Chapter Eight
Connectivity
Chronic inflammation can affect the entire body. For example, because of chronic gastrointestinal inflammation, overall antioxidant defenses may get depleted. This limits the brain’s ability to reduce reactive oxygen species, which increases vulnerability to inflammation.
This is relevant considering that some ASD people have gastrointestinal inflammation and a “variety of immune system abnormalities, which may reflect a system-wide inflammatory response (37).” This wide inflammatory action affects brain function.
Interestingly, researchers also noticed how differences in the timing of inflammation, whether in utero, postnatal, or adulthood, may cause different ASD symptoms found in clinical presentation (37). Inflammation timing probably affects conditions caused by immune system activation differently (37).
Inflammation timing is critical because different health conditions may begin depending on the time that chronic inflammation starts. For example, inflammation in the womb can cause ASD, whereas inflammation happening later in life could lead to attention deficit hyperactivity disorder (ADHD), depression, or anxiety.
As discussed earlier, inflammation can cause the blood-brain-barrier to become more permeable, which allows inflammatory molecules to have more access to the brain. Evolutionarily, more permeability during inflammation likely helped destroy dangerous bacteria and viruses in the brain.
However, now that inflammation is mainly coming from pollution, food, and lifestyle choices, simply increasing inflammation and brain permeability does not stop these problems. Instead, reactive oxygen species generation can be excessive and cause chronic brain inflammation.
Significant contributors to inflammation in the brain are astroglia and microglia, which are both glial cells. These cells function as support cells to neurons. In a military analogy, these glial cells are like logistical support, while neurons are infantry. For infantry to be effective, they require protection and supplies from supporting logistics, such as weapons, ammo, and medical care. Similarly, neurons need glial cells to provide antioxidants, change synapses, insulate neurons from each other, remove dead neurons, and destroy inflammation sources in the brain by releasing reactive oxygen species and inflammatory molecules.
As mentioned, glial cells help form synapses (534). Glial cells stabilize synapses and actively participate in changing synapses (535). This affects the organization of the complex neuron network in the brain and ASD symptoms.
Glial cells can also control cell death (536). Glial cells do so by releasing inflammatory cytokines and reactive oxygen species that damage the neurons (537). Importantly, neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease are associated with activation of glial cells (538).
Another way glial cells affect ASD is brain inflammation. Microglia take part in the important regulation of non-specific inflammation (539). Brain samples from ASD people showed activation of microglia and astroglia. as well as multiple inflammatory molecules (37). Chronic activation of microglia cells may be common in the ASD brain (540).
Pollution and the associated increased toxicity, discussed earlier, affect glial cells. For example, methylmercury increased microglial secretion of inflammatory cytokine IL-6 and reactive oxygen species (541). Other researchers found treatment with a glutathione synthesis inhibitor greatly increased creation of the reactive oxygen species superoxide induced by methylmercury (542). This indicates the importance of glutathione in reactive oxygen species control (542).
Other glial cells are oligodendrocytes and Schwann cells. Oligodendrocytes form the myelin in the central nervous system, whereas Schwann cells create the myelin in the peripheral nervous system. Myelin is like the insulation on a common electrical wire. Without insulation, the electrical signal cannot transmit normally.
Both oligodendrocytes and Schwann cells are susceptible to toxicity (543). Damage to these cells will weaken myelin, critical for nerve communication. Perhaps these cells are purposefully susceptible to limit electrical activity when there is too much inflammation.
Besides increasing inflammation, the glial cells also have anti-inflammatory functions. After the resolution of an inflammatory condition, either through the destruction of pathogens or dysfunctional neurons, then astroglia may release anti-inflammatory cytokines and antioxidant precursors. For example, astroglia supply glutathione precursors to neurons (544). One of the many anti-inflammatory cytokines released by the astroglia is IL-10.
The protective effects of IL-10 associate with suppression of microglial activation and the subsequent inflammation response (545). Interestingly, increased IL-10 activity is one reason for the beneficial health effects of curcumin, a phytochemical in the spice turmeric.
