Abstract
Autism Spectrum Disorders (ASD) encompass a range of neurodevelopmental conditions defined by behavioral criteria, which provide no insight into the underlying pathophysiology linking vaccines and infections to observed pathological changes. For a considerable time, the debate was between the use of the vaccine schedule recommended by the Centers for Disease Control and Prevention (CDC) and the onset of ASD within a group of young people. Thus far, the opponents’ main argument is that there exists no connecting mechanism between the vaccines as used and the onset of ASD. However, the CDC has not done studies looking at the CDC schedule in aggregate or comparing populations of unvaccinated to vaccinated children for the prevalence of autism. In this paper, I offer a well-demonstrated mechanism that would explain why a subset of children develop autism after vaccines.
It becomes evident, based on this hypothesis, that any adjuvant or condition boosting immune activation of certain cells, such as Central Nervous System (CNS) microglia and macrophages, if sequentially activated by the vaccination process, whatever the adjuvant or immune stimulation principle, will trigger this mechanism, not only in the CNS, but possibly other peripheral organs and tissues containing glutamate receptors. I coined the term βimmunoexcitotoxicity,β which describes the interplay between immune activation and excitotoxic neuronal injury, building on prior discoveries of the underlying mechanisms.
Introduction
The Rising ASD Rates and Potential Environmental Factors
We have seen exponential growth in ASD over the last 30 years, with the number reaching the millions in the United States [1]. What is rarely appreciated is that many of these children, in many cases, require ongoing care and supervision from their parents. Unfortunately, as the parents age and eventually die, these children are left to fend for themselves. There are no government programs for their care, and the medication and medical care they require are often expensive. Many such individuals may face such hardships without adequate support systems in place.
The current vaccine schedule prioritizes industry interests over rigorous scientific evaluation and individualized medical care. In the case of the Gardasil vaccine, for example, we know that the safety study was flawed: the adjuvant (now aluminum) was used as a placebo [2]. Many other vaccines on the childhood vaccine schedule (mandated for public school attendance) have very little evidence of efficacy and persistence of protection [3].
Many of the diseases that are justifications for the present vaccine schedule for children are for minor illnesses and several self-limiting diseases, such as hepatitis B and human papillomavirus (HPV) infection. In many cases, there is no evidence that the mother is either hepatitis B positive or a high-risk person. Hepatitis B vaccine is recommended for all newborns in the United States, even if the mother is hepatitis B negative, and thus the baby is not at risk in infancy. Some preventable diseases can be effectively treated through good nutrition, personal hygiene, and certain supplements.
I wrote a three-part article linking the mercury in vaccines to many of the changes we were seeing pathologically as well as clinically in the autistic brain; part 2 explains the connection between mercury and ASD [4-6].
Then, regulatory agencies, responding to growing public and scientific concern, oversaw the phase-out of mercury in most vaccines. The rate of the disorder continued to rise. Prior to the removal of mercury from vaccines, I proposed that ASD rates would likely continue rising due to aluminum adjuvants [7] βa hypothesis later supported by subsequent research. As new research by Exley, Shaw, Lyons-Weiler, and others emerged, my claim proved to be correct, and now most attention from autism researchers is focused on the aluminum used in vaccines as an adjuvant [8-11]. Yet, the actual mechanism linking vaccines to the maldevelopment and abnormal physiology of the brain continues to be mostly overlooked or ignored by many, except for Dr. James Lyons-Weiler.
Mercury, Autoimmunity, and Emerging Concerns
The idea of converting all vaccines to the mRNA model is, in my opinion, and the opinion of many other experts in this field, destined to lead to a world disaster. Should one be required to take three injections or more of the COVID-19 mRNA βvaccines,β immune activation will be severely suppressed, possibly resulting in alterations in neural development later in the process [12-17]. We know that neural development continues until approximately adulthood [14,18-20]. This means that certain areas of the brain will be affected even when getting vaccines later in life. I predict we will see a dramatic increase in ASDs, as well as many known neurodegenerative disorders, and some that we have never seen before. Emerging reports suggest a possible increase in prion-like neurodegenerative presentations following COVID-19 vaccination, though causality remains under investigation [21,22]. These vaccine-related prion diseases are different than the naturally occurring form in that they reportedly kill the person within days to weeks following the injection rather than the normal course. Normally, it would take years, even a decade, to develop neurodegeneration following exposure.
Studies comparing chronic health conditions in vaccinated children to those in unvaccinated children clearly demonstrate a difference in many such chronic conditions [23-25]. While these studies were focused on extracranial, non-neurological developmental diseases, they indicate a pathophysiological effect with full vaccination. Our study also found a dose-response relationship, which suggests a priming effect [23].
One of the main charges, levied by those claiming no connection between the vaccination process and the development of autism spectrum disorders, is a lack of a demonstrable mechanism linking ASD to the vaccination process early in life. In this paper, I hope to demonstrate such a mechanism, which also explains several observations seen in cases of ASD, such as why ASD cases are more common in males. The mechanism has been well documented in a number of other studies not connected to autism spectrum disorders.
