Concussions are a growing concern in athletics as we learn more about the consequences of multiple concussions and long-term dangers. Not only are large traumatic concussions of concern, mild traumatic brain injuries (TBI) that occur repetitively can also be damaging.

After the trauma of a concussion, the cell membrane is disrupted from stretching and increases the permeability of ions across the membrane. Large amounts of sodium and calcium enter the cell while potassium leaves the cell. Typically, sodium enters the cell for depolarization and potassium exits the cell only to re-establish the resting potential after depolarization. The flux of ions therefore, induces spontaneous depolarization of neurons.

Potassium levels are quickly re-establishing by potassium pumps. However, potassium pumps require energy from the hydrolysis of ATP to move potassium back into the cell. This requires a lot of ATP. Cells produce ATP through glycolysis in the mitochondria. Glycolysis uses sugars such as glucose to produce ATP, reducing power and pyruvate. Under normal conditions, pyruvate is converted to acetyl-coa and enters the citric acid cycle to produce further reducing power. The reducing power is used in the electron transport chain to produce large quantities of ATP. If glycolysis goes into overdrive, the pyruvate will be converted to lactate which is highly inefficient for ATP production. This hyperglycolysis depletes energy stores quickly and is unsustainable for the cell. Additionally, lactate can cause neuronal dysfunction, changes in blood brain barrier permeability, and brain inflammation, which are all associated with long-term damage triggered by concussions.

This period of hyperglycolysis lasts about 24 hours before the polar opposite process occurs. For this part of the story calcium is the star and villain. To combat high levels of calcium, the cell sequesters calcium in the mitochondria. However, the stress of sequestering calcium leads to the increase in reactive oxygen species (ROS) that typically act as signaling molecules. ROS impairs the mitochondria’s ability to perform glycolysis, which causes hypoglycolysis. As a result, the cell is in an extreme low energy state. During the period of hypoglycolysis, working memory is impaired. This phase will last between two and four weeks depending on the individual.

Neurometabolism gradually returns to normal, alleviating many of the symptoms. However, this can be deceiving because the brain is often inflamed for up to a year after the trauma. Though not completely understood, the event of repeated concussions can have long-term implications for individuals, such as the development of chronic traumatic encephalopathy (CTE) which is similar to Alzheimer’s and Parkinson’s.

The most vulnerable time for a repeated concussion is during the recovery period of a concussion. If a second concussion occurs while the cell is in hypoglycolysis, it is hypothesized that neurons cannot combat the extreme efflux of potassium as ATP in the cell is depleted. Therefore, it is common protocol to prohibit individuals with concussions to partake in activities that risk another concussion. A challenge is that recovery time differs greatly between individuals which makes it difficult to ascertain when the individual has recovered. More research in the indicators of concussions and the recovery thereof are essential to properly treat concussions and mild TBIs.

Rain Man, a breakthrough Hollywood film from the late eighties, brought us a representation of a man with autism. The film enabled us to better understand how one specific individual with autism perceives the world. We as a society can do better at giving individuals with autism the necessary resources to allow for them to have the comfort and safety in their everyday lives.

While this film brought autism to the public attention, we must be careful at what we take away from this film. We must not walk away from this film with the impression that all individuals with autism are savants, as Oscar winning actor Dustin Hoffman displayed in his portrayal of Raymond Babbitt. We must realize that autism falls under the umbrella term, autism spectrum disorder (ASD) and that individuals with ASD can express many different symptoms and behaviors.

The symptoms and behaviors that correspond with ASD affect each individual differently on how they understand and react to the world around them. No two people are affected in the exact same way.

“If you’ve seen ONE child with autism, you’ve seen ONE child with autism.”

There are many questions to why this statement is true. However, research has been done to help explain the complexity of the vast array of symptoms and behaviors.

GENETIC FACTORS

 There are a number of factors that can influence the development of ASD including genetics. Genetic mutations can be visible in many different proteins and genes such as SHANK, UBE3A, MECP2, and TSC1-TSC2. Increased risk of these mutations may also be due to environmental reasons, complications during pregnancy, or older aged parents.

