- Thionetic Nutrition, Richmond Hill, ON L4C 7T3, Canada
- Spoken Language Systems Group, Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA 02139, USA
Correspondence Address:
Stephanie Seneff
Spoken Language Systems Group, Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA 02139, USA
DOI:10.4103/2152-7806.134731
Copyright: © 2014 Morley WA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Morley WA, Seneff S. Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration. Surg Neurol Int 18-Jun-2014;5:97
How to cite this URL: Morley WA, Seneff S. Diminished brain resilience syndrome: A modern day neurological pathology of increased susceptibility to mild brain trauma, concussion, and downstream neurodegeneration. Surg Neurol Int 18-Jun-2014;5:97. Available from: http://sni.wpengine.com/surgicalint_articles/diminished-brain-resilience-syndrome-a-modern-day-neurological-pathology-of-increased-susceptibility-to-mild-brain-trauma-concussion-and-downstream-neurodegeneration/
Abstract
The number of sports-related concussions has been steadily rising in recent years. Diminished brain resilience syndrome is a term coined by the lead author to describe a particular physiological state of nutrient functional deficiency and disrupted homeostatic mechanisms leading to increased susceptibility to previously considered innocuous concussion. We discuss how modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, profoundly reduce the bioavailability of neuro-critical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional. Their diminished capacity triggers physiological and biochemical ‘work around’ processes that result in undesirable downstream consequences. Exposure to certain environmental chemicals, particularly glyphosate, the active ingredient in the herbicide, Roundup®, may disrupt the body's innate switching mechanism, which normally turns off the immune response to brain injury once danger has been removed. Deficiencies in serotonin, due to disruption of the shikimate pathway, may lead to impaired melatonin supply, which reduces the resiliency of the brain through reduced antioxidant capacity and alterations in the cerebrospinal fluid, reducing critical protective buffering mechanisms in impact trauma. Depletion of certain rare minerals, overuse of sunscreen and/or overprotection from sun exposure, as well as overindulgence in heavily processed, nutrient deficient foods, further compromise the brain's resilience. Modifications to lifestyle practices, if widely implemented, could significantly reduce this trend of neurological damage.
Keywords: Chronic traumatic encephalopathy, glyphosate, neurotoxins, postconcussion syndrome, sports-related concussion
INTRODUCTION
While the number of reported sports-related concussions (SRCs) has been steadily rising over the past decade, prompting increased media and medical attention, the number of children participating in the top five organized team sports (OTS), over the same time period, has actually been declining. This surprising juxtaposition is not limited to the world of sports. Neurological disorders are also disproportionately increasing, with neurological deaths increasing almost 2-fold, while total mortality rates have been declining.
In this paper, we introduce a new concept of how increasing nutrient functional deficiencies and dysfunctional homeostatic mechanisms are plausibly the central mechanism leading to the epidemic we are witnessing in concussion-related and other neurological damage. The study of physiology has well documented a number of innate regulatory and healing mechanisms in place in the human body to maintain homeostasis and enable physiological resilience. In its natural state, the body should be able to tolerate disturbances and withstand shocks without collapse, and to recover quickly from injury or illness. Research has identified, however, that a number of these innate resilience mechanisms and processes are nutrient-dependent and/or are particularly vulnerable to the effects of toxicants.
Concussion, as defined by the 3rd International conference on concussion in sport is “a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces”.[
Traumatic biomechanical forces can arise from:
a direct (to the head) or indirect (to the body) impact (e.g. through sports, workplace accidents), rapid acceleration or deceleration (e.g. motor vehicle accidents), or intense changes in pressure (e.g. blast exposure).[
STATISTICS AND TRENDING
The prevalence of concussion, a subset of mild traumatic brain injury (mTBI),[
It is estimated that concussion, which is more difficult to define than severe TBI, affects some 100-600 per 100,000 people annually.[
Furthermore, according to the CDC, US emergency departments (EDs) treat an average (estimate) of 173,285 children and adolescents aged birth to 19 years, for sports and recreation related TBI's per year. In a study conducted at Brown University, it was determined that, from 1997 to 2007, emergency room (ER) visits for concussion occurring from OTSs had almost doubled for children aged 8-13 years (from 3946 to 7791), and more than tripled among those youth aged 14-19 (from 7276 to 23,239).[
According to Michael A. McCrea, executive director of the ProHealth Care Neuroscience Centre and Research Institute in Waukesha, WI, “….some percentage of the increase should be attributed simply to more concussions. It feels evolutionary and seems natural to me that if we saw great speed, strength, and mass-all the requirements for a collision-at the professional level, we naturally saw it trickle down to the collegiate level, and now it is trickling down to the youth sports level.”[
Of more concern is that, while increases in concussion are well documented,[
A COMPELLING PARALLEL TREND
Genetically modified foods, and the use of pesticides and herbicides, most specifically glyphosate, the active ingredient of Monsanto's Roundup®, have been steadily increasing since the 1990s. In fact, according to data from the USDA: National Agricultural Statistics Service (NASS), and in contrast to claims made by the chemical industries, glyphosate use increased 6504% from 1991 to 2010.[
Despite being strongly discounted by Monsanto, there are mounting good-quality scientific studies that demonstrate negative effects of glyphosate on gut homeostasis, such as reductions in beneficial gut bacteria like Lactobacilli,[
A MISTAKEN ASSUMPTION
As noted earlier, most mainstream authorities in the field of SRCs maintain that the increase in concussion rates is largely due to the increased awareness and reporting, as well as increased availability of sports activities. However, as
We suggest that, at its core, this downward spiral of neurological demise reflects the inability of the body to maintain homeostatic balance of regulatory and healing mechanisms needed for brain resilience. We postulate that modern day environmental toxicant exposure, along with major changes in our food supply and lifestyle practices, has had a profound impact on the body's ability to absorb and utilize nutrients critical for brain health. Furthermore, we propose that these factors are markedly altering the body's natural state such that neuro-critical nutrients are so depleted and/or functionally deficient that the normal processes of homeostatic balance and resilience are no longer functional. At best, they are operating in a severely diminished capacity, which triggers physiological and biochemical ‘work around’ processes, resulting in undesirable downstream consequences.
