- Contusion – a bruise to the brain itself. A contusion causes bleeding and swelling inside of the brain around the area where the head was struck.
- Concussion– A concussion is an injury to the head area that may cause instant loss of awareness or alertness for a few minutes up to a few hours after the traumatic event.
- Hematoma – blood clots, in or around the brain. The different types are classified by their location in the brain.
- Chronic Traumatic Encephalopathy (CTE) – a progressive brain condition that’s thought to be caused by repeated blows to the head and repeated episodes of concussion
- What is a Traumatic Brain Injury?
- Important physiological responses to a TBI
- Nutrition Interventions
What is a Traumatic Brain Injury?
A traumatic brain injury (TBI) occurs when a sudden, external, physical incident causes the brain to move rapidly inside the skull, leading to harm1. It is a broad term that covers a variety of brain injuries; the most frequent symptoms include concussions, contusions, or both. The injury might affect multiple brain regions (diffuse) or just one (focal). A brain injury’s severity can range from a moderate concussion; a mild traumatic brain injury (mTBI), to a severe injury that leaves the victim in a coma or even causing death.
The definition is sometimes adjusted based on the context and risk exposure environment. For instance, the US Department of Defence expands the definition to include TBIs acquired as a result of injuries sustained during conflict as a result of blast injuries2. According to the NIH, road traffic accidents and falls are the leading causes, whilst sports-related injuries and other vocations with a high risk of assault also contribute significantly3. Each year, an estimated 69 million (95% CI 64-74 million) people are believed to suffer a TBI4. Nutritional therapies are among the interventions that are actively being investigated with the goal of enhancing and improving the speed and extent of recovery after brain injury and also the resilience of brain injury in those at greater risk.
Here we will discuss some of the common underlying neurochemical and metabolic responses to TBI, even though each instance of TBI is unique and affected people exhibit varied degrees of impairment, distinct areas of damage, and different recovery profiles. It may be possible to identify supporting nutritional therapeutic options for early intervention by recognising these recurring features.
Currently, the severity is categorised based on the Glasgow Coma Scale (GCS), from mild to severe, depending on clinical symptoms. Mild cases may result in a brief change in mental state or consciousness, while severe cases may result in cranial fractures, extended periods of unconsciousness, coma or even death. Individuals with TBI may experience pain in the form of headaches, motor dysfunction; whereby they have an inability to coordinate motor functions or struggle to balance; or their sensory abilities will suffer, such as inability to hear, dizziness or hypersensitivity to sound5. This is largely dependent on the area of the brain that has received the impact. In addition, cognitive abilities may be altered, causing changes in mood such as agitation; confusion or a shortened attention span. Finally, speech may be impacted, making it difficult to find the appropriate words or articulate ideas.
Mild to moderate TBI symptoms often go away in a few days or weeks. However, these injuries can occasionally cause long-term cognitive and behavioural problems. Additionally, there is evidence to show that moderate to severe TBI, as well as repeated mild TBI, may be linked to an increased risk of neurodegenerative illnesses like Alzheimer’s disease, Parkinson’s disease, and chronic traumatic encephalopathy (CTE).
The initial collision that causes the brain to move inside the skull is referred to as the primary injury. Secondary injuries progressively develop as a result of continuous biological processes that result in more harm. They are characterized by interrelated cascades of molecular, cellular, and biochemical events that increase harm but may be mitigated and reversible6. The overproduction of excitatory neurotransmitters, calcium overload, glucose dysmetabolism, free radical overproduction, mitochondrial dysfunction, and neuroinflammation are examples of secondary injuries6. These secondary injuries can result in neuropathologies, such as neurodegeneration and cognitive dysfunction.
