Grey Matters Journal VC Issue 1 Fall 2020

FEATURING The Changing Voices in Our Heads: Society’s Impact on Psychosis Battling COVID-19’s Mystifying Mental Fog Letting the Storm Pass: The Psychology and Neuroscience of Mindfulness

ISSUE 1

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TABLE OF CONTENTS 29

COVER ARTICLE

THE CHANGING VOICES IN OUR HEADS: SOCIETY’S IMPACT ON PSYCHOSIS

by Zoya Qureshi / art by Claire Iannetta Although there is no cure for schizophrenia, encouraging patients to develop relationships with their hallucinated voices and negotiating with them as though they are people, and not disembodied things, may hold therapeutic value.

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SCRATCHING THE SURFACE OF AN ITCH

by Ally Thayer / art by Alex Tansey

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BREAKING THE BROKEN BRAIN MODEL OF ADDICTION

by Brenna McMannon / art by Sophie Sieckmann

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BEYOND JUMBLED LETTERS: HOW DYSLEXIA AFFECTS LEARNING MATHEMATICS

by Emma Koolpe / art by Mara Russell

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Table of Contents

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THE GUT-BRAIN AXIS: CAN YOUR BELLY HEAL YOUR BRAIN?

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by Hannah Daley / art by Amelia Zah

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CUTTING OUT A CURE FOR HUNTINGTON’S DISEASE

by Alison Bond, Junjie Liu, and Anna Tidswell / art by Molly Berinato

CANNABIS USE DISORDER: THE GRIM REALITY OF CANNABIS ADDICTION

by Nick Beebe / art by Hannah Maver and Nick Beebe

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FEATURED ARTICLES

BATTLING COVID-19’S MYSTIFYING MENTAL FOG

by Nick Beebe / art by Karen Mogami and Nick Beebe Aside from death, the effects of COVID-19 on the brain are arguably the most malevolent repercussions of a COVID-19 infection.

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LETTING THE STORM PASS: THE PSYCHOLOGY AND NEUROSCIENCE OF MINDFULNESS

by Clement Doucette, Daniella Lorman, and Mara Russell / art by Allie Verdesca While mindfulness, in all of its associated definitions, is an intriguing prospect with numerous exciting and potential clinical applications, it’s important to both recognize the flaws in existing research and acknowledge that more time is needed to uncover its biological and behavioral correlates.

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REFERENCES

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Production Staff

DANIELLA LORMAN

LUCAS ANGLES

Editor-in-Chief

MARA RUSSELL Art Executive

Senior Managing Editor

KAYEN TANG

Production Manager

AUTHORS Zoya Qureshi Hannah Daley Ally Thayer Brenna McMannon Emma Koolpe Nick Beebe Anna Tidswell Junjie Liu Alison Bond Clement Doucette Daniella Lorman Mara Russell ARTISTS Mara Russell Sophie Sieckmann Claire Iannetta Molly Berinato Karen Mogami Hannah Maver

ELEANOR CARTER Senior Editor, Lay Review

ZOE CURRAN

Layout Executive and Outreach Coordinator

CHRISTOPHER CHO Senior Editor, Scientific Review

JULIĂ N AGUILAR Graphic Designer

Senior Editor, General Editing

FILIPP KAZATSKER

Social Media Manager

Alex Tansey Amelia Zeh Allie Verdesca Nick Beebe

Nanako Kurosu Elsa Wiesinger Nicholas Beebe Grace Willoughby

EDITORS

Scientific Review

General Editing

Dhriti Seth Sanaya Shikari Haylee Backs Jessica Porras Madison Wilson Haroun Haque Amber Huang Samata Bhattarai Ty Langford Joshua Kim Tori Armitage David Schwitzgebel Claire Tracey Andrea Tellez Ninamma Rai Keara Ginell

Lucy Volino Katherine Nelson Rebecca Zhao Catherine Hansa Claire Tracey Alex Tansey Haylee Backs Mina Turunc Ty Langford Tessa Charles Naomi Tomlin Caitlin Patterson Talia Mayerson Sophia Gaffney

HANNAH WEISMAN

BEN KHEYFETS Treasurer

Annie Xu Alex Eisert Ella Kolk Emma Trasatti Cesar Camacho Lay Review Anjali Krishna Clement Doucette Rebecca Zhao Lia Russo Gissette Noriega Benjamin Fikhman Alexandra Lau Caitlin Wong Nicole Stern Claire Tracey Hannah Thompson Naima Nader Adalyn Schommer

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Issue Notes

ON THE COVER Art by Claire Iannetta

LET US KNOW If you have questions or comments regarding this issue, please write a letter to the editor at brainstorm.vassar@gmail.com.

LEARN MORE Check out our website to read our blog, find out how to get involved, and more at greymattersjournalvc.org.

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Editor’s Note

EDITOR’S NOTE Societal fatigue, the virulent spread of misinformation, and the politicization of disease are palpable as the COVID-19 pandemic continues to ravage the globe. Scientists and medical experts have communicated public health practices— social distancing, maskwearing, testing, and tracing— that, if adopted, can save lives. But more is needed to combat the explosive spread of the virus.

The trajectory of this pandemic depends largely on our ability to build rapport in science and focus on shared goals for common health.

Deconstructing the divide between the scientific community and the general public means increasing transparency, accepting culpability, and opening lines of communication. And yet, a gap persists. Science is conducted to benefit the greater community, but science is too often an impenetrable conversation. The public’s lack of access to research journals and the struggle of scientists to discuss their work with individuals who do not share their same training creates a divide between those with scientific expertise and the general public, or simply, everyone else. Scientists and medical experts need to better engage with the largest beneficiaries of their work. To begin, scientific prose is inaccessible. The balkanization of scientific sub-fields and their respective laundry lists of jargon other lay audiences. It’s time to rethink the rhetoric and design of scientific communication. It’s time to have conversations on level ground.

Our goal at Grey Matters Journal VC is to dismantle barriers of access in neuroscience. We hope that Issue 1 provides you with comprehensive and interactive opportunities to engage in science dialogue.

Cheers,

Daniella Lorman Editor in Chief

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Scratching the Surface of an Itch

SCRATCHING THE SURFACE OF AN ITCH

by Ally Thayer art by Alex Tansey

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ou know the feeling. That irritating, all-consuming, and often hard-to-reach sensation: an itch.

Have you ever thought about why you itch? Or, what an itch even is? As you read this, you will probably start to feel itchy. Why is that? Were your parents right when they told you that scratching an itch will only make it worse? All of these questions seem very simple, but neuroscientists and doctors have been studying itching, medically known as pruritus, and its causes for centuries now to understand how and why we itch.

Nearly everyone has experienced an itch in their lifetime. But what causes itchiness? Itches have many causes, a few of which you may have experienced.

Maybe you have experienced an itch from an allergy, dandruff, lice, dry skin, or an unfortunate encounter with poison ivy. Maybe you have a skin condition that causes a more painful and chronic itch, such as eczema or psoriasis. Maybe you have an experience with some sort of psychosis that can cause an itchy sensation with no physical cause. Or maybe you have a very specific condition, such as brachioradial pruritus,

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in which a pinched nerve in the neck causes the outer arm to itch [4]. Because itching has so many causes, it is difficult to study and understand all kinds of itches as one condition. Regardless of the cause, the experience of an itch ranges from a brief annoying sensation to a relentless pain that has even led people to commit suicide [4]. By understanding an itch and how to treat it, we can not only better understand the human body and nervous system, but also improve and save lives.

In order to understand the science of itching, it is important to define what exactly an itch is. The widely accepted definition of an itch has not changed since it was first postulated in the 17th century by German physician Samuel Hafenreffer, who defined an itch as an “unpleasant sensation that elicits the desire or reflex to scratch� [3]. Although itching may seem easily defined, it is not yet completely understood. Itching can be classified into two categories: acute and chronic [2]. Acute itching refers to a severe and sudden onset of an itchy sensation that is not long-lasting, while a chronic itch refers to a persistent, debil-

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Scratching the Surface of an Itch itating itch that often has few treatment options [2].

With this knowledge of what itches are and how they are classified, we can begin to think about what happens neurologically when we itch.

In general, the nervous system receives sensory information through neurological pathways. Sensory receptors in the skin collect sensory information, which is then relayed to the spinal cord, which sends a message to a region in the top of the brain called the sensory cortex.

This area is where the conscious experience of physical sensation occurs, and it is where your brain alerts you to the itch. The sensory cortex then communicates with the motor cortex, another region of the brain, to move the body to scratch, ignore the sensation, or move away from it [1]. This may seem like a fairly simple pathway, but it quickly becomes more complex upon close examination.

Scientists used to believe that itching was a lesser form of pain and, conversely, that pain was an extreme form of itch. They believed that the sensory neurons on the skin responding to information for itching were the same ones that responded to information for pain [5]. However, a 2013 study disproved this theory and confirmed that the neurons that respond to itchy stimuli are different than those that relay pain signals to the brain, demonstrated by the discovery of a protein present in only some sensory neuron receptors: Nppb. Receptors without Nppb did not respond to itch-inducing stimuli but did respond to other sensory stimuli, such as pain or heat. Once the protein was reintroduced, scratching began [5].

This research has been pivotal to the conceptualization of an itch and how itchiness is currently treated and has led to the development of drugs to target this itch receptor. However, scientists still understand little about itching at the molecular and cellular level.

With all this discussion of itching, you may be feeling rather itchy yourself. In neuroscience, the compulsion of one individual to copy a certain behavior of others

is known as behavioral contagion and is often subconscious. Yawning and contagious itch are both examples of behavioral contagion.

Recent research in mice has identified the neural mechanisms in the brain that explain this phenomenon. When mice were shown videos of another mouse scratching, they began to scratch themselves. Researchers noticed increased activity in the suprachiasmatic nucleus (SCN), an area in the brain that is involved in the regulation of the sleep-wake cycle, when mice viewed videos of other mice who were experiencing an itch [10]. After further analysis, researchers found that the SCN releases a substance called gastrin-releasing peptide (GRP), which is involved in the transmission of itch signals between the brain and the spinal cord. [10]. When researchers then blocked GRP in a mouse’s brain, the mouse did not scratch while watching videos of other mice but would still scratch if exposed to an itch-inducing stimulus. The mouse could still itch, but because of GRP inhibition, it was not “catching” a contagious itch; this led researchers to the conclusion that itching is both an innate and instinctive behavior. As said by Dr. Zhou-Feng Chen of the Washington University School of Medicine in St. Louis research team, the “next time you scratch or yawn in response to someone else doing it, remember it’s really not a choice or a psychological response; it’s hardwired into your brain” [10].

Itchiness is undoubtedly an uncomfortable sensation, and when experiencing an itch, the immediate solution usually seems to be to scratch it. However, you have probably been told at some point not to scratch an itch, since it will only make the feeling worse. The Buddhist philosopher Nāgārjuna described how “there is pleasure when an itch is scratched. But to be without an itch is more pleasurable still” [2]. So, what does science tell us about scratching an itch? Don’t do it. But why? The answer lies within a mechanism called the Itch Scratch Cycle [9]. Scratching gives short term relief, as when we scratch our itches, we overwhelm the body’s itch signals with pain signals.

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Scratching the Surface of an Itch common treatment for itching is hydrocortisone skin cream, which treats itches associated with allergic reactions or irritation. During these allergic reactions or irritations, various chemicals in the skin are released that cause blood vessels to open and the skin to become red, swollen, and itchy. Hydrocortisone cream acts inside the skin cells to stop the releasing of these chemicals and prevents the itchy situation from beginning [7].

New information in itch science brings us closer to understanding and treating itchiness. In April of 2020, periostin, a new protein, was found in the skin and is believed to directly activate the itch receptors [6].

In September of 2020, a study was released arguing that rubbing of the skin, rather than scratching, could potentially activate an anti-itch pathway that travels through the spinal cord [8]. Perhaps we should be rubbing our itches rather than scratching them?

Hopefully, one day soon we will be able to completely understand what an itch really is and how to best treat them. But for now, to the best of your ability, do not scratch your itches!

References on page 47.

The itch does not stop, but rather the induced pain from the scratching of our nails on our skin is felt instead. While this may feel like relief, it is merely a distraction from the real discomfort: the itch. Because you have generated a pain sensation, the body responds by releasing serotonin, a chemical in the nervous system that helps deal with pain [9]. This release then causes itch receptors to become extra sensitive when responding to a stimulus. So, when scratching stops, the induced pain disappears, but the itch remains. The itch receptors are more sensitive now, so the next itch will be perceived as worse. You will then want to scratch again, and the cycle continues [9].

Whether you listen to science, NÄ gÄ rjuna, or your parents, it seems the consensus is to avoid scratching your itches. They will only feel worse.

While scratching an itch will just make it feel worse, an anti-itch cream can often lead to relief. Because itching is so diverse in its causes, it is also very diverse in its treatments. For example, in patients with mild eczema, a common treatment is to encourage moisturizing. Dry skin becomes flaky, and the flakes can act as irritants that cause the body to itch [7]. A

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Breaking the Broken Brain Model of Addiction

BREAKING THE BROKEN BRAIN MODEL OF ADDICTION

by Brenna McMannon art by Sophie Sieckmann

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hat comes to mind when you hear the word “broken?” A broken bone, a broken heart, broken trust? We use the word in many different ways.

What about a broken brain? The brain is an incredibly

complex and malleable part of us, so is it even possible to break it? And why is this term used to talk about addiction? Addiction has shrugged off much of its original stigma as new studies have demonstrated its base in neuroscience. But understanding addiction means going beyond a purely neurological classification. While addictive behavior does correlate to neurological mechanisms, these processes are greatly influenced by one’s environment, mental health, stress levels, and developmental factors.

The molecules that form the basis of all brain function are known as neurotransmitters, which are chemical compounds that allow neurons (nerve cells) to send messages to each other. Dopamine is a neurotransmitter that is most active in the brain when modulating reward and addiction. Known as the “feel good” neurotransmitter, dopamine is released by the brain when you are having a pleasurable experience, such as eating your favorite meal or spending time with your favorite person. We even see this in rodents: they will consume alcohol because it increases their dopamine release [16]. Because dopamine plays a critical role in reward, it also plays a crucial role in addiction.

In order to fully understand the neurological side of addiction, we need to take a closer look at how do-

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Breaking the Broken Brain Model of Addiction pamine is involved in reward processing in the brain.

The area of the brain that is implicated the most in addiction is the nucleus accumbens (NAc), which is the center of the reward-related learning system. In this system, reward related-stimuli are sent as signals from the limbic system and converge in the NAc to be processed for motor functioning of the reward behavior [18]. Put more simply, your hand reaches for the cookie because you know it is going to be a pleasurable experience to eat the cookie. The NAc receives information from dopamine neurons in the ventral tegmental area of the brain (VTA). This is an important connection because most drugs of abuse modulate dopamine-based activity in the VTA, where neurons then send signals to the NAc. In other words, the more that a person’s behaviors engage the dopamine neurons in the VTA, the more that the NAc is going to be activated. Drugs of abuse tend to activate dopaminergic neurons in the VTA, triggering the reward pathway more frequently and making it more susceptible to stimulation. Over time, disruption of this pathway can result in the changes of motivated physical behaviors characteristic of addiction. Certain situations may trigger the reward pathway more, causing the physical action of the addictive behavior to occur more often.

In the brain, these consequent motor functions are carried out through NAc activation and subsequent passing of information to the motor cortex, generating physical behaviors [3]. Addiction behavior is very much reward-based, which makes the reward pathway crucial to understanding the workings of addiction. In other words, if something makes you feel good, you will likely want to do it again.

Currently, many people accept the disease model, also known as the “broken brain” model, which focuses on the neurological mechanisms and effects of addiction-based behavior. This model uses a completely disease-based approach without acknowledging environmental and developmental factors that contribute to the learning of addictive behavior. Addiction research tends to hone in on dopamine signaling in the NAc because addiction tends to be correlated with disruptions in the reward circuit in the VTA and NAc regions of the brain [13]. Studies have shown that changes in neurotransmitter functions, specifically in dopamine circuits, contribute to abnormal brain function and increased addictive behavior [12]. In other words, the reward system works at the molecular level to affect changes in behavior Additionally, there is no evidence to suggest that there is only one part of the brain that is “broken” and causes someone to become an addict [18]. Although all of these are scientific claims, they only show us how the brain changes in

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response to learned addictive behaviors. The brain is incredibly plastic, meaning that it can change throughout your lifetime in response to experiences and the environment. Since addiction behavior is learned over time, the brain adapts and changes in response to learned behaviors. It is possible to acknowledge the science behind the disease model without dismissing it as the sole determinant of addiction.

Addiction is not purely a neurological disease, and we must change how we think about the development of addictive behavior. In her book, Unbroken Brain, Maia Szalavitz emphasizes the importance of recognizing addiction as a learned behavior. Szalavitz characterizes addiction as a developmental disorder rather than a neurological disease, defining it as a “learned relationship between the timing and pattern of the exposure to substances or other potentially addictive experiences and a person’s predispositions, cultural and physical environment, and social and emotional needs” [11]. In other words, you are not born destined to develop addictive behavioral patterns because your brain is not prewired with addictive tendencies. With this definition, Szalavitz rejects the notion of an “addictive personality,” asserting that the process of becoming addicted is much more complex and is rooted in the person’s individual, social, and cultural development.

Unfortunately, many do not understand the depth and complexity of addiction. Because people only see the external result of this learned behavior, they often assume that substance abuse is a personal and moral failure. In doing so, they fail to account for other factors –– such as a traumatic childhood or being bullied at school –– and make harmful assumptions about those who are struggling [17].

To make matters worse, while drug policies in the U.S. may cause people to feel like action is being taken, these policies fail to address the real problem at hand: the original afflictions that led people to seek refuge in drugs in the first place [11]. Consider the “War on Drugs” enacted by President Nixon in the 1970s, which set a precedent for the intense criminalization of drugs in the future and further damaged society’s relationship with addiction. These policies framed substance use disorders as criminal and the people who struggled with them as morally inept. This mindset preceded years of harmful drug policies that disproportionately impacted and continue to affect the vulnerable and low-income communities that they should be working to serve. Because individuals within these communities frequently face stressful situations, they are more

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Breaking the Broken Brain Model of Addiction prone to resort to substances in search of an escape.

Furthermore, it has been shown that increased stress levels are associated with a higher risk of developing a substance use disorder [2]. We know that high levels of stress hormones can cause damage to the hippocampus, a brain structure that plays a prominent role in learning and memory [10]. The hippocampus has also been found to play a role in the development of mood disorders [9]. Therefore, experiencing higher levels of stress puts people at higher risk of developing mental disorders. Because of this, we cannot apply the same substance abuse rehabilitation treatment offered in wealthy areas to people with a lower socioeconomic status. We, as a society, cannot create a “one size fits all” solution. Different environments invite different risk factors; lower socioeconomic status is correlated with increased risk of developing addictive behavior [2]. It doesn’t make sense to enforce a policy without thoroughly comprehending and addressing the root causes of the issue; this is akin to slapping a bandaid on an internal wound. It’s not going to stop the bleeding.

Understanding addiction is also important for college-age students, as the majority of people who develop substance-use addictions do so in their early to mid-twenties when they are going through big life changes, like moving out of their childhood home or going to college [5]. In fact, 90% of all substance use addiction begins in adolescence [4]. On the molecular level, dopamine may also play a role in this age-dependent vulnerability. There is evidence that the risk-taking and unpredictable behavior associated with adolescence is due, in part, to dopamine overactivity in the brain [15].

Young adults may experience higher levels of other mental health afflictions, like depression, anxiety, and acute or chronic stress, which puts them at a higher risk for developing addictive behavior [6]. The prevalence of mental health disorders is an important factor to consider in the learning of addiction and its neural mechanisms.

The overlap of addiction and other mental problems is called comorbidity, and it turns out to be fairly common. In fact, 32% of people with a substance use disorder also have a major depressive disorder (MDD),

and their overall risk of relapsing is increased because of this comorbidity [18]. Scientists believe that the comorbidity between depression and substance use disorders is due to parallel mechanisms involving dopamine in response to stress. Specifically, they

may share a common pathway through the nucleus accumbens [18]. Further studies have found similar brain imaging results and common changes in stress responses in people with MDD and substance use disorder [1]. Depression and substance use disorders

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are dangerously linked, increasing the risks of each of them when combined [18]. The interconnectedness of addiction and mood disorders, specifically depression, is an important example of how dangerous it is to oversimplify the mechanisms of addiction.

Another oversimplification would be to claim that physiological changes are the only qualifiers of disease. Scientists that support the disease model base their argument on the physiological changes observed in the brains of people with addictive behaviors. They use tissue damage in the brain as evidence for the model, claiming that it is specifically caused by drug use and increases compulsive behavior [14]. Therefore, the disease model argument is based simply on the premise that addiction changes the brain. However, this claim cannot be fully discredited; it is just not the whole story. In fact, the brain changes all the time; it’s called neuroplasticity.

In order to fully understand how addiction is learned, we must look deeper into developmental and envi-

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ronmental factors and how they affect neuroplasticity. The brain is made up of billions of synapses, or neural connections, that are all interconnected and make us who we are. This synaptic web is also incredibly sensitive to our environment and individual experiences and undergoes structural changes in response to events and behaviors. Over time, the synaptic pathways that we use more frequently become more prominent and sensitive when they are repeatedly activated [7]. These pathways become more solidified and less subject to change, usually as a result of learning and repeated behavior or thought. This process of synaptic strengthening is responsible for much of the neuroplasticity that occurs in the brain.

In other words, doing something more often makes the behavior easier and easier because the brain has essentially “carved out� and solidified this neural pathway.

