BACKGROUND

The most powerful agents in human physiology are a group of short-lived hormones called eicosanoids. Eicosanoids are derived from 20-carbon long fatty acids. The two main 20-carbon long fatty acids for eicosanoid production are arachidonic acid (AA) and eicosapentaenoic acid (EPA).

Fatty acids are a group of connected carbons with a carboxyl group at one end (-COOH). Fatty acids are either saturated or unsaturated. Saturated fatty acids are saturated with hydrogen atoms (-H).

Unsaturated fatty acids have one or more double bonds (C=C). To make a carbon-to-carbon double bond, two hydrogen atoms have to be eliminated, and therefore the fatty acid molecule is no longer saturated with hydrogen atoms. When the fatty acid molecule has more than one carbon-to-carbon double bond, it is referred to as a polyunsaturated fatty acid.

A representative saturated fatty acid, stearic acid, is represented as follows:

Its chemical formula is: 18:0

The 18 means it is 18 carbons long.

The :0 means that there are no carbon-to-carbon double bonds. This means it is a saturated fatty acid.

The 20-carbon long fatty acid arachidonic acid is represented as follows:

Its chemical formula is: 20:4n-6

The 20 means it is 20 carbons long.

The :4 means it has four carbon-to-carbon double bonds. This means it is a polyunsaturated fatty acid.

The n-6 means the first of the four double bonds is located at the sixth carbon from the end methyl carbon (the carbon on the far left, which would be attached to three hydrogen atoms).

The n-6 is pronounced omega-6. Using the Greek alphabet where omega means “the end,” n-6 means the first of the four double bonds is located at the sixth carbon from the end methyl group.

The eicosanoid hormones that are derived from the omega-6 fatty acid arachidonic acid are inflammatory.

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Omega-3 fatty acids come in three lengths:

• Alpha-linolenic acid (ALA): 18:3n-3
  Its primary source is flax seed oil.

• Eicosapentaenoic acid (EPA): 20:5n-3
  Its primary source is cold-water fatty fish and cold-water fatty fish oil supplements.

• Docosahexaenoic acid (DHA): 22:6n-3
  Its primary source is also cold-water fatty fish and cold-water fatty fish oil supplements.

The eicosanoid hormones that are derived from the omega-3 fatty acid eicosapentaenoic acid are anti-inflammatory.

Docosahexaenoic acid is the most abundant and most important fatty acid in the brain.

••••

On January 2, 2006, in Upshur County, West Virginia, USA, there was an explosion in the Sago Coal Mine. The blast trapped 13 miners for nearly two days; only one miner survived. The lone survivor was Randal L. McCloy, Jr., age 26. He was found practically dead, unconscious and suffering from carbon monoxide poisoning, a collapsed lung, brain hemorrhaging, edema, muscle injury, faulty liver and heart function, and almost no brain electrical activity. His initial prognosis for survival and recovery was grim, expecting permanent damage to his brain if he did survive. However, McCloy recovered almost fully.

McCloy is the person with the longest exposure to carbon monoxide poisoning to have survived. His doctors predicted that if he did survive, he would be severely brain damaged since the carbon monoxide had stripped the protective myelin sheath from most of his brain’s neurons.

McCloy’s neurosurgeon started to enternally feed him a daily dose of 15,000 milligrams (mg) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) fish oil (omega-3 fatty acids). Soon, his brain electrical activity returned and he emerged from his coma, gradually regaining his ability to walk, talk, and see. Apparently the omega-3s helped rebuild the damaged gray and white matter of his brain. McCloy is now married, has children, and is largely functioning normally.

••••

The incidence of all-cause traumatic brain injuries in the United States is 1.6 to 3.8 million annually, with the reported number of sport- or recreation-related concussions increasing dramatically, especially in youth sports (3).

Traumatic brain injury (TBI) is one of the most common causes of death and disability in United States. It is responsible for 220,000 hospitalizations, 52,000 deaths, and 80,000-90,000 patients suffering from permanent disability each year (1).

The use of roadside bombs in Iraq and Afghanistan has propelled the incidence of concussion and other traumatic brain injuries to the highest levels ever encountered by the US military. The wars in Iraq and Afghanistan cause about 300 concussions per month (4).

••••

In October 2011, Aiquo Wu and colleagues from the Department of Integrative Biology and Physiology, University of California at Los Angeles, published an article in the Journal of Neurotrauma titled (1):

The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma

These authors note that TBI results in long lasting consequences on the cognitive ability of patients. Even though over 30 major clinical trials have been performed, no efficient treatment for TBI has been found to date.

