Zika and Fetal Viruses: Sharing More Than A Motherly Bond

Catalyst Volume 10

Zika is a blood-borne pathogen primarily transmitted through mosquito bites and sexual activities. Pregnant women infected by Zika can pass the virus to their fetus, causing microcephaly, a condition in which the baby has an abnormally small head indicative of abnormal brain development. With the outbreak of the Zika virus and its consequences for pregnant women and their babies, much research has focused on how the infection leads to microcephaly in fetuses.

Current Zika research has been focused on uncovering methods for early detection of Zika in pregnant women and educating the public on safe sexual practices to contain the vector of transmission to just mosquitoes.¹ However, to truly end the Zika epidemic, there are three critical steps that need to be taken. First, researchers must determine the point at which maternal infections harm the neurological development of fetuses in order to ensure treatment is administered to the mothers before the brain damage becomes irreversible. Subsequently, researchers must determine the mechanism through which Zika spreads from mother to fetus. After this step, researchers can begin developing therapies to protect the fetus from Zika once the mother is already infected and also start creating a preventative vaccine. Although Zika seems like a mysterious new illness, there are several other well-studied viral infections that affect pregnancies, such as cytomegalovirus (CMV). CMV infection during pregnancy also leads to severe fetal brain damage. Previous research techniques could provide clues for researchers trying to understand more about Zika, and learning more about Zika will better equip us for handling prenatal viral outbreaks in the future.

The current detection of microcephaly of infants with Zika-infected mothers involves fetal ultrasound as early as 18 weeks into the gestation period.² However, this is a late diagnosis of fetal Zika infection and at this point the brain abnormalities caused by the virus are irreversible. Ultrasounds and MRI scans of infants with confirmed CMV infection can detect these neurological abnormalities as well.³ However, these brain lesions are also irreversible, making early detection a necessity for CMV infections as well. Fortunately, the presence of CMV or CMV DNA in amniotic fluid can be used for early diagnosis, and current treatment options include administration of valacyclovir or hyperimmunoglobulin in the window before the fetus develops brain lesions.⁴ Researchers must try to identify fetal Zika infection as early as possible as opposed to relying on fetal microcephaly as the sole diagnostic tool. Some potential early detection methods include testing for Zika in the urine of pregnant women as soon as Zika symptoms are present, as opposed to screening the fetus for infection.⁵

Discovering the mechanism through which Zika infects the fetus is necessary to develop therapies to protect the fetus from infection. Many viruses that are transferred to the fetus during pregnancy do so by compromising the immune function of the placental barrier, allowing the virus to cross the placenta and infect the fetus. The syncytiotrophoblast is the epithelial covering of placental embryonic villi, which are highly vascular finger-like projections that increase the surface area available for exchange of nutrients and wastes between the mother and fetus.⁶ In one study, experiments found that infection of extravillous trophoblast cells decreased the immune function of the placenta, which increased fetal susceptibility to infection.⁷ Determining which cells in the placenta are infected by Zika could aid research into preventative treatments for fetal infection.

Since viruses that cross the placental barrier are able to infect the fetus, understanding the interaction between immune cells and the placental barrier is important for developing therapies against Zika that increase fetal viral resistance. In one study, researchers found that primary human trophoblast cells use cell-derived vesicles called exosomes to transfer miRNA, conferring placental immune resistance to a multitude of viruses to other pregnancy-related cells.⁸ miRNAs are responsible for regulating gene expression, and different miRNAs exist in different cells so that those cells will have specific functions and defenses. Isolating these miRNA exosomes, using them to supplement placental cell strains, and subsequently testing whether those cells are more or less susceptible to Zika could support the development of drugs that bolster the placental immune defense mechanism already in place. Since viral diseases that cross the placenta lead to poor fetal outcome, developing protective measures for the placenta is imperative, not only for protection against Zika but also for protection against new viruses without vaccinations.⁹

Combating new and more elusive viral outbreaks is difficult, but understanding and preventing viral infection in fetuses is like taking a shot in the dark. Although the prospects for infants infected by Zika are currently poor, combining the research done on other congenital infections paints a more complete picture on viral transmission during pregnancy. Instead of starting from scratch, scientists can use this information to determine the tests that can detect Zika, the organs to examine for compromised immune system function, and the treatment types that have a higher probability of effectiveness. Zika will not be the last virus that causes birth defects, but by combining the efforts of many scientists, we can get closer to stopping fetal viral infection once and for all.