Our experiences throughout life change the way the neurons in our brain fire, making us more or less likely to engage in risky behaviors in the future. As discussed

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Breaking the Broken Brain Model of Addiction before, people living in stressful environments are at higher risk of engaging in addictive behaviors in the future. This is because the connections in their brains have been changed over time based on their experiences and environment. For this reason, addiction behavior is learned, and as with all habits, it is hard to break [7]. The synaptic connections in the reward pathway strengthen through repetitions of the behavior, making it easier to activate the reward pathway.

be more focused on prevention: providing equal opportunities to kids in schools at a young age, making resources available to children living in less than ideal environments, and working to manage and alleviate stress. No one should ever feel broken. This is where it starts.

References on page 47.

The disease model claims that addictive behavior causes changes and damage to the brain, while the development model claims that these changes are actually a result of the learned behavior. Yes, the brain does undergo physical changes because of addiction.

But the brain is always changing [8]. There are so many different factors that are responsible for someone developing a substance use disorder. Different environmental factors make people more vulnerable to depression and stress, which cause their brains to be more susceptible to engaging in addictive behavior. Over time, this behavior becomes learned and the reward pathway in the brain becomes strengthened.

It takes less stimulation for dopamine neurons in the VTA to be activated and send signals to the nucleus accumbens, generating the addictive behavior.

Although we know that addictive behavior is learned and strengthened through neural pathways in the brain, we should still reject the purely neurological disease classification. Addiction doesn’t change the way the brain works in the same way that diabetes changes the way the pancreas works [7]. Your brain has been adapting and changing your entire life; it is designed to change. Yes, the brain is a complex structure and there is much that we still do not know, but we know how behaviors are learned and we know that it is not because something is “broken.”

The disease model would like you to think that addiction is just like any other disease, because something broken simply needs to be fixed. This couldn’t be further from the truth. In the case of substance use disorders, there is no quick fix; there is no obvious solution. But this is not to say that there is no route for recovery. In fact, there are many rehabilitation methods that work for several people. The key to treatment of addictive behavior is recognizing that each person’s recovery must cater to their unique situation, based on their developmental and environmental conditions.

There is no “one size fits all solution.” The more that we learn about addiction, the better we get at developing solutions for people who are struggling. And it is becoming abundantly clear that our society should

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Beyond Jumbled Letters

BEYOND JUMBLED LETTERS: HOW DYSLEXIA AFFECTS LEARNING MATHEMATICS

by Emma Koolpe / art by Mara Russell but a gap persisted when it came to translating written language into equations. It wasn’t until the seventh grade that we understood why: dyslexia.

Dyslexia is a learning disorder that affects one’s ability to identify speech sounds. A majority of the research and discussion regarding this phenomenon has focused on differences in reading and language-based tasks. For instance, functional MRIs (fMRIs) demonstrate that dyslexic and non-dyslexic people utilize different parts of the brain when reading. However, dyslexia does not just stop at language learning issues. Dyslexic and non-dyslexic brains also use different neurological processes to learn and understand math.

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hen I was in third grade, my math teacher introduced the concept of the dreaded word problem: “Each watermelon costs $2 and you have $10. How many watermelons can you buy?” This simple two-sentence problem took the concept of division and added words into the mix, which frustrated me greatly. I remember asking my teacher, “When would I ever need to know how many watermelons I need to buy? And, why would I ever need more than one? I like watermelon, but not THAT much.” I took these problems home to my parents, who would spend countless hours trying to explain the process to me. My parents and I had no idea why I was experiencing such difficulty in solving word problems; I seemed to excel at all other concepts of math,

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As the utilization of fMRIs has become more common and prolific, further studies have focused on identifying and understanding the differences between the mechanics of dyslexic versus non-dyslexic brains.

Functional MRIs measure brain activity related to blood flow.

When an area of the brain is in use, increased blood flow is shown by the fMRI [1]. As more oxygen is needed in active portions of the brain, the oxygenated blood in the area alters the local magnetic field and results in a change in signal that is detected by the machine [1]. Functional MRIs have shown that the main cortical regions involved in reading are the language-dominant left hemisphere: the inferior frontal gyrus, the superior temporal gyrus, and the medial temporal gyrus [2]. The inferior frontal gyrus is part of the frontal lobe and is used for complex thinking, processing speech, and language. The superior temporal gyrus is used in processing audible sounds, making it a major area involved in language

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Beyond Jumbled Letters comprehension, or, for example, when you put the sounds “th” and “at” together and get the word “that.” Finally, the medial temporal gyrus is used for memory processing and visual perception. Think of “sight words” (the, he, at, etc).

When you are in kindergarten and early grade school, you learn the shapes of words, so you don’t need to read each sound separately. The more a child reads, the greater this bank of sight recognized words grows. When you go to read a word that you have seen before, the medial temporal gyrus activates and remembers the word, so you don’t have to start from the beginning and re-sound it out [2]. When all of these areas of the brain are activated together, a good reader can have phonological awareness (the ability to manipulate sounds and recognize the structure of words), rapid automatic naming (the speed to name familiar things out loud), and reading fluency (the ability to read words and connect the text with speed and accuracy to support c o m p r e h e n s i o n) .

Functional MRI imaging of a non-dyslexic reader who is actively reading will show activity in these portions of the brain [2].

In dyslexic readers, activation of these cortical areas is decreased. Studies have shown that dyslexics struggle with phonological awareness due to low activation in the superior temporal gyrus, creating difficulties with access to and the manipulation of sounds. Dyslexic children show a reduction in superior temporal gyrus (used for comprehension of language) activation when they are given an auditory phonological awareness test and they display no activation in the temporal lobe [2, 3]. Also, due to both underdeveloped language centers and struggles with using the left hemisphere of the brain, dyslexics tend to compensate via increased activity in the right hemisphere. In contrast to non-dyslexics, dyslexics activate the right inferior occipital gyrus in a separate area of the right hemisphere when trying to read [4]. This part of the brain is mostly used for visual processing of faces [11]. When dyslexics read less efficiently with the right hemisphere, it has been shown that tutoring can help provide the tools dyslexics need to strengthen their foundations in reading comprehension. Tutoring can train dyslexics to use the left hemisphere of their brains for reading, as well as reduce reliance on their right hemisphere.

A common myth about dyslexia is that it is purely a reading disability. However, the frontal and temporal lobes are also

vital to processing mathematics [3]. Math is an abstract subject, and it is taught to children beginning at a very young age.

Dyslexics may struggle to convert words into mathematical symbols, like knowing that “three”, 3, 1+1+1, and 2+1 all represent the same number [5]. Both long-term and short-term memory are needed for learning and understanding math. In the long term, numerous concepts in math build upon each other and are used to perform more difficult computations [5]. For instance, if a student is given a problem of 2x=4, they will need to access the concept of division in their long-term memory to “undo” the 2x multiplication to solve for x. In the short term, memory is used to process a question, hold it in the mind, and follow a procedure to reach an answer [5]. Solving 2x1=3 requires following more steps, as well as remembering the goal of the problem: solving for x. If a dyslexic student realizes that, when they add one to each side of the equation, they get 2x on the left and 4 on the right, they may forget the initial conditions and can have difficulty recalling what should follow in the process to achieve the answer.

The areas of the brain needed for reading comprehension are not only used for word processing, but also for memory storage and abstract understanding. In particular, the medial and superior temporal gyri have both been linked to memory processing, with the medial gyri used for long term memory storage and the superior gyri used for short term memory [6]. Because dyslexics have diminished neural activation in these areas, they also experience some difficulty in learning mathematics. This is often seen in dyslexics struggling to remember mathematical facts when attempting computations [5]. When dyslexics have challenges forming and recalling long-term memories, they have difficulty learning math facts by heart and remembering calculation procedures, even if they have mastered them. This demonstrates why dyslexic students tend to fail at generalizing knowledge throughout a subject: they are unable to make connections between concepts that will benefit them as the subject matter becomes more difficult. However, although dyslexics have difficulty accessing these facts due to poor long-term memory, they can compensate with strong problem-solving skills.

Poor long-term memory also contributes to difficulties in working memory. For example, envision a task where one has to do a series of steps in chronological order, such as

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Beyond Jumbled Letters doing laundry or calculating the tip on a restaurant bill.

When conducting one of these tasks, one must remember each step to take in order to successfully complete it (e.g. putting the laundry in the washer, putting the detergent in, and turning it on). After repeating the process several times, one no longer needs to actively remember each task, as the process is now stored in the working memory. Those with poor working memory, such as dyslexics, have trouble storing and recalling simple steps. This is evident in mental and oral calculations. Because math facts are not easily memorized, more mental strain is required for simple calculations [5]. For instance, instead of immediately knowing that 12+5=17 because 2+5=7, a dyslexic person has difficulty

breaking these numbers up into the smaller components and will instead count on their fingers or rely on a calculator to reach an answer. This slows down the process, leading to inefficient calculations [5]. Poor long-term memory also makes it more difficult to remember previous calculations, so when a new problem is presented, the entire process needs to be repeated [5]. For example, if the first problem required one to compute 5*8, a dyslexic person pauses and struggles to remember that the answer is 40. Now, when working on the third or fourth question, if the same computation is needed, a dyslexic person would not remember that they have previously calculated 5*8 in the first question and go through the entire process again. This is similar to when dyslexics read. If someone with dyslexia comes across an unknown word at the top of a page, it is mentally “sounded out.” If the reader then comes to the same word again, the whole process of sounding out the word is repeated.

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As stated previously, dyslexia is a language disability. When learning a new language, whether it be Spanish, French, or in this case, mathematics, dyslexics have difficulties comprehending the new syntax [5]. This is because the cortical regions originally used for comprehending language are also not activated when a dyslexic studies mathematics. Math uses multiple words to convey the same meaning. For example, the words “addition,” “add,” and “sum” all mean the process of calculating the total of two or more numbers.

The mathematical language also uses symbols (numbers) and words within the same sentences (word problems), and oscillating between numbers and words within a word problem can be extremely difficult for a dyslexic brain[5]. Take the word problem, “Joey is 37 and Karen is 12 years older than Joey. How old is Karen?” For a non-dyslexic, it is natural to understand that one would add 12 to 37 (37+12) to get 49. However, dyslexics have difficulty making this connection. For one, it is already difficult to read words, and adding the abstract component of symbolic numbers makes the task of solving this problem much more difficult. If this word problem were presented visually, the connection between the words to computation might be easier for a dyslexic to understand.

The final challenge dyslexics face in learning math is trouble with directional understanding, which is due to decreased activation in the superior temporal gyrus [2, 5]. The superior temporal gyrus decodes information in the brain. When information is decoded incorrectly, the output will also be inaccurate (Hudson, 2020). This is equivalent to comprehending language in the wrong order or writing things incorrectly, like 32 as 23. As one progresses in the mathematics discipline, computations change from a simple left to right calculation (2+3=5) to more complicated ones, such as 3+(5*3). To compute this example using the order of operations, one would begin with the multiplication inside the parentheses, 5*3=15, and then add 3 to that answer for 3+15=18. In this way, the first step is starting with the right and the second is starting from the left. If one were to calculate this example purely from left to right, they would get a completely different answer (3+5=8*3=24). This can become very confusing for non-dyslexics— let alone dyslexics— who have difficulty with directional analysis.

To help dyslexic students learn math, the way math is taught needs to be adapted. There are several methods teachers and researchers have discussed for teaching dyslexic children math. While every dyslexic is different, and practices and technologies are constantly evolving, helpful methods of

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teaching math to dyslexics exist. School systems tend to standardize their reading curriculum but vary in their instruction of math. Reading is taught through sub-skills that are learned and evaluated. In this way, a student’s strengths and weaknesses are shown frequently;therefore, an alternative teaching method can be introduced to help them.

Teaching math the same way as language would help non-dyslexics and dyslexics alike. However, when math is taught, it is evaluated based on a level of achievement of doing harder and harder problems. After 2+2=4 is learned, the concept of 4-2=2 is taught. However, if a student does not understand why one can add or subtract numbers and simply memorize these facts, when faced with a more difficult problem like 24-22, they would not know how to solve it. If a child has “bad” handwriting or is a “bad” speller, they are not necessarily considered a “bad” writer, whereas students who do not understand a mathematical concept are often labeled “bad” at math. Breaking down math subskills, teaching students physically (using objects to show addition) and audibly naming steps in a calculation all help organize simple mathematics to build a foundation to complete harder problems.

Dyslexic students are auditory and visual learners, so demonstrating stepby-step computations, as well as having a dyslexic student explain these steps in their own words, is helpful for solidifying understanding of concepts.

There are two distinct math learning styles for dyslexic and non-dyslexic learners: grasshopper style and inchworm style [10]. Grasshoppers are good at intuitive thinking and are able to visualize questions, but they struggle with the ability to follow procedures. Inchworms are very orga-

nized and good at working step by step, but they have limitations in visual and spatial reasoning, as well as difficulty forming an overview of problems [7]. To master math, one needs to move easily between these two styles of learning. This is where dyslexic learners struggle, as they tend to use only one of these thinking methods when understanding and performing computations [10]. When a learner is only using the inchworm style, they tend to focus on parts of the problem, isolating each step as it is presented in their minds. Grasshoppers, on the other hand, will estimate answers and “hop” to the end of the problem without fully computing the answer [10]. Whether you are a grasshopper or an inchworm, you are equipped with distinct strengths to compute and understand math. To be a good mathematician, one needs to be organized and able to visualize the process of a problem. Since most dyslexics struggle with using both of these methods at once, they are either very strong in algebraic analysis (inchworms), or mental arithmetic (grasshoppers) [10]. Those who favor the inchworm method should be encouraged to attempt to see an overview of the problem before solving it, whereas those who are grasshoppers should be motivated to write out their computational steps to find a solution.

Despite differences in learning styles, the gift of dyslexia is the ability to think differently. Dyslexics have excelled in making connections between different fields due to unusual combinations of ideas, compared to non-dyslexics [7]. Albert Einstein, a famous dyslexic mathematician and theoretical physicist, made connections in the world that others could not see. Einstein credited his discovery of the theory of relativity to conducting a thought experiment, where he saw himself riding a streetcar traveling at the speed of light.

Although dyslexia is defined as a learning disability, I view it as an advantage. Dyslexics make connections and view the world differently than everyone else. Despite the different ways that my brain works, my love of math has carried from the days of struggling with word problems to the Symbolic Dynamical Equations course that I am taking this semester.

I am not sure where my math major will take me after graduation, but I will inchworm and grasshopper my way in the real world to find out.

References on page 48.

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The Gut-Brain Axis

THE GUT-BRAIN AXIS: CAN YOUR BELLY HEAL YOUR BRAIN?

by Hannah Daley art by Amelia Zeh

H

ave you ever felt “butterflies in your stomach?” Had a “gut-wrenching” experience? Went with your “gut feeling?” These expressions are used for a reason: the gut and the brain are intimately connected. Though a gut-brain link was suspected as early as the eighteenth century, research on the subject has exploded within the past decade.

In fact, recent studies have shown that mental health and gut health affect each other. This information suggests that a novel approach may be possible for treating mental illness and gastrointestinal disorders by focusing on the disconnect between the systems. Probiotics, lifestyle changes, and psychological therapy are a few methods that have exciting potential to revolutionize clinical treatments for both types of disorders.

The connection between the gut and the brain, termed the “gut-brain axis” (GBA), is defined as the link between the central and enteric nervous systems [1]. The central nervous system (CNS) refers to the brain and spinal cord, while the enteric nervous system (ENS) refers to the neurons that govern intestinal function. Therefore, the emotional, behavioral, and cognitive centers of the brain communicate

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bidirectionally with the stomach. The ENS is often forgotten about during discussion of important branches of the nervous system, but it is vitally important in maintaining proper human functioning. Notably, the ENS is the largest division of the peripheral nervous system, containing all of the neurons outside of the central nervous system and 100 million neurons in the small intestine alone [2]. ENS neurons function largely in detecting the physiological condition of the gut and determining a remedial response. Due to its enormous number of neurons and autonomy, the ENS has been nicknamed the “second brain.”

The GBA not only incorporates the gut and the brain, but it also receives input from the endocrine system, immune system, and perhaps, most importantly, the gut microbiota [3]. The endocrine system is a chemical messenger network, using hormones to send messages to different organs throughout the body. One of the main networks of the endocrine system is called the HPA axis (hypothalamus-pituitary-adrenal gland). The HPA axis contains the main brain structures that are responsible for the body’s response to environmental stress. When organisms are exposed to en-

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The Gut-Brain Axis vironmental stimuli, the HPA axis evaluates if a stress response is necessary [4]. The adrenal gland is responsible for the famous “fight-or-flight” response through its release of the body’s principal stress hormone: cortisol. Hence, depressive episodes are associated with a dysregulated HPA axis and high cortisol levels, while the resolution of depressive symptoms is associated with a normalized HPA axis [5].

Additionally, depressed individuals lack chemical regulators to suppress the abnormally high HPA response [6]. In other words, those with depression experience an exaggerated response to everyday stressors and have problems mitigating this response.

The HPA axis is also closely connected to gut microbiota, the naturally occurring bacteria that colonizes the intestines, revealing another way that the two systems interact.

Studies show that germ-free mice (mice lacking any gut bacteria) have an exaggerated response to stress compared to specific-pathogen-free mice, suggesting that microbes have an observable effect on the stress response. Additionally, microbiota produce metabolites (products produced through its natural metabolic processes) that have been shown to alter nutrient availability, thus affecting the release of biologically significant proteins in the gut. One of the most important metabolites involved in the gut-brain axis, short-chain fatty acids (SCFAs), are fatty acids that have less than six carbon atoms. Gut microbes produce them by digesting dietary carbohydrates and fibers. SCFAs maintain stomach lining integrity, regulate mucus production, and protect against inflammation [3].

Additionally, SCFAs are able to cross the blood-brain-barrier (BBB) and impact the biological processes within the brain itself. The BBB is a highly selective, semipermeable membrane that prevents solutes in the blood from entering the brain.

The BBB protects brain tissue by blocking potentially toxic molecules from entering the brain. Once SCFAs cross this barrier, they are involved in regulating the brain’s waste management system. The cells responsible for this process, called microglia, are important for proper brain development, the health of the brain tissue, and behavioral modulation. Microglia are like the immune system cells of the brain, protecting it against pathogens and other dangers, further supporting their importance.

Interestingly, disruptions in acid metabolism have been opment of autism spectrum improper functioning of microglia [7]. This metabolism is important because it provides energy and nutrients for cells in the gastrointestinal tract. The administration

short chain fatty linked to the develdisorder due to the

of excess propionic acid (PPA) in the brain has been shown to produce autism-like symptoms in adult rats. PPA is a short chain fatty acid that is used as a food preservative in refined wheat and dairy products. PPA is also known to cause many of the gastrointestinal distress symptoms experienced by autism patients, such as decreased efficiency of digestion, intestinal muscle pain, and increased concentration of certain neurotransmitters responsible for pain.

Thus, it is possible that PPA is an environmental risk factor for the development of autism. Several studies have shown that eliminating certain dietary components, such as gluten and casein (a protein found in dairy products), can relieve symptoms of autism, further indicating that the gut may be involved in its onset [8]. Though there is clear evidence of a strong genetic basis of autism, this research suggests a possible environmental, diet-based component as well.

The GBA is also highly connected to the immune system.

The immune system is important because it is the body’s way of protecting itself from harmful pathogens that could cause disease. When a foreign particle enters the body, the immune system is supposed to activate in order to destroy it. Gut microbiota modulate the release of cytokine, which is the primary signaling molecule of the immune system [9]. Abnormal gut microbiota populations can activate an immune response in the stomach, altering the permeability of the intestinal lining [3]. The contents of the stomach are very acidic, and can have damaging effects if they are released into the bloodstream and spread throughout the body. This phenomenon, known as the “leaky gut,” causes low level chronic inflammation that is present in a variety of health problems [10, 11].

CNS socithe brain funct h e so-

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Not only is the gut microbiome a part of many gut-brain axis mechanisms, but it also is necessary for proper development and maturation of the and ENS [1]. In fact, the absence of gut bacteria in animal models is asated with chemical changes in and problems in gut motor tion in digestion. Additionally, absence of gut microbes is asciated with a dysregulated HPA axis, decreased serotonin (one of the main mood regulating neurotransmitters) production, and memory deficits. The decrease in serotonin production

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The Gut-Brain Axis is especially important, because the gut is responsible for the production of approximately 95% of it in the body [12].

In other words, without bacterial colonization in the gut early in life, the brain will have problems communicating with the rest of the body, potentially resulting in intestinal distress and/or mental illness.

How do these biological connections relate to specific illnesses and diseases? Irritable bowel syndrome (IBS), a prevalent yet misunderstood GI disease, is now beginning to be recognized as a gut-brain axis disconnection. IBS is an intestinal disorder that causes stomach pain, gas, diarrhea, and constipation, among other symptoms. It is so common that approximately 50% of GI complaints to general practitioners are because of IBS [13]. As there is no treatment or cure for IBS, the current solution is limited to alleviating symptoms. However, multiple studies have shown that IBS patients have abnormal gut microbiome profiles, indicating that gut bacteria plays a role in the development of the disease. Furthermore, IBS, depression, and anxiety have high rates of co-occurrence, suggesting bidirectional communication between the brain and the gut [13]. Due to this comorbidity, current research is focusing on treating depression, anxiety, and IBS simultaneously. For example, it has been shown that using cognitive behavioral therapy, a common psychotherapy technique for depression, can help eliminate symptoms of IBS [14].

One study used germ-free and control group rats to test the differences in HPA axis responses to stressful situations [15].

Researchers found that the germ-free rats displayed more anxiety-like behaviors and had higher concentrations of cortisol, the primary stress hormone, in their blood serum following the stress test. Additionally, germ-free rats had less dopaminergic turnover in certain areas of the brain, meaning that the neurotransmitter dopamine could not be utilized by the neurons. Dopamine is the main mood regulating neurotransmitter, so its unavailability can cause anxiety-like behaviors. This study suggests a direct correlation between the presence of gut microbes and anxiety by showing that animals lacking gut bacteria have a more active HPA axis during stressful situations.