The immunological changes seen with ASD have been well characterized in other studies and discussions [26,27]. Very little literature has been directed at excitotoxicity or glutamate as a contributing factor to the pathophysiology of autism [1,26-29].
Immunoexcitotoxicity as the missing link.
While most of the attention directed at mercury was proposed early on, despite compelling scientific evidence of a link to an interference with and toxicity to the developing brain by aluminum, the actual link to vaccines was missed β immunoexcitotoxicity [4,5,9,11,30]. The adjuvants, such as aluminum, and mercury, have their effects by not only activating immunity in the body and brain but also by their innate toxicity and the fact that, in the case of aluminum adjuvants, we see direct activation of the immune system (microglia and astrocytes) within the CNS on a continuous basis and for a protracted period [7-10]. The mercury in vaccines has several effects on neurons and glia [4-6].
Others, not entirely separate from the mercury link, made the case for vaccine-induced autoimmunity as a cause [26,27]. Once again, while there was some convincing scientific evidence, there were some flaws. For example, while autoimmunity was not always found, it can be linked to excitotoxicity as a most destructive element [31]. Yet, given that both mercury and aluminum can induce autoimmunity, it is possible that, in some cases, vaccine-induced autoimmunity plays a role alongside excitotoxicity as a destructive mechanism. Recently, it was proposed that fluoride exposure may be responsible for some cases of ASD. It is known that fluoride activates the brainβs microglia [32,33]. This would act like an infection or the first vaccine injection. Fluoride is also tightly bound to aluminum (fluoroaluminum), which is deposited in the brain and has many effects on brain biochemistry and physiology [33].
Acetaminophen is another suspect in cases of ASD [34]. While no single “autism gene” has been identified despite extensive research, over 100 genes have been implicated, influencing multiple biological pathways, including those involved in neurodevelopment, synaptic function, and immune regulation. In addition to genetic factors, environmental influences play a critical role in ASD risk. The link between acetaminophen and ASD may be related to per- and polyfluoroalkyl substances (PFAS), which have been shown to disrupt the gut-liver-brain axis. Acetaminophen, known to exert hepatotoxic effects, could further impair this pathway, potentially exacerbating ASD symptoms or even triggering ASD in genetically susceptible individuals [34,35]. Other environmental contributors, such as prenatal exposures, maternal immune activation, and oxidative stress, have also been proposed as factors in ASD development.
An increase or decrease in the activation of microglia/astrocytes alters neurodevelopment [8,12,36-42]. The main effect of IL-1Γ and TNF-a is the inhibition of glutamate transport into the glia, allowing an extraneuronal buildup of glutamate, thus increasing calcium waves and abnormal migration of axons and neurons. As the number of environmental toxicants grows, such as the extensive use of glyphosate-containing compounds, we can expect to see increased rates of neurodegenerative and neurodevelopmental diseases. However, the effects of these compounds on neurodevelopment and oxidative stress remain unknown, and they have been proposed as potential factors in ASD development [43,44].
Excitotoxicity and Neurodevelopment
Excitotoxicity (Immunoexcitotoxicity)
Dr. John Olney discovered excitotoxicity in 1969 [45]. I knew Dr. Olney and visited his lab in the 1980s. Since his discovery, a whole array of new receptors and the physiology and pathophysiology of these glutamate receptors have been discovered. I suggested a link to the ASD and Attention-Deficit/Hyperactivity Disorder (ADHD) in a book I wrote in 1990 [46]. Initially, I suspected excitotoxicity contributed to autism spectrum disorders. My research into chronic traumatic encephalopathy (CTE) revealed a critical link between immune activation and excitotoxicity, leading me to identify immunoexcitotoxicity as a central mechanism in ASD. I called this link between the two systems immunoexcitotoxicity. Although I coined the term, I did not make the initial link. Furthermore, I discovered a link between the adjuvants commonly used in vaccines, such as aluminum, and excitotoxicity [4-6,47].
How Immune Activation Triggers Excitotoxicity
Immunoexcitotoxicity Answers Many Questions
Not Answered by Other Mechanisms: Immunoexcitotoxicity During Neurodevelopment
Stimulating the immune system peripherally, especially repeatedly, will trigger brain excitotoxicity by a process of immunoexcitotoxicity. To understand excitotoxicity, one must understand glutamate receptor physiology, which is quite complex. In the newborn or small child, one must understand the effect of both pro-inflammatory cytokines and excitotoxins on neurodevelopment through their reaction with microglia. While microglia and astrocytes normally provide support to the neurons during brain development, in the face of inflammation, these cells are switched to a destructive mode [47]. Many physicians, including pediatricians and obstetricians, lack this understanding.