References

1. Wong, K. V. J. Epidemiol. Public Health Rev. 2016, 1.
2. Mlakar, J., et al. N. Engl. J. Med. 2016, 374, 951-958.
3. Malinger, G., et al. Am. J. Neuroradiol. 2003, 24, 28-32.
4. Leruez-Ville, M., et al. Am. J. Obstet. Gynecol. 2016, 215, 462.
5. Gourinat, A. C., et al. Emerg. Infect. Dis. 2015, 21, 84-86.
6. Delorme-Axford, E., et al. Proc. Natl. Acad. Sci. 2013, 110, 12048-12053.
7. Zhang, J.; Parry, S. Ann. N. Y. Acad. Sci. 2001, 943, 148-156.
8. Mouillet, J. F., et al. Int. J. Dev. Bio. 2014, 58, 281.
9. Mor, G.; Cardenas I. Am. J. Reprod. Immunol. 2010, 63, 425-433.

First World Health Problems

Catalyst VOlume 10

I am a first generation American, as both of my parents immigrated here from Myanmar, a third world country. There had been no occurrence of any Inflammatory Bowel Disease (IBD) in my family, yet I was diagnosed with Ulcerative Colitis at the beginning of my sophomore year of high school. Since IBD is known to be caused by a mix of genetic and environmental factors,^1,2 what specifically triggered me to develop Ulcerative Colitis? Was it the food in America, the air I was exposed to, a combination of the two, or neither of them at all? Did the “environment” of the first world in the United States cause me to develop Ulcerative Colitis?

IBD is a chronic autoimmune disease, characterized by persistent inflammation of the digestive tract and classified into two separate categories: Ulcerative Colitis and Crohn’s Disease.³ Currently, there is no known cure for IBD, as its pathogenesis (i.e. the manner in which it develops) is not fully understood.¹ Interestingly, the incidence of IBD has increased dramatically over the past century.¹ A systematic review by Molodecky et al. showed that the incidence rate of IBD was significantly higher in Western nations. This may be due to better diagnostic techniques or the growth of environmental factors that promote its development. This could also suggest that there may be certain stimuli in first world countries that can trigger pathogenesis in individuals with a genetic predisposition to IBD.

Environmental factors that are believed to affect IBD include smoking, diet, geographic location, social status, stress, and microbes.¹ Smoking has had varying effects on the development of IBD depending on the form; smoking is a key risk factor for Crohn’s Disease, while non-smokers and ex-smokers are usually diagnosed with Ulcerative Colitis.⁴ There have not been many studies investigating the causal relationship between diet and IBD due to the diversity in diet composition.¹ However, since IBD affects the digestive system, diet has long been thought to have some impact on the pathogenesis of the disease.¹ In first world countries, there is access to a larger variety of food, which may impact the prevalence of IBD. People susceptible to the disease in developing countries may have a smaller chance of being exposed to “trigger” foods. In addition, IBD has been found in higher rates in urban areas versus rural areas.^1,4,5 This makes sense, as cities have a multitude of potential disease-inducing environmental factors including pollution, poor sanitation, and microbial exposure. Higher socioeconomic status has also been linked to higher rates of IBD.⁴ This may be partly due to the sedentary nature of white collar work, which has also been linked to increased rates of IBD.¹ Stress used to be viewed as a possible factor in the pathogenesis of IBD, but recent evidence has indicated that it only exacerbates the disease.³ Recent research has focused on the microorganisms in the gut, called gut flora, as they seem to have a vital role in the instigation of IBD.¹ In animal models, it has even been observed that pathogenesis of IBD is not possible in a germ-free environment.¹ The idea of the importance of microorganisms in human health is also linked to the Hygiene Hypothesis.