Another mental disorder that has GBA implications is bipolar disorder. Bipolar disorder (BD) is characterized by episodes of mood swings, ranging from depressive lows to manic highs. BD is also associated with severe cognitive dysfunction and social impairment [16]. One study aimed

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to characterize gut microbiota in depressed BD patients before and after BD treatment, and to study microbiota’s

association with depressive severity. The study found that although quetiapine treatment did not affect gut microbiota, BD patients had very different gut microbiota species and less SCFA producing bacteria than controls. This study shows that BD patients can potentially be distinguished from healthy individuals by gut microbiota, introducing a potential diagnostic tool.

To return to the importance of the GBA in the development of autism, one study aimed to transplant gut bacteria from autism patients into germ-free mice to observe if more autism-like behavior occurred compared to a control group that received bacteria from typically developing children.

When researchers examined the contents of the gut samples before the transplant, they found that the samples from autistic patients differed in their diversity and the type of metabolites being produced. After the transplant, they found that the mice with donations from autistic patients developed autism-like behaviors compared to the control group. The authors propose that gut microbiota regulate ASD behaviors via the production of chemicals that alter behavior [17]. These findings suggest that there is potential for new treatments of ASD that include diet and supplement interventions with the goal of repopulating the gut with normal species.

Since recent studies have shown that those with various mental health disorders have different makeups of their gut bacteria, it may be possible to implement new treatment methods that target these differences. Research has begun

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The Gut-Brain Axis to investigate how specific diets and supplementation can alleviate symptoms of mental health disorders. For example, consuming a Western diet with high levels of fats, salt, sugar, and processed foods has a clear association with decreased gut microbiota diversity [18]. Western diets are also associated with an abundance of a specific species of bacteria that is often seen in obesity, further showing a direct relationship between diet, gut microbiota, and overall health. A healthier alternative to a Western diet is a Mediterranean diet, which consists of whole grains, nuts, fruits, vegetables, fish, poultry, and low amounts of other meats.

The Mediterranean diet is a potential treatment for several mental health disorders, as it has been shown to reduce incidence of clinical depression and usage of antidepressant medication [18]. Mediterranean diets are also high in omega-3, which has an anti-inflammatory effect on the body. As previously mentioned, anxiety and depression are associated with chronic low-grade inflammation, so taking additional omega-3 supplements has also been shown to help with these disorders [18].

prescription. The explosion of research in this field in the past decade has opened many doors for novel treatment ideas for those who have not found relief with traditional methods. At the very least, this new information sheds a light on how important taking care of gut health is to promote holistic health and overall well being.

References on page 48.

Another potential therapy method for treating GBA dysfunction is the consumption of probiotics. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. Probiotics, usually taken in pill form, are known to have enormous GI benefits. Multiple studies have shown that taking probiotics decreases anxiety and depression-like behavior in mice.

One study cites that anxiety-like behavior induced by a high fat diet can actually be prevented by probiotic treatment [19]. Administration of probiotics can also prevent the intestinal permeability of gut lining that is caused by stress, and also decrease plasma levels of cortisol. These findings suggest that probiotic treatment is able to dampen the HPA axis response to chronic stress, and in the process lessen anxiety and depression-like behaviors [19]. The results of these studies suggest that simply taking a probiotic pill can improve gut microbiota composition and thus alleviate symptoms of anxiety and depression.

In addition to taking supplements, other lifestyle changes can improve the health of the GBA. For example, eating fermented foods such as yogurt, sauerkraut, kimchi, cured meats, and kombucha. Fermented foods are made through controlled microbial growth and enzymatic conversions of different food components. Eating fermented food is beneficial because they contain live microorganisms which can act similarly to probiotics [20]. High fiber foods with prebiotics such as onions, leeks, asparagus, and bananas can also induce the growth of beneficial microbes in the gut [21].

Other methods that improve the health of the GBA that do not involve medication include lowering stress levels, getting enough sleep, eating slowly, staying hydrated, and getting tested for any food intolerances.

Understanding how the central and enteric nervous systems are connected and exactly how they interact has vast implications for the future treatment of both GI and mental health disorders. There are numerous ways in which one can try to improve their GBA health, many not even requiring a

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Cannabis Use Disorder

CANNABIS USE DISORDER: THE GRIM REALITY OF CANNABIS ADDICTION

by Nick Beebe art by Hannah Maver and Nick Beebe

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nstead of using logical reasoning, or really any reasoning at all, my tanning-devout middle school health teacher often remarked that any use of drugs would kill us all. Her one brief Powerpoint devoted to cannabis was heavily structured on the assumption that it would act as a gateway drug before eventually leading to death. On the contrary, young users of the drug often view cannabis as nothing more than a Saturday night ritual at Natty Light-sponsored basement

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gatherings. Suffice it to say, the reality of cannabis appears to be clouded by a diverse array of perspectives, some of which likely stem from the drug’s stigmatized past. Though cannabis hasn’t been demonstrated as a direct cause of death, it can lead to a decreased quality of life and the emergence of addiction: cannabis use disorder (CUD). Cannabis — also referred to as marijuana, weed, and pot — is heavily touted for its delivery of altering effects without any

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Cannabis Use Disorder apparent aftereffects, compared to drugs like alcohol, cocaine, and heroin. As such, cannabis is the most popular illicit psychoactive drug in all US states and every country [1].

While cannabis legalization in the U.S. becomes more widespread and its use normalized, it is crucial to acknowledge the expanding scientific literature that pertains to cannabis use disorder (CUD).

Research on CUD clearly signifies that cannabis can spark addiction, though this simple fact is continually undermined by the public. Epidemiologist Dr. Deborah Hasin of Columbia University links public ignorance of CUD to 25-year-old findings that dismissed the disorder as incredibly rare [2].

Twenty-five years ago, however, the common cannabis was 700-2000% less concentrated and obtaining the drug was nowhere near as simple as sending a dealer a Snapchat [3].

While cannabis addiction is by no means inevitable for all of the drug’s users, the potential for CUD to manifest noticeably increases in individuals who both extensively and continually administer the drug. In fact, there’s a 9% likelihood of transitioning from any cannabis use to complete cannabis dependence, though a number of additional factors can influence this rate [1]. With cannabis legalization on the rise — both medical and recreational — the likelihood of use is bound to consequently increase. In 2008, 72.8% of surveyed American drug users reported using cannabis, while 53.3% of this same group stated it is the only drug they use [4]. Due to a vast increase in cannabis potency and initial exposure at younger ages, there has also been a rise in overall cannabis use and reported CUD, in addition to cannabis-induced emergency room visits [2]. It is important to note that cannabis use disorder is preventable, and users should stay aware of their usage to avoid spiraling into substance abuse. Ultimately, the expansion of preventative intervention, grounded in sufficient CUD and cannabis research, is vital.

natural cannabinoids in the body, like AEA and 2-AG, but not the ones that come from cannabis, like THC, CBD, CBG, CBV, and THCVA [5]. Think of all cannabinoids as the same type of candy made by different brands — they are mere equivalents in regards to structure and function; it is where they come from that differs (either from the body or cannabis).

The endocannabinoid system (ECS), a metropolis of selfmade cannabinoids binding to appropriate body-spanning receptors, meticulously works to mediate the presence of cannabinoids — whether produced internally or externally [6]. These receptors, CB1R (cannabinoid 1 receptors), facilitate processes related to appetite, learning, anxiety, depression, schizophrenia, neurodegeneration, and addiction [7]. Despite being denoted as the peacekeeping switchboard of the body, the remarkability of the ECS has often been downplayed due to its association with cannabis.

THE NEUROBIOLOGY OF CANNABIS USE It is critical to understand how cannabis can alter brain chemistry and structure, especially as uncertainty surrounds both the acute and chronic effects of cannabis use on the central nervous system (CNS: the brain and spinal cord) [1]. The most popular method of cannabis administration has always been inhalation by smoking. However, other methods, like edibles or “dabs,” have steeply risen within the past decade, allowing users to consume even higher doses of THC [2]. Needless to say, when exploring the neural impacts of cannabis and ∆9-tetrahydrocannabinol (THC, the primary element of a cannabis high), it appears that cannabis isn’t exactly what popular culture makes it out to be.

Cannabis Inside the Body: Endocannabinoid System (ECS) To best understand CUD, one must inspect the physiological pathway of cannabis in the body. Upon the first inhale (or “hit”), THC, the main cannabinoid of cannabis, enters the bloodstream and circulates within the body. Cannabinoids are a group of compounds that share chemical structures to naturally found components of cannabis; humans produce

Anandamide (AEA) is a neurotransmitter that acts as a ligand in the ECS, meaning it has the vital task of biological signaling — invoking a certain response cascade — like all cannabinoids that interact with CB1R. Ligands and receptors act much like Rube Goldberg machines: once a ligand molecule binds to a receptor, the receptor initiates a signalling pathway as a result of the ligand’s presence. As such, ligands, and the processes they control, are highly specialized and lead to specific outcomes. AEA, when at low levels in the body, correlates with increased appetite, anxiety, depression, and hypertension [6]. Due to their similarity in structure and role, it wouldn’t be a stretch to expect such feelings from low AEA to low THC as well (a notable example being “munchies”). THC in cannabis is able to infiltrate the ECS by resembling AEA, again due to their similar shape —

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Cannabis Use Disorder hence both being classified as cannabinoids [7]. With the excessive usage of cannabis, THC’s mimicry of AEA overstimulates dopamine release, leading to an overtly euphoric state for an individual with minimized groundedness; this process also inhibits the emission of the neurotransmitter glutamate, which, as a result, promotes drug-seeking behaviors [8]. However, THC abuses this system into producing streams of dopamine for a “good feeling,” meaning the brain is activating the reward system for a behavior (i.e. smoking) that the pathway would not typically reward [3]. With constant stimulation of dopamine comes the body’s natural expectation of that constant amount of THC. This is what drives the formation of cannabis addiction.

Cannabis Inside the Body: The Brain With the prolonged use of cannabis also comes a lower quantity of CB1R, which fortunately respawn with continued abstinence [3,9]. CB1R are heavily concentrated within the striatum, hippocampus, amygdala, and prefrontal cortex regions of the brain [1]. The latter three brain regions all experience decreases in size with increased cannabis administration, rendering them most vulnerable to manipulation by cannabis use [3,10]. The striatum, part of the brain’s reward system, releases dopamine when an individual performs actions that keep them alive (i.e. eating, drinking water, exercising). As the hippocampus is most involved with one’s long-term memory, cannabis can inhibit one from being able to clearly pull upon recollections of the past, even leading its users to develop false memories at a higher rate [11]. Historically, long-term memory problems for cannabis users appear to be relatively rare; but, recent findings dispute this, remarking that CB1R density was restored in subjects recovering from addiction in all brain regions except the memory-related hippocampus [1,9]. The amygdala, just to the side of the hippocampus, controls feelings of fear, stress, and anxiety; cannabis’ impact on this structure may explain why many experience paranoia while getting high [12]. Lastly, the prefrontal cortex (PFC), responsible for executive functioning, presides over processes including decision-making, impulsivity control, and social behavior, much like the brain’s moral compass. It has also been determined that the overstimulation of CB1R — when excess cannabinoids flood the body — directly interferes with proper PFC development [13].

The prolonged use of cannabis has also been linked to decreased grey matter [1]. Grey matter is the information processing component of the brain, found right on its surface — the more grey matter, the healthier the brain since greater brain function is promoted. Grey matter and the intensity of cannabis use have an inverse relationship with each other: the more intense the cannabis use, the lower the available grey matter [14]. Furthermore, the neurons that occupy grey matter function abnormally in people with CUD

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and those whose cannabis use is heavy, but not definitively indicative of CUD. In experimental trials with rats, brain exposure to “high doses” of THC for 90 days or more reduced both the quantity of neurons within grey matter and their capabilities, even months after a rat’s final “hit” [3]. Because these findings were observed in rats, a species that is not vastly dissimilar from us genetically speaking, further research should directly explore the impact of THC on neuronal structures in humans.

EXTENSIVE CANNABIS USE When it comes to understanding humans, rodents truly act as great models given the similarities in the length of our genomes and the genes we share. One recent study with rats found that after rats were conditioned to become high, those exposed to THC-rich vapor were led to consistent THC use [12]. On average, each THC rat self-administered a peak of 18 puffs on the experiment’s tenth day, before use slowly decreased for the rest of the experiment. Notably, however, consumption of THC by these rats still remained considerably higher than the other groups (exposed to CBD

or a control vapor). Eighteen THC puffs may sound like nothing more than a frat boy’s breakfast, but it’s essential to understand that these are rats, a mere fraction the size of humans. Needless to say, this observed behavior ties directly to the significant psychiatric burden of CUD. These rats, upon THC exposure, went from hardly ingesting the vapor at all to taking in shockingly large amounts; this is addiction [12,3]. CUD is characterized by physiological, behavioral, and cognitive symptoms that lead cannabis use to become one’s utmost priority [15]. Cannabis inevitably became high-priority to the rats in this study, just as it does for many of its human users.

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Cannabis Use Disorder With CUD also comes risks of depression, anxiety, poor executive functioning, and subpar stress management; these make up some of the aforementioned cognitive and behavioral symptoms of CUD [3,4,2]. Though some might report feeling happier while high — caught in glittering rushes of dopamine and shuffling Tame Impala tracks — studies have repeatedly failed to determine this link in the long run. Rather, studies lend credence to the notion that cannabis actually makes depression and anxiety worse [3,16,1]. In fact, less than half of medical cannabis users report being relieved of any depressive symptoms at all. Numerous studies have consistently highlighted cannabis’ role in instigating mental health problems, rather than treating them — specifically connecting cannabis use to the development of depression and suicidal tendencies, most evident in young users [15].

Historically, once a state legalizes cannabis, prescriptions for antidepressants drop tremendously, meaning it is likely that many suffering from depression are led to cannabis for treatment, regardless of its lack of efficacy [2]. This relationship is clearly in dire need of clarification and attention in forthcoming literature, as cannabis has been found not to help, but rather, worsen conditions like depression and anxiety.

FACTORS THAT INFLUENCE ONE’S RELATIONSHIP WITH CANNABIS In 2015, nearly one-third of American cannabis users were diagnosed with CUD the year prior, a percentage similar to substance abuse amongst heroin (25%) and cocaine (36.5%) users [3]. On a global scale, approximately 13 million individuals have been found to meet the criteria for a CUD diagnosis from a 2015 UN report [1]. Clearly, it is imperative to investigate the myriad of neurobiological and interpersonal factors that influence one’s level of cannabis use and vulnerability to CUD development as both are issues for many around the world. So how do we know if someone is at greater risk for CUD, aside from just observing extensive cannabis use?

Admittedly, there is a tremendous complexity underlying the individual differences that diversify humankind, a phenomenon commonly referred to as “nature vs. nurture.” Nature refers to one’s genetics inherited from both of their parents, and nurture refers to one’s upbringing and the environment in which they’ve developed; it gets complicated when elements of an individual that seem solely nature-driven or solely nurture-driven are influenced by the other. An example of nature might be the flaming red hair someone is born with, as hair color results from the genes they’ve inherited from their parents. On the other hand, an example of nurture might be developing a Boston accent. This is because it’s probably not in your DNA to develop a certain dialect, but rather, it comes from who you grew up around and how they spoke to you. In the context of cannabis and CUD, the following can be explored through the lenses of nature and nurture: genetic precursors, age at exposure, gender identity, ancestral background, and sexuality.

Genetics and Cannabis Genetics don’t directly correspond to destiny, perhaps best

noted in the 1997 cult classic Gattaca. Given how complex our genomes are, it can be quite hard to link specific genetic markers to certain conditions and complex traits like CUD. Cannabis use disorder is understood to be a polygenic disorder, meaning it’s caused by a combination of several genes. However, genome-wide association studies (GWAS) that compare genetic codes between many individuals have failed to locate overlapping genetic risk loci (genes that act as “markers” for something, CUD in this case). Recent findings suggest the potential for cannabis abuse and dependence is approximated to be anywhere from 21% to 78% inheritable from one’s parents [3]. This estimate is likely so wide due to the diversity of genetic precursors that have been identified from past studies, signaling more research is needed to reach certainty and a refined range of heritability. One well-studied mutation exists within chromosome 1’s FAAH gene, which affects how the brain deals with addiction and reward. This mutation is directly involved with the decreased production of AEA (the “bliss molecule”) which affects the ECS and drug response centers while increasing risk of CUD development [17,18]. Any negative impact to these regions ultimately alters the brain’s chemistry and the subsequent well-being of the individual. Furthermore, variation in the gene responsible for coding CB1R (cannabinoid receptors) has been associated with cannabis dependence [7]. Clearly, the middle ground between genetics and cannabis dependence is one that requires tremendous examination in the immediate future.

Ancestral Background and Cannabis One’s ancestral background can also be a key component of CUD development; people with certain backgrounds appear more likely to develop the disorder than others. The most common primary illicit drug used by Whites, other than alcohol, is opiates, followed by cannabis. In comparison, cannabis has been found to be the most commonly used drug amongst Blacks, Latinos, Asians, and Pacific Islanders [19].

The gravitation towards cannabis by all is likely perpetuated by societal factors, that can be strengthened by genetic factors to result in CUD. As it turns out, recent epidemiological studies have determined that adolescents identifying as White, multiracial, or Native American are more likely to use cannabis than adolescents of Pacific Islander, Latino, Black or Asian backgrounds. Native American adults and adolescents who live on reservations report the highest levels of cannabis use amongst all groups in the United States, with over 20% of Natives reporting cannabis abuse or dependence [20,19].

Further, Black Americans have been noted as having a greater risk of developing cannabis use disorder than Whites [21].

However, Whites, compared to Blacks, have a much harder time ending cannabis use, reporting an average of 5.5 lifetime quit attempts, compared to 2.1 for Blacks [22]. Another study determined that cases of CUD grew noticeably higher among Blacks and Native Americans compared to Whites from 2005 to 2013. [19]. But what accounts for these variabilities in cannabis abuse vulnerability across different groups?

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Cannabis Use Disorder

It can be hypothesized that the high rates of CUD in Native and Black Americans spring from White-led dehumanization starting with the stealing of Native land to establish the New World. It is possible that this systemic oppression, violence, and consequent daily stress may drive these groups’ vulnerability to cannabis addiction. Additionally, with regard to the education received by marginalized groups, one study hypothesizes that a blatant lack of smaller class sizes for disadvantaged — often minority — students increases the risk of drug use nationwide. Smaller classes allow for higher academic achievement and a sense of belonging, while larger classes allow many students to slip through the cracks, feeling unnoticed with lower engagement, driving cannabis to potentially act as a means of coping with their position [21].

In the end, these findings should inspire more studies and more action when it comes to linking ancestral background and CUD, especially for individuals of mixed descent as they are considered in very few studies. If we know that certain populations are vulnerable to CUD development, what can we do to help them — instead of doing nothing?

Age at Cannabis Exposure As with other drugs, the age of one’s initial exposure to cannabis is closely linked to the severity of its later effects. Typically, first exposures to cannabis during youth highly increases the likelihood of future cannabis use [19]. Despite an overall dearth of research on the relationship between development and cannabis use, developmental research on cannabis has consistently scrutinized the period of adolescence.

Late adolescence through one’s early twenties is the highest-risk window of developing CUD, meaning that any cannabis exposure during or before this time poses a potential threat [3,16,19]. The age of one’s first exposure to cannabis has also continuously decreased as the drug’s acceptance by the general public increases [16]. Since the human brain continues to develop well into the twenties, adolescence is regarded as a sensitive period of emotional vulnerability because cannabis interferes with several systems of the brain that hold a stake in psychotic and affective disorders [3,18].

One study has even found that individuals who started using cannabis during adolescence experience greater structural differences in the brain compared to those who started using the drug as adults, exemplifying the true malleability of a young, developing brain — especially as one in six who start using cannabis in adolescence will be dependent on it by young adulthood [10,15]. Furthermore, anyone who heavily utilizes cannabis before the age of 17 is five times more likely to abuse other substances later in life [16]. By allowing

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CUD to go unnoticed, many, especially vulnerable adolescents, can face CUD and additional substance abuse which effective education could have prevented.

Gender Identity and Cannabis The popular “stoner” trope has often been tied to those that identify as male, which, interestingly enough, is strongly backed by research. Men experience greater odds of abusing and experiencing cannabis dependence, especially when they are young upon initial use and possess limited education [19]. Although there is a high number of men with cannabis dependence, the severity of CUD for women is greater; this is also the case for many other substance abuse disorders [3]. Individuals with transgender and non-binary identities were found to report a higher prevalence of cannabis use than their cisgender peers, though there is not yet a strong-enough consensus on the severity of CUD for these individuals. Amongst transgender populations, transgender men report higher usage rates of cannabis than transgender women, but non-binary individuals report more cannabis use than both of the aforementioned groups [23,24].

Men may be drawn towards cannabis because it can facilitate closeness, allowing for conventional gender expectations to be defied so that they can express themselves without fear of demasculinization [23].