SHANK

Genes encoding for the SHANK protein are seen in individuals with ASD. These proteins are known as scaffolding proteins, which function in synapse morphology. When this protein is mutated, which has been performed in animal studies, various symptoms and behaviors that fall under ASD are observed. Motor behavior and social interaction is most noticeably affected.

UBE3A 

UBE3A is a gene that is essential for neuronal growth and codes for an enzyme that breaks down other proteins within the cell. In ASD, this gene has been noticed to be mutated or deleted. Without this gene, an important protein known as ARC continues to be made. The ARC protein weakens the synapse by removing AMPA receptors. AMPA receptors are integral to plasticity and synaptic transmission. A weakened synapse leads to ASD related symptoms.

MECP2 

MECP2 acts a transcription repressor and is involved in ensuring that DNA is folded into chromatin properly. When this gene is mutated, DNA is not folded properly causing an imbalance between inhibition and excitation. Too much or too little MECP2 protein leads to ASD symptoms.

TSC1-TSC2 

TSC1-TSC2 are proteins that work closely with growth factors such as brain derived neurotropic factor (BDNF). When these proteins are activated a, GTPase activating protein (GAP) is reduced leading to a cascade of proteins being activated. Rheb is activated, followed by mTOR. When TSC1-TSC2 proteins are mutated, the activation cascade is disrupted leading to abnormal protein synthesis and ASD symptoms.

These genetic factors are just some of the reasons for the vast array of symptoms and behaviors associated with ASD. The effects of all disorders under the umbrella term are unpredictable and wide ranging. On top of that, many of it is not completely understood.

The umbrella has continued to expand. As more research continues to be done, the umbrella will most likely continue to expand. Whether you think it is right to have a broader spectrum or not, we can all take more time to brainstorm and educate ourselves on what falls under the umbrella.

The film, Rain Man, successfully brought massive public awareness towards one specific autism spectrum disorder. It is up to us, however, to maintain a momentum of interest and action so that efforts in understanding ASD and treating the disorders under the umbrella can continue to improve.

To follow the research summarized above, follow:

https://www.nature.com/articles/nature11860

To continue your education on ASD, follow:

https://www.mayoclinic.org/diseases-conditions/autism-spectrum-disorder/symptoms-causes/syc-20352928

Austism spectrum disorder (ASD) includes a large range of conditions that is characterized by difficulties with social skills, communication, and repetitive behaviors. As of right now, there is no cure for ASD, and the current treatments include behavioral management therapy, medication treatments, nutritional therapy, and more.

Since ASD is largely a genetic disorder, it is justified to presume any effective cure would be based in gene altering practices. However, with gene altering technology comes things such as protecting and securing DNA data bases and each family’s confidentiality. The most controversial of all considerations might be the abuse of further research of gene altering technology to moving into the realm of eugenics, which is controlled breeding by choosing favorable genetic traits. This begs the question, should we knowingly alter the genes of an unborn child because those genes might lead to ASD?

The Debate

Many believe a cure should be pursued. Those suffering from or supporting those that suffer from the more severely debilitating symptoms of ASD have seen the worst of what the disorder can bring: extreme difficulty with sleeping, focusing, communication, and much more. Those advocating for a cure might not see ASD as being an integral part of who someone is but more of a chain holding someone back from living a fulfilling life.

But of course, not everyone on the spectrum suffers from severe symptoms. Many that have experience with the less severe symptoms advocate that a cure is an unethical pursuit. They believe that by pursuing a cure for autism it would lead to completely and irrevocably changing a person, and there is no justifiable reason to do so.

A Slippery but Useful Slope

The pursuit of a cure would undoubtedly lead to major advancements in understanding the human genome with hopefully having the ability to know exactly what genes cause ASD and why. But the case made here is if a cure is pursued, one must be deliberate and proactive in their research.

This is to say, with the knowledge of how to alter gene expression ultimately comes the ability to change genes whether or not they are harmful, so preventative laws or policies to avoid the use of eugenics must be enforced. Pursuing scientific advances isn’t always ethical, and in the case of gene altering technology, crossing the line can be far too easy and appealing. (If you want to read more about the ethics of gene altering technology, click here.)

