Cobbers on the Brain

I’ve been playing soccer since I was about five years old, and it was not until college that I experienced someone on the field get a concussion. I had always known about how they occur, and had even seen football players get concussions in high school. But I had never really known what sort of effects a concussion had on someone, nor did I really understand what concussions did to the brain until I read the scientific article The Molecular Pathophysiology of Concussive Brain Injury. I always pictured a concussion sort of like the crash dummy shown in some of the car commercials. Once you get hit, your brain sort of rocks really hard and takes a beating. But there is much more going on than just a shaken up brain.
In contact sports such as boxing, football, soccer, and hockey, concussions are quite common. When a player suffers from a concussion, the brain is hit so hard that it sort of sends everything into overdrive. The concussion causes the brain to initiate unwanted action potentials that cause an increased release of glutamate, the brains main excitatory neurotransmitter. There is also a potassium efflux, which leads to an increase in membrane pumping in the neuron.   The increase in glutamate causes hyperglycolysis, and leads to the accumulation of lactate in the brain. The reason hyperglycolysis occurs is due to the brain’s ability to try and fix itself from having too much glutamate released at one time. Calcium sequestration also occurs along with mitochondrial dysfunction and oxidative phosphorylation. These occur due to the calcium influx that occurs at the same time as glutamate rushes into the neuron. Due to the mitochondrial dysfunction there is a decrease in ATP, the cell’s energy source. Lastly, due to the imbalance of calcium, glutamate, lactate and other ions within the cell, enzymes are activated that initiate apoptosis (cell death). Symptoms include headaches, nausea, dizziness, some memory loss, and even vomiting (depending on the severity of the concussion).
Although this may sound like there isn’t much to be done, measures are being taken to help protect those in contact sports from suffering from a concussion. Increased padding in helmets, head bands, and padded gloves are being required in most contact sports. This is certainly necessary since too many concussions can lead to neurodegenerative disorders such as Chronic Traumatic Encephalopathy (CTE) and dementia. CTE can also lead to other disorders such as Alzheimer’s Disease and Parkinson’s Disease.
But since contact sports are so popular, it is very unlikely that we will be able to completely prevent concussions from happening. Sometimes concussions may also happen just from falling down and hitting one’s head, or getting hit by an extremely hard snowball! So then, what is the best way to treat a concussion? A lot of rest! Doctors say that a lot of rest and little activity that could further your concussion is the best way to treat it. The severity of the concussion determines how long it may take for you to be completely recovered. So if you ever get hit a little too hard in the head, it is best to pop in your favorite trilogy (I would suggest Lord of the Rings), and sit back and relax.

Amyotrophic lateral sclerosis, more commonly referred to as ALS or Lou Gehrig’s disease was a relatively unknown topic to me until this week. ALS is a neurodegenerative disease whose end is the deterioration of motor neurons, causing loss of function to parts of the body. That’s the bigger picture anyway; there are a variety of mechanisms taking place in the pathology of this disease and in conjunction they create an extremely debilitating outcome. The main ALS story is an imbalance of calcium in different areas of the cell and the outcomes that this leads to. Namely the cytosol, mitochondria, and endoplasmic reticulum were discussed this week. The imbalance of calcium leads to a myriad of inconvenient outcomes, including protein misfolding and accumulation, as well as oxidative stress.

The symptoms of this disease are quite extensive and can make life extremely difficult for patients. Being that motor neurons are affected, bodily motion becomes exceedingly more challenging as the disease progresses. In the early stages muscle weakness and stiffness are common, accompanied by fatigue, poor balance, and other symptoms. The middle stage is characterized by some muscle paralysis and further weakening of others, as well as trouble swallowing and weakening of respiratory muscles. Late stages are characterized by paralysis of most voluntary muscles, extreme difficulty breathing, very limited mobility, impaired speech, and inability to eat or drink through the mouth. Since the respiratory system is so severely affected, this usually leads to death due to inability to properly breathe or swallow.

The intriguing part about this disease is that no one really knows how it is caused. Only about 10% of cases are hereditary, the rest are sporadic. There is no way of reversing the disease, but the drug riluzole was developed which helps counteract the disease. Riluzole decreases glutamate release in the brain which decreases motor neuron death, thereby extending the life of the remaining functional neurons.

