Grey Matters Journal VC Issue 4 Spring 2022 by greymattersjournalvc

FEATURING Your Brain Hates Zoom, Too The Scientific Magic of Belief: How Do Placebo Treatments Really Work? Animal Venom Neurotherapy Forges the Future Using the Past

ISSUE 4

greymattersjournalvc.org

Table of Contents

TABLE OF CONTENTS 7

CONTEMPORARY CYBORGS: HOW NEUROPROSTHETICS ARE CHANGING LIVES

by Gage Haden / art by Ayane Garrison

YOUR BRAIN ZOOM, TOO

HATES

by Maedot Abate / art by Anne Goldsmith The emerging discovery that the placebo effect occurs via neural pathways, instead of being an entirely psychological experience, has tremendous potential to transform the way clinical trials are administered and improve patient treatment for chronic illnesses.

by Dominic Matos / art by Iona Duncan Excessive virtual interactions interfere with our nonverbal communication, the brain’s reward systems, attention capabilities, self-perception, and important threat instincts.

PSYCHOSURGERIES: HACK-JOBS TURNED BRAIN-HACKS by Shawn Babitsky / art by Mindy Nguyen and Anna Bishop

THE SCIENTIFIC MAGIC OF BELIEF: HOW DO PLACEBO TREATMENTS REALLY WORK?

FACING OUR FEARS: EXTINGUISHING CONDITIONED FEARS WITH EXPOSURE THERAPY by Alex Tansey / art by Ella Larson

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Table of Contents

CONVERSION DISORDER: THE DIAGNOSIS HIDDEN IN EPILEPSY’S SHADOW

by Avery Bauman, Alexa Gwyn, and Carina D’Souza / art by Sneha Das

ANIMAL VENOM NEUROTHERAPY FORGES THE FUTURE USING THE PAST by Sloane Boukobza / art by Sophie Sieckmann

THE BRAT WITH A BAT: EXPLORING THE DARK PSYCHOLOGY OF SATOSHI KON’S PARANOIA AGENT by Cherrie Chang

EXERCISING NEURONS: HOW WORKING OUT CAN IMPROVE MEMORY & NEURODEGENERATION by Lucas Angles / art by Natalie Bielat

REFERENCES

Animal venom research may be a fruitful path in determining pain relief alternatives to opiates and finding a cure for neurodegenerative disorders.

ON THE COVER Art by Caleb Leeming

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.

art by Natalie Bielat

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Production Staff

PRODUCTION STAFF

DANIELLA LORMAN Editor-in-Chief

ELEANOR CARTER Senior Editor, Lay Review

MARA RUSSELL Art Executive

LIA RUSSO

Accessibility Director

LUCAS ANGLES

Senior Managing Editor

CLEM DOUCETTE

Senior Managing Editor & Treasurer

AMBER HUANG

AINSLEY SMITH

TALIA MAYERSON

KAYEN TANG

JULIÁN AGUILAR

SALOME AMBOKADZE

Senior Editor, Scientific Review

Production Manager

Layout Executive & Graphic Designer

FILIPP KAZATSKER

HAROUN HAQUE

Social Media Manager

Graduate Student Executive

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Senior Editor, General Editing

Outreach Coordinator

HANNAH DALEY

Graduate Student Executive

Production Staff

ARTISTS

AUTHORS

Ayane Garrison Iona Duncan Mindy Nguyen Anne Goldsmith Ella Larson Sneha Das Sophie Sieckmann Cherrie Chang Natalie Bielat Caleb Leeming Anna Bishop

Gage Haden Dominic Matos Shawn Babitsky Maedot Abate Alex Tansey Avery Bauman Alexa Gwyn Carina D’Souza Sloane Boukobza Cherrie Chang Lucas Angles

SCIENTIFIC REVIEW

LAY REVIEW

GENERAL EDITING

Christopher Cho Hailey Brigger Lotus Lichty Veronica Gomes Evelyn Li Monika Sweeney Runqi Liu Jessica Camacho Dimple Kangriwala Keara Ginell Dhriti Seth Victoria Armitage Annie Xu Anshuman Das Ninamma Rai Marina Alfano Alexander Roth Claire Tracey Remi Kauderer

River Zhao Luke Dyal Rileigh Chinn Frank Ryan Nandini Likki Caris Lee Claire Tracey Julia Vitale Lily Watson Emma San Filippo Anjali Krishna Lilah Lichtman Billy Fan Leah McLaren Elizabeth Leonard

Amaavi Miriyagalla River Zhao Nehal Ajmal Adah Anderson Juliana Ishimine Nanako Kurosu Sam Dorf Katherine Nelson Julia Vitale Kenza Squali Lilah Lichtman Ninamma Rai Zilan Ding Veronica Gomes Olivia Gotsch Jaya Moorjani Lillian Lowenthal Jaclyn Narleski Zayn Cheema Lucy Volino Claire Tracey

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Editor's Note

EDITOR’S NOTE Scientists aim to improve the world through their discoveries, but a scientific discovery is only as good as its communication. Without the ability to communicate the nuances, complexities, and importance of discoveries to a wide range of audiences, the potential of scientific work to benefit society is diminished. At Grey Matters, we recognize that the scientific journal article — despite being the currency of communication across scientific fields — may be anathema to participation and engagement from a lay audience. But science is incremental and in constant flux, and efforts to improve science communication must be, too. As I step down from my role and Grey Matters Journal continues to move forward, a brief reflection on these past few years seems appropriate. After my first year of college, I sat down for an interview and was asked to describe my neuroscience research to a panel of individuals with limited to no experience studying the sciences. I bombed it. Describing the role of astrocytes in cognition was challenging, but doable. But I had no clue how to describe the process of glutamate recycling (and how it relates to cognition) to a nonscience audience. Scientists do need jargon — after all, jargon homogenizes concepts, allowing people around the world to transmit and communicate in intelligible ways and via a universal language. But I was mortified by my inability to navigate and triage that conversation, and so I got to work. I crafted analogies in which I compared the very esteemed neuron to Beyoncé, and the under-appreciated and misunderstood astrocyte to Beyoncé’s very important backup dancers. I still use these analogies today when discussing my lab work to anyone who will listen. Perhaps this is intimate and telescopic, but it’s certainly more fun and colloquial than using strictly science lingo. The cognitive dissonance I experienced a year later when I was introduced to the scientific paper was astounding. I loved all things brain, but the scientific paper was boring and complex. It didn’t take long to discover that many of my peers were also grappling with this dichotomy, and it was this collective frustration with the inaccessibility of science dialogue that galvanized Vassar’s chapter of Grey Matters Journal. Over the past few years, the list of successes, as well as stressors and challenges, is far too long to enumerate. Importantly, we were buoyed by our passion for the work. In a lot of ways, our success as a journal is indebted to a collective drive to present science in an alternate way. But, at the most basic level, I really do believe that the impetus for change is merely the collective frustration and bravery — and to some, foolishness — to challenge the conventional. At Grey Matters, we recognize that to be lulled into the complacency of expertise means to impede learning, and worse, to distance ourselves from others. So instead

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Editor's Note

of highlighting endless editorial responsibilities during publication cycles, my memory primarily nourishes recollections of our “off seasons.” Summer breaks, winter breaks. Anytime outside of the publication cycle, where we get the opportunity to converse, reflect, and ask ourselves: what is it that we can be doing better? How can we better engage in conversation with each other? Though Grey Matters hasn’t been the whole of my college experience, it has certainly been the best and brightest part. It has been a privilege to lead such an impassioned group of peers, and I have a number of people to thank. My job would have been impossible without our team, whose tremendous enthusiasm for innovative and unconventional publication ideas was most helpful. Thank you for making me a better human, communicator, and leader. Thank you for being a team I could count on, and a team I have thoroughly enjoyed working with. You all have my utmost respect and gratitude. I owe a special thanks to my friend and Senior Managing Editor, Clem, who often entered my room while I was working on the Journal to see if I was still alive. And to my Senior Managing Editor, Lucas— who was the first person I called up in June of 2020 to share my desire to start the Journal — I can’t thank you enough for believing in me and joining me on this journey. Thank you to the Neuroscience and Behavior program, President Bradley, and to you, our readers, for your continued support. My term will end shortly after I graduate on May 22, and I am excited to announce that Grey Matters Journal at Vassar College will be in excellent hands. Lucas Angles will be stepping into the role of Editor-in-Chief, and I am as impressed by the dedication and care he is already bringing to this upcoming position as I have been by his talented leadership as Senior Managing Editor. We are so very fortunate to have him at the helm, welcoming another year of brilliant contributors, thoughtful editors, and inspiring artists. As I say farewell to the journal, I also welcome a new team. A team that — as we all made sure — is just as frustrated and courageous and foolish as we were when we began this line of work. Stay curious, and be well. Cheers,

Daniella Lorman Editor in Chief

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Contemporary Cyborgs tions surrounding science fiction and futuristic machinery. However, cyborgs are not far from existence in our current reality. While fabricated super strength or speed might still be a fantasy, mechanical assistance of physiological processes is already possible with today’s technologies. There are people walking around right now with machinery inside them, ranging from pacemakers and mechanical heart valves to cochlear implants and insulin pumps. These mechanical prosthetics can vastly improve a person’s quality of life. Now, neuroscience and biomedical engineering are collaborating to take these a step further: cybernetic prosthetics controlled by the brain.

CONTEMPORARY CYBORGS: HOW NEUROPROSTHETICS ARE CHANGING LIVES by Gage Haden art by Ayane Garrison hen most people hear the word cyborg, the image W that jumps to mind is that of a crime-fighting halfman, half-robot. The exciting depictions of cyborgs in

sci-fi movies and TV shows — such as Robocop or Inspector Gadget — leave us with fantastical assump-

SENDING MIXED SIGNALS: BUILDING A BRAINCOMPUTER CONNECTION

When you open your laptop to write an essay, surf the web, or send an email, a flurry of largely invisible processes occur within your computer’s hardware. In many ways, the human brain functions similar to an organic computer. At the most basic level, your brain — like your laptop — is a complex network capable of sending, encoding, receiving, and interpreting a multitude of electrical signals called impulses or action potentials. However, though brains and computers work similarly, they do not speak the same language; this is where the Brain-Computer Interface (BCI) steps in. The BCI translates our brain’s electrical signals into technical coding [1, 2]. Essentially, it works as a link between the brain and a computer, interpreting electrical signals from the brain and communicating them to a computer in the same “language.” Since its first

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Contemporary Cyborgs cipient doesn’t speak English, but understands Spanish, the only logical thing to do is write the letter in Spanish. Similarly, when encoding afferent signals, we must send them in a way that the brain can understand. If we are able to encode signals like this, they can be used to mechanically restore or augment sensory systems. Efferent signals, on the other hand, pose the opposite issue: decoding. Using our earlier example, this would be like translating the response to our letter from Spanish back to English so that we can understand it. In the case of the BCI, the efferent neural signals must be translated for the computer. This process of decoding facilitates the flashier side of neuroprosthetics: translating neural signals into complex movement such as manipulating a prosthetic hand [5]. Whereas the afferent functionality of the BCI offers solutions for disrupted sensory systems, the efferent pathways can help patients recover lost mobility.

