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Obesity and Body Positivity on the Brain

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Take a moment to look at the image above. Does something seem to be missing between the person standing on the scale, sad, then looking in a mirror, happy? If you jumped to the same conclusion as me, the answer is “weight loss”! In order to be so happy with their reflection, shouldn’t the person in the drawing have lost dozens of pounds and be smiling at their new, thinner figure?

Not only is it possible to reach the right side of the image without strictly focusing on losing weight, but finding happiness with your body may be even better for you than losing weight. Let’s take a look at obesity and body positivity on the brain!

Controlling Food Intake

First, it’s important to know how the brain normally maintains the appetite balance of being hungry and full. Two key players in this pathway are the hormones leptin and insulin.

Leptin:

  1. The hormone leptin is released from brain cells (neurons) after food is consumed
  2. Leptin binds to and activates leptin receptors on the outside of other neurons
  3. The activated leptin receptor in turn activates proteins called Janus kinases (JAK) which then activate signal transducer and activator of transcription (STAT) proteins
  4. STAT enters the neuron’s nucleus and causes certain portions of DNA to be transcribed into proteins
  5. These proteins transfer signals to neurons in the hypothalamus, a central brain region. These signals suppress the orexigenic pathway, which signals that you are hungry, and activate the anorexigenic pathway, which signals that you are full

Insulin:

  1. The hormone insulin is released from neurons after food is consumed
  2. Insulin binds to and activates insulin receptors on the outside of other neurons
  3. The insulin receptors activate a protein called IRS1, which in turn activates a cascade of proteins ending in protein kinase B, also known as Akt
  4. Akt enters the neuron’s nucleus and causes the FOXO1 protein to leave the nucleus
  5. When it is in the nucleus, FOXO1 causes DNA to transcribe proteins that suppress STAT activity. Looking back at the leptin pathway, STAT is necessary in the signaling pathway telling your brain that you are no longer hungry. By banishing FOXO1 from the nucleus, the insulin pathway also helps make you feel full

High-Fat Diet = Bad News for Appetite Control

The way the brain controls appetite and food cravings changes substantially after consuming foods high in fat. Like many “bad” habits, eating high-calorie, high-fat foods can be difficult to stop once you’ve become accustomed to the diet—some even argue that such foods are as addictive as drugs of abuse. The following changes take place in as little as 24 hours after initiation of a high-fat diet (HFD):

  1. Saturated fatty acids (SFAs) enter the brain through the bloodstream and bind to TLR receptors
  2. Now activated, TLR receptors activate a protein called IKK
  3. IKK goes on to free NF-κB to enter the nucleus, a transcription factor that is normally “blocked”
  4. NF-κB causes DNA transcription of the SOCS3 gene
  5. The SOCS3 protein inhibits the insulin and leptin signaling pathways described above, preventing your brain from telling you that you are “full” despite having consumed food

Since the SFAs prevent signaling that makes you feel full, you’re more likely to continue consuming unnecessary food. Not only does a high-fat diet prevent satiation, but it also leads to inflammation in the brain. Proinflammatory cytokines (small molecules inducing inflammation) such as TNF-α are produced following consumption of fatty food and bind to TNF receptors. These receptors activate JNK, a protein that inhibits IRS1, further preventing insulin signaling and compounding the effect of SFAs. Chronic inflammation in the brain, as well as the elevated appetite resulting from SFA consumption, results in bodily inflammation and weight gain.

In summary, eating a high-fat diet leads to brain inflammation and insulin and leptin resistance, resulting in bodily inflammation, increased food intake, and weight gain. But what do weight gain and obesity mean for the individual?

Obesity on the Brain

We’ve looked at how a high-fat diet impacts signaling in the brain leading to obesity. But how does obesity impact the brain and a person’s physical, mental, and emotional well-being?

First, let’s take a brief look at physical health. Obesity is a well-known risk factor for diseases including diabetes and cardiovascular disease. However, there is endless variety among bodies, and it is a simple fact that there is no “healthy weight”. People can be healthy across a wide range of weights, and the number on the scale provides little information about how healthy a person really is. As ingrained as it is in our brains, we must accept the idea that being thin is not equal to being healthy.

Obesity’s effect on mental and emotional health is another story. The modern Western attitude towards beauty informs us that our worth is reliant on our appearance, especially our weight, and that thinness is the ultimate ideal (this is nuanced in the muscular ideal for men, but we’ll loosely use thinness as the opposite of obesity for the purposes of this post). The evidence for the “thin ideal” is nearly endless: people perceived as attractive are more financially successful, the vast majority of models and actresses portrayed as beautiful are thin, and overweight people are stereotyped as lazy.