The Hygiene Hypothesis states that the lack of infections in western countries is the reason for an increasing amount of autoimmune and allergic diseases.⁶ The idea behind the theory is that some infectious agents guard against a wide variety of immune-related disorders.⁶ Animal models and clinical trials have provided some evidence backing the Hygiene Hypothesis, but it is hard to causally attribute the pathogenesis of autoimmune and allergic diseases to a decrease in infections, since first world countries have very different environmental factors than third world countries.⁶

The increasing incidence of IBD in developed countries is not yet fully understood, but recent research points towards a complex combination of environmental and genetic factors. The rise of autoimmune disease diagnoses may also be attributed to better medical equipment and facilities and the tendency of people in more developed countries to regularly get checked by a doctor. There are many difficulties in researching the pathogenesis of IBD including isolating certain environmental factors and obtaining tissue and data from third world countries. However, there is much promising research and it might not be long until we discover a cure for IBD.

References

1. Danese, S. et al. Autoimm Rev 2004, 3.5, 394-400.
2. Podolsky, Daniel K. N Engl J Med 2002,  347.6, 417-29.
3. Mayo Clinic. "Inflammatory Bowel Disease (IBD)." http://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/basics/definition/con-20034908 (accessed Sep. 30, 2016).
4. CDC. "Epidemiology of the IBD." https://www.cdc.gov/ibd/ibd-epidemiology.htm (accessed Oct.17, 2016).
5. Molodecky, N. et al. Gastroenterol 2012, 142.1, n. pag.
6. Okada, H. et. al. Clin Exp Immuno 2010, 160, 1–9.

Molecular Mechanisms Behind Alzheimer’s Disease and Epilepsy

Catalyst Volume 10

Abstract

Seizures are characterized by periods of high neuronal activity and are caused by alterations in synaptic function that disrupt the equilibrium between excitation and inhibition in neurons. While often associated with epilepsy, seizures can also occur after brain injuries and interestingly, are common in Alzheimer’s patients. While Alzheimer’s patients rarely show the common physical signs of seizures, recent research has shown that electroencephalogram (EEG) technology can detect nonconvulsive seizures in Alzheimer’s patients. Furthermore, patients with Alzheimer’s have a 6- to 10-fold increase in the probability of developing seizures during the course of their disease compared to healthy controls.² While previous research has focused on the underlying molecular mechanisms of Aβ tangles in the brain, the research presented here relates seizures to the cognitive decline in Alzheimer’s patients in an attempt to find therapeutic approaches that tackle both epilepsy and Alzheimer’s.

Introduction

The hippocampus is found in the temporal lobe and is involved in the creation and consolidation of new memories. It is the first part of the brain to undergo neurodegeneration in Alzheimer’s disease, and as such, the disease is characterized by memory loss. Alzheimer’s is different than other types of dementia because patients’ episodic memories are affected strongly and quickly. Likewise, patients who suffer from epilepsy also exhibit neurodegeneration in their hippocampi and have impaired episodic memories. Such similarities led researchers to hypothesize that the two diseases have the same pathophysiological mechanisms. In one study, four epileptic patients exhibited progressive memory loss that clinically resembled Alzheimer’s disease.⁶ In another study, researchers found that seizures precede cognitive symptoms in late-onset Alzheimer’s disease.⁷ This led researchers to hypothesize that a high incidence of seizures increases the rate of cognitive decline in Alzheimer’s patients. However, much is yet to be discovered about the molecular mechanisms underlying seizure activity and cognitive impairments.

Amyloid precursor protein (APP) is the precursor molecule to Aβ, the polypeptide that makes up the Aβ plaques found in the brains of Alzheimer’s patients. In many Alzheimer’s labs, the J20 APP mouse model of disease is used to simulate human Alzheimer’s. These mice overexpress the human form of APP, develop amyloid plaques, and have severe deficits in learning and memory. The mice also have high levels of epileptiform activity and exhibit spontaneous seizures that are characteristic of epilepsy.¹¹ Understanding the long-lasting effects of these seizures is important in designing therapies for a disease that is affected by recurrent seizures. Thus, comparing the APP mouse model of disease with the temporal lobe epilepsy (TLE) mouse model is essential in unraveling the mysteries of seizures and cognitive decline.

