Cobbers on the Brain

I think it’s one thing to be health condition but, it’s another to be able to get the help that you need. I grew up in an area that used to see mental illness as evil spirits, bad karma, family misfortunes. This not only caused stigmatization and discrimination against mental health patients but it also prevented the patients of the disease to be able to get the adequate help that they need.

In other words, Schizophrenic patients are prone to human rights violations in society and even in mental health facilities (WHO,2019).

Mental illnesses that attack the central nervous system such as Schizophrenia are mostly genetic and/or can be triggered by environmental stressors such as drug abuse, domestic abuse, other neurological illness, etc.

Schizophrenia is a psychosis largely characterized by cognitive, emotional, physical distortions. The actual cause of it is not fully known but hypotheses have been made of the possible reason behind the gradual deterioration and based on the symptoms. There are cognitive, positive, and negative symptoms. Positive include delusions, negative include lack of emotional expression, and cognitive symptoms include the inability to make decisions (PsychCentral, 2021).

Considering that a large probability of proneness to schizophrenia is linked to genetic and early development, it is important to understand the role of the Wnt signaling pathway in this cascade

The Wnt signaling pathway

It is involved in cell maintenance and renewal. Basically, Wnt ligands bind their receptor complex which causes the recruitment of APC to the membrane, facilitating the dissociation of the destruction complex. This results in decreased phosphorylation of β-catenin. When the destruction complex is dissociated, β-catenin is then able to get into the nucleus and influence the targeted genes.

In a study on the “Convergent functional genomics of schizphrenia“, the targeted genes, in this case, researched in different groups included African Americans and European Americans, and were graded and ranked out of 5points as seen in the illustration below

The top genes targeted include DISC 1 (protects synaptic plasticity), and decreased expression of MBP ( involved in protein formation for myelin formation). Both these genes for example allow responsiveness to stimuli and learning which is seen to be hindered in schizophrenic patients.

The question at this point is how can we better deal with it, in terms of prevention, treatment and awareness. Given that it can be heredited, to what extent to we start treating it? Do we wait for symptoms to show once the disease has progressed? Can technology and gene therapy be the future for mitigating schizophrenia gene vulnerability? And how can Schizophrenic patients get affordable help regardless of their economic standpoints?

These are the big questions to think about in my opinion in order to progress more in the treatment of schizophrenia for long-term.

References:

1. John M. Grohol, Psy.D. “Schizophrenia Symptoms: Negative, Positive, and More.” Psych Central, Psych Central, 4 Feb. 2021, https://psychcentral.com/schizophrenia/schizophrenia-symptoms?utm_account=&utm_medium=cpc&utm_semcampaign=&utm_adgroup=&utm_match=b&utm_query=&utm_term=&utm_content=540967374863&utm_source=google&marinid=s&gclid=CjwKCAjwhuCKBhADEiwA1HegOXz527pV8bxnc59QXv7zMOppnMTflRYTKeTiTg13jh_FpCC06OhxQRoCS3UQAvD_BwE.
2. “Schizophrenia.” World Health Organization, World Health Organization, https://www.who.int/news-room/fact-sheets/detail/schizophrenia.
3. Ayalew, M, et al. “Convergent Functional Genomics of Schizophrenia: From Comprehensive Understanding to Genetic Risk Prediction.” Nature News, Nature Publishing Group, 15 May 2012, https://www.nature.com/articles/mp201237.

Mental illness is a rising phenomenon in our society, and it is something that as a society we have failed to appropriately address. People with mental illnesses are often shunned or downright discriminated against for something that no one can control. Hopefully this post will shed some light on the concept of mental illness and what can be done to help rather than hinder the efforts to help people with mental illnesses.

What is a Mentally Ill Person? And Can They Control It?

Mental illness is often considered an attention seeking tool or lumped in with general psychosis, but neither could be farther from the truth. Mentally ill people have a chemical or genetic dysfunction that is causing either direct damage or indirect changes to the way the brain functions. For example, schizophrenia is based on a pathway called the Wnt pathway, when any one part of that pathway goes wrong the chances of developing schizophrenia skyrocket. Schizophrenia can also be caused by a number of genetic issues, but the moral of the story is that mental illnesses like schizophrenia are caused by major impacts to the brain and are under no control of individuals. More on schizophrenia and Wnt signaling

What Are Symptoms of Mental Illnesses?