Important physiological responses to a TBI
Altered Cerebral Glucose Metabolism in TBI
A distinctive response to TBI is known to include changes in cerebral glucose metabolism7. The adult brain’s main energy source is glucose, which is converted into carbons for the tricarboxylic acid (TCA) cycle, which produces energy in the form of ATP. A sudden rise in glucose uptake followed by a prolonged period of decline in glucose metabolism, has been observed in both experimental and clinical head injuries8. The hypothesis being, that these early increases are caused by an increased need for cellular energy to restore the ionic equilibrium and neuronal membrane potential9,10. After a serious brain injury, this acute period of hyperglycolysis, occurs due to the increased demand for ATP11.
Following the brief time of elevated glucose, there comes a sustained phase of reduced glucose, which begins approximately 6-hours post-injury, with the duration dependent on the injury severity6. Mitochondrial dysfunction and glucose dysmetabolism characterize this phase. The resulting reduced cerebral blood flow limits glucose metabolism by reducing the amount of oxygen and glucose delivered to the brain6. Excessive intracellular calcium build-up causes mitochondrial malfunction. The accumulation of too much intracellular calcium in the mitochondria, results in a loss of functioning, causing a cerebral energy crisis and starts necrotic and apoptotic cell death12.
Increased Energy Requirements
When cerebral blood fluid falls short of the metabolic requirements of the brain during the acute period, this imbalance, can trigger a series of secondary damaging events and a resulting energy crisis. It is not clear if changes in cerebral blood fluid limits glucose availability as plasma glucose levels in head injury patients are carefully controlled within certain thresholds13,14.
Impairment in glucose transport through blood arteries and into brain cells may also contribute to decreased glucose uptake after TBI. However, the expression of this neuronal glucose transporter (GLUT1) is inconsistent in clinical cases of TBI15. Adult rat studies have demonstrated decreased GLUT1, 2-4 hours after FP injury. According to Hattori et al., 2003, glucose transport deficiencies occur specifically at the sites of contusion16. Collectively, the results indicate that TBI significantly affects glucose transport across the blood-brain barrier (BBB) in both preclinical and clinical studies.
There is growing evidence that trauma affects how glucose is processed during the glycolytic process. The amount of glucose that is diverted toward the synthesis of the monosaccharide pentoses increased by 9–12%, according to proton nuclear magnetic resonance (NMR) spectroscopy (used in the synthesis of nucleic acids)17. Additionally, it has been demonstrated that nicotinamide dinucleotide (NAD+) concentrations drop following injury. The glycolytic enzyme GAPDH (glyceraldehyde 3-phosphate dehydrogenase) requires NAD+ as a cofactor, so decreases in NAD+ levels might result in glycolytic inhibition. The inability of glucose to be processed effectively for oxidative metabolism is ultimately decreased by these TBI-induced changes, which contributes to the post-TBI energy crisis as seen by decreases in ATP production.
The pathophysiology and energy crisis connected to brain damage heavily depend on mitochondria. According to one theory, excessive glutamate stimulation activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which causes oxidative stress19. Oxidative stress then activates Poly [ADP-ribose] polymerase (PARP1), which depletes NAD+ reserves and finally causes cell death by inactivating metabolism20. A different mechanism has been proposed, in which mitochondrial Ca2+ accumulation compromises membrane potential, producing too many free radicals that activate PARP1 and decrease NAD+ levels, which ultimately results in cell death21.
Increased Circulation of Free Radicals
Molecules with unpaired electrons are known as free radicals. These molecules try to absorb electrons from their surroundings, which makes them highly reactive and can harm DNA, proteins, and cell membranes22. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the two main groups of free radicals. ROS production levels from routine metabolic processes are effectively controlled by cellular antioxidant defence mechanisms. Only with cerebral injury do levels of ROS generation exceed scavenging systems and cause oxidative damage23.
Role of Feeding
In order to preserve the skeletal muscle mass, essential organ function, and cerebral metabolic homeostasis as much as possible after a severe brain injury, it is essential to start nutrition therapy as soon as possible. According to the IOM, nutrition therapy should be started ideally within the first 24 hours after injury, and should supply 50% more than the resting energy expenditure (REE) with 1.0 to 1.5 g protein/kg for two weeks following the injury73, 74.