Stimulating the systemic immune system (as with the flu, otitis media, or a series of vaccinations) will activate the microglia and astrocytes in the CNS, especially within the brain. This connection is made via pro-inflammatory cytokines traversing the blood-brain barrier, cytokine passage through the circumventricular organs (which contain only a partial barrier), and the cranial nerves connecting directly to the CNS (vagus and trigeminal nerves) [33,47-50]. During early birth, the blood-brain barrier (BBB) is immature and can allow the passage of toxic molecules and inflammatory cytokines, chemokines. The activation of the CNS glia is rather rapid (minutes) and can explain the shrill encephalopathic cry and sudden seizures sometimes seen in some children after vaccination, especially babies. It is not the pain of the injection, but an immune excitotoxic reaction affecting the brain. The COVID injection will be worse in many ways, as the spike protein is deposited throughout the vascular system (endothelium), other organs, and the CNS. It will act as an intense, continuous source of immune activation in microglia and astrocytes, resulting in immunoexcitotoxicity [17,18].
Impact on Neurodevelopment
Microglia, often referred to as the brain’s resident immune cells, play a nurturing and supportive role during normal brain development by maintaining homeostasis and promoting neural growth [38,40,41,51-53]. Within the CNS, microglia are the main resident immune cells. Yet, macrophages can enter the brain and act like resident microglia. Except for special staining, these cells cannot be distinguished from resident microglia. Microglia can also migrate within the brain to sites of activation. While microglia primarily support and balance brain cell function, they can switch to a pro-inflammatory, destructive mode under certain conditions, such as infection or immune activation. With immune stimulation, brain microglia and astrocytes become activated, releasing high levels of both inflammatory cytokines and chemokines, as well as several excitotoxins (Figure 1). As these excitotoxins reach a certain level, they will kill surrounding neurons. Glial cells are mostly protected from their own secreted excitotoxins.
Glutamate Receptors and Excitotoxicity
Excitotoxins trigger multiple destructive reactions, particularly by generating reactive oxygen species, which not only damage neurons, dendrites, and axons but also impair the glutamate reuptake proteins, resulting in increased extraneuronal glutamate (Figure 2). New evidence has shown that glutamate plays a crucial role in the development of the nervous system, and disruptions to glutamate can lead to neurodegeneration and neurodevelopmental alterations [28,54-60]. Appropriate levels of glutamate are necessary for normal alertness and cognition, highlighting its essential role in brain function. Several alterations in biochemistry occur in conjunction with the neurodegenerative effects of excitotoxicity, in addition to the direct destructive effects of glutamate, particularly on neurodevelopment [7,15,38,57,60,61].
Glutamate receptors are divided into basic and metabotropic glutamate receptors (Figure 3) [3,15,19,54,62]. The reason for the complexity is that these receptors elicit a wide range of reactions, utilizing a single neurotransmitter, glutamate. There are three basic types of glutamate receptors, named by the substance used to stimulate themβNMDA receptors, AMPA receptors, and Kainate receptors [15,46-48]. They all react to glutamate, but at different concentrations. Each is made of a series of subtype components, four in number. We know the most about NMDA receptors. All NMDA receptors contain the GluR1 component.
Figure 1.
Microglia switch from a ramified (resting) to an activated state with the release of neurotoxic levels of glutamate.
Figure 2.
Production of lipid peroxidation products and reactive oxygen species during excitotoxicity. It is these destructive elements that trigger excitotoxicity.
Figure 3.
Typical neural synapse with membrane glutamate receptors: NMDAR, AMPAR, and the Kainate Receptor. Illustration of cell signaling linked to the receptors linking glutamate to immune signaling, such as TNFR1, a destructive receptor. It also demonstrates the trafficking of AMPA calcium transport to the synaptic plate.
Fast transmission is by AMPA receptors. Normally, the AMPA receptor contains a GluR2 type of subunit that prevents calcium entry through this receptor. If the GluR2 subunit is absent, the AMPA receptor acts similarly to the NMDA receptor in transferring calcium and can be highly destructive (Figure 3). Normally, in the hippocampus, AMPA GluR2-lacking receptors operate to a limited extent, assisting in memory and learning [18,58,63,64]. When pathologically activated, this receptor can be very destructive [38,65-68].
The human brain cortex contains the highest levels of glutamate and its receptors in the entire CNS. In fact, the most abundant neurotransmitter in the cortex is glutamate [15,46,61]. For a healthy and functional brain, glutamate must be inside the neuron. Outside, it is very destructive and can alter neurodevelopment. Also, remember that the glutamate transport proteins, Excitatory Amino Acid Transporters (EAATs), constantly keep the glutamate inside the glia and neurons at safe, noninterfering concentrations. If the brain is inflamed, this system will be disrupted, resulting in high, destructive levels of glutamate in the nervous system. High levels of inflammation, or even low levels chronically, will also cause the release of high levels of another excitotoxin β quinolinic acid (QUIN) [69-71]. In essence, this process involves releasing or generating three excitotoxins: glutamate, QUIN, and aspartic acid.