NEUROPROSTHETICS IN ACTION: THE TECHNOLOGY clinical application as a spelling device for paralyzed patients, the BCI has become varied in form and even more versatile in function [3]. The BCI is a two-way street, meaning it must be able to both send and receive signals. These neural signals are classified as afferent or efferent based on their directionality. Afferent signals originate in the body and travel to the brain, while efferent signals move from the brain, through the spinal cord, and out to the body. The dilemma when working with afferent signals is how information should be encoded [4]. For instance, imagine that you are writing a letter to someone in another country. If you know that the re8

When something important in your home breaks, there are two options for what to do: fix it or replace it. Similarly, neuroprosthetics are intended to fix or replace disrupted physiological functions, such as the ability to hear or walk, and are widely varied in form and use. Manufactured sensory organs or enhancements, such as artificial retinas and cochlear implants, detect afferent signals to restore use of the senses [6, 7]. The first cochlear implants were designed in 1959 and have since become one of the most prevalent and accessible forms of neuroprosthetics [7]. Cochlear implants use an external microphone and speech processor to convert environmental sound into electrical impulses. These impulses then directly stimulate the

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Contemporary Cyborgs auditory nerve and engage afferent signaling, which restores deaf patients’ hearing [8]. In 2014, cochlear implants had been fitted for 300,000 people worldwide, and this continues to be a beneficial elective procedure [7]. Research on sight restoration with technology such as artificial retinas is slightly behind that of auditory aids, but is nonetheless hot on its heels [6]. However, these technologies still represent only one sort of neuroprosthetic technology. The other function of neuroprosthetics — decoding efferent neural signals — is where technological advancements begin to sound even more like science fiction. Neuroprosthetics that utilize efferent signals enable the brain to directly control mechanical limbs [9]. Such complex engineering is only possible because of the brain’s intrinsic ability to learn and rewire its own neural pathways, a phenomenon known as neuroplasticity [10]. Neuroplasticity allows our brain to learn how to interact with a machine and signal prosthetics in a way that can be understood by the apparatus. In order to consider the complexity of this brain-computer interaction, take a moment to turn over your hand, and wiggle your fingers. Now consider all of the muscles and tendons you feel flexing in your hand and arm as you make these movements. Imagine if each of those muscles and their basic movements were controlled by a separate switch or knob. Already we have an image of an immense switchboard jampacked with dozens of similar controls. It’s easy to imagine that the motions resulting from manual control of this board would be uncoordinated and jerky, similar to the classic 60s dance move “the Robot.” Now we can see just how broad and complex the information processing required for fine motor control of an arm must be. For years, decoding these signals seemed impossible — that is, until someone with an idea, a plan, and a good chunk of funding managed to succeed. This unprecedented advancement in the field of neuroprosthetics offers incredibly promising opportunities for tetraplegics and amputees in particular. When equipped with sufficient BCI training, a pair of implanted electrodes, and the brain’s natural ability to alter neural pathways, coordinated neuronal control of a prosthetic arm has proven viable [9, 11]. However, prosthetics cannot fully replicate the efficient functionality of a natural limb. These types of efferent signaling prosthetics are unidirectional and thus still fail to produce a large portion of coordinated movement [9]. While simple movement can be controlled by efferent neural signaling alone, more complex human movement requires proprioceptive feedback. Proprio-

ceptive feedback allows the body to receive environmental sensory information and translate it into signals that orient the body in space [12]. For example, close your eyes and touch your nose. Proprioceptive feedback should allow your brain to signal exactly where in space the two body parts are and connect them, even without visual cues from the eyes. Bidirectional neuroprosthetics are now in development to integrate motor control with sensory and proprioceptive functionalities [13, 14]. Simply put, this means that we are trying to develop a robotic limb that can not only move and feel, but also be perceived by the brain as an extension of the body.

WE’VE GOT A SIGNAL! ALTERNATIVE NEUROPROSTHETIC TREATMENT While it may seem like the only goal of neuroprosthetics is to replace a missing or nonfunctional piece of the body and link it directly to the brain, this method is not the only way to remedy such a problem. Another method of restoring function attempts to foster the regrowth or augmentation of the anatomically intact but functionally impaired structure [15, 16]. In cases like traumatic brain or spinal injury, stimulating nerve regrowth or therapies meant to promote neuroplasticity can foster the regrowth of relevant damaged structures [15, 16]. Alternative neuroprosthetic techniques like these offer a useful means of maintaining existing structures with technological integration rather than merely replacing dysfunctional parts. For example, individuals paralyzed by spinal injury in the neck or upper back can regain mobility of their own hand and arm after implantation of a functional electrical stimulation (FES) system [16]. FES is the coordinated electrical stimulation of muscles and nerves; it essentially shocks your muscles into contracting when necessary. After a BCI is integrated into the brain, FES allows patients to control their previously paralyzed limb [16]. Essentially, we can bypass the faulty wiring and add artificial electrical connections, linking the brain and the body to complete the circuit. Much like restoring an old house, we keep the metaphorical light fixtures and power source, opting to only replace the wiring in the walls to return them to working order. The same system of BCI and FES also produces longterm functional recovery of mobility in limbs affected by a stroke [17]. Even without direct stimulation by the FES, BCI training has also shown strong associative learning benefits for lasting stroke recovery. Using a device to externally move a paralyzed limb in response to motor cues from the brain enhances learning and bolsters neuroplasticity [17]. When paired with

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Contemporary Cyborgs physical therapy, this device improved recovery of mobility in stroke patients [18, 19]. Once again, the brain is more powerful than we give it credit for, and with a little assistance, it can recover and regain all sorts of functionality, even when following a severe injury.

goals for improving quality of life. Neuroprosthetics offer treatment options to a variety of people, ranging from amputees to those born deaf and beyond. More incredible developments and discoveries about the brain and the body lie on the horizon. Even proposed inventions so far-fetched they sound like fiction often become reality in time, so the question always remains, what’s next? References on page 53.

Therapies that regenerate lost neurons or directly repair severed neural connections also hold great promise in treating paralysis that stems from spinal cord injury [20]. One such therapy is cell-based transplantation, where healthy cells and scaffolding are added directly to damaged tissue to promote axonal regrowth in the spinal cord. Think of this therapy as a complex, partial organ transplant: the healthy cells are grafted into the injured or affected area and then supplied with the necessary materials to integrate into the pre-existing networks [20]. However, this therapy is greatly limited by the low survival rates of grafted cells, the tendency of implanted cells to migrate and spread out from localized injury, and the lack of effective strategies to direct cell growth [21]. Despite efforts to lessen these limitations, they still limit the clinical success of cell-based transplantation. Nevertheless, neuroprosthetics are much closer to becoming a viable and accessible option for amputees and other afflicted individuals.

EMERGING FROM SCIENCE FICTION: THE FUTURE OF NEUROPROSTHETICS The difference between science fiction and reality may just be a matter of time. Science fiction writers once wrote of fantastical networks that connected people across the world; now we have the internet. They wrote of flying cars, hoverboards that don’t touch the ground, and self-driving cars, all of which now have at least a viable prototype. The stories of cyborgs in science fiction have also been brought into reality, but in the form of integrated neuroprosthetics. While the colloquial purpose of such cybernetic additions, in sci-fi novels, have leaned toward superpowers or help fighting crime, scientists have exchanged these

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Your Brain Hates Zoom, Too

YOUR BRAIN HATES ZOOM, TOO by Dominic Matos art by Iona Duncan

s there any greater act of pleasure than pressing that Iyour big red “Leave meeting” button that’s been calling name since the Zoom call began? Why do virtual meetings always seem to warrant such an exasperated sigh afterward? We all know that feeling of postZoom exhaustion, when you find yourself much more fatigued than seems reasonable for such a passive activity. Now entering the third year of the pandemic, symptoms of excessive Zoom use are being reported across the country, such as unusual fatigue, disconnection from one’s body, and appearance insecurities [1]. Even though Zoom has been crucial in maintaining education, work, and all kinds of communication throughout the pandemic, constant virtual meetings seem to have seriously messed with our minds. While

virtual meetings themselves seem harmless, once they are turned into an everyday activity, the loss of authentic human interaction presents a host of potentially damaging effects on the brain. Excessive virtual interactions interfere with our nonverbal communication, the brain’s reward systems, attention capabilities, self-perception, and important threat instincts. These effects follow us into the real world, and may remain long after the pandemic has ended. Because Zoom was only recently employed on such a wide scale, we are still learning about the precise nature of these effects; doing so will be key to understanding our behaviors and stabilizing our moods in the age of virtual communication.

COMMUNICATION TAKES MORE THAN JUST WORDS To understand why too much Zoom can harm us, we first have to understand the essential components

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Your Brain Hates Zoom, Too of in-person human interactions and how they coincide with thinking, processing, and awareness. It may seem like our conversations happen solely through our words, but in-person interactions involve much more than merely verbal communication. Nonverbal communication (NVC) is just as important as verbal communication (VC) in exchanging information; facial expressions, body language, proximities, and eye contact are all important elements of an effective conversation [2]. NVC and VC occur simultaneously, but NVC is often more revealing of one’s true motives, thoughts, or feelings, as it is less consciously controlled. It’s easier to verbally tell a lie than it is to stop fidgeting or avoiding eye contact [3]. In fact, eye contact is a critical component of NVC due to how effectively it grabs our attention. As innately social creatures, we have evolved to use our eyes as social tools [4]. Making eye contact directs our attention toward a possible social interaction and alerts our brain of a potential reward, whether it’s a knowing look with your best friend across a crowded room or an accidental glance with a passing stranger. Eye contact positively influences our judgment of the likeability of others, our memory of their faces, and allows for gaze-following — the ability to tell where or how far someone is looking just from seeing their eyes. Gaze-following facilitates joint attention, another form of NVC which refers to instances where you and those around you pay attention to something together; joint

attention is integral in your ability to feel engaged with the people around you [4]. However, none of these social-interaction elements translate to Zoom. The screen barrier in virtual meetings severs the participants from the many benefits and intimacies of human connection; there is no opportunity to engage in the physicality necessary for authentic exchanges. Additionally, audio delay is a major contributor to Zoom meetings being draining and feeling unnatural. Even in-person interactions have pauses between sentences, but past a certain point these pauses last too long and begin to negatively affect the participants’ perception of the conversation as a whole [5]. It’s not fun to have to wait for your words to travel through the internet after every sentence. This lack of nonverbal communication is multiplied by every participant staring blankly at you through the screen. In a Zoom call, you’re presented with multiple faces all at once. It’s like standing at the front of a room with a close-up audience diligently watching your every move. In real life, this situation might at least be bearable, since the crowd might end up speaking or shuffling or leaving. But on Zoom, those silent observers in the audience don’t look away or leave — they’re just there. Consequently, you must dedicate a portion of your attention to each of them at all times. The mental strain of having to monitor everyone is amplified by technology issues (imagine if the audience’s faces and voices were delayed and blurry) and the lack of NVC cues. However, the frustration doesn’t just end there. Trying to communicate without the usual arsenal of nonverbal tools can be exhausting — like the strain of reading without your glasses or having a conversation in a language you only partially understand.