Researchers have demonstrated that patients who are not fed within 5 to 7 days following a TBI had a 2- to 4-fold higher chance of death75. As a result, they suggest that nutrition is a significant predictor of death after TBI and is one of the few therapeutic interventions that can directly influence TBI outcome, along with the avoidance of arterial hypotension, hypoxia, and intracranial hypertension24.
A phase of neuroinflammation, free radical production, excitatory toxicity, and oxidative stress follows the initial trauma. Early administration of enteral feeding to TBI patients is well-established, a detailed overview of clinical nutrition support and routes of administration can be found here. Wang and colleagues showed the advantages of early feeding on lowering mortality, enhancing functional results, and avoiding infectious complications in a systematic evaluation of randomized controlled trials and non-randomized prospective studies on nutritional support for TBI patients. Their findings also supported the use of immune-boosting formulas and small intestinal feeding to lessen infectious problems in this clinical scenario.
Combining immune-modulating nutrient supplementation with other well-known adjuvants that support and preserve the gastrointestinal mucosa’s structural integrity and immunological function may help TBI patients regain almost normal cerebral balance25. The main objectives of immune-enhancing techniques are to facilitate the repair of brain tissue and reduce neuronal death in the vulnerable but still functional regions close to the initial brain damage. These nutrients that may affect the immune system include branched chain amino acids, nucleotides, creatine, arginine, omega-3 fatty acids, glutamine, as described below. The macronutrient profile might also be crucial for the best recovery before single or combined micronutrients are taken into account.
Ketones may lessen inflammation through the mechanistic target of rapamycin (mTOR) signaling pathway and NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3)27. They have also been shown to reduce oxidative stress, and neurodegeneration while assisting in the fight against post-traumatic brain energy deficiencies28. Experimental TBI models indicate that giving ketones to TBI patients may have a major positive impact on their ability to recover, however the evidence in humans is still rather limited.
The body produces endogenous ketone bodies via lipolyzing free fatty acids in hepatic mitochondria and locally in astrocytes29,30. Acetoacetate, β- hydroxybutyrate, and acetone are the three types of ketone bodies. The main ketone body produced while the body is in the metabolic state of ketosis is β- hydroxybutyrate, which also serves as a reliable indication of ketosis. Ketone body synthesis is minimal under typical dietary circumstances with accessible carbohydrate storage. However, the body enters a state of ketosis, when the generation of ketone bodies is increased, if the body has limited carbohydrate reserves31. Because TBIs impair carbohydrate metabolism, ketone bodies can serve as an alternative energy source to glucose if the body can enter ketosis.
However, it takes 3-5 days for endogenous ketone body generation induced by a ketogenic diet and/or fasting to achieve therapeutic blood ketone body levels32, missing the window of opportunity to exert neuroprotective effects. However, within 30 minutes of dosing, exogenous ketone supplementation can raise blood ketone levels to therapeutic levels33. Exogenous ketones are substances that come in the form of liquids or powders and contain ketone bodies or precursors, such as medium-chain triglycerides (MCTs), ketone salts, and β- hydroxybutyrate esterified to precursor molecules. These substances are beneficial for treating patients because they raise circulating levels of β- hydroxybutyrate without dramatically reducing insulin or glucose levels.
- Medium chain triglycerides (MCTs) – are saturated fatty acids that are quickly absorbed and converted into ketone bodies in the liver. However, the administration dose is limited due to poor gastrointestinal tolerability34.
- Ketone salts – can be given intravenously or orally and typically consist of β- hydroxybutyrate attached to a salt like sodium, potassium, or calcium. The circulation levels of β- hydroxybutyrate can be increased by oral administration of ketone salts, but similar to MCTs, there are restrictions on gastrointestinal tolerability.
