Cobbers on the Brain

The Story of Schizophrenia

With symptoms ranging from quietness to experiencing hallucinations or delusions, schizophrenia is a mental health illness that is difficult to diagnose and difficult to biologically analyze. Generally, the symptoms of schizophrenia are manifested in individuals who are in their late teens to early twenties, but brain development before being born can cause varying susceptibility to the disorder.

It is thought that certain messenger chemicals in the brain (neurotransmitters) causing an imbalance of communication between neurons play a large role in the development of schizophrenia. The image below represents the hypothesized neurotransmitters/pathways responsible for the three classes of symptoms seen in schizophrenia: positive, negative, and cognitive.

Certain drug treatments target or act with these neurotransmitters to alleviate symptoms of the disorder. One example of this is a drug that blocks the receptor that dopamine (a neurotransmitter) would normally bind to. How would this help alleviate symptoms? After dopamine is bound to it’s receptor, Wnt, a signaling pathway in the brain can’t function properly. The final affect of this inhibited signaling is gene expression that is improperly regulated.

Artstract: The story of Wnt. This image depicts the Wnt signaling pathway including two scenarios, one with Wnt ligand binding and one without binding. Wnt binding is implicated in regulated gene transcription through TCF/LEF mediated transcription.

This is not a specific picture of schizophrenia, but does help to explain the large variety of symptoms and irregularities seen in the brains of individuals diagnosed with the disorder.

The unfortunate truth for schizophrenia is that there is still a long way to go before the full mechanism of the disorder is understood. For now, there is no real way to “cure” schizophrenia, and treatment options focus on alleviating the symptoms of faulty brain wiring, and hopefully leading to a more manageable and independent life. In future research, exploring treatment options including the Wnt signaling molecules as target cells could provide some relief from the wide range of symptoms. Overall, more understanding of specific mechanisms detailing the schizophrenia story is needed to truly unpack how the disorder is manifested and experienced.

References/Further research

• https://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml
• https://www.placesforpeople.org/hear-our-voices/
• http://www.mentalhealthamerica.net/conditions/schizophrenia
• https://youtu.be/6Qpl-3eR6eE
• https://www.placesforpeople.org/hear-our-voices/

WARNING: If you or your family have a history of mental illnesses or vertigo, we strongly advise that you DO NOT participate in this simulation as it could potentially trigger those illnesses to begin.

Image References

• https://progress.im/en/content/dopamine-synthesis-common-factor-genetic-and-environmental-risks-schizophrenia
• https://www.inspiremalibu.com/blog/drug-addiction/schizophrenia-and-the-risks-of-substance-abuse/
• https://www.mdpi.com/1422-0067/18/8/1689/htm

Schizophrenia is a severely debilitating disease for one’s psyche. Unfortunately, the only thing we have to separate reality from nightmares for individuals with this disease is constant use of mind-numbing anti psychotics.

What is the disease?

Schizophrenia is a psychiatric disease that results in severe impairments in daily life. Some common positive symptoms of schizophrenia are delusions, hallucinations, and disorganized thinking. This means that the person has a difficult time producing a normal perception of the world. Many see or hear things that are not there and have abnormal beliefs or paranoia. Some common negative symptoms of schizophrenia are lack of hygiene, reduced eye contact, and lack of emotion. The combination of all of these symptoms make it very difficult to live a normal life and people with schizophrenia are often medicated all of their life to improve these symptoms.

Looking beyond the symptoms

Recent research on the neural cause of schizophrenia has uncovered some clues as to why this disease occurs. The Wnt pathway in neurochemistry is a sequence of cellular events often used to facilitate the development of the central nervous system. It controls the amount of β-catenin in the cytosol of neurons which is a useful molecule for the transcription of developmental genes. It is believed that this Wnt pathway is abnormal in schizophrenia patients causing abnormalities in brain development. Neurons end up connecting incorrectly in the pre-frontal cortex and result in many of the common schizophrenic symptoms.

How should this disease be addressed in the future?