WHERE’S THE FUN IN LITTLE FACE BOXES & CRACKLY AUDIO? With NVC mostly eliminated, Zoom interactions can feel much less rewarding and engaging. Since social interactions are a key component of human existence, our brains are trained to recognize the difference between real-life and virtual social encounters. In-person interactions activate regions of the brain involved in reward, but vir12

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Your Brain Hates Zoom, Too tual interactions do not yield the same effect [6]. Dopamine, often referred to as “the reward chemical,” is a neurotransmitter mainly involved in pleasure, reward, motivation, and more. In the brain, differengt neural pathways are activated depending on the type of stimuli available; once activated, these pathways trigger the production and release of neurotransmitters relevant to produce particular feelings, sensations, and emotions [7]. In the case of pleasurable stimuli — like when you hear an amazing song for the first time, or open a textbook immediately to the right page — neurons in certain regions of the brain start producing dopamine. The release of this chemical activates the mesolimbic pathway, as it corresponds to feelings of reward and motivation. We become inclined to repeat actions that result in reward and seek out these positive stimuli again and again [8]. Oxytocin, a neural chemical involved in social bonding, regulates these pathways involved in reward processing, which is why positive social environments and interactions feel so good [9]. The difference between expectation versus reality of the incoming reward determines how much reward it actually produces. Zoom, however, does not provide us with many of the essential aspects of in-person interactions, and as a result, our brains don’t anticipate much reward [6]. Before every behavior, our brain analyzes a task’s potential reward versus the effort required to complete it [10]. We act based on our estimates of how to maximize reward while exerting the minimum effort, and this reward estimate is what helps activate our dopaminergic pathways [10]. Multiple areas of the brain related to reward and reward-processing are activated when positive social feedback is anticipated, but when interactions are mediated thplsrough a screen, it’s exponentially more difficult to predict someone’s thoughts and feelings, so less reward is felt. “Hi, Grandma!” over Zoom isn’t the same as “Hi Grandma!” at the front door. Sure, we’ll feel some reward — it’s still Grandma, after all — but it’s not quite the same. In Zoom meetings, without all the little signals we’re accustomed to through NVC and in the absence of almost any pre-

dicted reward, dopaminergic pathways are minimally activated. When you receive less reward than anticipated, it leads to a negative response, and no positive emotions are produced [11]. Since dopaminergic pathway activation is linked to increased alertness, energy, and motivation, talking to someone without the promise of these typical motivators can be incredibly fatiguing. Your brain is on a treadmill chasing a dangling reward that will never come.

THERE IS SUCH A THING AS TOO BORING The limited reward we experience in virtual interactions also plays a powerful role in our interest in the situation and likelihood to pay attention. Imagine sitting in your least favorite class. As the droning voice

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Your Brain Hates Zoom, Too of the incredibly dry lecturer drifts in and out of focus, your mind wanders to different places. Maybe you start thinking about an exciting party you’re attending that weekend, or you daydream about approaching the barista you’re in love with. You try your absolute hardest to pay attention, but still, something, anything else seems more interesting. Anyone who has experienced this sensation knows that our attention is a finite resource. A component of our complex cognitive, motor, sensory and visual functions, attention refers to a person’s ability to pick out and focus on specific, exciting stimuli, and engage with environmental stimuli sources [12]. Our working memory (WM) is an extremely powerful form of memory closely linked with attention; WM operates over periods of seconds, and only holds a limited amount of information. When we focus on an object, person, or idea, the information we know about it enters into our WM. Stimuli around us compete for our attention all day, but as soon as a stimulant gains control of our working memory, it wins, and the information is rapidly analyzed [11]. The brain has limited attention span and WM to distribute across different demands of concentration, and it prefers to use it on the more engaging, potentially rewarding, and exciting tasks rather than the mundane or tedious ones [13]. Engaging tasks, such as those with higher promised reward, novelty, stress, or irregularity, have a higher priority for receiving a share of our attention. The more engaged we are with a task, the more effort we put into our performance [13]. The more boring and routine tasks receive less of a priority for attention, making it unbearably difficult to focus on something boring. Boring tasks make us crave stimulation and may lead us to resort to multitasking. But multitasking isn’t as productive as it seems. When you multitask, each additional task or context you switch between costs efficiency and accuracy, referred to as the “task switch costs” [14]. It’s this act of switching between mental contexts that requires effort and slows your brain down; generating thoughts within a new context every time you switch tasks is not as neurologically seamless as it might seem [14]. Whether you’re talking to a friend about yesterday’s outing while simultaneously revising a paper, or preparing five different meal orders at once, switching tasks requires alternating between the different worlds of thought you’re considering. Therefore, your performance suffers when you constantly transition from one train of thought to another [15]. True multitasking without any drawbacks doesn’t really exist — it’s just not possible. Even worse, Zoom

makes it tremendously easier for you to get off task. Attending a virtual event opens up the opportunity for all kinds of multitasking: your computer is already open, and the vast realm of the internet is just a few clicks away. Unlike sitting through an incredibly boring in-person lecture with few physical distractions, on Zoom you are surrounded by a world of readily accessible — and more interesting — things. It’s probably rare for you to be in a Zoom meeting without your phone either actively in your hand, or right beside you ready to deliver a constant stream of stimulation. During a Zoom meeting, you can comfortably browse your phone, do other work on your computer, and engage in a plethora of other distractions happening around you. Media multitasking, like checking your phone or listening to music while on a Zoom call, is recognized as a separate, and even more taxing form of multitasking. Media multitasking drastically reduces the performance of your working memory and can impair your long-term remembrance of what you’re trying to focus on [16]. Chronic media multitasking can cause these deficits to arise in situations where there aren’t even any distractions [16]. Not only does Zoom have a tendency to result in multitasking, but the content of the actual Zoom call usually isn’t particularly exciting. Anyone who has been in a Zoom call knows the experience usually lacks novelty and irregularity, and the promised reward is usually small. This is not a good recipe for engagement. As a result, the brain doesn’t really “want” to use up valuable attention on Zoom; it would much rather focus on the meme your friend just sent you, or the lyrics and drum rhythm of the song you’re listening to. Both of which are definite winners in the novelty category [17].

IF YOU FEEL LIKE YOU LOOK WORSE ON ZOOM, YOU’RE RIGHT How often have you logged on to a Zoom call and stared at the tiny, distorted box containing your face? Maybe you tilt your head and adjust your hair, attempting to find the best angle on your laptop’s smudged, low-resolution webcam. In virtual meetings, we engage not just with others, but with our own images as well; our miniature selves enclosed within that Zoom window also demand some of our attention. Constantly looking at this alienating, up-close mirror image of your face on Zoom can warp your self-perception. Zoom Dysmorphia refers to the effects of Zoom’s self-distortions, which are similar to those of Body Dysmor-

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Your Brain Hates Zoom, Too

phic Disorder [18]. In brief, Body Dysmorphic Disorder (BDD) is a mental illness involving obsessive focus on perceived imperfections of one’s own appearance, typically to an extent that it gets in the way of everyday life [19]. Mirrors, in general, can be extremely distracting and sometimes even dangerous to those with BDD because of how much time they spend staring at themselves [19]. Unsurprisingly, staring at yourself on Zoom all day can exacerbate these effects for those with BDD, and can also influence these tendencies to arise in people without the disorder. With the prevalence of online meetings, Zoom Dysmorphia is becoming increasingly common. People are reportedly unable to stop looking at themselves while using Zoom, and hyper-fixate on their flaws, real or not [20]. In general, it’s unnatural for us to see ourselves as frequently as we do nowadays. Even when we would see ourselves in the past, it would only be brief moments in a mirror or a moment captured in a photo. Never before would we constantly see our real-time movements and reactions — giving us all the more to critique ourselves.

Not only does Zoom obligate us to stare at a seemingly relentless mirror, but front-facing cameras distort our faces by default by causing our eyes to appear smaller and our noses bigger [21]. Being able to “touch up” your face on Zoom and modify your facial features, or having the option to choose between a reflected or non-reflected view of yourself makes it easier to distort your self-perception. It is this ability and option to manipulate the appearance of our zoom-self that separates it from the “real” us, and what we look like in person. This raises the question: “Which way do I prefer to look?” It’s a lot to think about during a Zoom meeting, and definitely doesn’t help with mental fatigue. During the pandemic, there was no doubt a spike in screentime and social media usage, and the increased use of filters, video conferencing, and social media have been identified as causes for worsening self-perception, anxiety, and mental health. Even as we return to in-person activities, these Zoom-related problems can persist [1]. To put this into perspective, dermatol-

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Your Brain Hates Zoom, Too ogists are seeing a significant rise in cosmetic consultations in the midst of the global pandemic [20]. Eighty-six percent of these patients cited video conferencing as the reason for their visit. In a survey of over 7,000 participants, 70% reported stress or anxiety related to returning to in-person activities, referencing concerns of appearance as a significant source of the anxiety; even further, more than 70% of participants use filters for video conferences and social media with the desire to improve their appearance [21]. And maybe it is just a coincidence, but TikTok gained 85% of its users during the pandemic [22]. Transitioning back to in-person interactions has people searching for ways to change our real-world appearance as we were able to do over Zoom, and maintain our digital persona; this return is where the danger of filters and digital facial effects presents itself. The societal pressure to appear flawless is generally present, but to a much greater extent for women; Zoom Fatigue is usually greater for women as well because of this higher expectation to appear put together and professional [23]. Constantly checking your own Zoom box to make sure you look perfect is yet another thing to add to the Zoom Multitask checklist, and adds another burden to the cognitive load.