- Ketone esters – are composed of β- hydroxybutyrate esterified to precursor molecules. They are well tolerated and regarded by the FDA as a food additive that is generally recognized as safe (GRAS)35. Within 30 minutes, oral consumption can increase the levels of circulating β- hydroxybutyrate36. The main drawback of ketone esters is their lack of prescription availability, as they are more commonly manufactured as a sports supplement. The fact that oral ketone ester delivery is limited to oral, nasogastric, and orogastric administration may be another drawback. As some individuals may not be able to feed orally or nasally because the insertion of a gastric tube could raise intracranial pressure.
Exogenous ketones need to be further studied before they can be considered a viable therapeutic option, despite the fact that data suggests they may be helpful in the treatment of TBI. More research is required to comprehend changes in ketone metabolism caused by age and sex, the best time to provide ketone treatments, and how to apply findings from animal models to patients, as summarised by Daines, SA., 2021.
Hypercatabolism is evident in TBI patients and frequently leads to excessive protein breakdown and high calorie demand resulting in negative nitrogen balance37,38. It is acknowledged that protein losses during this time can only be minimized, not eliminated. Typically, 1.2 to 1.5 g/kg/d of protein intake is advised39. However, in more recent times, some have suggested an upper limit of 1.5-2.5 g/kg/d or even 2.25 g/kg/d40. Similar to energy requirements, protein requirements will vary depending on the patient’s clinical condition and whether sepsis, other injuries, or organ failure are present41. It seems that protein catabolism peaks 8–14 days after injury and that it is correlated with the degree of injury42.
After a TBI, increased protein supplementation has not been reliably shown to preserve muscle mass or balance nitrogen excretion43. However, recent evidence exploring the protein intake of patients admitted with mild-to-moderate TBI showed that the median protein intake was only 61.3% relative to protein requirement44. Studies of other significantly unwell, catabolic patients have likewise demonstrated that high protein supplements do not work to stop the breakdown of muscle in cases of cachexia45.
Studies demonstrating a higher mortality rate in critically ill patients receiving growth hormone have raised questions about the use of anabolic medicines like growth hormone or IGF-146. However, the only treatment that has produced results in TBI patients is IGF-147. Nevertheless, to compensate for the excessive catabolism, recommendations for feeding acute TBI patients between 1.5 and 2 g/kg/day of protein are most commonly followed48.
Branched-chain Amino Acids (BCAAs)
The use of BCAAs (leucine, isoleucine and valine) has also emerged as a promising treatment option for TBI49. Multiple trials and outcome metrics, such as the Disability Rating Scale (DRS) and plasma and brain BCAA concentrations, have shown that administration of BCAAs may be effective. Additionally, endogenous BCAA concentration are consistently reported to be reduced post injury50. As crucial metabolic building blocks for the production of proteins and neurotransmitters including dopamine, serotonin, and norepinephrine, BCAAs play a crucial role in metabolism. There use as a nutritional intervention may be a viable option given there accessibility and safety, with dosages of 60 g, which are three to seven times the daily requirements for healthy adults, given without the detection of any negative side effects51. Given that BCAAs are transported by sodium ion-mediated channels through the BBB, they are easily accessible in the brain. Following the successful findings in animal studies, numerous clinical investigations were conducted and achieved equivocal conclusions.
Ozgultekin et al., (2008), showed no effect following administration of 500 mL/d of amino acid solution containing 45% BCAAs and a total of 30.7 g of protein. The researchers reported that patients in ICU who had suffered severe head trauma were given parenteral BCAA and parenteral glutamine in addition to the typical enteral diet. Regarding nutritional indicators, sepsis risk, and length of hospital stay, no pronounced effects of glutamine solutions and solutions high in BCAAs supplied as additional supplements were found.