With immunoexcitotoxicity, we see that certain proinflammatory cytokines, such as TNF-Ξ±, can biochemically and physiologically change the sensitivity of these receptors and lead to enhanced excitotoxicity [47,67]. For example, TNF-Ξ± at higher levels can react with the TNFR1 receptor, thereby enhancing the destructive nature of glutamate by several mechanisms, such as enhancing glutaminase, which converts glutamine into glutamate, and suppressing glutamine synthase, which converts glutamate into harmless glutamine. TNF-Ξ± can also affect subunit trafficking, such as increasing the trafficking of GluR2 lacking AMPA receptors to the synaptic plate and moving the inhibitory GABA receptors into the cell’s interior. This shifts the brain into an excitatory mode (Figure 4).
Figure 4.
Illustration demonstrating the effect of TNF-Ξ± on excitatory neuron neurophysiology.
Microglial and Astrocyte Control of ExtraNeuronal Glutamate Concentrations
Control of extraneuronal levels of glutamate is crucial in both neurological disease states (neurodegeneration) and neurodevelopment [53]. Intraneuronal glutamate is harmless, whereas in the extraneuronal space, high levels can result in neurodegeneration and/or abnormal neurodevelopment (Figure 4). Control of the levels is mainly performed by EAATs [13,55,56,62,72-74]. In nonhuman primates, these are referred to by a different nomenclature, with GLT-1 (EAAT-2 in humans) being the most common transporter found in the brain, and GLAST (EAAT-1 in humans) the second most commonly found. The microglia and astrocytes very carefully control the extraneuronal to intraneuronal glutamate ratio. Normally, glutamate is the most commonly found neurotransmitter in the brains of both non-human primates and humans [15,46,54]. It has been shown that free radicals, IL-1Γ, and TNF-alpha prevent this system from functioning properly [47].
In some instances, glutamate transport is reversed towards the outside of the microglia and astrocyte into the extraneuronal space [48,74]. This can occur with inflammation in the CNS. Excitotoxicity, through the production of free radicals and increased inflammatory cytokine generation, also interferes with this transport.
Elevation of extraneuronal glutamate can occur by different mechanisms, such as the glutamine/glutamate antiporter, Xc, which depends on a functional EAATs system to prevent extraneuronal accumulation of glutamate [47,75]. These transport proteins play a major role in neurodevelopment by preventing higher levels of glutamate from interfering with the progression of neuronal migration and differentiation, both of which have been demonstrated in individuals with autism [28,56,76].
The microglia are activated in cases of living autism patients, as shown by Suzuki and co-workers using a microglial activation scanning technique, 11c-PK11195 [37]. Increased binding was seen in the cerebellum, midbrain, pons, fusiform gyri, anterior cingulate, orbitofrontal cortex, corpus callosum, midfrontal cortical areas, superior temporal cortex, and orbitofrontal cortices. Most prominently affected was the cerebellum. With intense immune activation, as occurs with the childhood vaccine schedule, we can expect the release of proinflammatory cytokines and glutamate, along with widespread microglial activation.
Microglial Activation and Priming
Baseline Microglial Function in Normal Development
Brain Development and Cytokines and Excitotoxins
Stress accelerates the colonization of microglia in the postnatal brain [29,77]. In addition, the timing of the switch from a resting (ramified) to an activated (ameboid) state profoundly affects neurodevelopment. As we shall see, this is important because variations in microglial activation contribute to neurodevelopmental differences between males and females.
Microglia are known to be involved in all aspects of neurodevelopment, including synaptogenesis, neuron elimination (pruning), angiogenesis, migration, proliferation, differentiation, migration of progenitor cells, and synaptic refinement [16,36,38,41,42,57,76-78]. The release of chemokines, cytokines, and excitotoxins from these cells plays a vital role in the ultimate architectonic development of the brain, its physiology, and biochemistry. Glutamate uptake proteins are negatively affected by inflammatory cytokines and free radicals. Tumor necrosis factor-alpha and IL-1Γ are the most involved proinflammatory cytokines in impaired glutamate transport. Free radicals also impair these transport proteins.
Microglia are not derived from macrophages/monocytes during development but are produced within the brain, except for the cerebellum and retina [40,79]. From embryonic day 12 onward, increasing numbers of microglia are found throughout the developing cortex. The densest population of microglia is seen in the two most proliferative zones of the developing brain: the ventricular zone (VZ) and the subventricular zone (SVZ) [2,19,20]. Activation of microglia in these zones, as occurs with mass vaccination administered closely together, would be expected to affect neuron development in these areas negatively [1,5,33,37,61,80].