WHY IS EVERYBODY STARING AT ME? Close-proximity interactions like those in Zoom can trigger the same physiological reaction as a physical threat or attack [24, 26]. During Zoom calls, each person’s square consists only of their face, including your own, and they constantly appear to be staring back at you. From an evolutionary standpoint, if there was a very large human face up close and staring at you, your primal instinct would inherently expect to either engage in conflict or flee the situation; neither of these elicit a good response for being in a meeting [25]. The “fight or flight” response pumps the hormone adrenaline into the bloodstream, which jump-starts reactions like increased heart rate, blood pressure, oxygen sent to the brain, alertness, and nutrients in the bloodstream — again, not the most useful for a Zoom meeting [26]. While these reactions won’t happen as intensely in a Zoom call as they would while you’re running from a lion, it’s confusing to our brain if these systems are engaged during a situation that doesn’t seem to warrant them. This reaction could also be induced by our inability to distance ourselves from the faces. In real-life conversations, you can move yourself, readjust your body position, lean away — anything you want to control your personal space and where you are. In 16

Zoom meetings, however, your personal space is defined by how big the participant squares are, and not only are there multiple faces near you, but you can’t do anything to get away from them. The conflict between subconsciously undergoing a stress response and not doing anything besides staring at a screen is probably a contributor to mental strain during zoom.

AM I EVEN REALLY HERE RIGHT NOW? Zoom not only skews your perception of others, but can also change how you think about yourself. Depersonalization may be an unfamiliar word but a familiar feeling. A complex term to discuss, depersonalization is the persistent feeling of observing yourself from outside your body or having a sense that your surroundings aren’t real. It can feel like things are happening around you but there’s something separating you from the outside world, or that you don’t feel connected to the reflection you see in a mirror [27]. High digital and social media consumption can lead to feelings of depersonalization, and too much Zoom use can easily detach one from their body [28]. It’s difficult to resonate with that person you see on your Zoom screen; it’s a broadcast of yourself, but there’s nothing to guarantee or prove that it’s really you. The pandemic drastically reduced how frequently we’re involved in genuine social settings, and with many of our interactions being through a screen and lacking typical conversation novelty, the “not feeling real” aspect of depersonalization can be easily amplified. Everything you see through a screen is just digital imagery: none of the people, objects, animals, or anything else are real, they’re just projections o f

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Your Brain Hates Zoom, Too light; you can’t actually reach out and touch someone’s face through a screen. Spending all day looking at faces composed of pixels in a screen instead of looking at tangible objects or people can make everything feel a little disconnected even if you’re not having a depersonalized episode.

LIFE IN AN ARTIFICIAL WORLD IS UNSUSTAINABLE You’re not making it up: Zoom does cause ridiculous exhaustion. The way in which Zoom interacts with our brain is somewhat of a chain reaction, as most of its effects act as catalysts for others. Zoom doesn’t allow for most of the components of real-life social interactions, which makes calls less rewarding. This lack of reward makes the experience tiring and exceedingly difficult to pay attention to, ultimately increasing our tendency to multitask, harming memory, productivity, and accuracy. All this occurring simultaneously in our brains is cause for the annoyingly excessive postZoom exhaustion, and is all dramatically amplified by the pandemic’s sudden halt of in-person interactions. This frustrating phenomenon is only one example of how modern technology is rapidly developing and forcing society to learn how to adapt. Social interactions are one of the core components of our lives, and abruptly transitioning our social settings to the virtual world is a change our brains aren’t necessarily prepared for. The pandemic was the first time the world attempted to simulate real life through a technological interface, and we are now beginning to confront the repercussions of doing so. Because of how ingrained technology is in our world, it’s easy to forget that the human brain isn’t wired for these types of social interactions. And, while Zoom has put everyone through countless painfully mundane hours of sitting in front of a screen, there is a silver lining in what it has taught us. Zoom Fatigue has warned us of the repercussions of taking advantage of what we can do with technology. We have to remember that just because we can’t immediately feel the impact, substituting technology for real-life interactions can still affect our brains in harmful ways. So next time you find yourself staring at that red button, why not give it a press? References on page 54.

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Psychosurgeries

PSYCHOSURGERIES: HACKJOBS TURNED BRAIN-HACKS by Shawn Babitsky / art by Mindy Nguyen and Anna Bishop

camera pans to Jack Nicholson’s lifeless expresTly hesion: his slackened mouth hangs open just slightand his body lays unreactive to the movements of his hospital cot. Randall McMurphy (one of Nicholson’s most famous film characters) is soon approached by his hospital pal, Chief, who hopes to be greeted by his friend. It’s immediately clear to Chief, however, that McMurphy isn’t truly there. Although he’s breathing and his eyes are open, he lies in the bed like a corpse in a tomb. McMurphy has had forced brain surgery; his unnervingly plain disposition suggests that he will never again recognize his friend sitting in front of him, much less behave like the person he once was. This disturbing scene, pulled from the award-winning 1975 movie adaptation of One Flew Over the Cuckoo’s 18

Nest, depicts a previously common form of psychosurgery: the infamous lobotomy. The protagonist, McMurphy, is subject to the procedure as punishment for wreaking havoc in a psychiatric hospital; the surgery ultimately renders him incapable of physical movement and all forms of normal human behavior. Although McMurphy is still technically “alive,” it is clear to the audience that their beloved character is approaching a disastrous fate. McMurphy’s eerie tale is one of many popular media examples demonstrating psychosurgery stigmatization, and misconceptions of the procedure’s capabilities run rampant throughout society today due to such persisting concerns. Modern psychosurgeries, however, are a far cry from the infamous lobotomies of the past. In fact, many constitute safe and effective treatments for psychiatric conditions, especially for those resistant to other non-surgical interventions [1, 2].

THE UN-NERVE-ING HISTORY OF PSYCHOSURGERY Brain surgery that aims to address mental illness, or psychosurgery, has been practiced for nearly a century [3]. The first recorded case was the “ice-pick” lobotomy in the 1930s –– the surgery that Randle Mc-

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Psychosurgeries

Murphy received. This procedure involved inserting a small metal spike through the eye with the intention of disrupting faulty connections in the brain and would often leave patients with little to no brain function [4]. A well-known lobotomy example was that of John F. Kennedy’s sister, Rosemary, who was forcibly lobotomized in 1941 to treat her seizures and “erratic behavior,” the outcome of which was infamously disastrous. Rosemary lost most of her ability to walk and speak and was immediately institutionalized after the procedure [5]. These first attempts at surgically correcting mental illness were notoriously brutal and ineffective; the practice has understandably become stigmatized. And while modern psychosurgeries bear no resemblance to these lobotomies of the past, the current perception of these procedures continues to

be stained by their historical manifestation in both real life and the media. Unlike the “ice-pick” method, modern psychosurgeries are minimally invasive and capable of producing favorable results [6]. The surgery uses the minimum number of incisions, decreasing the risk of complications [6, 7]. Therefore, modern psychosurgeries take a much more precise approach than that of their origins in lobotomy, in which significant portions of brain tissue were damaged. Instead, surgeons use controlled electrical currents to create small lesions in a targeted brain region in order to disrupt dysfunctional neuronal signals [4]. All neurological functions are dependent on precise electrical signals; misfiring, or errors in the patterns of these signals, can result in mental illness

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Psychosurgeries [8]. Psychosurgical treatment can disrupt dysfunctional pathways in a controlled manner, thus healing the symptoms caused by previous misfiring [4]. The efficacy of these new treatments is evident in deep brain stimulation (DBS), a once-taboo psychosurgical procedure that has found significant clinical success in recent years [9]. DBS is a neurosurgical therapy that involves implanting a small device, also known as an electrode, that delivers constant electrical pulses to a specific area of the brain [9]. The implanted electrode can then alleviate symptoms associated with neural misfiring. During surgery, detailed imaging is used to implant the electrode in a precise region of the brain. The electrode is then connected to a pacemaker under the skin of the chest below the collarbone. Each pacemaker and electrode pair is specially programmed to counteract an individual’s specific abnormal firing pattern, counteracting signals associated with tremors and faulty motor control [10]. Since its approval, DBS has revolutionized how certain diseases are treated [11]. For instance, individuals diagnosed with Parkinson’s, a severe neurodegenerative disorder, often experience dyskinesia, or involuntary muscle movements. This debilitating symptom can be almost entirely alleviated by implanting a DBS electrode near the part of the brain responsible for motor control. But, although DBS has been relatively successful for the treatment of Parkinson’s disease, in its early days, the procedure was often compared to lobotomies in an effort to discredit the practice. For many years, members of the medical community considered DBS unethical due to the controversy surrounding its initial use [12]. In essence, despite its continuous evolution and potential to treat many impairing conditions, psychosurgery continues to face resistance due to its tragic roots [9].

A TACTICAL STRIKE AGAINST SEVERE MENTAL ILLNESS: THE ANTERIOR CINGULOTOMY Picture a city’s public transport system: there are hundreds of tracks and trains, as well as passengers trying to get from station A to station B. Now imagine this busy scene unfolding in the brain, where the stations are located in different hemispheres of the brain. The cingulum is a part of the brain that acts as this entire transit system; its fibers are the individual trains, and the electrical signals trying to get from one hemisphere to the other are the passengers. The frontmost portion of the cingulum, near your forehead, is called

the anterior cingulate cortex (ACC) [13]. The ACC exists in a vital physical position between two major brain structures: the limbic system and the prefrontal cortex. The limbic system is composed of multiple smaller structures that work together to process emotion, acting as a bridge between emotions and our ability to feel them. The prefrontal cortex, on the other hand, is a region of the brain which modulates cognitive processes [14]. Consequently, the ACC is responsible for both processing emotional responses and conveying those responses. Due to its unique position within the brain, any neuronal misfiring in the ACC could lead to psychiatric dysfunction [8]. Similar to DBS, the anterior cingulotomy is both a revolutionary and controversial modern psychosurgery [9, 14]. The anterior cingulotomy aims to alleviate symptoms of refractory (i.e. treatment-resistant) mental illness. The surgery uses a minimally invasive approach with a precise imaging system to surgically access and modify the ACC [13]. A surgeon then uses a small probe with a controlled electrical current to create small lesions around the ACC [2]. These lesions create an interruption in a dysfunctional brain circuit loop associated with psychiatric disorders, called the cortico-striatal-thalamic (CSTC) loop. When the CSTC loop is strategically disrupted in this way, the symptoms associated with misfiring neurons — such as obsessive compulsions or depression — are reduced [2]. Due to the fear that psychosurgery elicits in society, the anterior cingulotomy has not been widely used; however, all existing clinical trials for the procedure have yielded favorable results [2]. One clinical trial followed 64 patients for five years after undergoing cingulotomies to treat refractory obsessive-compulsive disorder (OCD). Thirty of those patients had all of their symptoms alleviated, and fourteen had some of their symptoms diminished [2]. The symptom relief experienced by these OCD patients following cingulotomies is also evident in those who had the procedure for the purpose of refractory depression treatment. Many trials of the procedure suggest that major depressive disorder (MDD) patients and OCD patients will. experience symptom relief after having the procedure [2]. Importantly, it appears that these improvements will persist for some time, as over 70% of both MDD and OCD patients continued to experience relief in the five years following surgery [15]. It’s important to note that those patients whose symptoms did not improve, did not have their symptoms worsen following surgery; therefore, no patients reported worsened conditions following the procedure [2].