This disease was made famous by the baseball player Lou Gehrig, hence the name. In recent years however, there has been some controversy over this, as it turns out that Gehrig might not have had ALS at all. In fact, many professional athletes may have been falsely diagnosed with ALS in the past, when they actually had a completely different disease. Chronic traumatic encephalopathy (CTE) is characterized by the same symptoms as ALS, but is caused by multiple brain traumas or concussions. Before CTE was discovered, athletes that received many concussions in their career were diagnosed with ALS. It is hypothesized that CTE might be under the “ALS umbrella” of disorders, as it is characterized by the build up of the same proteins in cells.

ALS is a nasty disease, no question about it. The real question is, what more can be done? In our discussion this week our professor brought up a good point: Do people really know that much about ALS? Do you think if people knew more about it, more money would be given towards research for a cure? Personally I didn’t know very much at all about ALS before this week, and I think that if people were more aware about how horrible and debilitating the disease can be, more work would be done towards finding a cure. Hopefully our blogs from this week will spread some awareness and make a small impact in the path towards a cure.

This fall I had the opportunity to take neurochemistry, both for my neuroscience minor as well as for the Capstone requirement for my core. When I signed up, I really had no idea what a Capstone was supposed to be; to me it just sounded like a sort of academic “cherry on top.” I have to say, it has been more than just something sweet, meant to sweeten the deal or look good on a transcript. This semester has been a great interdisciplinary experience, which would not have been complete without neurochemistry. Before I talk about my experience this semester, I would like briefly explain the structure of the class. During the first three weeks, we covered basic information that laid the groundwork for the rest of the course. For the duration of the course, each week was devoted to covering a specific topic such as obesity, diabetes and Alzheimer’s disease, concussions, Parkinson’s disease, or endocannabinoids. One of the most interesting, yet challenging parts of these papers was their recent publishing. All of the research we used was published within the last three years, making our course material extremely relevant to developments in the world of medicine. During the first day of class for the week, we would cover the basics of the assigned article. On the second day, we would cover topics mentioned in the paper or related to the issue at hand that we wanted to learn more about. Last, we would have a discussion on the paper and related topics and try to relate the information to society at large.
I was really nervous to start classes and get into the swing of things this semester, and for good reason as Neurochemistry, integrated Anatomy and Physiology, and Drugs and Behavior proved to be a challenging combination, taking many hours out of my already abysmal sleep schedule. Despite sacrifices in leisure time and REM sleep, I can safely say I enjoyed my material this semester more than any other. I was very enthused by the physiology of the body, how substances are absorbed, their pharmacological profiles, effects on behavior, and the neurochemical correlates behind said behaviors. The intimidating course load I took on this semester turned out to be one of the most rewarding interdisciplinary experiences I could ask for, especially during discussions; I did not expect sociology to complement any of my other classes and was pleasantly surprised to discover the information learned there allowed me to speak about healthcare on a broader scale, examine both biological and social phenomena, and thereby enhance my own experience in the discussion portion of the class.
At the beginning, our class was told that we would get out what we put into the class. For me, this ended up being very close to the truth. Going into the class, I already had a passion for neuroscience as I one day wish to pursue a career in medicine pertaining specifically to the brain in some way. I was able to learn about things that I was interested in from the articles themselves and further explore these interests with the related topics we presented each week. The integrative type of learning encouraged in this class is not implemented often enough in the academic world; it feels so bittersweet that I only got to experience this at the end of my undergraduate career. Concluding, I would just like to say I am a huge proponent of interdisciplinary learning; after quizzes, tests, presentations, and other academic evaluations are no longer present, informational boundaries are blurred by the applications of this knowledge. Medical innovation for innovation’s sake is intriguing, but these emerging products and procedures must be relevant to the needs of the world and safe for use, not to mention practical. Dissemination of information regarding new discoveries and subsequent integration of new technology or procedures into everyday life requires a broad understanding the many facets of organization, including entrepreneurial ventures, corporations, societal needs, or governmental regulation. I am therefore more than satisfied with my experience this fall and hope many others receive similar opportunities.