The societal obsession with thinness often has significant detrimental effects on the mental health of obese and overweight individuals. The constant outright or subliminal messaging that fat bodies are not wanted, not ideal, and worth less than thin bodies can cause serious stress in people who feel they don’t fit the “correct” beauty image. Not only is constant stress and negative body image clearly bad for mental health and quality of life, but elevated rates of cortisol, the stress hormone, can also further interrupt the appetite regulation pathway discussed above, leading to further weight gain and often compounding stress and body dissatisfaction.

Body Positivity

The body positivity movement seeks to combat the stigma around bodies that don’t fit the thin ideal or other aspects of the Western beauty standard. By promoting acceptance of all body types, body positivity advocates for love and shifting the idea that a person’s intrinsic worth is wrapped at all in their physical appearance. And body positivity is not just for overweight and obese individuals: a jaw-dropping 2% of women report being “totally happy” with their bodies. With such rampant dissatisfaction with our bodies, we can all benefit from a shift towards body positivity.

Critics of the movement claim that body positivity simply excuses obesity and ignores the health risks that go along with it. However, studies have shown that body positivity movements have nothing but positive effects on health: individuals who think positively about their physical appearance tend to have better mental health and are more likely to take care of themselves. By first destigmatizing obesity and fat bodies, we can send the message that all bodies are beautiful and worthy of love, and thus have a strong foundation from which to build healthy eating and exercise habits for the purpose of health rather than adherence to thin beauty standards.

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Obesity: A Mental Disorder?

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If you live in the US, you’re probably aware of the problem we have with obesity. Even if you don’t live in the US you most likely have the perception that all Americans are fat, which isn’t completely false. America has nearly 40% of the world’s McDonalds, and over 11,000 more restaurants than the country with the

2nd most McDonalds. Eating badly is ingrained in our culture, and in some cases, is our culture. 

With the existence of concepts such as fat shaming, some people believe that obese individuals can simply stop eating more than they have to. Now I don’t want to say that overeating isn’t a part of being overweight or being unhealthy, because it is, but are overweight individuals as in control as we think they are? Everyone has the choice of what they eat (assuming you have the income, although this isn’t a fair assumption either), but in a lot of ways, overweight people should not be fully blamed for the pounds they put on. Recent research shows that certain types of food, such as food that is high in fat, can be neurologically addictive. Because of this addictive quality, some are arguing for a place to be made in the Diagnostic and Statistical Manual (DSM V) for obesity as a mental disorder. 

It has been found that there are a number of ways in which food, specifically food that is high in fat, can have addictive qualities. In some ways this assertion is already intuitive, as you never just want to have one donut. However, we can see the effects of this addictive quality on a deeper, more scientific level than simply being aware of its effects. For instance, deficits in dopamine transmission are induced within a high fat diet. Simplified, this means you don’t feel as good over time while eating the same amount of unhealthy food; the enjoyment diminishes on a neurological level. This in many ways parallels when a tolerance has been built up through repeated drug use. 

It is commonly understood in research that obesity most likely causes increased inflammation, and inflammation may result in higher levels of obesity, though all the exact mechanisms for this loop aren’t known yet. What we do know is that obesity-related systemic inflammation reduces the integrity of brain structures involved in reward and feeding behaviors. To simplify this, this means that obesity triggers system-wide inflammation, which reduces the amount of control that we have over rewarding behaviors, including our food intake. Over time, our mental system of self-protection against resisting treats may be eroded by the fact that we’re eating these treats. A reduced integrity of reward systems has been found in drug addicts, where cortical brain regions involved in executive control and decision making have been heavily implicated. Through eating a high fat diet, we might be allowing our brains to think that eating more high fat items is what should occur. 

One study looked at fibrinogen (a protein that’s found in blood) as a marker for inflammation, in which more fibrinogen means more inflammation. Unsurprisingly, fibrinogen was higher among obese individuals. An interesting finding however was that volumes of the orbitofrontal cortex in obese participants were negatively associated with fibrinogen levels. One of the functions of the orbitofrontal cortex is impulse control, and so damage to this area can lead to both impulsivity and compulsivity. Just because there is a difference in volume here however doesn’t mean it’s due to fibrinogen, so researchers controlled for variables within lean subjects, and found that 9% of the variance in OFC volume could be explained by fibrinogen. This, unfortunately, doesn’t bode well for obese individuals. In the case of obesity, we might be our own worst enemies, as we may be unintentionally sabotaging our own willpower by consuming a high-fat diet. 

