day is generally the RDA for DHA and EPA. Therapeutic dosages of DHA and EPA often provide 2-3g/day. These researchers have shown that the DHA found in fish oil is a safe brain macronutrient which improves prognosis of TBI in both rodents and humans.

B Complex

TBI is the leading cause of death among the population under age 44 given combat casualties, sports-related injuries, and motor vehicle accidents. B complex vitamins are the second macronutrient vital to maintaining and restoring brain tissue damaged by TBI. B complex vitamins are important for nerve production and used as cofactors for

Page 9 of 34

 

protein synthesis including DNA/RNA synthesis and neurotransmitter formation. TBI causes motor and cognitive dysfunction, memory problems, scar tissue buildup, apoptosis, and balance problems. While few therapeutic B complex studies have yet to be reported for TBI, individual B vitamin studies have reported the restoration of brain tissue and neurological function following TBI.

Riboflavin

Riboflavin (B2) is vital to cellular respiration. Riboflavin enables energy production from the electron transport chain through flavin adenine dinucleotide. Additionally, riboflavin has vital roles in the production of glutathione and DNA synthesis. Given TBI, Haar found the benefits of riboflavin “lead to substantial functional recovery in sensorimotor function and working spatial memory, less edema, less reactive astrocytes and smaller lesions” in rodents (Haar, 2015). Additionally, Hoane found that riboflavin decreased behavioral impairment, lesion size, reactive astrocytes and cortical edema (Hoane, 2005). He determined that riboflavin likely functions as a free radical scavenger. Hoane treated 41 rodents with either vitamin B2 or saline. Treatment was administered 15 minutes and 24 hours post injury. The rats were examined on a variety of tests to measure sensorimotor performance and cognitive ability in the Morris water maze.” Results showed that riboflavin “significantly reduced behavioral impairments observed on the bilateral tactile removal test, through improved acquisition of both reference and working memory tests”. “B2 showed a reduction in the size of the lesion, reduced the number of glial fibrillary acidic protein positive (GFAP+) astrocytes (indicating healthier tissue), and significantly reduced cortical edema.” Hoane indicates that riboflavin likely functions through the reduction of oxidative damage (Hoane, 2005).

Niacin

Niacin (B3) produces nicotinamide adenine dinucleotide which like riboflavin has a critical role in cellular respiration produced through the electron transport chain. Niacin additionally participates in cholesterol, fatty acid and protein catabolism. Following TBI, Hoane found that functional recovery in rodents can be improved with niacin treatment. “Nicotinamide supplementation was shown to improve sensory, motor and cognitive function following frontal lobe injury (Hoane et al., 2003).” In this cortical contusion model injury, 30 male Sprague-Dawley rats, 3 months old were utilized. Following injury, 9 rats were given niacin (500mg/kg) and 9 control rats were given saline solution (1ml/kg) 15 minutes and 24 hours post injury. Hoane (2003) found that rats administered niacin post cortical contusion “significantly lessened the behavioral impairments observed following injury and led to a long-lasting improvement in functional recovery. The data from the bilateral tactile removal test showed that administration of niacin following injury … prevented the occurrence of a working memory deficit in the Morris Water Maze (MWM) model. The acquisition of a reference memory task in the MWM was significantly improved compared to saline-treated rats following injury.” Niacin did not improve skilled use.

Page 10 of 34

 

“The administration of niacin following injury significantly reduced the number of GFAP+ reactive astrocytes (GFAP+ astrocytes are thought to correlate with scar tissue production and lesion size.)” Niacin’s ability to prevent depletion of nicotinamide adenine dinucleotide (NAD+) and ATP are the likely mechanisms which improve TBI (Hoane et al., 2003). Hoane’s researchers have consistently shown positive results through a number of rodent studies. Hoane studies have demonstrated “reduced apoptosis and improved blood-brain-barrier (BBB) function (Hoane et al., 2006)”. In 2011, however, Swan found “no improvement at a standard [niacin] dose and increased impairment at higher doses (Swan et al., 2011).”

Pyridoxine

Pyridoxine (B6) is a cofactor for amino acid reactions including the production of neurotransmitters such as gamma amino butryric acid (GABA), the most prevalent inhibitory neurotransmitter in the body, as well as for the dopamine pathway, critical to motor movement and adrenaline production. While there are few research studies therapeutically utilizing pyridoxal phosphate for TBI, one important study evaluates the effect of high homocysteine (Hcy) levels on trauma outcomes. Pyridoxine (B6) is a key enzyme in the conversion of the deleterious homocysteine to methionine. In this study, there was a significant correlation between plasma Hcy levels and severity of trauma and prognosis in patients with TBI.” This prospective study examined the “relationship between Hcy plasma levels and the outcome of patients with traumatic brain injury (TBI).” “Outcome was evaluated according to the Glasgow Outcome Scale score at the time of discharge from the hospital and 6 months after hospitalization. The case group comprised of 150 patients with TBI (men, 54.7%; mean age, 55.90 years ± 12.31), and a control group of 150 healthy individuals (men, 52%; mean age, 49.56 years ± 15.64) were studied. The mean ± SD plasma Hcy level in the TBI group (20.91 μmol/L ± 15.56) was significantly higher than plasma Hcy level in the control group (7.45 μmol/L ± 13.54, P = 0.000). There was a significant relationship between Hcy plasma levels, Glasgow Coma Scale score, and computed tomography findings. Also, there was a significant difference in mean Hcy plasma between patients who died as a result of TBI and patients who were still alive at the end of the study period (Rahmani et al., 2016).” Additionally, high pyridoxine levels have been found to cause peripheral abnormalities and Schaeffer found in mice that high doses may cause central nervous system abnormalities (Schaeffer, 1993).” Should B complex be given on a regular basis, pyridoxine levels should be monitored.

Folate

Folate (B9) is likely the most critical of the B complex vitamins as deficiency during pregnancy may result in neural tube and heart defects. Folate is critical in DNA and RNA synthesis, as well as amino acid metabolism. One study gives extensive support to folate’s role in CNS axonal repair. In Naim’s piglet model, folate was found to improve cognitive and neurobehavior after TBI (Naim et al., 2011). “Piglets have a similar cortical grey-white differentiation gyral pattern and physiologic response to TBI in humans”. In this study, half the piglets (n=15) “received inertial rotation of the head to

Page 11 of 34

 

induce TBI” while 15 were uninjured. Seven piglets were given folic acid (80ug/kg) 15 minutes post injury and for the following 6 days, while eight piglets were given saline. “Piglets were assessed on memory, learning, behavior and problem solving ability.” “Cognitive Composite Dysfunction scores …were based on a variety of tests including open-field behavior, a mirror test, glass barrier task, food cover task, balance beam performance, and maze test.” Results demonstrate “that there was significant improvement in functional ability of the injured piglets given folic acid between day 1 and day 4, post injury.” Results showed more rapid completion of the balance beam task, improved motor function, increased visual problem solving with folate supplementation. Folate, however, was not found to reduce lesion size.

This study gives additional credence to folate’s role in DNA repair in that the mechanism was identified. Haar’s researchers found that folate can prevent DNA de-methylation. These researchers utilized a spinal cord injury model in rodents. They determined that when spinal cord injury occurs, DNA is de-methylated. Folate is attracted to the injury site via receptor expression and can prevent this de-methylation. There is a correlation between receptor expression, DNA methylation and regeneration of axons, thereby acknowledging that reduced folate has these pro-regenerative effects.

Folate Polymorphism

New genetic evidence supports the existence of polymorphisms in the gene producing the enzyme responsible for folate (B9) metabolism. This frequent polymorphism affects the methyl-tetrahydrofolate reductase gene. This enzyme, methylene-tetrahydrofolate (MTHFR) which requires folate (B9) is responsible for re-methylation of the neurotoxic homocysteine into methionine (Paul et al., 2004). The polymorphism can significantly reduce production of new DNA, making new tissue formation following TBI difficult (Paul et al, 2004). Individuals with this polymorphism may require additional folate to effect repair.

There are approximately 40 single nucleotide polymorphisms (SNP) identified with this MTHFR gene. The C677T SNP is located on the short p arm of the first chromosome at locus 36.3 (Lizer et al., 2011)(Bhatia & Singh, 2015). The cytosine base errantly codes for thymine, resulting in the amino acid product of valine instead of alanine (Paul et al., 2004). Patients with genetic profiles containing this SNP have reduced functionality of the MTHFR enzyme by perhaps 50%. The thermolabile genotype may have 64% reduction in enzyme activity (Paul et al., 2004). This is the major pathway for methionine production. Methionine is the lead nucleotide on each new strand of DNA, and methionine maintains adrenal neurotransmitter production. Healing the brain requires new DNA production. Lack of a fully functioning MTHFR gene may result in a plethora of neurological disease including Parkinson’s Disease, neural tube defects (NTDs), and depression (Paul et al., 2004) which are common TBI sequelae.

Nazki’s study reports that heterozygotes (C677CT) have 65% and homozygotes (C677TT) have 30% of the MTHFR enzymatic activity to convert

Page 12 of 34

 

methylenetetrahydrofolate to methytetrahydrofolate (Nazki et al., 2014). There are a number of mechanisms by which the C677T allele reduces MTHFR action (Paul et al., 2004). 5-methyltetrahydrofolate dominates circulation and re-methylates homocysteine (Hcy) into methionine (Bhatia & Singh, 2015). Methionine is a major methyl donor. Low methionine, thus low S-adenylmethionine (SAMe) causes dysregulation of neurotransmitter production (Paul et al., 2004). Catecholamine production and membrane fluidity are reduced, and neuronal transmission becomes inadequate (Bhatia & Singh, 2015). Glutathione production is reduced increasing oxidative stress. Methylation is required for serotonin, DNA, and RNA synthesis (Bhatia & Singh, 2015). Without methylation DNA strands become weakened and mutagenic (Nazki et al., 2014). Additionally, with the C677T SNP’s reduced conversion of Hcy to methionine, Hcy levels elevate (Delport et al., 2014). Hcy is neurotoxic at high levels thus promoting neuronal damage and increased production of reactive oxygen species. Hcy may directly break DNA strands and cause apoptosis (Bhatia & Singh, 2015), and the lack of regulated Hcy levels may cause depression and neurotransmitter imbalance (Bhatia & Singh, 2015).

Given the prevalence of this SNP, researchers have addressed whether supplementation of the B complex vitamins including folate can impact the successful conversion of homocysteine to methionine, compensating for the genetic MTHFR C667T defect. One study treated 282 major depressive disorder (MDD) subjects with either reduced B vitamins/micronutrients or placebo, Mech showed an 82.4% reduction in Hcy levels, and 42% complete remission with B complex vitamins (Mech & Farah, 2016). Achour randomized 132 hemodialysis patients and supplemented with both folate and cobalamin (Anchour et al., 2016). His team found that Hcy in MTHFR patients could be significantly reduced. Should supplementation fail, genetic testing could be completed to identify an MTHFR polymorphism. Patients with the C667T allele may benefit from the highly bioavailable L-methylfolate (Lizer et al., 2011).
Furthermore, B vitamins are best delivered in a complex. Mech supplemented B complex vitamins and normalized several systemwide pathways (Mech & Farah, 2016).

Cobalamin

Cobalamin (B12) has a function in producing DNA, RNA, and red blood cells. This vitamin has a role in creating nerve tissue and in relieving neuropathy. Cobalamin makes methionine, critical for methylation DNA and neurotransmitter production. One human cross-sectional study was conducted by Veterans Affairs to determine the prevalence of cobalamin deficiency in subjects with spinal cord injury (SCI). SCI studies are important correlates to brain trauma given the extension of brain meningeal tissue into the spinal cord. This cobalamin study by Petchkrua is entitled “Prevalence of vitamin B12 deficiency in spinal cord injury.” Medical records were reviewed retrospectively with prospective blood collection. Cobalamin deficiency is known to impair DNA synthesis and cause “white matter demyelination of spinal cord and cerebral cortex, and distal peripheral nerve” damage. “Common clinical findings [of deficiency] are paresthesias and numbness, gait ataxia, depressed mood, and memory impairment (Petchkrua et al., 2003).” “These symptoms can be reversed with parenteral or high-

Page 13 of 34

 

dose oral cobalamin supplements, but can worsen and become irreversible if not treated early.” In this study 105 men (mean age 54.1 years) with SCI mostly due to trauma were assessed. Fasting blood samples were utilized to evaluate nutrient levels including cobalamin, folate, and methylmalonic acid. Researchers concluded that “13% of patients with SCI …. had high MMA or low cobalamin levels. Neuropsychiatric symptoms possibly due to cobalamin deficiency were seen in half of these patients.” “Vitamin B12 deficiency was more common in persons with complete SCI or subacute degeneration of the spinal cord.” “Given the possible risk or irreversible neuropsychiatric deficits, such as weakness or dementia, and given the relatively low cost of screening and the low cost and high efficacy of high-dose oral B12 replacement, clinicians should consider screening and early treatment of B12 deficiency (Petchkrua et al., 2003).”

B complex vitamins are critical to brain tissue function and restoration. B complex is water soluble and thus must be replaced in the diet daily. B complex vitamins are critical to function with amino acids in protein synthesis. Human studies have demonstrated dietary B complex deficiencies given injury and disease conditions. A research study on spinal cord injury (SCI) conducted with funding from the Canadian Institute of Health Research, by Walters et al is entitled “Evidence of dietary inadequacy in adults with chronic spinal cord injury” (Walters et al, 2009). Researchers found that B complex vitamins were deficient in women and men who suffered from chronic SCI. This study utilized 24 hour food frequency questionnaires in comparison with the Daily Recommended Intakes (DRIs). Subjects had experienced spinal cord trauma at least 12 months prior, and used assistance for mobility. Dietary recalls were conducted in the home where recipes, food items, and brands could be verified by the double-pass method. Baseline food frequency questionnaires were collected from 77 subjects initially and from 68 subjects at 6 months. Approximately, 50% of the participants regularly ingested supplements.

Walters’ results showed that men (n=63) had only 22% and women (n = 14) 14% of the DRI intake of thiamine. Men had a 5% of DRI intake of riboflavin and a 24% of DRI intake of pyridoxal phosphate. Folate intakes were 75% of DRI for men and 79% of DRI for women. Cobalamin intake was 6% of DRI for men and 29% of DRI for women.

Prior to this study “little had been known about dietary intake or adequacy among people with SCI.” These researchers recognized that “the DRIs are intended for healthy- able bodied persons, and meeting the recommended intakes for nutrients does not necessarily provide enough for individuals with acute or chronic disease.” Most multi- vitamin supplements do not appear to contain all B complex vitamins in adequate amounts.

B complex vitamins provide vital cofactors to facilitate brain healing. Riboflavin (B2) improves sensorimotor function, memory and decreases reactive astrocytes, edema, lesion size, and behavioral impairments. Niacin (B3) provides ATP and NAD for cell energy, improves sensory, motor, cognitive, behavioral, memory and decreases reactive astrocytes under TBI conditions. Pyridoxine (B6) decreases deleterious Hcy levels toxic to brain tissue. Both pyridoxine (B6) and folate (B9) are involved with producing methionine required for neurotransmitter pathways, transmethylation, transsulfuration,

Page 14 of 34

 

and DNA synthesis. Cobalamin (B12) was found to be deficient in SCI patients, and cobalamin supplementation reverses paresthesias, numbness, gait disorders, memory and mood disorders commonly found with cobalamin deficiency. Under injury conditions, B vitamin DRIs intended for healthy persons are not likely sufficient. B complex vitamins are water soluble and should either be replaced daily in the diet or supplemented. Given their prevalence in brain tissue, B vitamins are an important macronutrient to effect TBI repair in conjunction with DHA and amino acids.

Amino Acids

TBI brings lingering deficits in concentration, depression, sleep-wake cycle, behavior, and motor skills. In addition, is the concern of long term neurological sequelae of chronic traumatic encephalopathy, dementia, and Alzheimer’s disease. The “resting metabolic expenditure of the severely injured brain is almost 40% higher”. “Insufficient availability of essential amino acids cannot only negatively influence cell survival and function in the injured brain, but also can impair the function of other organs.” (Dash et al., 2016). The third most important brain macronutrients are the amino acids. Researchers have demonstrated amino acid deficits following TBI, as well as benefits of amino acid therapy post TBI.

Amino Acid Deficits with TBI.

Several studies have evaluated amino acid deficits as related to TBI. Researchers from the University of Texas evaluated 17 moderate to severe TBI patients living in long term care facilities. TBI patients had individual and essential amino acid levels significantly lower than 24 controls. Researchers suggest these findings demonstrate that TBI is a chronic disease state, where low amino acid levels persist long term (Durham et al., 2017).

Italian researchers suggest that hypoacidemia is an important force acting upon the traumatized brain. They evaluated concentrations of free amino acids post mTBI and sTBI. Modest changes in the levels of arginine, glycine, and GABA were found within the first week post mTBI. While sTBI patients experienced significantly longer lasting modifications of “glutamate, glutamine, aspartate, GABA, serine, glycine, alanine, arginine, taurine, methionine, tyrosine and phenylalanine.” Additionally, the Glu-Gln/ GABA and methyl cycles were disturbed (Amorini et al., 2017).

This Italian research team demonstrated that two months post TBI all essential amino acids (EAA) and most nonessential amino acid levels are reduced (Aquilani et al., 2003). Stroke victims were also found to have low plasma concentrations of amino acids (Aquilani et al., 2014). A Shriner’s research team from Texas looked at plasma amino acid concentrations in six male, sTBI patients. These were motor vehicle accident victims with a mean GCS of 5, but were generally able to perform basic living activities. TBI patient amino acid concentrations were 12% lower than controls. Even given a variety of diet, most amino acid levels remain stable in normal controls. Most of

Page 15 of 34

 

the reduction in TBI patient amino acids was due to valine which was 33% lower than controls. A 7g EAA drink was given to the six patients and six healthy controls. Total EAA increased after the drink, however, non-EAA production increased more in controls than TBI patients. Arginine and glutamine increased to higher levels in controls. Thus, TBI patients were not producing non-EAA. This report points to the need for TBI patients to maintain amino acid levels, particular valine long term (Borsheim et al., 2007).

The BCAAs isoleucine, leucine, and valine are critical to brain function in that they control protein synthesis. (Vuille-Dit-Billie, et al., 2012). Jeter found that mTBI patients had lower plasma branched-chained amino acids (BCAA) levels and sTBI patients had significantly lower plasma BCAA levels (Jeter et al., 2013). Following fluid percussion injury in adult, male mice, glutamate and GABA levels were not altered, however valine (50.8%), isoleucine (21.2%), and leucine (52.3%) were reduced. Compared with healthy controls, critically ill, sTBI patients demonstrate venous isoleucine, leucine, and valine levels which were 35% lower than controls during the first two weeks post TBI. However, tryptophan, phenylalanine, and tyrosine levels were increased by 19% in the weeks following TBI. Subjects received enteral nutrition in a dose dependent manner, which elevated but did not normalize plasma BCAA levels. Tryptophan, tyrosine, isoleucine, leucine and valine amino acid levels correlated with enteral nutrition received, while phenylalanine levels did not.