Another trial investigated the effects of BCAAs administered enterally over a 30-hour period52. Relative to 44 healthy controls, 19 severe TBI patients had significantly lower BCAA concentrations in the first week following the administration of the amino acid complex. Leucine and valine concentrations were still lower in patients than in controls at 2 weeks after dosing, however there was a nonsignificant trend toward rising plasma BCAA concentrations in TBI patients.
In the chronic stages of injury (17±4 months after injury), Borsheim et al. evaluated the effects of BCAA and administered a 7 g solution of essential amino acids. Prior to treatment, critical amino acid levels in TBI patients were found to be considerably lower than in controls. The two study groups’ respective essential amino acid concentrations stopped varying an hour after consumption of the essential amino acid solution. This shows that within one hour after delivery, BCAA supplementation can lead to the normalization of plasma BCAA levels.
Significant increases in plasma BCAA concentrations from baseline to follow-up were seen in the BCAA-supplemented group in a randomized trial of 53 patients with severe TBI53. This study examined the effects of BCAA supplementation of 19.6 g daily for 15 days. At the time of admission to a rehabilitation facility (64±32 days after the injury), the BCAA intervention group showed a substantial improvement on the DRS, whereas the placebo group did not.
Glutamine synthetase is an ATP-dependent enzyme found in most species, in the brain it is exclusively located in astrocytes where it serves to maintain nitrogen metabolism. In critical illness, the rapid depletion of glutamine has been associated with increased mortality. This has led to the concept that early glutamine suppletion would be beneficial in patients with TBI. Some studies in adult patients have shown a trend towards reduced fatality rates, infections and length of ICU stay in those supplemented with glutamine in combination with other nutritional supports, such as alanine and probiotics,. However, other studies, showed no beneficial effects in patients with severe TBI.
Omega-3 Fatty Acids
The brain contains considerable quantities of omega-3 polyunsaturated fatty acid (n-3 PUFAs), which are required for the creation of synapses, dendrites, and other crucial neuronal processes like neurotransmission58. The most important n-3 PUFAs for human health, are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), must be acquired through dietary intake, with the primary sources being fish and fish oil59. Researchers have previously documented that both preventive and prolonged dietary n-3 PUFAs significantly improves cognitive deficits following TBI in animal models. For example, experimental findings have demonstrated that mice exposed to cortical impact or sham operations, and treated with fish oil and n-3 PUFA injections combined for up-to 35-days, had a consistent favourable effect on lowering cognitive deficits, but they had no effect on reducing gross tissue loss60.
Mechanistically, the combination therapy may support the brain’s recuperative post-TBI processes, each of which was strongly associated with the enhanced cognitive recovery. Suggesting a possible role in enhancing brain remodelling post trauma, however, this has not been successfully translated to clinical use. Whilst others have focused on pre-TBI supplementation, with the majority of n-3 PUFA preclinical trials employing a pre-TBI treatment paradigm, achieved through preventative dietary supplementation, which gave limited information when thinking about transferring this treatment from the bench to the patient61,62. Further clarity is required on dosage and dose timing, as preclinical studies vary widely in their regimens, from 5 mins post-TBI63, to 2hrs, an others documenting improvements when administered within the first day64. Due to its potential to lessen numerous crucial steps in secondary injury, the use of high-dose omega-3s for the treatment of severe traumatic and hypoxic brain injuries has lately gained attention65.
In one exploratory study conducted by Bailee et al (2020), 9 patients having suffered severe TBI were treated with high-dose omega-3 fatty acids. The investigators administered a nutritional supplement of 16.2 g of purified omega-3 oil daily, over 2 doses, either orally or via feeding tube, containing a 2:1 ratio of EPA and DHA. Over the course of the therapy, all patients’ clinical outcome scores improved, which may have been aided by supplements in improving neurological results. However, every patient received the necessary clinical care. The study’s notable flaws include a small sample size, open label, non-randomized design, and the absence of a placebo arm.