Freedom is Key

Ultimately, the choice of whether to change a child’s genome before they are born to prevent ASD would be left up to the parents. If this were to ever become a reality, it should never be forced upon a parent given the sheer lack of knowledge of how ASD would affect the child in the future.

The Science

As mentioned before, ASD is predominantly a genetic disorder. Furthermore, the implicated causes for ASD are genetic in nature.  A mutation in the following proteins are linked to certain forms of ASD:

• L-VSCC in Timothy syndrome
• RSK2 in Coffin-Lowry syndrome
• CBP in Rubinstein-Taybi syndrome
• Ube3A in Angelman syndrome
• MECP2 in Rett syndrome

Additionally, strong evidence has linked mutations of neuroligin and neurexin synaptic adhesion molecules to ASD. Neuroligin and neurexin work together to modulate the formation and function of synapses. For example, neuroligin-3 ASD missense mutations in knock-in mice showed similar characteristics known to ASD.

Another example of a gene mutation linked to ASD is the mutation of the FMR1 gene that causes Fragile X Syndrome, which leads to the decreased expression of the protein FMRP, which regulates the translation of certain mRNAs at the synapse.

When we hear the word “autism,” there are likely several things that come to mind. For many, it’s likely the image of the stereotypical “gifted” child – a child who often talks obsessively about unusual subjects, speaks in a specific tone, has trouble with social interactions or cues, and struggles to make friends. Maybe it’s the vaccination debate – if you’ve been around long enough, you’ve likely heard the social argument that “vaccination causes autism.” Or perhaps you’ve heard the term “autistic” thrown around as a derogatory slang term. Then again, some of us don’t even know what “autism” exactly is. Whatever it may be, the ever expanding subject of autism has made its way into modern day media through news, entertainment, stories, and even TV shows such as Netflix series Atypical, shaping the way that we define or view autistic individuals. Despite the stereotypes or television tropes you might have become familiar with, autism disorder is, quite literally, a spectrum – a complicated disorder that presents uniquely for each person, and one we are still far from understanding. Fortunately, advancements in research have allowed us to peer into the minds of these brilliant, fascinating individuals, and like most disorders, an understanding starts with studying things down at the cellular level. In this way, autism disorder is no different from the rest.

What is Autism?

The begging question still stands – what exactly is Autism Spectrum Disorder? Autism spectrum disorder, or ASD, as defined by the CDC, is “a developmental disability that can cause significant social, communication, and behavioral challenges.” This definition seems, frankly, quite vague. Typical symptoms include:

• Intellectual and verbal impairments, especially during development, failure to hit developmental milestones
• Repetitive actions and motions
• Problems with coordination and motor development
• Trouble interacting with, but having interest in others
• Prefer to be alone and avoid physical contact
• Trouble reacting to social cues
• Avoiding eye contact
• Does not understand sarcasm
• Lose skills they once had over time
• Hyperactivity
• ADHD
• Unusual reactions, temper tantrums
• Aggression and self injury
• Digestive or gastrointestinal disorders
• Potential seizures

For a full list of symptoms, be sure to visit the CDC’s ASD symptom page here.

But what’s the deal with the word “spectrum?” Because the severity of autism manifest themselves to varying degrees, the disorder is characterized by a spectrum. The stereotypical “gifted” child often depicted in media is an example of High Functioning Autism, characterized by someone who can function normally. For example, someone with Asperger’s Syndrome has a mild form of autism. They likely have deficits in social interaction and may either excel in school, or be stressed out by the social situation, but otherwise they can perform day-to-day functions. On the other end of the spectrum, there is Severe Autism. In this form of the disorder, those afflicted might struggle to perform day-to-day tasks such as getting dressed, eating, and even walking and sitting. The graphic below summarizes three notable markers on the autism spectrum.

Symptoms often manifest when a child is 2-3 years of age, and the disorder is often diagnosed around this time as well, though diagnosis is more common in males than females. Above all, what can explain the curiously diverse range of symptoms seen in a single disorder? Keep reading to find out!