This altered natural state is manifested in:
Increased susceptibility to brain injury, by the priming of the microglia, a key step in immunoexcitotoxicity, which is strongly linked to mTBI, chronic traumatic encephalopathy (CTE), and other neurological disorders Reduced ability to appropriately modulate physiological response to brain injury, as a function of deficiencies in key micronutrients, such as magnesium, sulfur, and zinc, which are substrates or catalysts in the biochemical responses to brain injury, Disruption and dysfunction of the normal ‘on/off’ regulation switching of biochemical processes engaged with brain injury Deficiency of neuro-essential fatty acids (neuro-EFAs), specifically docosahexaenoic acid (DHA), and of monoamine neurotransmitters, which leads to impaired antioxidant capacity and sulfate supply to the brain and associated pathologies Hyper-reactive excitatory response due to persistently primed microglia A chronic state of persistent secondary neurodegeneration, with an impaired ability to recycle cellular debris.
We believe that this altered state profoundly affects the body's ability to heal spontaneously from brain injury or assault, whether innocuous or traumatic.
We propose that, over the past decade, these lifestyle and environmental changes have resulted in profound, yet often unidentified, functional deficiencies of various nutrients within the body. For instance, deficiencies in important minerals such as magnesium and zinc prevent engagement of normal protective and control mechanisms of excitotoxicity. Changes in accessible substrates likely set off a complex ‘work around’ process, which the body initiates as a fail-safe back-up in reaction to brain injury, but which creates undesirable by-products and downstream consequences, such as increased amyloid-β peptide/plaque (glucose metabolism work around) or encephalopathy (sulfur deficiency).
UNDERSTANDING THE INNATE BRAIN MECHANISMS INVOLVED IN BRAIN INJURY AND DEGENERATION
Before we can present our theory of altered physiology, as it pertains to modern day concussion, it is useful to understand the now currently accepted view of concussion pathophysiology, sequelae, and the underpinning brain mechanisms in play.
Over the past several decades there has been an explosion of research and evolving concepts on the innate mechanisms of the brain at a cellular level. This scientific exploration has essentially shifted the focus of concussions from a more crude structural and anatomical view to a more precise awareness of the biochemical properties involved. The foundational work of Blaylock in the field of brain immunity, excitatory response and immunoexcitotoxicty[
Of particular relevance to the issue of modern day concussion, and more specifically DBR Syndrome, is the work of Blaylock and Maroon presented in 2012, which brought to light the awareness that a number of stimuli may interfere with the microglial switching mechanism including occult infections, exposure to neurotoxic metals and pesticides/herbicides, as well as their work outlining the impact of metal toxicity (especially aluminum), documenting that aluminum toxicity is mostly due to its enhancement of excitotoxicity by immune system mediators, via crosstalk between cytokine receptors and glutamate receptors.[
PATHOPHYSIOLOGY OF CONCUSSION
00Many studies indicate that “rotational forces seem to be a prerequisite for producing the diffuse damage in the brain that underlies the signs and symptoms associated with a concussion.”[
However, Blaylock and Maroon[
Furthermore, as noted by Shipley,[
In the following section, we will develop our hypothesis for the mechanisms by which the brain protects itself from, and heals following, sudden impact damage. However, we need to introduce early the key argument that is foundational to our hypothesis, which centers on the critical molecules, DHA and cholesterol sulfate (CS). DHA is the most abundant omega-3 fatty acid in the brain and retina,[
In summary, there are a few salient points to remember with respect to the pathophysiology of concussions. First, while rotational forces are known to be a prerequisite for the diffuse damage that underlies the signs and symptoms of concussion, in mild injury, most of the axonal damage is now thought to occur from a secondary event that is neurodegenerative in nature rather than mechanical. Second, it is recognized that, with unaltered physiology, uncomplicated, single concussions typically spontaneously heal within 24-72 h via intrinsic brain mechanisms. These intrinsic brain mechanisms interact with specific nutrients as control mechanisms involved with the release of immune factors and excitatory neurotransmitters post injury.