The most important thing to know about mental illness symptoms is that no two people present their symptoms in the same way. Sometimes the symptoms are not visible to outside view, which further complicates the matter. Using schizophrenia as an example, there are symptoms that are described as both positive and negative. Positive symptoms are symptoms specific to schizophrenia, which is primarily described by hallucinations and delusions that feel completely real to the person. On the other hand, negative symptoms could be cause by a variety of things: these symptoms include lack of emotion, lack of joy, speech issues, and lack of initiative. Figure 1 below visualizes the important distinction between these symptoms. Not only are these symptoms challenging to see and diagnose, they also are very individual based on the type of hallucinations and type of negative symptoms experienced. More on schizophrenia symptoms

What Are We Doing, and What Can We Do?

Mental illnesses are challenging to treat due to their direct impact on the brain and the stigma that comes with being mentally ill. There are a fair amount of medicines that focus on management of symptoms, such as anti psychotics and lithium, but in addition to symptoms and varying effectiveness these treatments don’t do much to actually manage schizophrenia in a patient. When the illness becomes too overwhelming or the behaviors become out of control, hospitalization may be necessary, but for the majority of other people impacted by mental illness they live in the same world as neurotypical people. The best way to “treat” schizophrenia and other mental illnesses is to interact with these people with empathy and grace. People may seem weird or even dangerous to you, but it’s entirely possible they just have a different brain chemistry than you. The more society begins to understand and welcome these people, the better off they will be and the better science can begin to understand these people. As the Platinum Rule says; treat others the way they want to be treated

Figure 1; Picture Provided by Me

Alright, before you go any further in this blog post please just know that the information provided might make for an uncomfortable read. Now that you’ve been warned…. let’s begin. We’ve talked for a while now about schizophrenia and the underlying mechanisms that are related with the disease. In our conversations we’ve mentioned the side effects of antipsychotics; weight gain, dry mouth, constipation, hormonal imbalances, muscle twitches, etc. But it is important to look at the past and see where we have come as a scientific community. Treatments for schizophrenia have not always been so mild, if you can even consider the above side effects as being mild. Although I am a huge fan of imagery for learning I will not be including any images of many of the procedures that are listed. Reading about some of these things is distressing enough, seeing them seems unnecessary.

So, we are all probably aware that we require insulin to stay alive. As a reminder insulin acts on a tyrosine kinase receptor. Although we require insulin, more importantly we require regulated levels of insulin. If we receive excessive levels there is a potential that we could go into a coma. Medical professionals in the past thought that these comas had the potential to “jolt” someone out of their current mental illness. So, over the course of several weeks they would directly inject enough insulin to put someone into a coma, then after several hours they would administer glucose to bring their patients out of their induced state. Over the course of treatment, insulin levels would be increased until the staff felt that the treatment had reached its maximum “helpfulness.” What could go wrong when you induce 30-50 comas in the span of a month or two? Well of course the answer is a lot, some of the side effects included obesity, brain damage, and death, none of which sound overly pleasant to me. Sadly, even with extensive use of this treatment there was never any proof that inducing comas was an effective treatment method, yet the technique was used for quite a long time (JSTOR DAILY).

Wow, such a pleasant start to this blog post, let’s get into a slightly less appalling technique… the use of trephining, leucotomies, and lobotomies. Of course today we look at these techniques and consider them to be rather barbaric, although they did have the potential to erase behaviors attributed to schizophrenia. Trephining we are probably pretty familiar with, the surgery essentially boiled down to drilling a hole into someone’s head in order to “let out the demons!!!” I mean come on, of course that’s what drilling a massive hole into someone’s skull would do for them, there couldn’t possibly be any negative side effects. Below you can see the results of these surgeries, many of which people surprisingly survived (Faria, M., 2013). Sadly though there weren’t any improvements for the most part because demons are not known to actually reside in the skull. If there was improvement it was because the technique happened to damage brain tissue that coincidentally stopped the target behavior. Although it was never stated that these surgeries were done to schizophrenics one can assume that they were likely the victims of these procedures. “Madness” and “demons” are similar to voices and other positive symptoms of schizophrenia, there wasn’t a real definition for the disease until the end of the 19th century.

Figure 2 

Figure 3

Leucotomies and lobotomies are very similar, just with a small difference between the two. Leucotomies focused on destroying the underlying white matter in the brain, while lobotomies were more focused on the prefrontal cortex and destroying the exterior grey matter (Faria, M., 2013). Look below for a visual representation of the separation between grey and white matter within the brain.

Figure 4

Although there is technically a distinction, lobotomies are usually thought of as the accumulation of both procedures. Interestingly enough leucotomies seem to have come before the lobotomy. Both leucotomies and lobotomies were performed initially using direct injections of alcohol into the target region in order to destroy brain matter. However, surgeons preferred to use a modified ice pick later on in the development of the surgery in order to directly damage the target region. It is actually super interesting to note that these doctors did actually have a method to their own madness. They would move their technique either posterior or anterior based on the illness that they were trying to treat. In some ways this does make sense, different regions of the brain are responsible for different behaviors. These surgeries did impact patients with schizophrenia, surgeons often noted that their patients had a much more flat personality, and that they did not have as many schizophrenia related symptoms (Faria, M., 2013). They would also note that after surgery these patients were easier to manage, leading one to ask the question, “were these surgeries out of necessity or because they were convenient for the facility.” These procedures essentially turned people into vegetables and assumed that these states were better than schizophrenia, a bold take. Just because something technically alleviates a problem does not mean that the end result is better.