The pathology of traumatic brain injury is characterized by neuronal membrane damage, oxidative stress, failure in the capacity of neurons to metabolize energy and sustain synaptic function, and likely resulting in cognitive and emotional disorders.

These authors assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of traumatic brain injury on important aspects of neuronal function and cognition. Specifically, they investigated the healing capacity of DHA dietary supplementation when provided immediately after a traumatic brain injury in rats.

DHA is a crucial omega-3 fatty acid abundant in the brain, is important for brain development and plasticity, and has been shown to support learning and memory and neurodegerative disorders such as Alzheimer’s disease. It is known that TBI causes degradation of membrane phospholipids. Synaptic membrane phospholipids are preferentially enriched in omega-3 fatty acid DHA. Increased dietary DHA content helps prevent the loss of DHA from membrane lipids.

The overall results of this study emphasize the potential of dietary DHA to counteract broad and fundamental aspects of the TBI pathology that can preserve cognitive capacity. Not only was there a homeostatic effect of DHA dietary supplementation when provided immediately after TBI, but also suspicion that dietary supplementation of fish oil before brain injury can protect the brain from the deleterious effects of TBI on cognition and plasticity. These authors state:

A short period of DHA supplementation “significantly counteracted the negative effects of the injury on cognitive function, neuronal signaling, and membrane homeostasis.”

“These results indicate that DHA supplementation can provide the type of broad protection important for counteracting the effects of TBI.”

“Given the role of DHA in membrane homeostasis and neuronal signaling,

these findings implicate dietary DHA as a potential candidate for counteracting the adverse effects of TBI on synaptic plasticity and cognition.”

“The increase in DHA content may help maintain membrane fluidity, thereby preserving cognitive function in TBI animals.”

“Our findings suggest that supplementation of DHA may help the TBI brain preserve synaptic membrane integrity and fluidity, thereby enhancing membrane related cellular function and subsequent cognitive improvement.”

“Our results demonstrate that DHA dietary supplementation applied immediately after TBI counteracts the related cognitive decay.”

Traumatic brain injury often leaves the patient with serious long-tern cognitive and functional consequences. This article suggests that an important therapeutic intervention to markedly improve the clinical outcome is to immediately supplement the patient with fish oil (as it is high is DHA).

••••

In August 2012, physician Michael Lewis, MD, and colleagues published an article in The American Journal of Emergency Medicine titled (2):

Therapeutic use of omega-3 fatty acids in severe head trauma

The authors of this study state:

“We are aware of only one report where n-3FA were used, that being the survivor of the Sago Mine accident in January 2006 suffering from hypoxia and exposure to toxic gases, dehydration, and rhabdomyolysis.” (3)

Recall, in the Sago Mine accident, the patient, Randall McCloy, was enternally give 15 grams of EPA + DHA fish oil per day.

These authors present a case study stating:

“To our knowledge, this is the first report of specific use of substantial amounts of omega-3 fatty acids following severe TBI.”

A teenager sustained a severe TBI in a motor vehicle accident. His extrication was prolonged, he was in a coma, and he sustained a subdural hematoma that was surgically decompressed. The attending neurosurgeons believed the injuries were likely fatal. On day 10, (still in a coma), MRI showed significant subdural hemorrhage and diffuse axonal injury. His doctors believed him to be in a permanent vegetative state. A tracheotomy and percutaneous endoscopic gastrostomy tube were placed for custodial care and enteral feedings were started.

On Day 11, 9,756 mg eicosapentaenoic acid (EPA) and 6,756 mg docosahexaenoic acid (DHA) per day were added to enteral feedings.

On day 21, he was weaned off the ventilator and transported to a specialized rehabilitation institute 3 days later.

Three months after the injury the patient attended his high school graduation to receive his diploma. Four months after the injury the patient was discharged to home.

For the following year, the patient continued to take 16,500 mg of EPA + DHA fish oil supplements per day along with 6000 IU of vitamin D3; his improvement continued and he experienced no adverse effects.

The primary management of severe traumatic brain injury (TBI) is often surgical or intensive care unit, with the goals of maintaining adequate oxygenation, controlling intracranial pressure, and ensuring proper cerebral perfusion pressure. “The secondary injury phase of TBI is a prolonged pathogenic process characterized by neuroinflammation, excitatory amino acids, free radicals, and ion imbalance. There are no approved therapies to directly address these underlying processes.”