During early brain development, a specialized glial scaffolding network, derived from astrocytic cells, is formed, known as the radial glial cell network [28,51,81,82]. The progenitor cells for both the glia and neurons migrate along this radial glial network to form the multilayer cortical cell layer. Microglia, with their pulsed release of glutamate, play a major role in this process. These microglia are derived from mesodermal cells (macrophage population) progenitors at approximately 4.5 weeks of gestation in the human brain, during the development of blood circulation [19,20,41,60,83-85]. These macrophage progenitors enter via the meninges and choroid plexus, then travel to the germinal zones to form the functional zones of the brain. Factors controlling this process include cytokines, chemokines, as well as morphogens, growth factors, and glutamate released from microglia [33,40,55,58,59,76,82,86,87]. The microglia use axons, perivascular sheaths, and radial glia cells as a migratory scaffold. It is during this period of migration that the six-layered cortex eventually forms. In autism, this period of migration and cortical formation is often disrupted by alterations in microglial function, leading to atypical cortical development and neurodevelopmental abnormalities.
Disruption of the column architecture and connectivity of the columns appears to be characteristic of autism spectrum disorders. Damarla demonstrated this disconnection by examining high-functioning autistics using a combination of behavioral testing, functional MRIs, and measures of functional connectivity between the higher-order working memory executive area and visuospatial regions, as well as between frontal and parietal-occipital regions [88]. Others demonstrated functional connectivity defects between the anterior and posterior insula, as well as between these regions and brain areas involved in emotional and sensory processing [89].
Using DTI imaging (Diffusion Tensor Imaging), researchers described significant abnormalities in the white matter development of the cingulum bundle among 21 adolescents with ASD compared to healthy controls [13]. They also found that measures of tract malformation within the cingulum bundle had a worse prognosis.
A recent study found that synaptogenesis and synaptic pruning follow a programmed timeline specific for each area of the developing brain [90]. Synaptic pruning begins to decline at puberty and is complete within the prefrontal cortex during adolescence. Elimination of synapses in the CNS continues well into the third decade [12,28,33,36,38,41-43,52,58].
During neurodevelopment, glutamate receptors, as well as microglia and astrocytes, play a special role in every aspect of brain development. Astrocytes are the primary depository of glutamate, and microglia contain a significant amount of glutamate, which is released in response to inflammatory stimulation. As the NMDA receptors control intracellular calcium and are located on the growth cones used to guide neural connections, these receptors are implicated in regulating neural migration, which is crucial for proper neurodevelopment [15,28,53,56,60,81,82].
NMDA receptors generate calcium waves that control the migration of these connections and neurons [58]. Secreted glutamate controls calcium waves. Glutamate gradients, ultimately responsible for these neuronal and axonal migrations, are being altered by systemic vaccination during the childhood vaccination process via immunoexcitotoxicity. Variations in the oscillation of calcium waves by NMDA receptors on the growth cones will alter this migration [82,85]. High levels of glutamate can increase migration, and low levels reduce it by controlling these calcium waves [87,91]. As with vaccination, immune stimulation can activate CNS microglia and astrocytes, which alters glutamate levels in the CNS [4,5,10,47].
Microglia and Neuronal Migration in Different Areas of the Brain
Microglia colonize the developing brain at significantly different rates [37,38,42,62,79,82]. For example, in rats, and most likely humans, the first areas to be populated include the hippocampus, the amygdala, and the cortex. Immune stimulation switching of the microglia also significantly affects brain maturation and development [14,37].
In the adult brain, the microglia are heterogeneously distributed, with the highest concentrations in the substantia nigra and second, in the hippocampus. In addition, microglia can migrate to areas of inflammation or invasion, as well as during development [71,77]. These microglial cells are located throughout the entire central nervous system.
It should be appreciated that in addition to cytokines, growth factors, and glutamate, microglia also release other excitotoxins, such as QUIN. Under normal conditions, the kynurenine pathway releases mostly neuroprotective compounds, but in the face of inflammation, it switches to the production of the excitotoxin QUIN, which stimulates the NMDA glutamate receptor [69,70,71]. So, we see a number of excitotoxins, such as glutamate, aspartic acid, and QUIN, being released from activated microglia in the CNS under conditions of immune stimulation. Childhood vaccines could be such a stimulus even at the periphery of the body [50,80].
The activation of NMDA receptors on the growth cones is not only responsible for neuron and axon movement but also determines neurite outgrowth, motility, axon turning, and Rho GTPases, which are all responsible for the brainβs eventual architecture. Therefore, we can see that the level and timing of glutamate pulses, as well as other immune excitotoxic factors, play a crucial role in brain development. The calcium gradients produced by the glutamate also play a major role in neuron proliferation, dendrite formation and extension, and growth cone function.
Within the intermediate germinal zone, a site of precursor cell proliferation, and the cortical plate, where neuronal differentiation occurs, further changes in brain maturation become apparent. The neurons express fully functional receptors. There is evidence that NMDA receptors appear in neurons of the cortical plate soon after they migrate from the ventricular zone (VZ) with fully functional receptors [38,53].
Why are Males Affected More Often?