 

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The Complexity of Autistic Spectrum Disorder

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Recently in class discussions we had the chance to look at Autism Spectrum Disorders (ASD). ASD currently affects roughly 1 in 68 children. ASD shows abnormalities in social behavior. While I was growing up, I was fortunate enough to get to know two kids with ASD. The two kids were both in my grade and each of the showed a skill that they exceeded in. One of the kids would take sports statistics and memorize them. His brain loved numbers, but only numbers specific to sports. If I had asked him a certain score of a game played in 1990 between the Minnesota Vikings and Green Bay Packer, he would have told me right on the spot. The other kid was a walking calculator. He knew any math problem laid in front of him.

As these skills continued to progress, the two kids’ social behaviors drastically continued to decrease. Social interactions and communication started to become exceedingly difficult and that is when I found out they had ASD. Both kids also shared a rare diagnosis of savant’s syndrome as well. Savants syndrome basically sums up to be where one area of your brain shows extreme supremacy over others. This would explain the rare skills that both these kids showed. In most cases, savant patients also have ASD. After reading our class discussion, it started to make sense to me on how this might come to be. One of the theories discussed in the development of ASD is neural connectivity. In autism, patients undergo an overabundant number of neurons. This overabundance disables connections between the brain interactions. So, we ultimately get cut off connections which impair the brain in certain areas down the way, but in some cases these neurons may drastically increase the capability of the portion of the brain they are stuck in. This would perhaps explain savant syndrome.

There are many other theories that tie into the development of ASD with one of them being the impairment of synaptogenesis. This theory explains how in early life, our brain has a lot of synapse formation and with synaptogenesis, the removal of certain synapses takes place. This process is important in the fact that synapses are being taken out and they are the correct ones. In ASD this process is impaired, and the consequences would be brain underdevelopment leading to dysfunctional behaviors.

Although both theories make sense, I like to focus on neural connectivity. Again, bringing it back to my experience and relating savant syndrome to autism, I feel neural connectivity is the main issue. In savants I now can picture their brain. In my artstract below you can see an outline of what I feel is going on. In a human brain connection are supposed to connect the dots. These connections are supposed to be smooth and transfer from one to another without issues. In a ASD or savant syndrome brain we see that only a few of the dots are connected before there is a barrier where you cannot get to the next dot. In my experience, the portion of the brain that was controlling numbers was the dot that was connected, but then there became a barrier when trying to connect to the social interaction dot.

Of course, ASD is a lot more complicated then connecting dots but it is a graphic that helps me. In my experience with ASD  I never had the chance to see others. In the cases where I knew the individual I thought their behavior was normal for ASD. However, they also had the rare diagnosis of Savants as well. Learning about ASD more in depth and the complexity of the disease has opened my eyes to the severity that ASD holds.

Disease/Health

Polycystic Ovarian Syndrome (PCOS) and Obesity: A “Chicken or the Egg” Paradox

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What is PCOS?

Polycystic Ovarian Syndrome (PCOS) is a condition in which the ovaries produces excessive amounts of androgens, the male sex hormone. Excess of the male sex hormone in women disrupts the fragile balance that is maintained between estrogen, progesterone, and the androgens. This hormonal imbalance often results in the development of cysts within the ovaries, contributing to irregular menstrual cycles, infertility, and anxiety/depression. Additionally, overproduction of these androgens leads to excess hair all over the body, acne, and insulin resistance and obesity.

Studies have concluded that women affected by obesity have a greater risk for PCOS and women diagnosed with PCOS have an increased risk for obesity.

Obesity as Risk Factor for PCOS

The majority of women with PCOS are obese or overweight and/or have insulin resistance (50-90%). Resistance to insulin is a primary driving factor for obesity and type 2 diabetes, as insulin is a key regulator in maintaining normal blood sugar levels. An emerging theory of the cause of insulin resistance can be seen in studies of the hypothalamus, a structure of the brain responsible for regulating appetite, hormone release, and many other key metabolic roles. When there is inflammation occurring in the hypothalamus, however, there is disruption to many of these metabolic pathways that are vital for normal insulin signaling. This inflammation within the hypothalamus is prompted by a high-fat diet, further emphasizing the importance of a healthy diet in the maintenance of effective peripheral and neurological functioning.

Insulin resistance in peripheral tissues was actually found to enhance steroidogenesis in the ovaries, leading to higher production and consequent levels of androgens. This feature results in the hormone imbalance that contributes to many of the symptoms of PCOS. 

PCOS as Risk Factor for Obesity

On the other side of the paradox, elevated androgen levelsin women with PCOS have been shown to impair insulin signaling, contributing to insulin resistance. As demonstrated above, insulin resistance promotes androgen production. As androgen elevations promote insulin resistance, the positive feedback mechanism present between PCOS and obesity can clearly be seen. 

As indicated in the figure, there are a number of additional overlapping factors that perpetuate this sort of positive feedback mechanism that can be found between PCOS and obesity within patients.