Reducing the severity of schizophrenic symptoms is all we have at this point in the treatment of schizophrenia. Anti psychotics are used to essentially “numb” the person from their positive symptoms to better help them to connect to reality. However, these drugs to not treat the disease at its source. The abnormal brain connections seen in schizophrenia still exist while anti psychotics are being used leaving the person still susceptible to emotional and social impairments. Although the use of anti psychotics is helpful for some symptoms, it is in no way a cure.

In the future, it may be beneficial to look deeper into the underlying causes of this disease. Recent research has uncovered many things that we did not know about schizophrenia but has created just as many new questions. What genes are involved? How is development changed from abnormal Wnt signaling? What specific brain regions are impacted? All of these questions need to be answered more entirely to begin developing a cure for this disease. Rewiring an adult brain is a tall order and perhaps we will never get to the point of curing this disease but will find effective ways at preventing it. Targeting the Wnt pathway specifically may bring new light in the treatment of schizophrenia. Perhaps at an early age everyone would get a checkup on their risk of getting the disease based on gene expression tests. We would then know if Wnt would need to be inhibited or activated to prevent abnormal development.

It has become very apparent that the neural mechanism of schizophrenia is unimaginably complex. No one in the world can tell you exactly what is going on in the brains of schizophrenic patients but one thing is certain; further research is necessary to effectively treat and prevent this disease. Treatments we have today do help but have limits. People on anti psychotics essentially have their personalities taken away from while being numbed with schizophrenic drugs. Sure their positive symptoms improve but they are stripped of who they are as a person. It is important for us to understand how treatments of complex diseases like schizophrenia have consequences that we do not always think about.

When you hear the world schizophrenia what comes to mind? Crazy? Violent? Perhaps unpredictable? In the world we live in media influences our idea of what metal illness is, and how it affects a person.

In order to understand this metal illness, let’s dive into the science behind schizophrenia.

What’s going on in the brain?

There is a pathway in the brain called the dopamine pathway, which plays a large role in the function of the brain. In a properly working dopamine pathway the enzyme, GSK3 or glycogen synthase kinase 3, plays a key role in the regulation of the dopamine pathway. GSK is activated by the dopamine pathway with the help of the molecule Akt, which phosphorylates GSK to its active form.  However, in schizophrenia GSK3 becomes overactive due to too much signaling of the dopamine pathway. This over-activation leads to behaviors associated with this mental illness.

There is another pathway, the Wnt pathway, where GSK is affected in a brain with schizophrenia. Dopamine receptors are also shown to inhibit Wnt signaling. This pathway works to regulate the enzyme GSK, by inactivation through the presence of  ß-Catenin. If the balance of  ß-Catenin is off, GSK becomes overactive, and much like the previous example leads to the symptoms of schizophrenia.

Risk Factors

There are many different risk factors associated with schizophrenia. Having a family history of illness is the highest risk factor for schizophrenia, however there are also many environmental factors that can cause an increased risk of the disorder. Childhood trauma is another risk factor schizophrenia. Dopamine plays a large part in the interpretation of threat-related stimuli. When a person experiences trauma they have increased levels of dopamine. These increased levels puts an individual at a higher risk.

Maternal infection, along with other prenatal risks increase the odds of developing schizophrenia. During the first trimester if the mother is exposed to influenza, or during the second or third trimester is exposed to rubella or a respiratory infection, that child is at an increased risk for the development of schizophrenia. Birth month is also a risk factor. If a child is born in late winter, or early spring they are at an increased chance of developing the disease. This is thought to be caused by the mother suffering from seasonal depression.

While these are not all of the risk factors, these are some of the biggest, and or most unique risk factors associated with schizophrenia.

Treatments

As with many mental illnesses, current treatments of schizophrenia focus on treating the symptoms of the disease rather than the cause. Due to the fact little is know about the cause of schizophrenia there are no medications that treat the mechanisms behind the disease. Medications that are used to help with symptoms of schizophrenia focus on inhibiting GSK. Lithium is most often used due to the fact it directly inhibits the activation of GSK. In addition, dopamine blockers are also used to help inhibit the dopamine pathway, which in turn inhibits GSK.