These authors present a case that was intentionally treated with substantial amounts of omega-3 fatty acids to provide the nutritional foundation for the brain to begin the healing process following severe TBI. They note that Omega-3 fatty acids “must be in place if the brain is to be given the opportunity to repair itself to the best possible extent.”

The authors note that omega-3 fatty acids attenuate the deleterious inflammatory cascade that occurs following traumatic brain injury. They advocate that omega-3 administration is best if given early in the course of treatment, in the emergency department or sooner. Also, omega-3s may help improve clinical outcomes when administered before or following TBI, spinal cord injury, and brain ischemia.

These authors state:

“It is well recognized that omega-3 fatty acids are important for proper neurodevelopment and function.”

“Average Western dietary intakes result in a deficiency of omega-3 fatty acids and an over-dominant intake of pro- inflammatory omega-6s.”

“The ratio of omega-3:omega-6 fatty acids in the Western diet can be as low as 1:50. Such imbalance is reflected directly in the composition of neuron membrane phospholipids favoring inflammatory processes.”

“Docosahexaenoic acid, in particular, promotes neuronal survival, neurogenesis, neurite development, neuronal cell migration, synaptogenesis, and modulation of inflammatory cascade.”

Omega-3 fatty acids “significantly reduce the number of injured axons.”

“When DHA was given within an hour of spinal cord injury, neuromotor function was maintained; but the effect was lost when treatment was delayed for 4 hours.”

“Early nutritional intervention in TBI is underappreciated. Patients not fed within 5 and 7 days after TBI have a 2- and 4-fold increased likelihood of death, respectively.”

Our experience suggests that aggressively adding substantial amounts of omega-3 fatty acids to optimize the nutritional foundation of severe TBI patients will significantly improve clinical outcomes. “An optimal nutritional foundation must be in place if the brain is to be given the best opportunity to repair itself.”

••••

In November 2012, physician Joseph Maroon, MD, and colleagues published an article in the journal The Physician and Sportsmedicine titled (4):

Postconcussion Syndrome:

A Review of Pathophysiology and Potential Nonpharmacological Approaches to Treatment

Dr. Maroon, from the University of Pittsburgh, is the neurosurgeon for the Pittsburgh Steelers football team.

These authors note that as a consequence of the incidence of traumatic brain injury, there is a marked increase in post-concussion syndrome (PCS) and the associated cognitive, emotional, and memory disabilities associated with the condition. They also note that there have been no significant advancements in the understanding or treatment of PCS for decades. The current management of PCS mainly consists of rest, reduction of sensory inputs, and treating symptoms as needed.

Most traumatic brain injuries (TBIs) are mild traumatic brain injuries (mTBIs) and are often referred to as concussions. These concussions can cause long-term disability.

The short-term symptoms of concussion, such as immediate confusion and disorientation, usually resolve within minutes to several hours and are probably due to electrochemical changes.

Other signs and symptoms of a cerebral concussion will spontaneously resolve within 2 to 7 days, including:

• Head­ache
• Nausea
• Visual disturbance
• Balance abnormalities
• Fogginess
• Poor concentration

Up to 15% of concussion individuals “may experience prolonged and intractable physical, cognitive, emotional, and/or sleep disturbances that result in severe debilitation—the so-called post-concussion syndrome (PCS). These symptoms often result in significant disruption and even withdrawal from school, job, or military activity.”

Post-concussion syndrome requires at least 3 symp­toms for a minimum of 4 weeks following a head injury, including:

• Headache
• Dizziness
• Sleep problems
• Psychological disturbances
• Cognitive disturbances

Management of PCS includes rest and reduction of sensory input from schoolwork, computers, and any processing of new information.

These authors present evidence that indicates that traumatic brain injury pathology and the signs/symptoms associated with the PCS are linked to a chronic inflammatory cascade that involves omega-6 derived inflammatory eicosanoids, excitotoxins, and activation of the brain immune cells (microglia). Consequently, they advocate an anti-inflammatory approach be included in the management of both traumatic brain injury and post-concussive syndrome, noting:

“Omega-3 essential fatty acids (EFAs), vitamin D3, curcumin, resveratrol and other poly­phenols, and magnesium have all been shown to clinically reduce inflammation, reduce microglial activation, affect excitotoxic cell signaling processes, and are used worldwide to treat inflammatory-related conditions.”