Cell Danger Response
Glial cells also have purinergic receptors that respond to the release of adenosine triphosphate (ATP) outside cells. ATP is kept primarily inside cells, where ATP provides energy for cellular functions. However, ATP leaks outside when cell walls are damaged, such as from an invading pathogen or injury.
Importantly, cells also release ATP when stressed, even when the cell wall remains unbroken (139). A major type of cell stress is too many reactive oxygen species.
An increased amount of ATP outside the cell, also known as extracellular ATP (eATP), is a stress signal that the area needs more help. This help often comes in the form of inflammation. Extra eATP causes purinergic receptors to release various inflammatory molecules (546).
Interestingly, researchers found an association between the removal of eATP and reduced inflammation (547). Also, research saw blocking purinergic signaling is associated with less inflammation (548). Glial cells may inhibit neurons by releasing ATP molecules (549) (550).
Overall, there is a big release of inflammatory molecules and reactive oxygen species because of purinergic activation. Evolutionarily, the design of this release is to stop pathogens and destroy dysfunctional neurons, which are both dangerous to brain health. The continual release of inflammatory molecules by purinergic receptors affects brain function and ASD.
Amazingly, research using a classic animal model of ASD found that antipurinergic therapy corrected all 16 of 16 “multisystem abnormalities that defined the ASD-like phenotype (551).” This included the “correction of the core social deficits and sensorimotor coordination abnormalities” and “prevention of cerebellar Purkinje cell loss (551).”
The research found that cells were entering a defensive survival mode when many inflammatory molecules were present. This defensive survival mode in cells is called the Cell Danger Response (CDR) (139).
The Cell Danger Response is an “evolutionarily conserved metabolic response that protects cells and hosts from harm and is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis (139).” The CDR causes cells to retract from one another, like how most people do not want to socialize when feeling sick.
By retracting cells, the CDR increases permeability to improve the removal of pathogens, dying cells, and cell waste. The survival of healthy nearby cells also improves. The retraction and subsequent worsening of symptoms might appear as a problem. However, in the brain, this method helps preserve the neurons for later reconnection once there is no longer as much cell stress (37).
The CDR affects ASD symptoms by causing the neurons to retract their dendrites, reducing connections between neurons. Reduced connectivity combined with inflammation changing the excitation/inhibition ratio increases many ASD symptoms.
However, the main cause of ASD is inflammation in the womb starting and affecting the CDR, which disrupts the formation of an organized neuron network. In the womb, children are much more vulnerable to inflammation and CDR effects because neurons are beginning to organize into a complex network. Disrupting this organization can cause a disordered neuron network and result in ASD. This disordered network leads to a lack of connectivity, which creates limited pathways between neurons. This increases the likelihood of repetitive behavior and other ASD symptoms.
Often there will also be too much excitation and not enough inhibition because of inflammation and the CDR. This excitation leads to oversensitivity, anxiety, restlessness, and difficulty maintaining focus.
Excitation and Inhibition
Glutamate, an excitatory neurotransmitter, affects brain inflammation. Too much glutamate creates toxic effects by further increasing calcium entry into the cell. A study found a substantial increase of intracellular calcium may shrink dendritic spines and cause eventual collapse (552).
Interestingly, magnesium limits toxic glutamate effects by blocking specific glutamate receptors (553). Magnesium also inhibits the effects of the calcium wave activating the glutamate channel. This magnesium effect is one reason magnesium supplementation often increases relaxation.
There is an association between less glial coverage near synapses and reduced glutamate clearance (554). Since glial cells influence synapse formation, excess glutamate may reduce the number of synapses formed, which affects how well neurons communicate with each other.
Glutamate also helps to destroy neurons with impaired energy metabolism (555). Whereas, neurons with intact electrical activity can limit the amount of damage received (556).
In balance, glutamate performs an essential function by clearing away impaired cells and helping form synaptic connections. However, if glutamate release is excessive, then significant damage to the neuron network occurs.