Synaptic pruning is critical as neurodevelopment progresses because more synaptic connections are generated during development than are needed in the final cerebral and cerebellar architecture [35]. This process is influenced by microglial activity, which varies between males and females. Males have a significantly greater number of microglia early after birth (P4-postnatal day 4) than females in regions of the brain concerned with cognition, learning, and memory (hippocampus, amygdala, and parietal lobe) [33,44]. It has also been shown that with a rise in testosterone in males, a dramatic increase in microglia in their brain occurs around E18 (embryonic day 18). This is a possible mechanism that could contribute to the early onset of neurological disorders such as dyslexia, ASD, and ADHD in males.
Ironically, females have been shown to have more microglia than biological males, but this occurs much later during development, specifically between postnatal days 30 and 60. It was also demonstrated that most microglia in males at day P4 exhibited an activated morphology. In contrast, even at P30-P60, the females were more likely to have ramified (resting) microglia. The secretion of chemokines and cytokines has also been shown to be sex-related [33,43,44,92,93]. This indicates drastic differences in susceptibility to induced ASD among biological males and females, based on the timing and activation of microglia in males and females.
Another enigma is the link between ASD and mitochondrial dysfunction. It is known that many children have borderline mitochondrial function and that in one instance, a young girl developed autism after getting the childhood vaccine series. She was known to have a mitochondrial defect. It has been shown that even normal levels of glutamate can become excitotoxic when energy levels are deficient [94,95].
Mitochondrial disorders are known to be more common in males, making them more susceptible to immunoexcitotoxicity, especially at a young age [96].
Vaccine-Induced Microglial Priming
As with other immune cells, such as macrophages, microglia normally exist in a resting state. Once stimulated, enzymes responsible for producing pro-inflammatory cytokines are up-regulated, but the actual proteins are not released. If the immune system is activated subsequently, even several weeks to a month later, these primed microglia will release proinflammatory products at a rate about three times higher than normal. Once the primed microglia and astrocytes, including intracranial macrophages and mast cells, are activated and begin to release high levels of excitotoxins and proinflammatory cytokines, alterations in neurodevelopment and neurophysiology become apparent. One of the common observations made by observant parents is that often the child destined to develop ASD following vaccination is either systemically ill or has a localized infection, most often an ear infection, at the time the series of injections begins. The infection represents the first episode of immune stimulation (Figure 5). The microglial activation will do more than release proinflammatory cytokines and chemokines. They will also release high levels of excitotoxins, especially glutamate and QUIN (Figure 5) [41,47,68,71,78,97].
Figure 5.
Priming of immune cells, including microglia. Note that vaccination is not the only priming event- systemic infections, such as a sore throat or otitis media, also act as priming events for the CNS microglia [94]. In addition, head trauma, subsequent systemic infections, and even minor surgery are known to act as priming events for these immune cells [30].
As we shall see, this priming effect within the CNS will have a detrimental effect on neurodevelopment. The cytokines are elevated, as are the levels of released glutamate and other excitotoxic molecules, such as aspartate and QUIN. In an article by Wilcox and Jones, the question of the effects of vaccinating a pregnant woman is discussed [87]. It has been shown that a mother can have an infection without a fetal infection, which can alter the childβs immune system, initiating priming. In addition to this, extensive research by Ashwood and Van de Water on maternal immune activation during pregnancy has demonstrated that alterations in the immune system during pregnancy can significantly impact the fetus, potentially leading to neurodevelopmental disorders, including autism [26,27]. Their work highlights the critical role of maternal immune responses in influencing offspring’s brain development, further supporting the notion that immune activation in utero may contribute to developmental abnormalities. It could also elevate glutamate levels and trigger immunoexcitotoxicity, resulting in subsequent abnormal fetal development. The possibility of immune priming of the infant by vaccinating the woman during pregnancy was entertained. This would represent the 1st priming event.
Consequences of Repeated Immune Stimulation
After birth, subsequent vaccinations would further prime the childβs microglia and macrophages. As we shall see, this holds the potential to alter post-birth neurodevelopment significantly. One must also consider the sick child or the child with a preexisting active infection being vaccinated. Several pediatricians told me, as well as a number of mothers, that after the child developed autism, the parents were told by the doctor or the doctorβs nurse that βwe frequently vaccinate such infected children.β It is often overlooked and unknown to pediatricians that the infection serves as a priming event, activating brain microglia and macrophages, and that this can significantly alter brain development during the critical period of neurodevelopment.
The nurse then injects the child with a series of injections, such as DTaP, MMR, or now the COVID-19 injections. Often, the child will receive 7 to 9 injections on a single office visit. That represents a very large dose of immune adjuvants. Overall, these infants and children will receive more than 65 injections. We must acknowledge that this represents a substantial immune load and a very high dose of aluminum.
