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Welcome back to Tan Couch, where we take you from wherever you are in the world to the comfort of this couch, where together we push our boundaries and explore issues never out of your reach. 

Once again my name is Arin Hendell and I am a Sophomore majoring in communication at Cornell University. For those of you new with us, What even is communication? Within the College of Agriculture and Life Sciences here in Ithaca, we explore how humans understand and process messages to create meaning and relationships with the world around them. How this may take form in studies, either in understanding which cigarette ads are more effective for attitude and behavioral change, or creating a content analysis on tweets about the 2020 election, professors, graduate students, and even undergraduates major work together towards this powerhouse of empiricism. In a class for one of my communication focus areas, Communication, Environment, Science, and Health, we explore the most optimal ways to convey and frame these topics of-- you guessed it-- environment, science, and health-- in a way humans will best understand and relate to. I have been assigned to explore a science research topic and share the process and relevance involved with you all.  

While the Communication department is largely focused on social sciences related to humanities issues, I wanted to go outside my comfort zone by picking a more “hard” science topic and communicate it to those who may think they are as unexposed and seemingly inexperienced as I am. As I was anticipating, the density and science literacy required for this assignment, I was nervously checking the website of Cornell research projects and came across an article about a research study called Learning Fear (Hayes 2018) about how humans “learn” to become creatures that are fearful and anxiety-ridden, and what neurological mechanisms might be responsible for that. As I found myself nervous and intimidated to digest research on a topic I know less than nothing about, I decided to see the work of Francis S. Lee, M.D. Professor in Psychiatry at Weill Cornell Medicine had to offer me--us-- about anxiety and fear. Let’s get after it, shall we?

How did this study come about? 

A large part of communication as a social science of our cognitive systems involves studying how different people interpret messages and stimuli differently from a holistic lens. Lee appreciates that in humans, we hold on to fear and internalize threats differently from one another depending on the individual (Hayes 2018). With some anxieties and fears fleeting, and some chronic, he and his colleagues study the brain’s fear circuit itself to find out what neurological mechanisms really cause anxiety, and for whom. 

He introduces us into the concept of a changing neurological function with brain plasticity. If you’re like me, you kind of knew what brain plasticity was, but was not confident you could explain it to someone if asked.  To put it in slightly more understandable terms, Lee gives us the analogy of visual plasticity, which essentially refers to the ability to correct your visual cortex when you’re young. These changing abilities are analogous to certain neurological functions, in this case, fear response. In the case of both visual and neuroplasticity, after about 10 years, this self-correction becomes harder and harder. This period of heightened plasticity is known as the “critical period”. So Lee poses the question: What else can this “critical period” tell us about the changing of emotional circuits?

“How does a juvenile versus an adolescent versus an adult, for example, regulate their fear responses?” (Hayes 2018) 

Lee shares extremely current findings of the periods of brain growth, as he and his fellow colleagues are learning new things about the brain they may not have believed as recent as six years ago. Lee recently discovered that the fear system essentially “goes offline” during adolescence, which suggests the nonlinear nature of brain development. This “plasticity” could explain why those who experience trauma as a child or adolescent may not be affected by it until later in life, when their fear response is more pronounced. The main goal of Lee’s research, and his leading question, is how to intervene in the fear circuitry in periods of increased plasticity, in order to combat potential anxiety or depressive disorders that can manifest later.

What is this “fear circuit” that seems so important?

Lee’s main point of research is around the mechanism of “BDNF polymorphism”. Don’t worry-- I was confused at first too.  BDNF, or brain-derived neurotrophic factor as it is less affectionately known, comes from a family called “neurotrophins”, which help regulate brain activity (Shen et al., 2018). When studying this protein in the context of fear response, researchers have found particular relevance in the polymorphism known as “Val66met”. Polymorphism, in this case relating to the changing strength of certain synoptical processes, leads to an “amino-acid residue substitution” (Shen et al. 2004, p. 198) which changes the amino acid in the BDNF protein from valine to methionine at position 66 within a certain region of the brain. Put more simply, the building blocks of these proteins can change throughout one’s life, causing a change in the amount of BDNF present.  So, when you hear the term “Val66met”, know that it refers to this dysregulation, often associated with cognitive and emotional dysfunction, as is consistent with Lee’s mission and confirmed by an original research article from Frontiers in Human Neuroscience (Park et al., 2017). What a mouthful!

Okay, what do other journals have to say about the effects of this polymorphism?