Shared Pathology of the Two Diseases

The molecular mechanisms behind the two diseases are still unknown and under much research. An early observation in both TLE and Alzheimer’s involved a decrease in calbindin-28DK, a calcium buffering protein, in the hippocampus.¹⁰ Neuronal calcium buffering and calcium homeostasis are well-known to be involved in learning and memory. Calcium channels are involved in synaptic transmission, and a high calcium ion influx often results in altered neuronal excitability and calcium signaling. Calbindin acts as a buffer for binding free Ca²⁺ and is thus critical to calcium homeostasis.

Some APP mice have severe seizures and an extremely high loss of calbindin, while other APP mice exhibit no loss in calbindin. The reasons behind this is unclear, but like patients, mice are also very variable.

The loss of calbindin in both Alzheimer’s and TLE is highly correlated with cognitive deficits. However, the molecular mechanism behind the calbindin loss is unclear. Many researchers are now working to uncover this mechanism in the hopes of preventing the calbindin loss, thereby improving therapeutic avenues for Alzheimer’s and epilepsy patients.

Seizures and Neurogenesis

The dentate gyrus is one of the two areas of the adult brain that exhibit neurogenesis.¹³ Understanding neurogenesis in the hippocampus can lead to promising therapeutic targets in the form of neuronal replacement therapy. Preliminary research in Alzheimer’s and TLE has shown changes in neurogenesis over the course of the disease.¹⁴ However, whether neurogenesis is increased or decreased remains a controversial topic, as studies frequently contradict each other.

Many researchers study neurogenesis in the context of different diseases. In memory research, neurogenesis is thought to be involved in both memory formation and memory consolidation.¹² Alzheimer’s leads to the gradual decrease in the generation of neural progenitors, the stem cells that can differentiate to create a variety of different neuronal and glial cell types.⁸ Further studies have shown that the neural stem cell pool undergoes accelerated depletion due to seizure activity.¹⁵ Initially, heightened neuronal activity stimulates neural progenitors to divide rapidly at a much faster rate than controls. This rapid division depletes the limited stem cell pool prematurely. Interestingly enough, this enhanced neurogenesis is detected long before other AD-linked pathologies. When the APP mice become older, the stem cell pool is depleted to a point where neurogenesis occurs much slower compared to controls.⁹ This is thought to represent memory deficits, in that the APP mice can no longer consolidate new memories as effectively. The same phenomenon occurs in mice with TLE.

The discovery of this premature neurogenesis in Alzheimer’s disease has many therapeutic benefits. For one, enhanced neurogenesis can be used as a marker for Alzheimer’s long before any symptoms are present. Furthermore, targeting increased neurogenesis holds potential as a therapeutic avenue, leading to better remedies for preventing the pathological effects of recurrent seizures in Alzheimer’s disease.

Conclusion

Research linking epilepsy with other neurodegenerative disorders is still in its infancy, and leaves many researchers skeptical about the potential to create a single therapy for multiple conditions. Previous EEG studies recorded Alzheimer’s patients for a few hours at a time and found limited epileptiform activity; enhanced overnight technology has shown that about half of Alzheimer’s patients have epileptiform activity in a 24-hour period, with most activity occurring during sleep1. Recording patients for even longer periods of time will likely raise this percentage. Further research is being conducted to show the importance of seizures in enhancing cognitive deficits and understanding Alzheimer’s disease, and could lead to amazing therapeutic advances in the future.