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Psychosurgeries Similar to any other neurosurgery, there are inevitable side effects and risks to this procedure; however, the likelihood of serious adverse effects is slim [14]. Some negative side effects from the anterior cingulotomy are possible in the long-term, but they remain rare. Individuals who receive the surgery may experience urinary incontinence (the inability to control urination) for a short period of time following the procedure [1, 2]. Additionally, people might exhibit a postoperative decline in memory and learning or decreased decisiveness [16]. However, in most cases, these effects resolve within just a few days after the surgery. During the recovery process, it takes approximately a month for soreness at incision sites to diminish, and it could take up to three months for potential motor or speech deficits to resolve [17]. Even so, these temporary effects are no different than those caused by any other brain surgery. Of course, this procedure is by no means a cure-all for mental illness; physicians should be cautious in presenting the anterior cingulotomy as

an option to people before their condition proves to be treatment-resistant [2, 17, 18, 19]. It is essential that this option is presented only to the roughly 20% of people with major depressive disorder (MDD) and 30% of people with OCD who do not respond to alternative treatments and continue to suffer from their respective symptoms [18, 19]. One other psychosurgery exhibits favorable results with a similarly minimal risk. The amygdalotomy is a procedure used to treat symptoms of aggression associated with severe learning disabilities [20]. The amygdala, a structure of the limbic system, modulates neural responses associated with fear, anxiety, impulsivity, and aggression. Similar to other psychiatric disorders, overactivity in the CSTC loop can result in the aggression associated with severe learning disabilities. To treat this aggression, a surgeon will cut lesions around the amygdala in order to interrupt the CSTC loop and alleviate symptoms [20]. Akin to the cingulotomy, the amygdalotomy brings with it the typical risks and recovery complications of any neurosurgery, yet it offers a new horizon for those struggling with unnecessary or disruptive bouts of aggression.

(ICE-)PICKING AWAY AT THE STIGMA SURROUNDING PSYCHOSURGERY From deep brain stimulation to the cingulotomy and the amygdalotomy, there is a long list of potentially revolutionary yet stigmatized psychosurgeries that offer great promise. In the future, research on psychosurgery should include more extensive clinical trials to improve surgical technique and increase response rates. It has been well established that these surgeries produce favorable results with minimal risk [6, 7]. Nevertheless, research on many of these procedures remains halted by an outdated fear of repeating the catastrophic lobotomy [4, 15]. However, as demonstrated, the cruelty and destruction essential to McMurphy’s horrifying demise bears no resemblance to present-day psychosurgeries. The medical community should continue to cautiously explore these procedures in order to make advances in psychiatric medicine. Exploring new psychosurgeries and perfecting those previously created is imperative if we wish to improve the lives of many people who currently find no hope in alternative treatments for their psychiatric disorders [18, 20]. References on page 55.

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The Scientific Magic of Belief

by Maedot Abate art by Anne Goldsmith 22

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The Scientific Magic of Belief hey’re not called “gazebos,” as Eddie from the 2017 Tcolloquially film IT so passionately proclaims. Placebos, while referred to as “sham” treatments, are es-

sential components of research within the field of clinical medicine [1]. They are primarily used as a point of comparison to determine if newly developed drugs have any sizable positive impact on a patient’s health. Ideally, those receiving the real treatment should see significantly better outcomes than those receiving the “sham” treatment — otherwise, the drug serves no medical purpose! But how exactly do placebos work? And why do they work despite seemingly not affecting the physical body? Perhaps you have experienced the placebo effect in your day-to-day life. Let’s say you’re sitting in a hot, stuffy room, and are desperate for a breeze to cool off. You ask a friend to open the window in the next room to let some air in, and after agreeing to do so, they walk into the other room. Unbeknownst to you, your friend prefers the room’s current temperature, and has left the window closed without letting you know. You, however, believe that the window is now open, and that cool air is coming in. This belief induces a placebo effect: you now feel cooler due to the incoming “breeze.” In reality, the temperature of the room has not changed in the slightest, so why are you able to physically feel a difference? The perceived environmental cues — verbal compliance from your friend, and them heading to the other room — are processed at the cognitive level, resulting in a positive physical outcome. You now feel much cooler, thanks to that “open” window! Placebos in clinical trials operate similarly, with the goal being that the “breeze” — or the effect of the treatment — is much more potent after taking an active drug than with the placebo [1]. Just as you physically “cooled off” after processing cues from your surroundings, placebos in clinical settings also rely on the environmental context in which they are administered [2]. The environmental context can include factors ranging from verbal cues from the person administering the placebo, whether or not the patient is in a clinical environment (at home vs. a doctor’s office, for instance), and personal variables such as the patient’s preexisting beliefs about the treatment’s efficacy [2]. All these factors can impact how successful the placebo is in producing the desired health outcome. For example, let’s say a new drug for arthritis has just been developed. To approve the drug, scientists must first ensure that the drug treatment will generate a far better outcome for the patient than receiving no treatment at all. To control for any bias, all partici-

pants in a placebo trial are usually made to believe that they are receiving the actual drug. Some patients will then be treated with the actual drug (group A), while others will be treated with a harmless and inactive substance such as a sugar pill, or saline (group B). This inactive substance is the placebo [1]. After some time, researchers compare the symptoms of the participants in groups A and B. In the case of this arthritis drug, symptoms like joint stiffness, pain, or swelling would be noted. If all other variables are controlled for, and the patients in group A fare significantly better after treatment, their health improvement is assumed to be caused by the medication [1]. If both groups of patients retain a similar set of symptoms, then the actual drug is no more effective than a placebo, and it’s back to the drawing board for the scientists. Until a few decades ago, the placebo effect was thought to be a purely psychological phenomenon, or the result of cognitive and behavioral changes that emerge when a person expects or believes something [3]. However, the nervous system — comprising the brain, nerves, and spinal cord — has recently been found to play an active role in producing the effect [3]. This newfound understanding emerged when naloxone (commonly known as Narcan), a drug that is used to counteract opioid overdose by blocking its dangerous symptoms, was found to simultaneously counteract the placebo effect [4]. Natural opioid compounds synthesized by the body, such as endorphins, play a role in reducing pain — a process which naloxone prevents from occurring. If a patient is given a placebo but is told it’s an opiate painkiller, they report feeling less pain, a typical example of the placebo effect. However, if a patient receives naloxone in addition to the placebo, they report much higher pain levels. Considering placebos are usually associated with pain reduction, the strange painful consequence of combined placebo and naloxone treatment suggests that the placebo effect may be both a psychological and physiological phenomenon [4]. The discovery that physiological changes can inhibit the placebo effect brought about new questions of how placebos can affect the neurochemical makeup of our brains. Now, a new subcategory of research has begun incorporating both the psychological and physiological elements of placebo processing in the brain, with the goal of implementing this knowledge to improve the field of drug discovery and patient treatment.

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The Scientific Magic of Belief

UNLOCKING PAIN RELIEF: THE PHYSICAL EFFECTS OF PLACEBOS ON OUR BRAINS Placebos rely on a complex system of neurons that get activated to stimulate a response in the brain

and produce a physical outcome. Neurons are cells that receive and process sensory information from the outside world, including pain, heat, and light [5]. Picture these neurons as a long chain of rooms and hallways, where each room is a neuron’s cell body responsible for receiving this sensory input. The hallway represents the neuron’s axon, responsible for carrying signals to the next room (the subsequent neuron). Signals moving through these doors and hallways produce an electrical signal called the action potential, which originates in the cell body and travels down the axon to the next neuron. However, the action potential cannot open the door to the next room alone; it requires chemicals called neurotransmitters to do so. These “keys” are molecules that convey the received

information from one neuron to the next by interacting with specialized receptors on the doors, or “locks” [6]. After these neurotransmitters unlock the doors, the signal is taken on a journey through billions of rooms and hallways, all in a span of seconds, until a physical response occurs. When a placebo is administered to a person, their expectations can influence which neurotransmitters relay the signal from neuron to neuron, and therefore what health benefits the patient ultimately experiences [7]. Neurotransmitters do not work in isolation; the placebo effect modulates communication between several of these molecules to bring about an appropriate response to environmental cues. Dopamine is one such neurotransmitter, playing a role in the brain’s reward, pleasure and motor-control systems [8]. The rush of relief you felt when your friend “opened” the window, for instance, was likely a result of neural activity tied to dopamine release. Placebo administration can also prompt the release of a neurotransmitter called serotonin, which functions as a mood stabilizer [9]. Opioids are another type of chemical that function similar to neurotransmitters, attaching to receptors on our neurons to act as pain and immunity regulators [10]. This is why patients who ingest naloxone report feeling more pain; naloxone blocks opioids from activating these receptors, effectively “barricading” the doors needed to activate their neural networks and weakening their brain’s ability to regulate pain [4]. In order to understand the neural mechanisms underlying the placebo effect, scientists turn to innovative brain imaging techniques to identify which brain regions are activated in response to placebo administration. One such technique is functional magnetic resonance imaging (fMRI), which tracks brain activity via changes in blood flow that occur in response to neural activation [3]. fMRI imagery has demonstrated that opioid receptors in the brain are activated following placebo administration; when these receptors are triggered, they ultimately lessen pain levels [8]. This is

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The Scientific Magic of Belief because the placebo activates a pathway that causes the brain to release endogenous opioids — or opioids secreted within the brain— which then activate these receptors to facilitate pain relief. The increase in endogenous opioid levels is traced by fMRI through changes in blood flow [11, 4]. Another imaging technique that allows us to visualize placebos neurologically is Positron Emission Tomography (PET), which tracks molecular movement using radioactivity and identifies changes in biochemical activity within brain tissue [12]. PET scans can demonstrate if administering a placebo leads to increases in metabolic activity, which includes the synthesis and breakdown of essential molecules in the body [12]. These molecules affect the secretion and activation of the neurotransmitters involved in generating the placebo effect. For patients diagnosed with depression, PET scans have shown that administering a placebo leads to higher levels of glucose metabolism in the brain, which facilitates the synthesis of neurotransmitters that improve patients’ ability to regulate their emotions [13]. These imaging techniques demonstrate that the placebo effect impacts neurological function through its alterations to metabolic activity and neurotransmitter levels within particular brain regions [9].