These studies have identified the essential, non-essential, and branched-chained amino acid group deficits in the TBI patient. Additional deficits exist for the TBI patient with individual amino acid levels. Deficits of the following individual amino acids may impede critical neurotransmitter pathway operations within the brain.

Methionine Deficit.

Methionine is the first amino acid in each new strand of DNA. Methionine is one of the body’s few methyl donors providing substrate to the transmethylation and transsulfuration pathways. The transmethylation provides methylation for DNA and histone production to package DNA, as well as phosphotidylcholine synthesis. Phosphotidylcholine is an integral cell membrane lipid, important for signaling and cell- cell communication. S-adenylmethionine (SAM), which is produced in the transsulfuration pathway, “is one of the most commonly used molecules in living organisms.” (Dash et al., 2016). SAM supplementation directly correlates with Hamilton Depression Rating scores. Levels of SAM products such as choline and other methionine metabolite levels were diminished with TBI (Dash et al., 2016).

University of Pennsylvania researchers found that “both mild and severe TBI causes significant reductions in plasma methionine levels (Dash et al., 2016).”

Additionally, a single nucleotide polymorphism (SNP) exists in catechol-o- methyltransferase (COMT) which metabolizes catecholamine neurotransmitters catalyzed by methionine. Given reduced degradation of the dopamine pathway metabolites, this SNP may influence nonverbal cognitive function post TBI.

Page 16 of 34

 

Researchers found that both mTBI and sTBI patients with the COMT Met158 allele have better prognoses, and the allele may be neuroprotective (Winkler et.al., 2017)(Winkler et al., 2016). Post TBI, this SNP discovery identifies how methionine epigenetic anomalies affect the efficacy of the dopamine pathway, in conjunction with methionine deficits being deleterious to the dopamine pathway, transmethylation, and transsulfuration.

Tyrosine and Tryptophan Deficit.

The amino acids tyrosine and tryptophan are critical to brain function. Tyrosine works with methionine in the dopamine pathway to provide dopamine, norepinephrine and epinephrine, important catecholamines for neural function. COMT degrades the final product epinephrine in this dopamine pathway. Tryptophan creates serotonin through 5- HTP which supplies the gut and brain. Tyrosine and tryptophan are essential in the diet. While small amounts of tyrosine are formed from phenylalanine, the conversion rate is low. Nutritional intake may be insufficient to correct plasma abnormalities in a catabolic state.

An investigation was undertaken to monitor levels of tyrosine, tryptophan and BCAAs post TBI. Ten men (15-60y/o) with severe TBI were admitted in a stupor due to traffic collisions causing diffuse brain damage. The best Glasgow Coma Scale was 8. Six healthy men were selected as controls. Total amino acid plasma and tryptophan levels of TBI patients and controls were similar. TBI patients had a significantly lower tyrosine level and reduced plasma availability of BCAAs, methionine and phenylalanine. Up to 110 days post trauma, patients continued to have low tyrosine and EAA plasma concentrations, but normal tryptophan. Aquilani found that subjects with sTBI showed reduced levels of tyrosine, tryptophan and other EAAs at admission and discharge.

In rodents, low tyrosine resulted in low catecholamine production reducing cognitive activity, motor performance, and memory (Aquilani et al., 2003). Reducing mice dietary intake of tyrosine by 40% reduces maze performance. Tyrosine and Tryptophan deficits are apparent with TBI and may impair cognitive, motor and memory function.

GABA-Glutamyl Deficit.

Following injury, de novo synthesis of GABA and glutamine are impaired in the hippocampus. Under gas chromatography mass spectroscopy (GC-MS) examination, TBI hippocampal brain slices as compared with control slices showed a 61.4% reduction in glutamate, 86.6% reduction in GABA, and a 92.2% reduction in aspartate. Specific enzymes required to produce these amino acids were found to be reduced (Cole et al., 2010).

“The balance of glutamatergic and GABAergic tone is crucial to normal neurologic function (Guerriero et al., 2015).” Glutamate is the primary excitatory neurotransmitter in the brain, while gamma-amino-butyric-acid (GABA) is the predominant inhibitory

Page 17 of 34

 

neurotransmitter. TBI causes brain cell membrane to swell and eventually burst. The Na+/K+ pump fails and chemicals including stored neurotransmitters such as GABA and glutamate are released into the damaged tissue. Injury disturbs the delicate cortex excitability:inhibitory neurotransmitter ratio of GABA and glutamate within the brain. Glutamate is interconverted to glutamine and GABA in the presence of vitamin B6.

Citric acid cycle intermediates are involved in GABA production, making production more complex. Complicated pathways such as balancing these GABA and glutamine neurotransmitter levels may be easily disrupted within the injured brain.

The brain stores GABA and glutamate in neurotransmitter pools to prevent neurotransmitter level disruptions. However, these pools are likely damaged during injury. TBI increases glutamate levels, perhaps through release of pooled glutamate or through amino acid remodeling, since glutamate is the end product of most amino acid breakdown. High levels of glutamate appear to be indicators of poor prognosis. Additionally, the disruption of GABA production by the loss of GABA neurons and increased nutrient requirements appears to be deleterious. As GABA neurons are lost, long term decreased inhibition may contribute to neurocognitive impairments, behavioral impairments, and eventually seizures. “As the [glutamate] excitability: [GABA] inhibitory ratio shifts towards excitability, neuronal injury, dysfunction, and apoptosis increases, resulting in an increase in morbidity (Guerriero et al, 2015).”

Amino Acid Interventions.

Neuron and brain function require an ample pool of free amino acids to utilize as precursors to form neurotransmitters “involved in motor, cognitive, neuroendocrine, and behavioral functions (Aquilani, 2003).” These metabolic and synaptic amino acid pools may require replenishment following TBI. Post TBI, the non-essential amino acids may not be produced (Borsheim et al, 2007), and the storage and production level of amino acid derivatives may be decreased (Jeter et al., 2013).

Shen found in a systematic review of five databases from 2005 to 2015 that antioxidant therapies such as amino acid replacement were generally beneficial in TBI patients. He notes that it is secondary TBI damage that causes the most injury through hematomas, edema, rising intracranial pressure (ICP) and decreased cerebral blood flow (CBF). Free radical damage such as mitochondrial dysfunction and apoptosis also occurs. The indication is that with secondary damage some element of prevention and/or restoration can occur. This review encourages providers that “by incorporating antioxidant therapies into practice, clinicians can help attenuate the oxidative post traumatic brain damage and optimize patients’ recovery (Shen et al., 2016).”

Providing amino acids for the brain to rebuild and reconstruct post injury is important for restoration of macronutrient levels and brain function. In Dal Negro’s study, essential amino acid (EAA) supplementation versus placebo was compared in severe COPD patients. These patients are important to EAA brain trauma studies as they showed altered cognition. Eighty-eight subjects were randomized to received a 4g oral mixture dose of essential amino acids or placebo for 12 weeks. Cognitive function was

Page 18 of 34

 

measured by the Mini Mental State Examination one week before EAA administration, then 4 and 12 weeks following EAA administration. This study found improved cognition, muscle metabolism, physical activity in the EAA supplemented cohort (Dal Negro et al., 2012). Additionally, the effect of supplemental EAAs vs. placebo was assessed in 41 elderly, coronary artery disease patients (mean age 79.8 yrs). Oral supplementation of EAAs was found to improve nutritional status, muscle strength, depressive symptoms, physical performance, and quality of life (Rondanelli et al., 2011)

Vuille-Dit-Bille considered aeromatic amino acid (AAA) and BCAA amino acid levels fortified through enteral nutrition as related to ICP and jugular venous oxygen saturation. Excitotoxicity has commonly been deleterious for TBI concomitantly with increased edema and cerebral pressure. Researchers compared retrospective analyses with 19 severe TBI patients under pharmacological coma with 44 healthy volunteers. Plasma TBI BCAA levels were significantly decreased in the first week, then trended higher with leucine and valine remaining lower than controls. Tyrosine, phenylalanine, and tryptophan levels gradually increased in TBI patients. Phenylalanine was associated with lower cerebral oxygen consumption and lower ICP, whereas BCAAs increased ICP and cerebral oxygen consumption (Vuille-Dit-Bille et al., 2012).

BCAA Intervention.

Some amino acid studies have considered intervention with the BCAAs of valine, isoleucine, and leucine. BCAA supplementation improved cognitive performance in several rodent and human research reports. Dietary BCAAs have been found to promote cognitive improvement by restoration of hippocampal function, where cognitive deficits often manifest following TBI. Additionally, BCAAs are found to help maintain synaptic and metabolic pools of GABA and glutamate. Rodents were treated with BCAA drinking water for 5 days which restored BCAA concentration levels similar to sham animals. Mice consuming BCAA drinking water showed no change from control mice to conditioned fear response as utilized to identify hippocampal cognitive impairment, and injury induced hippocampal deficits and cognitive impairment was reversed in study mice. “All brain injured mice that consumed BCAAs demonstrated cognitive impairment with a simultaneous restoration of net synaptic efficacy”. Additionally, BCAA applied brain slices demonstrated restoration of net synaptic efficacy.

Aquilani’s study of 40 male patients with severe TBI showed cognitive improvement with BCAA therapy. This study provided the intervention of 19.6g/day BCAA intravenously. Aquilani analyzed cognitive recovery, plasma BCAA concentrations, and plasma tyrosine and tryptophan levels. Patients receiving BCAA therapy significantly elevated their BCAA and tyrosine plasma levels. Tryptophan levels were higher in controls. Fifteen days post admission, while both patients and controls had improvement in the Disability Rating System scores, only BCAA supplemented patients had significant cognitive improvement (Aquilani et al., 2005).

In addition to improving cognitive deficits, BCAA supplemented in the drinking water of mice decreased sleep difficulties and increased wakefulness. Post TBI, 72% of patients

Page 19 of 34

 

experienced sleep difficulties. These sleep and wakefulness improvements were accomplished by “dietary amino acids [which] have [been] shown to act directly on orexin neurons to modulate membrane excitability” and increase orexin neuron stability (Lim et al., 2013). In eleven studies reviewed by Sharma, BCAA supplementation was found to have a neuroprotective role when low BCAA levels were restored. No study reported adverse effects with BCAA supplementation. In one case, a 60g dose was utilized (Fenstrom JD, 2005). This review article supports the beneficial effect of BCAA therapy for severe TBI (Sharma B et al., 2017).

In addition to cognitive and sleep improvements given BCAA, further studies found BCAA therapy to be neurorestorative (Cole et al., 2010). “BCAAs are essential amino acids and are precursors for de novo synthesis of GABA and glutamate, and intermediates for the citric acid cycle.” Supplemental BCAAs restored hippocampal network excitability, and wakefulness as evidence by EEG rhythms. They likely accomplish this task through glutamate and GABA pool restoration. Freezing response was restored analogous to naive animals indicating cognitive restoration. Hippocampal network excitability became normal. To determine BCAA treatment dose and duration, researchers fed FPI mice with 100mM BCAA drinking water ad libitum or 0.26 g/kg via oral gavage. Hippocampal performance and cognitive impairment improved after 5 and 10 days of therapy. Study findings report that a minimum of 5 days of BCAA treatment is required to restore normal fear conditioning. Functional deficits return if therapy is discontinued after 5 days (Elkind et al., 2015).

These findings demonstrating generally low amino acid levels post TBI are of critical importance given the need for adequate amino acid substrate to produce new proteins to heal TBI. The finding of Borsheim that non-essential amino acids were not being produced is significant to heal TBI. Elemental formulas containing all 20 amino acids are available. Supplemental protein drinks often provide 20 essential and non-essential amino acids to boost protein production in malnourished patients. The Institute of Medicine found that when sufficient elemental nutrient substrate was provided to brain trauma patients that second injury was reduced (IOM, 2011). Providing sufficient amino acid nutrition is now possible using supplemental enteral and parental formulas. Albeit, the benefits of intervening with these elemental amino acids must become better recognized for brain trauma patients.

Tyrosine and Tryptophan Intervention

TBI catabolism causes massive amino acid loss and skeletal muscle degradation. Given TBI damage, its likely that nutritional intake does not address plasma insufficiencies, and catabolic needs dwarf nutrient supplies. In rodents, researchers found that 45 minutes post tyrosine administration, brain tyrosine levels increased by 81% and DOPA levels increased 13%. Tyrosine improves behavioral anomalies, cognitive deficits, and working memory. Increasing tyrosine intake to the hypothalamus and cerebral cortex reversed maze impairment and improved behavioral deficits in both animal and humans. In humans, tyrosine affects memory, mood and performance due to hypoxia. Oral tyrosine increased dopa in CSF of Parkinson’s Disease (PD) patients (Aquilani et

Page 20 of 34

 

al., 2003). Prior human investigations with tyrosine have shown behavioral, cognitive, and stress response improvements post TBI. Tryptophan was found to improve myoclonus, reduce sleep latency, mania and depression (Aquilani et al., 2003). These nutrients are important in the diet to ensure proper function of the tyrosine-dopamine and tryptophan-serotonin neurotransmitter pathways and are critical to restoring brain function.

Cysteine and Glutamine Intervention

Cysteine is another important amino acid providing neuroprotective effects given TBI. N-acetyl-cysteine(NAC) improves behavioral, auditory and vestibular abilities following brain injury. Eakin’s study with male Sprague-Dawley rats “documents the efficacy of NAC in reversing or preventing cognitive abnormalities in rodent models of mild to moderate TBI” (Eakin et al., 2014). This study included a cognitive assessment using the novel object recognition and Y maze (spatial memory) behavioral tests. Early administration of NAC to TBI rodents eliminated cognitive Morris water maze deficits. More platform crossings were seen in rodents treated with NAC and sham rodents as compared with injured non-treated rodents. “Treatment with NAC reversed behavioral deficits associated with TBI.” NAC is likely neuroprotective working through the mechanism of having anti-oxidant, anti-inflammatory, and mitochondrial enhancing effects. The potent anti-oxidant glutathione which reduces oxidative stress is produced from cysteine. Memory and motivation regulation may be associated with cysteine.

Neuroprotective effects are apparent with cysteine derivative, N-acetyl-cysteine amide (NACA) administration in this next study. Given cysteine’s low bioavailability, NACA is utilized with its higher permeability. Gunther studied male Sprague-Dawley rats with focal penetrating TBI. They were administered intraperitoneally 300mg/kg NACA, immediately post TBI and 4 hours post TBI. At 24 hours, neural degeneration (Fluoro- Jade) was reduced by 35.0%, apoptosis (TUNEL staining) reduced by 38.7%, and the antioxidant manganese superoxide dismutase increased by 35.9%. NACA treatment reduced degenerating neurons and apoptosis (Gunther et al., 2015).

The neuronal uptake of the amino acid cysteine is regulated by a transporter gene which Choi, evaluated. His study found that the cysteine transporter EAAC1 is “an important antioxidant system for reducing TBI-induced neuronal death.” “NAC significantly prevented neuronal death and reactive oxygen species production in the hippocampus” and reduced zinc’s accumulation (Choi et al., 2016). Finally, in one study using injured hippocampal slices, glutamine was found to reverse dentate gyrus hyperexcitability and injury-induced net synaptic imbalance in a restorative effect (Cole et al., 2010).

Taurine Intervention.

The most abundant free amino acid in the brain is taurine. “Taurine is involved in neuroprotection and regeneration after injury in the nervous system”. “Studies have

Page 21 of 34

 

demonstrated that taurine plays a critical role in the aspects of detoxification, membrane stabilization, osmoregulation, neurotransmission, calcium homeostasis and antioxidant (Huxtable 1992; Schaffer et al. 2000; Georgia et al. 2003; El Idrissi 2008).” “Taurine has been helpful for TBI recovery (Curtis and Epstein 2014)”. “Sun demonstrated that treatment with taurine markedly reduce neurological deficits, lessened brain swelling, attenuated cell death, and decreased the infarct volume 72h after ischemia in a rat model of stroke (Sun et al, 2012)(Wang et al., 2016).”

The protective effects of taurine were evaluated in this next investigation. The left cortex of adult, male Sprague-Dawley rats was damaged by fluid percussion injury (FPI). Taurine 200mg/kg was given by tail IV once daily for 7 days post TBI. CBF in the left cortex significantly improved within 30 minutes post injury and more so after 7 days of treatment. The ultrastructure of nerve cells almost returned to normal. Edema was further alleviated and ICP elevated. Data from this study suggested that taurine could exert a similar effect as anticoagulant therapy and improve the post TBI hypercoagulable state. “Mitochondria abnormalities cause progression in neuronal injury post TBI. Taurine treatment for 7 days alleviated the swelling of mitochondria and other organelles.” This study showed improved efficacy of the mitochondrial respiratory complexes, and improved their enzymatic activity. Taurine lowered the apoptosis rate, prevented calcium overload, and prevented endoplasmic reticulum stress. Taurine appears to exert a protective function in numerous pathways specifically by reducing cortex and hippocampal neuron damage (Wang et al., 2016).

Many enteral/parenteral nutrition formulas supply the eight essential amino acids in the form of peptides or protein. These proteins and peptides require digestion before they are available in the blood stream for use. Elemental amino acid formulas are available, however the use of these formulas for brain trauma may not yet be widespread. Rondanelli found that free amino acid ingestion increased plasma essential amino acid (EAA) levels more quickly than dietary protein ingestion. Free amino acids were readily usable versus proteins requiring digestion prior to new tissue incorporation. As amino acid plasma levels increased, extra-intestinal tissue/organ uptake increased. Additionally, free amino acids were found to disappear more quickly, suggesting increased uptake and usability. Nine voluntary elderly subjects and nine younger subjects were fed in a random alternate manner either free essential amino acids diluted with 100ml water or dietary protein components. EAA levels peaked in younger subjects at 30 minutes whereas, EAA levels peaked in older subjects at 90 minutes. Free EAAs were found to provide a greater stimulus to replenish cells (Rondanelli et al., 2017).