Ultimately, though, the ways in which gender influences cannabis use are complex: this intersection is largely dependent on social, cultural, and political contexts [23]. In other words, variability of cannabis use in gender groups may be due to socially constructed differences rather than biological ones. It is possible, though, that biology might play into cannabis use gender differences. For example, the nucleus accumbens, a brain region that engages one in rewarding behaviors, has been demonstrated to exhibit a smaller response to drug stimuli in female rats than in male rats [25]. In other studies, where male and female rats are given the choice between a reward of food or cocaine, more females opted for cocaine than males [25]. However, there’s a dearth of studies pertaining to the sex differences of human neural mechanisms in drug-taking behavior which would be critical to consider when understanding CUD development on the basis of sex [26]. Because cannabinoids largely concentrate in fat tissue, and biological women physiologically tend to have more fat tissue, it was once posited that it would take females more cannabis to reach the same ‘level’ of high as men [26]. However, a study published this year directly contradicts this theory, determining that when men and women smoked identical cannabis cigarettes (joints), THC concentrations in the blood of females were higher, even when they smoked less [27]. However, both of these studies point to the absence of ample testing on this subject and argue this interplay should further be analyzed.

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Cannabis Use Disorder

Sexuality and Cannabis Similar to the complex entity of gender, sexuality often has close ties to one’s relationship with cannabis. As such, some studies have been able to identify variance in cannabis use amongst those with differing sexualities. In one study, queer women utilized cannabis, in any form, more than three times the average heterosexual woman, with bisexual women, particularly, using it the most [28]. Heterosexual men, on average, utilized cannabis more than men that identify as bisexual. However, gay men utilized cannabis significantly more often than heterosexual men [28].

Considering that more men suffer from CUD than women, it’s reasonable to infer that gay men both utilize cannabis and experience CUD at a very high rate [3,19]. Inevitably, this variation in CUD could stem from the brain’s cortical thickness — how much of the brain there actually is. Thinning of the cortical surface has been linked to impulsivity, leading to urges taking precedence over logic, even being linked to conditions like ADHD and bipolar disorder [30]. Homosexual men were noted as having slightly thinner cerebal cortices than heterosexual men, on average, along with other significant differences in various structural volumes [29]. It is clear that prejudice, discrimination, and stigma contribute to an increased risk of substance abuse and mental health problems for queer people, though this relationship is in need of greater investigation [28].

ENDING CANNABIS USE Withdrawal Studies of cannabis withdrawal syndrome (CWS) have been quite limited, though research on the topic should, and will likely, persist following its inclusion in the DSM-5 (a recently revised diagnostic manual that assesses mental disorders) and increasing legalization [1,3,10]. When the DSM-IV was published in 2000, very little was known about cannabis withdrawal, which helped bolster the widespread myth that cannabis couldn’t be addictive. Even today, many professionals, along with the public, remain naïve to the existence of cannabis w i t h d rawa l [2].

CWS consists of anxiety, irritability, restlessness, depression, anger, shakiness,

nausea, sweating, stomach pain, and even boredom, as well as disturbances to one’s appetite, sleep, and weight [1,22]. The significance of CWS has been greatly disputed, though its range of symptoms vastly impair in one’s daily life [1]. The assemblage of withdrawal symptoms that many face should come as no surprise given how far the endocannabinoid system (ECS) internally spans; undoubtedly, the negative sensations following the end of cannabis use affirm the importance of a properly functioning ECS. The human body likes stability and predictability, so when one’s use of cannabis goes from persistent to nonexistent, the body (and ECS) is thrown into high alert. Further, relapse is common for many, as these withdrawal symptoms are so undesirable and difficult to endure. As found by patient observation in a Yale University-funded addiction facility, the most common reasons for relapse included negative moods, anxiety, cravings, boredom, stress, and trauma. Similarly, the presence of these psychological withdrawal symptoms are tied to worse outcomes for many patients with substance abuse disorders, though how this occurs specifically with individuals with CUD requires more investigation [31]. Ultimately, given how many cannabis users CWS affects, it would be inhumane to continue to essentially ignore what those suffering from CWS are facing, by not providing CWS (or CUD) with proper recognition or research [3].

Treatment Although there are millions of people who suffer from CUD, there are no FDA-approved pharmacotherapies to aid with CUD or CWS. It has been hypothesized that therapies for both CUD and CWS should target the ECS, taking advantage of the great similarity between AEA and THC. But, such suggestions remain largely speculative as the role of cannabis in the field of medicine is considerably controversial [32]. Fortunately, psychosocial therapy has been found to help quell cravings by improving grey matter volume and the connectivity between different cortices of the brain [3].

Another promising approach is the administration of cannabidiol, also known as CBD. CBD, interestingly enough, comes from cannabis, but it doesn’t produce the “high” that many look to THC for. There is also no indication of addictive properties in CBD, which is especially important for someone living with CUD [3]. CBD, in the complete absence of THC, has been found to greatly reduce the desire for cannabis within recovering users, as well as the paranoia and memory impairment it induces [3,12]. However, more studies must corroborate the potential for CBD to help one through CUD/CWS, as the substance, classified as an unregulated supplement, has only recently come into light as a potential treatment option [9].

LOOKING TO THE FUTURE It’s likely that the information available on CUD has been limited by the sociopolitical quagmire of the US. Until this gap of research is closed, a true understanding of the ex-

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Cannabis Use Disorder tent of cannabis’s control over brain growth will remain obstructed [3]. Of the studies that do exist, however, there is a clear need for standardization of metrics, especially as the development of CUD is likely linked more to cannabis potency than one’s duration of use [1]. Additionally, taboos surrounding addiction must be eliminated in order for individuals to have open, honest, and evidence-based dialogues that allow substance abuse to be combatted head-on. Rather than try to entirely prevent individuals from experimenting with drugs without explanation, revised education about addictive substances, like cannabis, is urgently needed [16].

This means rejuvenating the mundane middle school health class with critical, current information to teach students how to avoid substance abuse and, if applicable, manage addiction. State legislators should also deeply contemplate the various risk factors for CUD when it comes to the passage of medical and recreational cannabis laws [2].

Although cannabis hasn’t been proven to be as physically dangerous as other substances like alcohol, cocaine, and opiates, it can be incredibly dangerous on neurological and psychological levels. Ultimately, proper education on cannabis, CUD, and CWS, is desperately needed for all, from the doctors who will diagnose CUD and CWS to the teenagers attending daily smoke circles. CUD is entirely preventable and cannot be disregarded any longer. Cannabis is addictive and requires further research and recognition, especially when it comes to CUD (and consequent CWS). More research on cannabis and its effects on human users are in dire need as countless states progress with legalization.

In the end, being able to “outsmoke” everyone at the party isn’t something to be admired. It’s problematic. A plant can, in fact, throw your life off track, despite how “natural” it may seem; after all, aren’t tobacco, alcohol, opium, cocaine, and meth derived from plants, too?

References on page 49.

THE CHANGING VOICES IN OUR HEADS: SOCIETY’S IMPACT ON PSYCHOSIS

by Zoya Qureshi art by Claire Iannetta

The Changing Voices in Our Heads

“I

know you don’t want to, but it’s okay. Go bathe, then go to the shop. When you come back, you can go into the kitchen and prepare food for your family.” “You’re a waste, give up now.” The first quote is a description of a voice heard by a woman with schizophrenia in Chennai, India [1]. The second quote is one of many voices heard by a man with schizophrenia in Lee’s Summit, Missouri [2]. The first voice, though it nags, mainly addresses the patient like

of schizophrenia are categorized into positive (behaviors not present in a neurotypical individual) and negative (lack of neurotypical behaviors) symptoms [4, 5]. The positive symptoms of schizophrenia include hallucinations (hearing voices or seeing things that are not there) and delusions (fixed, false beliefs), while the negative symptoms include reduced emotional expression, difficulty in social relationships and in finding motivation to accomplish goals, and both cognitive and motor impairments. Thought disorder (in which one experiences unusual and disorganized thinking, such as an unintelligible mixture of seemingly random words) is another prevalent symptom of schizophrenia but is not usually categorized as either positive or negative [5].

Schizophrenia is one of the top 15 leading causes of disability globally and affects 20 million people worldwide [4,6]. People with this illness are 2-3 times more likely to die early compared to the general population; they are also more likely to face stigma, discrimination, and human rights violations [6]. Additionally, individuals with schizophrenia are more likely to be enrolled in criminal justice programs or social services due to failings in our system, thus increasing the impact of this disorder on the economy [7,8]. Many people with schizophrenia have a higher risk of arrest and incarceration compared with the general population, not because of unlawful behavior on their part, but often due to unfair victimization: not only are individuals with schizophrenia frequently the victim of a crime themselves, but they may be accused of a crime that they have not actually committed simply because their disorder makes for an easy scapegoat. Those who do commit crimes often do so when they are not adhering to antipsychotic medication -- sometimes due to a lack of access-- that can be necessary to keep the disorder under control [8]. A 2010 study attempted to break down the prevalence of encounters with the criminal justice system experienced by individuals with schizophrenia, as well as the costs attributable to this disorder [8]. The numbers were astounding. Individuals with schizophrenia were left to pay heightened costs, often due to factors beyond their control. These findings have a larger economic impact as well: the ineffective funneling of patients into governmental systems ultimately increases taxes for everyone. While you may not be aware of it, this disorder affects you too.

HOW IS SCHIZOPHRENIA EXPERIENCED DIFFERENTLY AROUND THE WORLD? her relatives do, giving guidance and the occasional scolding. The other voice is violent; it is impatient, unforgiving, and harsh, and it taunts the man whose head it lives in.

But why are these two voices different? Can it be that people living with schizophrenia in different parts of the world experience the disorder differently due to distinct cultural norms?

SCHIZOPHRENIA: WHAT IT IS AND WHY WE SHOULD CARE Schizophrenia is an often persistent mental disorder that can be severe and disabling [4]. The most common symptoms

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Although early studies focused mainly on Western society, researchers have been discussing the impact of society and culture on mental disorders for decades [9]. Recent studies looking at schizophrenia, and specifically at auditory hallucinations (the most commonly reported schizophrenia symptom across cultures) are being conducted on a global scale [10]. A compelling study conducted in 2002 aimed to compare the influence of culture and immediate environment on the auditory hallucinations in three groups of patients with schizophrenia: white people living in Britain, Pakistanis living in Britain, and Pakistanis living in Pakistan [10]. By distinguishing between these three groups, the re-

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The Changing Voices in Our Heads searchers could separate the effects of differences in cultural thinking (due to distinct environments) from ethnic differences. Interestingly, scientists found that both sets of patients living in Britain experienced significantly more auditory hallucinations in their day-to-day than patients living in Pakistan, implying that one’s immediate environment plays a greater role than ethnicity. The researchers also found that the content of auditory hallucinations differed significantly between the British groups and the group in Pakistan: while both British groups experienced violent negative hallucinations (voices cursing and telling patients to kill themselves), patients living in Pakistan (though they did experience negative/unpleasant hallucinations) had markedly fewer voices encouraging suicide or other forms of violence [10].

said “mostly, the voices are good [2].”

More than half of the Chennai sample heard familial voices (including those of parents, in-laws, and siblings) who spoke as though they were elders advising younger people. They would sometimes scold the patients, but usually the voices were helpful and taught the patients skills, such as domestic tasks. When speaking of their experiences with negative voices, the majority of patients in Accra insisted that their good voices were more powerful than any bad voice; oftentimes, their good voice was the voice of God, providing guidance. Patients in both Chennai and Accra described negative voices as the voices of people they knew or the voices of spirits but never described them as disembodied or intrusive. Meanwhile, the latter description illustrates how patients in California spoke of their auditory hallucinations [1,3].

A study conducted soon after looked at patients with schizophrenia in Nigeria and compared their auditory hallucinations to those of patients in the U.K. [11]. Researchers found that the number of British patients experiencing unfriendly and unfamiliar voices was higher than in the Nigerian group; meanwhile, patients in the Nigerian group heard voices that were less aggressive and usually familiar, in comparison to their British counterparts [11]. These two studies taken together suggest that auditory hallucinations may differ in patients living in distinct parts of the world. But the most compelling evidence was yet to come.

BREAKING DOWN THE DIFFERENCE: INDIVIDUALISM VS. COLLECTIVISM

PATIENTS IN THE U.S. HEAR HARSHER VOICES THAN PATIENTS IN INDIA OR AFRICA A 2014 study spearheaded by Stanford anthropologist Tanya Luhrmann suggested that people with schizophrenia in certain countries don’t hear the same harsh, violent voices that many Americans do [1]. In her study, she and her colleagues, many of whom were psychiatrists, interviewed 60 adults diagnosed with schizophrenia: 20 each in San Mateo, California; Accra, Ghana; and Chennai, India. Respondents were asked to describe how many voices they heard, how often they heard them, and what the voices were like. Individuals in all cultures described hearing a mixture of good and bad voices. Strikingly, while many of the African and Indian subjects reported predominantly positive experiences with their voices, not one American did. Instead, the U.S. subjects were more likely to report experiences as violent and hateful [1,3].

Luhrmann and her team attributed the differences in how the voices were perceived to distinct societal values[1,3].

Americans view themselves as individuals and place an overarching cultural emphasis on independence, so the voices experienced due to schizophrenia were perceived as an intrusion into the patient’s distinct, self-made mind.

Meanwhile, Indian and Ghanan cultures emphasize collectivism and relationships within a community, so additional voices were likely to be interpreted as more people in an already extensive social network. The widely accepted presence of supernatural elements in both these cultures (partially attributed to religion) also meant that people in Chennai and Accra were already used to the idea of beings beyond their comprehension; therefore, they were not as troubled by the presence of voices outside of their control. In the future, Luhrmann is hopeful that she can use these societally distinct ways of thinking to her advantage [1,3]. Although there is no cure for schizophrenia, encouraging patients to develop relationships with their hallucinated voices and negotiating with them as though they are people, and not disembodied things, may hold therapeutic value.

References on page 51.

One American patient described his voices being consistently violent, “like torturing people, to take their eye out with a fork… really nasty stuff,” while one participant from Ghana

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Cutting Out a Cure for Huntington’s Disease

H

ow far would you go to save your own life?

Would you undergo highly experimental treatments? Would you be willing to alter your own DNA -- the very thing that makes you you? This might seem like a far-fetched hypothetical dilemma, but for hundreds of thousands of people affected by Huntington’s disease (HD) across the globe, this fanciful hypothetical is becoming a present-day reality.

To date, the only treatments available for HD relieve symptoms; but, they are unable to target the root of the disease. However, new research about CRISPR/ Cas9 technology may provide a cure for this devastating disease. This controversial Nobel prize-winning mechanism is progressing towards clinical trials for the treatment of genetic diseases.

Huntington’s disease is a neurodegenerative disease characterized by motor, cognitive, behavioral, and psychiatric symptoms. The average age of onset is 40 years, although symptoms can appear any time from early childhood to one’s elder years [1]. Among these symptoms, one of the most recognizable is a movement disorder, chorea, which presents as erratic fidgeting and twitching [2]. Although deficits in motor functionality are typically the most prominent symptoms of HD, cognitive and neuropsychiatric symptoms also develop as a result of the disease.

In most cases, cognitive impairments that affect executive functioning (i.e. processing speed, problem solving, planning, organization), attention deficits, and memory retrieval precede the onset of motor symptoms [2]. Furthermore, HD has a high rate of comorbidity with depression, anxiety, and obsessive compulsive disorder (OCD), which exacerbate the cognitive decline associated with HD [2].

CUTTING OUT A CURE FOR HUNTINGTON’S DISEASE

by Alison Bond, Junjie Liu, and Anna Tidswell / art by Molly Berinato 32

Within the human genome, Huntington’s arises from a dominantly inherited mutation in the Huntingtin gene (also called the HTT gene), located on chromosome 4 [3]. The HTT gene is expected to code for a protein involved in many aspects of cell development and function [4]. However, the proper functionality of this protein can be impaired by a mutation in the coding region of the HTT gene. The coding region of a gene is the sequence of DNA that codes for the production of a protein. In order to do this, cells transcribe DNA into mRNA before using this mRNA transcript as a guide to assemble a protein. This process can be compared to the process of baking a cake: transcribing the DNA into mRNA is equivalent to writing down the recipe while putting the ingredients together, and baking the cake is analogous to translating mRNA to a protein. Within the coding region of the HTT gene, there is a consecutive stretch of repeats of the CAG codon (or three nucleotides that code for a specific amino acid—in this case, glutamine) which is found in the huntingtin protein [3]. In those with HD, an insertional mutation results in the addition of too many CAG repeats, leading to the production of a mutated protein; therefore, HD is classified as a CAG trinucleotide repeat disease [1]. Not only does having too many CAG repeats predict development of HD, but the number of additional CAG codons is correlat-

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Cutting Out a Cure for Huntington’s Disease ed with the age of onset of the disease [1]. As a result, the primary objective of genetic testing for HD predictors is to assess the amount of CAG repeats a patient has in their HTT gene. Most individuals without HD have 26 repeats or fewer [1]. Those with a count of 27 to 35 repeats will not develop the disease themselves, but can possibly pass the disease to offspring, depending on their partner’s genetic predisposition. Having 36 to 39 repeats yields ambiguous results, meaning that HD may or may not develop; it is past 40 repeats when the disease generally develops.

In general, higher numbers of repeats indicate earlier onset of Huntington’s [1].

Now that we have discussed the symptomatic presentation and genetic basis of HD, it is essential to understand the neuroscience behind Huntington’s. HD is neurodegenerative, meaning that it causes neuronal cell death, which leads to “shrinkage” of the brain (atrophy) [3]. While HD can progress to affect several brain regions, the basal ganglia system is the most directly impacted. The basal ganglia are made up of nuclei—interconnected clusters of neurons that work together and are highly involved in motor control [5]. In regulating movement, the basal ganglia system must communicate with the rest of the brain by receiving and sending information; this means that the system acts as a loop. It takes the information in, processes it, and then sends appropriate responses to other brain regions. When considering motor control, we can think about our ability to both initiate and inhibit movements.

Within the basal ganglia, these oppositional functions of excitation and inhibition are processed by two different pathways, termed the direct and indirect pathways, respectively [5]. In addition to bearing opposing effects on movement, the neurons that primarily make up each pathway differ slightly in terms of their receptors [6]. There is a loss of neurons in both pathways as a result of HD; however, cells of the indirect pathway are most affected. This means the ability to inhibit movement is greatly impaired, leading to many of the motor symptoms observed in those with HD. Needless to say, individuals with Huntington’s disease experience a range of symptoms that affect their day-today lives. Think about your typical morning routine. In the morning, you might wake up and stretch by extending your arms in front of you. Hopefully, your hands and arms are generally still, with minimal involuntary movement. If you are actively exhibiting symptoms of HD, your arms might jerk and flail around with very little control or effort. This movement disorder is the aforementioned chorea, which results from a loss of neurons that contribute to the basal ganglia system [2]. Because the transmittance of too much dopamine (a neurotransmitter) can produce uncontrollable movement, medications that target the production of dopamine can be used to treat chorea [7]. Prior to 2017, there was only one FDA-approved medication available to treat chorea in individuals with Huntington’s disease: Tetrabenazine. Unfortunately, Tetrabenazine is quickly broken down by the body and requires multiple doses throughout the day [7]. Researchers with the Huntington Study Group

(HSG)— a research group dedicated to finding treatments for HD— strived to find a drug that offered the same benefits as Tetrabenazine, but would not degrade as quickly .

In 2016, a groundbreaking study conducted by multiple HSG research centers determined Deutetrabenazine to be a new and effective drug for treating

chorea in HD [7]. Deutetrabenazine has a longer half-life, meaning one dose of the drug will take longer to metabolize upon consumption, thus eliminating the frequent doses required of Tetrabenazine. In the end, regaining control of one’s movement with medications of this nature can significantly enhance the quality of life for an individual with HD. Now, imagine you are getting ready to have breakfast before the start of your day. You take a massive spoonful of your cereal without realizing that it is simply too large to swallow. As a result, you choke and cough. You cannot get the food down, and you inhale it into your lungs [8]. This scenario, though simple, can help illustrate an incredibly deadly symptom of HD: aspiration. Individuals with HD inhale food and saliva into their lungs, potentially causing pneumonia or other dangerous side effects [8]. HD can also affect the ability to estimate the size of one’s bite. According to a sixteen year study that tracked individuals with HD-induced dysphagia (difficulty swallowing), the majority of HD patients had difficulties regulating the ingestion of excessively large quantities of liquid or solid food [9]. Several approaches can be taken to prevent harm, but none of them completely alleviate the problem. Speech language pathologists recommend coughing after swallowing large bites of food to confirm that the food has not travelled into the individual’s windpipe [10]. Additionally, physical supports like back braces and leg weights can also help to stabilize the body and position of the esophagus [9]. Furthermore, changing the texture of liquids and foods that will be consumed can

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Cutting Out a Cure for Huntington’s Disease help slow the eating or drinking process down for those with HD [9]. As HD progresses, a feeding tube may be required to sustain nutrition and hydration.

cific locations [15,16]. Many scientists believe the answer to treating and potentially curing diseases deemed incurable, such as HD, lies within this remarkable system.

Some of the most devastating effects of HD are cognitive and psychological. As individuals progress to the point of persistent physical symptoms of HD, they may also experience a cognitive decline in a form of dementia known as “frank dementia.” This type of dementia is classified by memory issues that result in a decreased ability to solve complex problems and process new information [2]. These symptoms, however, are often complicated by a lack of awareness on the part of the individual, making it difficult for family members to help them, let alone for those with HD to recognize their own mental decline. Even the most common class of medications for dementia, known as cholinesterase inhibitors, are not largely effective for individuals with HD [2]. This means that support should be offered in the form of cues and additional time for completing tasks.

It is undeniable that to make the most immediate impact on individuals with HD, scientists and health care providers must direct further research efforts towards effective drugs and treatments that can alleviate symptoms until a cure is found. Or might that cure have already been found with CRISPR/Cas9?

So how can CRISPR/Cas9 be engineered to help treat HD? One method is to directly cut up the mutant HTT gene itself.