Clinical Implications

Since PCOS and obesity undoubtedly compound the effects of the other, it is necessary to develop novel, effective treatments that will target both conditions. A strategy that has been used for a while to combat PCOS symptoms and infertility is hormonal oral contraception. This form of contraception provides supplemental estrogen and progesterone, thereby attempting to restore hormonal balance and allow for normal ovarian function. Additionally, antiandrogens have been reported to be effective in both lowering androgen levels improving insulin sensitivity. These drug strategies hold great potential for effective treatment of those who struggle with both PCOS and obesity. 

Promotion of exercise and a healthy diet in those with PCOS is important in the clinical setting, as these strategies help to both undermine the severity of PCOS symptoms and combat the effects of obesity. However, this feat is easier said than done, as many women with PCOS also struggle with anxiety or depression that may hinder efforts to stay active and eat well. 

It is ultimately necessary to increase research about PCOS and obesity so that more effective treatments emerge in the hopes of minimizing the difficulties that each condition brings about. 

 

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To go or not to go: how excitatory/inhibitory imbalances can shape ASD

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Hello everyone! Today I’d like to talk a little bit about some factors that influence the development of Autism Spectrum Disorders (ASD), specifically how maternal infection/stress can increase the risk of ASD.

ASD is a spectrum of neurodevelopmental disorders that affects 1/58 children in the United States.  The key symptoms of ASD, which can range widely in severity, are impaired social interactions, problems with language/communication, and repetitive behaviors.

A lifelong condition, the cause of ASD is not yet known, although strides are being made to identify risk factors and molecular mechanisms that cause ASD.  Changes in the typical balance between neurons that stimulate other neurons (excitatory: Glutamate) and those that inhibitory other neurons (GABA) represent a key process that may explain ASD.

GLUTAMATE & GABA:

Picture two different neurons—If you’d like you can even color-code them in your head, one green one red. The green neuron produces and uses a neurotransmitter called glutamate to communicate with the other neurons it talks to, while the red neuron uses GABA.

When the green neuron is activated, glutamate is released into the synapse. Glutamate then binds to its receptor on the post-synaptic membrane and ultimately opens up a sodium channel. Positively charged sodium (highly concentrated outside the cell) rushes inside the post-synaptic neuron and makes that neuron more likely to fire, hence glutamate is excitatory. Cool!

Conversely, the red neuron does all the same steps, just swap out glutamate for GABA and chloride for sodium. Just like sodium, chloride is highly concentrated outside the cell and rushes inside once the chloride channel is opened. However, because chloride is negatively charged, increasing intracellular chloride decreases the likelihood of post-synaptic neuronal activation—making GABA inhibitory. The interactions between glutamate and GABA maintain balance in the brain.

At this point, you might be wondering how exactly this relates to ASD etiology. This is the part of the post where I admit that some of what I just told you was wrong. You see, every first-year neuroscience student learns about glutamate and GABA as I just described it, it’s a foundational “ying-and-yang” pillar of neurotransmission. And while it’s true that GABA works like that “most” of the time,  GABA works the exact opposite way during brain development.

During development, GABA is excitatory—as crazy as that might sound! The brain achieves this by implementing two different chloride ion pumps at different stages of development; an importer and an exporter. During fetal development, the chloride importer (NCKK1) is active and establishes a high intracellular chloride concentration. Once GABA binds and opens its receptor negatively-charged chloride rushes out, causing a net positive effect which makes the neuron more likely to fire—essentially excitatory. This mechanism is critically important during early development, but as fetal development draws to a close an excitatory-inhibitory GABA shift happens. NCKK1 is deactivated and the chloride exporter pump (KCC2) is activated, establishing the typical inhibitory functions of GABA.

This GABA shift is hypothesized to malfunction/be delayed in the context of ASD. This can cause the brains of individuals with ASD to have too many connections, sensory overload, enlarged cerebrums, and other symptoms of ASD. This begs the question, what dysregulates the chloride ion pumps and causes the malfunctional GABA shift in the first place?

Interestingly, these changes are impacted by changes in the maternal environment during pregnancy. Specific factors (especially prenatal infection and stress) can elevate pro-inflammatory cytokines, one of which (IL-1b) may directly impair the excitatory-inhibitory GABA switch! A rat model of ASD demonstrated that the administration of an NKCC1-blocking drug one day before birth restores many brain functions, especially in the hippocampus, compared to controls. This shows that birth is a critical period for the GABA shift and by proxy ASD development. This same drug decreases ASD symptom severity in humans with few side effects and is a promising avenue of treatment.

https://www.nature.com/articles/s41398-020-01027-6/figures/1

The take-home message is that maternal inflammation can cause prenatal neuroinflammation and impair the inhibitory-excitatory GABA shift, which can cause excitatory-inhibitory imbalances throughout postnatal development, increasing the risk of ASD. Understanding how these ion pumps initially go “out of whack” can help researchers design better drugs that more effectively repair the GABA switch with the fewest side effects!