This is important because glutamate release increases in response to inflammation (557). Researchers found serum levels of glutamate are significantly higher in ASD people versus controls and that glutamate levels correlated to the Autism Diagnostic Interview-Revised (ADI-R) social scores in ASD patients (558). Research also found variations of several other molecules in the glutamate system (559). Reductions in the glutamic acid decarboxylase enzyme, which removes glutamate, may influence the increased glutamate (560). There are also associations between ASD and a higher excitation/inhibition ratio in social, sensory, and emotional systems (561).
Interestingly, D-cycloserine, which antagonizes various glutamate receptors, improved some ASD symptoms (562). However, taking drugs that block a purposeful action of the body may cause serious negative side effects in the future. In contrast, natural lifestyle changes applied with a deeper understanding of the body may lead to lasting health benefits without the side effects.
Glutamate has a strong association with ASD because glutamate activity “peaks during the second year of life, which coincides with the onset of synaptic pruning (563).” Importantly, the second year of life is around the time regressive ASD symptoms begin (564) (565). This specific age-related increase of glutamate activity happens because the body starts making additional glutamate receptors. Researchers found glutamate receptors on microglia can increase inflammation when activated by glutamate (566). Therefore, more glutamate receptors can lead to more inflammation and suddenly increased ASD symptoms.
It is critical to understand that the disruption of neuron network organization probably already happened while the child was in the womb. The increased inflammation in early childhood simply exposes the disrupted neuron network by activating the Cell Danger Response, which worsens neuron communication and ASD symptoms. In hindsight, many may notice less obvious ASD symptoms were present since birth.
Some ASD people also have higher levels of ammonia in the body, which might result from diminished activity of the enzyme glutamine synthetase. This enzyme converts glutamate and ammonia into glutamine, which does not have the inflammatory effects of glutamate. Researchers found inflammation increased the expression of inducible nitric oxide synthase, which can reduce glutamine synthetase activity by as much as 50% (567).
During times of inflammatory stress, the body may want to make sure glutamate is available to destroy pathogens, dysfunctional neurons, and retract dendrites. Therefore, the body may purposefully reduce the transformation of glutamate into glutamine during chronic inflammation. This limitation negatively affects the efficient removal of ammonia. This is a reason to not eat an excessive amount of protein since its digestion increases ammonia levels.
In addition to raising excitation levels, inflammation may also purposefully lower inhibition to maximize excitation. One way the body can reduce inhibition is by eliminating many Purkinje cells in the brain. Purkinje cells are the principal neurons of the cerebellar cortex in the brain (568). These neurons are responsible for a significant amount of inhibition control in the brain and ASD people often have fewer of these cells (569). Others also found fewer Purkinje cells in ASD people (570) (571). Microglia can cause the death of these cells through respiratory burst (536).
Interestingly, insulin-like growth factor-1 (IGF-1) promotes the development of Purkinje cells, including dendritic growth (572). The addition of IGF-1 increases Purkinje cells in culture (573). This is significant because ASD children had much lower levels of IGF-1 (574).
Glutamic acid decarboxylase is an important enzyme highly expressed in adult Purkinje neurons (575). This enzyme converts the excitatory molecule glutamate to GABA, an inhibitory molecule. Receptors for GABA can reduce the effects of excitation in the brain (576).
Purkinje cells are vulnerable to glutamate toxicity (577). If the body needs more excitation and less inhibition, then this Purkinje cell vulnerability allows the body to quickly disable some of these inhibitory cells. This supports the function of inflammation in increasing excitation and limiting inhibition for defensive purposes.
The depletion of serotonin is another way that the body purposefully reduces connectivity to increase excitation. Serotonin receptors strongly limit glutamate release (578). This limitation of a major excitatory neurotransmitter decreases the ability to raise inflammation for defensive purposes.