References

1. Vossel, K. A. et. al. Incidence and Impact of Subclinical Epileptiform Activity. Ann Neurol. 2016.
2. Pandis, D. Scarmeas, N. Seizures in Alzheimer Disease: Clinical and Epidemiological Data. Epilepsy Curr. 2012. 12(5), 184-187.
3. Chin, J. Scharfman, H. Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms. Epilepsy & Behavior. 2013. 26, 343-351.
4. Carter, D. S. et. al. Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus. Epilepsy Res. 2008. 79(2-3), 213-223.
5. Jin, K. et. al. Increased hippocampal neurogenesis in Alzheimer’s Disease. Proc Natl Acad Sci. 2004. 101(1), 343-347.
6. Ito, M., Echizenya, N., Nemoto, D., & Kase, M. (2009). A case series of epilepsy-derived memory impairment resembling Alzheimer disease. Alzheimer Disease and Associated Disorders, 23(4), 406–409.
7. Picco, A., Archetti, S., Ferrara, M., Arnaldi, D., Piccini, A., Serrati, C., … Nobili, F. (2011). Seizures can precede cognitive symptoms in late-onset Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 27(4), 737–742.
8. Zeng, Q., Zheng, M., Zhang, T., & He, G. (2016). Hippocampal neurogenesis in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Neuroscience, 314, 64–74. https://doi.org/10.1016/j.neuroscience.2015.11.05
9. Lopez-Toledano, M. A., Ali Faghihi, M., Patel, N. S., & Wahlestedt, C. (2010). Adult neurogenesis: a potential tool for early diagnosis in Alzheimer’s disease? Journal of Alzheimer’s Disease: JAD, 20(2), 395–408. https://doi.org/10.3233/JAD-2010-1388
10. Palop, J. J., Jones, B., Kekonius, L., Chin, J., Yu, G.-Q., Raber, J., … Mucke, L. (2003). Neuronal depletion of calcium-dependent proteins in the dentate gyrus istightly linked to Alzheimer’s disease-related cognitive deficits. Proceedings of the National Academy of Sciences of the United States of America, 100(16), 9572–9577. https://doi.org/10.1073/pnas.1133381100
11. Research Models: J20. AlzForum: Networking for a Cure.
12. Kitamura, T. Inokuchi, K. (2014). Role of adult neurogenesis in hippocampal-cortical memory consolidation. Molecular Brain 7:13. 10.1186/1756-6606-7-13.
13. Piatti, V. Ewell, L. Leutgeb, J. Neurogenesis in the dentate gyrus: carrying the message or dictating the tone. Frontiers in Neuroscience 7:50. doi: 10.3389/fnins.2013.00050
14. Noebels, J. (2011). A Perfect Storm: Converging Paths of Epilepsy and Alzheimer’s Dementia Intersect in the Hippocampal Formation. Epilepsia 52, 39-46. doi:  10.1111/j.1528-1167.2010.02909.x
15. Jasper, H.; et.al. In Jasper’s Basic Mechanisms of the Epilepsies, 4; Rogawski, M., et al., Eds.; Oxford University Press: USA, 2012

The Fight Against Neurodegeneration

Catalyst Volume 10

“You know that it will be a big change, but you really don’t have a clue about your future.”A 34-year-old postdoctoral researcher at the Telethon Institute of Genetics and Medicine in Italy at the time, Dr. Sardiello had made a discovery that would change his life forever. Eight years later, Dr. Sardiello is now the principal investigator of a lab in the Jan and Dan Duncan Neurological Research Institute (NRI) where he continues the work that had brought him and his lab to America.

Throughout his undergraduate career, Sardiello knew he wanted to be involved in some manner with biology and genetics research, but his passion was truly revealed in 2000: the year he began his doctoral studies. It was during this year that the full DNA sequence of the common fruit fly was released, which constituted the first ever complete genome of a complex organism. At the time, Sardiello was working in a lab that used fruit flies as a model, and this discovery served to spur his interest in genetics. As the golden age of genetics began, so did Sardiello’s love for the subject, leading to his completion of a PhD in Genetic and Molecular Evolution at the Telethon Institute of Genetics and Medicine. It was at this institute that his team made the discovery that would bring him to America: the function of Transcription Factor EB, colloquially known as TFEB.