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The Tangled Web of Autism Spectrum Disorder

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Do you remember the first time you saw a spider’s web? If you are like me, you were a young kid looking at it in a state of wonder. How can a spider create such a thing? Each thread looks perfectly placed and is clearly there for a reason. The threads come together to paint a picture of one of the most awe-inspiring parts of nature. I like to think of our brains in a similar way. Millions upon millions of connections come together, painting an intricate web between our ears, that ultimately makes up who we are.

The Web of ASD

Now I want you to think about taking that web and adding more and more threads. Now the perfect spider web is becoming muddled, with threads on top of each other where there shouldn’t be. Where there should be threads, there are too many, and now this perfect picture is becoming more and more confusing the more you look at it. This web does not look as functional, and it leads one to wonder what went wrong.

We can think of the brain, in almost an identical way to the muddled web as it relates to ASD. The causes of ASD are complex, to say the least, and involve a myriad of genetic and environmental risk factors. The effects, particularly on neural circuitry, are much better understood. Revisiting the spider web analogy, there are simply too many neuronal connections in ASD, as there would be in a crowded web. In a normal brain, around early childhood, neurons are pruned and refined to make connections more efficient. So in a more complex web, if a spider wants to travel from one side of the web to another, they are met with many more crossroads than would normally be anticipated. The spider ultimately takes longer to cross the web. Similarly in the brain, if a message needs to be sent across a greater distance the extra neuronal connections will mean that message is delivered slower and less efficient.

artract created by B. Swanson

Further complicating the brain in ASD, neurons can also simply be in the wrong place. Indeed, neural migration is also affected during ASD and during development. Now you can imagine a web with threads where they should not be, it does not look right, and maybe not even function right. With neurons in the wrong place, the issues of neural communication are further complicated.

Bringing it all Together

            With the brain seeming so out of whack, it’s hard to imagine a scenario where this brain even work. In ASD, the brain is largely functional, however it would not be considered neurotypical. The inefficient wiring leads to some of the big picture symptoms such as:

  • Difficulty with verbal and non-verbal language
  • Gestures
  • Facial expressions
  • Expressions of emotion
  • Lack of understanding of person space

The big picture symptoms are a result of a tangled web of neurons. However, the neurons mostly get the job done, and the messages sent, despite the difficulties. Much like a tangled spider’s web, it may not look and act how it should, but in the imperfection, there is a level of beauty.

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Pandemic Pregnancies and Autism

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Pregnancy during the time of a pandemic can turn a beautiful, life changing experience into a scary, life changing experience. Most women while pregnant experience paranoia and worries already about getting sick, but during a pandemic this fear most likely heightens immensely. It has been noted that infection during pregnancy can negatively effect the fetus, especially if the immunological response to the infection reaches the fetuses blood circulation supply. Some responses, such as certain antibodies, can be helpful to building the fetus’s immune system, but others, like cytokines, can harm the fetus’s development. Some studies have found that if the fetus is exposed during time of infection or if the mom has a fever in response to infection, there is a higher risk of autism diagnoses. So, the question remains, how will Covid-19 affect children whose mothers tested positive while pregnant?

What happens during infection?

Image showing the events leading up to cytokine storm and how cytokine storms can affect the body.

Over the past year, scientists have been trying to become more familiar with the novel Covid-19 pandemic that has struck all around the world. It seems to be a bit of a difficult task, although, due to the variety of symptoms and uniqueness of each  case. It has been shown in case studies of patients with Covid-19 that those who present with existing conditions (hypertension, diabetes, obesity) have a higher risk of death or longer recovery period with longer lasting symptoms. Depending on the severity of symptoms and infection, patients can experience a multitude of aspects caused by the virus. This includes a vulnerable immune system, implications to the neural system, a correlation to the hyperandrogenic phenotype, or cytokine storms. Here we will focus on the cytokine storm aspect of Covid-19. Cytokines are pro-inflammatory molecules that are activated in response to infection. In normal amounts, cytokines can be extremely important in immune responses, but at too high of an amount, they can become dangerous to the health of the patient. An interesting aspect about cytokines is that specific ones, such as IL-6, are able to cross into the placental blood supply for the fetus causing adverse neurodevelopment problems.

Covid-19 and Autism

Diagram showing the similarities between Covid-19 immune responses and aspects that contribute autism.