SEQUELAE OF CONCUSSION
Some individuals suffering from mild traumatic brain injuries, especially repetitive mild concussions, are thought to develop a slowly progressive encephalopathy characterized by a number of neuropathological elements shared with various neurodegenerative diseases.[
While the final pathological manifestation closely resembles that of sporadic AD, there are some differences, especially the predominance of tau pathology over amyloid accumulation in affected regions of the brain. According to Blaylock and Maroon,[
IMMUNOEXCITOTOXICITY: FROM CONCUSSION TO CTE
00While a central pathological mechanism explaining the development of progressive neurodegeneration (in the subset of individuals who develop slowly progressive encephalopathy after repetitive mild concussions) has yet to be fully elucidated or accepted, a number of studies indicate that a process called immunoexcitotoxicity may be playing a central role in both neurodegenerative diseases as well as CTE. The term immunoexcitotoxicity, originally coined to explain the evolving pathological and neurodevelopmental changes in autism and in the Gulf War Syndrome, refers to the process whereby the interaction between immune receptors within the central nervous system (CNS) and excitatory glutamate receptors trigger a series of events, such as extensive reactive oxygen species (ROS)/reactive nitrogen species generation, accumulation of lipid peroxidation products, and prostaglandin activation. This then leads to dendrite retraction, synaptic injury, damage to microtubules, and mitochondrial suppression.[
A BIOCHEMICAL CASCADE
Glutamate is the most abundant neurotransmitter in the brain,[
Magnesium efflux from mitochondria follows calcium uptake.[
Microglia, the major immune cells of the brain, not only are intimately involved with the process of excitotoxicity, but also act as mediators in an inflammatory cascade that accompanies brain trauma. Recent studies have pinpointed the activation of the brain's microglia as an early and primary event in traumatic brain injuries. Proinflammatory immune cytokine receptors interact with glutamate receptors in complex ways. Intracellular messengers, including calcium, cyclic AMP, and ROS, respond to both ionotropic and metabotropic glutamate receptors to initiate multiple signaling cascades.[
Microglia, the resident macrophages of the brain, play an important role in mediating the inflammatory response. They respond rapidly to disturbances in homeostasis, and it is the induction of proinflammatory cytokines in response to excitotoxins that leads to neurodegeneration. Three basic states of microglial activation have been proposed: Neurotrophic/phagocytic (ramified/resting/inactive); intermediate (primed); and predominantly neurodestructive (fully activated).[
LPS is a toxic by-product present in gut dysbiosis. Dysbiosis is a state of imbalance between pathological and beneficial gut bacteria. It is a common condition and is brought on by many modern day triggers such as antibiotics and environmental toxicant exposure (beneficial gut bacteria are preferentially vulnerable to pesticides and herbicides), as well as poor dietary choices such as high sugar diets and overconsumption of processed foods. We propose that both exposure to environmental toxins, as well as the resulting dysbiosis, are potent catalysts to a state of persistent immune stimulation within the brain.