Ok, now that we have discussed things that really don’t work at all, let’s talk about something that is still used today and quite useful. Electroshock therapy (ECT) is used to induce a seizure, which has been shown to relieve symptoms of mental illness. I don’t know exactly how, perhaps you could blog about it? ECT has serious benefits and is actually known to improve the lives of those that fail to respond to other treatments. The older equipment that was used is shown below.

Figure 5

Sadly however, ECT has a disturbing past. The technique was used to often as a punishment rather than a treatment, staff would administer ECT in order to control difficult patients and to maintain order in the hospital. Additionally, ECT did not use modern techniques in the past that make it safer today Although the following resources were technically available, for some reason those that conducted ECT procedures elected not to use any of them. There was no use of muscle relaxants to alleviate physical damage from the seizure itself, and no anesthesia was used to stop the pain from the actual shock. If that doesn’t sound pleasant enough, ECT was used for all of the wrong reasons in order to “cure” things that weren’t actually mental illnesses. A prime example of this would be the use of ECT to “treat” homosexuality (Sadowsky, J., 2017). 

Okay so it is hard to sit here in my comfy chair and write about the things that were being done to those in the past. However, context is an important part of any intellectual conversation and I think it is important to include some now that we have concluded our conversation. The doctors and medical professionals of the time were in a real pickle, the mental hospitals were overflowing and they needed ways to help the patients who were otherwise never going to leave the systems that were in place to try and help them. Psychiatric medicine is not like it is today, there were so many people who were hospitalized for things that we can treat easily in modern times through the use of over the counter medications. Although it seems barbaric to us now, and frankly it was considered barbaric even in the past, the surgeons were trying to help even though they probably did more harm than good. Remember though that the individuals of the past did not know what we do now, we have the luxury of sitting here knowing as much as we do, only because of their trials and tribulations. The patients of the past suffered so that we can better treat those in society today.

The (unproven, deadly) common cure for … – JSTOR DAILY. (n.d.). Retrieved October 6, 2021, from https://daily.jstor.org/the-unproven-deadly-common-cure-for-schizophrenia/. 

Faria, M. A. (2013, April 5). Violence, mental illness, and the brain – A brief history of psychosurgery: Part 1 – from trephination to lobotomy. Surgical neurology international. Retrieved October 6, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640229/. 

Phutane, V. H., Thirthalli, J., Kesavan, M., Kumar, N. C., & Gangadhar, B. N. (2011, April). Why do we prescribe ECT to schizophrenia patients? Indian journal of psychiatry. Retrieved October 6, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136018/. 

Sadowsky, J. (2017, January 13). Electroconvulsive therapy: A history of controversy, but also of help. Scientific American. Retrieved October 6, 2021, from https://www.scientificamerican.com/article/electroconvulsive-therapy-a-history-of-controversy-but-also-of-help/. 

Treatment of schizophrenia. Treatment of Schizophrenia – an overview | ScienceDirect Topics. (n.d.). Retrieved October 6, 2021, from https://www.sciencedirect.com/topics/medicine-and-dentistry/treatment-of-schizophrenia. 

Schizophrenia

Schizophrenia is a chronic disorder affecting how a person thinks, feels, and behaves. Around 1% of the United States population is diagnosed with schizophrenia. Now, 1% may not seem like a lot, however, it is about 3.3 million people. 3.3 million people just like you suffer from delusions, hallucinations, disorganized speech, mood disturbances, disorganized motor behaviors, and

disturbances of volition. At that is just in the U.S.! It is estimated by the World Health Organization that 20 million people worldwide are diagnosed with schizophrenia.

During 2009-2011, an estimated 382,000 ER visits in the US related to schizophrenia. Of those visits 32.7% had to be admitted to the hospital. Schizophrenia diagnoses occupy 20-40% of psychiatric hospital beds. Figure 1, shows the age ranges of these patients and the differences in gender.

Individuals with schizophrenia have a set of positive and negative symptoms. Positive symptoms are distortions of a person’s thinking. Negative symptoms make feeling and expressing emotions for the person a challenge. In figure 2, the distinction between positive and negative symptoms is depicted.

It is incredibly important for research on schizophrenia to continue. As of now the cause of schizophrenia is still quite wonky.