Enteral and parental formulas supply essential amino acids, however, Borsheim found that the non-essential amino acids are not produced given TBI. The simultaneous presence of all 20 amino acids is required for construction of new DNA and cell protein structures. The TBI hyper-metabolic state may require the increased efficiency of having these 20 free amino acids simultaneously available in the blood supply for efficient new protein construction. Rondanelli found that amino acid derivatives may not be produced given TBI (Rondanelli et al., 2017). Pathways and/or communication may be damaged

Page 22 of 34

 

post TBI. Thus, derivatives such as GABA and taurine must be individually supplied to receive benefit. Finally, as discussed previously, B complex vitamins are required as cofactors to metabolize amino acids. Patients ingesting nutrition formulas supplying amino acids would benefit from the addition of B complex vitamins.

In conclusion, there currently is no cure for TBI. Amino acids, B-complex vitamins and DHA are three critical macronutrients necessary to replenish the damaged brain and mitigate injury. These macronutrients function akin to the bricks, mortar, and rebar to reconstruct a damaged wall. Given sufficient individual substrates, the brain is able to immediately begin repair of TBI, repairing tissue with substrate analogous to the nutrients found in original brain tissue. Working with macronutrient biochemistry to provide original nutrients to effect repair is more likely to restore original function to cerebral tissue. It is hopeful that the detailed research presented in this report will heighten the awareness of medical practitioners as to the efficacy of biochemical nutrients improving TBI prognosis. According to the research findings presented in this report, the three important, basic macronutrients of DHA, B-complex and amino acids may provide long term improvement in TBI prognosis. We currently have no cure for TBI. Given the increased incidence, staggering cost, disabling injuries, long term mental decline, and epidemic status of TBI, patients are desperately in need of health care providers to offer a simple biochemical therapy to fortify and rebuild their brain tissue. The brain macronutrients of DHA, B-complex vitamins and elemental amino acids may be the long term solution.

DHA References:

Warden D. (2006). Military TBI during the Iraq and Afghanistan wars. J Head Trauma Rehabil 21, 398–402.

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.

Humphreys, I., Wood, R.L., Phillips, C.J., and Macey, S. (2013). The costs of traumatic brain injury: a literature review. Clinicoecon. Outcomes Res. 5, 281–287.

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.

Omalu BI, DeKosky ST, Hamilton RL, et al. (2006). Chronic trau- matic encephalopathy in a national football league player: Part II. Neurosurgery 59, 1086–1092; discussion 92–93.

Guskiewicz KM, Marshall SW, Bailes J, et al. (2007). Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc 39, 903–909.

Page 23 of 34

Omalu BI, Bailes J, Hammers JL, and Fitzsimmons RP. (2010). Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: The role of the forensic pathologist. Am J Forensic Med Pathol 31, 130–132.

Flanagan, S.R., Cantor, J.B., and Ashman, T.A. Traumatic brain injury: future assessment tools and treatment prospects. (2008). Neuropsychiatr. Dis. Treat. 4, 877– 892

Scrimgeour AG, Condlin ML (2014). Nutritional Treatment for Traumatic Brain Injury. Journal of Neurotrauma 31:989-999. (NIH-R)

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

DeMar JC Jr. Ma K, Bell JM, Igarashi M, Greenstein D, et al. (2006). One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J. Lipid Res 47:172-180.

Desai A, Kerala K, Hee-Yong K. (2014). Depletion of brain docosahexaenoic acid impairs recovery from traumatic brain injury. PLOS one, volume 9, issue 1.

Lewis M, Ghassemi MS, Hibbein MD. (2013). Therapeutic use of omega-3 fatty acids in severe head trauma. Am J Emerg Med 31(1): 273.e5-273.e8. Doi:10.1016/j.ajem. 2012.05.014

Kris-Etherton PM, Taylor DS, Yu-Poth S, et al. (2000). Poly- unsaturated fatty acids in the food chain in the United States. Am J Clin Nutr 71, 179S–88S.

Raper NR, Cronin FJ, and Exler J. (1992). Omega-3 fatty acid content of the US food supply. J Am Coll Nutr 11, 304–308.

Tur JA, Bibiloni MM, Sureda A, and Pons A. (2012). Dietary sources of omega 3 fatty acids: Public health risks and benefits. Br J Nutr 107, S23–52.

Simopoulos, A.P. (2011). Importance of the omega-6/omega-3 bal- ance in health and disease: evolutionary aspects of diet. World Rev. Nutr. Diet 102, 10–21.

Singh M. (2005). Essential fatty acids, DHA and human brain. Indian J Pediatr 72, 239– 242.

Dyall, S.C., and Michael-Titus, A.T. (2008). Neurological benefits of omega-3 fatty acids. Neuromolecular Med. 10, 219–235.

Salem, N., Jr., Litman, B., Kim, H.Y., and Gawrisch, K. (2001). Mechanisms of action of docosahexaenoic acid in the nervous sys-

Page 24 of 34

tem. Lipids 36, 945–959.

Cao, D., Xue, R., Xu, J., and Liu, Z. (2005). Effects of docosahex- aenoic acid on the survival and neurite outgrowth of rat cortical neurons in primary cultures. J. Nutr. Biochem. 16, 538–546.

Robson, L.G., Dyall, S., Sidloff, D., and Michael-Titus, A.T. (2010). Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurones throughout development and in aged animals.
Neurobiol. Aging 31, 678–687

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.

Homayoun, P., Parkins, N.E., Soblosky, J., Carey, M.E., Rodriguez de Turco, E.B., and Bazan, N.G. (2000). Cortical impact injury in rats promotes a rapid and sustained increase in polyunsaturated free fatty acids and diacylglycerols. Neurochem. Res. 25, 269–276.

Horrocks, L.A., and Farooqui, A.A. (2004). Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukot. Essent. Fatty Acids 70, 361–372.

Ying Z, Feng C, Agrawal R, Zhuang Y, Gomez-Pinilla F. (2012). Dietary omega-3 deficiency from gestation increases spinal cord vulnerability to traumatic brain injury- induced damage. PlosOne volume 7, issue 12, e52998.

Wu Z, Ying Z, Gomez-Pinilla F. (2013). Exercise facilitates the action of dietary DHA on functional recovery after brain trauma. Neuroscience 248 (2013) 655-663.

Agrawal R, Tyagi E, Vergnes L, Reue K, Gomez-Pinilla F. Coupling energy homeostasis with a mechanism to support plasticity in brain trauma. Biochim Biophys Acta. 2014 Apr; 1842(4):535-46. doi: 10.1016/j.bbadis.2013.12.004. Epub 2013 Dec 15. PMID: 24345766

Stillwell W, and Wassall SR. (2003). Docosahexaenoic acid: Mem- brane properties of a unique fatty acid. Chem Phys Lipids 126, 1–27.

Stillwell W, Shaikh SR, Zerouga M, Siddiqui R, and Wassall SR. (2005). Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reprod Nutr Dev 45, 559–579.

Page 25 of 34

Valentine RC, and Valentine DL. (2004). Omega-3 fatty acids in cellular membranes: A unified concept. Prog Lipid Res 43, 383–402.

Hering H, Lin CC, and Sheng M. (2003). Lipid rafts in the mainte- nance of synapses, dendritic spines, and surface AMPA receptor
stability. J Neurosci 23, 3262–3271.

Innis SM. (2008). Dietary omega 3 fatty acids and the developing brain. Brain Res 1237, 35–43.

Turner N, Else PL, and Hulbert AJ. (2003). Docosahexaenoic acid (DHA) content of membranes determines molecular activity of the sodium pump: Implications for disease states and metabolism. Nat- urwissenschaften 90, 521–523.

Innis SM. (2007). Dietary (n-3) fatty acids and brain development. J Nutr 137, 855–859.

Lane MA, and Bailey SJ. (2005). Role of retinoid signalling in the adult brain. Prog Neurobiol 75, 275–293.

Ahmad A, Moriguchi T, and Salem N. (2002). Decrease in neuron size in docosahexaenoic acid-deficient brain. Pediatr Neurol 26, 210– 218.

Aid S, Vancassel S, Poumes-Ballihaut C, Chalon S, Guesnet P, and Lavialle M. (2003). Effect of a diet-induced n-3 PUFA depletion on cholinergic parameters in the rat hippocampus. J Lipid Res 44, 1545– 1551.

Chalon S. (2006). Omega-3 fatty acids and monoamine neurotrans- mission. Prostaglandins Leukot Essent Fatty Acids 75, 259–269.

Innis SM, Gilley J, and Werker J. (2001). Are human milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed term infants? J Pediatr 139, 532–538.

WainwrightRE,Bulman-FlemingMB,Lev́esqueS,MutsaersL,andMcCutcheonD. (1998). A saturated-fat diet during development alters dendritic growth in mouse brain. Nutr Neurosci 1, 49–58

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.

Page 26 of 34

Neuroscience 2013;255-1-18. doi: 10.1016/j.neuroscience.2013.09.012. Epub 2013 Sep 14

Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells autacoids in anti-inflammation. J Biol Chem 278: 14677– 14687.

Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA 101: 8491–8496

Schober ME, Requena DF, Abdullah OM, Casper TC, Beachy J, Malleske D, Pauly JR. (2016). Journal of Neurotrauma 33:390-402.

Kraft PR, Bailey EL, Lekic T, Rolland WB, Altay O, Tang J, Wardlaw JM, Zhang JH, Sudlow CL. (2012). Etiology of stroke and choice of models. Int. J. Stroke 7, 398-406.

FDA. Substances affirmed as generally recognized as safe: Menhaden oil. (1997). Final Rule: Federal Registry 30751–30757.

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

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.

Nowrangi MA, Kortte KB, Rao VA. A perspectives approach to suicide after traumatic brain injury: case and review. Psychosomatics. 2014 Sep-Oct;55(5):430-7. doi: 10.1016/ j.psym.2013.11.006. Epub 2013 Nov 28. Review. PMID: 25223637

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

Academy of Nutrition and Dietetics Evidence Analysis Library (2014). “Dietary Fatty Acids for Healthy Adults”. Position paper.

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.

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

Page 27 of 34

Harris, W.S., Kris-Etherton, P.M., and Harris, K.A. (2008). Intakes of long-chain omega-3 fatty acid associated with reduced risk for death from coronary heart disease in healthy adults. Curr. Atheroscler. Rep. 10, 503–509.

Lien, E.L. (2009). Toxicology and safety of DHA. Prostaglandins Leukot. Essent. Fatty Acids 81, 125–132.

Maresta, A., Balduccelli, M., Varani, E., Marzilli, M., Galli, C., Heiman, F., Lavezzari, M., Stragliotto, E., and De Caterina, R.;ESPRIT Investigators. et al. (2002). Prevention of post-coronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for Prevention of Restenosis Italian Study (ESPRIT). Am. Heart. J. 143, E5.

Filion, K.B., El Khoury, F., Bielinski, M., Schiller, I., Dendukuri, N., and Brophy, J.M. (2010). Omega-3 fatty acids in high-risk cardio- vascular patients: a meta-analysis of randomized controlled trials. BMC Cardiovasc. Disord. 10, 24.

Marik, P.E., and Varon, J. (2009). Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin. Cardiol. 32, 365–372.

Woodman, R.J., Mori, T.A., Burke, V., Puddey, I.B., Barden, A., Watts, G.F., and Beilin, L.J. (2003). Effects of purified eicosa- pentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients. Atherosclerosis 166, 85–93.

Kris-Etherton, P.M., Harris, W.S., and Appel, L.J. (2003). Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler. Thromb. Vasc. Biol. 23, 151–152.

Bays, H.E. (2007). Safety considerations with omega-3 fatty acid therapy. Am. J. Cardiol. 99, 35C–43C.

Calo, L., Bianconi, L., Colivicchi, F., Lamberti, F., Loricchio, M.L., de Ruvo, E., Meo, A., Pandozi, C., Staibano, M., and Santini, M. (2005). N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J. Am. Coll. Cardiol. 45, 1723–1728.

Covington, M.B. (2004). Omega-3 fatty acids. Am. Fam. Physician 70, 133–140.

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.

Painter TJ, Rickerds J, Alban RF. (2015). Immune enhancing nutrition in traumatic brain injury – A preliminary study. International Journal of Surgery 21, 70-74.

McClave SA, Martindale RG, Vanek VW, et al., Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of

Page 28 of 34

Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenteral Enteral Nutr. May-Jun;2009 33(3):277-316. PubMed ID: 19398613

McClave SA, Taylor B, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) J Parenteral Enteral Nutr. Feb 2016 159-211.

Colombo, J., Carlson, S.E., Cheatham, C.L., Shaddy, D.J., Kerling, E.H., Thodosoff, J.M., Gustafson, K.M., and Brez, C. (2013). Long- term effects of LCPUFA supplementation on childhood cognitive outcomes. Am. J. Clin. Nutr. 98, 403–412.

Fleith, M. and Clandinin, M.T. (2005). Dietary PUFA for preterm and term infants: review of clinical studies. Crit. Rev. Food Sci. Nutr. 45, 205–229.

Stonehouse, W. (2014). Does consumption of LC omega-3 PUFA enhance cognitive performance in healthy school-aged children and throughout adulthood? Evidence from clinical trials. Nutrients 6, 2730–2758.

Russell, K.L., Berman, N.E., Gregg, P.R., and Levant, B. (2014). Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury. Prostaglandins Leukotr. Essent. Fatty Acids 90, 5–11.

Nestle Health Science “Impact Peptide 1.5 Product Details” (2017). https://

http://www.nestlehealthscience.us/brands/impact/impact-peptide-1-5
Fresenius Kabi “SMOFLIPID Description” (2017). http://smoflipid.com/Smoflipid-PI.pdf

B-complex references:

Haar, C.V., Peterson, T.C., Martens, K.M., Hoane, M.R. (2015). Vitamins and nutrients as primary treatments in experimental brain injury: clinical implications for nutraceutical therapies. Brain Research 1640, 114-129. doi: 10.1016/j.brainres.2015.12.03

Hoane, M. R., Wolyniak, J. G., & Akstulewicz, S. L. (2005). Administration of riboflavin improves behavioral outcome and reduces edema formation and glial fibrillary acidic protein expression after traumatic brain injury. Journal of Neurotrauma, 22(10), 1112-22. doi:http://dx.doi.org.libproxy1.usc.edu/10.1089/neu.2005.22.1112

Hoane, M.R., Akstulewicz, S.L., Toppen, J. Treatment with Vitamin B3 Improves Functional Recovery and Reduces GFAP Expression following Traumatic Brain Injury in Rats. (2003) Journal of Neurotrauma. 20(1): 1189-1199

Page 29 of 34

Hoane MR, Kaplan SA, Ellis AL. The effects of nicotinamide on apoptosis and blood- brain barrier breakdown following traumatic brain injury. Brain Res. 2006 Dec 13;1125(1):185-93. Epub 2006 Nov 14. PMID: 17109832

Swan AA, Chandrashekar R, Beare J, Hoane MR. Preclinical efficacy testing in middle- aged rats: nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact. J Neurotrauma. 2011 Mar;28(3):431-40. doi: 10.1089/neu.2010.1519. Epub 2011 Jan 9. PMID: 21083416

Rahmani A, Hatefi M, Dastjerdi MM, Zare M, Imani A, Shirazi D. Correlation Between Serum Homocysteine Levels and Outcome of Patients with Severe Traumatic Brain Injury. World Neurosurg. 2016 Mar;87:507-15. doi: 10.1016/j.wneu.2015.09.016. Epub 2015 Sep 18. PMID: 26386458

Schaeffer MC. Excess dietary vitamin B-6 alters startle behavior of rats. J Nutr. 1993 Aug;123(8):1444-52. PMID: 8336216

Naim, M.Y., Friess, S., Smith, C., Ralston, J., Ryall, K., Helfaer, M.A. & Margulies, S.S. (2011). Folic acid enhances early functional recovery in a piglet model of pediatric head injury. Developmental Neuroscience, 32(5-6), 466-79. doi:http:// dx.doi.org.libproxy2.usc.edu/10.1159/000322448

Paul RT, McDonnell AP, Kelly CB. Folic acid: neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol. 2004 Oct;19(7):477-88. Review. PMID: 15378677

Lizer MH, Bogdan RL, Kidd RS. Comparison of the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in depressed versus nondepressed patients. J Psychiatr Pract. 2011 Nov;17(6):404-9. doi: 10.1097/01.pra.0000407963.26981.a6

Bhatia P, Singh N. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression. Fundam Clin Pharmacol. 2015 Dec;29(6):522-8. doi: 10.1111/fcp.12145. Epub 2015 Sep 17. PMID 26376956

Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20. doi: 10.1016/j.gene.2013.09.063. Epub 2013 Oct 1. PMID: 24091066

Delport D, Schoeman R, van der Merwe N, van der Merwe L, Fisher LR, Geiger D, Kotze MJ. Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application. Metab Brain Dis. 2014 Jun;29(2):377-84. doi: 10.1007/ s11011-014-9506-7. Epub 2014 Feb 18.

Page 30 of 34

Mech AW, Farah A. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2016 May;77(5):668-71. doi: 10.4088/JCP.15m10166. PMID: 27035272 Free Article.

Achour O, Elmtaoua S, Zellama D, Omezzine A, Moussa A, Rejeb J, Boumaiza I, Bouacida L, Rejeb NB3, Achour A, Bouslama A. The C677T MTHFR genotypes influence the efficacy of B9 and B12 vitamins supplementation to lowering plasma total homocysteine in hemodialysis. J Nephrol. 2016 Oct;29(5):691-8. doi: 10.1007/ s40620-015-0235-8. Epub 2015 Nov 11. PMID: 26559681

Petchkrua W, Burns SP, Stiens SA, James JJ, Little JW. Prevalence of vitamin B12 deficiency in spinal cord injury. Archives of Physical Medicine and Rehabilitation. November 2003, Vol.84(11): 1675-1679, doi:10.1053/S0003-9993(03)00318-6. http:// http://www.sciencedirect.com.libproxy1.usc.edu/science/article/pii/S0003999303003186?via %3Dihub.

Walters JL, Buchholz AC, Martin Ginis KA. Evidence of dietary inadequacy in adults with chronic spinal cord injury. Spinal Cord (2009) 47, 318-322;doi:10.1038/sc.2008.134 published online 11 November 2008. http://www.nature.com/sc/journal/v47/n4/full/ sc2008134a.html

Amino Acid References:

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

Dash PK, Hergenroeder GW, Jeter CB, Choi HA, Kobori N, Moore AN. Traumatic Brain Injury Alters Methionine Metabolism: Implications for Pathophysiology. Front Syst Neurosci. 2016 Apr 29;10:36. doi: 10.3389/fnsys.2016.00036. eCollection 2016. PMID: 27199685

Durham WJ, Foreman JP, Randolph KM, Danesi CP, Spratt H, Masel BD, Summons JR, Singh CK, Morrison M, Robles C, Wolfram C, Kreber LA, Urban RJ, Sheffield-Moore M, Masel BE. Hypoaminoacidemia Characterizes Chronic Traumatic Brain Injury. J Neurotrauma. 2017 Jan 15;34(2):385-390. doi: 10.1089/neu.2015.4350. Epub 2016 Jun 16. PMID: 27178787

Amorini AM, Lazzarino G, Di Pietro V, Signoretti S, Lazzarino G, Belli A, Tavazzi B. Severity of experimental traumatic brain injury modulates changes in concentrations of cerebral free amino acids. J Cell Mol Med. 2017 Mar;21(3):530-542. doi: 10.1111/jcmm. 12998. Epub 2016 Oct 3. PMID: 27696676 Free PMC Article

Page 31 of 34

Aquilani R, Iadarola P, Boschi F, Pistarini C, Arcidiaco P, Contardi A. Reduced plasma levels of tyrosine, precursor of brain catecholamines, and of essential amino acids in patients with severe traumatic brain injury after rehabilitation. Arch Phys Med Rehabil. 2003 Sep;84(9):1258-65.