Microglia can become “primed” in response to exposure to a number of environmental toxicants, as well as in response to immune stimulation, LPS, ischemia or hypoxia, and brain trauma.[
Primed microglia release much higher concentrations of inflammatory cytokines and excitotoxins, such as glutamate, aspartate, and QUIN, in response to insults, resulting in much greater injury to the soma, the dendrites and the synaptic connections. Thus, even a mild concussion might result in a neurodestructive cascade in the context of previously primed microglia,[
Figure 2
Diagram demonstrating the conversion of a resting microglia in the uninjured brain to a primed microglia with an initial injury. Subsequent injuries, even separated by prolonged periods, can then trigger a hyper-reaction by the fully activated microglia. This in turn results in a more intense immunoexcitotoxic reaction (reprinted from Blaylock and Maroon[
We suggest that this secondary event manifested as a neurodegenerative state, as noted by Blaylock and Maroon,[
MECHANISMS OF BRAIN PROTECTION/HOMEOSTATIC BALANCE
The body has a number of innate regulatory and healing mechanisms and processes in place to maintain homeostasis and enable physiological resilience, most of which are vulnerable to nutritional deficiencies and environmental toxicants. One such mechanism is a switching mechanism, which normally shuts off microglial activation, once the danger has been contained. Although not fully understood, it involves interactions with various cytokines and fractalkines, all of which reduce microglial activation and downregulate the release of proinflammatory cytokines.[
In neurodegenerative conditions such as AD, abnormalities in many stages of the glutamate cycles have occurred, leading to increased levels of glutamate in the extracellular space outside of the synapse, suggesting that glutamate clearance may be impaired in patients with AD.[
Here, we introduce a novel concept that the pineal gland, a tiny gland in the center of the brain, appears central to the pathology associated with PCS and related conditions, most critically with impact trauma. Specifically, deficiencies in heparan sulfate (HS) dramatically impair the buffering ability of the brain against impact injury due to insufficiently gelled water in the cerebrospinal fluid (CSF). We argue that the pineal gland responds to light stimuli by producing sulfate, and that the sulfate, conjugated to melatonin, is distributed throughout the brain via the CSF. Sulfate plays a critical role in buffering the brain against physical impact, and in degrading and recycling damaged proteins and mitochondria. The pineal gland is outside of the blood–brain barrier (BBB), and it is profusely supplied with blood, second only to the kidney. This makes it vulnerable to exposure to environmental toxicants. Thus, impaired sulfate supply, due to impaired function of the pineal gland, might explain the increased sensitivity to concussion and inability to recover from concussion observed in modern times.
In the remainder of this section, we will develop the argument that PCS can be characterized mainly as a response to deficiencies in sulfate and glutathione (GSH) in the brain, both of which are sulfur-containing molecules. We first discuss the role of heparan sulfate proteoglycans (HSPGs) in neuronal healing, followed by a discussion of their role in protection from impact injury. We then show the role of sleep in clearing cellular debris, an essential function following trauma. Next, we discuss how the pineal gland, through release of melatonin sulfate at night, normally resupplies sulfate to the brain. We propose that the chronic low-grade inflammatory state characterized by PCS is a mechanism to replenish sulfate levels in the brain. After showing how melatonin is integrally connected to GSH up-regulation, thus restoring protective mechanisms in the face of oxidizing agents, we discuss the proposed role of DHA working in concert with CS to catalyze the synthesis of sulfate in the pineal gland in response to sunlight.
HEPARAN SULFATE AND NEURONAL HEALING
HSPGs, attached to the exterior side of membrane-bound proteins in most cells, have profound effects at the cellular, tissue, and organismal level.[
Cerebroglycan is a glycophosphatidylinositol- (GPI)- anchored glypican that is unique to neurons during development.[
It had long been believed that neurons have a limited capacity for regeneration. However, this concept has been dispelled by experimental evidence that neuronal tissues in the hippocampus harbor progenitor stem cells that can differentiate into functioning pyramidal neurons and that they do so in massive numbers when neurons have been damaged through ischemia.[
Because HS participates in neurite outgrowth,[
A ROLE FOR SULFATES IN LOAD RESISTANCE
The glycocalyx is a negatively charged complex network of proteoglycans, glycoproteins, and glycolipids that decorates the plasma membrane of most cells.[
Sulfation, the last step in the synthesis of GAGs, consumes two ATP molecules for every sulfate ion attached to the GAG chain. There must be something highly significant about the need for such sulfation, given its costly energy requirements. Haskin et al.[
We propose that the same concept applies in the brain; specifically, in the ventricular system that houses the CSF. The ependyma is the thin epithelial membrane that lines the ventricular system of the brain and spinal cord, part of whose role is to produce CSF. It has a thick glycocalyx, extending into the ventricular fluid area, which is likely to provide mechanical buffering to the delicate brain tissues.[