Think of a computer’s many electrical cords, which provide the electricity to power the computer. By cutting one of the cords, you can reduce or destroy the function of the computer. Scientists can use this train of thought to disrupt the mutant codons in the HTT gene by de-

signing an

CRISPR/Cas9 is a natural defense mechanism that bacteria use to defend against other viruses [13]. After being infected by a virus, bacteria remember viruses by incorporating some of the viral DNA into their own genome, in what is termed “the CRISPR array” [14]. Bacteria then produce CRISPR-derived RNAs (crRNA), which bind and work with an enzyme called Cas9. The crRNA helps guide the Cas9 enzyme to viral DNA through complementary base pairings (molecular interactions between nucleic acids), while the Cas9 enzyme does the bulk of the workload by cutting up the DNA, allowing for an enhanced immune response [13, 14].

sgRNA that targets the increased number of CAG repeats responsible for HD. In order to insert CRISPR/Cas9 into the brain, scientists must package the genes for the Cas9 enzyme and the gRNA into an Adeno-Associated Virus (AAV) vector: a type of virus manipulated to deliver genetic material for gene therapy [17]. Normally, viruses are seen as harmful pathogens, but AAV vectors have been deemed safe and effective gene delivery vehicles. After the direct injection of AAV vectors into the brain, the AAV delivers genetic material into the cell. The cell transcribes this genetic material into RNAs, with some RNAs translated into proteins like Cas9 [17].

Scientists have long been able to accurately design nucleic acids in laboratories, which gives us some control over CRISPR/Cas9. By designing guide-RNAs (gRNA) similar to bacterial crRNAs, researchers can mimic natural processes, allowing the Cas9 cutting site to be chosen; this means that the CRISPR/Cas9 system can be used to cut genes at spe-

Finally, the customized gRNA and Cas9 enzyme join to start the process. The gRNA helps Cas9 locate the HTT gene, driving Cas9 to cut the gene and create a double-stranded break in the DNA. As the cell frantically tries to repair this lesion, it is bound to make mistakes, leaving the repaired HTT gene slightly different from the original. The next time

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Cutting Out a Cure for Huntington’s Disease this HTT gene is transcribed, the cell rightfully recognizes mistakes in the mRNA and degrades the RNA before mutant HTT proteins can be produced [18]. By using CRISPR/Cas9 to cut mutant HTT genes in 4-week-old mice, scientists were able to reduce the prevalence of mutant HTT proteins, improve life span, reduce dystonia, and improve motor function [19].

Compared to pharmaceutical approaches that treat symptoms on a short-term basis, gene-editing provides an unparalleled long-term solution. There is no need for regular dosage of pharmacological agents following CRISPR/Cas9 implementation because gene-editing is believed to be permanent, especially for the non-dividing cells of the brain.

However, CRISPR/Cas9 treatments are far from perfect.

Genetic editing increased lifespans of the mentioned mice subjects, but they all still died prematurely [19]. CRISPR/ Cas9 treatments can accidentally target cellular processes that mediate important functions by cutting up important genes. Since DNA is only made of four different “letters,” there are bound to be repeats or similarities in the genetic code and, subsequently, unintended mistakes by CRISPR/ Cas9. To improve CRISPR gene therapy, researchers continue to meticulously engineer Cas enzymes, gRNAs, and viral vectors to improve safety and effectiveness, while minimizing the treatment’s risks. As CRISPR systems rapidly improve, we may soon see clinical trials of using CRISPR/ Cas9 to treat Huntington’s disease in humans. Ultimately, we hope to one day be able to edit nucleic acids to treat Huntington’s disease and other neurodegenerative diseases without unintended repercussions.

Research is rapidly advancing in the field of neurodegenerative diseases, but more work is required to find a safe and effective cure for Huntington’s disease. A myriad of drugs have been developed to treat HD symptoms, though these only act as short-term solutions. Nonetheless, scientists are determined to find a permanent treatment. While current research regarding CRISPR/Cas9 shows promise as a longterm treatment, more time is needed to reduce both inefficiencies of CRISPR/Cas9 editing and address ethical considerations before scientists can conduct successful clinical trials. Ideally, the implementation of CRISPR/Cas9 in individuals with HD would result in a complete cure, rather than a reduction in symptoms, which would largely eliminate the need for prescriptions. CRISPR/Cas9 may provide hope and a cure for those living with incurable, neurodegenerative diseases in the form of a microscopic pair of scissors.

References on page 51.

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LETTING THE STORM PASS: THE PSYCHOLOGY AND NEUROSCIENCE OF MINDFULNESS

by Clement Doucette, Daniella Lorman, and Mara Russell / art by Allie Verdesca

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Letting the Storm Pass

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t’s the dead of winter, and you’ve decided that you need a break from the bitter cold of Upstate New York. As soon as you start driving south, a massive blizzard churns up, but it’s too late to turn back now. Shimmering flakes of white snow bombard your windshield, and you begin to feel dizzy and disoriented. The long strip of asphalt in front of you rapidly fades from view; no headlights can penetrate the raging squall that has engulfed your car. You decide to pull into the breakdown lane until the storm passes. Eventually, the snow settles, and the sun emerges and illuminates the road ahead, meaning you can continue your journey south. Like the maelstrom of a blizzard, practitioners of mindfulness argue that, by default, thoughts chaotically swirl through our minds. They believe that by practicing mindfulness, one can settle these chaotic thoughts and achieve personal clarity.

cal behavioral therapy (DBT) in an effort to treat symptoms of mood disorders, substance abuse, and suicidal ideation.

Linehan developed the practice of radical acceptance, which aims to reduce suffering that arises from painful and traumatic experiences by interpreting and accepting present situations and emotions without judgement. If you simply experience, rather than repress or attempt to resist unpleasant emotions, Linehan argues that you will experience less anxiety and depression[7]. In a 24-week study conducted on 100 non-suicidal, non-self harming individuals, participants reported improved emotional regulation and better coping mechanisms, indicating that DBT may be beneficial for individuals with mood disorders [8].

In the contemporary Western sense, mindfulness refers to a mental state in which an individual observes and focuses on their current thoughts, emotions, and inner experiences without judgement [1]. For over two thousand years, attaining this mental state has been integral to Buddhist religious practice. The teachings of Zen, which arose in seventh century China as a school of Buddhist thought especially professed the importance of breathing meditation in attaining self awareness [2]. Additionally, in the seventeenth century, teachers of Vipassana, a revived ancient Burmese Buddhist movement, instructed that spiritual insight could be attained through mindfulness meditation [3]. Mindfulness practices in psychotherapy were popularized and secularized in the Western world beginning in the 1960s and 1970s, as the general public became increasingly familiar with Zen Buddhist and East Asian spirituality and religious schools of thought.

Mindfulness-based cognitive therapy (MBCT) is another psychotherapy approach that infuses traditional cognitive behavioral therapy (CBT) with mindfulness components.

CBT aims to help people replace maladaptive coping mechanisms (such as isolating or substance abuse) with productive ones, changing the ways in which an individual reacts to stressful situations. CBT is commonly used to treat a myriad of disorders, including depression, substance abuse disorders, and obsessive compulsive disorder (OCD) [9]. MBCT takes these core practices of CBT and modifies them by introducing mindfulness practices. Integral and unique to MBCT, however, is the concept of decentering. The name itself is somewhat misleading; decentering oneself in MBCT involves being aware of and accepting incoming thoughts and feelings, but not judging or attaching oneself to them.

Similar to radical acceptance, the individual remains centered in the present moment [10]. A common MBCT exercise involves eating a raisin and taking note of the various sensations you experience. For example, you may notice that parts of the raisin stick in your teeth, or how its sticky and wrinkled surface feels when the raisin rests on your tongue.

By tuning in to your surroundings, you can learn to perceive subtle mental and physical sensations, equipping you with the tools to better address arising anxiety and discomfort [11].

DIFFERENT TYPES OF MINDFULNESS-BASED THERAPY The development of the pioneering Mindfulness-Based Stress Reduction (MBSR) program by Dr. Jon Kabat-Zinn in 1979 sparked interest in potential medical applications of mindfulness activities. Inspired by both Zen Buddhist teachings and Vipassana practices, Kabat-Zinn developed MBSR to assist people with chronic pain, anxiety, depression, and stress. Individual components of MBSR include body scans, mindfulness meditation, and mindful breathing [4]. The body scan is a crisis survival technique that involves focusing on and accounting for each individual part of your body, from head to foot, and noticing how each part feels [5]. Similar to how laser copiers scan documents from top to bottom to record them, the body scans evaluates each portion of your body in order to center you in the present moment.

Mindfulness meditation achieves a similar goal of centering oneself incorporating mindful breathing, which focuses on the motion’s of one’s breath, and exercises that compel the meditator to focus on different parts of their body [6].

DIALECTICAL BEHAVORIAL THERAPY (DBT) MBSR practices influenced other schools of mindfulness-based therapy that emerged in subsequent decades.

In the late 1980s, Dr. Marsha Linehan developed dialecti-

MINDFULNESS-BASED COGNITIVE THERAPY (MBCT)

This piece will discuss mindfulness practices as they impact psychological and neurological processes. Numerous studies have shown that mindfulness can lead to an increased tolerance of painful and uncomfortable situations, the reorganization of the brain, and an increased ability to engage in emotional processing.

MINDFULNESS AND PAIN Everyone has felt the twinge of a pulled muscle, the sting of pricking yourself on a sharp object, or the pulsing throb of a headache. But have you ever wondered why we feel these miserable sensations? Pain, the perception of unpleasant sensations arising from a part of the body, teaches us to avoid harmful situations. When you stub your toe against a door or pull a muscle after a strenuous workout, your body and your brain work together to let you know that you have been hurt, prompting you to respond. Frequently, respond-

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Letting the Storm Pass ing entails removing yourself from the damaging situation or resting an injured body part so it can heal.

The sensory process that triggers the feeling of pain is called nociception. Free nerve endings, activated by a wide

range of stimuli (extreme changes in temperature, oxygen deprivation, and mechanical force) that signal the damage of body tissue, are called nociceptors [12]. There are even specialized nociceptors that respond to selective stimuli; thermal nociceptors respond to scorching heat or extreme cold, while mechanical nociceptors respond to changes in pressure. In fact, most nociceptors are polymodal, meaning that they respond to a variety of categories of stimuli. When you prick your finger on a thumbtack, nociceptors transduce the painful stimulus into an electrical signal, which is sent up a bundle of nerves. These nerves synapse (or connect) onto your spinal cord, passing the signal up the spinal cord and to the brain. In the brain, the signals pass to the thalamus [13]. Think of the thalamus as the relay center of the brain; it processes and distinguishes between sensory stimuli, and directs input towards other brain regions which produce and remember feelings of pain (the amygdala and the hippocampus).

One important caveat of the standard pain pathway is that signals can be modified at several points. In 1965, Dr. Ronald Melzack and Patrick Wall proposed the Gate Control Theory of pain, suggesting that our spinal cord employs a “gate” mechanism, which opens to allow pain messages to reach

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the brain [13]. The Gate Control Theory proposes that pain signals can be amplified, blocked entirely, or slightly modulated, altering the perception of pain on a neurological level [13]. Recall an instance in which you were injured while being occupied with another task, perhaps during a sports game.

It is likely that your perception of pain may have been diminished, as your brain decided to focus on the task at hand. In other words, your brain shut the “gate,” allowing you to pay attention to other messages.

There are two major categories of pain: chronic pain and acute pain [14].

Acute pain is a sudden, short-lived sensation that arises when you twist your ankle or step on a Lego. Following acute pain, sensory nerves carry the message of “ouch, that hurts” to your spinal cord, and then, your brain. Think of your brain as a database that stores knowledge of similar painful incidents in your life. Your brain files through previous painful situations, sorting through information to find a record of a similar type of injury, in order to decide an appropriate response. Sometimes, this response is a release of adrenaline or an increase in heart rate; other times, this response prompts you to remove yourself from the potentially damaging situation. Acute pain resolves once the injury is healed.

On a neurological level, this means that nociceptors stop firing when the injury resolves [14]. Chronic pain is a long-lasting, persistent pain that lasts at least three months [14]. Individuals who experience chronic pain often have conditions that require long-term treatment and therapy to manage. One example of this is arthritis, a joint disease signaling disrepair. In contrast to acute pain, nociceptors in chronic pain continue to fire after the injury, resulting in a continued pain response even if there is no physical cause of pain present [14]. Chronic pain is a major health problem today, severely impacting the physical, social, and emotional functioning of individuals who suffer from it [15].

Now that we have explored the feeling of pain on a neurological level, it is important to note that response to pain is unique to the individual [16]. In other words, what may be slightly uncomfortable to one person may be excruciatingly painful to another. Because pain stimuli reach brain regions that process emotion, such as the amygdala, your experience of pain is shaped by emotional, social, and psychological factors. Your upbringing, social and cultural influences, beliefs and values, and previous pain memories are all contributory factors for interpreting pain [16]. For example, the pain response to stepping on a Lego will be different depending on the events preceding the accident: getting into an argument or celebrating an achievement will most likely

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Letting the Storm Pass result in differing pain perceptions and responses. In fact, your feelings about the experience may be impacted if your foot became infected the last time you stepped on a lego, perhaps hindering your rate of recovery. Because the causal factors of pain are multidimensional, the treatment of chronic pain is often challenging.

Recently, mindfulness in the form of meditation has been explored as an alternative for chronic pain patients seeking self-facilitated, drug-free therapy in an experimental setting [17.18,19]. While it remains unknown whether mindfulness meditation can directly intercept pain pathways, it has been found to alter activity in various brain regions and, in some cases, decrease sensitivity to pain [17,18,19]. One study required participants to focus attention on their breath while acknowledging any thoughts or emotions that arose without judgment, for just 20 minutes a day [17]. Participants showed a significant reduction in activity in the hippocampus— a brain region involved in processing the evaluation of pain— after just four days of practicing mindfulness mediation [17]. Another MBSR study that measured brain activity in long-term Zen meditation practitioners showed similar findings; participants showed a reduction of activity in their prefrontal and orbitofrontal cortices, two brain regions also active in processing the evaluation of pain [18]. The prefrontal cortex can be thought of as the control tower of your brain; it plays a cardinal role in higher-order decision making processes, focusing your attention, and in managing emotional reactions. The orbitofrontal cortex is an area of the prefrontal cortex that is involved in emotion and memory processing. In fact, the aforementioned study found that long-term Zen meditation practitioners exhibited increased activation in brain regions that process sensory (nociceptive) stimuli, such as the thalamus and the insula [18,19,20].

Additionally, mindfulness meditation has consistently been found to reduce chronic pain symptoms [21,19,22]. These findings suggest that individuals who practice mindfulness may experience increased feelings of control and reduced levels of anxiety when faced with painful situations.

MINDFULNESS AND NEUROPLASTICITY Your brain is powerful and malleable. It has the ability to reorganize itself and change its structure over time. The technical term for this phenomenon is neuroplasticity. The human brain is composed of 100 billion neurons, or specialized cells that carry information throughout the body using electrical and chemical signaling processes. In the small pocket of space between two neurons, called the synapse, connections can form. In fact, the average adult brain is believed to have over 100 trillion neural connections [23]. Each time we learn something new, synaptic connections called neural pathways are “carved out” in the brain; your brain is constantly changing as new neural pathways are formed.

[25]. Neuroscientist Dr. Carla Shatz suspected a fine-tuning mechanism in the brain, coining one of the best known aphorisms in neuroscience: “neurons that fire together wire together,” and its corollary “neurons that fire out of sync lose their link” [25]. As you practice or repeat learned skills, you maintain the neural pathway for that skill. This is akin to strengthening a new friendship. After befriending someone, hanging out and communicating are great ways to sustain your new relationship. However, if you never speak to your new friend, the relationship will fade. Shatz’s theory of neuroplasticity insinuates that the connections we sustain in our brain change as we age. The skills vital to your survival and functioning at age two are likely very different than those valuable to you today. Shatz’s theory postulates that pathways for skills that haven’t been used in a while get pruned away to make room for other, more useful connections; in other words, use it or lose it. Now that we have a handle on human brain plasticity, let’s explore mindfulness meditation’s ability to reorganize neural pathways and brain structure.

Several studies have surfaced with research supporting the claim that mindfulness meditation can lead to neurological changes. In one study, Western meditation practitioners were found to have increased thickness in cortical regions associated with sensory processing and attention [26]. Your cortex is the outermost part of your brain, primarily composed of grey matter, or neuronal cell bodies. As the largest site of neuronal integration (neurons receiving and transmitting information) in the brain, your cortex plays a critical role in attention, awareness, thought and memory-processing. As you age, your cortex thins out; however, different regions of the cortex have different susceptibility to aging, and therefore, thinning [27, 28]. The thinning of your cortex is correlated with a decrease in cortex-mediated processes, such as those aforementioned. Therefore, mindfulness practitioners with increased cortical thickness in distinct regions are more likely to retain sustained regulation of cortex-mediated processes than those who do not practice mindf u l ness.

I n

In 1949, Dr. Donald Hebb published neuroscience’s widely-used explanation of how learning is accomplished in the brain: Hebbian Theory, which says that neurons strengthen their neural connections by firing electrical impulses in sync [24]. However, these neural connections are not permanent

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Letting the Storm Pass other words, individuals who practice mindfulness may have increased attention and thought-processing ability. Another study found that after eight weeks of mindfulness meditation, participants’ amygdala size shrunk compared to those who were not practicing mindfulness, correlating with a decrease in stress [29].

MINDFULNESS AND EMOTIONAL REGULATION Emotions are short-lived and defined states of positive or negative reactions to stimuli or situations [12]. There are three main components of emotion: physiological, behavioral, and cognitive. Imagine someone about to give an important presentation. Their palms are sweaty, their heart starts to race, their breathing becomes shallower. These are physiological responses. Sitting in their chair, they bounce their leg up and down, open their eyes wider, and twirl a pencil in their fingers. These are behavioral responses. Thinking to themselves, they remark, “I am so anxious, I just want this presentation to be over!” This is a cognitive appraisal of the emotion: anxiety.

There is much debate in the field of neurophysiology about how emotions are actually processed. However, most sci-

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entists agree that a network known as the limbic system, a loose collection of structures surrounding the thalamus, is responsible for emotion generation. Once generated by the limbic system, emotional information must be processed, and behavioral responses, regulated. This emotional regulation in the brain can be broken into two components: explicit and implicit regulation. Implicit regulation includes all the automatic and unconscious processes of emotion.

Areas like the anterior cingulate cortex and medial (middle) prefrontal cortex are implicated in bottom-up regulation [31, 32]. Explicit regulation includes all the conscious and voluntary mental activity associated with emotional processing.

In the brain, the central executive network (CEN) is usually involved in this explicit regulation. Although scientists define the regions included in the CEN differently, most agree that it includes the lateral (side) prefrontal cortex, and posterior (back) parietal cortex [20, 31, 32]. Simply put, when the brain regulates emotion, explicit regulation regions in the prefrontal cortex, such as the amygdala, control systems that generate emotions [31]. Implicit regulation areas work with emotion-generative areas to help inform the topdown system.

Now, just for a moment, take a break for yourself. Notice your emotions.

What are you feeling?

Confusion?

Sadness? Joy? Hunger? As you sit with these feelings, simply observe them, without judgement.

Try to name these emotions. What you have just performed is a common mindfulness task known as affect labelling. This and other mindful tasks have been linked to neural activation in key areas for emotional regulation [20].

Tasks like affect labeling affect the top-down system by simultaneously increasing activation in the prefrontal cortex and decreasing activation in the amygdala.

This activation pattern suggests the prefrontal cortex regulates negative emotional responses like anger and fear.

After and while performing an affect labeling task, several

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Letting the Storm Pass fMRI studies have demonstrated increased activation in areas of the prefrontal cortex, with a simultaneous decrease in amygdala activation [20, 32]. The increased activation of the prefrontal cortex leads researchers to believe that more emotional regulation is occurring [20].

Imagine a toddler who drops his ice cream cone on the ground. The subsequent responses are screams and tears: a temper tantrum. Young children, without a developed prefrontal cortex, have poor emotional regulation, especially in regulating negative emotions like sadness, anger, or fear. As a result, they have exaggerated emotional reactions to minute stimuli. Emotional regulation is a vital skill. In adults, many psychological disorders (such as depression, bipolar disorder, obsessive-compulsive disorder, and PTSD) are associated with reduced or dysfunctional emotional regulation [31]. Major depressive disorder, for example, is tied to higher levels of resting amygdala activity and lower prefrontal cortex activity compared to healthy subjects. Also, depressed patients demonstrate higher levels of amygdala reactivity to stimuli [33, 35]. However, studies comparing the neural correlates of mindfulness and depressive symptoms found great spatial overlap in the amygdala and medial prefrontal cortex, suggesting that practicing mindfulness could potentially alleviate symptoms of depression [34, 35]. An analysis of several studies found that while mindfulness was not as effective as medication and long-term therapy for mood disorders like depression and anxiety, mindful practices like meditation had a significant positive effect on relieving symptoms of those conditions [36].

as anyone who has done mindful exercises for only a few weeks.

FINAL THOUGHTS While mindfulness, in all of its associated definitions, is an intriguing prospect with numerous exciting and potential clinical applications, it’s important to both recognize the flaws in existing research and acknowledge that more time is needed to uncover its biological and behavioral correlates.

Fortunately, mindfulness is an easy skill to practice. Being mindful can simply entail carving out five minutes a day to tune in to your thoughts and feelings or complete a targeted exercise. Take a walk in the park without headphones in. Do a body scan. Download a mindfulness app to guide you. Regardless, if you find yourself stressed or fatigued, remember that relaxing your body may help to relax your mind.

References on page 52.

THE DUALITY OF MINDFULNESS Since the early 2000s, the frequency of the terms “mindfulness” and “meditation” in newspaper articles and scientific literature has increased exponentially [37]. However, delving into the findings of these studies presents a murky picture. Vague and inconsistently defined terminologies plague many of the articles. Significant methodological errors and small sample sizes render the data produced from several studies effectively meaningless. Furthermore, some of this literature suggests that mindfulness practices may be over-prescribed and even harm individuals by bringing repressed traumatic memories to light [37].