PMID: 13680559

Aquilani R, Boselli M, Paola B, Pasini E, Iadarola P, Verri M, Viglio S, Condino A, Boschi F. Is stroke rehabilitation a metabolic problem? Brain Inj. 2014;28(2):161-73. doi: 10.3109/02699052.2013.860470. PMID: 24456056

Børsheim E, Bui QU, Wolfe RR. Plasma amino acid concentrations during late rehabilitation in patients with traumatic brain injury. Arch Phys Med Rehabil. 2007 Feb; 88(2):234-8. PMID: 17270522

Vuille-Dit-Bille RN, Ha-Huy R, Stover JF. Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous oxygen saturation in patients with severe traumatic brain injury. Amino Acids. 2012 Sep;43(3):1287-96. doi: 10.1007/s00726-011-1202-x. Epub 2011 Dec 22. PMID: 22189890

Jeter CB1, Hergenroeder GW, Ward NH 3rd, Moore AN, Dash PK. Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J Neurotrauma. 2013 Apr 15;30(8):671-9. doi: 10.1089/neu. 2012.2491. Epub 2013 Apr 6. PMID: 23560894

Winkler EA, Yue JK, Ferguson AR, Temkin NR, Stein MB, Barber J, Yuh EL, Sharma S, Satris GG, McAllister TW, Rosand J, Sorani MD, Lingsma HF, Tarapore PE, Burchard EG, Hu D, Eng C, Wang KK, Mukherjee P, Okonkwo DO, Diaz-Arrastia R, Manley GT; TRACK-TBI Investigators.COMT Val 158 Met polymorphism is associated with post- traumatic stress disorder and functional outcome following mild traumatic brain injury. J Clin Neurosci. 2017 Jan;35:109-116. doi: 10.1016/j.jocn.2016.09.017. Epub 2016 Oct 18.PMID: 27769642

Winkler EA, Yue JK, McAllister TW, Temkin NR, Oh SS, Burchard EG, Hu D, Ferguson AR, Lingsma HF, Burke JF, Sorani MD, Rosand J, Yuh EL, Barber J, Tarapore PE, Gardner RC, Sharma S, Satris GG, Eng C, Puccio AM, Wang KK, Mukherjee P, Valadka AB, Okonkwo DO, Diaz-Arrastia R, Manley GT; TRACK-TBI Investigators. COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury. Neurogenetics. 2016 Jan;17(1):31-41. doi: 10.1007/s10048-015-0467-8. Epub 2015 Nov 17. PMID: 26576546

Cole JT, Mitala CM, Kundu S, Verma A, Elkind JA, Nissim I, Cohen AS. Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):366-71. doi: 10.1073/pnas.0910280107. Epub 2009 Dec 7. Erratum in: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2373. PMID: 19995960

Page 32 of 34

Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015 May;15(5):27. doi: 10.1007/ s11910-015-0545-1. Review. PMID: 25796572

Shen Q, Hiebert JB, Hartwell J, Thimmesch AR, Pierce JD. Systematic Review of Traumatic Brain Injury and the Impact of Antioxidant Therapy on Clinical Outcomes. Worldviews Evid Based Nurs. 2016 Oct;13(5):380-389. doi: 10.1111/wvn.12167. Epub 2016 May 31. Review. PMID: 27243770

Dal Negro RW, Testa A, Aquilani R, Tognella S, Pasini E, Barbieri A, Boschi F. Essential amino acid supplementation in patients with severe COPD: a step towards home rehabilitation. Monaldi Arch Chest Dis. 2012 Jun;77(2):67-75. PMID: 23193843

Rondanelli M, Opizzi A, Antoniello N, Boschi F, Iadarola P, Pasini E, Aquilani R, Dioguardi FS. Effect of essential amino acid supplementation on quality of life, amino acid profile and strength in institutionalized elderly patients. Clin Nutr. 2011 Oct;30(5): 571-7. doi: 10.1016/j.clnu.2011.04.005. Epub 2011 Jun 1. PMID: 21636183

Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, Boschi F, Arcidiaco P, Viglio S. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil. 2005 Sep;86(9):1729-35.

Lim MM, 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

Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005 Jun;135(6 Suppl):1539S-46S. PMID: 15930466

Sharma B, Lawrence DW, Hutchison MG. Branched Chain Amino Acids (BCAAs) and Traumatic Brain Injury: A Systematic Review. J Head Trauma Rehabil. 2017 Jan 5. doi: 10.1097/HTR.0000000000000280. [Epub ahead of print] PMID: 28060208

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

Eakin K1, Baratz-Goldstein R2, Pick CG2, Zindel O2, Balaban CD3, Hoffer ME4, Lockwood M1, Miller J1, Hoffer BJ5. 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.

Page 33 of 34

Günther M, Davidsson J, Plantman S, Norgren S, Mathiesen T, Risling M. Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats. J Clin Neurosci. 2015 Sep;22(9):1477-83. doi: 10.1016/j.jocn. 2015.03.025. Epub 2015 Jun 19. PMID: 26100161

Choi BY, Kim IY, Kim JH, Lee BE, Lee SH, Kho AR, Jung HJ, Sohn M, Song HK, Suh SW. Decreased cysteine uptake by EAAC1 gene deletion exacerbates neuronal oxidative stress and neuronal death after traumatic brain injury. Amino Acids. 2016 Jul; 48(7):1619-29. doi: 10.1007/s00726-016-2221-4. Epub 2016 Apr 4. PMID: 27040821

Wang Q, Fan W, Cai Y, Wu Q, Mo L, Huang Z, Huang H. Protective effects of taurine in traumatic brain injury via mitochondria and cerebral blood flow. Amino Acids. 2016 Sep; 48(9):2169-77. doi: 10.1007/s00726-016-2244-x. Epub 2016 May 7. PMID: 27156064

Huxtable RJ (1992) Physiological actions of taurine. Physiol Rev 72:101–163

Schaffer S, Takahashi K, Azuma J (2000) Role of osmoregulation in the actions of taurine. Amino Acids 19:527–546

Georgia B, Schuller L, Eunkyue P (2003) Taurine: new implications for an old amino acid. FEMS Microbiol Lett 226:195–202

El Idrissi A (2008) Taurine increases mitochondrial buffering of cal- cium: role in neuroprotection. Amino Acids 34:321–328

Curtis L, Epstein P (2014) Nutritional treatment for acute and chronic traumatic brain injury patients. J Neurosurg Sci 58:151–160

Sun M, Zhao Y, Gu Y, Xu C (2012) Anti-inflammatory mechanism of Taurine against ischemic stroke is related to down-regulation of PARP and NF-κB. Amino Acids 42:1735–1747

Rondanelli M, Aquilani R, Verri M, Boschi F, Pasini E, Perna S, Faliva A, Condino AM. Plasma kinetics of essential amino acids following their ingestion as free formula or as dietary protein components. Aging Clin Exp Res. 2017 Aug;29(4):801-805. doi: 10.1007/ s40520-016-0605-7. Epub 2016 Jul 12. PMID: 27406393

Thank you to all of the researchers cited in this article for their tedious work and dedication.

Page 34 of 34

A Brain Food Macronutrient Study of Fish Oil and B-Complex

 

IMG_4189

Traumatic Brain Injury: A Brain Food Macronutrient Study (BFNS) of Fish Oil and B- Complex.

Introduction

Traumatic Brain Injury (TBI) is taking a sizable toll on society. Given military, sports and motor vehicle injuries there has been a 4.2 fold case increase since 1998 (Barrett et al., 2014). “TBI is one of the most disabling injuries causing motor and sensory deficits and leading to severe cognitive, emotional, and psychosocial impairment, crippling vital areas of higher functioning.” (Hasadri et al., 2013). Neurodegenerative disease, cognitive deficits, and Parkinson’s Disease affect patients in the long term (Omalu et al., 2006)(Omalu et al., 2010). Currently, there is no cure for TBI.

Utilization of macronutrients to replenish the brain biochemical nutrients upon injury is still in its infancy despite the Institute of Medicine’s TBI Nutrition report of 2011. More recently, the National Institute of Health (NIH) has published details on the efficacy of several brain nutrients including fish oil. They note that a cure must simultaneously attenuate several biochemical factors and “if used appropriately, there may not be a downside to using food agents for therapy.” (Scrimgeor & Condlin, 2014). Nutrition restores vital nutrients, is cost effective, and can possibly restore healthy tissue for the long term.

The brain macronutrient docosahexaenoic acid (DHA) is found in fish oil, free range meat, eggs, milk, and supplements. DHA forms a strong and flexible brain cell membrane given its double bonded structure. Having cell membrane constructed from DHA enables membrane signaling and transmission to function properly. Proper function manifests in accurate cognitive, motor and sensory activities in the brain. B-complex vitamins are the second major brain macronutrient. The B-complex vitamins found in grains, provide energy for mitochondria in the body, cofactors for neurotransmitter production, and substrates for nerve tissue construction.

Concussion patients in the Think Head First LLC, clinic are regularly treated with DHA and B- complex macronutrients in addition to vitamin D, magnesium, and probiotics for concussion. While 26 patients at the clinic completed surveys for this study, only 17 patients were returning patients able to report post concussion (pre-nutrient) symptoms in addition to symptoms one month later (post nutrient). These 17 returning patients are grouped into three groups for analysis purposes. The first group consists of eight returning patients who report ingesting all five nutrients. The second group became our controls. They are five returning patients who ingested no nutrients. One goal of this study was to determine the efficacy of DHA. However, given that these five nutrients are prescribed simultaneously, we evaluate DHA in a third group of patients who at least ingested DHA.

Our data compare the average number of post concussion symptoms per patient (pre-nutrient ingestion) against the average number of symptoms per patient one month later (post nutrient ingestion). A one page questionnaire is utilized asking the patient to check initial post concussion symptoms (pre-nutrient ingestion) from a list of symptoms, list nutrients/drugs taken, then check symptoms from the same list one month later (post nutrient ingestion). We hypothesize that patients who are provided the brain macronutrients of fish oil, specifically docosahexaenoic acid (DHA) and B-complex vitamins, along with the micronutrients of magnesium, vitamin D, and probiotics will have fewer symptoms one month later. We also expect patients who have at least taken DHA will have fewer symptoms one month later.

 

Methods

Patients

All patients surveyed in this Brain Food Macronutrient Study (BFMS) were concussion patients who randomly visited the Think Head First LLC. outpatient concussion treatment clinic. They were informed of the research study, consented, and asked to complete the questionnaire. Patients completed the post concussive symptoms (pre-nutrient), nutrient/drug, and one month (post nutrient) symptoms sections. New patients only completed the post concussive (pre- nutrient) symptoms section. New patient post concussive (pre-nutrient) data is included in these analyses to identify the frequency of post concussive symptoms in the Results section below.

Supplemental Protocol

The concussion clinic regularly prescribes DHA, B-complex, vitamin D, magnesium and probiotic to their patients for concussion therapy. The brain macronutrient docosahexaenoic acid (DHA) is found in fish oil, free range meat and eggs, milk, and supplements. DHA makes strong and flexible brain cell membrane given its double bonded structure. Having cell membrane constructed from DHA enables membrane signaling and transmission to properly function which manifests in cognitive, motor and sensory activities in the brain. The nutrient dosage prescribed was 390mg DHA and 430mg EPA.

B-complex vitamins are the second brain macronutrient evaluated in this study. B-complex vitamins are found in grains, provide energy for the mitochondria in the body, cofactors for neurotransmitter production and substrates to construct nerve tissue. The B-complex prescribed contained: thiamine (B1) 100mg, riboflavin (B2) 50mg, niacin (B3) 50mg, pantothenic acid (B5) 100mg, pyridoxine (B6) 50mg, biotin (B7) 2mg, folate (B9) 200mcg, and cobalamin (B12) 250mcg.

Vitamin D is responsible for regulating bone health through control of calcium, phosphate and magnesium absorption. It is considered a hormone and actively circulates as calcitriol in the blood. Vitamin D is thought to have immune activity, decrease inflammation and be involved with neuromuscular control. The prescribed dosage was 5,000 IU.

Magnesium (Mg) is important in ATP energy production for the cell and phosphate regulation. Magnesium, potassium, calcium and sodium minerals interrelate. A large percentage of the population is magnesium deficient. The magnesium dosage prescribed was magnesium citrate 50mg, magnesium glycinate 50mg, magnesium maleate 50mg, and malic acid 275mg.

Probiotics aid in intestinal absorption of nutrients. As good bacteria for the intestines, probiotics keep gut tissue healthy and keep bacterial overgrowth under control. The probiotics prescribed are Theradophilus containing 3.0 billion viable microorganisms as Lactobacillus helveticus, Lactobacillus rhamnosus, and Bifidobacterium longum. Two capsules daily.

 

Results

Baseline post concussion symptoms for all patients

The questionnaires were completed by 26 patients. Patients were either new patients (n=9) completing the questionnaire post concussion (pre-nutrient) at the zero month timeline or returning patients (n=17) completing the questionnaire at the one month timeline (post-nutrient). All patients completed the post concussion (pre-nutrient) symptom section of the survey. In this first section, patients checked all symptoms experienced initially post concussion. There were 29 symptoms listed including: headache, ringing ears, depression, anxiety, eye tracking, unequal pupils, emotional, sad, tired, seizures, nausea, concentration, painful neck, blurred vision, agitated, unusual behavior, irritable, sleeping, slurred speech, double vision, memory, balance, restless, can’t recognize, lost concentration, dizzy, no energy, convulsions, and stutter.

The average number of post concussive (pre-nutrient) symptoms per patient given data from all 26 participants was 11.85. The most frequently experienced symptoms for these participants was 88% headache, 81% eye tracking difficulties, 69% balance, 65% tired and dizzy, 62% painful neck and memory problems, 60% sleeping difficulties, 58% nausea and concentration problems, and 54% anxiety. The remaining symptoms were experienced by less than 50% of the patients.

Findings for Group One – All five prescribed nutrients ingested

Of the returning patients, Group One (n=8) ingested all five prescribed nutrients (DHA, B- complex, vitamin D, Mg, and probiotics) during the one month post concussion. The average number of post concussive (pre-nutrient) symptoms reported in Group One was 18.06. Following ingestion of all five nutrients, the average number of symptoms at one month (post nutrient) reported was 10.75.

One patient experienced 12 concussions and reported 23 post concussion (pre-nutrient) symptoms, ingested the nutrients, then reported 24 symptoms one month later (post nutrient). This patient was atypical in having 12 concussions and in reporting an increase in the number of symptoms, all other patients reported decreases. If this patient is removed from Group One data, the average symptoms post concussion (pre-nutrient) is 17.21 and one month later (post nutrient) is 8.86.

Headache, eye tracking, painful neck, memory, balance and dizziness problems were experienced by 100% of the Group One patients while anxiety was experienced by 94%. Tiredness and sleeping problems were experienced by 88% while nausea and concentration difficulties were experienced by 75%. Group One, after ingesting all five nutrients, experienced the following reduction in symptoms: headache 35%, eye tracking 25%, balance 56%, dizzy 19%, tired 28%, memory 19%, painful neck 44%, sleeping 44%, nausea 33%, concentration 43%, anxiety 28%, depression 33% and emotional 16%.

 

Findings for Group Two – No prescribed nutrients ingested

Group Two (n=5) of the returning patients ingested no prescribed nutrients in the one month post concussion. Group Two reported a 7.80 average number of post concussive symptoms. One month later, these patients reported an average of 5.40 symptoms.

Initially post concussion, headache was experienced by 100% of these control patients. Eye tracking, nausea, blurred vision, balance, and dizziness were experienced by 60%. One month later, eye tracking, dizziness, concentration and sleeping problems were not reduced. Headache was reduced by 20%, nausea and balance difficulties were reduced by 33%, blurry vision reduced by 67%, and anxiety and tiredness by 50%.

Findings for Group Three – At least DHA ingested

Group Three (n=11) ingested at least the prescribed DHA. The average number of post concussive symptoms in Group Three was 16.55. During the following month, Group Three ingested the DHA. The average number of symptoms one month later (post nutrient) was 10.09.

The one atypical patient who experienced 12 concussions and reported an increase in symptoms after one month is included in the above findings for Group Three. If this patient is removed from Group Three data, the average number of symptoms post concussion (pre- nutrient) is 15.85 and one month later (post nutrient) is 8.05.

Eye tracking difficulties were experienced by 100% of Group Three, while sleeping, headache, tired, memory, painful neck, balance, and dizziness were experienced by 91%. Nausea, concentration problems and anxiety were experienced by 82%. One month later (post nutrient) symptoms were reduced by: headache 25%, eye tracking 20%, balance 70%, dizzy 65%, tired 35%, memory 35%, painful neck 55%, sleeping 51%, nausea 56%, concentration 45%, and anxiety 39%.

 

Number of Patients

Avg. Number of Post Concussion (Pre-nutrient) Symptoms

Avg. Number of Symptoms at One Month (Post nutrient)

Symptom Reduction

All Patients

26

11.85

Returning Patients

17

13.62

7.68

44%

Group One – All 5 Nutrients

8

18.06

10.75

40%

Group One – All 5 Nutrients (exclude atypical patient)

7

17.21

8.86

49%

Group Two – No nutrients

5

7.8

5.40

31%

 

Number of Patients

Avg. Number of Post Concussion (Pre-nutrient) Symptoms

Avg. Number of Symptoms at One Month (Post nutrient)

Symptom Reduction

Group Three – At least DHA (exclude atypical patient)

11

16.55

10.09

39%

Group Three – At least DHA

10

15.85

8.05

49%

Table 1. BFMS – Results: Average Number of Concussion Symptoms Pre/Post Nutrient.