THE IMPORTANCE OF SLEEP AND METABOLIC CLEARANCE
In a recent study, Xie et al.[
Neurodegenerative disorders such as AD and Parkinson's disease disrupt the circadian-pineal system,[
A CRITICAL ROLE FOR THE PINEAL GLAND
The pineal gland is a small endocrine gland situated in the center of the brain behind the optic chiasma. It is responsible for synthesizing melatonin at night, which is distributed to neuronal tissues as melatonin sulfate via the CSF.[
Exposure to sunlight induces 3-O sulfation of HS in the pineal gland, catalyzed by HS 3-O-sulfotransferase.[
Not only melatonin, but also serotonin, dopamine, and norepinephrine, three other important neurotransmitters, are all sulfated during transport, and their sulfated forms typically greatly exceed their unsulfated forms in the CSF.[
Mice engineered with a knockout gene for 3-mercaptopyruvate sulfurtransferase (MST) exhibited increased anxiety along with elevated levels of serotonin in the brain.[
Depigmentation of the substantia nigra is a characteristic feature of Parkinson's disease, and increased depigmentation is associated with a reduced level of dopamine and increased degeneration.[
An experiment examining the effects of transient global ischemia in the rat brain on extracellular metabolites revealed that dopamine concentrations increased 700-fold immediately following the blockage, and that this level was sustained throughout the duration of ischemia, returning to baseline within 10 min of reperfusion.[
ENCEPHALOPATHY AS A “WORK-AROUND” MECHANISM TO RENEW SULFATE IN THE BRAIN
The excitotoxic response in the brain to inflammatory agents is a well-orchestrated process associated with encephalopathy (CTE). Seneff et al.[
Highly significant is the activity of astrocytes to extract ammonia from glutamine, producing and releasing glutamate, while using the ammonia to maintain the basic pH of mitochondria. Ammonia can now substitute for taurine in this role, and taurine is freed up for its release and subsequent metabolism to sulfate. Hypochlorite, released by neutrophils, reacts with taurine to produce taurine chloramine, which serves a dual role of protecting neurons from the toxic effects of hypochlorite and converting taurine to a more reactive form. Fever and seizures that are associated with encephalopathy help activate the reaction. Ultimately, taurine chloramine is metabolized, yielding sulfate, which can then resupply sulfate to the HSPGs. Details can be found in Seneff et al.[
Thus, while encephalopathy is associated with a high risk of collateral damage to neurons through excitotoxicity, it serves an essential role in boosting sulfate levels in the extracellular matrix, which is required in order to replace damaged neurons with newly differentiated progenitor cells, regain the ability to metabolize glucose as a fuel,[
IMPORTANCE OF GLUTATHIONE TO THE CENTRAL NERVOUS SYSTEM
The brain is the most energy-consuming organ, and therefore it generates a significant amount of ROS that makes it particularly vulnerable to oxidative stress. GSH, a tripeptide consisting of glutamate, cysteine, and glycine, is a major antioxidant in the brain. GSH synthesis requires two enzymatic steps including ATP. Studies have shown that intracellular GSH is important for limiting oxidative stress-induced neuronal injury.[
The presence of methylenetetrahydrofolate reductase (MTHFR) genotypes, in particular, C677T, or A1298C mutations, directly impact enzymatic activity in the methylation process as well. The methylation process follows a number of enzymatic steps in the process from methionine to cysteine and then to synthesis of GSH. Those with these rare MTHFR genotypes are found to have lower GSH levels, and therefore increased risk to oxidative damage.[
MELATONIN PROTECTS ASTROCYTES VIA GLUTATHIONE UPREGULATION
Much of the neurotoxicity following brain injury relates to free radical oxidative damage to the delicate fatty acids in neuronal plasma membranes. As we have already discussed, GSH plays an important role in protection from the effects of oxidizing agents like superoxide and hydrogen peroxide. In the CNS, GSH is concentrated mainly within the glial cells,[
“Reactive astrocytosis” is a term to describe the phenomenon of astrocyte activation subsequential to brain injury. Glial fibrillary acidic protein (GFAP), a marker of reactive astrocytes, is overexpressed at the lesion site in brain injury.[
THE ROLES OF DHA AND CHOLESTEROL SULFATE IN INDUCING ELECTRON FLOW
Lipid rafts are specialized areas of the plasma membrane that are rich in cholesterol and sphingolipids and that serve as signaling platforms by clustering proteins.[
The pineal gland normally contains substantial amounts of DHA.[
Concussive injury to rats induced edema and brain swelling, which was partially alleviated by prior treatment with zinc protoporphyrin (Zn-PP).[
GLYPHOSATE, PROCESSED FOOD AND THEIR IMPACT ON INNATE HOMEOSTATIC AND PROTECTIVE MECHANISMS
It is our view that chronic systemic exposure to environmental toxicants, especially glyphosate, while relatively modern, is a significant catalyst to nutrient functional deficiency, disrupted and dysfunctional homeostatic mechanisms as well as compromised gut health; all aspects that contribute to DBR syndrome. Furthermore, the increased consumption of packaged goods and processed foods, which are laden with GMO sourced ingredients and predominantly use omega-6 oils, further disrupts the ideal omega 3:6 ratio. The resulting relatively low omega-3 intake further reduces the amount of brain-supporting eicosapentaenoic acid (EPA) and more specifically DHA available in the diet.
