Key points

Introduction

Introduction

Acupuncture

Acupuncture is a form of energy medicine and is one of the more common and more researched of the CAM modalities; however, it shares with the others a similar treatment setting. Acupuncture also shares a conceptual framework similar to tai chi or qigong, in that life energy, called Qi (pronounced chee), is thought to be circulating though all parts of the body via energy channels, called meridians. These meridians connect the exterior to the interior, the organs to each other and the exterior.

The classical Chinese explanation is that channels of energy run in regular patterns through the body and over its surface in channels, called meridians. Much like blood flow may cause infarction, an obstruction in the movement of these energy rivers will cause the flow of Qi to become blocked or unbalanced, thus causing abnormality. Acupuncture is one of the treatments used to re-establish the flow of Qi by placing needles at points along the meridians, thus allowing the body to return to a homeostasis, easing the ailment for which it was prescribed.

The modern scientific explanation is that needling the acupuncture points stimulates the nervous system to release chemicals in the muscles, spinal cord, and brain. These chemicals will either change the experience of pain or they will trigger the release of other chemicals and hormones that influence the body’s own internal regulating system.

The physiology of acupuncture effects is beginning to emerge. Stimulation of acupuncture points has been shown to create signal change in the amygdala, anterior hippocampus, and subgenual cingulate cortex on functional MRI (fMRI). Other studies confirm these findings, defining the role of the amygdala in affect, fear, and defensive behavior as well as the processing of pain and motivation. The hippocampus is thought to link affective states with memory processing. The signal decrease within the amygdala and anterior hippocampus is consistent with past acupuncture fMRI studies at acupoints LI-4 and GB-34 as well as ST-36.

Ahsin and colleagues linked electroacupuncture to functional improvement they thought was related to the measured increase in endorphins and a decrease in cortisol, in subjects given electroacupuncture.

The improved energy and biochemical balance produced by acupuncture results in stimulating the body’s natural healing abilities, and in promoting physical and emotional well-being. The anatomy of acupuncture points is not clear; however, a theory proposed by Langevin and Yandow suggests that the meridians are located within tissues planes, that acupuncture points occur at a convergence of these, that meridian qi is the connective tissue biochemical and bioelectrical signaling, and that a blockage of qi may lead to an altered connective tissue matrix composition leading to altered signal transduction and therefore pain or other symptoms.

Clinically, acupuncture does appear to be of benefit in some patients; however, there is no good evidence for the use of acupuncture in TBI. According to a Cochrane Review in 2013, “The small number of studies together with their low methodological quality means that they are inadequate to allow any conclusion to be drawn about the efficacy and safety of acupuncture in the treatment of TBI.” Acupuncture has, however, been found helpful for some often seen comorbid conditions such as headache, pain, spasticity, and posttraumatic stress disorder (PTSD). For example, one Cochrane Review concluded that acupuncture was effective for treating frequent episodic or chronic tension–type headaches, and another stated, “Available studies suggest that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment, and has fewer adverse effects. Acupuncture should be considered a treatment option for patients willing to undergo this treatment.” According to the Journal of Rheumatology , there is sufficient evidence to warrant positive recommendations for osteoarthritis, low back pain, and lateral epicondylitis in routine care of rheumatic patients. Acupuncture has shown to be effective in low back pain, lateral epicondylitis, shoulder pain due to subacromial impingement, and headache pain. Nausea and vomiting has also shown to be effectively managed by acupuncture. A meta-analysis showed that acupuncture significantly decreased spasticity after stroke, noting most significant decreases in the wrist, knee, and elbow. Finally, a systematic review and meta-analysis by Kim and colleagues in 2013 suggested that the evidence of effectiveness of acupuncture for PTSD is encouraging but further qualified trials are needed to prove its effectiveness. Acupuncture is an ancient medical modality, with physiologic changes that seem to suggest neurologic and neurochemical effects that can lead to clinical improvement in patients with TBI.

Nutraceuticals

In recent years, much attention has been paid to TBI. This attention has not yet yielded a successful pharmaceutical clinical trial. The reasons for this are likely multifactorial because TBI is a varied and complex injury that scientists are just beginning to understand. Although many of today’s treatments focus on maximizing residual function, minimizing damage via interruption of the cellular pathologic mechanisms may be more effective. Given its heterogeneous nature, TBI may not be well suited for the typical pharmacologic approach to intervention testing, that is, aiming for an isolated target within the currently known biochemical pathways. Nutritional supplements often have influence in more than one pathway and have the potential of a multitargeted approach.