Many knew of the existence of TFEB, but no one knew of its function. Dr. Sardiello and his team changed that. In 2009, they discovered that the gene is the master regulator for lysosomal biogenesis and function. In other words, TFEB works as a genetic switch that turns on the production of new lysosomes, an exciting discovery.¹ Before the discovery of TFEB’s function, lysosomes were commonly known as the incinerator or the garbage can of the cell, as these organelles were thought to be essentially specialized containers that get rid of cellular waste. However, with the discovery of TFEB’s function, we now know that lysosomes have a much more active role in catabolic pathways and the maintenance of cell homeostasis. Sardiello’s groundbreaking findings were published in Science, one of the most prestigious peer reviewed journals in the scientific world. Speaking about his success, Sardiello said, “The bottom line was that there was some sort of feeling that a big change was about to come, but we didn’t have a clue what. There was just no possible measure at the time.”

Riding the success of his paper, Sardiello moved to the United States and established his own lab with the purpose of defeating the family of diseases known as Neuronal Ceroid Lipofuscinosis (NCLs). NCLs are genetic diseases caused by the malfunction of lysosomes. This malfunction causes waste to accumulate in the cell and eventually block cell function, leading to cell death. While NCLs cause cell death throughout the body, certain specialized cells such as neurons do not regenerate. Therefore, NCLs are generally neurodegenerative diseases. While there are many variants of NCLs, they all result in premature death after loss of neural functions such as sight, motor ability, and memory.

“With current technology,” Sardiello said, “the disease is incurable, since it is genetic. In order to cure a genetic disease, you have to somehow bring the correct gene into every single cell of the body.” With our current understanding of biology, this is impossible. Instead, doctors can work to treat the disease, and halt the progress of the symptoms. Essentially, his lab has found a way using TFEB to enhance the function of the lysosomes in order to fight the progress of the NCL diseases.

In addition to genetic enhancement, Sardiello is also focusing on finding drugs that will activate TFEB and thereby increase lysosomal function. To test these new methods, the Sardiello lab uses mouse models that encapsulate most of the symptoms in NCL patients. “Our current results indicate that drug therapy for NCLs is viable, and we are working to incorporate these strategies into clinical therapy,” Sardiello said. So far the lab has identified three different drugs or drug combinations that may be viable for treatment of this incurable disease.

While it might be easy to talk about NCLs and other diseases in terms of their definitions and effects, it is important to realize that behind every disease are real people and real patients. The goal of the Sardiello Lab is not just to do science and advance humanity, but also to help patients and give them hope. One such patient is a boy named Will Herndon. Will was diagnosed with NCL type 3, and his story is one of resilience, strength, and hope.

When Will was diagnosed with Batten Disease at the age of six, the doctors informed him and his family that there was little they could do. At the time, there was little to no viable research done in the field. However, despite being faced with terminal illness, Will and his parents never lost sight of what was most important: hope. While others might have given up, Missy and Wayne Herndon instead founded The Will Herndon Research Fund - also known as HOPE - in 2009, playing a large role in bringing Dr. Sardiello and his lab to the United States. Yearly, the foundation holds a fundraiser to raise awareness and money that goes towards defeating the NCL diseases. Upon its inception, the fundraiser had only a couple of hundred attendees- now, only half a decade later, thousands of like-minded people arrive each year to support Will and others with the same disease. “Failure is not an option,” Missy Herndon said forcefully during the 2016 banquet. “Not for Will, and not for any other child with Batten disease.” It was clear from the strength of her words that she believed in the science, and that she believed in the research.

“I have a newborn son,” Sardiello said, recalling the speech. “I can’t imagine going through what Missy and Wayne had to. I felt involved and I felt empathy, but most of all, I felt respect for Will’s parents. They are truly exceptional people and go far and beyond what anyone can expect of them. In face of adversity, they are tireless, they won’t stop, and their commitment is amazing.”