GLYPHOSATE
Today, glyphosate is the most widely used herbicide on the planet, due in large part to its perceived minimal toxicity and its relatively low cost. This is a very dangerous trend, as there are now enough published studies on the various pathological effects of glyphosate to provide convincing evidence of its negative effects on our health.[
Glyphosate is the active ingredient in Roundup®. Glyphosate's claimed mechanism of action in plants is the disruption of the shikimate pathway, which is involved in the synthesis of the essential aromatic amino acids, phenylalanine, tyrosine, and tryptophan.[
Glyphosate has been found to have a striking impact on micronutrients of plants exposed to it. It was determined that, in addition to abnormally low levels of tryptophan, phenylalanine and tyrosine (the three aromatic amino acids), glyphosate-sensitive cells also had 50-65% reduced levels of serine, glycine, and methionine.[
A number of animal studies have shown strong evidence of disruption of gut bacteria by glyphosate.[
Glyphosate, through its disruption of cytochrome P450 (CYP) enzymes, interferes with several functions in the liver that would ultimately impact the brain. The liver depends upon CYP enzymes to activate vitamin D3, to produce CS and bile acids, and to detoxify other environmental toxins, including pharmaceutical drugs. Furthermore, glyphosate, through its tendency to increase blood viscosity, a property that sulfate also possesses, would interfere with the transport of free sulfate from the gut to the liver, requiring transporters that contain a carbon ring to distribute the negative charge and carry the sulfate anion through the hepatic portal vein. Thus, the toxic phenols produced by the pathogenic gut bacteria serve a useful function in delivering sulfate to the liver, but ultimately damage the liver through their high reactivity. The enzyme that activates vitamin D3, 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1) is a CYP enzyme, and therefore is subject to suppression by glyphosate.[
ALUMINUM WORKS SYNERGISTICALLY WITH GLYPHOSATE
Microglia and astrocytes are primary sources of immune cytokines and glutamate in the brain and are material factors in immunoexcitotoxity. Evidence is compelling and significant from both in vitro and in vivo studies that aluminum exposure increases both of these compounds in the brain.[
A critical discovery of synergistic effects in relation to immunoexcitatoxicity is also well documented throughout Blaylock's work. There is indisputable evidence that subtoxic compounds such as glutamate, aluminum or LPS,[
Aluminum toxicity is a documented cause of encephalopathy,[
Aluminum toxicity in the liver leads to a disruption of mitochondrial energy production, a switch to anaerobic metabolism in hepatocytes, the production of excessive amounts of α-ketoglutarate by the liver, and the development of fatty liver.[
Dietary sources are undoubtedly the biggest contributor to aluminum exposure, but biological mechanisms normally exist to keep all but small amounts of the aluminum from penetrating past the gut barrier. However, citrate is known to facilitate the absorption of aluminum, through its ability to cage aluminum via chelation.[
The rates of AD have steadily climbed during the past decade and beyond. In fact, as illustrated in
Figure 3
Comparison between the amount of glyphosate applied to corn and soy crops in the US (purple), the percentage of corn and soy that is GMO (red), and the number of deaths from Alzheimer's disease in the US (yellow). Figure reproduced with permission from Swanson[
CONSUMPTION OF PACKAGED FOODS AND THE IMPACT ON OMEGA 6:3 RATIO
There is strong documentation as to the antiinflammatory benefits of omega-3 EFAs as well as the pathway of omega-6 EFAs toward a more inflammatory prostaglandin E1 E2 series. Chronic inflammation is increasingly being linked to chronic illnesses. It is viewed that our ancestors’ diet included far more fish, seafood, and algae, which leads to a healthier ratio of 4:1 omega 6:3 EFAs diet, and that they experienced reduced chronic illness compared with our modern day Western counterparts. The typical standard American diet (SAD) has a ratio closer to 22:1. This is largely due to the amount of omega-6 polyunsaturated fats from vegetable oils that are used in packaged foods. Omega-3 EFAs are critical for optimal brain health and function. We suggest that the risk to athletes aged 14-19 is pronounced, as this age group tends to consume more processed foods for a number of reasons, and processed foods are laden with GMO sourced ingredients. They also predominantly use omega-6 oils, which further disrupt the ideal omega 6:3 ratio. The relatively low omega-3 intake further reduces the amount of brain-supporting EPA and more specifically DHA available in the diet.
At the same time, our food has become increasingly processed, and there has been a dramatic shift from omega-3 to omega-6 fatty acid consumption. Deficiencies in omega-3 fatty acids, especially DHA, likely also contribute to brain vulnerability, in ways previously outlined.