Survivors of trauma need proper nutrition to counter the catabolic metabolism that occurs after injury. The Brain Trauma Foundation Guidelines recommend initiation of nutritional support by day 7. They do not, however, provide specific guidelines. Further exploration is needed to establish recommended nutritional components that can not only provide the required calories, but foster recovery from TBI. Many of the current nutrition-based research targets have deficiency states with known neurologic deficits (eg, zinc [Zn], vitamin B3). Some of the more promising nutritional supplements for TBI are addressed in later discussion.

Omega-3 fatty acids

Omega-3 fatty acids (FA) are polyunsaturated fats unable to be synthesized in the human body, and therefore, must come from dietary sources. The important omega-3 FA are docosahexaenoic acid (DHA), eicosapentaenoic acid, and alpha-linolenic acid. Omega-3 FA are found in significant concentrations in cold water marine food sources (eg, oily fish, krill). Non-marine animal and plant-based sources exist. Omega-3 FAs are key factors in membrane organization, function, and plasticity, thereby influencing cell adhesion, synapse maintenance, and neurotransmission speed. A major structural component of the mammalian cerebral cortex, DHA supplementation has been showed to enhance learning during aging. A body of animal studies on omega-3 FAs has shown the potential benefits of these compounds after TBI.

Consumption of omega-3 FAs reduces reactive oxygen species (ROS) production. DHA pretreatment for 30 days before TBI leads to decreased axonal injury, apoptotic marker, and improved memory in rodents. Postinjury treatment with omega-3 FA for 30 days demonstrated decreased β-APP-positive neurons when compared with controls in rodents. An array of studies supports the role of omega-3 FA in ameliorating TBI-related injury in areas such as mitochondrial malfunction, apoptotic cell death, oxidative stress, inflammation, and excitotoxicity. To date, no human studies involving omega-3 FA on TBI have been published, but several clinical trials are underway ( NCT01814527 , recruiting, mild TBI; NCT01903525 , recruiting, mild, adolescents; NCT02762539 , not yet recruiting). Use of omega-3 FA in TBI is a promising area of effort.

Zinc

Zn is an essential trace element, which has been linked to a variety of neurologic disorders. Occurring in both protein-bound and free forms, the balance between the 2 is critical for normal brain performance. Zn participates in neurotransmitter activity, cell signaling, DNA binding of transcription factors, enzymatic activity, and adult neurogenesis. Zn is required for normal central nervous system development. Mild gestational Zn deficiency has been shown to have learning and memory abnormalities in animals. Free Zn is postulated to be responsible for developmental programmed neuronal pruning. Free Zn is stored in neuronal synaptic vesicles and is released into the synaptic cleft triggering post–synaptic neuronal death, and excessive Zn has been associated with neuronal morbidity and mortality. After TBI, Zn serum levels decline and urinary levels are elevated. Research has demonstrated that Zn deficiencies after TBI are more problematic than elevated levels. Choi and colleagues demonstrated in animals that removal of Zn reduced TBI-induced progenitor cell proliferation and neurogenesis. A human randomized controlled trial (RCT) involving 68 severe TBI patients reported lower mortality at 1 month after injury when compared with controls. Mean Glasgow Coma Scale (GCS) of the Zn-supplemented group was higher at day 28, and mean motor GCS was higher on days 15, 21, and 28; however, the control group had a greater number of craniotomies for hematoma evacuation. Although Zn appears to have some promise, more work needs to be done for a better understanding of its impact on TBI.

Vitamin D

Vitamin D is a fat-soluble vitamin that is synthesized by human skin upon exposure to sunlight, specifically UV-B rays, or gained through dietary sources such as fatty fish, cod liver oil, mushrooms, and eggs. Vitamin D gained through dietary sources, light exposure, and supplements must undergo transformation of 2 hydroxylations to be biologically useful. Vitamin D deficiency has been linked with neurodegenerative processes and cognitive impairment.

A human study from Iran compared 3 groups (control, progesterone, vitamin D and progesterone) of 20 severe TBI patients. At 3 months, 35% of the progesterone and vitamin D had good recovery on Glasgow Outcome Scale (GOS); progesterone alone had 25% had good recovery, and 15% of placebo had good recovery. Jamall and colleagues performed a retrospective chart review on patients that attended a TBI clinic. They examined the relationship between vitamin D and outcome measures such as cognitive testing, while controlling for confounding variables such as time from injury and injury severity. Vitamin D levels were correlated with cognition; depression was correlated between the vitamin D–depleted and –insufficient groups. Currently, no listing for an RTC was found on ClinicalTrials.gov .