 

Group One:
All Five Nutrients

Post Concussion Symptom Prevalence (Pre-Nutrient %)

One Month Symptom Prevalence
(Post Nutrient %)

Reduction in Concussion Symptoms
(Post Nutrient %)

Balance

100

44

56

Painful Neck

100

56

44

Eye tracking

100

75

25

Dizzy

100

44

56

Memory

100

81

19

Headache

100

65

35

Sleeping

94

50

44

Tired

88

63

28

Anxiety

88

63

28

Concentration

88

50

43

Nausea

75

50

33

Depression

75

50

33

Emotional

75

63

16

Table 2. BFMS – Results: Group One – All Five Nutrients. Most Prevalent Concussion Symptoms Pre/Post Nutrient.

 

Group Two: No Nutrients

Post Concussion Symptom Prevalence (Pre-Nutrient %)

One Month Symptom Prevalence
(Post Nutrient %)

Reduction in Concussion Symptoms
(Post Nutrient %)

Headache

100

80

20

 

Group Two: No Nutrients

Post Concussion Symptom Prevalence (Pre-Nutrient %)

One Month Symptom Prevalence
(Post Nutrient %)

Reduction in Concussion Symptoms
(Post Nutrient %)

Eye Tracking

60

60

0

Nausea

60

40

33

Blurred Vision

60

20

67

Balance

60

40

33

Dizzy

60

60

0

Concentration

40

40

0

Anxiety

40

20

50

Tired

40

20

50

Sleeping

40

40

0

Table 3. BFMS – Results: Group Two – No Nutrients. Most Prevalent Concussion Symptoms Pre/ Post Nutrient (control).

 

Group 3
At Least DHA

Post Concussion Symptom Prevalence (Pre DHA) (%)

One Month Symptom Prevalence (Post DHA) (%)

Reduction in Concussion Symptoms (Post DHA) (%)

Eye tracking

100

80

20

Sleeping

91

45

51

Headache

91

68

25

Tired

91

59

35

Memory

91

59

35

Painful Neck

91

41

55

Balance

91

27

70

Dizzy

91

32

65

Nausea

82

36

56

Concentration

82

45

45

Anxiety

82

50

39

Table 4. BFMS – Results: Group Three – At least DHA. Most Prevalent Concussion Symptoms Pre-Post Nutrient.

 

Discussion

Initially, 26 patients completed questionnaires, of these 9 were new patients who had not yet begun nutrients. The data from these 9 patients initial post concussion symptoms was included in the results section above demonstrating that in our surveyed population the concussion patient experiences an average of 11.85 symptoms. Among these symptoms headache and eye tracking difficulties are most predominant.

The 17 returning patients became our main analysis dataset as these patients’ symptoms could be initially evaluated post concussion and one month post concussion. These returning patients were grouped into three groups. Group One (n=8) had ingested all five prescribed nutrients of DHA, B-Complex, Vitamin D, Mg, Probiotic. Group Two (n=5) had not ingested any of the prescribed nutrients. Group Three (n=11) had ingested at least DHA. (Members of Group Three may also be included in Group One.)

The Think Head First, LLC concussion clinic prescribes the five nutrients together (DHA, B- Complex, Vitamin D, Mg, Probiotic), such that our best analysis comes from evaluating the number of post concussion symptoms (pre-nutrient) as compared with symptoms one month later (post nutrient) given ingestion of all five nutrients. These Group One patients demonstrate an average of 18.06 post concussive (pre-nutrient) symptoms, and an average of 10.75 symptoms one month later (post nutrient). Group One patients having ingested all five nutrients show a 40% reduction in the average number of post concussion (pre-nutrient) symptoms as compared with average number of symptoms one month later (post-nutrient). If the one atypical patient (who demonstrates an increase in symptoms) is excluded from the dataset, the average number of post concussion (pre-nutrient) symptoms is slightly reduced to 17.21, however, the average number of symptoms at one month (post nutrient) is 8.86. These results indicate a 49% reduction in post concussion symptoms given the five nutrient ingestion of Group One.

While we would like to have evaluated DHA alone for this study, it is difficult to isolate the effect of DHA since these five nutrients were most frequently taken together. However, Group Three patients at least took DHA. These patients had an average of 16.55 post concussion (pre- nutrient) symptoms and reported an average of 10.09 symptoms one month later (post nutrient). Group Three patients demonstrate a 39% reduction in symptoms. If the one atypical patient is excluded from the dataset, an average of 15.85 post concussion (pre-nutrient) symptoms are reported with a reduction to 8.05 symptoms one month later (post nutrient). These Group Three results show a 49% reduction in symptoms in patients who at least ingested DHA.

Finally, Group Two consists of five control patients took no prescribed nutrients. These patients reported an average of 7.80 post concussion symptoms and an average of 5.40 symptoms one month later. Their average number of concussion symptoms reduced by 31%.

The five nutrient therapy given to Group One reduced concussion symptoms by at least 40% and possibly by 49% excluding the one atypical patient. These results are impressive. Albeit our sample population is small, but the results represent a 9% improvement over the no nutrient controls and an 18% improvement over the no nutrient controls if the one atypical patient is removed from the Group One dataset. Group Three, supplementing at least DHA, reduced concussion symptoms on average by 39% for these 11 patients, and 49% if the atypical patient is removed. Comparing the Group Three at least DHA dataset with the five nutrient dataset from Group One leads us to question whether a majority of the improvement in both groups has come from DHA supplementation. The results from this study demonstrate the efficacy of supplementing the five nutrients dataset as well as supplementing DHA post concussion. A larger more focused study with a more specific dataset, a larger sample size, and more controlled nutrient/drug intake would likely report additional data.

Additionally, we evaluated individual symptoms given the five nutrient and at least DHA therapies. In Group One, the five nutrients reduced the concussion symptoms of balance and dizziness by 56%, painful neck and sleep difficulties by 44%, and concentration problems by 43%. In Group Three, the at least DHA reduced the concussion symptoms of balance anomalies by 70%, dizziness 65%, nausea 56%, painful neck 55%, and sleeping difficulties by 51%.

 

Given these results in this small data set, the five nutrient therapy of DHA, B-Complex, vitamin D, Mg, and probiotic reduces post concussion symptoms. DHA ingestion reduces concussion symptoms approximately the same amount, however, DHA shows increased efficacy in decreasing dizziness and nausea. Further studies to evaluate these macronutrients would continue to alert health care providers and patients as to the efficacy of utilizing brain macronutrients to heal brain trauma.

References

Barrett EC, McBurney MI, Ciappio ED. ω-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. Review. PMID: 24829473

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.

Omalu BI, DeKosky ST, Hamilton RL, et al. (2006). Chronic traumatic encephalopathy in national football league player: Part II. Neurosurgery 59, 1086-1092: discussion 92-93

Omalu BI, Bailes J, Hammers JL, Fitzsimmons RP (2010). Chronic traumatic encephalopathy, suicides and parasuicides in professional American athletes: The role of the forensic pathologist. Am J Forensic Med Pathol 31, 130-132

Scrimgeour AG, Condlin ML (2014). Nutritional Treatment for Traumatic Brain Injury. Journal of Neurotrauma 31:989-999. (NIH-R)

We express sincere appreciation to Think Head First, LLC for providing the opportunity to survey concussion patients for this study.  Thank you!!

 

B Complex Articles for TBI and SCI

img_0066The Brain and B-Complex

B-Complex slide show:  b-complex-show

Nutritionally, we know that B complex vitamins are found in grains. Instructors tell us that B complex vitamins are critical to the development of the human brain, and they are utilized as cofactors in neurotransmitter production. They say that genetically, B complex vitamins may not be well absorbed, and that the B vitamin Dietary Reference Intakes (DRIs) may not be sufficient. Additionally, wheat gluten free patients may not be consuming adequate amounts. As nutritionists, we recognize the important of the B complex vitamins. Should a brain injury patient present, we would likely choose to normalize B complex levels. However, our treatment strategies should be evidence based. In reviewing the evidence, there are many animal studies that demonstrate efficacy of B complex vitamins after brain, spinal cord, and nerve injury, but what human studies are available?

This first human research study reviewed on spinal cord injury (SCI) was conducted with funding from the Canadian Institute of Health Research, by Walters et al. entitled “Evidence of dietary inadequacy in adults with chronic spinal cord injury” (2009). The findings were that B complex vitamins were deficient in women and men who suffered from chronic spinal cord injury. This study utilized 24 hour food frequency questionnaires in comparison with the DRIs. Subjects had experienced spinal cord trauma at least 12 months prior and used assistance for mobility. Dietary recalls were conducted in the home where recipes, food items, and brands could be verified by the double-pass method. Baseline FFQs were collected from 77 subjects initially and from 68 subjects at 6 months. Approximately, 50% of the participants regularly ingested supplements. Results showed that the men (n=63) had only 22% and women (n = 14) 14% of the DRI intake of thiamine. Men had a 5% of DRI intake of riboflavin and a 24% of DRI intake of pyridoxal phosphate. Folate intakes were 75% of DRI for men and 79% of DRI for women. Cobalamin intake was 6% of DRI for men and 29% of DRI for women. Prior to this study “little had been known about dietary intake or adequacy among people with SCI.” These researchers recognized that “the DRIs are intended for healthy-able bodied persons, and meeting the recommended intakes for nutrients does not necessarily provide enough for individuals with acute or chronic disease.”
A second human cross-sectional study on SCI evaluating cobalamin was conducted by Veterans Affairs to determine the prevalence of cobalamin deficiency in subjects with spinal cord injury (SCI). This study was by Petchkrua W (2003) entitled “Prevalence of vitamin B12 deficiency in spinal cord injury.” Medical records were reviewed retrospectively with prospective blood collection. Cobalamin deficiency is known to impair DNA synthesis and cause “white matter demyelination of spinal cord and cerebral cortex, and distal peripheral nerve” damage. “Common clinical findings are paresthesias and numbness, gait ataxia, depressed mood, and memory impairment.” These symptoms can be reversed with parenteral or high-dose oral cobalamin supplements, but can worsen and become irreversible if not treated early.” In this study 105 men ( mean age 54.1 years) with SCI mostly due to trauma were assessed. Fasting blood samples were utilized to evaluate nutrient levels including cobalamin, folate, and methylmalonic acid. Researchers concluded that “13% of patients with SCI …. had high MMA or low cobalamin levels. Neuropsychiatric symptoms possibly due to cobalamin deficiency were seen in half of these patients.” “Vitamin B12 deficiency was more common in persons with complete SCI or SCD.” “Given the possible risk or irreversible neuropsychiatric deficits, such as weakness or dementia, and given the relatively low cost of screening and the low cost and high efficacy of high-dose oral B12 replacement, clinicians should consider screening and early treatment of B12 deficiency.”

Four articles were identified relating to human cobalamin neuropathy research. The first article, a retrospective review, “Vitamin B for treating peripheral neuropathy” by Ang CD, et al. (2008) researched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE, EMBASE, and Philippine databases (of various timeframes) selecting random and quasi-random studies. “Thirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included”.  They only found that 1 trial showed a short term benefit in perceived vibration threshold with the supplementation of a thiamine derivative. Another study found that vitamin B supplementation was dose responsive in that higher doses seemed to reduce clinical symptoms such as pain.  Drugs worked better for pain.

The second human cobalamin neuropathy was a review article entitled “Is there an association of vitamin B12 status with neurological function in older people?” by Miles LM, et al (2015). This review evaluated the association of vitamin B12 status with neurological function and clinically relevant neurological outcomes. A systematic search of nine bibliographic databases (up to March 2013) identified twelve published articles describing two longitudinal and ten cross-sectional analyses.” Subjects were 65-81 years of age. “One longitudinal study reported no association, and four of seven cross-sectional studies reported limited evidence.” “One longitudinal study reported an association of vitamin B12 status with some …neurological outcomes.” “Three cross-sectional analyses reported no association. Overall, researches [found] there is limited evidence from observational studies to suggest an association of vitamin B12 status with neurological function in older people.”

In a third human cobalamin neuropathy study by Brito et al (2016) entitled “Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status.” The elderly Chileans consumed bread fortified with folate. 51 participants with serum vitamin B-12 concentrations < 120 pmol/L were given a single intramuscular injection of 10mg of vitamin B-12, 100mg vitamin B-6, and 100mg of vitamin B-1. “The response to treatment was assessed by measuring combined B-12 and neurophysiologic variables at baseline and 4 mo after treatment.” “Treatment produced consistent improvements in conduction in myelinated peripheral nerves.” “A total of 10 sensory potentials were newly observed in sural (leg calf muscle) nerves after treatment.”

In a fourth human cobalamin neuropathy article by Trippe et al (2016) “Nutritional management of patients with diabetic peripheral neuropathy with L-methyfolate-methylcobalamin-phyridoxal-5-phosphate: results of a real-world patient experience trial.” This researcher recently conducted a study investigating the effect of L-methylfolate-methylcobalamin-phyridoxal-5-phosphate supplementation on … peripheral neuropathy and found self-reported improvement. However, researchers did not look at clinical neurological function

As a collection, these human research studies and reviews demonstrate that SCI patients have vitamin B complex deficiencies as related to DRI. A second study reported only a small percentage of SCI patients have cobalamin deficiencies as related to DRIs, however, the majority of these SCI patients demonstrated clinical symptoms of cobalamin deficiency, indicating the DRIs could be insufficient for SCI. Finally, regarding neuropathies and cobalamin therapy, retrospective reviews show little correlation of cobalamin to relieving pain while prospective studies show that cobalamin improves neuronal conduction time, impulse strength, and surveyed patients report improvement.

There are not many vitamin B complex studies on TBI, SCI, or neuropathy utilizing human subjects partly due to the ethical issue of performing clinical trials on humans with TBI and as Haar mentions perhaps because there is not sufficient revenue in marketing B complex vitamins to recover a $2.5 billion pharmaceutical investment. Thus, many TBI and SCI studies are completed on animals.

In a piglet folate study by Naim et al. entitled “Folic acid enhances early function recovery in piglet model of pediatric head injury”,  3-5 day old piglets were utilized because they “provide a better model of the human brain than rodents.” “Piglets have a similar cortical grey-white differentiation gyral pattern and physiologic response to TBI in humans.” Half the piglets (n=15) “received inertial rotation of the head to induce TBI” while 15 were uninjured. Seven piglets were given folic acid (80ug/kg) 15 minutes post injury, while eight were given saline. Treatment continued for 6 days post injury. Of the 15 uninjured, 8 were folate controls and 7 were saline controls. “Piglets underwent cognitive and neurobehavioral tests 1 day and 4 days post injury. They were assessed on memory, learning, behavior and problem solving ability through a variety of tests.” “Cognitive Composite Dysfunction scores or CCDs were used to assess the neurobehavioral performance of the animals on days 1 and 4. The CCD scores for the piglets were based on a variety of tests including open-field behavior, a mirror test, glass barrier task, food cover task, balance beam performance, and maze test.” Results demonstrate “that there was significant improvement in functional ability of the injured piglets given folic acid between day 1 and day 4 post injury.” Additionally, results showed more rapid completion of the balance beam task, improved motor function, increased visual problem solving with folate supplementation. The “volume of brain injury was not found to be significantly reduced by folic acid supplementation.”
One study summarized riboflavin, niacin, pyridoxine and folate interventions on rodents entitled “Vitamins and nutrients as primary treatments in experimental brain injury: clinical implications for nutraceutical therapies (Haar et al, 2015)”. Haar found the benefits of riboflavin to “lead to substantial functional recovery in sensorimotor function and working spatial memory, less edema, less reactive astrocytes and smaller lesions (Barbre and Horne, 2006).” “Nicotinamide supplementation was shown to improve sensory, motor and cognitive function following frontal lobe injury (Hoane et al., 2003).” Further Hoane studies demonstrated “reduced apoptosis and improved blood-brain-barrier (BBB) function (Hoane et al., 2006)”, however Swan found “no improvement at a standard dose and increased impairment at higher doses (Swan et al., 2011).” Pyridoxine “showed tissue sparing effects at very high doses (600mg/kg) but not at lower doses (300mg/kg).” “Chronic high B6 supplementation has been shown to cause neural toxicity and gait and balance problems (Kringle et al., 1980).” Folic acid did not show benefits in this rodent model. Haar identified the “lack of clinical interest in many of these treatments” being “primarily a monetary issue. It is difficult to convince pharmaceutical companies to develop a drug that cannot be patented.” He states that both riboflavin and nicotinamide (neuroprotective effects) have beneficial research supporting their use in the treatment of TBI. The researcher additionally mentions that a combination therapy will be needed to treat TBI.

The Hoane rodent study on riboflavin of 2005 is entitled “Administration of Riboflavin Improves Behavioral Outcome and Reduces Edema Formation and Glial Fibrillary Acidic Protein Expression after TBI”. Reported are 41 male Sprague-Dawley that “were assigned to B2 or saline treatment conditions and received contusion injuries or sham procedures. Drug treatment was administered 15 minutes and 24 hours following the injury. The rats were examined on a variety of tests to measure sensorimotor performance and cognitive ability in the Morris water maze.” Results showed that riboflavin “significantly reduced behavioral impairments observed on the bilateral tactile removal test, and through improved acquisition of both reference and working memory tests”. B2 showed a reduction in the size of the lesion, reduced the number of GFAP+ astrocytes” (indicating healthier tissue) and significantly “reduced cortical edema.” The article states that “there is strong evidence in the literature that the mechanisms of action for riboflavin is its ability to reduce oxidative damage”. In Hoane’s earlier 2003 report, niacin was found to provide “a much stronger reduction in the initial magnitude of injury deficit on the bilateral tactile remove and working memory test than riboflavin.” Niacin’s “prevention of depletion of nicotinamide adenine dinucleotide (NAD+) and prevention of ATP depletion” are the likely mechanisms of action to improve TBI.

Hoane’s niacin study of 2003 was entitled “Treatment with Vitamin B3 improves functional recovery and reduced GFAP expression following TBI in rats”. In this cortical contusion model injury, 30 male Sprague-Dawley rats, 3 months old were utilized. Following injury, 9 rats were given niacin (500mg/kg) and 9 control rats were given saline solution (1ml/kg) 15 minutes and 24 hours post injury. Sham rats (n=12) received niacin or saline. “The Morris Water Maze (MWM) was used to assess cognitive function following injury.” Somatosensory dysfunction was tested through the Bilateral Tactile Adhesive Removal Test. Fine motor control was tested through a staircase model. Lesion analysis with the ImageToolSoftware was conducted 35 days post injury. GFAP immunochemistry was used to label reactive astrocytes. The “administration of niacin following cortical contusion injury ….significantly lessened the behavioral impairments observed following injury and led to a long-lasting improvement in functional recovery. More specifically, the data from the bilateral tactile removal test showed that administration of niacin following injury …prevented the occurrence of a working memory deficit in the MWM model. The acquisition of a reference memory task in the MWM was significantly improved compared to saline-treated rats following injury.” The “skilled forelimb use in the staircase task was not significantly improved” after treatment. “The administration of niacin following injury significantly reduced the number of GFAP+ reactive astrocytes. Glial Fibrillary Acidic Protein is an intermediate protein which is produced to regenerate astrocytes in the brain. While not well understood, smaller quantities of GFAP+ are thought to correlate with smaller quantities of scar tissue production, thus reduced lesion size.  In this 2003 article, Hoane and his team astutely proposed several potential mechanisms for the action of niacin including 1) ATP support, 2) poly-ADP ribose polymerase inhibition 3) lipid peroxidation inhibition and/or 4) apoptosis prevention. He confirmed the first mechanism in his 2005 article above. Overall, the benefits of niacin are significant in this rodent study, and Hoane’s researchers have shown consistently positive results through a number of rodent studies.