Some researchers appreciate the negative effects of pathogenic priming but attribute the link to ASDs to autoimmunity [26,27]. I am convinced that the evidence indicates that the major damage of autoimmunity is excitotoxic [28,67]. This is not to say that immune cytokines and chemokines do not affect neurodevelopment and neural physiology, because the evidence also suggests they play a significant, albeit not major, role.
One of the key events in the process of immunoexcitotoxicity is the physiological process of priming. When the immune system is stimulated to a moderate extent, the released proinflammatory cytokines stimulate the microglia, leading to an upregulation of enzymes that augment the immune and excitotoxic reactions. Yet, the immune products and excitotoxins are not released at that moment.
Subsequent injections, especially when spaced closely together, activate the brainβs microglia and astrocytes. When fully activated, they release high levels of pro-inflammatory cytokines and excitotoxins, including glutamate, aspartate, and QUIN. At this stage, immunoexcitotoxicity occurs, significantly interfering with neurodevelopment through direct effects on both brain development and neurodegeneration.
Disrupted Pruning and Learning
Dendritic development begins early, with cortical neurons developing dendrites during the first two trimesters of gestation [19,20,33,41,49,83]. The earliest formation of dendrites begins in the subplate and deeper cortical layers, and accelerates from the third trimester, remaining high until the first postnatal year. This gives a broad period of vulnerability during which vaccination may interfere with brain development. In the human neocortex, dendritic development and molding are most active during infancy and early childhood [12]. This is when the childhood vaccine schedule begins and continues.
Cerebellar Development in Autism Spectrum Disorders: Microglial Activation in the Cerebellum in Autism Spectrum Disorders Neurodevelopment and the Microglia
Vargus and co-workers found that the cerebellum is the most heavily affected part of the brain among people diagnosed with autism, found at autopsy [60]. In fact, there was an almost complete absence of Purkinje cells in the cerebellum. Interestingly, the cerebellum has many non-motor functions, including memory, language, emotional elaboration, reward, and other higher brain functions [24,42,92,98-102].
Once the primed microglia and astrocytes, including intracranial macrophages and mast cells, are activated and begin to release high levels of excitotoxins and pro-inflammatory cytokines, alterations in neurodevelopment and neurophysiology become apparent. It has been shown within the cerebellum that GluA2 receptors, an AMPAR subunit that reduces Ca2+ influx, which is required for normal development of Purkinje cell dendrites, were defective [99]. It was also shown that excess Ca2+ inhibited dendrite formation and maturation, which would occur with either GluA2βlacking AMPAR insertion and/or overactivity of NMDARs. Increased trafficking of GluA2βlacking AMPARs (Ca2+ permeable) occurs with inflammation, which is common in the brain in autism (Figure 3) [5,58,65,66,78].
This effect of altered immunoexcitotoxicity and microglial/astrocyte activation was observed across different age groups of ASD patients, including both younger individuals and those up to 40 years old [96]. Notably, microglial activationβinitiating immunoexcitotoxicityβwas evident early in development and persisted into adulthood. In the cerebrum, microglia play a crucial role in various aspects of brain development, which also extends to the cerebellum [94]. Similarly, calcium oscillation induced by glutamate pulsation is fundamental to cerebellar development, just as in the cerebrum [72,89,95,96]. Vargas et al. further noted that the greatest loss of neurons in autism occurs in the cerebellum, with the Purkinje cells being almost entirely absent [103]. During cerebellar development, microglia undergo activation, which, when excessive, can lead to increased glutamate levels in the extracellular space [1,78,99,101]. This excess glutamate may disrupt dendrite formation, contributing to long-term neurodevelopmental dysfunction, which may be influenced by repeated immune activation from multiple childhood vaccinations, with effects that persist into adulthood. In addition to the effects on neurodegeneration and neurodevelopment, we would also expect alterations in brain neurophysiology and biochemistry.
This consideration leaves open the possibility of multiple overlapping pathways contributing to ASD, reinforcing the connection between mass vaccination and ASD based on both clinical observations and research findings [104]. Now that we have a mechanism that links exposure to multiple vaccines, spaced relatively close together, we have the necessary mechanism explaining the findings. This mechanism, immunoexcitotoxicity, logically links these findings to the vaccines.
Conclusion
Neurodevelopment and Vaccine Exposure in Early Life
I have demonstrated in this paper that the nervous system undergoes considerable development during the last trimester of intrauterine life and the first 2 years of post-birth life. Approximately 90% of the brain’s development occurs during this period. During this period, children are exposed to an overwhelming number of vaccine injections, and the most common adjuvant used, aluminum compounds, is not only neurotoxic but also accumulates in the brain over a lifetime. It also acts as a source of neuroinflammation within the brain itself.
The rate of colonization of the brain by microglia also varies with age, with the hippocampus, amygdala, and cortex being the first to be populated by glia. The density of microglia also varies, with the highest density found in the substantia nigra and next in the hippocampus [16,47].