Serotonin also conflicts with CDR function, which seeks to reduce connections between neurons. This is because serotonin increases connectivity. In rats, research found an association between serotonin depletion and synaptic loss (579). Other rat research found a reduction of serotonin receptors associated with decreased synaptic density (580). Serotonin receptor activity plays a crucial part in altering brain structure (581).
Fitting this inverse relationship between serotonin and the CDR, some ASD people have lower serotonin. A study found low serotonin synthesis in young ASD children (582). Compared to the control group, researchers found lower serotonin in the plasma of mothers with ASD children (583). There are also serotonin transporter genetic variants in some families with ASD individuals (584).
In addition, the body may also reduce acetylcholine levels to support cell retraction and inflammation caused by the CDR. Acetylcholine is a neurotransmitter that helps to form connections between the neurons. Acetylcholine can increase attention and memory (585). There is also a link between acetylcholine and additional neuronal growth (586). Research found that biomimetic acetylcholine polymers enhanced the growth of certain neurons (587). Acetylcholine also has anti-inflammatory effects. Therefore, the body may purposefully decrease acetylcholine to enhance the inflammatory response.
Research found ASD people had significantly lower levels of acetylcholine (588). Decreased levels of choline-containing compounds were also found in ASD children (589). Adding acetylcholine reduced ASD symptoms in mice (590). Others note there may be a dysfunction of the cholinergic system in ASD (591).
Nicotinic receptors, which respond to acetylcholine, affect other health conditions as well. Health conditions such as epilepsy, depression, Alzheimer’s, and Parkinson’s may involve nicotinic receptors (592). Acetylcholine dysfunction in these health conditions is not surprising, considering they are frequently caused by inflammation, which limits acetylcholine.
As a side note, nicotine activates the cholinergic anti-inflammatory pathways (593). One of the many reasons for nicotine addiction is some individuals do not have enough acetylcholine because of inflammation and lack of choline in the daily food plan. Smoking cigarettes is a dangerous way to try and compensate for issues with acetylcholine supply. Rather than smoking, a better way to increase focus and mood is to reduce inflammation and eat more foods containing choline.
To summarize this section, destruction of Purkinje cells and increased glutamate enhance excitation and neuron disconnection. The body purposefully reduces serotonin and acetylcholine to further strengthen the disconnection and excitation. By reducing the inhibitory functions, the body strengthens the inflammatory response and further disconnects neurons for protection.
Evolutionarily, the design of this process was to destroy the inflammation source, which in the past, would have probably been bacterial or viral. Now the main sources of inflammation are wrong nutrition and lifestyles choices. Therefore, the secret to lowering the excitation ratio and reconnect neurons is to reduce inflammation using many nutrition and lifestyle changes.
Neuron Density
During chronic CDR, the body may try to compensate for the limited connectivity between neurons. For example, in the gestation of a fetus without chronic CDR, the fetus creates more synapses and neurons than are necessary and removes some of these connections later to form an organized network of neurons. This process of synaptic pruning typically begins in late gestation (594).
During the pregnancy of a fetus with chronic CDR, the fetus may try to compensate for reduced connectivity by limiting the removal of neurons and synapses. Research found ASD people often have an increased neuron density in the prefrontal cortex as children (595). Other researchers found many ASD people have less synaptic pruning (596).
Importantly, this compensatory activity may not occur in some ASD people. This activity likely depends on severity and other factors.
The fetus may also sometimes create extra neurons to try and fill in the gaps created by reduced connectivity. The brain can make more brain-derived neurotrophic factor (BDNF) to achieve this compensatory activity. BDNF is a protein that promotes creation of new neurons and extra synapses. Research found higher concentrations of serum BDNF in ASD people (597). Other researchers also note that BDNF levels are higher in ASD people than in controls (598). The same researchers noticed the BDNF levels were only elevated in mild ASD, whereas the more severe ASD type did not have a BDNF elevation (598).
This is likely the compensatory mechanism, where people less severely affected partially compensate for the lack of neuron connectivity by increasing their BDNF levels. The brain can also reduce natural synaptic pruning to help compensate for limited connectivity between neurons. BDNF and less synaptic pruning create a higher density of neurons and more synaptic connections that increase communication in the neuron network.