There is little consensus in the scientific community regarding the definition of mindfulness. Some adopt a definition referring to the regimen of meditative and centering practices included in MBSR therapy. Recently, others have considered mindfulness in much broader terms, interpreting it as the ability to be consciously aware of oneself and one’s feelings in the present moment [37]. These different definitions and practices of mindfulness may involve different regions of the brain and have different psychological effects.

Even when using the same definition, empirical trials vary widely in the duration and intensity of mindfulness practice.

In some studies, participants are “experts” at mindfulness; but, the level of practice required for such a title varies from paper to paper [37]. While one paper may utilize trained and practicing Buddhist meditators, others may define an expert

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Battling COVID-19’s Mystifying Mental Fog

BATTLING COVID19’S MYSTIFYING MENTAL FOG

by Nick Beebe / art by Karen Mogami and Nick Beebe

W

hen it struck me, I was one month in as a newly transferred Boston University sophomore, right out of spin class. Completely lost along Back Bay’s Newbury Street, I felt somehow frazzled in an area I already knew quite well; however, I dismissed my confusion as stemming from post-workout exhaustion and the adrenaline rush following my half-sister’s pregnancy announcement. I stared at Maps to get home. After that, things got worse. It was just a matter of time before my grades began to slip. BU’s notoriously merciless General Chemistry became more and more abstract and the entire process of DNA replication left my mind during a Biology exam, despite my love for genetics. Again, I dismissed my perplexing condition, attributing everything to the stress of a new school and city. Little did I know, something far bigger was transpiring. Ultimately, my

experience with COVID19’s “brain fog” is just one of the many brought by the persisting pandemic, though the experience that I, and many others, have faced has largely been ignored.

Contrary to popular belief, the signs of COVID-19 extend beyond the well-known symptoms of hypogeusia and anosmia, the loss of taste and smell, respectively. In fact, many don’t even experience these symptoms [1]. The lesser discussed burdens of memory loss, confusion, and delirium caused by COVID-19 form the mental “fog” I experienced for weeks, inhibiting my focus and abilities I had never even thought about, like coming up with everyday words. Other COVID-19 survivors detail this fog as debilitating, feeling similar to dementia and white static [2].

Unfortunately, the diverse and vague symptoms associated with COVID-19 have greatly complicated efforts to contain the pandemic. As physician Dr. Kari Nadeau of Stanford University remarks, a family with the same genetics that contracts the same strain of COVID-19 can experience widely different symptoms. Thankfully, there are several ongoing studies tracing which biomarkers influence the severity and symptoms of one’s infection [3]. Aside from death, the effects of COVID-19 on the brain are arguably the most malevolent repercussions of a COVID-19 infection.

Without memory, who would we be?

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MEMORY AFTER AN IMMUNE RESPONSE

MEMORY & OTHER CORONAVIRUSES

Following a strong immune response instigated by an infection, the strength of one’s memory often deteriorates. The hippocampus of the brain has the essential task of capturing experiences and transforming them into memories to be stored away; it reconsolidates memories by strengthening existing connections of the brain or establishing new ones on the brain’s outer surface. Any time you think of an experience from your past, whether it be from childhood or even just waking up this morning, your hippocampus is activated. The body, still overwhelmed by the fight it has endured post-infection, experiences amnesia due to hippocampal dysfunction [4]. Hippocampal dysfunction obstructs processes like spatial memory, fear conditioning (recalling certain stimuli as negative forewarnings), and novel object recognition (recognizing new items and/or changes in previously observed settings). For more than 1 in 4 patients with a major illness, alterations in memory processes are experienced, which can continue years after recovery [4]. Although this statistic isn’t specific to COVID-19, it can be used as a foundation for understanding how a major illness like COVID-19 links to the impairment of memory.

Since there is less research on SARS-CoV-2, knowledge of other coronaviruses can be helpful in understanding this novel strain. SARS-CoV-2 is one of the seven known coronaviruses to infect human hosts. Of the remaining six, two (SARS-CoV and MERS-CoV) have remarkable similarities to SARS-CoV-2 [7].

When it comes to COVID-19, inflammation can come, in large part, from cytokine storms. Cytokines are molecules that initiate an immune response through both the production of antibodies and killing of infected cells. A “storm” of cytokines occurs when the body overreacts to an initiated immune response and begins to kill its own cells instead of just antigens. Despite their similar spellings, antigens and antibodies are completely different things — antibodies are produced by the body’s immune system as a result of the presence of antigens, the invading particles that the immune system wants to eradicate. So, think of a cytokine “storm” as the same chaos that occurs when hypercompetitive WASP moms raid Vineyard Vines on Black Friday; it is very, very bad for nearly all parties involved. In fact, cytokine storms are so dangerous that upon hospital discharge following a COVID-19 infection, one can still die days later as a result of the inflammation inflicted [5]. The shortterm brain inflammation that results from a strenuous immune response to viruses like SARS-CoV-2 (which causes COVID-19) can also trigger neurodegeneration, increasing the risk of conditions like Alzheimer’s [6]. Neurodegeneration doesn’t just impact future connections formed in the brain, but also pre-existing connections thought to be lifelong. To demystify the neural mechanisms underlying the progressive cognitive deficits following illness recovery, a better understanding of the interplay between neuroscience and pathology is crucial [4].

SARS-CoV-2 doesn’t yet have ample trial results available, as it emerged a year ago and thorough studies are hindered by precautions like social distancing and travel restrictions.

As a result, much initial research has looked to SARS-CoV and MERS-CoV in order to reach conclusions about SARSCoV-2. In the presence of SARS-CoV and MERS-CoV, human memory is predicted to have been impaired in over a third of admitted patients [8]. From this knowledge, SARS-CoV-2 has been hypothesized to impact and kill neurons. This is problematic because unlike the common, natural death of neurons (apoptosis), the death of neurons due to inflammation (necrosis) often impacts fully functioning neurons.

Since neurons pass messages from one to another, the demise of neurons that weren’t meant to die greatly affects the relaying of crucial informational signals, the success of the neuronal network, and thereby, memory overall.

However, every question about SARS-CoV-2 can’t be answered by investigating other strains of coronaviruses, as different strains have shown different potentials for infecting neurons. For instance, infections in the brain were not commonly reported in SARS-CoV patients. A preliminary report led by Yale University has confirmed the role of SARSCoV-2 in neuronal death, noting changes in both infected and neighboring cells. However, since this research is so new, it has yet to undergo the scientific review process, meaning it hasn’t been entirely verified [9]. Further contemporary research will strengthen the validity of this finding, but definite answers will only be reached when comprehensive trials can be safely performed [10,1].

As infectious disease expert Dr. Jacomine Krijnse-Locker illustrates, SARS-CoV-2 acts like “a balloon on a string,” slithering along the surface of cells on the hunt for ACE2 receptors to attach to — which are highly concentrated on epithelial cells of the respiratory system [31]. These spike proteins are aided by protein dimers — two protein units clumped together — called hemagglutinin esterases, which assist in the invasion and breakdown of host cells [32]. Upon invading a host cell, the virus replicates its own genetic material (RNA) with an RNA template, which mostly codes for structural proteins that build the new virion (basic structure of the virus) along with non-structural proteins that help aid in the replication of RNA. Three more of SARS-CoV-2’s essential proteins are the N, E, and M proteins. The N protein helps protect RNA; if unprotected, there could be no replication of viral genetic material meaning the production process of viral particles to cause infection would be jeopardized. The E and M proteins of SARS-CoV-2 are responsible for managing the envelope encasing the particle and its progeny in all stages of development for new particles, from

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Battling COVID-19’s Mystifying Mental Fog its capsulation to assembly to budding off of the host cell [33]. After budding off, newly made virus particles attack the rest of the body in the same process. However, this is not to say that COVID-19’s attack strategy is entirely understood as many questions still remain unanswered.

As infectious disease expert Dr. Jacomine Krijnse-Lock-

er illustrates, SARS-CoV-2 acts like “a balloon on a string,” slithering along the surface of cells on the hunt for ACE2 receptors to attach to — which are highly concentrated on epithelial cells of the respiratory system [31]. These spike proteins are aided by protein dimers — two protein units clumped together — called hemagglutinin esterases, which assist in the invasion and breakdown of host cells [32]. Upon invading a host cell, the virus replicates its own genetic material (RNA) with an RNA template, which mostly codes for structural proteins that build the new virion (basic structure of the virus) along with non-structural proteins that help aid in the replication of RNA. Three more of SARS-CoV-2’s essential proteins are the N, E, and M proteins. The N protein helps protect RNA; if unprotected, there could be no replication of viral genetic material meaning the production process of viral particles to cause infection would be jeopardized. The E and M proteins of SARS-CoV-2 are responsible for managing the envelope encasing the particle and its progeny in all stages of development for new particles, from its capsulation to assembly to budding off of the host cell [33]. After budding off, newly made virus particles attack the rest of the body in the same process. However, this is not to say that COVID-19’s attack strategy is entirely understood as many questions still remain unanswered.

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SARS-COV-2 & THE BRAIN Neurotropism Substantial evidence suggests that COVID-19 affects systems other than the respiratory system (lungs, airways, and blood vessels), including the central nervous system, meaning it is neurotropic [11]. Neurotropic viruses can attack and ultimately obliterate neuronal cells. SARSCoV-2, in turn, hinders the mental capabilities of an infected individual by attacking their neurons, within which the virus can mindlessly replicate [12,13,14]. Evidence supports the theory that SARS-CoV-2 has a negative impact on neurological function, as an early Chinese observational study associated COVID-19 infection with increased mental confusion, corroborating presence within the brain and its true danger [10]. In a study from northeastern France, 65% of observed COVID-19 patients reported confusion [15]. Of another study led in Germany, roughly 36% of COVID-19 cases were found to involve neurological symptoms — 25% of which involved the central nervous system — including dizziness, headaches, seizures, and brain fog [6]. Even after hospital discharge, one of the most persistent symptoms, as reported by over a third of COVID-19 patients, has been the loss of memory [16,6].

Olfactory Bulb & Inside the Brain SARS-CoV-2 is theorized to primarily travel through the nostrils and into the olfactory bulb (the part of the brain where receptor cells transform odorants into neural stimuli to indicate what one is smelling) [7]. When the olfactory bulb fails to control SARS-CoV-2, symptoms of COVID-19 often arise after five days of the virus’ incubation within the body, but may remain veiled for up to two weeks [17]. Though the olfactory bulb has been regarded as highly efficient at controlling neuroinvasion, many viruses, like SARS-CoV-2, can successfully enter the body this way, leading to inflammation and demyelination of neurons [18,19]. Demyelination refers to the unraveling of the myelin sheath within neurons, which proves to be extremely detrimental. Myelin sheath operates like one of those moving walkways, or travelators, found in airports. Just like when people get onto a travelator, receptors called dendrites that branch off from a neuron’s cell body obtain signals from neighboring neurons. As this communication from other cells is processed, “action potentials” result which, in this analogy, are the travelers heading down the moving walkway. When travelers exit the travelator, they head in varying directions with different destinations. Neurons, similarly, release a myriad of neurotransmitters that target specific receptors after achieving an action potential, going on to mediate different bodily

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Battling COVID-19’s Mystifying Mental Fog functions. SARS-CoV-2, when in the brain, rips this travelator away from neurons and its dendrites, leaving its “passengers” (action potentials) completely stranded. There is, inevitably, no other way for the signals within the neuron to travel than by the myelin sheath.

COVID-19’s extension into the brain from the olfactory bulb has been supported by the detection of SARS-CoV-2 genetic code in the cerebral-spinal fluid (CSF) of admitted patients [20,19,17]. CSF is meant to protect the brain and spinal cord from injury and also acts as a garbage disposal for unwanted matter housed in the brain (i.e. SARS-CoV-2). However, the detectability of SARS-CoV-2 in CSF can be influenced by the severity of infection, the time between initial infection and sample collection, and even the sensitivity of the test administered [21]. The discovery that SARS-CoV-2 invasion is greatly restricted by removing the olfactory bulb in mice also heavily suggests the involvement of this structure in infection [22].

UNDERSTANDING “BRAIN FOG” Simply put, scientists aren’t in agreement about what causes brain fog. It remains especially boggling as it even affects those who became only slightly ill with COVID-19 and those with no pre-existing brain conditions [6]. Current theories of the origin of COVID-19’s fog range from the prolonged activation of the immune system after COVID-19 to inflammation within blood vessels and cells to the possibility of antibodies attacking neurons [2].

Medical literature is often intentionally impersonal, but listening to the experiences of individuals that have faced COVID19’s fog can lead researchers and their studies in cogent directions, and even warn of what those fighting COVID-19 may face. For one 59-year-old woman, cognitive impairment was noted by her attending medical personnel, as she expressed difficulty with memory and executive reasoning [23].

Prior to hospitalization, she was forgetting her children’s names, her work schedule, and the names of grocery stores near her home.

A CT scan of the woman revealed a lower density of the brain in the left

frontal lobe, which is responsible for attention, concentration, and memory [23]. Though this particular patient was in her late 50s, a number of sources have wrongly associated issues of memory loss and confusion from COVID-19 with older age. Pre-existing conditions like Alzheimer’s and the deterioration of the blood-brain barrier in older adults can leave them more susceptible to neuroinvasion, but old age is certainly not a prerequisite for experiencing mental fog [24,6,4].

In fact, a recent study has found a prevalence of COVID-related confusion in groups with mean ages around 40 [8].

To claim that the fog mainly affects older and more vulnerable populations does a great disservice to the public as they navigate this pandemic, minimizing the struggles faced by younger people like me, 19 at the time, and 16-year-old Natalia Ruspini, a Californian who also endured brain fog for months [3]. Another young victim, 32-year-old Hanna Lockman, asserts that COVID-19 has “eaten” her brain. The disease has made it difficult to remember words and to take her medications [25]. Lockman even feels like there’s a physical fog housed in her head [25]. Michael Reagan, 50, remembers “nothing at all” about his twelve-day Parisian vacation with his boyfriend after contracting coronavirus just weeks later. Julia Donahue, 61, details her failure to call to mind the simple word “toothbrush,” needing to explain its function instead to get the point across. Erica Taylor, 31, couldn’t recall that the only Toyota Prius in her apartment building’s parking lot belonged to her [2]. As these various experiences show, COVID-19 can bring about the most bewildering of new-onset cognitive impairment in nearly anyone [23]. The inflammation caused by the brain’s response to SARS-CoV-2 means there is a strong chance neurodegeneration and cognitive decline can progress, even years after contracting the disease. Recent findings strongly suggest a positive correlation between COVID-19 infection and the

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Battling COVID-19’s Mystifying Mental Fog risk for developing neurological disease later in life, though this hypothesis lacks an ironclad research backbone [6].

The Necessity for Additional Studies

MOVING FORWARD

As the literature pertaining to COVID-19 continues to expand as time progresses, it is my hope that the scientific community can come to an understanding about what links COVID-19 to confusion, memory loss, and delirium — the infrastructure of this brain fog. Large-scale studies that span countries, and even continents, will have the opportunity to greatly diversify public knowledge pertaining to COVID-19 and ancestral background, particularly with regard to its impact on the brain. With the information currently available, researchers are now advocating the need for neurological assessment and timely evaluation for those that have been afflicted by COVID-19 [23].

Roughly 91% of 640 survey respondents who have recovered from COVID-19 expressed several ongoing symptoms, one being its relentless brain fog [25]. Additionally, “long haulers,” individuals who have been battling COVID-19 for a prolonged period of time, often describe their most debilitating and persistent symptom to be the impairment of memory and concentration [25].

Confronting Eurocentrism After all of this, you may wonder: Why haven’t I heard anything about this COVID-19 “brain fog”? When they haven’t been discussing the skyrocketing numbers of COVID-19 cases and deaths or the U.S. government’s blatant failure of a pandemic response, media outlets frequently have emphasized the symptoms of loss of smell and loss of taste, stemming from a German virologist’s conclusion in early March [26]. It is now known that cisgender females of European descent are the most likely to lose both senses. Admittedly, anosmia (loss of smell) and ageusia (loss of taste) are very obvious indicators that one may have COVID-19, but not everyone experiences these symptoms. Comparatively, it was sensations of delirium that were found in 31.2% of COVID-19 patients upon hospital admission in France, while anosmia affected only 3.2% [27]. Furthermore, over one-third of patients infected with SARS-CoV-2 in Wuhan, China were regarded as experiencing a range of neurological impairment from a very early study [28]. So why was decreased mental clarity and function ignored in early COVID-19 patients for anosmia and ageusia? The answer likely lies in Eurocentrism.

There are stark differences between the reported rates of chemosensory dysfunction (loss of smell and/or taste) in countries with majority East Asian populations and countries with majority White populations [26,29]. This disparity was noted by one study, which, at the time of its writing, noted there were only 5 published studies conducted on East Asians compared to the 33 on Whites pertaining to COVID-19-induced smell loss. For taste loss, there were only 4 conducted on East Asians compared to the 26 conducted on Whites. How are researchers going to understand the differences in symptoms across different populations if they are primarily studying Whites? And how does COVID-19 affect those of other ancestral backgrounds? These questions are in dire need of being addressed. Though I am entirely of European descent, it was the simple fact that I didn’t lose my senses of taste or smell — alongside the U.S. government’s downplaying of the virus until after I beat COVID-19 — that led me to dismiss the possibility of actually having the illness. With diversity in research participants, answers about this Earth-stopping pathogen will finally begin to reflect all of whom it has affected. This same call for diversity is needed to best comprehend the inner workings of COVID-19’s brain fog as well.

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Moving forward, collaboration between researchers is desperately needed around the globe to better understand how COVID-19 impacts memory and causes mental fog in patients [30,1]. In order to directly combat COVID-19, we must work together in unity — in collaboration — for the sake of our country and the world. There are many people dismissing this science that absolutely does exist, or failing to understand how their ignorance to social distancing and safety protocols negatively impacts the population at large.

Everyone must grasp that SARS-CoV-2 is a self-serving anarchist on its own team, targeting any human it comes in contact with. In the end, it is imperative to wear a mask and social distance; although few of us might want to remember 2020, experiencing the mental fog of COVID-19 is truly not worth it.

References on page 54.

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References

REFERENCES

Breaking the Broken Brain Model of Addiction

Scratching the Surface of an Itch

1. Brady, K. T., & Sinha, R. (2007). Co-occurring mental and substance use disorders: The neurobiological effects of chronic stress. Focus, 5(2), 229-239. doi:10.1176/ foc.5.2.foc229.

1. Andrew, D. & Craig, A.D. (2001). Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nature Neuroscience, 4: 72-77. doi:10.1038/82924.

2. Bautista, D.M., Wilson, S.R., & Hoon, M.A. (2014). Why we scratch an itch: the molecules, cells and circuits of itch.

Nature Neuroscience, 17(2): 175-182. doi:10.1038/nn.3619.

3. Han, L., & Dong, X. (2014). Itch mechanisms and circuits.

Annual review of biophysics, 43: 331–355. doi:10.1146/ annurev-biophys-051013-022826.

4. Mayo Clinic. (2018). Itchy skin (pruritus). Retrieved September 23, 2020, from https://www.mayoclinic.org/ diseases-conditions/itchy-skin/symptoms-causes/syc20355006 5. Mishra, S.K. & Hoon, M.A. (2013). The cells and circuitry for itch responses in mice. Science, 340: 968-971. doi:10.1126/science.1233765.

2. Compton, W. M., Thomas, Y. F., Stinson, F. S., & Grant, B. F. (2007). Prevalence, correlates, disability, and comorbidity of DSM-IV drug abuse and dependence in the United States. Archives of General Psychiatry, 64(5), 566-576. doi:10.1001/archpsyc.64.5.566.

3. Dafny, N., & Rosenfeld, G. (2017). Neurobiology of drugs of abuse. Conn’s Translational Neuroscience, 715-722. doi:10.1016/b978-0-12-802381-5.00052-x 4. Heyman, G. M. (2013). Addiction and choice: Theory and new data. Frontiers in Psychiatry, 4. doi:10.3389/ fpsyt.2013.00031.

5. Krohn, M. D., Lizotte, A. J., & Perez, C. M. (1997). The interrelationship between substance use and precocious transitions to adult statuses. Journal of Health and Social Behavior, 38(1), 87-103. doi:10.2307/2955363.

6. Mishra, S. K., Wheeler, J. J., Pitake, S., Ding, H., Jiang, C., Fukuyama, T., . . . Olivry, T. (2020). Periostin activation of integrin receptors on sensory neurons induces allergic itch.

Cell Reports, 31(1), 107472. doi:10.1016/j.celrep.2020.03.036.

6. Kuo, P., Gardner, C. O., Kendler, K. S., & Prescott, C. A. (2006). The temporal relationship of the onsets of alcohol dependence and major depression: Using a genetically informative study design. Psychological Medicine, 36(8), 1153-1162. doi:10.1017/s0033291706007860.

7. National Health Service. Hydrocortisone skin creams.

(2017). Retrieved November 05, 2020, from https://www. nhs.uk/medicines/hydrocortisone-skin-cream/

7. Lewis, M. (2017). Addiction and the brain: Development, not disease. Neuroethics, 10(1), 7-18. doi:10.1007/s12152-0169293-4.

8. Sakai, K., Sanders, K. M., Lin, S., Pavlenko, D., Funahashi, H., Lozada, T., Chen, C. C., & Akiyama, T. (2020). Low-threshold mechanosensitive VGLUT3lineage sensory neurons mediate spinal inhibition of itch by touch. The Journal of Neuroscience. doi:10.1523/ JNEUROSCI.0091-20.2020.