 During the week of December 1st, we talked about amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease. ALS is a neurodegenerative disease that selectively kills off motor neurons travelling from the brain to the spinal cord, causing motor dysfunction, which is typically the first sign that brings patients to a doctor. The disease has a very fast progression with diagnosed patients only having a five year life expectancy after diagnosis. Death from ALS usually results from the inability of a patient to breathe by his/her own accord.
The causes of ALS are relatively unknown and could be the result of genetic predisposition or even purely environmental factors. The pathway leading to motor neuron death, however, has been studied extensively. Overstimulation of excitatory glutamate receptors leads to repeated cell signaling, which is harmful in excess for two reasons. First, near-constant signaling leads to chronic calcium influx into the cell. In other cells, this excess intracellular calcium is not as much of a concern because the cell contains proteins to bind it and also remove it from the cell. The affected motor neurons are unable to keep up with constant stimulation because the cell does not contain enough proteins to bind the excess calcium and maintain balance within the cell. This alone can cause stress to the cellular organelles, especially through the buildup of reactive oxygen species which are a common cause of cellular destruction in neurodegenerative diseases. Second, this repeated stimulation leads to increased protein production, specifically proteins that are secreted from the cell. These proteins are made in an organelle called the endoplasmic reticulum, which normally has a system to check if all protein production is going as planned and to take care of mistakes when they arise. Protein misfolding is liable to occur, especially under increased production demand and oxidative stress. When these misfolded proteins build up to a point where they cannot be removed and degraded, they can inhibit this regulation system causing extreme stress to the endoplasmic reticulum. Once this occurs, the cell will signal for self-destruction.
This intricate pathway has led to many ideas for treatments of ALS. One surprising treat can actually add a few years onto a patient’s life. Doctors advise patients to eat so as to gain as much weight as possible, so long as blood pressure and other vitals are manageable. A cure seems to be far from likely as the causes, as previously stated, are unknown. Links between concussion and ALS were being investigated due to similarities in the degenerative mechanisms of ALS and chronic traumatic encephalopathy (CTE), which is often seen with chronic concussions. Thus far, there have been not been extensive leaps in the path toward a cure. The primary pharmaceutical treatment designed for patients with ALS is a glutamatergic antagonist, which has the potential to cause many adverse side effects due to the widespread glutamate activity in the nervous system. This potential for a variety of side effects holds true for the targeting of many pathways associated with ALS, complicating the issue of treatment development. It is very unfortunate to see a disease be nearly unstoppable once onset begins. Personally, I believe more research should be done on early detection of ALS as well as treatments aimed at more effectively halting progression, while avoiding side effects. In the case of a disease like this with such a low life expectancy, all fronts must be addressed so as to provide the best care possible to patients.