A complex study elucidating the folate mechanism is entitled “Folate regulation of axonal regeneration in the rodent central nervous system (CNS) through DNA methylation” written by Iskandar, BJ et al. (2010). This article discusses how the CNS, composed of the brain and spinal cord is difficult to repair after injury. This study is based upon research demonstrating axonal regrowth and functional recovery of the injured adult CNS with dose-dependent folate. This study was designed to identify the mechanism by which folate improves growth and recovery.

These researchers utilized a spinal cord injury model in rodents. Both cervical dorsal columns were injured and the left sciatic nerve completely transected. The Methods section is extensive depending upon the many experiments performed. The researchers identified the following information about the mechanism of folate in injury repair:

  • Injury induces expression of the folate receptor to attract folate to the injured site.
  • Global de-methylation of the spinal cord DNA accompanies injury.
  • The regeneration of injured CNS axons is inhibited due to dihydrofolate reductase.
  • Folate regulates its receptor activation and re-methylated DNA in a dose dependent manner.
  • Folate prevents DNA de-methylation in a dose dependent manner.
  • Reduced folate (via dihydrofolate reductase) is essential for folate’s pro-regenerative effects.
  • There is a direct, biphasic correlation between the proportion of regenerating afferent axons in the spinal cord, folate receptor expression, global DNA methylation, and methylation of a Gadd45a gene which is associated with spinal cord injury and neurite outgrowth.

The combined injury model is interesting because it causes an axonal response important to this research, however, it would not be a likely injury in rodents or humans. The results are important because they identify folate’s mechanism. Given our knowledge regarding the function of folate in methylation, this folate repair mechanism is likely to be similar in both rodents and humans. This report gives extensive support to folate’s role in CNS axonal repair, given the identification of the mechanisms.

Let’s summarize the various animal articles. In the piglet model, folate was found to improve cognitive and neurobehavior after TBI, however, folate was not found to reduce lesion size. In Haar’s rodent model, riboflavin was found to improve functional recovery in sensimotor function, working spatial memory, less edema, fewer reactive astrocytes and smaller lesions. Hoane found that riboflavin reduced behavioral impairment, lesion size, reactive astrocytes and cortical edema. Riboflavin likely works as a free radical scavenger. Niacin was found to increase sensorimotor function and cognitive function, decrease apoptosis, and increase blood-brain-barrier function. However, Swan saw no improvement at a standard niacin dose and toxicity at higher doses. Niacin’s likely mechanism is to provide NAD and ATP. Niacin has been shown to decrease both behavior impairments and reactive astrocytes, and prevent a working memory deficit. Niacin in this model did not improve skilled use. Pyridoxine showed tissue sparing at higher doses, but Kringle cautioned about neural toxicity. With folate, benefits were not shown in the rodent model in one report, however, benefits of folate in axonal regrowth and functional recovery have been demonstrated in other reports. The final report discussed identifies the mechanisms by which folate methylates DNA.

Presented with the brain injury patient, we have been trained to consider normalizing B complex vitamin levels. We know that B complex vitamins are critical for neural support, but we are encouraged to use evidence based therapies. Given the nature of TBI research and the difficulty of recovering a $2.5B pharmaceutical drug investment, more rodent studies are available than human as supportive evidence. The majority of human and animal researchers appear supportive of normalizing B vitamin levels with brain injury.

A final note, our government “gave away the internet” on October 1st to an international body. The United States developed the internet. Health care providers have enjoyed free access to the internet to research data for problem solving. Health care organizations have worked diligently to follow regulations enacted by the U.S. Government requiring these organizations to spend millions of dollars to protect patient information. Stiff penalties are levied for non-compliance. While the U.S. Government has provided poor internet security in years past, they no longer must provide any internet security to assist health care providers and organizations in protecting personal health data secure. We are all now at the world’s mercy. Let us all hope and pray that security and freedom prevail with our lost ownership and oversight.

References:

Ang CD, Alviar MJ, Dans AL, Bautista-Velez GG, Villaruz-Sulit MV, Tan JJ, Co HU, Bautista MR, Roxas AA. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev. 2008;(3):CD004573.

Brito A, Verdugo R, Hertrampf E, Miller JW, Green R, Fedosov SN, Shahab-Ferdows S, Sanchez H, Albala C, Castillo JL, Matamala JM, Uauy R, Allen LH. Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status. Am J Clin Nutr. 2016;103(1):250-7.

Haar, C.V., Peterson, T.C., Martens, K.M.,  Hoane, M.R. (2015). Vitamins and nutrients as primary treatments in experimental brain injury: clinical implications for nutraceutical therapies. Brain Research 1640, 114-129. doi: 10.1016/j.brainres.2015.12.03

Hoane, M.R., Akstulewicz, S.L., Toppen, J. Treatment with Vitamin B3 Improves Functional Recovery and Reduces GFAP Expression following Traumatic Brain Injury in Rats. (2003) Journal of Neurotrauma. 20(1): 1189-1199

Hoane, M. R., Wolyniak, J. G., & Akstulewicz, S. L. (2005). Administration of riboflavin improves behavioral outcome and reduces edema formation and glial fibrillary acidic protein expression after traumatic brain injury. Journal of Neurotrauma, 22(10), 1112-22. doi:http://dx.doi.org.libproxy1.usc.edu/10.1089/neu.2005.22.1112

Iskandar BJ, Rizk E, Meier B, Hariharan N, Bottiglieri T, Finnell RH, Hogan (2010). Folate
regulation of axonal regeneration in the rodent central nervous system through DNA
methylation. The Journal of Clinical Investigation, 120(5), 1603-1616.

Naim, M.Y., Friess, S., Smith, C., Ralston, J., Ryall, K., Helfaer, M.A. & Margulies, S.S. (2011). Folic acid enhances early functional recovery in a piglet model of pediatric head injury. Developmental Neuroscience, 32(5-6), 466-79. doi:http://dx.doi.org.libproxy2.usc.edu/10.1159/000322448

Miles LM, Mills K, Clarke R, Dangour AD. Is there an association of vitamin B12 status with neurological function in older people? A systematic review. Br J Nutr. 2015;114(4):503-8.

Petchkrua W, Burns SP, Stiens SA, James JJ, Little JW. Prevalence of vitamin B12 deficiency in spinal cord injury. Archives of Physical Medicine and Rehabilitation. November 2003, Vol.84(11): 1675-1679, doi:10.1053/S0003-9993(03)00318-6. http://www.sciencedirect.com.libproxy1.usc.edu/science/article/pii/S0003999303003186?via%3Dihub.

Trippe BS, Barrentine LW, Curole MV, Tipa E. Nutritional management of patients with diabetic peripheral neuropathy with L-methylfolate-methylcobalamin-pyridoxal-5-phosphate: results of a real-world patient experience trial. Curr Med Res Opin. 2016;32(2):219-27.

Walters JL, Buchholz AC, Martin Ginis KA. Evidence of dietary inadequacy in adults with chronic spinal cord injury. Spinal Cord (2009) 47, 318-322;doi:10.1038/sc.2008.134 published online 11 November 2008. http://www.nature.com/sc/journal/v47/n4/full/sc2008134a.html

Bone Nutrients:

IMG_0409

Calcium

Medicine often points the finger to high sodium levels as being contributory to heart disease when in fact the culprit may be low calcium, potassium or magnesium levels. These nutrients work as a team to make nerve impulses conduct and muscles contract. These minerals must be present concurrently and in adequate amounts.

Potassium, magnesium and calcium levels can be measured in blood serum. However, the calcium blood measurement is not so useful, because when blood calcium is low, the body takes calcium out of bone to raise the blood calcium levels. When bone tissue is broken down in this manner, both calcium and phosphate are released from the bone into the blood stream, thus elevating blood serum levels. This regulation process is great to keep nerves conducting and muscles contracting. However, the process weakens bones because it removes calcium and phosphate. If this calcium and phosphate are never replaced, bone breakdown and eventually osteoporosis results.

Since blood calcium measurements do not give us an accurate indication of whether calcium levels are being maintained through dietary methods or from bone storage, medicine measures bone calcium levels through density scanning techniques such as DEXA scan. DEXA scan measurements that are between +1 and -1 are considered normal. Measurements between -1 and -2.5 are considered osteopenic (reduced bone mass) and measurements less than -2.5 are considered osteoporosis. More information can be found on http:// http://www.niams.nih.gov/health_info/bone/Bone_Health/bone_mass_measure.asp.

Noticeable physical indications of low blood calcium levels include muscle cramps, restless legs and broken bones. Muscles need adequate calcium, sodium, and potassium to contract and relax. Calcium supplements help relax a muscle cramp. This is due to lactic acid build up during exercise. Calcium may bind lactic acid, relaxing the muscle and releasing the cramp. Sparkling water and club soda, given their alkali nature, also help to neutralize the lactic acid relieving a muscle cramp. While massaging and stretching a tight muscle feels good, this may damage the fibers. Muscle relaxation and contraction is best restored when adequate minerals are provided. While a calcium supplement and alkali water, club soda, or sparkling water may be a temporary remedy to relieve muscle cramps or restless legs, a long term dietary and supplement plan will be important to maintain muscle, bone, and nerve health.

Calcium Sources

Because calcium is critical to humans, the bones have been cleverly designed to be the body’s mini storage units for calcium. We maintain these storage units and blood calcium levels through food intake and supplementation. Some of the best calcium foods according to WebMD are “cheese, yogurt, milk, sardines, dark leafy greens (spinach, kale, turnips, and collard greens) and orange juice”. You can find specific food calcium and nutrient information on NutritionData.com. Some of the best calcium supplements contain calcium citrate, calcium phosphate, and magnesium. Many supplements contain calcium carbonate which is lime. Current calcium recommendations range from 1000mg – 1500mg/day. Vitamin D also has an important role in transporting calcium into bone.

Collagen

While calcium supplementation is frequently recommended. It is less recognized that calcium citrate and phosphate are important supplements, given that they constitute a larger percentage of bone. The remaining portion of bone is composed of collagen. The collagen component of bone is never mentioned, yet it comprises anywhere from 10-30% of bone. Collagen is a flexible tissue found in young bone, tendons and ligaments. Collagen is found throughout the body in tissues, organs, joints, gums and teeth. In addition to calcium citrate and phosphate to make the calcium salts in bone, we need all of the nutrients to maintain the collagen network found in bone. The collagen network is formed by vitamin C and the amino acids lysine, proline and glycine. Collagen fibers can be damaged by injury, repetitive use, stretches or strains when muscles are weak. Collagen can additionally be damaged by our immune system. This is due to the attachment of wheat gluten to collagen fibers throughout the body. Our immune system sees wheat gluten and wheat defense proteins as foreign invaders. This causes the secretion of immune system chemicals contributing to arthritis, asthma, and many organ diseases. (More information can be found on http://www.wheatfreediseasefree.com.)

In summary, all of the nutrients: calcium citrate, phosphate, magnesium, vitamin D, vitamin C, lysine, proline and glycine must be present concurrently to build flexible collagen and healthy bone tissue. They can be found in a variety of foods and these supplements are available at nutrition stores. (Teeth may be a lysine storage site, and adequate lysine and vitamin C levels may contribute to gum and teeth health.)

So, we discussed calcium’s importance to muscle and nerves, and the body’s brilliant regulation mechanism for calcium such that when blood calcium levels are low, the body removes calcium from bone to maintain the blood calcium levels. As we mentioned, this regulation mechanism is great for maintaining nerve and muscle function, but not so great at maintaining bone strength and density. A good visual analogy might be a Corvette production line. All of the parts to build the Corvette must be supplied to build the car. If one part is missing, the technicians and robots build what may look like a car and feel like a car, but may not function like a car. One small part may make the difference. Bones and collagen work the same way. They are composed of many “parts” (calcium citrate, phosphate, magnesium, vitamin D, vitamin C, lysine, glycine, and proline). All nutrients must be supplied in adequate amounts for your body to build bone, tendon and ligaments. If “parts” are missing, the body may build structures that look like bone, tendon and ligaments, but they might not function that way. Bones may break easily and muscles may cramp easily. Restless legs may result. Tendons may tear. Adequate parts produce beautiful, zero to 60mph in 4 seconds Corvettes, and adequate nutrients produce healthy, functional bones, tendons and ligaments.

Why is Calcium Removed from Bone ??

As we discussed, our bodies remove calcium from bone tissue to maintain critical muscle and nerve function. This eloquent measure is likely designed to work temporarily when dietary/ supplemental calcium is insufficient. Alas, in osteoporosis, this calcium removal measure is apparently being forced to work long term. There is a second important reason calcium may be lost from bone. Many of our foods are acidic. The blood is carefully regulated to be around pH of 7.4, this is critical for chemical pathways. Acidic foods would drive the blood pH below 7.4.  Recycled bone calcium contains bicarbonate which acts as a pH buffer in the blood to balance these acidic foods, maintaining the pH. Alkali water, club soda, and sparkling water all bind acid to help maintain this normal blood pH. This process might be somewhat like bath water. If the bath water is too hot, cold water can be mixed with hot water to neutralize it’s effect. Finally, calcium can be removed from bone and excreted when the adrenals are fatigued. Both mental and physical stress, can fatigue the adrenals. Our high consumption modified grain and sugars fatigues our adrenals. As a result, calcium leaves the body.

Calcium Buildup in Tissues Other than Bone

Often, calcium builds up in tissues other than bone. Calcium buildup is found in breast tissue, kidney stones, gallstones, cysts and many other tissues, where it doesn’t belong. Why? What should we do? Should we reduce calcium intake to reduce this tissue buildup? Interestingly, calcium buildup in the wrong tissues appears to occur when individuals have insufficient dietary/supplemental calcium intake. Researchers have found that increasing dietary calcium and supplements decreases calcium buildup in the wrong tissues and increases calcium buildup in the right place, bone (Gul and Monga, 2014).

Your curious mind may ask, why is calcium showing up in the wrong tissues when dietary/ supplemental calcium levels are low? We would like to propose a theory to answer this question. We know that when blood calcium levels are low, recycled calcium (and phosphate) being released from bone to raise blood calcium levels. It is likely that the recycled bone calcium is structurally different from the calcium we eat in food and/or supplement, and possibly the recycled calcium from bone cannot be redeposited into bone tissue once blood levels normalize. Perhaps, the body can’t easily excrete excess recycled bone calcium, thus it builds up in tissues where it doesn’t belong. Certainly, releasing calcium from bone, to maintain blood calcium levels, was meant to be a temporary measure, not a long term process.

What is the impact of having recycled calcium delivered to the wrong tissues? “Insufficient intake of dietary calcium (<600mg/day) can increase… the risk of stone formation“, (Gambara, 2016). Gambara confirms that “stone formation is frequently associated with other diseases of affluence such as hypertension, osteoporosis, cardiovascular disease, metabolic syndrome, and insulin resistance.” Research studies such as the 2012 NHANES find “a 70% increase from the 1994 NHANES” in urinary tract stone disease, (Gul and Monga, 2014). Thus, our calcium deficiencies are worsening. These researchers report that “newer research is finding that stones are associated with several serious morbidities”.

Researchers have found that calcium buildup in the form of hydroxyapatite in breast tissue contributes to breast cancer (Cooke, 2003). Let’s repeat this sentence. Calcium build up in breast tissue is involved with breast cancer. One in eight women will have breast cancer. Researchers also recognize that radiation can modify healthy cells and turn them into uncontrollable cancerous cells. Mammograms contain radiation and radiation damage is additive in the body. Researchers have found that citrate and phosphate may have a role in removing hydroxyapatite deposits in breast tissue.  In one research study, women taking phosphate bone density drugs had reduced incidence of breast cancer.

How to Deliver Calcium to Bone

Given this information, how shall we best increase calcium in our bones and decrease calcium tissue deposits and stones?

One common solution, is to take a calcium supplement such as calcium citrate and/or calcium phosphate. Bone is composed of calcium citrate, calcium phosphate, magnesium, vitamin D, and collagen (vitamin C, lysine, proline, and glycine). It used to be that many calcium supplements were composed of calcium carbonate. Calcium carbonate is lime. Many supplements are now changing ingredients to calcium citrate or calcium phosphate. We need both.

Why calcium citrate? Citrate works in two ways. First, citrate is a buffer. Therefore, when the blood pH is low, citrate will buffer the pH and calcium will not be pulled from bone tissue to normalize pH. Alkali water, club soda or sparking water are alkali drinks that help to increase blood pH. Secondly, calcium citrate is found to combine well with phosphate and collagen components to make bone. Calcium citrate appears to be a key strength component in bone tissue. More information on citrate properties: https://www.sciencedaily.com/releases/ 2011/06/110608153548.htm. Finally, citrate and phosphate help remove calcium buildup in the wrong tissues: http://www.ncbi.nlm.nih.gov/pubmed/?term=breast%2C+hydroxyapetite %2C+citrate%2C+phosphate. Researchers found that citrus bioflavonoids and lemon peel inhibit stone formation: http://www.ncbi.nlm.nih.gov/pubmed/?term=27241030. This is critical information to the long term prevention calcium build up in the wrong tissues and maybe critical to the long term prevention of breast cancer. Many calcium supplements are now calcium citrate.

Calcium phosphate is the other important component of bone. Calcium citrate and phosphate can be found in supplements. Researchers have found that citrate and phosphate may have a role in removing hydroxyapatite deposits in breast tissue. These deposits found on mammograms may contribute to the formation of breast cancer. In one research study, women taking phosphate bone density drugs had reduced incidence of breast cancer.