However, randomly adding extra neurons and synapses to partially compensate for chronic inflammation and the Cell Danger Response will not create a well-organized neuron network. Although adding extra neurons and synapses may provide more function than would otherwise occur, the overall effect is frequently a chaotic, unsynchronized electrical activity between different areas of the neuron network.
Despite the problems with overall connectivity, one of the functional improvements may be additional neurons in localized areas of the brain. The increased neuron density in specific brain areas is why some ASD individuals have incredible abilities and yet may still struggle with other seemingly simple activities. As many as 1 in 10 ASD people have “remarkable abilities in varying degrees” and “whatever the particular savant skill, it is always linked to massive memory (599).”
The connectivity issues in ASD are most noticeable when long-distance connections between different areas of the brain are needed. These long-distance neuron pathways are known as white matter, whereas gray matter makes localized connections. Because of greater distance, white matter connections need better organization to connect different brain areas efficiently. Therefore, white matter connections are not as improved by the compensation of increased neuron density, which is disorganized because of inflammation and the CDR.
Some ASD people have more white matter volume, but as mentioned, that does not significantly improve the more specific long-distance connection pathways. Researchers note white matter volume is 40% larger in ASD infants (575). Also, a particular white matter that develops later and primarily affects frontal lobe connections to other lobes, had a more significant volume increase in ASD people (600).
Likely, the increase in BDNF and reduction in synaptic pruning create additional gray matter to compensate for limitations with long-distance white matter connectivity. For an analogy, if gray matter is like county roads, then white matter is the interstate highway. If the highway has problems, then construction may build more county roads to help access different areas of the state. Since the creation of more neurons and synapses is a compensatory mechanism, this process is often inefficient.
The problems with white matter connections combined with increased BDNF create improved local connectivity and less long-range connectivity in the brain. In line with this concept, research found high local connectivity and a lack of long-range connectivity in ASD people (601). Another study found locally elevated coherence frequencies and reduced global coherence frequencies in ASD people (602). Research also found ASD people have disordered neuron connections and diminished connectivity between various local neuron networks in the brain (603). Others found less connectivity and a thinning of the corpus callosum, which links the two sides of the brain (604).
ASD people also often have less synchronization between the inhibition neuron network and the frontal region of the brain (605) (606). In some ASD people, complex association brain areas partly disconnect from the frontal lobe during development (607).
Interestingly, issues with high-functioning autistics can occur when there is information processing that places a higher demand for integrating and sharing information across multiple different neural systems in the brain (608). Many of these research studies indicate reduce long-range connectivity in the ASD brain.
Even in a high-functioning ASD person, this reduction of connectivity can be obvious during socialization, which requires the synchronization of multiple different brain areas. During socializing, many streams of information require integration, such as body language, analogies, hearing, eye movement, storyline, and tone of voice. In an individual with an organized and well-connected neuron network, integrating many information streams happens subconsciously and is relatively easy.
However, for someone with fewer connections between neurons and a more disordered network, this integration requires greater effort and may not even happen. These factors often make social situations more difficult. Also, increased excitation from inflammation can contribute to becoming overwhelmed easily by the volume and number of stimuli. These difficulties are why some ASD people want to avoid socializing.
Summarizing the key points so far, forms of stress, such as pathogens and excess reactive oxygen species, cause ATP release outside of the cells. This extracellular ATP activates purinergic receptors, increasing inflammation. This then can cause cells to enter a type of survival mode, known as the Cell Danger Response (CDR). The CDR limits connectivity by causing neurons to retract their dendrites. This reduced connectivity when combined with inflammation worsens many ASD symptoms.
Glutamate levels increase to destroy damaged cells and further raise inflammation. Because inhibitory molecules limit excitatory activation of the inflammatory response, the body may purposefully reduce serotonin, acetylcholine, and Purkinje cells.