The brain regions that are most responsive to the placebo effect typically receive and transmit signals associated with pain, emotional expectation, and motor function [14]. These regions include the anterior cingulate cortex (essential for emotional regulation and pain management), the prefrontal cortex (involved in complex decision making and emotional regulation), and the amygdala (responsible for our emotional processing) [7, 14]. Opioid receptor activity tracked via fMRI reveals that patients’ expectation of pain relief activates the anterior cingulate cortex, increasing this region’s endogenous opioid activity [4]. The PET scans tracking metabolic activity post-placebo show a spike in activity in the thalamus (transmitter of external signals to other brain regions) and anterior cingulate, suggesting that the emotional regulatory pathways activated by placebos could have mood-stabilizing effects comparable to active antidepressant treatments [12]. It’s important to note, however, that ample data exists on how placebos affect these brain regions because they are the most frequently studied in drug efficacy trials [14]. Further research that focuses on other brain regions may reveal placebo-induced neural activity elsewhere in the brain. Using these imaging techniques, however, is limited by

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The Scientific Magic of Belief the level of precision with which they can track brain function. PET scans have restricted spatial resolution, which means that due to the large pixel sizes of images, the ability to distinguish between different regions of the brain situated close together is diminished [15]. fMRI does not directly measure neural activity, but rather relies on increases in brain blood flow to determine where activity is taking place [1]. This may prevent it from tracking the precise effects of placebos on neurotransmitter release and metabolic activity. These limitations can make it difficult to determine whether or not brain activity is the direct result of the placebo effect. Despite their drawbacks, these techniques are standard in the field of neuroscience to track the effects of injury, disease and drug intake on brain function, making them generally reliable in revealing the complex neural mechanisms underlying these phenomena [16].

enter a calmer emotional state, activating the brain areas necessary to regulate pain [17]. People with chronic (i.e. long-term) motor disorders, like Parkinson’s disease, have also benefited from placebo treatments. For instance, many patients with Parkinson’s who believe that they are receiving treatment medication experience improvements in hand movement even without the administration of active medication. Data from PET scans has revealed that this effect in the brain likely results from an activa-

“SHAM” TREATMENTS BECOME GENUINE: TARGETING DISEASE WITH PLACEBOS Tracking placebo-responsive neural activity has become an increasingly popular technique in recent clinical trials exploring this fascinating phenomenon [4]. Many of these trials target pain-related disorders, because the physiological processes underlying pain reception in the brain are particularly well understood in clinical medicine [4]. Disorders like Irritable Bowel Syndrome (IBS) and chronic migraines, for example, are characterized by periods of prolonged pain and discomfort [17, 18]. Current research focuses on how brain activity changes when pain-relieving placebos are administered, and how successfully they can alleviate any associated symptoms. For instance, PET scans have been used to determine how placebo treatment affects the level of intestinal discomfort felt by IBS patients [17]. PET data reveals an increase in prefrontal cortex activity and reduction in amygdala activity following placebo administration [17]. These findings indicate that when IBS patients expect pain relief they

tion of dopamine receptors in response to expectation-driven dopamine release [19]. However, there are still drawbacks to these applications, as the benefits gained from placebo treatment have only been successful short-term [20]. Because it appears that the placebo effect is only a temporary method of alleviating pain and improving movement control, clinical research is now pointed towards identifying ways to sustain these responses over longer periods of time — at least until an active pharmaceutical drug is found to be more effective for treatment [20].

WHEN PLACEBOS MEET GENOMES: THE PLACEBOME THEORY

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The Scientific Magic of Belief Placebos vary extensively in how they interact with one’s neurological system, as well as how the person being treated responds. But what if we could accurately predict how well one would benefit from being given a placebo, even before administering it to them? By examining an individual’s DNA, could we reliably determine who will respond well to a certain placebo treatment? The newly emerging placebome (placebo + genome) theory suggests that we can, positing that genetic differences among patients can give rise to differences in neural responses when a placebo is administered [21]. Our genetic makeup is intricately linked to neural and biochemical activity in our bodies; common traits like lactose intolerance and having a sweet tooth, for example, are the result of chemical activity driven by the instructions encoded in our genes [22, 23]. Similarly, the placebome theory states that individual differences in the genes coding for essential molecules in neural systems, such as proteins and neurotransmitters, can also alter how the placebo effect manifests in patients [21]. Understanding how genes mediate a placebo response requires the identification of genetic biomarkers, which are the specific sections of genes involved in encoding the molecules of interest [21]. Biomarkers differ from patient to patient, and help account for individual differences in the number of molecules that are synthesized as well as the rate at which they are made; both the number and rate of molecule production can impact the degree of placebo response induced [21]. In patients with IBS, three variations of biomarkers, which code for a key protein that interacts with dopamine, have been identified [24]. Of these variations, only one activates a dopamine pathway that reduces pain significantly after a placebo is given [24]. In addition, fMRI imaging on people with social anxiety disorder has shown that those bearing a particular biomarker experience higher levels of serotonin release in response to a placebo, which is indicated by a reduction in amygdala activity [25]. By utilizing patients’ genetic predispositions to placebo treatment, it is possible to identify the most placebo responsive patients, and choose them to participate in clinical trials [21]. Doing so can generate more precise data on the efficacy of actual drugs in drug-test trials, and reduce the cost of recruiting participants. The placebome-focused approach is also a great preventative measure for identifying individuals that have the potential to react adversely to placebo administration, which can prevent risking patient health during clinical research trials [26]. While our understanding of the placebome theory is in its early stages, it holds great

potential to pave the way for personalized medical care for patients with chronic illnesses.

FAKE IT ‘TILL YOU MAKE IT Evidence of the placebo’s peculiar effect on the brain suggests that our expectations and beliefs have tremendous potential to influence our physical states. However, there is still a lot to learn about the neurological processes underscoring this phenomenon. We have yet to determine if there is a primary neural pathway or cluster of pathways associated with placebo activity, or if it is possible to modify genetic biomarkers to make patients more placebo-responsive. These questions may soon be answered as the many new drug-discovery projects exploring this field of clinical medicine begin transforming how we approach treatment for short-term and chronic illnesses. And maybe with our newfound appreciation for the mind’s great potential, we can change how we approach our responses to daily life, too. Perhaps the next time you’re stuck in a steamy space and ask a friend to let in some air from another room, you may not have to bother checking to confirm if the breeze is real – just sit back, relax, and let your brain cool you down. References on page 56.

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Facing Our Fears

by Alex Tansey art by Ella Larson

FACING OUR FEARS: EXTINGUISHING CONDITIONED FEARS WITH EXPOSURE THERAPY GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 4

Facing Our Fears ou wake up one Sunday morning, ready for a proYsmell ductive day of studying. Everything is just right; the of freshly-brewed coffee wafts from your mug,

your laptop is charged and ready to go, and your favorite album plays through your headphones. Then you see it. No more than ten feet away, a tiny, fuzzy black speck crawls across the floor. It’s heading right towards you! As it moves closer and closer, your heart begins to race at a million miles per second, sweat streams from your palms and forehead, and your chest tightens. You throw the heaviest book you can find at the tiny spider as you flee from the room crying for help. These moments of utter panic are common for someone who suffers from arachnophobia, the clinical term for a fear of spiders. Arachnophobia is just one common fear that people can develop, but it is possible to have a fear of virtually anything; for instance, many people fear confined spaces, snakes, or public speaking. For some individuals, these fears can be intense and debilitating, causing anxiety that interferes with work, social life, and general wellbeing. Psychologists can help to reduce these negative effects of anxiety through a treatment known as exposure therapy, in which individuals are repeatedly exposed to objects and situations they fear without being harmed by them, thus learning that there is no true threat. Those who try exposure therapy may find that the anxiety returns with time, or when encountering their fear in a new place. It is therefore crucial to explore how to reduce the possibility of the anxiety returning. This can be accomplished by adapting exposure therapy so that it translates to broader scenarios in the real world. To maximize the effectiveness of exposure therapy for anxiety disorders, treatment needs to be altered to include a greater number and variety of environments where an individual may encounter fearful stimuli.

ANXIETY, FEAR, & WHY HIDING FROM SPIDERS WON’T WORK FOREVER To explore how to most efficiently treat anxiety disorders, we must first understand its symptoms and triggers. Anxiety disorders are characterized by excessive, persistent fear and anxiety leading to emotional distress and impaired functioning [1]. Fear is defined as the emotional reaction to a perceived real or imminent threat, while anxiety is a reaction to the anticipation of a future or hypothetical threat [1]. For example, you may experience fear when you see a spider next to your bed, but you may feel anxious for the next few days when it escapes and you are waiting for it to

return. Anxiety can be temporarily reduced via avoidant behaviors, like sleeping on the couch in the living room, in order to avoid encountering the spider. Avoidant behaviors can prove to be detrimental to one’s life, as they add stress and limit a person’s ability to accomplish everyday tasks. In the long run, avoidant behaviors fail to address the root of your anxiety; two or three weeks after seeing the spider in your room, the anxiety-inducing association between the spider and your bedroom may linger. This is because of a difficult-to-break phenomenon known as fear conditioning. Fear conditioning is the framework through which anxiety-related disorders can develop. This concept is a form of Pavlovian conditioning, which occurs when an animal or human subject learns to associate an unconditioned stimulus with a conditioned stimulus [2]. The unconditioned stimulus can be any object, environment, or event which elicits a natural response in the subject. For instance, if you see your favorite food at a buffet, your mouth might start to salivate — the salivation is your natural response to the unconditioned stimulus (i.e. food). The conditioned stimulus, on the other hand, is something that becomes linked with the unconditioned stimulus, eventually causing the natural response by association. Fear conditioning is defined by when this conditioned stimulus, like the unconditioned stimulus, induces fear [2]. One infamous example of fear conditioning in humans is the Little Albert experiment, in which a toddler learned to associate a lab rat, the conditioned stimulus, with a loud and scary sound, the unconditioned stimulus; eventually this association caused the toddler to fear the rat itself [3]. The loud sound is the unconditioned stimulus as it caused a natural reaction in Albert. The rat is the conditioned stimulus because it only elicited fear in Albert once he learned to associate it with the scary sound. As Albert heard the loud sound, his amygdala –– a brain region involved in emotions, social learning, and memory –– was activated, causing

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Facing Our Fears Albert to associate the rat with fear and then consolidate that memory to make it more stable [4, 5]. Once a conditioned fear is cemented in your memory, breaking the association between the two stimuli can be incredibly difficult. This is where extinction becomes useful. The goal of extinction is to attenuate the learned relationship between the conditioned stimulus and the unconditioned stimulus. Extinction occurs through the repeated presentation of the conditioned stimulus by itself, not followed by the unconditioned stimulus [6]. For example, a therapist treating a patient with arachnophobia may repeatedly present their patient with a spider in a controlled, safe manner so that the patient can learn that there is no threat. Using fear extinction to treat anxiety disorders in a therapeutic context is called exposure therapy [6]. As exposure to a spider may feel unmanageable for those with arachnophobia, people can be exposed to their distressing stimulus in increasingly intense stages in order to help them feel more comfortable. Rather than jumping straight into using a real spider in therapy sessions, a therapist may begin by presenting their patient with a photo of a spider, followed by live spiders from a distance, then spiders up close, until they are eventually comfortable enough to hold a spider in their hand. If someone with arachnophobia is exposed to a spider multiple times and consistently experiences no harmful consequences, they will begin to form a new associative memory encoding spiders as safe [7, 8]. Their amygdala would then work to stabilize this new association into long-term memory [5].