The Role of Microglia and the Impact of Mass Vaccination
The sculpting of the brain is rather intense during this period of mass vaccination. It was noted that microglia not only remove dead cells, but they can also remove living neurons during this period of brain sculpting [39,79,84]. This pruning of the developing brain is carefully regulated and depends significantly on the timing and concentration of glutamate. Stimulation of microglial and astrocytic activation by mass vaccination during this critical period can disrupt this process. Bilbo and Schwartz have demonstrated that activating these glial cells can have long-term consequences for brain function, even into adulthood [43]. This has been completely ignored by those promoting mass vaccination of children during the period of maximum brain growth and maturation.
In fact, with the addition of the COVID βvaccinationβ to the childhood mandatory vaccine schedule, brain development will be at even more risk [90,91]. This is because the spike protein and the nano-lipid carrier are distributed throughout the body, resulting in constant immune activation [17,18,21,95]. We do not know when this will terminate, but itβs known to last for months [14,22].
In addition, many children will receive sequential vaccine doses spaced fairly close together, maximizing the priming phenomenon [68,87,97]. Priming is essential to the process of immunoexcitotoxicity. The live viruses are a special case, as they can provide a continuous source of immune stimulation, as seen with the COVID-19 injections. In addition, it has been demonstrated that certain vaccines, such as the MMR vaccine, can induce colitis, which can continuously activate brain microglia [4,5,6,68,78,80,85,104].
This brings us to the immunoexcitotoxicity reaction, which is intimately linked to the βsickness behaviorβ reaction. Sickness behavior is the clinical manifestation of the interaction between the immune system and the excitatory system [49,50].
Sickness Behavior and Long-Term Neurological Consequences
It was named based on the effects of a systemic reaction to an infection, such as a viral illness, on behavior. A systemic infection, such as the flu, triggers sickness behaviorsβincluding a lack of appetite, lethargy, sleep disturbances, and a tendency to isolate socially. These behaviors are driven by changes in the CNS, particularly the activation of brain glial cells [49,89]. This immune-driven brain response may serve a physiological role by promoting rest and reducing the spread of infection within a group.
These studies demonstrate that peripheral immune stimulation activates brain microglia and astrocytes, resulting not only in the release of brain immune cytokines but also in the release of neurotoxic levels of glutamate and other excitotoxins. The mechanism for the vaccine link to ASD appears to be priming of microglia and eventual release of excitotoxins that alter neurodevelopment and initiate neurodegeneration, a process known as immunoexcitotoxicity.
Implications for Medical Practices and the Need for Further Research
It should be appreciated that 90% of brain development occurs during the last trimester of pregnancy and the first two years of extrauterine life, both of which are now being compromised by the administration of potent immune activators (vaccine adjuvants) in a priming sequence. Pregnant women are encouraged by physicians, who should be aware of the effects on neurodevelopment, to adhere to vaccination schedules, despite neurodevelopment being highly active during this period of pregnancy. These physicians should also know that brain development and maturation continue long after birth, even into early adulthood.
We should no longer hear that the science is settled and that no further studies are needed. Frequently, we hear from major medical institutions that we should no longer consider childhood vaccination schedules as highly suspect, given the evidence that is screaming to be seen. Furthermore, we should acknowledge that a mechanism has been well demonstrated in several neurological diseases, and this can most likely be replicated by systemic vaccination, especially if done sequentially at a time when the brain is undergoing intense neurodevelopment. Additionally, epigenetic effects have been too often overlooked by critics.
Microglial priming has been largely overlooked when these vaccines are administered, thereby replicating the process. If scientists are genuinely interested in ending this epidemic, then appropriate studies must be done. This would include selecting an animal model that mirrors the results in humans, such as non-human primates. These animals should be given equivalent doses of human vaccines, in equal numbers to children, and on a schedule that resembles the childhood vaccine schedule. These vaccines should also contain the same adjuvants used in humans.
Diffusion Tensor imaging (DTI) should also be done to demonstrate fiber changes. Serial CSF and brain glutamate measurements should be taken on a schedule after the vaccine injection, and should include microglial activation imaging performed serially. This should also include the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the brain. These studies should be done over time following the injection.
Finally, a careful anatomical study of the animalsβ brains must be conducted, looking for developmental changes, microglia, astrocyte activation, connectivity, and other pertinent neuroanatomical findings.
Acknowledgments
The author would like to sincerely thank Dr. James Lyons-Weiler, who has been a tremendous supporter in this search for a mechanism resulting in autism spectrum disorders.
I also extend my thanks to Sheri Gagnon, who has been enormously helpful in preparing this paper for final publication.
Finally, I would like to thank Dr. James Ausman, the retired head of the neurosurgery program at UCLA and Henry Ford Hospital, who carefully read the manuscript and made important suggestions. Dr. Ausman has been supportive of me from the beginning.
Funding: None.
Conflicts of Interest: None.
Institutional Review Board Statement: The study did not require ethical approval.
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