The major components of omega-3 EFAs, eicosapentaenoic acid (EPA) and doco­sahexaenoic acid (DHA), can inhibit production of proin­flammatory eicosanoids.

Docosahexaenoic acid (DHA) constitutes > 25% of brain phospholipids, “maintaining membrane integrity, fluidity, excitability, and function.”

Oral supplementation of DHA for 30 days following TBI significantly decreases the number of swollen, disconnected, and injured axons, attenuates glutamate-induced neuronal injury and death.

Omega-3 EFAs increase neuronal survival following brain injury by reduc­ing excitoxicity through inhibition of glutamate-induced neuronal toxicity.

Therapeutic EPA+DHA dosing for TBI is a total of 1.5 to 5.0 g per day.

These nutritional approaches for TBI and PCS attack the pathophysiology of the disorder, shortening its duration, not just ameliorating the symptoms.

••••

In January 2013, physician John Wang, MD, and colleagues from the Department of Neurosurgery, University of Illinois College of Medicine, published an article in the Journal of Neurotrauma titled (5):

Omega-3 Fatty Acids as a Putative Treatment for Traumatic Brain Injury

These authors note that traumatic brain injury (TBI) is a global public health epidemic that may “cause motor and sensory deficits and lead to severe cognitive, emotional, and psychosocial impairment, crippling vital areas of higher functioning.”

TBI is the “signature injury” in wounded soldiers in Iraq and Afghanistan. TBI may have devastating impact on athletes playing contact sports. Long-term health disorders associated with TBI include:

1. Post-traumatic stress disorder (PTSD)
2. Neurodegenerative diseases (Alzheimer’s disease or Parkinsonism)
3. Neurocognitive deficits
4. Psychosocial health problems (e.g., binge drinking, major depression, impairment of social functioning and ability to work, suicide)
5. Epilepsy
6. Pain
7. Other alterations in personality or behavior

There has been little progress in developing effective TBI interventions. Nutritional intervention may provide a unique opportunity to enhance the neuronal repair process after TBI. The two omega-3 fatty acids that are most promising for their neuro-restorative capacities in TBI are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA comprises more than 50% of brain neuronal membrane phospholipids.

In the brain, omega-3s, especially DHA are known to do the following:

1. Increase the size of neurons
2. Increase the complexity of dendritic arboritizations
3. Increase the number of neurons
4. Increase serotonin and acetylcholine receptors
5. Improve attention, task performance, learning, exploratory, and memory
6. Improved dopamine neurotransmission, increases dopamine receptors, which improves motivational behavior and emotional functions

Case studies show great benefit on the use of omega-3s in the acute phase of severe head injury. These authors note:

“Omega-3 fatty acids have long been known to play a restorative role in several pathways implicated in traumatic insult to the brain.”

Omega-3 fatty acids are uniquely protective against degeneration induced by TBI, and they improve behavioral and cognitive outcomes in patients with TBI.

DHA is neuroprotective, and supplementation significantly ameliorates secondary mechanisms of injury and reduces the number of damaged axons.

“Omega-3 fatty acids mitigate the consequences of several key pathological pathways in TBI, such as mitochondrial malfunction, apoptotic cell death, glutamate-triggered excitotoxicity, and injury-induced oxidative stress and inflammation.”

“Omega-3 fatty acids may play a critical role in the restoration of cellular energetics and repair of neuronal damage after TBI.”

Omega-3 fatty acids in the brain appear be neuroprotective in TBI because they protect against inflammation, apoptosis, and oxidative stress mechanisms.

••••

In March 2013, Ethika Tyagi and colleagues from the University of California, Los Angeles (UCLA) published an article in the journal Public Library of Science ONE titled (6):

Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype:
Implications for Post-Traumatic Stress Disorders

These authors note that post-traumatic stress disorder (PTSD) is a condition in which “individuals exposed to trauma develop high levels of anxiety and inability to cope with routine living conditions.” Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD).

These authors are critical of the typical Western diet primarily because it is loaded with excessive inflammatory omega-6 fatty acids and with excess sugars (refined carbohydrates). They note that this diet enhances the deleterious cascade of traumatic brain injury which would increase the probability, severity, and duration of PTSD in brain injured patients. They indicate that the Western diet is a typically maladaptive dietary habit, which lowers the threshold for neurological disorders in response to challenges, including mTBI. Adoption of unhealthy dietary habits is increasingly common in the modern society, and this may act as a vulnerability factor for neurological disorders.