What does this have to do with preconceived notions?

It is important to remember that media does not always accurately portray schizophrenia. For many people their only information about this disease comes from movies, and TV shows. This leads to the stigma surrounding schizophrenia, such as a person with this disease is violent, delusional, and experience intense hallucinations. By educating the public about the science behind schizophrenia it can help end the negative stigma surrounding mental illness. It is also important to remember that a person is more than their diagnosis. By proving empathy for those dealing with schizophrenia you can help play a role in ending the stigma surrounding mental illness.

Image 1: https://newroadstreatment.org/signs-of-schizophrenia/

Image 2: http://schizophrenia.com/hypo.php#

In the DSM V, a diagnosis of Schizophrenia involves a range of cognitive, behavioral, and emotional symptoms–including delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms such as diminished emotional expression. These symptoms must be persistent for a consistent period of time, as defined in the DSM V depending on the symptom category, prior to diagnosis.

Due to the portrayal of Schizophrenia in the media, many individuals incorrectly assume that all individuals with Schizophrenia experience intense hallucinations, delusions, and violent outbursts. Although often inaccurate, these portrayals are usually the only exposure to psychiatric disease that an individual may experience–especially Schizophrenia. Research has shown that the movies which include a character with a severe psychiatric illness also tend to be the movies with the most inaccurate portrayals of mental illness. A content analysis on movies depicting at least one character with Schizophrenia was found to most frequently display the negative symptoms of the illness, including delusions and violent behaviors toward self and others. The perpetuation of these negative stereotypes regarding Schizophrenia misinform the public and contribute to the stigma preventing further research into the condition.

Although delusions and hallucinations are symptoms of Schizophrenia, other symptoms exist too. And despite the media’s portrayal of violent individuals with Schizophrenia, very few individuals with the condition become violent. Additionally, these individuals are not “psycho” or “crazy.” Every symptom that an individual with Schizophrenia experiences is due to their neurological functioning. Educating the public remains an important step in humanizing and de-stigmatizing Schizophrenia. Likewise, it is important to note that Schizophrenia can be successfully treated and managed. Just because someone has been diagnosed with Schizophrenia doesn’t mean that they cannot have a fulfilling life.  

https://ps.psychiatryonline.org/doi/10.1176/appi.ps.201100371

https://www.helpguide.org/articles/mental-disorders/schizophrenia-signs-and-symptoms.htm

The Basics

Symptoms of Schizophrenia can vary greatly in the ways they present themselves in different people. This mental disorder is defined as the abnormal interpretation of reality.  The symptoms displayed in Schizophrenia include, hallucinations, delusions, extremely disordered thinking and behavior that impairs daily functioning. Hearing voices, impaired communication by disorganized speech, and lack of emotion or eye contact are common signs of Schizophrenia.

            A major sign of Schizophrenia in the brain is a significant loss of gray matter in the medial and superior temporal regions as well as in the prefrontal region of the brain. Gray matter is crucial to the function of episodic memory, processing auditory information and short-term memory.

What’s going wrong in the brain?

In a properly functioning dopamine pathway, there is an enzyme that plays an important role in regulation and ensuring the desired outcomes of the pathway are occurring. This enzyme is called glycogen synthase kinase 3 (GSK3). The main problem in schizophrenia is the overactivation of GSK which leads to the symptoms experienced in the disorder. The dopamine pathway functions to activate GSK through with the help of another molecule, Akt which phosphorylates GSK to its active form. However, when there is too much dopamine signaling, it leads to the overactivation of GSK in this pathway.

The Wnt pathway is another place where GSK is being affected in schizophrenic brains.  The dopamine receptors were also shown to inhibit Wnt signaling. This pathway works to regulate GSK by inactivating through the presence of ß-Catenin. When the balance of GSK is off and causing GSK to be overactive, that is when schizophrenia symptoms begin to develop.