8. Mcewen, B. S. (2012). The ever-changing brain: Cellular and molecular mechanisms for the effects of stressful experiences. Developmental Neurobiology, 72(6), 878-890. doi:10.1002/dneu.20968.

9. Twycross, R. (2003). Itch: Scratching more than the surface. Qjm, 96(1), 7-26. doi:10.1093/qjmed/hcg002.

9. McEwen, B. S., Nasca, C., & Gray, J. D. (2016). Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology, 41(1), 3-23. doi:10.1038/npp.2015.171.

10. Yu, Y., Barry, D. M., Hao, Y., Liu, X., & Chen, Z. (2017).

Molecular and neural basis of contagious itch behavior in mice. Science,355(6329), 1072-1076. doi:10.1126/science. aak9748.

10. Sapolsky, R. M. (1993). Potential behavioral modification of glucocorticoid damage to the hippocampus. Behavioural Brain Research, 57(2), 175-182. doi:10.1016/01664328(93)90133-b.

11. Szalavitz, M. (2017). Unbroken brain: A revolutionary new way of understanding addiction. New York: Picador St. Martin’s Press.

12. Volkow, N. D., & Li, T. (2004). Drug addiction: The neurobiology of behaviour gone awry. Nature Reviews Neuroscience,5(12), 963-970. doi:10.1038/nrn1539.

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

47

References 13. Volkow, N. D., Michaelides, M., & Baler, R. (2020). The neuroscience of drug reward and addiction. Physiological Reviews, 99(4), 2115-2140. doi:10.1152/physrev.00014.2018.

14. Volkow, Nora D., George F. Koob, and A. Thomas McLellan. (2016). Neurobiologic advances from the brain disease model of addiction. New England Journal of Medicine, 374, 363–371. doi:10.1056/NEJMra1511480.

15. Wahlstrom, D., White, T., & Luciana, M. (2010).

Neurobehavioral evidence for changes in dopamine system activity during adolescence. Neuroscience & Behavioral Reviews, 34(5), 631-648. doi:10.1016/j.2009.12.007.

16. Weiss, F., Lorang, M., Koob, G., & Bloom, F. (1993). Oral alcohol self-administration stimulates dopamine release in rat nucleus accumbens: Genetic and motivational determinants. The Journal of Pharmacology and Experimental Therapeutics, 267(1), 250-258. PMID: 8229752

6. Colombo, M., D’Amato, M. R., Rodman, H. R., Gross, C. G. (1990). Auditory association cortex lesions impair auditory short-term memory in monkeys. Science, 247(4940), 336338. doi:10.1126/science.2296723.

7. Cancer, A., Manzoli, S., & Antonietti, A. (2016). The alleged link between creativity and dyslexia: Identifying the specific process in which dyslexic students excel. Cogent Psychology, 3(1), 14-19. doi:10.1080/23311908.2016.1190309.

8. Schneps, M. H. (2014). The Advantages of Dyslexia.

Scientific American.

9. Evans, T. M., Flowers, D. L., Napoliello, E. M., Olulade O. A., Eden G. F. (2014). Neuroimage, 101(4), 644-652. doi:10.1016/j.neuroimage.2014.07.028.

10. Chinn, S. (2010). Maths and Dyslexia: A View from the UK. Learning Works.

17. Wolke, D., Copeland, W. E., Angold, A., & Costello, E. J. (2013). Impact of bullying in childhood on adult health, wealth, crime, and social outcomes. Psychological Science, 24(10), 1958-1970. doi:10.1177/0956797613481608.

11. Rehman, A., & Al Khalili, Y. (2020). Neuroanatomy, occipital lobe.StatPearls Publishing, 2020 Jan. PMID: 31335040

18. Xu, L., Nan, J., & Lan, Y. (2020). The nucleus accumbens: A common target in the comorbidity of depression and addiction. Frontiers in Neural Circuits,14(37). doi:10.3389/ fncir.2020.00037.

The Gut-Brain Axis: Can Your Belly Heal Your Brain?

Beyond Jumbled Letters: How Dyslexia Affects Learning Mathematics 1. Berger, Y. A. (2002). Magnetic resonance imaging. British Medical Journal, 324(7328), 35. doi:10.1136%2Fbmj.324.7328.35.

2. Norton, E. S., Beach, S. D., & Gabrieli, J. D. (2015).

Neurobiology of dyslexia. Current opinion in neurobiology, 30(1), 73–78. doi:10.1016/j.conb.2014.09.007.

3. Schulz, E., Maurer, U., van der Mark, S., Bucher, K., Brem, S., Martin, E., & Brandeis, D. (2008). Impaired semantic processing during sentence reading in children with dyslexia: Combined fMRI and ERP evidence. NeuroImage, 41(1), 153-168. doi:10.1016/j.neuroimage.2008.02.012.

1. Carabotti, M., Scirocco, A., Maselli, M. A., & Severi, C. (2015). The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Annals of gastroenterology, 28(2), 203–209.

2. Kulkarni, S., Ganz, J., Bayrer, J., Becker, L., Bogunovic, M., & Rao, M. (2018). Advances in enteric neurobiology: The “brain” in the gut in health and disease. Journal of Neuroscience, 38(44), 9346-9354. doi:10.1523/ JNEUROSCI.1663-18.2018.

3. Appleton J. (2018). The gut-brain axis: Influence of microbiota on mood and mental health. Integrative medicine (Encinitas, Calif.), 17(4), 28–32. PMID: 31043907 4. Smith SM, Vale WW. The role of the hypothalamicpituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8(4):383-395. doi:10.31887/DCNS.2006.8.4/ssmith.

4. Waldie, K. E., Haigh, C. E., Badzakova-Trajkov, G., Buckley, J., & Kirk, I. J. (2013). Reading the wrong way with the right hemisphere. Brain Sciences, 3(3), 1060–1075. doi:10.3390/ brainsci3031060.

5. Foster, J. A., & Neufeld, K. M. (2013). Gut–brain axis: How the microbiome influences anxiety and depression.

Trends in Neurosciences, 36(5), 305-312. doi:10.1016/j. tins.2013.01.005.

5. Kay, J., & Yeo, D. (2003). Dyslexia and Maths. David Fulton Publishers.

6. Barden N. (2004). Implication of the hypothalamicpituitary-adrenal axis in the physiopathology of depression.

Journal of psychiatry & neuroscience : JPN, 29(3), 185–193.

PMID: 15173895

48

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

References Header 7. Macfabe, D., Cain, D., Rodriguezcapote, K., Franklin, A., Hoffman, J., Boon, F., . . . Ossenkopp, K. (2007).

Neurobiological effects of intraventricular propionic acid in rats: Possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioural Brain Research, 176(1), 149-169. doi:10.1016/j.bbr.2006.07.025.

8. White, J. F. (2003). Intestinal pathophysiology in autism.

Experimental Biology and Medicine, 228(6), 639–649. doi:10.1177/153537020322800601.

9. Schirmer, M., Smeekens, S. P., Vlamakis, H., Jaeger, M., Oosting, M., Franzosa, E. A., . . . Xavier, R. J. (2016). Linking the human gut microbiome to inflammatory cytokine production capacity. Cell, 167(4), 1125–1136.e8. doi:10.1016/j. cell.2016.10.020.

10. Evrensel, A., & Ceylan, M. E. (2015). The gutbrain Axis: The missing link in depression. Clinical Psychopharmacology and Neuroscience: The Official Scientific Journal of the Korean College of Neuropsychopharmacology, 13(3), 239–244. doi:10.9758/ cpn.2015.13.3.239.

11. Jia, H., Li, Q., Zhou, C., Yu, M., Yang, Y., Zhang, H., . . . Zou, Z. (2016). Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression. Scientific Reports, 6(1). doi:10.1038/srep23441.

12. Carpenter, S. (2012). That gut feeling. Monitor on Psychology, 43(8). http://www.apa.org/monitor/2012/09/gutfeeling 13. Kennedy, P. J., Cryan, J. F., Dinan, T. G., & Clarke, G. (2014). Irritable bowel syndrome: a microbiome-gut-brain axis disorder?. World Journal of Gastroenterology, 20(39), 14105–14125. doi:10.3748/wjg.v20.i39.14105.

14. Jones, M., Koloski, N., Boyce, P., & Talley, N. J. (2011).

Pathways connecting cognitive behavioral therapy and change in bowel symptoms of IBS. Journal of Psychosomatic Research, 70(3), 278-285. doi:10.1016/j. jpsychores.2010.10.004.

15. Crumeyrolle-Arias, M., Jaglin, M., Bruneau, A., Vancassel, S., Cardona, A., Daugé, V., Naudon, L., & Rabot, S. (2014).

Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats. Psychoneuroendocrinology, 42, 207–217. doi:10.1016/j. psyneuen.2014.01.014.

16. Hu, S., Li, A., Huang, T., Lai, J., Li, J., Sublette, E., … Xu, Y. (2018). Dynamic change of gut microbiota characteristics following quetiapine treatment in patients with bipolar depression. Advanced Science 6(14):1900752. doi: 10.1002/ advs.201900752.

17. Sharon, G., & Cruz, N. J. (2019). Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. ScienceDirect, 177(6), 1600-1618. doi:10.1016/j.cell.2019.05.004.

18. Sandhu, K. V., Sherwin, E., Schellekens, H., Stanton, C., Dinan, T. G., & Cryan, J. F. (2017). Feeding the microbiotagut-brain axis: Diet, microbiome, and neuropsychiatry.

Translational Research, 179, 223-244. doi:10.1016/j. trsl.2016.10.002.

19. Luna, R. A., & Foster, J. A. (2015). Gut brain axis: diet microbiota interactions and implications for modulation of anxiety and depression. Current Opinion in Biotechnology, 32, 35–41. doi:10.1016/j.copbio.2014.10.007.

20. Marco, M. L., Heeney, D., Binda, S., Cifelli, C. J., Cotter, P. D., Foligné, B., Gänzle, M., Kort, R., Pasin, G., Pihlanto, A., Smid, E. J., & Hutkins, R. (2017). Health benefits of fermented foods: microbiota and beyond. Current Opinion in Biotechnology, 44, 94–102. doi:10.1016/j. copbio.2016.11.010.

21. Slavin J. (2013). Fiber and prebiotics: mechanisms and health benefits. Nutrients, 5(4), 1417–1435. doi:10.3390/ nu5041417.

Cannabis Use Disorder: The Grim Reality of Cannabis Addiction 1. Balodis, I. & MacKillop, J. (2018). Cannabis use disorder.

In W. Costain & R. Laprairie (Eds.), Recent advances in cannabinoid research (pp. 137–153). Croatia: IntechOpen. doi:10.5772/intechopen.80344.

2. Hasin, D. (2018). US epidemiology of cannabis use and associated problems. Neuropsychopharmacology, 43(1), 195–212. doi:10.1038/npp.2017.198.

3. Ferland, J.-M., & Hurd, Y. (2020). Deconstructing the neurobiology of cannabis use disorder. Nature Neuroscience, 23(5), 600–610. doi:10.1038/s41593-0200611-0.

4. Gruber, S., Silveri, M., Dahlgren, M.K., & Yurgelun-Todd, D. (2011). Why so impulsive? White matter alterations are associated with impulsivity in chronic marijuana smokers.

Experimental and Clinical Psychopharmacology, 19(3), 231–242. doi:10.1037/a0023034.

5. De Petrocellis, L., Ligresti, A., Moriello, A.S., Allarà, M., Bisogno, T., Petrosino, S., … Di Marzo, V. (2011). Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes.

British Journal of Pharmacology, 163(7), 1479–1494. doi:10.1111/j.1476-5381.2010.01166.x.

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

49

References 6. Pacher, P., Bátkai, S., & Kunos, G. (2006). The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews, 58(3), 389– 462. doi:10.1124/pr.58.3.2.

7. Zou, S. & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. International Journal of Molecular Sciences, 19(3). doi:10.3390/ijms19030833.

8. D’Souza, M. (2015). Glutamatergic transmission in drug reward: Implications for drug addiction. Frontiers in Neuroscience, 9. doi:10.3389/fnins.2015.00404.

9. Zehra, A., Burns, J., Liu, C.K., Manza, P., Wiers, C.E., Volkow, N.D., & Wang, G.-J. (2018). Cannabis addiction and the brain: a review. Journal of Neuroimmune Pharmacology, 13(4), 438–452. doi:10.1007/s11481-018-9782-9.

10. Orr, C., Spechler, P., Cao, Z., Albaugh, M., Chaarani, B., Mackey, S., … Garavan, H. (2019). Grey matter volume differences associated with extremely low levels of cannabis use in adolescence. The Journal of Neuroscience, 39(10), 1817–1827. doi:10.1523/jneurosci.3375-17.2018.

11. Kloft, L., Otgaar, H., Blokland, A., Minds, L.A., Toennes, S.W., Loftus, E., & Ramaekers, J.G. (2020). Cannabis increases susceptibility to false memory. Proceedings of the National Academy of Sciences, 117(9), 4585–4589. doi:10.1073/pnas.1920162117.

12. Freels, T., Baxter-Potter, L.N., Lugo, J.M., Glodosky, N.C., Wright, H.R., Baglot, S.L., … McLaughlin, R.J. (2020).

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats.

The Journal of Neuroscience, 40(9), 1897–1908. doi:10.1523/ jneurosci.2416-19.2020.

13. Renard, J., Rushlow, W., & Laviolette, S. (2018).

Effects of adolescent THC exposure on the prefrontal GABAergic system: implications for schizophrenia-related psychopathology. Frontiers in Psychiatry, 9. doi:10.3389/ fpsyt.2018.00281.

14. Koenders, L., Cousijn, J., Vingerhoets, W.A.M., van den Brink, W., Wiers, R.W., Meijer, C.J., … de Haan, L. (2016).

Grey matter changes associated with heavy cannabis use: a longitudinal sMRI study. PLoS One, 11(5). doi:10.1371/journal. pone.0152482.

15. Leung, J., Hall, W., & Degenhardt, L. (2020). Adolescent cannabis use disorders. In C. Essau & P. Delfabbro (Eds.), Practical Resources for the Mental Health Professional, Adolescent Addiction (pp. 111–135). London, UK: Academic Press. doi:10.1016/B978-0-12-818626-8.00004-9.

16. Konopka, L. (2014). Marijuana use: neuroscience perspective. Croatian Medical Journal, 55(3), 281–283. doi:10.3325/cmj.2014.55.281.

50

17. Boileau, I., Mansouri, E., Williams, B., Le Foll, B., Rusjan, P., Mizrahi, R., Tyndale, R., … Tong, J. (2016).

Fatty acid amide hydrolase binding in brain of cannabis users: imaging with the novel radiotracer [11C]CURB. Biological Psychiatry, 80(9), 691–701. doi:10.1016/j. biopsych.2016.04.012.

18. Hurd, Y., Manzoni, O.J., Mikhail, M.V., Lee, F.S., Bhattacharyya, S., & Melis, M. (2019). Cannabis and the developing brain: insights into its long-lasting effects. The Journal of Neuroscience, 39(42), 8250–8258. doi:10.1523/ jneurosci.1165-19.2019.

19. Wu, L.-T., Zhu, H., & Swartz, M. (2016). Trends in cannabis use disorders among racial/ethnic population groups in the United States. Drug and Alcohol Dependence, 165, 181–190. doi:10.1016/j.drugalcdep.2016.06.002.

20. Stanley, L., Swaim, R., & Dieterich, S. (2017). The role of norms in marijuana use among American Indian adolescents. Prevention Science, 18(4), 406–415. doi:10.1007/s11121-017-0768-2.

21. Keyes, K., Wall, M., Feng, T., Cerda, M., & Hasin, D. (2017).

Race/ethnicity and marijuana use in the United States: Diminishing differences in the prevalence of use, 2006 to 2015. Drug and Alcohol Dependence, 179, 379–386. doi:10.1016/j.drugalcdep.2017.07.027.

22. Copersino, M., Boyd, S.J., Tashkin, D.P., Huestis, M.A., Heishman, S.J., Dermand, J.C., … Gorelick, D.A. (2010).

Sociodemographic characteristics of cannabis smokers and the experience of cannabis withdrawal. The American Journal of Drug and Alcohol Abuse, 36(6), 311–319. doi:10.31 09/00952990.2010.503825.

23. Hemsing, N. & Greaves, L. (2020). Gender norms, roles and relations and cannabis-use patterns: a scoping review.

International Journal of Environmental Research and Public Health, 17(3). doi:10.3390/ijerph17030947.

24. Scandurra, C., Mezza, F., Maldonato, N.M., Bottone, M., Bochicchio, V., Valerio, P., & Vitelli, R. (2019). Health of non-binary and genderqueer people: a systematic review.

Frontiers in Psychology, 10. doi:10.3389/fpsyg.2019.01453.

25. Becker, J., McClellan, M., & Glover Reed, B. (2017). Sex differences, gender, and addiction. Journal of Neuroscience Research, 95(1-2), 136–147. doi:10.1002/jnr.23963.

26. Fattore, L. & Fratta, W. (2010). How important are sex differences in cannabinoid action? British Journal of Pharmacology, 160(3), 544–548. doi:10.1111/j.14765381.2010.00776.x.

27. Matheson, J., Sproule, B., Di Ciano, P., Fares, A., Le Foll, B., Mann, R.E., & Brands, B. (2020). Sex differences in the acute effects of smoked cannabis: evidence from a human laboratory study of young adults. Psychopharmacology, 237(2), 305–316. doi:10.1007/s00213-019-05369-y.

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

References 28. Trocki, K., Drabble, L., & Midanik, L. (2009). Tobacco, marijuana use and sensation-seeking: across gay, lesbian, bisexual and heterosexual groups. Psychology of Addictive Behaviors, 23(4), 620–631. doi:10.1037/a0017334.

6. World Health Organization. (2019, October 4).

Schizophrenia: Key Facts. Retrieved Oct 5, 2020, from https://www.who.int/news-room/fact-sheets/detail/ schizophrenia

29. Abé, C., Johansson, E., Allzén, E., & Savic, I. (2014).

Sexual orientation related differences in cortical thickness in male individuals. PLoS One, 9(12). doi:10.1371/journal. pone.0114721.

7. Knapp, M., Mangalore, R., and Simon, J. (2004). The global costs of schizophrenia. Schizophr Bull, 30(2), 27993. doi:10.1093/oxfordjournals.schbul.a007078.

30. Schilling, C., Kühn, S., Romanowski, A., Schubert, F., Kathmann, N., & Gallinat, J. (2012). Cortical thickness correlates with impulsiveness in healthy adults. NeuroImage, 59(1), 824–830. doi:10.1016/j. neuroimage.2011.07.058.

31. Sinha, R. (2013). New findings on biological factors predicting addiction relapse vulnerability. Current Psychiatry Reports, 13(5), 398–405. doi:10.1007/s11920-0110224-0.

32. Walentiny, D.M., Gamage, T.F., Warner, J.A., Nguyen, T.K., Grainger, B.D., Wiley, J.L., & Vann, R.E. (2011). The endogenous cannabinoid anandamide shares discriminative stimulus effects with Δ9-tetrahydrocannabinol in fatty acid amide hydrolase knockout mice. European Journal of Pharmacology, 656(1-3), 63–67. doi:10.1016/j. ejphar.2011.01.056.

The Changing Voices in Our Heads: Society’s Impact on Psychosis 1. Luhrmann, T. M., Padmavati, R., Tharoor, H., & Osei, A. (2015). Differences in voice-hearing experiences of people with psychosis in the USA, India and Ghana: interviewbased study. The British Journal of Psychiatry, 206(1), 4144. doi:10.1192/bjp.bp.113.139048.

2. Carey, B. (2011, August). Learning to cope with a mind’s taunting voices. The New York Times. Retrieved from https://www.nytimes.com/2011/08/07/health/07lives. html?pagewanted=all&_r=0 3. Parker, C. (2014, July). Hallucinatory ‘voices’ shaped by local culture, Stanford anthropologist says. Stanford News.

Retrieved from https://news.stanford.edu/2014/07/16/ voices-culture-luhrmann-071614/ 4. National Institute of Mental Health (2018). Schizophrenia.

Retrieved Oct 5, 2020, from https://www.nimh.nih.gov/ health/statistics/schizophrenia.shtml 5. National Health Service UK (2019). Symptoms of Schizophrenia. Retrieved Oct 30, 2020, from https://www. nhs.uk/conditions/schizophrenia/symptoms/

8. Ascher-Svanum, H., Nyhuis, A.W., Faries, D.E., Ball, D.E., and Kinon, B.J. Involvement in the US criminal justice system and cost implications for persons treated for schizophrenia. BMC Psychiatry, 10(11), doi:10.1186/1471244X-10-11.

9. Murphy, J. M. (1976). Psychiatric labeling in cross-cultural perspective. Science, 191(4231), 1019-1028. doi:10.1126/ science.1251213.

10. Suhail, K., & Cochrane, R. (2002). Effect of culture and environment on the phenomenology of delusions and hallucinations. International Journal of Social Psychiatry, 48(2), 126-138. doi:10.1177/002076402128783181.

11. Okulate, G. T., & Jones, O. B. E. (2003). Auditory hallucinations in schizophrenic and affective disorder Nigerian patients: phenomenological comparison. Transcultural psychiatry, 40(4), 531-541. doi:10.1177/1363461503404004.

Cutting Out a Cure for Huntington’s Disease 1. Myers R. H. (2004). Huntington’s disease genetics.

NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics, 1(2), 255–262. doi:10.1602/ neurorx.1.2.255.

2. Wyant, K. J., Ridder, A. J., & Dayalu, P. (2017).

Huntington’s disease-update on treatments. Current Neurology and Neuroscience reports, 17(4), 33. doi:10.1007/ s11910-017-0739-9.