Autism is defined as a developmental brain disorder in which the affected individual typically has problems with social interactions and may tend to exhibit a heightened focus on narrow topics and repetitive procedures. The prevalence of autism has risen from 1 in 5000 in 1975 to 1 in 110 in 2009, which, needless to say, has been a cause for a lot of concern. There could be a few societal factors that contribute to this alarming statistic, but also some biological and neurochemical factors that contribute to the increased prevalence.
Currently, there is not a clear-cut biological test for autism, which means diagnosis is made based on general behavior and response to certain stimuli, both social and physiological. Because of the current subjective nature in recognizing autism, diagnostic criteria are subject to change and have done so as to expand the definition of autism. In fact, autism diagnosis and classification has progressed from that of a single disorder to a spectrum of disorders with similar symptoms, with the identification of certain symptomatic dissociations to describe the specific type of disorder within the spectrum. This increasing number of diagnostic criteria and inclusion of different disorders in the spectrum has also led to a movement towards increased education among parents and earlier diagnosis, both of which have case-dependent benefits and/or detriments. Increasing education helps parents look for potential signs of autism, but it can also lead them to misinterpret certain behaviors as dysfunctional. The push for earlier diagnosis can facilitate potentially effective treatment at a younger age, but also could lead to false diagnosis based on variation in development. The expanding spectrum, increased education for parents and physicians, and earlier identification has certainly contributed to increased diagnosis, but it is doubtful that 100% of the increasing prevalence is due to societal views.
In class, we looked at some of the neurological factors that can lead to the onset or aggravation of autism. One phenomenon worth noting is the dysfunction of adhesion molecules between cells in the brain and concomitant abnormality in the development of new connections between brain cells. Some intrauterine inflammation has been correlated with the onset of autism. Another interesting finding in autism research is the involvement of polyunsaturated fatty acids (PUFAs; such as those found in fish oil, olive oil, and others) in synaptic formation during central nervous system development and maintenance after birth as well as the prevention of central inflammation. It has been found that a diet rich in the necessary PUFAs that also avoids, trans-fats, unnecessary sugar, products treated with pesticides, and allergenic foods can reduce some gastric sensitivity while also improving the cognitive and behavioral symptoms of autism, especially when properly supplementing this diet with probiotics, vitamins, and minerals. Treatment of autism is typically multifaceted, involving aforementioned diet changes, parental training, and cognitive-behavioral therapy to address social and mental patterns. Last, we discussed a drug called Suramin, which has been researched as a potential cure for autism. Suramin research is based on the hypothesis of mitochondrial dysfunction being the root of autism. As cells are damaged due to this abnormality, a “danger response” is elicited, thus increasing the body’s defense against chemical stressors. Suramin acts to prevent some of these hyperactive responses by the body and has been shown to correct some of the behavioral hallmarks and multisystem comorbidities seen in autism.
Because of a lack of biological diagnostic mechanism, autism can be difficult to identify. Despite this, treatments can be very effective if initiated early enough and continued throughout life. More research is currently being done on the “cure” and hopefully positive results will be continually seen so as to assist both current and future patients and parents. More research also should be done on prevention so as to combat this issue on both sides of the spectrum, so to speak.

During the week of November 10th, we discussed a rather controversial article about obesity and the possibility that it could be caused by disease-like factors. Many people view obesity as the result of choice though it is well-known that some people have a higher metabolism than others and can maintain a healthy weight without much work. Recent research has shown that many neurological factors are involved in development of obesity. First is the decreased sensitivity to leptin at its receptors along with some insulin resistance as seen in type 2 diabetes mellitus. Together, these two problems create a dysfunctional appetite which is not curbed when a person should feel full, and also irregular glucose metabolism, which can lead to many neurodegenerative paths similar to Alzheimer’s disease. Studies have shown that maternal high-fat diet before pregnancy maintained through breast feeding leads to increased lipid peroxidation (a precursor to neurodegeneration) and lowered production of cells in the hippocampus, an area of the brain associated with formation of long-term memory. High-fat diet also leads to inflammatory factors that are associated with memory impairment. Obesity, as defined by body mass index, is not actually necessary to have some of these neurological markers. Healthy people who have high-carbohydrate and high-fat diets are also susceptible to memory deficits seen in obese patients. Simply having a high-fructose diet has been shown to increase lipid peroxidation and decrease insulin effects on its receptor. Thus, the human body is subject to dietary effects on cognition from conception until death. There is some evidence, however, that weight loss can stimulate some cognitive improvement, though the mechanisms behind this have yet to be explored fully. Sleep also plays a role in the cognitive deficits of obesity as circadian rhythm alteration can elicit memory deficits in some individuals and further weight gain, causing an unfortunate positive feedback loop. Weight gain may also be associated with declining activation of the reward circuit in the brain, which also happens in chronic drug abuse.
The discussion and topics covered in class reminded me of a similar discussion in my Drugs and Behavior class concerning addiction. I feel like as a society we are so ready to place blame on an individual’s character rather than fully examining the situation each person is in. We label obese people as lazy and unmotivated without knowing their diet as a child or their socioeconomic status. Socioeconomic status plays a huge role in what foods are available to people. Processed, cheap foods are readily available for working-class individuals while wholesome foods necessary for a balanced diet not only cost a lot more, but take longer to prepare. With the demands of education and work, maintaining a healthy diet for oneself is difficult and even harder when working multiple jobs to support a family. The view of obesity and addiction as diseases is a double-edged sword. While it does remove some stigma from the two conditions, it also eliminates some sense of personal responsibility. Those with either of these controversial conditions must also realize that personal volition can help improve one’s life, though the path to recovery may well be bumpier than the path to disease.