Risk Factors

            Having a family history of Schizophrenia is the highest risk factor and significantly increases the chances of developing this disorder. However, other environmental factors can also influence the likelihood of developing Schizophrenia. Experiencing trauma during one’s childhood can increase the risk for the development of Schizophrenia. Dopamine plays a role in interpreting threat-related stimuli, which can lead to the formation of delusions observed in schizophrenia. The increase of dopamine levels in people that have experienced traumatic events puts them at a higher risk of developing this disorder.

Additionally, there are some prenatal risks associated with the development of schizophrenia. If the mother is exposed to influenza during the first trimester, or acquires rubella or a respiratory infection, the chances of the child developing schizophrenia significantly increase. Migration is also a significant risk factor if people are migrating to regions where they are exposed to viruses that their bodies have not previously been exposed to.

Treatments

Current treatments of schizophrenia focus on treating the symptoms rather than the cause. This is because there is a significant deficit in the understanding of the biological mechanisms of the disease. Therefore, it is difficult to come up with something that targets what is still unknown. Medications used to treat schizophrenia work to inhibit GSK. Lithium is most commonly used because it directly inhibits the activation of GSK. Additionally, dopamine receptor blockers are used because too much dopamine is being produced so through inhibiting the dopamine pathway, the activation of GSK is inhibited.

Imagine sitting at your desk in your bedroom while trying to hurriedly finish up your homework that is due tomorrow. While focusing intensely on a problem, you begin to hear whispering. Thinking that it is just a result of the silence in your room mixed with exhaustion from studying all evening, you brush it off even though the whispering persists. After you get ready for bed and are lying still trying to fall asleep, the whispering seems to get louder and you cannot help but feel as though someone is there whispering into your ear. You want to speak out to the whispering, but feel confident that there is no one there.

This could be just one symptom of schizophrenia, as auditory hallucinations are the most common type of hallucination occurring for most people with schizophrenia. There are many other symptoms, including:

• delusions
• disorganized thinking or speech
• disorientation
• memory loss
• disorganized behavior
• abnormal motor behaviors
• speech issues
• lack of ability in various areas

The cause of schizophrenia creates a difficult conversation, as there are many different theories. However, most theories conclude that schizophrenia is caused by some type of genetic predisposition combined with environmental factors that allow the affected genes to become expressed. There are also risk factors that can increase the likeliness of developing schizophrenia, including:

• family history of schizophrenia
• increased immune system activation
• being born with older parents
• some pregnancy and birth complications
• taking mind-altering drugs during teens

Some of the risk factors for schizophrenia correlate with the environmental factors that can also increase the development of schizophrenia:

• childhood trauma
• prenatal risks
• migration
• place of birth
• infections

When looking at how schizophrenia occurs in individuals, it is often a misconception that these individuals are in control of their symptoms and actions, causing them to be stereotyped against in society. The true cause of schizophrenia is located in the brain and in many different brain regions. The brain regions that are most affected and involved in schizophrenia are:

• gray matter
• dorsolateral prefrontal cortex
• inferior prefrontal cortex
• medial temporal cortex
• primary auditory cortex
• visual cortex
• auditory language regions such as Wernicke’s area and Broca’s area
• basal ganglia

When seeing the number of brain regions involved in schizophrenia and how they impact the symptoms most generally exhibited, it becomes clear that schizophrenia is a much more genetic based condition and although influenced by environmental factors, is definitely not directly caused without any type of genetic influence.