According to an article from the Aging and Disease journal, dysregulation of this protein also implies the increased risk of what researchers call “neurodegenerative diseases” (Shen et al. 2004, p. 198) which progressively kill nerve cells in the brain. Diseases we are unfortunate to know such as Parkinson’s, Alzheimer’s, and Huntington’s disease are exacerbated by this dysregulation of BDNF. I hope you all never have to either suffer from these diseases yourself or know someone who does. However, there is existing and ever-growing research about what causes BDNF polymorphism in the hopes of finding new and innovative treatments for those who are mentally ill.

The BDNF dysregulation on the effects of these neurodegenerative disorders is one of the main focuses of this research area. Along with these diseases, which are exacerbated by BDNF rather than a direct result of it (Park et a., 2017), researchers have found changing levels of BDNF in individuals with major depression or anxiety symptoms (Shen et al. 2004, p. 211).  As the work of Shen (2004) and their research team shows us, a reduction of BDNF concentration is found in patients with major depression and increased concentration of BDNF after taking antidepressants.

So, how has this protein in humans been studied in practice?

While starting with human patients for psychological experiments might be unwelcomed in the medical community, Lee, along with the larger community of Psychiatric development studying this polymorphism, conducts these studies on mice; Lee and his research team employed a group of mice to see how they would react to the changes in BDNF. He took imaging of their brains given certain stimulus conditions to highlight which parts of the brain respond to which stimuli. In order to see how this information would really apply to humans, he collaborated with B.J. Casey, a former colleague of his, who he met at the Sackler Institute for Developmental Psychology. Along with Casey, who had parallel neuroimages of human brain circuit activity, the two were able to compare the circuitries of the mice and human brains. After comparing the images of mice brains to human brains, they found that these exact circuits of BDNF functions are related directly to heightened anxiety and fear responses (Hayes 2018). 

Why do we care?

To be honest, I initially thought this was all simply jargon and not palatable for a non-neurologist to digest, but the more I learned about this work, the more I realized how applicable and relevant it truly is; as we now live in a world increasingly aware of anxiety and its effects, it’s reassuring that there is a plethora of research about this specific mechanism of fear response working to combat anxiety.

Normal fear-learning mechanisms in humans can retain cues that signify safety, which are then extinguished when these cues are no longer present and the fear is no longer rational. These mechanisms in anxiety disorders don’t function properly, and so, those with phobias or posttraumatic stress have a different cognitive process, which is seen in the context of this BDNF protein character you’ve been hearing about (Soliman et a., 2010). This expanding field of research provides insight into the mechanism that indicates the risk of these anxiety disorders. Not only could a deeper understanding of these circuits refine pre-existing treatments, but could also lead to a more personalized form of treatment for anxiety (Hayes 2018).

Ok, learning about this, in theory, is cool, but how does BDNF actually help us diagnose or treat anxiety disorders? Lee and Casey’s amazing collaboration led them to develop a co-patent related to this single BDFN nucleotide, Val66met. With this patent outlining this emotional circuit, medical tests will be able to test for this specific kind of polymorphism to be a “biomarker”, as they call it, of how certain patients might respond to certain treatments. By implementing this “biomarker” into modern medicine and even psychiatry, we may be able to understand patterns of fear learning as it relates to each individual, which will ultimately create more treatment of anxiety or post-traumatic stress (Hayes 2018).

Lee wanted to find out more concretely how understanding this polymorphism is relevant to helping society. So, currently, Lee and JoAnn Difeded, collaborators of Weill Cornell Medicine, are conducting a study of war veterans from Iraq and Afghanistan. These individuals, potentially affected by PTSD, will benefit from an understanding of the plastic -- changing-- nature of these proteins as it relates to their disorder. Also, as young people, likely in their early twenties, they provide a good insight into the still-developing brain, and how responsive or unresponsive their brain is to certain stimuli. Based on his goal for research, I think Lee and his team could compare these images perhaps with soldiers from Vietnam or World War II in order to compare the differences in ages and the effect of BDNF polymorphism in the context of posttraumatic stress. What do you guys think?

Maybe first we have to know how far along we are.

So how long has this research actually been going on? While certain polymorphic genes have been studied for over a decade, and we have discovered more and more with ever-improving technology and neuroimaging, Lee gives us new ideas about how to best approach the study of these disorders. As he puts it, “to get at underlying mechanisms for psychiatric disorders is daunting” (Hayes 2018). With all of the stigma surrounding mental illness, especially the focus on improving medications to mute the chemical imbalances in the brain, Lee focuses on a different approach to medicating problems away: to fix them. In his studies, Lee not only uncovered new elements to these brain circuits but learned that soon, we will be able to actually understand them. 