When one hears about science and labs, it usually brings to mind arrays of test tubes and flasks or the futuristic possibilities of science. In all of this, one tends to forget about the people behind the test bench: the scientists that conduct the experiments and uncover the next step in the collective knowledge of humanity, people like Dr. Sardiello. However, Sardiello isn’t alone in his endeavors, as he is supported by the members of his lab.

Each and every one of the researchers in Marco’s lab is an international citizen, hailing from at least four different countries in order to work towards a common cause: Parisa Lombardi from Iran, Lakshya Bajaj, Jaiprakash Sharma, and Pal Rituraj from India, Abdallah Amawi, from Jordan, and of course, Marco Sardiello and Alberto di Ronza, from Italy. Despite the vast distances in both geography and culture, the chemistry among the team was palpable, and while how they got to America varied, the conviction that they had a responsibility to help other people and defeat disease was always the same.

Humans have always been predisposed to move forwards. It is because of this propensity that humans have been able to eradicate disease and change the environments that surround us. However, behind all of our achievements lies scientific advancement, and behind it are the people that we so often forget. Science shouldn’t be detached from the humans working to advance it, but rather integrated with the men and women working to make the world a better place. Dr. Sardiello and his lab represent the constant innovation and curiosity of the research community, ideals that are validated in the courage of Will Herndon and his family. In many ways, the Sardiello lab embodies what science truly represents: humans working for something far greater than themselves.

References

1. Sardiello, M.; Palmieri, M.; di Ronza, A.; Medina, D.L.; Valenza, M.; Alessandro, V. Science. 2009, 325, 473-477.

The Depressive Aftermath of Brain Injury

Catalyst Volume 10

One intuitively knows that experiencing a brain injury is often painful and terrifying; the fact that it can lead to the onset of depression, however, is a lesser known but equally serious concern. Dr. Roberta Diddel, a clinical psychologist and member of the adjunct faculty in the Psychology Department at Rice University, focuses on the treatment of individuals with mental health issues and cognitive disorders. In particular, she administers care to patients with cognitive disorders due to traumatic brain injury (TBI). Dr. Diddel acquired a PhD in clinical psychology from Boston University and currently runs a private practice in Houston, Texas. Patients who experience TBI often experience depression; Dr. Diddel uses her understanding of how this disorder comes about to create and administer potential treatments.

Traumatic brain injury (TBI) affects each patient differently based on which region of the brain is damaged. If a patient has a cerebellar stroke, affecting the region of the brain which regulates voluntary motor movements, he or she might experience dizziness and have trouble walking. However, that patient would be able to take a written test because the injury has not affected higher order cognitive functions such as language processing and critical reasoning.

Dr. Diddel said, “Where you see depression the most is when there is a more global injury, meaning it has affected a lot of the brain. For example, if you hit your forehead in a car accident or playing a sport, you’re going to have an injury to the front and back parts of your brain because your brain is sitting in cerebrospinal fluid, causing a whiplash of sorts. In turn, this injury will cause damage to your frontal cortex, responsible for thought processing and problem solving, and your visual cortex, located in the back of your brain. When your brain is bouncing around like that, you often have swelling which creates intracranial pressure. Too much of this pressure prevents the flow of oxygen-rich blood to the brain. That can cause more diffuse brain injury.”

In cases where people experience severe brain injury such as head trauma due to an explosion or a bullet, surgeons may remove blood clots that may have formed in order to relieve intracranial pressure and repair skull fractures.⁴ They may also remove a section of the skull for weeks or months at a time to let the brain swell, unrestricted to the small, cranial cavity. That procedure alone significantly reduces the damage that occurs from those sorts of injuries and is especially useful in the battlefield where urgent care trauma centers may not be available.

Depression is a common result of TBI. The Diagnostic and Statistical Manual of Mental Disorders (DSM) defines depression as a loss of interest or pleasure in daily activities for more than two weeks, a change in mood, and impaired function in society.¹ These symptoms are caused by brain-related biochemical deficiencies that disrupt the nervous system and lead to various symptoms. Usually, depression occurs due to physical changes in the prefrontal cortex, the area of the brain associated with decision-making, social behavior, and personality. People with depression feel overwhelmed, anxious, lose their appetite, and have a lack of energy, often because of depleted serotonin levels. The mental disorder is a mixture of chemical imbalances and mindstate; if the brain is not correctly functioning, then a depressed mindstate will follow.