What a normal 90’s kid thinks after he/she hears the “Lithium”
What a 90’s kid in neurochemistry thinks when he/she hears “Lithium”

During the week of November 3rd, we reviewed an article concerning the efficacy of lithium in neurological diseases. As much of the public is aware, lithium has been used in the treatment of bipolar disorder for decades. When patients suffering from Major Depressive Disorder are unresponsive to all other popular treatments, lithium is actually one of the first “alternative” treatments considered. Lithium’s mood-altering effects come from its ability to inhibit GSK3. GSK3 activates serotonin autoreceptors, which prevent serotonergic action by facilitating its reuptake into the neuron. GSK3 is involved in many other pathways, especially those involved in neurodegeneration. Because of its actions on the normal constituents of a common pathway, lithium has been studied and shown to be effective in many other disorders and diseases. Lithium has also been shown to be neuroprotective when given as pretreatment before stroke through its prevention of excitotoxicity. After stroke, lithium treatment can even have benefits due to its ability to induce transcription and proliferation, leading to neuronal recovery. In Parkinson’s, lithium has been shown prevent apoptotic (programmed) cell death. In Huntington’s disease, lithium treatment prevents excitotoxicity and increases the expression of neuroprotective factors leading to improved mood and also some improvement in motor function. Lithium has also been effective in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) for similar reasons, though it is most effective when supplemented with antioxidants as oxidative stress has been implicated in ALS onset. Lithium has been shown to be effective in slowing the progression of multiple sclerosis (MS) by reducing inflammatory responses. Lithium’s neuroprotective role in MS was shown to be greatest when used before the disease’s onset. Lithium even has been shown to curb alcohol-induced degeneration in utero and greatly diminishes the symptoms of fetal alcohol syndrome; this protection was even seen when lithium was administered after alcohol consumption. Lithium can also be used to counteract some of the adverse effects of antipsychotics without decreasing their efficacy. Lithium also has been shown to be effective in preventing the hyper-phosphorylation of tau proteins and amyloid-β aggregation.
As we can plainly see, lithium has numerous benefits in neurological treatment and also can be used to prevent many adverse effects. On paper, it appears to be a neuroprotective wonder-drug. Why is the public not taking lithium supplements? In the lab, lithium also shows promise; clinical trials are another story. Some studies show great effect, while others are inconclusive at best. Also, a simple WebMD search shows that side effects include nausea, diarrhea, dizziness, muscle weakness, and fatigue. There also are some potential interactions with many commonly-prescribed and over-the-counter medications. Members of the general public should not jump to conclusions and buy lithium supplements with a 30-day supply in one pill like they do with vitamin C. Because of its many routes of action, lithium has the potential to cause a slew of adverse effects if not dosed properly. When used to treat bipolar disorder, lithium levels are monitored very carefully to prevent toxicity. As human studies on neurodegeneration attenuation show conflicting results, more research should be done with consistent methods and longitudinal designs to evaluate the long-term efficacy of lithium treatment in degenerative diseases.