Due to their capacity to repair the non-pathogenic gut flora that frequently is reduced as a result of various diseases or after receiving medical treatment with drugs like antibiotics, probiotics have been increasingly investigated in their possible management of infectious conditions.
Probiotics’ effect on patients with severe TBI was the subject of one prospective randomized pilot study66. The main goal of the pilot study was to ascertain whether and how probiotics alter T-helper type 1 (Th1) to T-helper type 2 (Th2) cytokine responses. Along with the incidence of infections, antibiotic use, ICU stay duration, and mortality rate after 28 days. After being admitted to the hospital, all patients (n=52) were given enteral nutrition (EN) through a nasogastric tube within 48 hours. The initial energy objective for each patient was 10 kcal/kg/day, which was gradually increased to 30 kcal/kg/day and 0.2 gN/kg/day on day 3. For 21 days, the probiotic group underwent nasogastric administration of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus three times each day. The study demonstrated that the introduction of probiotics might correct the Th1/Th2 imbalance brought on by severe TBI, which could lower the rate of infections during the late period, lower the need for antibiotics, and shorten the length of stay in the intensive care unit.
As reported by Brenner et al., in 2017, although research in this area is still in its infancy, results so far ‘do not support some claims within the extensive coverage of probiotics in the popular press’67. Whilst more recent investigations continue to support early enteral feeding mixed with probiotics and lower serum levels of inflammatory markers such as; ET-1, CRP, and IL-6, IL-10, and TNF-α68. Again this open intervention, enrolled adults with severe TBI, more needs to done to understand the potential benefits in milder injuries.
In addition to diminished BCAA levels, concentrations of zinc are notably lower following a TBI. Patients with TBI have increased urine zinc losses that continue for weeks after the injury and lower serum zinc levels. Additionally, it seems that urinary zinc deficits correlate with the severity of TBI69. Zinc is an important cofactor for substrate metabolism, immune function, and N-methyl-D-aspartate (NMDA) receptor function70. Animal models have demonstrated that, compared to zinc-adequate controls, zinc shortage enhanced cell death at the location of the cortical damage, with evidence of both apoptotic and necrotic cell death for 4 weeks following the injury71.
In a human study, 68 patients were randomly randomized to receive zinc supplements (12 mg/day) or adequate zinc levels (2.5 mg/day) within 72 hours of injury for a total of 15 days72. After the first week, patients received enteral zinc (22 mg/day) or a placebo for the following three months. After three weeks, the zinc supplemented group showed a considerable increase in visceral proteins (prealbumin and retinal-binding protein). One month after TBI, there was a 26% mortality rate in the zinc adequate control group compared to a 12% mortality rate in the supplemented zinc group. The statistics certainly indicate that a zinc supplement may increase survival, however the lack of heterogeneity in the injury characteristics of the patient groups was significant.
The inclusion of zinc supplements to TBI therapy may be an effective way to enhance recovery after damage while also improving brain injury outcomes. As per other nutritional interventions, both the animal and human work have studied moderate and severe brain injury. No work has explored the use of zinc in milder forms of TBI, such as concussion.
The benefits of nutritional supplements in mild TBI or as a neuro-preventative strategy in people who engage in high-risk activities are not yet supported by enough evidence. The promise of BCAAs as an intervention in severe TBI is clear among all dietary supplement regimens examined to date, but future study should look at BCAAs’ effects in milder brain injury.
The data is more compelling for ketone regimen when it comes to immediate post-injury therapies. Single-arm studies may be the only option for studies evaluating or screening treatments for TBI in which the use of placebos may be deemed unethical and opportunities for controlled trials are limited, notwithstanding the disadvantages and little human intervention data.
In these circumstances, medical interventions should rely on data from uncontrolled studies; a usual approach for estimating the incremental benefit of the therapy is to compare it to a “historical control,” or, more precisely, a baseline state. More information is needed, as many have documented, the timing of therapies and the differences in sex play a substantial role in success rate but these differences are relatively unexplored.
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