As previously discussed, the treatment of schizophrenia is a tricky one and there are constant developments in the best and most effective ways to treat individuals with schizophrenia. The most common ways used today are medication and psychosocial treatment, with many people with schizophrenia requiring frequent visits with a psychiatrist. Below is a link to a video of an emerging finding of a schizophrenia “switch” and how it may impact treatment:

https://www.youtube.com/watch?v=m6YE6BJVwtg

The lifestyle of someone living with schizophrenia can be very difficult and often comes with many judgements and obstacles. First, finding the correct combination of medication for individuals with schizophrenia is a very long and difficult journey and can be extremely expensive and tasking on the individual, especially if the medication does not work immediately or is the wrong combination and the symptoms are not controlled. Second, most people in the general population have preconceived stereotypes about those with schizophrenia based on what they have heard, what they have understood from others, or what they have seen in media. Finally, managing symptoms with or without medications for individuals with schizophrenia is very difficult and their symptoms often arise without notice and in unexpected ways.

http://2018neurochem.pbworks.com/w/page/129829617/Wnt%20and%20Schizophrenia

“Stressful events evoke a long-lasting impact on behavior”

In our society today, it is no secret that mental illness is a major topic of discussion. Mental illness disorders affect ourselves, our friends, family members, colleagues, and more. Specifically, anxiety disorders are the most prevalent mental illness in the US. 18.1 percent of adults suffer from this illness. 70 percent of adults in the US have experienced a traumatic event at some point in their lifetime. An estimated 8 percent of adults have PTSD in the US at any given time. These statistics show that there are some underlying factors with these illnesses. Is it all environmental, genetic, only in our brain, or a mix of everything? Below, we will explore parts of the brain that are in overdrive when dealing with illnesses such as PTSD and anxiety.

When a person is under stress, research has found that learning and memory processs can often get messed up. The area of the brain that have shown this happening is the limbic system, which is made up of the thalamus, hypothalamus, hippocampus, amygdala, and the fornix. The area to focus on with anxiety but especially with PTSD is the amygdala. The amygdala is responsible for the preception of, response to, and memory formation of emotions, especially fear. This means that when a person experiences a negative emotion that is associated with a traumatic event, their amygdala will be sure to remember it. Psychologists often call this idea emotional learning. For example, if a child gets bit or attacked by a dog, that is clearly a traumtic childhood event. The amygdala will take the negative stimulus of getting bit by a dog and store that traumatic memory fairly quickly. The negative emotions that were felt during this event are then associated with the dog biting event, which includes dog barks, dog parks, and even simply seeing a dog in public. The amygdala is a major reason for why getting bit by a dog as a child can cause someone to have a phobia of dogs for the rest of their life.

With PTSD and the amygdala, these two words go hand in hand. Several studies have shown that in patients with PTSD, there was hyperactivity, or a large increase in activity, in the amygdala when stimuli were shown that were connected with their traumatic experience. This stimuli can range from pictures from an event, talking through the specific details of the event, noises, etc. This hyperactivity occurs directly after the traumatic event as well as during sessions where triggering stimuli is shown. This all is basically general knowledge. What is not is that in stressful or traumatic events, many parts of the brain are inhibited or weakened, such as the prefrontal cortext. The amygdala is opposite. Because this part of the brain consolidates so many of these traumatic memories, when the memories are triggered, the amygdala springs in to action.

A more recent finding with these PTSD brains and the amygdala is that the same hyperactivity that was found when the patient was shown associated stimuli was also found when shown material unrelated to their event. This included pictures of random people with fearful expressions or event doing oddball, continuous tasks. This finding may suggest that brains with an overactive amygdala may be over-resoinding to inputs that are not deemed dangerous or traumatic to a brain that does not have PTSD. My question is this: In PTSD brains, can there be such a thing as a happy medium of your amygdala detecting what is truly dangerous and what is not? PTSD is a horrible illness that effects far more than those traumatic memories that are stored away.

It is already known there are many factors that contribute to PTSD and anxiety disorders. Traumatic events, memory consolidation, and the amygdala are only a few of them. Sometimes, diving into one part of the big problem makes it seem less daunting. If a researcher can figure out how to keep the amygdala to a normal activity rate, who knows what else could be solved?

https://www.sciencedirect.com/science/article/pii/S2352289514000101

https://pdfs.semanticscholar.org/d3e0/f4c57b4cd63ec0ee1d2a447bef25d960b65c.pdf