Most importantly, inflammation and the CDR disrupt the formation of an organized neuron network in the womb and cause ASD.
Changing Connections
Fortunately, the brain is changeable. The connections between the neurons can improve by changing both nutrition and multiple lifestyle patterns. Dendritic growth, which affects neuron connectivity, is remarkably responsive to signals and patterns of activity (609).
Chapter 10 has some ideas on how to use this flexibility to improve neuron connections. However, first reducing inflammation is necessary for successfully using methods that reconnect neurons. Using the many strategies in this book to reduce inflammation improves the likelihood of better neuron connectivity in the future.
As an important side note, some types of ASDs are more severe because of extreme inflammation or rare genetic changes that lead to massive disorganization of neuron connections. The severe type of ASD, categorized as level 3, will not respond as well to improvement efforts because of the extreme disorganization. Specific genetic changes can interrupt critical functions, which affect the ability to create neural connections. The genetic changes also limit other functions, which lifestyle improvements cannot fix. Therefore, strategies in this book will likely not improve neuron network connectivity in level 3 ASD.
Distinguishing between different severities and levels of ASD is important because less severe ASD might have amazing improvements using the ideas in this book.
Importantly, some of the rise in the rate of ASD over the last few decades is because of an increased diagnosis of ASD with mild symptoms. Research found the “symptom score for autism decreased on average 30% over more than a decade in birth cohorts 1992-2002” and there was “an average decrease of 50% in the autism symptom score from 2004 to 2014 (610).” Therefore, since more ASD is of the less severe type, there may be major improvements for many ASD people by using the ideas in this book.
Overall, ASD individuals have less connectivity between neurons, which inflammation and the CDR can cause. Therefore, reducing inflammation combined with efforts to reconnect neurons may dramatically improve the lives of many ASD people.
Wide Lens
There are also connections between chronic inflammation and many other health conditions, such as depression, anxiety, autism, stroke, epilepsy, Alzheimer’s, Parkinson’s, and post-traumatic stress disorder (PTSD). Chronic inflammation may also be the primary cause of many more health conditions.
Sadly, splitting medicine into many specializations is a powerful barrier to understanding the causes of many health conditions. A bigger perspective and unification of medical research is necessary to find more effective long-term solutions.
Because of technology and finances, overspecialized researchers focus on making synthetic drugs with negative side effects for suppressing symptoms, rather than using a wide lens to see the actual cause of a health condition.
For example, researchers have created drugs that alter glutamate receptors to limit the negative effects of excess glutamate (611). However, drugs designed to inhibit these receptors have multiple negative side effects (612). From a different viewpoint, this may be unsurprising, since the body performs many actions purposeful reasons, such as raising glutamate to increase inflammation and destroy a pathogen. Using drugs to block a purposeful function of the body often has many negative side effects.
Rather than continually relying on synthetic drugs, the secret to healing is to know the primary cause of a health condition. This is often going to be nutrition and lifestyle choices. Focusing on simple everyday choices and habits discussed in this book may create amazing health results.
This deeper understanding allows future doctors to use natural methods to treat conditions of excitation, such as autism, ADHD, anxiety, and epilepsy. Treatment using nutrition and lifestyle changes is a massive improvement compared to the current pill-based methods that simply suppress symptoms. Medicine of the future will focus on causes and prevention of health conditions, rather than profit-focused symptom suppression.
Overall, current medical study and practice needs more perspective. The human body needs to be understood and appreciated as a sophisticated vehicle that took millions of years to create. The view of disease as something in the body simply breaking needs to end.
An amazing paradigm shift is to see how many health conditions provide temporary benefits. Although this is not true for some conditions, many fit into this pattern, especially common conditions, such as cancer and type 2 diabetes.
Of course, this does not mean that someone should desire a challenging health condition, just that there might be a purposeful reason for the condition. Understanding this reason will help in finding natural and effective healing.
Hopefully, this paradigm shift improves medical research and leads to effective treatments, which will frequently be gradual nutrition and lifestyle changes.