Using experiments on rats that included early life supplementation with omega-3 fatty acids, adult life brain trauma, the inflammatory Western diet and measuring markers of PTSD, these authors concluded that dietary DHA is protective and improves cognitive impairment following TBI. Specifically, they state:

The balance between brain health and disease is likely dependent on “factors acquired particularly during early life.”

“Dietary factors are surfacing as strong modulators of brain plasticity with the capacity to alter the course of brain disorders.”

“Dietary DHA has been shown to protect against cognitive impairment following brain trauma.”

“Consumption of DHA is below recommended levels while the consumption of high fat and high sugar is on the rise in the western society, and this hardship has been attributed to increased incidence of psychiatric disorders.”

“We found that exposure to an n-3 diet during gestation and throughout maturation of the brain is crucial for building neural resilience during adulthood. The lack of dietary n-3s during brain maturation worsened the effects of transition to a Western diet and subsequent TBI on anxiety-like behavior and its molecular counterpart.” In TBI, the Western diet enhances inflammation in animals deprived of n-3s during development.

“Our results showed that the effects of mTBI were more pronounced in the n-3 deficient animals switched to a Western diet, arguing about the critical role of dietary n-3s to protect against the development of anxiety like disorders after TBI.”

“Our results emphasize the powerful action of diet during early life for determining later susceptibility to brain insults, involving elements associated with plasma membrane signaling, synaptic plasticity, and immune system.”

“Given the increasing consumption of unhealthy diets in environments with high prevalence of brain trauma, diet may be a factor for predisposing towards the development of disorders like PTSD.”

“The amount of n-3s during gestation and early life influences the vulnerability of the brain to future challenges (changes to Western diet or TBI) during adult life.”

Key messages for this study include:

• Omega-3 fatty acids, especially EPA and DHA, are critical for optimum brain function.
• In utero and infant dietary omega-3s greatly influence adult brain physiology, including response to traumatic brain injury and PTSD.
• Supplemental omega-3s are both preventative and therapeutic for TBI and PTSD.

••••

The articles reviewed in this presentation are all recent, the oldest being 2011 and the most recent from last month (March 2013). In total they indicate:

• Omega-3 fatty acids, especially EPA and DHA are crucially important for optimum brain function.
• Early life and pre-injury omega-3 states influences the severity, duration, and recovery from traumatic brain injury, post-concussive symptoms, PTSD, and future neurodegenerative diseases.
• Supplementation with omega-3 fatty acids is both safe and effective for patients who have suffered from traumatic brain injury and post-concussive symptoms and/or PTSD.
• Individuals with severe traumatic brain injury, including traumatic coma, may benefit greatly from enternally given, high doses (15,000 – 16,500 gm/day) of EPA+DHA fish oil.

REFERENCES

1. Wu A, Ying Z, Gomez-Pinilla F;The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma; Journal of Neurotrauma; October 2011; Vol. 28; No. 10; pp. 2112-2122.
2. Lewis M, Ghassemi P, Hibbeln J; Therapeutic use of omega-3 fatty acids in severe head trauma; The American Journal of Emergency Medicine August 3, 2012 [epub].
3. Roberts L, Bailes J, Dedhia H, et al.; Surviving a mine explosion; J Am Coll Surg, 207 (2) (2008), pp. 276–283.
4. Joseph C. Maroon, MD; Darren B. LePere, BS; Russell L. Blaylock, MD; Jeffrey W. Bost; Postconcussion Syndrome: A Review of Pathophysiology and Potential Nonpharmacological Approaches to Treatment; The Physician and Sportsmedicine; November 2012, Volume 40, Issue 4, pp. 73-87.
5. Huan (John) Wang, MD; Hasadsri L MD, PhD; Wang BH MD; Lee JV PhD; Erdman JW PhD; Llano DA MD, PhD; Wszalek T PhD; Sharrock MF; Omega-3 Fatty Acids as a Putative Treatment for Traumatic Brain Injury; Journal of Neurotrauma; January 30, 2013 [epub].
6. Ethika Tyagi, Rahul Agrawal, Yumei Zhuang, Catalina Abad, James A. Waschek, Fernando Gomez-Pinilla F; Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype: Implications for Post-Traumatic Stress Disorders; Public Library of Science ONE; March 12, 2013; Volume 8; Issue 3; e57945.