With all of the immune responses caused by the Covid-19 virus, there are potentially complications that could be seen in the future with children whose mothers had Covid-19 during their pregnancy. A problem that could possibly be seen is a correlation in Covid-19 patients and those with autism. But, since autism spectrum disorder (ASD) is defined behaviorally, a correlation between Covid-19 during pregnancy and autism may not be determined for years when the children begin to develop social behaviors. Although, there are some similarities between Covid-19 and other viruses that have been seen to increase the risk of autism. Studies have shown that infections that have the ability to induce a cytokine storm, for example influenza, that occur during pregnancy correlate to a higher risk for autism. One study even showed that there were higher levels of cytokines in the amniotic fluid of women whose children develop autism. Noting this correlation raises the awareness that children born to mothers who had Covid-19 while pregnant and had increased cytokine levels may develop autism in their future. Scientists have already started case studies with moms who have tested positive while pregnant and their babies to hopefully have an understanding of what effects this virus has on fetuses. Even if the outcomes won’t come for years, the research will be extremely beneficial for moms and children effected.

 

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Be Wary of Gut Inflammation!

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Knock-knock brain, it’s your partner-in-crime, the “second brain of the body”, me, your gut! I have more inflammation for you, ready or not. Research has only seemed to have just started revealing how interconnected our brain and gut are to each other. Things that happen in your gut impact your brain and vice versa, so if I were to tell you that not taking care of your gut increases the risk of the development of a handful of disorders, would I have your attention? If you have kids, what about looking out for their chances for something called autism spectrum disorder, or ASD?

Taking a Closer Look at ASD

What’s the big deal with inflammation, anyways? It seems to be involved in more and more diseases/disorders as science progresses, but one that continues to stand out is ASD. This is due to the broad range of pathophysiology that all circles back to an ASD diagnosis. Although the main cause of ASD still remains largely unclear, there are still many contributions and/or possibilities that are currently being explored, including:

  • Neural connectivity
  • Impaired neural migration
  • Impaired synaptogenesis
  • Excitation-inhibition imbalance
  • Broken mirror theory
  • Impaired immunity and neuroinflammation
  • Epigenetics
  • Single gene mutations

There is good reason to believe that ASD originated from disruptions in more than one of these listed above and that one may very well cause another (or more) to become discombobulated. Instead of going through every point listed above, we will analyze just one of the ideas down below: inflammation, specifically originating from the GI.

GI + Inflammation = ASD?

Although there remains to be no scientific proof of gastrointestinal (GI) inflammation being the solo-contributor or major player of ASD development, there seems to be good reason for a relationship between the gut and brain to exist. Chronic or increased amounts of exposure to cytokines in the brain seem to lead to chronic inflammation and ultimately neuron damage and death. The popular term “leaky gut” may play a role in how inflammation even develops within the brain. The gut-blood barrier is very important inside of the body, which prevents things such as undigested food, toxins, and pathogens from crossing over from the GI tract into blood vessels that can then be carried anywhere within the body via the circulatory system.

Scary, right?!

This will trigger an immune response, and when these invaders reach specific places inside the both, like the brain, will cause an “alarm system” to go off and force cells inside the brain to start attacking the invaders. Changes in some of these protector cells in the brain can ultimately result in neuronal dysfunction, some of the same associations with the mechanisms of ASD.

Fig. 1

There is also an incredible overlap with kids who already have ASD that also suffer from GI issues. This in turn has also been reported to make their ASD symptoms worse. A study examined different groups of children, with one group having ASD and GI issues, and found that this group, compared to the rest, not only had increased levels of cytokines, but also different gut bacteria and increased levels zonulin. All groups with ASD individuals experienced decreased levels of a protein that regulates both neurodevelopment and the immune system.

An Optimistic Closing

As the science field continues to make strides towards opening new doors to answer questions about disorders such as ASD, there is bound to be something relating back to the GI tract. These discoveries will have the ability for early diagnosis/prevention as well as effective treatment options for patients and their family. So, until there is enough evidence, be mindful of your body by keeping your gut happy and healthy!

Health

ASD an Overview

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Autism spectrum disorder (ASD) is an umbrella term for a developmental disability that can cause significant social, communication, and behavioral challenges. These individuals typically aren’t distinguishable by appearance but rather exhibit different methods of learning, interaction, and behavior. ASD is described as a spectrum since individuals can exhibit a diverse range of behaviors that vary in severity. High functioning autistic individuals may not be distinguishable from others, they can pursue education, earn a salary, and live independently while low functioning individuals may be nonverbal and require assistance.

ASD is a complex condition with many underlying conditions that influence and contribute to the risk of development. Challenges in studying ASD arise from the complex pathophysiology of the condition which involves neural connectivity, neural migration, excitatory and inhibitory imbalances, increased synapses, lack of mirroring in neurons, neuroimmunity disturbances, epigenetics, and dysfunctional genes, all of which have complex signaling and cross-communication of their own. To keep this article brief, we will only examine a couple of these to observe how they may impact the development of ASD.