FEARS DON’T REMAIN QUITE AS EXTINCT AS THE DINOSAURS After weeks of observing and touching spiders in your therapist’s office, you finally feel like your arachnophobia is fading. That is, until you return home one night to see a spider sitting right in the middle of your bedroom. The fear floods back. Had all of those weeks in therapy been fruitless? It is important to note that extinction and exposure therapy are context-specific; while an arachnophobic individual may have felt less fear in the therapy room context, the fear may return if they are exposed to a spider in the wild. The hippocampus, a brain structure known for its role in memory, plays an important part in this contextual aspect of fear, as it is involved with remembering when and where an aversive experience occurred [9, 10, 11]. The context-specificity of exposure therapy makes it difficult for the development of long-term benefits. Fear can return when in a new environment because, de-

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Facing Our Fears

spite its name, extinction does not actually erase the original fear [12]. Rather, extinction only provisionally suppresses fear, and may not work well in contexts other than that of the practice sessions. The phenomenon known as renewal demonstrates that a seemingly-extinguished fear can return when outside of the extinction context [12]. Imagine that Little Albert went through exposure therapy enough times in the lab without a loud sound for him to learn that the rat is no longer a threat. If he were to then see a rat in a different context, such as in his house, his fear may return. The specificity of context-dependent extinction thus causes many people who go through exposure therapy to experience relapses of their fear and anxiety when they encounter the stimulus in a new place. Relapses of fear following exposure therapy are based on activity in the prefrontal cortex and the hippocampus — the two brain regions largely responsible for the retrieval of extinction learning. The prefrontal cortex aids in the recall of extinction learning over time, reducing the chances that your fear returns spontaneously [13]. Conversely, activity in the hippocampus can hinder extinction learning; hippocampal activity strengthens the connection between extinction training and environment, increasing the chances that the fear will return outside of the original extinction context [10, 11, 9]. This high likelihood of fear renewal following exposure therapy underscores the need to adapt therapy to be efficacious both in the long term and in many different environments. Such an adaptation may be possible via a process known as generalization. Generalization of extinction learning is necessary for

exposure therapy to work outside of the therapeutic context. The Little Albert experiment not only exemplified fear conditioning but also demonstrated the phenomenon of stimulus generalization, or the ability to learn from a specific experience and apply that learning to similar situations [3, 2]. Little Albert reacted with fear not only towards the rat but also generalized his fear towards other vaguely rat-like objects and animals, such as fur coats and rabbits. This may be beneficial in some cases as it allows us to learn from aversive experiences and avoid them in the future. Yet, the Little Albert experiment shows that over-generalization of fear-inducing stimuli causes harmful anxiety when there is no actual threat present [2]. Generalization of extinction learning can be used to combat anxiety by increasing the number of environments in which fear is reduced. Using a variety of contexts and stimuli in exposure therapy increases the number of characteristics associated with extinction. This expands the quantity of situations that extinction learning can generalize to [14]. Exposure therapy is most effective when the learning can be applied beyond the therapy room itself due to the ever-changing nature of the real world. So how can we design and access a variety of therapy contexts without having to travel to different places or refurbish the therapist’s office? The answer may lie in virtual reality (VR) technology.

EXTINGUISHING REAL-WORLD FEARS IN VIRTUAL ENVIRONMENTS While you may only associate VR with epic new video games or avant-garde art exhibits, this technology is actually incredibly useful for exposure therapy as it can provide a wide range of contexts and stimuli not otherwise accessible; when participants practice exposure in a broad scope of scenarios it may increase the generalizability of the treatment. You might be thinking: won’t our brains know that the environment is fake? While it may seem like we are exceptionally talented at distinguishing reality from the virtual world, our brains actually respond very similarly to movements and perceptual changes in virtual env i ro n m e n t s as they do in reality [15]. P a n oramic

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Facing Our Fears are essential to extinction training in order to reduce the chances of fear or anxiety relapse. This relapse could occur when the patient is exposed to the conditioned stimulus somewhere other than the place where the patient first became afraid. Similarly in virtual exposure therapy, exposure to a virtual fear-inducing stimulus in different virtual extinction contexts successfully reduced chances of fear relapse [25, 26]. Studies like this and the shark study take advantage of the freedom that VR can give to easily adjust realistic contexts. VR may prove exceedingly useful in an everyday clinical setting as well.

virtual environments elicit emotional and physical reactions and are therefore effective tools for measuring reactions to real environments [16]. Exposure therapy using VR has already been shown to be as effective as real-life exposure in reducing specific phobias and agoraphobia, or fear of places in which one may feel panic or embarrassment [17]. In one case, a patient sought therapy for a debilitating fear of sharks. Clearly, obtaining a live shark, bringing it inside a therapist’s office, and safely exposing it to the patient would be practically impossible. Instead, the therapist provides the patient with a virtual body of water to “swim” in [18]. As the patient swims, the therapist makes a 3D model of a shark move close to the surface. As soon as the patient expresses excessive anxiety, the therapist makes the shark retreat, and reappear when the patient’s anxiety has diminished enough that they are ready to try again. Many other anxiety disorders, such as fear of flying, fear of blood, or fear of injury, are difficult or impossible to treat with real-world equivalents.VR technology truly expands treatment possibilities by conveniently reproducing a wide variety of contexts and stimuli. The VR shark experiment used a variety of virtual environments, including an outdoor swimming pool, a lake complete with fish and moving water, and a sandy beach in order to increase the effectiveness of therapy [18]. Rather than using just one environment, multiple extinction contexts like these can increase the generalizability of extinction learning. For instance, exposure to a real-life spider in multiple extinction contexts reduces fear renewal for people who are highly anxious of spiders [19, 20, 21]. Numerous extinction sessions, long-term exposure practice, and the incorporation of exposure environments similar to the initial fear acquisition context all improve this intensity of this effect [22, 23, 24]. Thus, multiple surroundings 32

VR can be utilized not only to increase the availability of contexts in exposure therapy, but also the options for stimuli, in order to improve the generalization of exposure therapy. For example, exposing someone with arachnophobia to multiple types of virtual spiders may be more effective at reducing fear in comparison to just using one type of spider. This has been supported in a real-world lab setting, as those exposed to four different real-life tarantulas showed reduced fear in the long term in comparison to those exposed to only one [27]. However, it may be unrealistic or unsafe for therapists to have access to live spiders in their sessions. VR is therefore a much more viable alternative for deploying multiple stimuli, successfully leading to a long and short term reduction of fear [28]. This method of increasing generalization could be applied to other phobias by using virtual stimuli such as different animal species, people, and heights. Though, there does not seem to be any special benefit to incorporating both context cues and stimulus generalization simultaneously [28]. This could be due to expectancy violation theory, in which extinction learning has a stronger effect when there is an unexpected occurrence in comparison to when there is an expected occurrence [28]. Imagine you enter a familiar room and see a spider; you would naturally be more surprised than if you are going into a completely new room and encounter a spider. While both a variety of contexts and a variety of stimuli may increase the success of exposure therapy, therapists may need to focus on only one of the two methods. Further study should explore which of the two treatments is more effective depending on specific patient needs. Future VR studies should also distinguish a means to incorporate other sensory elements such as touch and smell, which may be important in order to translate more realistically to real-world contexts and triggers. One case study did successfully incorporate tactile elements, in which a spider-phobic patient could touch a physical replica of a spider during virtual exposure

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Facing Our Fears sessions [29]. Including other sensory elements consequently elevates the realism of virtual exposure. VR is indeed a fascinating field to expand the possibilities for what can be accomplished within a single therapy space. It can be used as one of the first steps of exposure to distressing stimuli prior to more invasive real-world exposures.

WE’RE NO LONGER DOOMED TO FEARFUL FATES

they are being exposed to is not real. In fact, it has been found that more people report willingness to do VR exposure therapy than in-vivo exposure therapy [30, 31]. Perhaps this new technology can be an incentive for more people to seek and benefit from exposure therapy. And maybe when you find yourself confronted with that little black spider next time, you can think back to this article and remember he wasn’t so dangerous after all. References on page 57.

Exposure therapy is a go-to treatment for anxiety disorders, and while it is beneficial, improvement is needed in order to maximize its effectiveness in the long term. By introducing a greater number of contexts and stimuli during exposure training, extinction learning will be able to generalize towards a more diverse amount of real-world scenarios, decreasing anxiety beyond the controlled lab environment. Since gaining access to these environments and stimuli may not always be feasible, VR fills that gap to provide an extended amount of realistic virtual environments for patients to explore. VR may also encourage more people to seek help for phobias, as it may feel more approachable to know that w h a t

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Conversion Disorder

CONVERSION DISORDER: THE DIAGNOSIS HIDDEN IN EPILEPSY’S SHADOW by D’Souza / artCOLLEGE by Sneha 34 Avery Bauman, Alexa Gwyn, GREYCarina MATTERS JOURNAL AT VASSAR | ISSUE 4Das

Conversion Disorder At twelve years old, it feels like every social rejection is the end of the world. Every jab at your outfit feels paralyzing. Every unreceived party invitation feels like a stab in the back. But what if we weren’t just speaking metaphorically? For twelve-year-old Lucy, daily bullying at Westbrook Middle School led to strange physical symptoms that landed her in the office of Dr. Weston, a pediatric neurologist specializing in epilepsy. It’s here that one of our authors met Lucy, became interested in her complex condition, and began considering the insight it offers on the connection between mind and body.

clinics. This alarming percentage is explained by the fears surrounding delayed epilepsy diagnosis; physicians often rush to interpret symptoms as epilepsy, even when conversion disorder may be a possibility [4]. By understanding PNES’s origins, diagnostic criteria, treatment options, and distinctions from epilepsy, we can reduce dangerous misdiagnoses and get patients the help that they need.