Changes in the brain

Through brain imaging, researchers have found that schizophrenia in the brain can look like: a reduction of gray and white-matter, temporal lobe volume reductions, anomalies of the superior temporal gyrus, enlargement of the

ventricles, and reduced connection between temporal and frontal lobe white matter. In figure 3, you can see the changes in the brain of 34-year-old female patient with schizophrenia. These images clearly show a reduction in white matter and enlargement of the ventricles over the course of several years.

An emerging view is that schizophrenia is a developmental disease caused by changes in the structure and functioning of important brain systems involved in working memory, declarative memory, language processing, etc. These changes appear to be influenced by genetic and environmental risk factors present during development prenatal, childhood, and adolescence.

Molecular changes in the brain 

There is evidence accumulating on the Wnt signaling pathway and its role in schizophrenia. This pathway may lead to answers on how to best treat symptoms of schizophrenia and possible causes of these symptoms.

Schizophrenics have an overactive dopamine system in their brain. When dopamine binds to its D2 receptors it inhibits the enzyme known as Akt, which decreases inhibitory phosphorylation of GSK3-beta. In a pathway known as Wnt, if GSK3-beta cannot be inhibited it will remain in a “destruction complex”, that is responsible for breaking down beta-catenin. Beta-catenin is the molecule that binds to a set of transcription factors to tell them to start transcribing a certain gene. If the destruction complex destroys beta-catenin, then we cannot express genes that are important for neural development and neural system functioning.  Figure 4, represents the wnt signaling pathway. On the left, there is no Wnt signal attached to the receptor, leading to the degradation of beta-catenin. On the right, there is a Wnt signal on the receptor, so beta-catenin can initiate gene transcription.

This is what we see in schizophrenia. The brain is not reading important genes, so abnormal development and functioning occurs, which can lead to the disease state of schizophrenia.

Substance Abuse Disorder 

47% of patients with schizophrenia have serious problems with drug or alcohol abuse during their lifetime. The following are estimated percentages of drug abuse for people diagnosed with schizophrenia:

• 60-90% cigarette smoking
• 21-86% alcohol
• 17-83% cannabis
• 15-50% cocaine

The common theory behind why those with schizophrenia have substance abuse disorders is it helps lessen pain, symptoms of the disease, and adverse side effects of medications. A biologically based theory is that schizophrenia and substance use disorders may share a common pathophysiology in overlapping neural circuits, thus may relate to dysfunction of the brain reward circuit in patients.

Final word 

I bring up the prevalence of substance abuse disorder with schizophrenia to push empathy on to you for those with schizophrenia. These patients have chemical and structural changes occurring inside their brain. They have no control over this. Something occured in their development, at what point we don’t know, but something happened that caused this disease. A disease that is so painful, many turn to self-medication with drugs to survive. The stereotype of people with schizophrenia is that they are crazy. But, these people are people. Life for them is not like it is for us, but it is not their fault. So, the best thing for us to do is to show the empathy. We can never understand what it’s like to have a brain like theirs, but we can give kindness, compassion, and empathy.

Resources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800495/

https://pubmed.ncbi.nlm.nih.gov/23379509/

https://www.cdc.gov/nchs/products/databriefs/db215.htm

Different models have been used in order to determine whether an animal is showing signs of schizophrenia due to them being unable to self-report hallucinations, scattered thinking and other features of the disease. These models include developmental, drug-induced, genetic, and sex differences in animal models. Neuropsychiatric disorders, including schizophrenia, include symptoms such as paranoid delusions and auditory hallucinations that are uniquely human and make interpretation of results obtained from animal models more difficult. Increased locomotor activity in response to psychotomimetic compounds such as amphetamine or noncompetitive NMDA glutamate receptor antagonists is commonly used as an indication of positive symptoms in schizophrenia, a deficit in prepulse inhibition (PPI, where a weaker sound prepulse delivered prior to a stronger sound pulse inhibits the natural startle response to the second stimulus) is used as a proxy for sensorimotor gating problems, and changes in social interaction are used as an indicator of negative symptoms.  

Developmental Model  

The methylazomethanol (MAM) model involves prenatal administration of MAM into pregnant rats. MAM is an antimitotic and antiproliferative agent that methylates DNA47 and acts specifically on proliferation of neuroblasts without affecting glia or producing teratogenic effects in peripheral organs. Administering MAM to pregnant rat’s results in neuroanatomical, electrophysiological, and behavioral changes in the offspring that depend on the gestational day (GD) of administration, with GD17 animals being the most used in schizophrenia animal models.  

Figure 1. Behavioral tests that are conducted on animals that present positive, negative or cognitive symptoms of schizophrenia and how this effects their results.Continue reading →