Dr. Diddel mentioned that in many of her depressed patients, their lack of motivation prevents them from addressing and improving their toxic mindset. “If you’re really feeling bad about your current situation, you have to be able to say ‘I can’t give in to this. I have to get up and better myself and my surroundings.’ People that are depressed are struggling to do that,” she said.

The causes of depression vary from patient to patient and often depends on genetic predisposition to the disease. Depression can arise due to physical changes in the brain such as the alterations in the levels of catecholamines, neurotransmitters that works throughout the sympathetic and central nervous systems. Catecholamines are broken down into other neurotransmitters such as serotonin, epinephrine, and dopamine, which are released during times of positive stimulation and help increase activity in specific parts of the brain. A decrease in these chemicals after an injury can affect emotion and thought process. Emotionally, the patient might have a hard time dealing with a new disability or change in societal role due to the trauma. Additionally, patients who were genetically loaded with genes predisposing them to depression before the injury are more prone to suffering from the mental disorder after the injury.^2,3

Depression is usually treated with some form of therapy or antidepressant medication. In cognitive behavior therapy (CBT), the psychologist tries to change the perceptions and behavior that exacerbate a patient’s depression. Generally, the doctor starts by attempting to change the patient’s behavior because it is the only aspect of his or her current situation that can can described. Dr. Diddel suggests such practices to her patients, saying things like “I know you don’t feel like it, but I want you to go out and walk everyday.” Walking or any form of exercise increases catecholamines, which essentially increases the activity of serotonin in the brain and improves the patient’s mood. People who exercise as part of their treatment regimen are also less likely to experience another episode of depression.

The efficacy of antidepressant medication varies from patient to patient depending on the severity of depression a patient faces. People with mild to moderate depression generally respond better to CBT because the treatment aims to change their mindset and how they perceive the world around them. CBT can result in the patient’s depression gradually resolving as he or she perceives the surrounding stimuli differently, gets out and moves more, and pursues healthy endeavors. Psychologists usually begin CBT, and if the patient does not respond to that well, then they are given medication. Some medications increase serotonin levels while others target serotonin, dopamine, and norepinephrine; as a result, they boost the levels of neurotransmitters that increase arousal levels and dampen negative emotions. The population of patients with moderate to severe depressions usually respond better to antidepressant medication. Medication can restore ideal levels of neurotransmitters, which in turn encourages the patient to practice healthier behavior.

According to the Center for Disease Control and Prevention, the US saw about 2.5 million cases of traumatic brain injury in 2010 alone.⁵ That number rises every year and with it brings a number of patients who suffer from depression in the aftermath.⁵ Though the mental disorder has been studied for decades and treatment options and medications are available, depression is still an enigma to physicians and researchers alike. No two brains are wired the same, making it very difficult to concoct a treatment plan with a guaranteed success rate. The work of researchers and clinical psychologists like Dr. Diddel, however, aims to improve the currently available treatment. While no two patients are the same, understanding each individual’s depression and tailoring treatment to the specific case can vasty improve the patient’s outcome.

References

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC, 2013.
2. Fann, J. Depression After Traumatic Brain Injury. Model Systems Knowledge Translation Center [Online]. http://www.msktc.org/tbi/factsheets/Depression-After-Traumatic-Brain-Injury (accessed Dec. 28, 2016).
3. Fann, J.R., Hart, T., Schomer, K.G. J. Neurotrauma. 2009, 26, 2383-2402.
4. Mayo Clinic Staff. Traumatic Brain Injury. Mayo Clinic, May 15, 2014. http://www.mayoclinic.org/diseases-conditions/traumatic-brain-injury/basics/treatment/con-20029302 (accessed Dec. 29, 2016).
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