3. Reiner, A., Dragatsis, I., & Dietrich, P. (2011). Genetics and neuropathology of Huntington’s disease. International Review of Neurobiology, 98, 325–372. doi:10.1016/B978-012-381328-2.00014-6 4. Schulte, J., & Littleton, J. T. (2011). The biological function of the Huntingtin protein and its relevance to Huntington’s Disease pathology. Current Trends in Neurology, 5, 65–78.

5. Lanciego, J. L., Luquin, N., & Obeso, J. A. (2012).

Functional neuroanatomy of the basal ganglia. Cold Spring Harbor Perspectives in Medicine, 2(12), a009621. doi:10.1101/ cshperspect.a009621

6. Raymond, L. A., André, V. M., Cepeda, C., Gladding, C. M.,

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

51

References Milnerwood, A. J., & Levine, M. S. (2011). Pathophysiology of Huntington’s disease: Time-dependent alterations in synaptic and receptor function. Neuroscience, 198, 252– 273. doi:10.1016/j.neuroscience.2011.08.052.

7. Huntington Study Group. (2016). Effect of Deutetrabenazine on chorea among patients with Huntington Disease: A randomized clinical trial. JAMA, 316(30), 40-50. doi:10.1001/jama.2016.8655.

8. Heemskerk, A. W. & Roos, R. A. (2011). Dysphagia in Huntington’s Disease: A review. Dysphagia, 26(1), 62-66. doi:10.1007/s00455-010-9302-4.

9. Kagel, M. C., & Leopold, N. A. (1992). Dysphagia in Huntington’s disease: a 16-year retrospective. Dysphagia, 7(2), 106–114. doi:10.1007/BF02493441.

10. Hamilton, A., Heemskirk, A. W., Loucas, M., TwistonDavies, R., Matheson, K. Y., Simpson, S. A., & Rae, D. (2012).

Oral feeding in Huntington’s disease: A guideline document for speech and language therapists. Neurodegenerative Disease Management, 2(1). 45-53. doi:10.2217/nmt.11.77.

11. Paulsen, J.S., Ready, R.E., Hamilton, J.M., Mega, M.S., & Cummings, J.L. (2001) Neuropsychiatric aspects of Huntington’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 71(3), 310-314. doi:10.1136/jnnp.71.3.310.

19. Ekman, F. K., Ojala, D. S., Adil, M. M., Lopez, P. A., Schaffer, D. V., & Gaj, T. (2019). CRISPR-Cas9-mediated genome editing increases lifespan and improves motor deficits in a Huntington’s Disease mouse model.

Molecular Therapy Nucleic Acids, 17, 829-839. doi:10.1016/j. omtn.2019.07.009.

Letting the Storm Pass: The Psychology and Neuroscience of Mindfulness 1. Hill, C.L.M., & Updegraff, J.A. (2012). Mindfulness and its relationship to emotional regulation. Emotion, 12(1), 81–90. https://psycnet.apa.org/doi/10.1037/a0026355 2. Singla, R. (2011). Origins of mindfulness & meditation interplay of Eastern & Western psychology. Psyke & Logos, 32(1), 220–239. https://tidsskrift.dk/psyke/article/view/8802 3. McMahan, D. L. (2009). The Making of Buddhist Modernism. New York, NY: Oxford University Press.

4. Kabat-Zinn, J. (2003), Mindfulness-based interventions in context: past, present, and future. Clinical Psychology: Science and Practice, 10: 144-156. https://doi.org/10.1093/ clipsy.bpg016

12. Epping E.A., & Paulsen J.S (2011). Depression in the early stages of Huntington disease. Neurodegener Dis Manag, 1(5), 407-414. doi:10.2217/nmt.11.45.

5. Fischer, D., Messner, M., & Pollatos, O. (2017).

Improvement of interoceptive processes after an 8-week body scan intervention. Frontiers in Human Neuroscience, 11. doi:10.3389/fnhum.2017.00452

13. Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., … Horvath, P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes.

Science, 315(5819), 1709-1712. doi:10.1126/science.1138140.

6. Baer, R.A. (2003), Mindfulness training as a clinical intervention: A conceptual and empirical review. Clinical Psychology: Science and Practice, 10: 125-143. https://doi. org/10.1093/clipsy.bpg015

14. Wiedenheft, B., Sternberg, S. H., & Doudna, J. A. (2012). RNA-guided genetic silencing systems in bacteria and archaea. Nature, 482(7385), 331-338. doi:10.1038/ nature10886.

7. Linehan, M. (1993). Cognitive-Behavioral Treatment of Borderline Personality Disorder. New York: The Guilford Press.

15. Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., ... & Zhang, F. (2013). Multiplex genome engineering using CRISPR/Cas systems. Science, 339(6121), 819-823. doi:10.1126/science.1231143.

16. Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A programmable dual-RNA– guided DNA endonuclease in adaptive bacterial immunity.

Science, 337(6096),816-821. doi:10.1126/science.1225829.

17. Ojala, D. S., Amara, D. P., & Schaffer, D. V. (2015). Adenoassociated virus vectors and neurological gene therapy. The Neuroscientist, 21(1), 84-98. doi:10.1177/1073858414521870.

8. Kells, M., Joyce, M., Flynn, D., Spillane, A., & Hayes, A. (2020). Dialectical behaviour therapy skills reconsidered: applying skills training to emotionally dysregulated individuals who do not engage in suicidal and self-harming behaviours. Borderline Personality Disorder and Emotion Dysregulation, 7, 3. https://doi.org/10.1186/s40479-0200119-y 9. An, H., He, R., Zheng, Y., & Tao, R. (2017). Cognitivebehavioral therapy. Advances in Experimental Medicine and Biology Substance and Non-substance Addiction, 321-329. doi:10.1007/978-981-10-5562-1_16

18. Hentze, M. W., & Kulozik, A. E. (1999). A perfect message: RNA surveillance and nonsense-mediated decay.

Cell, 96(3), 307-310. doi:10.1016/s0092-8674(00)80542-5.

52

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

References 10. Kuyken, W., Hayes, R., Barrett, B., Byng, R., Dalgleish, T., Kessler, D., … Byford, S. (2015). Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): A randomised controlled trial. The Lancet, 386(9988), 63–73. https://doi.org/10.1016/S01406736(14)62222-4 11. Felder, J.N., Dimidjian, S., & Segal, Z. (2012).

Collaboration in mindfulness-based cognitive therapy. J. Clin. Psychol., 68: 179-186. https://doi.org/10.1002/jclp.21832 12. Bear, M. F., Connors, B. W., & Paradiso, M. (2006).

Neuroscience: Exploring the brain. Baltimore, MD: Lippincott Williams & Wilkins.

13. Garland, E. L. (2012). Pain processing in the human nervous system: a selective review of nociceptive and biobehavioral pathways. Primary care, 39(3), 561–571. https://doi.org/10.1016/j.pop.2012.06.013 14. Raffaeli, W., & Arnaudo, E. (2017). Pain as a disease: an overview. Journal of Pain Research, 10, 2003–2008. https:// doi.org/10.2147/JPR.S138864 15. Veehof, M. M., Trompetter, H. R., Bohlmeijer, E. T., & Schreurs, K. M. G. (2016). Acceptance- and mindfulnessbased interventions for the treatment of chronic pain: A meta-analytic review. Cognitive Behaviour Therapy, 45(1), 5–31. https://doi.org/10.1080/16506073.2015.1098724 16. Bekanich, S. J., Wanner, N., Junkins, S., Mahoney, K., Kahn, K. A., Berry, C. A., ... Gardner, A. J. (2014). A multifaceted initiative to improve clinician awareness of pain management disparities. American Journal of Medical Quality, 29(5), 388–396. https://doi. org/10.1177/1062860613503897 17. Zeidan, F., Emerson, N. M., Farris, S. R., Ray, J. N., Jung, Y., McHaffie, J. G., & Coghill, R. C. (2015).

Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia. Journal of Neuroscience, 35(46), 15307–15325. https://doi.org/10.1523/ JNEUROSCI.2542-15.2015 18. Zeidan, F., & Vago, D. R. (2016). Mindfulness meditationbased pain relief: a mechanistic account. Annals of the New York Academy of Sciences, 1373(1), 114–127. https://doi. org/10.1111/nyas.13153 19. Gard, T., Holzel, B. K., Sack, A. T., Hempel, H., Lazar, S. W., Vaitl, D., & Ott, U. (2012). Pain attenuation through mindfulness is associated with decreased cognitive control and increased sensory processing in the brain. Cerebral Cortex, 22(11), 2692–2702. https://doi.org/10.1093/cercor/ bhr352

20. Hölzel, B. K., Carmody, J., Vangel, M., Congleton, C., Yerramsetti, S. M., Gard, T., & Lazar, S. W. (2011).

Mindfulness practice leads to increases in regional brain gray matter density. Psychiatry Research: Neuroimaging, 191(1), 36–43. https://doi.org/10.1016/j. pscychresns.2010.08.006 21. Morone, N. E., Greco, C. M., & Weiner, D. K. (2008).

Mindfulness meditation for the treatment of chronic low back pain in older adults: a randomized controlled pilot study. Pain, 134(3), 310–319. https://doi.org/10.1016/j. pain.2007.04.038 22. Lutz, A., McFarlin, D. R., Perlman, D. M., Salomons, T. V., & Davidson, R. J. (2013). Altered anterior insula activation during anticipation and experience of painful stimuli in expert meditators. NeuroImage, 64, 538–546. https://doi. org/10.1016/j.neuroimage.2012.09.030 23. Zimmer, C. (2011). 100 trillion connections: new efforts probe and map the brain’s detailed architecture. Retrieved December 25, 2020, from https://www.scientificamerican. com/article/100-trillion-connections/ 24. Abraham, W. C., Jones, O. D., & Glanzman, D. L. (2019).

Is plasticity of synapses the mechanism of long-term memory storage?. NPJ science of learning, 4, 9. https://doi. org/10.1038/s41539-019-0048-y 25. Shatz C. J. (2009). MHC class I: an unexpected role in neuronal plasticity. Neuron, 64(1), 40–45. https://doi. org/10.1016/j.neuron.2009.09.044 26. Lazar, S. W., Kerr, C. E., Wasserman, R. H., Gray, J. R., Greve, D. N., Treadway, M. T., ... Fischl, B. (2005). Meditation experience is associated with increased cortical thickness: NeuroReport, 16(17), 1893–1897. https://doi.org/10.1097/01. wnr.0000186598.66243.19 27. Fjell, A. M., Grydeland, H., Krogsrud, S. K., Amlien, I., Rohani, D. A., Ferschmann, L., … Walhovd, K. B. (2015).

Development and aging of cortical thickness correspond to genetic organization patterns. Proceedings of the National Academy of Sciences, 112(50), 15462–15467. https://doi. org/10.1073/pnas.1508831112 28. Hurtz, S., Woo, E., Kebets, V., Green, A. E., Zoumalan, C., Wang, B., … Apostolova, L. G. (2014). Age effects on cortical thickness in cognitively normal elderly individuals.

Dementia and Geriatric Cognitive Disorders Extra, 4(2), 221–227. https://doi.org/10.1159/000362872 29. Hölzel, B. K., et al. (2010). Stress reduction correlates with structural changes in the amygdala. Social cognitive and affective neuroscience, 5(1), 11–17. https://doi. org/10.1093/scan/nsp034

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

53

References 30. Hölzel, B. K., Carmody, J., Evans, K. C., Hoge, E. A., Dusek, J. A., Morgan, L., … Lazar, S. W. (2010). Stress reduction correlates with structural changes in the amygdala. Social Cognitive and Affective Neuroscience, 5(1), 11–17. https://doi.org/10.1093/scan/nsp034 31. Guendelman, S., Medeiros, S., & Rampes, H. (2017).

Mindfulness and emotion regulation: insights from neurobiological, psychological, and clinical studies.

Frontiers in Psychology, 8, 220. https://doi.org/10.3389/ fpsyg.2017.00220 32. Lutz, A., Jha, A. P., Dunne, J. D., & Saron, C. D. (2015).

Investigating the phenomenological matrix of mindfulnessrelated practices from a neurocognitive perspective.

The American Psychologist, 70(7), 632–658. https://doi. org/10.1037/a0039585 33. Burklund, L. J., Creswell, J. D., Irwin, M. R., & Lieberman, M. D. (2014). The common and distinct neural bases of affect labeling and reappraisal in healthy adults.

Frontiers in Psychology, 5, 221. https://doi.org/10.3389/ fpsyg.2014.00221 34. Quirk, G. J. & Beer, J.S. (2006). Prefrontal involvement in the regulation of emotion: convergence of rat and human studies. Current Opinion in Neurobiology, 16(6), 723-727, https://doi.org/10.1016/j.conb.2006.07.004 35. Way, B. M., Creswell, J. D., Eisenberger, N. I., & Lieberman, M. D. (2010). Dispositional mindfulness and depressive symptomatology: correlations with limbic and self-referential neural activity during rest. Emotion (Washington, D.C.), 10(1), 12–24. https://doi.org/10.1037/ a0018312 36. Goyal, M., Singh, S., Sibinga, E. M. S., Gould, N. F., Rowland-Seymour, A., Sharma, R., … Haythornthwaite, J. A. (2014). Meditation programs for psychological stress and well-being: A systematic review and meta-analysis.

JAMA Internal Medicine, 174(3), 357. https://doi.org/10.1001/ jamainternmed.2013.13018 37. Van Dam, N. T., van Vugt, M. K., Vago, D. R., Schmalzl, L., Saron, C. D., Olendzki, A., … Meyer, D. E. (2018). Mind the hype: a critical evaluation and prescriptive agenda for research on mindfulness and meditation. Perspectives on Psychological Science, 13(1), 36–61. https://doi. org/10.1177/1745691617709589

Battling COVID-19’s Mystifying Mental Fog 1. Alam, S., Willows, S., Kulka, M., & Sandhu, J. (2020).

Severe acute respiratory syndrome coronavirus 2 may be an underappreciated pathogen of the central nervous system. European Journal of Neurology, 27(11), 1–13. doi:10.1111/ene.14442.

54

2. Belluck, P. (2020, October 14). ‘I feel like I have dementia’: brain fog plagues COVID survivors. Retrieved October 18, 2020, from www.nytimes.com/2020/10/11/ health/ covid-survivors.html.

3. Reddy, S. (2020, September 28). Four different family members. Four different COVID-19 outcomes. Retrieved October 13, 2020, from www.wsj.com/articles/fourdifferent-family-members-four-different-covid-19outcomes-11601299859.

4. Tchessalova, D. & Tronson, N. (2019). Memory deficits in males and females long after subchronic immune challenge. Neurobiology of Learning and Memory, 158, 60–72. doi:10.1016/j.nlm.2019.01.003.

5. Isacson, O. (2020). The consequences of coronavirusinduced cytokine storm are associated with neurological diseases, which may be preventable. Frontiers in Neuroscience, 11, 1–2. doi:10.3389/fneur.2020.00745.

6. Heneka, M., Golenbock, D., Latz, E., Morgan, D., & Brown, R. (2020). Immediate and long-term consequences of COVID-19 infections for the development of neurological. disease. Alzheimer’s Research & Therapy, 12(1). doi:10.1186/ s13195-020-00640-3.

7. Diaz, A. & Baweja, R. (2020). The role of neurotropism in psychiatric patients with COVID‐19. European Archives of Psychiatry and Clinical Neuroscience. doi:10.1007/s00406020-01197-w.

8. Rogers, J., Chesney, E., Oliver, D., Pollak, T.A., McGuire, P., Fusar-Poli, P., … David, A.S. (2020). Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and metaanalysis with comparison to the COVID-19 pandemic.

Lancet Psychiatry, 7(7), 611–627. doi:10.1016/s22150366(20)30203-0.

9. Song, E., Zhang, C., Israelow, B., Lu, P., Weizman, O., Liu, F., … Iwasaki, A. (2020). Neuroinvasion of SARSCoV-2 in human and mouse brain. bioRxiv. doi:10.1101/ 2020.06.25.169946.

10. Chu, H., Chan, J.F., Yuen, T.T., Shuai, H., Yuan, S., Wang, Y., … Yuen, K. (2020). Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study. Lancet Microbe, 1(1). doi:10.1016/s26665247(20)30004-5.

11. Beghi, E., Feigin, V., Caso, V., Santalucia, P., & Logroscino, G. (2020). COVID-19 infection and neurological complications: present findings and future predictions.

Neuroepidemiology, 54(5), 364–369. doi:10.1159/000508991.

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 1

References 12. Debnath, M., Berk, M., & Maes, M. (2020). Changing dynamics of psychoneuroimmunology during the COVID-19 pandemic. Brain, Behavior, and Immunity - Health, 5, 1–3. doi:10.1016/j.bbih.2020.100096.

13. Scoppettuolo, P., Borrelli, S., & Naeije, G. (2020).

Neurological involvement in SARS-CoV-2 infection: A clinical systematic review. Brain, Behavior, and Immunity Health, 5. doi:10.1016/j.bbih.2020.100094.

14. Bougakov, D., Podell, K., & Goldberg, E. (2020).

Multiple neuroinvasive pathways in COVID-19. Molecular Neurobiology, 1–12. doi:10.1007/s12035-020-02152-5.

15. Aghagoli, G., Marin, B.G., Katchur, N.J., ChavesSell, F., Asaad, W.F., & Murphy, S.A. (2020). Neurological involvement in COVID-19 and potential mechanisms: a review. Neurocritical Care, 1–10. doi:10.1007/s12028-02001049-4.

16. Garrigues, E., Janvier, P., Kherabi, Y., Le Bot, A., Hamon, A., Gouze, H., … Nguyen, Y. (2020). Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. Journal of Infection. doi:10.1016/j.jinf.2020.08.029.

17. Asadi-Pooya, A. & Simani, L. (2020). Central nervous system manifestations of COVID-19: a systematic review.

Journal of the Neurological Sciences, 413. doi:10.1016/j. jns.2020.116832.

18. Desforges, M., Le Coupanec, A., Dubeau, P., Bourgouin, A., Lajoie, L., Dubé, M., & Talbot, P.J. (2019).

Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? Viruses, 12(1). doi:10.3390/v12010014.

19. Ogier, M., Andéol, G., Sagui, E., & Dal Bo, G. (2020).

How to detect and track chronic neurologic sequelae of COVID-19? Use of auditory brainstem responses and neuroimaging for long-term patient follow-up.

Brain, Behavior, and Immunity - Health, 5. doi:10.1016/j. bbih.2020.100081.

20. Lu, Y., Li, X., Geng, D., Mei, N., Wu, P., Huang, C., … Yin, B. (2020). Cerebral micro-structural changes in COVID-19 patients - an MRI-based 3-month follow-up study.

EClinicalMedicine, 25. doi:10.1016/j.eclinm.2020.100484.

21. Espíndola, O., Siqueira, M., Soares, C.N., de Lima, M., Leite, A., Araujo, A., … Silva, M. (2020). Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid. International Journal of Infectious Diseases, 96, 567–569. doi:10.1016/j.ijid.2020.05.123.

22. Wu, Y., Xu, X., Chen, Z., Duan, J., Hashimoto, K., Yang, L., … Yang, C. (2020). Nervous system involvement after infection with COVID-19 and other coronaviruses.

Brain, Behavior, and Immunity, 87, 18–22. doi:10.1016/j.

bbi.2020.03.031.

23. Garg, A., Marji, A., Goyal, S., & Ismail, R. (2020). A case of COVID-19 with memory impairment and delayed presentation as stroke. Cureus, 12(8), 1–9. doi:10.7759/ cureus.10025.

24. Hascup, E. & Hascup, K. (2020). Does SARS-CoV-2 infection cause chronic neurological complications?

GeroScience, 42(4), 1083–1087. doi:10.1007/s11357-02000207-y.

25. Rubin, R. (2020). As their numbers grow, COVID-19 “long haulers” stump experts. JAMA, 324(14). doi:10.1001/ jama.2020.17709.

26. von Bartheld, C., Hagen, M., & Butowt, R. (2020).

Prevalence of chemosensory dysfunction in COVID-19 patients: a systematic review and meta-analysis reveals significant ethnic differences. ACS Chemistry, 11(19), 2944– 2961. doi:10.1101/2020.06.15.20132134.

27. Steinmeyer, Z., Vienne-Noyes, S., Bernard, M., Steinmeyer, A., Balardy, L., Piau, A., & Sourdet, S. (2020).

Acute care of older patients with COVID-19: clinical characteristics and outcomes. Geriatrics, 5(4). doi:10.3390/ geriatrics5040065.

28. Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., …

Hu, B. (2020). Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology, 77(6), 683–690. doi:10.1001/ jamaneurol.2020.1127.

29. Azhideh, A., Menbari-Oskouie, I., & Yousefi-Asl, M. (2020). Neurological manifestation of COVID-19: a literature review. International Clinical Neuroscience Journal 7(4), 164–170. doi:10.1016/j.jocn.2020.05.017.

30. Varatharaj, A., Thomas, N., Ellul, M., Davies, N., Pollak, T., Tenorio, E.L., … Michael, B. (2020). Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry, 7(10), 875–882. doi:10.2139/ssrn.3601761.

31. Beck, M. & Hummer, G. (2020, August 18) Spike protein of the new corona virus is more flexible than expected.

Retrieved October 21, 2020 from www.mpg.de/15269546/ sars-cov-2-spike-protein.

32. Zeng, Q., Langereis, M., van Vliet, A., Huizinga, E., & de Groot, R. (2008). Structure of coronavirus hemagglutininesterase offers insight into corona and influenza virus evolution. Microbiology, 105(26), 9065–9069. doi:10.1073/ pnas.0800502105.

33. Schoeman, D. & Fielding, B. (2019). Coronavirus envelope protein: current knowledge.Virology Journal, 16(1). doi:10.1186/s12985-019-1182-0.

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