[Autism spectrum disorder] is a developmental disability that can cause significant social, communication, and behavioral challenges

Where Does the Spectrum Arise – Why does ASD Happen?

As we learned, autism can present as various combinations of symptoms across the spectrum. Behind it all, though, what happens in the body that leads to such a vast array of symptoms? What dictates whether or not a child will be born “gifted?” Like many pathologies and disorders in modern medicine, it all traces back to the brain – that big, pink, wrinkly organ that dictates our every move, behavior, judgment, and thought. Down to the core, autism is largely a genetic disorder, meaning that the changes in the brain that predispose someone to autism are already there, even before birth (though that’s not to say that behavior of autistic children can’t be shaped by their social environment as well). Other factors, such as exposure to toxins and parental age can increase a child’s likelihood of developing autism as well. Despite some misconceptions, autism is not a result of poor parenting, and it is a legitimate brain disorder – thus the term “autistic” should not be used as a negative label or slang term.

Fortunately, recent research has shed some light on the microscopic processes that lie behind the broad spectrum. Normally, when learning, neurons in the brain fire and result in one of two processes: long term potentiation (which results from high intensity firing and memory formation, such as reciting a word over and over to remember it) or long term depression (which results from low intensity firing and weakening of memory formation). To learn more about LTP , LTD, and synapses, be sure to visit my previous blog post, or the previous links. Both processes must be regulated to ensure a child’s brain develops properly, with just the right amount of neural connections, or synapses, in a process called pruning.

The best way to explore the spectrum is to find which genes are affected to begin with. Notably, these include:

• UBE3A: This gene is mutated or deleted in ASD. UBE3A normally codes for an enzyme that breaks down substances in cells. One of these substances is another protein, named ARC. The job of ARC is to reduce neuron excitation by pruning and weakening a synapse by removing AMPA receptors. When there’s too much ARC, too many of these receptors are removed, promoting LTD and decreasing synaptic strength.
• SHANK: This creatively named protein refers to a protein found in synapses. It is quite literally a scaffold that supports the placement of receptors. It’s safe to say that mutations in genes that code for SHANK proteins could result in defective scaffolds and poor or irregular placement of receptors in a synapse. This could lead to deficits in learning, memory, and development.

Depending on the severity of the mutation and the degree of biochemical damage done downstream, autism symptoms can manifest at various points along the spectrum. Because autism is so complicated, another easier way to understand the spectrum is by studying other disorders that share common mutations with the disorder:

• Angelman Syndrome: This genetic disorder often has a comorbidity of ASD and shares many common symptoms. Similar to ASD, it is marked by the loss of a gene called UBE3A.
• Tuberous Sclerosis: Also a genetic disorder, this syndrome is marked by mutations in genes called TSC1 and TSC2. Normally, these genes are tumor suppressors. Mutations in these genes might lead to the development of benign tumors, or too much growth or hyperconnectivity as seen in ASD.
• Fragile X: Yet another genetic disorder (see a trend here?). The gene at focus here is called FMR1, found on the X chromosome (as noted by the name, Fragile X). Mutation to this gene prevents the production of a protein called FMRP, which is important in proper brain development.

By connecting what we know about autism and similar disorders, we can get a small glimpse into the microscopic world that creates the spectrum and each unique case of autism. At the end of the day, some might find themselves asking, should we cure autism, if the advances of modern day technology and genetics allow us to? Throughout history, autism has been viewed as a gift, a blessing, and for some, a curse. For some, if a cure allows their child to eat, talk, sit, and even walk on their own, then a cure might be the blessing they need to improve their child’s quality of life. But then again, history has seen dozens of gifted individuals who have been, or are suspected to have been, on the spectrum. Among these are Hollywood director Tim Burton, actor Dan Aykroyd, and Scottish artist Susan Boyle. Records even suggest that the genius himself – Albert Einstein – might have shown symptoms characeristic of the spectrum! It’s no doubt that the contributions these people brought to the world have been gifts. But whether you view autism as a blessing or a curse, it all goes to affirm one true statement – at the end of the day, we are all, simply, unique.

For more information about autism, be sure to visit this page, by the Autism Speaks program.