THE DOWNSTREAM EFFECT: FUNCTIONAL DEFICIENCIES IN CRITICAL NUTRIENTS
Zinc
The white matter abnormalities seen in patients with TBI are strikingly similar to those associated with AD.[
Phytate, found in wheat and nuts, binds to and chelates important minerals such as zinc.[
A recent study on the response of mutant forms of the yeast microbe, Saccharomyces cerevisiae, revealed that zinc deficiency activated expression of Tsa1, a “holdase” chaperone that binds to unfolded proteins to prevent them from aggregating.[
Inflammation plays a fundamental role in the pathogenesis of AD, and it is believed to be a powerful pathogenic force. Amyloid-β oligomers and fibrils have been labeled as “danger-associated molecular patterns” (DAMPs), due to their ability to activate a wide array of pattern recognition receptors such as toll-like, (NOD)-like, formyl peptide, Receptor for Advanced Glycation Endproducts (RAGE), and scavenger receptors.[
Magnesium
Magnesium is one of the most abundant ions in the brain, and it plays a major role in the plethora of biochemical and physiological CNS tissue functions, as well as numerous other processes that affect muscle function, including oxygen uptake, energy production, and electrolyte balance. Magnesium is also essential for lysosomal function. Magnesium activates the formation of microtubule-lysosome complexes,[
Studies suggest that strenuous exercise increases urinary and sweat losses, which may increase magnesium requirements by 10-20%.[
In both humans and animals, low magnesium levels alone can trigger inflammation in a number of tissues, including the brain, as well as lowering seizure thresholds. Since glyphosate has been shown experimentally to reduce the magnesium uptake by soy,[
A study of impact-acceleration brain injury in rats confirmed that intracellular free magnesium concentration experienced a sustained decline for several days following injury, along with a significant neurological deficit, suggesting that repeated administration of magnesium may be necessary following brain trauma.[
Omega-3 EFAs
Brain omega-3 EFAs are the most extensively studied fatty acids in the body.[
Studies utilizing rodent models of experimental injury have shown that preinjury dietary supplementation with fish oil effectively reduces posttraumatic elevations in protein oxidation resulting in stabilization of multiple molecular mediators of learning, memory, cellular energy homeostasis, and mitochondrial calcium homeostasis, as well as improving cognitive performance.[
When brain slices from the hippocampus are treated with DHA, but not with EPA, they show remarkably reduced excitotoxicity following AMPA-type glutamate receptor response.[
Vitamin D3, dehydroepiandrosterone sulfate, and immunity
The sunscreen industry in the US has grown on average by 4.2% per year during the past two decades, such that it now represents a $1.3 billion industry. The use of sunscreen reduces the body's natural process of vitamin D synthesis. This lifestyle choice contributes significantly to vitamin D deficiencies, which are problematic, especially when it comes to brain health and resilience. Sunscreen also likely interferes with CS synthesis in the skin, particularly since it typically contains both retinoic acid and aluminum, both of which would interfere with the synthesis of sulfate by eNOS.[
Vitamin D deficiency is endemic in the adolescent, adult, and elderly populations in the US,[
Vitamin D exists in a sulfated form, vitamin D3 sulfate [
A relationship has been proposed between adverse cognitive and behavioral effects and vitamin D deficiency.[
Vitamin D3 modulates the immune response, and vitamin D3 deficiency is associated with increased risk to infection.[
Polyphenols, flavonoids, and mucopolysaccharides: A sulfate connection
Aside from omega-3 fatty acid supplements, a wide range of natural remedies have been used to treat concussion. These include curcumin, resveratrol, vitamin D, green tea, coffee, vitamin C, and vitamin E.[
Polyphenols and flavonoids have become popular supplements due to their alleged benefits to memory and cognition, although studies have thus far failed to explain the underlying physiological mechanism of their supposed benefit.[
Sulfomucopolysaccharide treatment of aging male rats induced reduced dopamine turnover in the nucleus accumbens associated with improvements in learning and memory.[
Conclusion: Sports-related concussion is a modern day problem prompted by diminished brain resilience.
It is quite evident there is an alarming increase of reported concussion in sport (up to 3-fold in some cases) despite confirmed lower levels of participation rates. This surprising juxtaposition is not limited to the world of sports. Neurological disorders are also disproportionately increasing, with neurological deaths increasing almost 2-fold, while total mortality rates have been declining. In short, more of us are getting sick and dying from neurological disorders and injury.
We believe this phenomenon is a manifestation of increased susceptibility to neurological damage, specifically relatively mild brain trauma, such as concussion, with sometimes devastating long-term degenerative damage, as seen with increasing evidence of CTE in athletes after careers of repetitive sub-concussive episodes.
This susceptibly to neurological damage, in turn, is due, both directly and indirectly, to profound and systemic changes in modern life, including but not limited to long-term pesticide and chemical exposure, reduced exposure to natural sunlight, poor omega 3/6 ratio within the diet (particularly, deficiencies in DHA), insufficient dietary sulfur, and over-consumption of processed foods. We propose that one of the most troubling contributions, which in our opinion is a major catalyst of the altered physiology in humans, is the explosive increase in glyphosate exposure. Glyphosate was first introduced in the US in 1974, and its usage has steadily escalated in the intervening years. We believe that this cumulative exposure results in a systemic depletion in sulfate supplies to the neural tissues, leaving them especially vulnerable to jostling through sudden impact, on account of insufficient water structuring in the CSF. Furthermore, sulfate depletion impairs two important repair mechanisms following injury, neuronal repair through neurite outgrowth and lysosomal recycling of cellular debris.