Let’s begin by exploring imbalances in Glutamate (primary excitatory neurotransmitter) and GABA (primary inhibitory neurotransmitter). The Excitatory/Inhibitory balance between glutamate and GABA is critical for the proper functioning of neuronal networks and brain functions. It has been found that there are disturbances in glutamatergic and GABA-ergic receptors within ASD patients leading to an Excitatory/Inhibitory imbalance. This results in excessive glutamatergic excitation which may lead to excitotoxicity and cell death, as well as activation of glial cells that stimulate neurotransmission. To summarize, an imbalance in these important chemicals within the brain can lead to overstimulation of the brain and cause damage to neurons which ultimately results in reduced or altered brain function.

Another pathology relates to synaptic pruning. In neurotypical brains, the initial overabundance of dendritic spine formation is selectively pruned to support brain maturation, and this is regulated through a complex process abbreviated as mTOR regulated autophagy. In autism, there is a reduction in developmental dendritic spine pruning resulting in an impairment in mTOR regulated autophagy. Put simply, as we develop from infancy, our neurons make connections with one another some of which (in a healthy brain) are removed to reduce overstimulation and strengthen/reinforce the important pathways. In autistic individuals, this removal of unnecessary neural connections is not performed leading to an overabundance of connections and decreased efficiency in brain processing and communication.

Mirror neurons have also been found to contribute to the development of ASD. In a healthy brain, the mirror neuron system works to help with learning observed actions and emotions, but in autistic brains, fMRI have shown cortical thinning of regions belonging to the mirror neuron system. This means ASD symptom severity can be correlated to the limited development of the mirror mechanism which may appear in behavioral differences between autistic individuals and others.

Though there are several other contributions we could examine, the final component we will explore is genetic mutations which negatively impact synaptic transmission and synaptic growth. Dysregulation in gene networks forming both the synaptic transmission supporting system and the synaptic growth rate are implicated in the development of ASD, but no specific single gene modulation is sufficient to cause ASD symptom formation. This means more research is needed to elucidate the specific gene-environment & gene-gene interactions giving rise to ASD symptoms. This describes that genes play a significant role in the regulation of neural communication and that issues with this are found in patients with ASD. It’s also understood that it isn’t the dysfunction of a single gene that leads to the development of ASD but rather likely the contributions and combinations of multiple genes and uncovering these genes has yet to be done.

This was a brief overview exploring the very basics of a couple factors out of many that contribute to the complexities of understanding ASD. There remains much research to be done on the subject and a cure has yet to be discovered. Understanding the complex pathophysiology of this condition could provide insight into the dysfunction of countless other conditions and yield future treatment strategies.

Sources

https://pubmed.ncbi.nlm.nih.gov/28499914/

https://www.cdc.gov/ncbddd/autism/facts.html#:~:text=Autism%20spectrum%20disorder%20(ASD)%20is,social%2C%20communication%20and%20behavioral%20challenges.

http://neurochemistry2020.pbworks.com/w/page/141966597/Advances%20in%20understanding%20the%20pathophysiology%20of%20autism%20spectrum%20disorders

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Broken Mirrors: Mirror Neurons and ASD Symptoms

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We learn by watching others. As we grow and develop, we learn how to speak, behave, and even think based on our observations of other humans. Much of this learning is dependent on a part of the brain known as the mirror neuron system. But what happens when the mirror breaks? Read on to find out how this system works and how its dysfunction may contribute to symptoms of ASD.

ASD on the Brain

Autism spectrum disorder (ASD) is diagnosed in roughly 1 in 68 children as of 2017. ASD is characterized by a triad of symptoms: 1. impaired social interaction, 2. language difficulties, and 3. stereotypical (repetitive) behavior.

Many theories have been raised to suggest what causes ASD in the brain. As of yet there is no definitive, accepted, all-encompassing theory. However, most prevalent modern theories boil down to four abnormalities on the neuronal (brain cell) level: synapse construction, impaired protein turnover, impaired regulation of protein expression, and structural modification. Let’s define those terms and take a look at how they’re implicated in ASD.

Synapse Construction

  • Synapses are the spaces between neurons. If one neuron sends a signal to another, the chemicals (known as neurotransmitters) that transmit the signal have to cross over the synapse between them.
  • In ASD, the brain has many more neurons than expected. Normally, the brain prunes (gets rid of) extra neurons that are not being used. This way the neurons aren’t wasting energy and resources that could instead be used to strengthen connections among neurons that often communicate with one another.
    • With the elevated number of neurons in ASD, the connections are not as strong, and there is a lot of extra ‘noise’ from connections that are not necessarily needed.