Vitamin B3

Nicotinamide in the body originates from dietary intake or primarily plant sources or can be synthesized. Current clinical usage is treatment of the deficiency state, pellagra, and to decrease cholesterol (high doses) and atherosclerosis. Nicotinamide serves as a source of energy supplementation by functioning as the precursor for β-nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+). It has been shown to inhibit both poly(adenine dinucleotide phosphate [ADP]-ribose) polymerase-1 and sirtuins that balance the repair of DNA damage. Inhibition of these has been shown to improve outcomes after TBI in rodent models. Histologically, nicotinamide reduced degenerating neurons, edema, and apoptosis, and decreased lesion size in the acute period. In the more chronic phase, reduced lesion size and active astrocytes were found. Examination of downstream markers substantiated these findings. Use of nicotinamide in TBI animal models has improved sensory, motor, and cognitive function and reduced lesion volume. Of concern, a study in middle-aged rats demonstrated no improvement, and higher doses trended toward impairment for a variety of measures, including vestibulomotor and lesion size compared with high- and low-dose nicotinamide across 3 different TBI animal models. Low-dose administration provided no benefit. At high-dose level, the controlled cortical impact model had significant tissue sparing. Concern has been expressed about converting the high doses used in animal studies for human consumption.

Vitamin E

Vitamin E is a group of fat-soluble compounds that includes tocopherols (α, β, γ, δ) and tocotrienols. Of these, α-tocopherol is the most widely studied. Vitamin E inhibits ROS formation during fat oxidation. Wu and colleagues found vitamin E–pretreated rats performed better on the Morris water maze; neurotrophic factors were restored, and there was evidence of less oxidative stress. Ishaq and colleagues studied vitamin C and vitamin E at 2 dosing levels as well as a combination of vitamins. The intervention drug started before injury and continued after injury. The combination of C and E group had significantly reduced mortalities that were not dose dependent.

A randomized clinical trial on severe TBI patients (N = 100) divided subjects into 1 of 4 groups: placebo, vitamin E, high-dose vitamin C, and low-dose vitamin C. At discharge, the vitamin E group had lower mortality and better GOS ( P = .04). Of note, both vitamin C groups had higher rates of unfavorable outcome at discharge. Perilesional edema was measured by imaging and found to be decreased by 68% in the high-dose vitamin C group. The small sample size is a noteworthy limitation of this study.

Creatine

Humans synthesize creatine in the liver, kidneys, pancreas, and brain, and the primary dietary source of creatine is meat. Intracellular creatine exists in 2 forms: free creatine and phosphocreatine. Creatine kinase (CK) metabolizes creatine and catalyzes the reversible transfer of a phosphate group between ATP and creatine. Creatine/phosphocreatine (Cr/PCr) serves as a temporal and spatial energy buffer (connecting energy production with utilization sites). Although CK is functionally coupled to ATP-consuming processes, creatine maintains local ATP/ADP ratios. Cr/PCr prevents inactivation of cellular ATPases by limiting elevations of intracellular ADP.

In addition to energy metabolism, creatine inhibits opening of mitochondrial permeability transition pore (MPTP), thereby assisting in Ca ²⁺ homeostasis, decreasing ROS production (Mazzeo A) and inhibiting apoptosis. Creatine can serve as an antioxidant by scavenging ROS and by decreasing production of ROS by mitochondria. Creatine inhibits many of the processes associated with TBI-related secondary injury, including providing an alternative energy source, inhibiting MPTP, decreasing apoptosis, and acting as an antioxidant.

Creatine-specific genetic anomalies reveal the importance of creatine for normal brain function. The three known genetic errors of creatine transport and production exist, each of which is associated with decreased to absent creatine levels in the brain. Each deficiency clinical picture includes cognitive impairment and developmental delay, highlighting the relationship between cognition and Cre. In non-TBI humans, creatine supplementation has demonstrated reduced mental fatigue, improved working memory, increased intelligence test scores, and in the face of sleep deprivation, improved central executive function tasks. In summary, it appears that creatine-deficient and physically stressed but otherwise healthy humans have a positive response to creatine supplementation.

Curcumin

Curcumin is a yellow pigment that comes from the Curcuma longa rhizome and is typically used as a flavoring in curries. Prior work supports the wide variety of biological actions of curcumin (anti-inflammatory, antioxidant, inhibitor of proinflammatory cytokine interleukin-1β]). Curcumin crosses the blood-brain barrier. Animal studies have demonstrated an energy regulatory control function when pretreatment with curcumin is used in a TBI fluid percussion model. Post-TBI use of curcumin in fluid percussion TBI animal models showed normalized brain-derived neurotrophic factor, and a transcription factor involved in learning and memory (CREB). Zhu and colleagues demonstrated reduced cerebral edema, neurologic deficit, and cytokine release in mice after weight drop TBI model. Using a hypoxia model of injury on rats, Yu and colleagues found reduced apoptosis and cerebral edema using pretreatment with curcumin. No human studies of curcumin in the TBI population were located.