In this article, we have described a perfect storm of events such as immunoexcitotoxicity, excitotoxicity, and neuroinflammation, and have argued that these are due to exposure to subtoxic substances such as aluminum and LPS that turn fully neurotoxic and neuro-damaging in the presence of a heightened excitatory immune response. This perfect storm of events results in a profoundly reduced bioavailability of neurocritical nutrients such that the normal processes of homeostatic balance and resilience are no longer functional, as summarized in
SEQUELAE OF AN ALTERED FOOD SUPPLY: PESTICIDE EXPOSURE AND INCREASED CONSUMPTION OF PROCESSED FOODS
We propose that the following factors are all implicated as sequelae to DBR syndrome prompted mainly by modern day levels of environmental toxicant exposure, nutrient functional deficiencies, poor gut health, improper balance of omega 3:6 EFAs, and reduced exposure to natural sunlight.
Microglia activation
It is well supported that exposure to pesticides, herbicides, and fungicides activates microglia, shifting the microglia from a resting (ramified) state to an intermediate (primed) state.[
Interference with the normal switching to the quiescent (ramified) phenotype (the resting state)
Research shows that pesticides interfere with the mechanism that normally switches off the microglia activation when the danger has passed.[
Disruption of gut flora, leading to gut dysbiosis
Gut dysbiosis both disrupts the bioavailability of important nutrients and produces toxic by-products such as LPS and toxic phenols.[
Increased inflammation and oxidative stress Activation of microglia (prompted by presence of LPS) Hippocampus and amygdala damage Reduced levels of serotonin, dopamine, 5-hydroxytryptamine (5-HTP), melanin, and norepinephrine Damage to mitochondria (through oxidative stress) Decreased absorption of zinc Decreased GSH Decreased ability to detoxify toxins via the liver by destruction of CYP enzymes.
Nutrient functional deficiencies
Magnesium deficiencies linked to increased TNF-α, which triggers the process of calcium dysregulation at the synapses and is instrumental in excitotoxicity Deficiencies in omega-3 fatty acids, especially DHA Deficiencies in critical nutrients including, but not limited to sulfur, zinc, magnesium, and cobalamin.
Disruption of sulfate supply to the brain
Interference with synthesis of CS due to its dependence on CYP enzymes Disruption of synthesis of aromatic amino acids by plants and by gut bacteria, reducing the bioavailability of the derivative neurotransmitters and hormones that transport sulfate Promotion of aluminum toxicity from dietary sources leading to liver impairment Interference with transport of free sulfate in the serum due to competitive inhibition by glyphosate, contributing to high blood viscosity.
In
CONCLUSION
In summary, we have brought to light a compelling juxtaposition of decreasing participation in the top five OTSs and overall mortality rates, in sharp contrast to increasing rates and incidence of brain injury, specifically SRC, as well as neurological illness and death. This juxtaposition suggests that a more pervasive cause is at play.
Considering the known physiological changes that modern life effects on the human body, and the corresponding increase in neurological injury, illness, and deaths, we suggest that systemic and cumulative exposure to the environmental toxicant, glyphosate, compounded by other lifestyle and dietary changes, is a prominent catalyst of a modern day neurological syndrome, DBR syndrome, currently being manifested in a new type of SRC, PCS, CTE, and other neurological disorders than we have seen historically.
With glyphosate now being detected in our water and air supply, in addition to our food supply and human urine samples, fully eliminating toxic exposure is improbable, thus leading to a state of constant hypersensitivity or susceptibility to mild brain trauma. It is unclear if the physiological damage already caused by glyphosate exposure is reversible, so interventions should be focused on minimizing the damage, prophylactically.
Finally, while a number of recent papers describe promising positive effects of natural nutritional compounds as neuro-protective, translating those promising benefits from preclinical studies to real life has been limited. We argue that simple supplementation may not be enough to achieve the desired benefit if patients are functionally unable to absorb or utilize the supplemented nutrient. More studies are required to determine the optimal levels of nutrients required to maintain neurological resilience in response to SRC and the role that functional deficiencies play in susceptibility to and severity of concussion. Secondary to that, further studies are required to test the effectiveness of various nutritional and lifestyle interventions designed to offset the impact of modern day life on brain resilience, specifically, minimizing glyphosate exposure and its sequelae through the adoption of organic non-GMO foods, improvement of gut health through probiotics, increased consumption of omega-3 fatty acids, especially DHA, dietary enrichment in micronutrients, particularly minerals involved in brain resilience, such as sulfur, zinc, and magnesium, and increased exposure to sunlight.
ACKNOWLEDGMENTS
This work was funded in part by Quanta Computers, Taipei, Taiwan, under the auspices of the Qmulus Project.
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