As Lee’s work shows us, we are on the cutting edge of changing the approach to treating these psychiatric disorders, whether they are severe, mild, chronic, or fleeting. Scientists who work in this field are then left to navigate these processes as they themselves change. As of now, according to Lee (Hayes 2018) scientists are working to make bets on “where the future will be”. If I were a betting woman, I would go with Lee’s projection: we need to move on from the adult circuits to the developing circuits. As we know from looking into his PTSD study of young patients, he appreciates the significance of this portion of the development, where many of these disorders continue to evolve.

Why is this relevant now?

As a young college student myself, with a still-developing brain, I have experienced both first and second-hand how mental illness can arise in adolescence. I think part of this budding research and focus on psychiatric disorders goes hand and hand with the increasingly prevalent conversations and awareness about mental illness, particularly for kids and young adults. In fact, Lee was inspired by the New York-Presbyterian Youth Anxiety Center (Hayes 2018) in his involvement with research and his understanding of how important studying the causes of anxiety is. 

More than any other time in my life, I have felt the need to find peace in my everyday life, as the monotony of quarantine due to the COVID-19 pandemic day after day for months on end took a serious toll on my mental health. Each day, I had to create my own space of comfort to limit my anxieties. Basking in the plethora of fear-inducing media has made me shift my mindset and actively seek the “cues” that signal safety. Whether this is yoga, banana bread recipes, or simply lighting a candle, conditioning myself to alleviate anxiety has been the number one tool in my survival during these crazy times. As Soliman et al. (2010) said, fear-learning mechanisms require the removal, or extinguishing of these associations with fear cues when no longer relevant. Will I be irrationally afraid when I have a dry cough at any point in my lifespan? Will I ever receive a call from an unknown number and not fear it is a call from the state putting me in mandatory quarantine? Will I ever miss out on a social opportunity for fear it may be the last one I have years and years into my “best years” of life? Are there anxieties looming in my adult life I cannot even foresee? Now, with our academic and social lives through a screen, some kids only know what life is like with a mask, and with increased deaths nationwide, developing brains are at risk for impairment due to these severe circumstances. Let us trust that Lee, Casey, Difede, and the rest of those researching this topic find conclusive evidence to help us maintain a peaceful state of mind.

For minorities, this pandemic further highlighted their lack of access to health and mental health resources as we all try to keep ourselves and our families safe. While researchers studying this topic, I have found, do not spend much time discussing the demographics of their study samples, I hope this research is being approached from an intersectional perspective. Studying trauma and fear responses in people in the context of their race, sexuality, ethnicity, or social class is the most versatile approach to understanding what is responsible for this fear response. 

Thank you for tuning in! I’ll be Saving a spot for you on this tan couch for next time!

References

Giza, J. I., Kim, J., Meyer, H. C., Anastasia, A., Dincheva, I., Zheng, C. I., ... & Lee, F. S. 

(2018). The BDNF Val66Met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron, 99(1), 163-178.

Hayes, C. (2018, September 18). Learning fear. Retrieved March 29, 2021, 

fromhttps://research.cornell.edu/news-features/learning-fear#highlight-1487185901937

Johnstad, P. G. (2018). Powerful substances in tiny amounts: an interview study of 

psychedelic microdosing. Nordic Studies on Alcohol and Drugs, 35(1), 39-51.

Matsunaga, M., Masuda, T., Ishii, K., Ohtsubo, Y., Noguchi, Y., Ochi, M., & Yamasue, H. 

(2018). Culture and cannabinoid receptor gene polymorphism interact to influence the perception of happiness. PloS one, 13(12), e0209552. https://doi.org/10.1371/journal.pone.0209552

Liu, J. J., Bao, Y., Huang, X., Shi, J., & Lu, L. (2020). Mental health considerations for 

children quarantined because of COVID-19. The Lancet Child & Adolescent Health, 4(5), 347-349.

Park, C. H., Kim, J., Namgung, E., Lee, D. W., Kim, G. H., Kim, M., ... & Yoon, S. 

(2017). The BDNF Val66Met polymorphism affects the vulnerability of the brain structural network. Frontiers in human neuroscience, 11, 400.

Pezawas, L., Verchinski, B. A., Mattay, V. S., Callicott, J. H., Kolachana, B. S., Straub, 

R. E., ... & Weinberger, D. R. (2004). The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. Journal of Neuroscience, 24(45), 10099-10102.

Shen, T., You, Y., Joseph, C., Mirzaei, M., Klistorner, A., Graham, S. L., & Gupta, V. (2018). 

BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders. Aging and disease, 9(3), 523–536. https://doi.org/10.14336/AD.2017.0717

Soliman, F., Glatt, C. E., Bath, K. G., Levita, L., Jones, R. M., Pattwell, S. S., ... & 

Casey, B. J. (2010). A genetic variant BDNF polymorphism alters extinction learning in both mice and humans. Science, 327(5967), 863-866.