The 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.
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
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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
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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