The Linus Pauling Institute has found that many other minerals and vitamins are found in bone such as magnesium, fluoride, sodium, vitamin A, D and K. More information can be found on: http://lpi.oregonstate.edu/mic/micronutrients-health/bone-health#minerals. More individuals than recognized may be deficient in vitamin A, as seen in dry eyes and in vitamin K as seen in nose bleeds. (Caution: vitamin K, found in leafy green vegetables, allows the blood to clot when vessels are damaged. Blood thinners interfere with vitamin Ks ability to clot blood. Ingesting additional vitamin K interferes with blood thinner drugs)

Secondly, drink plenty of fluids to produce at least 2.5L of urine per day (Gul and Monga, 2014). Gul recommends avoiding the colas which are acidic, yet not being quite as concerned with the “citric acid containing sodas, which include most clear soft drinks.” As we learned above, citric acid found in lemons and limes can be beneficial to bone health.

Remember that if you are eating a lot of protein, taking amino acids for brain or sports health, or drinking wine your blood may be more acidic which will pull carbonate from your bones to buffer the pH of your blood. So you may want to increase your calcium citrate or alkali water, club soda, and/or sparkling water consumption to balance these actions.

Finally, stressing your adrenals, the little walnut shaped organs that sit on top of your kidneys, (the adrenals produce neurotransmitters) results in the loss of calcium. Minimizing both mental stress activities and physical stress, often caused by the consumption of manufactured wheat and sugar, will help the adrenals. High glucose (grains, sugars) levels result in high stone levels (Gul and Monga, 2014).

References:

Cooke MM1, McCarthy GM, Sallis JD, Morgan MP. Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1beta and cyclooxygenase-2 mRNA in human breast cancer cell lines. Breast Cancer Res Treat. 2003 May;79(2):253-63.

Gambaro G1, Trinchieri A2., Recent advances in managing and understanding nephrolithiasis/ nephrocalcinosis. F1000Res. 2016 Apr 18;5. pii: F1000 Faculty Rev-695. doi: 10.12688/ f1000research.7126.1. eCollection 2016

Gul Z1, Monga M2., Medical and dietary therapy for kidney stone prevention.
Korean J Urol. 2014 Dec;55(12):775-9. doi: 10.4111/kju.2014.55.12.775. Epub 2014 Nov 28.

Additional Materials:

Citrate helps reduce stone formation:

http://www.ncbi.nlm.nih.gov/pubmed/?term=22908773 http://www.ncbi.nlm.nih.gov/pubmed/?term=26614113

http://www.ncbi.nlm.nih.gov/pubmed/?term=20576821 http://www.ncbi.nlm.nih.gov/pubmed/?term=21747586

http://www.ncbi.nlm.nih.gov/pubmed/?term=17509313 http://www.ncbi.nlm.nih.gov/pubmed/?term=26582172 http://www.ncbi.nlm.nih.gov/pubmed/?term=27072174 http://www.ncbi.nlm.nih.gov/pubmed/?term=25855777 http://www.ncbi.nlm.nih.gov/pubmed/?term=26439475 http://www.ncbi.nlm.nih.gov/pubmed/?term

Chronic alcohol use may weaken bones: http://www.ncbi.nlm.nih.gov/pubmed/1854370.

EGCG (epigallocatechin gallate) found in green tea shows promise inhibiting the formation of kidney stones in rats:

http://www.ncbi.nlm.nih.gov/pubmed/?term=26281564 http://www.ncbi.nlm.nih.gov/pubmed/?term=16047215 http://www.ncbi.nlm.nih.gov/pubmed/?term=26898643

Mediterranean/fruit/vegetable diet may protect against stone formation: http://www.ncbi.nlm.nih.gov/pubmed/24502605

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.

Tryptophan’s Affect on Depression: A Review Article

IMG_4815

 

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

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

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

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

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

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

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

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

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

Tryptophan’s Effect on Human Mood

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

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

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

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

Tryptophan’s Effect on Human Mood and Sleep

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

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

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

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

III. A Systems Approach to Rebuilding the Serotonin Pathway

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

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

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

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

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

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

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

Tryptophan, Gastrointestinal Disease, and Inflammation

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

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

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

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

IV. Conclusion

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

References:
aan het Rot, M., Moskowitz, D. S., Pinard, G., and Young, S. N. (2006) Social behaviour and mood in everyday life: the effects of tryptophan in quarrelsome individuals. J. Psychiatry Neurosci. 31, 253–262

Aparicio S, Garau C, Nicolau MC, Rivero M, Rial RV (2007) Chrononutrition: use of dissociated day/night formulas to improve the development of the wake-sleep rhythms. Effects of tryptophan. Nutr Neurosci 10(3–4):137–143

Bailey, R. L., Fulgoni, V. L., 3rd, Keast, D. R., Dwyer, J. T. (2012) Examination of vitamin intakes among US adults by dietary supplement use. J. Acad. Nutr. Dietetics 112, 657–663

Banovic I, Gilibert D, Cosnes J. Perception of improved state of health and subjective quality of life in Crohn’s disease patients treated with infliximab. J Crohns Colitis. 2009; 3(1): 25-31

Blair, R. J. (1995) A cognitive developmental approach to mortality: investigating the psychopath. Cognition 57, 1–29

Bravo R1, Matito S, Cubero J, Paredes SD, Franco L, Rivero M, Rodríguez AB, Barriga C (2012). Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. Age (Dordr). 2013 Aug;35(4):1277-85. doi: 10.1007/s11357-012-9419-5. Epub 2012 May 24.

Bubenik GA, Konturek SJ (2011) Melatonin and aging: pros- pects for human treatment. J Physiol Pharmacol 62(1):13–19

Chalon, S. (2006) Omega-3 fatty acids and monoamine neuro- transmission. Prostaglandins Leukot. Essent. Fatty Acids 75, 259–269

Crockett, M. J. (2009) The neurochemistry of fairness: clarifying the link between serotonin and prosocial behavior. Ann. N. Y. Acad. Sci. 1167, 76–86

Cubero J, Otalora BB, Bravo R, Sánchez CL, Franco L, Uguz AC, Rodríguez AB, Barriga C (2011) Distribution of 5-HT receptors in the mammalian brain. Trends Cell Mol Biol 6:41–46

de la Presa Owens, S., and Innis, S. M. (1999) Docosahexaenoic
and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic acid deficient diet in formula-fed piglets. J. Nutr. 129, 2088–2093

Druker SM, “How The U.S. Food And Drug Administration Approved Genetically Engineered Foods Despite The Deaths One Had Caused And The Warnings Of Its Own Scientists About Their Unique Risks”, Alliance For Bio-Integrity, 2001

Educational Research (ERB); http://wheatfreediseasefree.com/category/neurotransmitter-brain-food/

Escriba, PV, Wedegaertner, PB, Goni FM and Vogler O. (2007) Lipid-protein interactions in GPCR-associated signaling. Biochim. Biophys. Acta 1768, 836-852.

Fälth-Magnusson K, Magnusson KE. Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease. Pediatr Allergy Immunol. 1995 May;6(2):98-102

Forbes Magazine, 2013 http://www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/

Ginde, A. A., Liu, M. C., and Camargo, C. A., Jr. (2009) Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch. Intern. Med. 169, 626–632

Goodhand JR, Greig FI, Koodun Y, et al. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm Bowel Dis. 2012; 18(7):1232-1239

Greenberg, B. D., Li, Q., Lucas, F. R., Hu, S., Sirota, L. A., Benjamin, J., Lesch, K. P., Hamer, D., and Murphy, D. L. (2000) Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am. J. Med. Genet. 96, 202–216

Groves, N. J., Kesby, J. P., Eyles, D. W., McGrath, J. J., Mackay-Sim, A., and Burne, T. H. (2013) Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav. Brain Res. 241, 120–131

Gu ̈nther, J., Schulte, K., Wenzel, D., Malinowska, B., and Schlicker, E. (2010) Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L-826,266. Naunyn Schmiedebergs Arch. Pharmacol. 381, 21–31

Heinrichs, S. C. (2010) Dietary omega-3 fatty acid supplemen- tation for optimizing neuronal structure and function. Mol. Nutr. Food Res. 54, 447–456

Heron, D. S., Shinitzky, M., Hershkowitz, M., and Samuel, D. (1980) Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes. Proc. Natl. Acad. Sci. USA 77, 7463–7467

Hibbeln, J. R., Linnoila, M., Umhau, J. C., Rawlings, R., George, D. T., and Salem, N., Jr. (1998) Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics. Biol. Psychiatry 44, 235–242

Hill RH Jr, Caudill SP, Philen RM, Bailey SL, Flanders WD, Driskell WJ, Kamb ML, Needham LL, Sampson EJ, “Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome.”, Arch Environ Contam Toxicol. 1993 Jul;25(1):134-42.

Hudson, C., Hudson, S., and MacKenzie, J. (2007) Protein- source tryptophan as an efficacious treatment for social anxiety disorder: a pilot study. Can. J. Physiol. Pharmacol. 85, 928–932

Kiank, C., Zeden, J. P., Drude, S., Domanska, G., Fusch, G., Otten, W., and Schuett, C. (2010) Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on im- munosuppression in mice and humans. PLoS ONE 5, e11825

Kurina LM, Goldacre MJ, Yeates D, Gill LE, Depression and anxiety in people with inflammatory bowel disease. J Epidemiol Community Health. 2001; 55(10):716-720

Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri,S.,Benjamin,J.,Mu ̈ller,C.R.,Hamer,D.H.,andMurphy, D. L. (1996) Association of anxiety-related traits with a poly- morphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531

Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new “5-HT” hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of deterimental tryptophan catabolites (TRYCATS), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3): 702-721

Mansbach, J. M., Ginde, A. A., and Camargo, C. A., Jr. (2009) Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics 124, 1404–1410

Markus CR, Jonkman LM, Lammers JHCM, Deut NEP, Messer MH, Nienke R (2005). Evening intake of α-lactalbumin increases plasma tryptophan availability and improves morning alertness and brain measures of attention. Am J Clin Nutr 81:1026–1033

Martin-Subero M1, Anderson G2, Kanchanatawan B3, Berk M4, Maes M3 (2015).
Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways. CNS Spectr. 2015 Aug 26:1-15. [Epub ahead of print]

Mendelsohn D, Riedel WJ, Sambeth A (2009). Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev 33:926-952.

Mohajeri MH, Wittwer J, Vargas K, Hogan E, Holmes A, Rogers PJ, Goralczyk R, Gibson EL (2015). Chronic treatment with a tryptophan-rich protein hydrolysate improves emotional processing, mental energy levels and reaction time in middle-aged women. Br J Nutr. 2015 Jan 9:1-16. PMID: 25572038

Most EIS, Scheltens P, Van Someren EJW (2010) Prevention of depression and sleep disturbances in elderly with memory- problems by activation of the biological clock with light— a randomized clinical trial. Trials 11:19

Muszyńska B1, Łojewski M1, Rojowski J2, Opoka W2, Sułkowska-Ziaja K1. Natural products of relevance in the prevention and supportive treatment of depression (2015). Psychiatr Pol. 2015;49(3):435-453. doi: 10.12740/PP/29367. PMID: 26276913

Nielsen, D. A., Goldman, D., Virkkunen, M., Tokola, R., Rawlings, R., and Linnoila, M. (1994) Suicidality and 5- hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch. Gen. Psychiatry 51, 34–38

Paila, Y. D., Ganguly, S., and Chattopadhyay, A. (2010) Metabolic depletion of sphingolipids impairs ligand binding and signaling of human serotonin1A receptors. Biochemistry 49, 2389–2397

Paredes SD, Terrón MP, Valero V, Cubero J, Barriga C, Reiter RJ, Rodríguez AB (2007) Tryptophan increases nocturnal rest and affects melatonin and serotonin serum levels in oldringdove. Physiol Behav 90:576–582, Pergamon-Elsevier Science Ltd. (I.S.S.N.: 0031–9384)

Patrick, R. P., and Ames, B. N. (2014) Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism. FASEB J. 28, 2398–2413

Portanova, J. P., Zhang, Y., Anderson, G. D., Hauser, S. D., Masferrer, J. L., Seibert, K., Gregory, S. A., and Isakson, P. C. (1996) Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. J. Exp. Med. 184, 883–891

Raimo S1, Trojano L, Spitaleri D, Petretta V, Grossi D, Santangelo G. (2015) Psychometric properties of the Hamilton Depression Rating Scale in multiple sclerosis. Qual Life Res. 2015 Aug;24(8):1973-80. doi: 10.1007/s11136-015-0940-8. Epub 2015 Feb 11.

Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013; 70(1): 31-41

Retz, W., Retz-Junginger, P., Supprian, T., Thome, J., and Ro ̈sler, M. (2004) Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology. Behav. Sci. Law 22, 415–425

Reus GZ, Jansen K, Titus S, Carvalho AF, Gabbay V, Wuevedo J. (2015) Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. Journal of Psychiatric Research. 2015; 68(2015) 316-328

D, Riedel WJ, Sambeth A (2009) Effects of acute tryptophan depletion on memory, attention and executive functions: a systematic review. Neurosci Biobehav Rev 33:926–952

Sánchez S, Sánchez CL, Paredes SD, Barriga C, Rodríguez AB (2008a) Circadian levels of serotonin in plasma and brain after oral administration of tryptophan in rats. Basic Clin Pharmacol 104:52–59

Sánchez S, Sánchez CL, Paredes SD, Rodríguez AB, Barriga C (2008b) The effect of tryptophan administration on the circadian rhytms of melatonin in plasma and the pineal gland of rats. J Appl Biomed 6:177–186

Sanfey, A. G. (2007) Social decision-making: insights from game theory and neuroscience. Science 318, 598–602

Sarris J, Byrne GJ (2011). A systemic review of insomnia and complementary medicine. Sleep Med Rev 15:99-106

Schlicker, E., Fink, K., and Go ̈thert, M. (1987) Influence of eicosanoids on serotonin release in the rat brain: inhibition by prostaglandins E1 and E2. Naunyn Schmiedebergs Arch. Pharmacol. 335, 646–651

Su, K. P., Lai, H. C., Yang, H. T., Su, W. P., Peng, C. Y., Chang, J. P., Chang, H. C., and Pariante, C. M. (2014) Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol. Psychiatry 76, 559–566

Su, K. P., Huang, S. Y., Peng, C. Y., Lai, H. C., Huang, C. L., Chen, Y. C., Aitchison, K. J., and Pariante, C. M. (2010) Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol. Psychiatry 67, 550–557

Sung, HM, Kim JB, Park YN, Bai DS, Lee SH, Ahn HN. A study on the reliability and the validity of Korean version of the Beck Depression Inventory-II (BDI-II) J Korean Soc Biol Ther Psychiatry. 2008;14:201–12.

US Department of Agriculture, ARS. (2014) Nutrient Intakes from Food: Mean Amounts Consumed per Individual, by Gender and Age, US Department of Agriculture, Washington, DC

Varna ̈s, K., Halldin, C., and Hall, H. (2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum. Brain Mapp. 22, 246–260

Wassal SR and Stillwell W (2009). Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes. Biochim. Biophys. Acta 1788, 24-32.

Way, B. M., Lac ́an, G., Fairbanks, L. A., and Melega, W. P. (2007) Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey. Neuroscience 148, 937–948

Yao K, Fang J, Yin YL, Feng ZM, Tang ZR, Wu G (2011) Tryptophan metabolism in animals: important roles in nu- trition and health. Front Biosci (Schol Ed) 1(3):386–397

Young, S. N., Rot, M., Pinard, G., and Moskowitz, D. S. (2007) The effect of tryptophan on quarrelsomeness, agreeableness, and mood in everyday life. Int. Congr. Ser. 1304, 133–143

Young, S. N., and Leyton, M. (2002) The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels. Pharmacol. Biochem. Behav. 71, 857–865

Zhang, X., Beaulieu, J. M., Sotnikova, T. D., Gainetdinov, R. R., and Caron, M. G. (2004) Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305, 217

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.

Amino Acid Therapy for TBI and Concussion: A literature review

IMG_0679

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

IMG_4453

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

 

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.

 

 

 

Adrenal Tremor, Parkinson’s Disease and the Wheat Free Diet

photo-4

This is a Case Study of a 13 y/o boy who was raised on a wheat free diet (WFD) since age 4.  As an infant,  he  experienced monthly ear infections and was placed on prophylactic antibiotic therapy.  His pre-school years were mired with monthly strep throat infections. Occasionally, he had concurrent small red blotches, indicative of rheumatic fever, on his  torso.  A tonsillectomy was recommended by his pediatrician.

He began a WFD at age 4, the strep throat infections ceased …. unless he ingested wheat without antihistamine prophylaxis. Occasionally, he ate a piece of wheat pizza at school without a immediate anti-histamine.  Subsequent strep throat infections would ensue resulting in swollen cervical lymph nodes, a flushed face, swollen, red and pussy tonsils, but no fever.  All infections presented similarly, however not all tested positive for strep.   This condition was treated with antibiotics and resolved in a few days.  (Please see the www.wheatfreediseasefree.com post on “Keep the Tonsils, Pull the Strep Throat”).

As a pre-schooler,  the boy had wound healing difficulties.  During his middle school years, he experienced anxiety, fatigue, a lack of physical maturation, restless legs, painful joints, middle belly weight, athlete’s foot, and a slightly curved back.

At age 13, he ate two pieces of wheat pizza without antihistamine prophylaxis.  In the days following, his face flushed intensely, cervical lymph nodes swelled, but no fever was present.  His back was painful at the level of his adrenals. He experienced extreme fatigue, his eyes were sensitive to light, and he had a tremor.  The tremor traveled down his spine and caused his fingers to vibrate.  He was started on his standard Azithromycin antibiotic therapy. However, the condition did not resolve.

Within a couple days he “crashed“.  He had sufficient energy to be active for a couple of hours in the morning and then he lived on the couch for the remainder of the day.  He headed for bed shortly after dinner. Any form of stress intensified the tremor including homework or attending school.  He was started on a second antibiotic.

Differentials considered included infection, PANDAS, serotonin syndrome, and depression.  Medical personnel questioned whether he was avoiding school.  Blood panels were negative.  EEG was negative.  He was prescribed Zoloft to control the tremor.  This drug made him sick and was discontinued.

One month later, a naturopathic physician identified the boy’s flushed face as being caused by adrenal problems.  Through intracellular saliva testing, he was found to be adrenal insufficient.  The flashlight adrenal insufficiency test was positive.  To support his adrenals he began began a supplemental therapy of vitamin C (1000mg/day), B complex (200mg/day), adrenal cortical extract, minerals, vitamin A, CoQ10, vitamin E, spirulina, quercetin, a probiotic, 1g/day of omega-3 fish oil (DHA+EPA) and 1000mg/day of calcium citrate.  His energy levels gradually improved but the tremor continued.

Sugar, high fructose corn syrup, caffeinated drinks, and deep fried, greasy foods harmful to his adrenals were removed from his diet.  The high levels of fruit juice previously consumed were replaced with low, no sugar, or sugar substitute  juices.