Before beginning my capstone experience in Neurochemistry, I was very curious as to how this would be different from any other class.  I imagined all of the chemistry behind what I learned in my previous neuroscience courses would clarify everything, and it would all suddenly make sense.  As the semester progressed, I realized that some of the things I hadn’t understood before were indeed starting to make more sense, but it became more and more apparent that I would never get to the point where I would truly feel as if I fully understood everything.  Now, as the semester comes to a close, I realize that in many ways, this is part of the beauty of science: though we will continue to constantly try and learn more, there will still always be more to discover, just as there will always be more I myself can learn.  The way we learned in this course was very different than anything I’ve ever experienced in any of my other classes, and seems to be very appropriate given that my classmates and I will all be leaving Concordia perhaps sooner than we fully appreciate, and it will start to fall upon us more and more to take responsibility for our own learning.  In this class, we didn’t sit and listen to a lecture during every class period, but instead we looked at articles regarding recent research in neurochemistry, and then worked as a class to dissect and look for the aspects of the article we didn’t understand.  We would then seek out more information, and bring it to class to share with everyone else, and finally at the end of the week, we would sit and discuss the article and some of its implications.  It seems as if this is a much more realistic way of learning information than sitting in a classroom, and this experience gave us a much more realistic picture of how we must continue to be life-long learners.
To be totally honest, I don’t know whether I will remember in five years what Akt does and all of the different pathways it can impact, but some of the broader themes of the course are ones I will surely carry with me.  We learned many different things about obesity, endocannabinoids and marijuana, Alzheimer’s, Parkinson’s disease, and concussions.  Several things struck me as we studied these diseases and their related neurochemical mechanisms.  First of all, the mechanism for any one of these diseases is by no means simple.  We usually would study one or two aspects of it as they pertained to the article we were looking at that week, and then through our research as we tried to understand the article better, found several other pathways that might also play a role, or contribute in some form.  Secondly, I came to understand how much public opinion can do to mask the science behind certain things.  I am speaking with endocannabinoids and marijuana in mind, as I discovered that there are certainly substantial potential medical benefits that may be a result of the use of cannabis, and these benefits had previously seemed almost mythical to me and simply an argument people used as they were trying to legalize marijuana.  I also learned about how important some small changes we make in our lives can make a huge difference.  From drinking a cup of green tea every so often to working to develop better diet and exercise habits, the smaller changes can make a huge difference in both the future health of both yourself and your children.  It has become apparent that there is no wonder-drug, and that side-effects are sometimes unavoidable when you are trying to treat one thing without throwing other systems out of balance.  It suddenly makes a lot more sense why we spend so much time trying to learn more about disease and develop a treatment for it, but often are still unable to find a perfect solution.  This class has taught me to think critically about a lot of things that I might have taken at face value before, and overall, has taught me to be more inquisitive about the world around me, which is perhaps one of the most useful things I can take away from a course.
 

Amytrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig’s disease, is a disease which appears in adults and affects motor neurons.  There are two different forms, of which sporadic ALS is by far the most common.  It now appears that an imbalance of calcium could play a huge role in the pathogenesis of ALS.  A variety of proteins and transport mechanisms exist to ensure that the appropriate levels of calcium are in various cellular organelles, namely the endoplasmic reticulum, which is important in modifying proteins as they are produced, and the mitochondria, which is important in energy production for the cell.  When inappropriate levels of calcium are in the endoplasmic reticulum, ER stress occurs and a mechanism called the unfolded protein response is activated in response.  In ALS, too much calcium is taken out of the ER and put in the mitochondria, and so proteins are not folded properly in the endoplasmic reticulum, and the increased levels in the mitochondria can have a variety of detrimental effects such as defects in energy metabolism, the generation of reactive oxygen species (which are not good things to have around, and are part of the reason it is so good for us to consume things high in antioxidants like green tea), and the activation of apoptosis (which ultimately means cell death).  As a result of these abnormalities in motor neurons, the motor neurons die, and we see ALS.  The reason only motor neurons are affected in ALS is due to a certain kind of receptor motor neurons have called an AMPA receptor.  When the neurotransmitter glutamate is released, it binds to AMPA and allows calcium into the cell and throws everything out of balance.  AMPA receptors on the motor neurons of those with ALS lack a certain component which results in more calcium being allowed into the cell.
There are a number of different molecules and mechanisms that also play a role in regulating calcium levels in the cell, and thus provide targets for treating ALS.  Of course, as always, we must add in the caveat that it is much more complicated than it appears at first glance to actually treat this, as we don’t want to affect other pathways that use the same molecules and/or mechanisms.  As ALS affects motor neurons, it should come as no surprise that these molecules also play a large role in things like muscle contraction, and so we have to be careful to not harm that by going too far with modifying the levels of all of these molecules in the body.
There is also the issue that it is currently somewhat unknown whether misfolded proteins are misfolded because the motor neurons have degenerated, or if the motor neurons degenerate because the proteins are misfolded.  There are many things that remain to be known about this, but at least we are starting to make good headway in starting to learn what exactly is going on in the spinal cord of patients with ALS.