Impaired Protein Turnover

  • Learning occurs due to a process known as long-term potentiation (LTP) in the brain that semi-permanently strengthens connections among neurons. In order for LTP to occur, expression (creation) of certain proteins needs to occur. Creation of these proteins is dependent on a signaling pathway known as the mTOR pathway.
    • In ASD, there may be an impairment in the mTOR pathway, resulting in interruptions in LTP and learning.
    • mTOR is also important in pruning neurons, so impairment in the pathway could impact synapse construction as well.

Impaired Regulation of Protein Expression

  • As explained above, correct levels of protein expression are essential for all of the brain’s functions. Protein expression is dependent on genes; DNA in genes is ‘read’ and transcribed to make proteins.
  • Epigenetics is the process of genes being modified by environmental factors. If genes are methylated, methyl molecule groups are added to them, and these block the gene from being read. Methylation is important so that genes coding for development stop being read and transcribed, but too much methylation can silence genes that should be being transcribed into proteins. Epigenetics have been proposed as a factor in causing ASD as environmental factors may impact development.
  • Hundreds of gene defects have been found to result in autism, but there is no one ‘autism gene’. Some impacted genes have been found to affect synaptic growth while others impact synaptic transmission (communication among neurons). The problem seems to involve the suppressors of these genes being incorrectly expressed.

Structural Modification

  • Altered synaptic activity due to reasons explained above may cause demands that physically change the synapse’s structure such as altered numbers of ion channel receptors (receptors that react to neurotransmitters to let electrically charged ions into and out of the cell).
  • Reelin is a gene that plays an important role in organizing the brain and making sure neurons are where they need to be during development. Mutations in the reelin gene have been implicated in ASD.

Phew; that was a (maybe not so) brief overview of neuronal differences that have been found in ASD. Causes of these abnormalities have been theorized, as mentioned in some of the bullet points: genetic and environmental causes have been theorized, as has inflammation. We’re going to look into a recent theory of what might be causing some of those above molecular changes and the symptoms of ASD: the mirror neuron system.

Mirror Neurons

So, what are mirror neurons? First of all, they’re normal neurons with specific functions. Many mirror neurons are located in the motor cortex of the brain, which involves motion, and fire when the body does a specific action. Others are in the somatosensory cortex, which involves pain and sensation, and are activated when touching something or experiencing pain. However, what makes mirror neurons special is that they don’t just activate when you move or feel pain; they also activate the exact same way when you observe another person moving or feeling pain. This ‘mirroring’ activation is important in learning and empathy.

The mirror neuron system has a wide variety of functions when working normally. It develops in infants before they have reached 12 months of age and begins to let them understand others’ actions. As the famous Hebbian theory of neuroscience states, “cells that fire together, wire together”. This means that cells that are activated simultaneously form connections. This is also known as associative learning as it results in the brain forming an association between the two objects or concepts (for example, a glass of water and the feeling of thirst). Language development, which is in some ways a form of associative learning, also involved this system.

Mirror neurons have also been implicated in intention understanding; the deductive understanding not just what a person is doing (drinking a glass of water) but why they are doing it (that person must be thirsty). Mirror neurons are often involved in emotions and empathy as they system allows us to understand and relate to fellow humans. Finally, the mirror neuron system is important in what is known as the theory of mind, being able to imagine what another person is thinking or feeling on a more nuanced level than simple intention understanding.

The ‘Broken Mirror’ in ASD

With that brief introduction, we can see that the mirror neuron system is quite important in many higher-order brain functions like language, learning, and empathy and that issues with the system could result in significant developmental problems. The “broken mirror” mirror neuron theory suggests that an issue in this system is the cause of ASD. The theory posits that problems with dendritic morphogenesis (the shape of a neuron’s dendritic spines, an area that forms the receiving end of the synapse) resulting from synapse-related causes mentioned above are a large factor contributing to ASD.

Evidence for this theory is found in the fact that the mirror neuron system doesn’t activate the same way in ASD as it does in the non-ASD brain. As mentioned above, the mirror neuron system typically activates in the exact same way when you complete an action and when you observe another person complete that same action. In individuals with ASD, the mirror neurons activate when they complete the action, but not to the same extent when observing another person do so. It’s not all-or-nothing; the system typically still activates, and some studies have found that there isn’t a significant difference since there is so much variability, but on average there is less activation in the ASD brain.

When we consider all the functions that the mirror neuron system is responsible for, it makes sense that abnormalities could be blamed for ASD symptoms including difficulty with language, self-identification, imitating others, and intention understanding. The theory remains far from conclusive and more research needs to be done to find the role that the mirror neuron system plays in ASD, but for now, it presents a compelling theory for what could be causing ASD symptoms: a broken mirror.

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