It was determined that wheat contains methionine, lysine and threonine.  Methionine controls the hypophyseal-pituitary-adrenal (HPA) axis and is involved with cardiac rhythm.   Lysine is found in collagen thus supports wound heading and dental pulp formation. Threonine supports tooth enamel formation. Hypothesizing that the patient was deficient in these amino acids due to his WFD,  he was started on 1500mg/day of methionine and 1000mg/day of lysine. The boy craved red meat and eggs.  His diet was modified to include methionine containing foods such as brown rice, oranges, additional red meat, eggs, nuts, spinach, onions, peas, yogurt, and popcorn.  Within a week, the boy had regained sufficient energy to work on small hobbies.

Within a month, he began to experience some quick, sharp chest pain.  Methionine is stored in the heart.  The methionine dosage was reduced to 1,000mg/day.  Although he had more energy and felt better, the facial flushing, swollen lymph glands, fatigue, back adrenal pain, and tremor continued.

A urine amino acid profile showed the boy’s methionine level (with supplementation) in low normal range.  Also in low normal range were phosphoserine, taurine, phosphoethanolamine, aspartic acid, hydroxyproline, serine, asparagine, alanine, tryptophan, carnosine, and anserine.   Some success has been found with taurine in relieving tremor.  He was given a trial of 1000mg/day of taurine.  His energy levels increased, however evening doses made it difficult to sleep and there was no improvement in the tremor.

Repeat urine and blood amino acid profiles showed phosphoserine as the only amino acid below normal range.  The patient was supplemented with 1,000mg/day of serine.  One week post therapy, he developed a skin rash on his arms and legs.  Serine therapy was discontinued then reduced to 500mg/twice each week.  The tremor persisted.

Next, the physiological function of each of these amino acids was addressed in relation to the patient’s signs/symptoms.  Proline was found to be a critical component of cartilage and important to joint structure.  Proline works with vitamin C in this capacity and can be synthesized by glutamic acid.  Arginine was important in wound healing, the production and release of growth hormone, insulin, and glucagon release, collagen synthesis, and GABA production. Arginine can be produced from glutamic acid or proline.  Glycine was critical to GABA neurotransmitter and energy production. GABA was important to inhibitory nerve function. Tyrosine was important to the production of neurotransmitters dopamine, norepinephrine, epinephrine, and melanin.  This patient’s grandfather had Parkinson’s Disease which involves low neurotransmitter levels in the Tyrosine – Dopamine Pathway.

Hypothesizing that the boy’s current amino acid levels may not be sufficient for the age dependent physical growth, adrenal stress due to methionine deficiency, and adrenal stress due to the wheat hypersensitivity reaction, this patient was additionally supplemented with 1500mg/day glutamine,  1500mg/day glycine, and 1000 mg/day tyrosine.  After one week of therapy,  the tremor was alleviated and would resume only  under stressful conditions.

After several months, the individual dosages of amino acids were replaced with a 750mg amino acid complex capsule, three times each day. The patient continued to improve.  This complex differed from ingesting protein rich foods in that all 20 amino acids were given concurrently through the complex.  All 20 amino acids must be present concurrently for  protein synthesis to occur.  Supplementation of the 20 amino acid complex relieved the tremor whereas his protein rich diet did not.

The patient returned to school six months post amino acid therapy initiation with improved physical activity levels, reduced anxiety, and alleviation of restless legs.  The daily tremor was absent except under stressful conditions.  His night time activities were kept to a minimum to ensure sufficient rest.

In subsequent years, he remained on 1500 mg/day amino acid complex, 1 gram of DHA+EPA omega-3 fish oil, B complex 100mg/day, vitamin C 1000mg/day, bovine adrenal cortex 340 mg/day, calcium 1000mg/day,  lysine 500mg/day, choline 500mg/day, 5-HTP 100mg/day, probiotic, and minerals.  It appeared that minimal amounts of these supplements are required to maintain good health.

Six years post presentation, this patient continues with occasional stress and fatigue. This is typically visible as facial flushing on the outer periphery of his cheeks.  The tremor has been alleviated under normal and stress conditions.  This patient continues on a WFD and ingests no wheat.  He ingests minimal sugar and deep fried foods, and no caffeine.  Accidental wheat ingestion receives immediate antihistamine and aspirin prophylaxis. The patient is careful to obtain sufficient rest, take supplements, and eat healthy food.  His back continues to be hunched causing him back, neck, and knee pain, but is otherwise most healthy.

 

Copyright © 2013.  All rights reserved.

Photograph: 8 week old dobie pup

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.

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

securedownloadNeurotransmitter 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:

.
Coplan JD, Hodulik S, Mathew SJ, Mao X, Hof PR, Gorman JM, Shungu DC. The Relationship between Intelligence and Anxiety: An Association with Subcortical White Matter Metabolism. Front Evol Neurosci. 2011;3:8. Epub 2012 Feb 1

De Simone R, Aloe L.  Influence of ethanol consumption on brain nerve growth factor and its target cells in developing and adult rodents. Source Istituto di Neurobiologia, Consiglio Nazionale delle Ricerche, Rome, Italy.  Ann Ist Super Sanita. 1993;29(1):179-83.

Glenn MJ, Adams RS, McClurg L. Source Department of Psychology, Colby College, 5550 Mayflower Hill Dr., Waterville, ME 04901, USA. Supplemental dietary choline during development exerts antidepressant-like effects in adult female rats. Brain Res. 2012 Mar 14;1443:52-63. Epub 2012 Jan 17.

Growdon JH, Gelenberg AJ, Doller J, Hirsch MJ, Wurtman RJ. Lecithin can suppress tardive dyskinesia. PMID: 642995 [PubMed – indexed for MEDLINE]. N Engl J Med. 1978 May 4;298(18):1029-30.

Guttierez-Fernández M, Rodríguez-Frutos B, Fuentes B, Vallejo-Cremades MT, Alvarez-Grech J, Expósito-Alcaide M, Díez-Tejedor E. Source Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neurosciences Area of IdiPAZ, Health Research Institute, Autónoma University of Madrid, Madrid, Spain. CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. Neurochem Int. 2012 Feb;60(3):310-7. Epub 2011 Dec 30.

Hasler CM (October 2000). “The changing face of functional foods”. Journal of the American College of Nutrition 19 (5 Suppl): 499S–506S. PMID 11022999.

Hirsch MJ, Wurtman RJ. Lecithin consumption increases acetylcholine concentrations in rat brain and adrenal gland. Science. 1978 Oct 13;202(4364):223-5.

Institute of Medicine, Food and Nutrition Board. Dietary reference intakes for Thiamine, Riboflavin, Niacin, Bitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National Academies Press;1998

Johnson AR, Lao S, Wang T, Galanko JA, Zeisel SH.  Source Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.  Choline dehydrogenase polymorphism rs12676 is a functional variation and is associated with changes in human sperm cell function.PLoS One. 2012;7(4):e36047. Epub 2012 Apr 27.

Kadaveru K, Protiva P, Greenspan EJ, Kim YI, Rosenberg DW.  Source  Molecular Medicine, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030. Dietary Methyl Donor Depletion Protects Against Intestinal Tumorigenesis in ApcMin/+ Mice.  Cancer Prev Res (Phila). 2012 Jul;5(7):911-20. Epub 2012 Jun 7.

Kushikata T, Fang J, Krueger JM. Platelet activating factor and its metabolite promote sleep in rabbits. Source Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki 036-8506, Japan.  Neurosci Lett. 2006 Feb 20;394(3):233-8. Epub 2005 Nov 2.

Linus Pauling Institute. http://lpi.oregonstate.edu/infocenter/othernuts/choline//

Oshida K, Shimizu T, Takase M, Tamura Y, Shimizu T, Yamashiro Y. Effects of dietary sphingomyelin on central nervous system myelination in developing rats. Peditr Res. 2003; 53:589–593

Pitkin RM. Folate and neural tube defects. Am J Clin Nutr 2007;85(1):285S-288S.  (PubMed)

Sha W, da Costa KA, Fischer LM, Milburn MV, Lawton KA, Berger A, Jia W, Zeisel SH.Source Bioinformatics Research Center, University of North Carolina at Charlotte, USA.Metabolomic profiling can predict which humans will develop liver dysfunction when deprived of dietary choline. FASEB J. 2010 Aug;24(8):2962-75. Epub 2010 Apr 6.

Xu X, Gammon MD, Zeisel SH, Bradshaw PT, Wetmur JG, Teitelbaum SL, Neugut AI, Santella RM, Chen J.  Source  Department of Community and Preventive Medicine, Box 1057, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. High intakes of choline and betaine reduce breast cancer mortality in a population-based study.  FASEB J. 2009 Nov;23(11):4022-8. Epub 2009 Jul 27.

Zeisel SH, da Costa KA. Source  Department of Nutrition at the Nutrition Research Institute, School of Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.  Nutr Rev. Choline: an essential nutrient for public health. 2009 Nov;67(11):615-23.

Zhang W, Bai M, Xi Y, Hao J, Liu L, Mao N, Su C, Miao J, Li Z. Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: involvement of oxidative stress and cholinergic dysfunction. Source Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi’an City, Shaanxi Province 710038, China. Free Radic Biol Med. 2012 Apr 15;52(8):1443-52. Epub 2012 Feb 2.

Zurkovsky L, Bychkov E, Tsakem EL, Siedlecki C, Blakely RD, Gurevich EV. Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity. Dis Model Mech. 2012 Aug 3. [Epub ahead of print]

Serotonin References:
.
Bogen IL, Haug KH, Myhre O, Fonnum F (2003). “Short- and long-term effects of MDMA (“ecstasy”) on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo”. Neurochemistry International 43 (4–5): 393–400. doi:10.1016/S0197-0186(03)00027-5. PMID 12742084.
.
Donnerer J, Lembeck F (2006). The chemical languages of the nervous system: history of scientists and substances. Karger Publishers. pp. 161–. ISBN 978-3-8055-8004-5. Retrieved 23 May 2011
.
.
Fattore L, Piras G, Corda MG, Giorgi O (2009). “The Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration”. Neuropsychopharmacology 34 (5): 1091–101. doi:10.1038/npp.2008.43. PMID 18418365.
.
Fitzgerald JL, Reid JJ (1990). “Effects of methylenedioxymethamphetamine on the release of monoamines from rat brain slices”. European Journal of Pharmacology 191 (2): 217–20. doi:10.1016/0014-2999(90)94150-V. PMID 1982265.
.
Florin SM, Kuczenski R, Segal DS (August 1994). “Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment”. Brain Res. 654 (1): 53–62. doi:10.1016/0006-8993(94)91570-9. PMID 7982098.
.
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.
.
Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D (2001). “Fructose malabsorption is associated with decreased plasma tryptophan”. Scand. J. Gastroenterol. 36 (4): 367–71. doi:10.1080/003655201300051135. PMID 11336160.
.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (1996). “Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region”. Science 274 (5292): 1527–31. Bibcode 1996Sci…274.1527L. doi:10.1126/science.274.5292.1527. PMID 8929413.
.
Murphy SE, Longhitano C, Ayres RE, Cowen PJ, Harmer CJ.  “Tryptophan supplementation induces a positive bias in the processing of emotional material in healthy female volunteers.” Source Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.  Psychopharmacology (Berl). 2006 Jul;187(1):121-30. Epub 2006 May 4.
.
Neurophysiology Website:  http://www.neurophysiology.ws/neuroactivechemicals.htm
.
Schwartz AR, Pizon AF, Brooks DE (September 2008). “Dextromethorphan-induced serotonin syndrome”. Clinical Toxicology (Philadelphia, Pa.) 46 (8): 771–3. PMID 19238739.
.
Titeler M, Lyon RA, Glennon RA (1988). “Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens”. Psychopharmacology (Berl.) 94 (2): 213–6. PMID 3127847.
.
Tryptophan Foods Website:  http://www.healthinformationnews.com/health_by_category/Nutrition/nutrition_pages/Foods_High_Tryptophan.html.
.
Understand and Cure Website:  http://www.understand-andcure-anxietyattacks-panicattacks-depression.com/5-htp.html
.
Young SN (2007). “How to increase serotonin in the human brain without drugs”. Rev. Psychiatr. Neurosci. 32 (6): 394–99. PMC 2077351. PMID 18043762.
.

Dopamine Pathway References:

Barch, DM; Braver, TS; Nystrom, LE; Forman, SD; Noll, DC; Cohen, JD (1997). “Dissociating working memory from task difficulty in human prefrontal cortex”. Neuropsychologia 35 (10): 1373–80. doi:10.1016/S0028-3932(97)00072-9. PMID 9347483.

Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 545–547. ISBN 0-9626523-7-7.

Devauges V, Sara SJ, Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav. Brain Res., 1990 Jun 18;39(1):19–28.

Eisenberger, N. I.; Lieberman, M. D.; Williams, K. D. (2003). “Does rejection hurt? An FMRI study of social exclusion”. Science 302 (5643): 290–2. Bibcode 2003Sci…302..290E. doi:10.1126/science.1089134. PMID 14551436.

Falkenstein M, Hohnsbein J, Hoorman J, Blanke L. (1991). Effects of crossmodal divided attention on late ERP components: II. Error processing in choice reaction tasks. Electroencephalogr. Clin. Neurophysiol. 78:447–55

Furuyashiki T, “Roles of Dopamine and Inflammation-Related Molecules in Behavioral Alterations Caused by Repeated Stress”.  Source Department of Pharmacology, Kyoto University Graduate School of Medicine, Japan.  Pharmacol Sci. 2012 Sep 15. [Epub ahead of print]

Gehring, WJ; Goss, B; Coles, MGH; Meyer, DE; Donchin, E. (1993). “A neural system for error detection and compensation. Psychol”. Sci 4: 385–90.

Grace AA, Bunney BS (1984). “The control of firing pattern in nigral dopamine neurons: single spike firing” (pdf). Journal of Neuroscience 4 (11): 2866–2876. PMID 6150070

Guyton, Arthur; Hall, John (2006). “Chapter 10: Rhythmical Excitation of the Heart”. In Gruliow, Rebecca (Book). Textbook of Medical Physiology (11th ed.). Philadelphia, Pennsylvania: Elsevier Inc.. p. 122. ISBN 0-7216-0240-1.

Hinz M, Stein A, Uncini T. Clinical Research, NeuroResearch Clinics, Inc., Cape Coral, FL, USA; “Amino acid management of Parkinson’s disease: a case study.” Int J Gen Med. 2011 Feb 28;4:165-74.

Lutzenberger, W., Elbert, T., Rockstroth, B. (1987). A brief tutorial on the implications of volume conduction for the interpretation of the EEG. Journal of Psychophysiology, 33. S56

Nelson, L.; Cox, M. (2004). Lehninger Principles of Biochemstry (4th ed.). New York: Freeman. p. 908. ISBN 0-7167-4339-6

Nieuwenhuis, S.; Aston-Jones, G.; Cohen, J. D. (2005). “Decision making, the P3, and the locus coeruleus-norepinephrine system”. Psychological Bulletin 131 (4): 510–32. doi:10.1037/0033-2909.131.4.510. PMID 16060800.

Patrick RL, Kirshner N (1970). “Acetylcholine-Induced Stimulation of Catecholamine Recovery in Denervated Rat Adrenals after Reserpine-Induced Depletion.”  Department of biochemistry, Duke University Medical Center, Durham, North Carolina.  Molecular Pharmacology, 7, 389-396.

Raymondos, K.; Panning, B.; Leuwer, M.; Brechelt, G.; Korte, T.; Niehaus, M.; Tebbenjohanns, J.; Piepenbrock, S. (2000). “Absorption and hemodynamic effects of airway administration of adrenaline in patients with severe cardiac disease”. Ann. Intern. Med. 132 (10): 800–803. PMID 10819703.

Sabyasachi Sircar (2007). Medical Physiology. Thieme Publishing Group. pp. 536. ISBN 3-13-144061-9.

Szot P, “Common factors among Alzheimer’s disease, Parkinson’s disease, and epilepsy: possible role of the noradrenergic nervous system.”  Northwest Network for Mental Illness Research, Education, and Clinical Center, Veterans Administration Puget Sound Health Care System, 1660 S Columbian Way,Seattle, WA 98108, U.S.A Epilepsia. 2012 Jun;53 Suppl 1:61-6. doi: 10.1111/j.1528-1167.2012.03476.x.

Tanaka M, et al. (2000). Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. doi:10.1016/S0014-2999(00)00569-0

Usher, M.; Cohen, J. D.; Servan-Schreiber, D.; Rajkowski, J.; Aston-Jones, G. (1999). “The role of locus coeruleus in the regulation of cognitive performance”. Science 283 (5401): 549–54. Bibcode 1999Sci…283..549U. doi:10.1126/science.283.5401.549. PMID 9915705.

Viisanen H, Ansah OB, Pertovaara A. “The role of the dopamine D2 receptor in descending control of pain induced by motor cortex stimulation in the neuropathic rat”. Source Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, FIN-00014 Helsinki, Finland.  Brain Res Bull. 2012 Nov 1;89(3-4):133-43. doi: 10.1016/j.brainresbull.2012.08.002. Epub 2012 Aug 9.

.

Street Drugs, Nicotine, Caffeine, Alcohol and Neurotransmitters:

Bogen IL, Haug KH, Myhre O, Fonnum F (2003). “Short- and long-term effects of MDMA (“ecstasy”) on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo”. Neurochemistry International 43 (4–5): 393–400. doi:10.1016/S0197-0186(03)00027-5. PMID 12742084.

Fattore L, Piras G, Corda MG, Giorgi O (2009). “The Roman high- and low-avoidance rat lines differ in the acquisition, maintenance, extinction, and reinstatement of intravenous cocaine self-administration”. Neuropsychopharmacology 34 (5): 1091–101. doi:10.1038/npp.2008.43. PMID 18418365.

Fitzgerald JL, Reid JJ (1990). “Effects of methylenedioxymethamphetamine on the release of monoamines from rat brain slices”. European Journal of Pharmacology 191 (2): 217–20. doi:10.1016/0014-2999(90)94150-V. PMID 1982265.

Florin SM, Kuczenski R, Segal DS (August 1994). “Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment”. Brain Res. 654 (1): 53–62. doi:10.1016/0006-8993(94)91570-9. PMID 7982098.

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.

Schwartz AR, Pizon AF, Brooks DE (September 2008). “Dextromethorphan-induced serotonin syndrome”. Clinical Toxicology (Philadelphia, Pa.) 46 (8): 771–3. PMID 19238739.

Titeler M, Lyon RA, Glennon RA (1988). “Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens”. Psychopharmacology (Berl.) 94 (2): 213–6. PMID 3127847.

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

Copyright © 2012.  All rights reserved.

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.

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.