Seventh grade had been a challenging year for Lucy. When she first started experiencing back pain, her parents brought her to see a chiropractor. It didn’t help. When Lucy told her parents her vision was blurry and her eyes hurt, they brought her to an eye doctor. She started wearing glasses, but that only seemed to make the blurriness and pain worse. The most concerning symptom was her staring spells; during these 10 to 20 second intervals, Lucy would stare blankly into space, almost as if she were in a different world. Her parents worried that these might be seizures, so they made an appointment with Dr. Weston. She ran a few tests and informed the family, to their relief, that there were no neurological abnormalities. While in the office, Dr. Weston also asked Lucy a few questions about her friends, media use, and life at school. Lucy’s parents were confused: what could this possibly have to do with all the pain she had been experiencing? Dr. Weston explained that Lucy may have conversion disorder, a physical manifestation of the psychological stress of bullying. Conversion disorder (CD) is a psychiatric illness in which traumatic events and psychological distress manifest as physical symptoms [1, 2]. As its name implies, psychological stressors are quite literally “converted” into physical ailments, which typically manifest as the loss of function of body parts. These physical symptoms are labeled psychogenic: the prefix “psycho- ‘’ refers to the mind, while “-genic” denotes production. Therefore, psychogenic symptoms refer to those generated by the mind. The symptoms that patients with CD experience are very real, however, and failure to correctly diagnose their condition may only lead to more pain and suffering. Unfortunately, conversion disorder is often misdiagnosed as epilepsy due to the conditions’ overlapping symptoms [3]. In fact, misdiagnosis rates have risen to 20% as of 2016 [4]. Our subtype of particular interest — psychogenic nonepileptic seizures (PNES) — accounts for 10-20% of the cases mistakenly referred to epilepsy

DAVID: ANOTHER PERPLEXING CASE The causes for conversion disorder can vary from person to person. Whereas Lucy’s disorder stemmed from bullying, CD can occur due to many kinds of traumatic events, surfacing as a variety of symptoms. A case study of a 17-year-old high school junior named David is one such example: he was violently beaten and shot in the head several times, sustaining numerous severe

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Conversion Disorder brain injuries and subsequently falling into a coma for a year [2]. David was initially diagnosed with post-traumatic epilepsy, a condition characterized by epileptic seizures related to a traumatic brain injury. These seizures typically present as physical convulsions and can lead to loss of consciousness [5]. For the next 20 years, David suffered from convulsive seizures up to eight to nine times per month. Strangely, his prescribed antiepileptic drugs — which are usually effective in treating epilepsy-related conditions — were of little help [6]. In addition to debilitating seizures, David was left with temporary paralysis for days, blindness, and bipolar disorder [2]. Doctors discerned that the symptoms were not a result of physical damage in David’s brain due to the violent attack; so, they began looking into neurological disorders that could present as David’s symptoms. While these symptoms might have pointed towards post-traumatic epilepsy, David’s neurological exams came back normal [2]. Could it be possible that, as with Lucy’s case, something else was causing David’s symptoms? Though post-traumatic epilepsy was ruled out, his report did meet the diagnostic criteria of PNES [1, 2].

PINNING DOWN THE ORIGINS OF A SEIZURE: PNES VS. EPILEPSY Simply put, PNES is psychologically based while epilepsy manifests physiologically and can be identified by detectable brain abnormalities [7]. However, PNES is commonly misdiagnosed as epilepsy because both disorders share a main symptom: seizures. With epileptic patients, seizures can present as irregular electrical activity in the brain [8]. Let’s break this down: the neurons in your brain create electrical signals through the movement of charged particles across cell membranes, and this neuronal signaling is what allows for typical brain function. When viewed through a computer, these electrical signals then appear as waves [9]. These waves have properties known as frequencies, heights, shapes, and locations; these are the markers used to determine what’s considered “normal” in healthy patients. Disruptions of these normal patterns are known as seizures; if they occur twice in 24 hours, doctors diagnose the patient with epilepsy [10]. However, PNES patients exhibit normal

wave readings. Since brain scans measure physical abnormalities in the body, psychologically-generated seizures cannot be detected. These results suggest that the seizures in PNES are non-epileptic –– one of the most important delineations between these two disorders. Stress-induced, non-epileptic seizures are related to traumatic psychological experiences [11]. For David, it was an isolated traumatic event, rather than chronic trauma or stress, that coincided with the start of his symptoms. For Lucy, it was prolonged social struggles that culminated in physical distress, and ultimately her symptoms. What makes the manifestation of this CD subtype so interesting is its similarities to epilepsy and how the resulting misdiagnosis can have detrimental effects on the patient.

SOLVING A DIAGNOSTIC PUZZLE: THE NEUROLOGICAL DIAGNOSIS OF PNES Determining the proper diagnosis for a neurological disorder requires looking through a magnifying glass, metaphorically speaking. We can glance at an individual from afar and assess their general behavior, but the pathological underpinnings of their disorder require a closer look. One approach to identifying PNES is by conducting neurological assessments. Electroencephalograms (EEG) are neurological assessments performed by attaching electrodes to a patient’s scalp in order to monitor electrical activity [9]. This is an effective method to assess neuronal communication, as neuron behavior is largely electric. When neurons function properly, a normal EEG shows consistent electrical wavelengths without added spikes or waves [8]. However, epileptic patients experiencing seizures show EEGs that look more like a scribble with a multitude of peaks. The issue arises when an EEG comes back normal, showing signals without spikes, even though an individual is visibly displaying seizure activity [12]. This is a common sign that the patient may suffer from PNES; since PNES is a purely psychological disorder, rather than physical, electrical activity in the brain is unchanged. In addition to EEG findings, magnetic resonance im-

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Conversion Disorder aging (MRI) can help to determine whether or not a PNES diagnosis is possible; similar to EEGs, when these scans indicate “normal” neural structure results, we can rule out the diagnosis of epilepsy [2]. Using the body’s magnetic properties, MRIs produce images that provide insight into the brain’s structure [13]. MRIs detect pathological anomalies in the brain, such as tumors, blood vessel malformations, or damage to the different areas of the brain [14]. In epileptic patients, structural brain differences can be the missing piece that contributes to the disordered state. Doctors use MRIs to see if these abnormalities are causing the seizures and if they can be surgically removed. In PNES patients, no such anomalies exist; just like with EEGs, a normal MRI scan helps to confirm a PNES diagnosis. Interestingly, this means that a PNES diagnosis needs two “normal” neurological exams as criteria for diagnosis [1]. In other words, these neurological tests aid in diagnosis by showing the absence of abnormality rather than identifying neural dysfunction. As demonstrated in David’s case study, MRI and EEG results for individuals with PNES often present identical results to those who are healthy [2]. By conducting these assessments, doctors can essentially rule out epilepsy as a cause of seizures and explore other explanations, like PNES. Because PNES has a psychological basis, however, doctors must delve beyond the neurological characteristics of the disorder.

ANOTHER PIECE OF THE PUZZLE: PSYCHOLOGICAL DIAGNOSIS OF PNES From afar, epilepsy and conversion disorder appear nearly identical. To differentiate between them, physicians must look not only at the neurological, but also the psychological aspects of the individual presenting symptoms. Psychological assessments, like patient health questionnaires, seek to quantify the specific symptoms of an individual, supplementing neurological assessments with qualitative experiences.

Although neither neurological nor psychological assessments suffice for diagnosis alone, using them in combination can increase the likelihood of proper diagnosis [15]. In David’s case, his post-traumatic stress arose as specific physical symptoms in the body — a defining occurrence among PNES patients [2]. Using an objective personality test, physicians can assess the clinical significance of these symptoms [16]. A range of quantitative parameters is used in personality tests to provide a full picture of the patient’s psychological functioning. Personality tests are coupled with patient health questionnaires to dive even deeper into why a patient may be experiencing symptoms. More often than not, PNES patients tend to believe their symptoms are largely physical and downplay the contribution of psychological conditions to their disorder [16]. By listening to described symptoms like stomach pain, fatigue, and mood changes, physicians can determine whether or not to screen for disorders with psychological underpinnings [15].

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Conversion Disorder

REWIRING THE BRAIN TO TREAT PNES After tackling the gigantic hurdle of diagnosing PNES, the next step is to explore treatment options. Given that a plethora of drugs exist to treat seizures in epileptic patients, you may wonder: why can’t these same medications be administered to people suffering from PNES? David was originally misdiagnosed with epilepsy and provided with multiple antiepileptic medications. Despite being the leading treatment option for epilepsy, these antiepileptic drugs offered no relief, illustrating the ineffectiveness of epilepsy treatment for PNES patients [2]. Even just the process of testing the different antiepileptic medications can take enough time to extend the misdiagnosis of epilepsy and further impede a conversion disorder diagnosis [17]. Treating these seizures incorrectly with medication is also extremely risky. David — and anyone with misdiagnosed PNES — can attest to this, as antiepileptic drugs can have dangerous adverse effects on the body [2, 18]. Interestingly, patients with psychogenic nonepileptic attacks have a reduction in seizure frequency and improved health when taken off antiepileptic drugs [19]. David’s misdiagnosis and improper treatment caused him to suffer for 20 years, only to be cured of his symptoms six days after receiving a PNES diagnosis and proper treatment [2]. Common treatments for conversion disorder, such as cognitive-behavioral therapy (CBT), include attempts to retrain the brain to fix damaged connections between the mind and body. As opposed to taking medication for epilepsy, where treatment induces physiological changes, CBT focuses on individual psychology and aims to address the root of PNES. This is accomplished by evaluating the mental and environmental triggers underlying the disorder. Patients then learn to be more mindful since they have identified what may actually be contributing to the disorder [20]. Fortunately, this therapeutic technique may be successful in treating PNES, as it has been found to reduce seizures by 50% of disordered patients tested [21]. In addition to CBT, other treatment options include managing stress and using antidepressants or anxiolytics to treat the underlying causes of stress in the patient [21]. The medical risks to people are not the only issue, though — the misdiagnosis of PNES is burdensome and costly to the healthcare system at-large. Just the initial diagnosis requires expensive tests that are billed to the individual; once the diagnosis has been made, they would likely be prescribed antiepileptic medications that are not only costly but also use up valuable 38

resources [22, 23]. In addition, the individual was likely subject to exorbitant fees for unnecessary diagnostic testing as a result of this simple misdiagnosis [24]. Thus, in order to avoid these financial burdens to both the individual and the healthcare system, it’s essential that a proper diagnosis be made as soon as possible.

PULLING CONVERSION DISORDER OUT OF THE SHADOWS Modern advancements have allowed the medical field to be characterized by the “knowns:” we know the severe health repercussions of smoking, we know how to treat a broken bone, we know that the appendix is not necessary for survival. However, psychogenic nonepileptic seizures seem to be characterized by the “unknowns;” we don’t yet know how to diagnose it, what causes it, or what treatments will work best. This unfortunate fact makes it extremely difficult to efficiently alleviate PNES patients’ symptoms. Even when a doctor suspects a patient might have PNES, the lack of substantive research on the disorder prohibits them from offering a definitive diagnosis or effective treatment. Further research exploring this unique condition is essential in helping doctors correctly diagnose PNES from the start. Considering that the disorder appears quite treatable, the more promptly a diagnosis can be made, the more quickly a patient can get relief from their debilitating symptoms. Luckily, new technology and data offer some hope for future proper diagnoses. For instance, functional MRIs — a specific type of MRI focused on how blood flow changes in the brain — show great promise in accurately diagnosing conversion disorder [25]. And, although normal EEGs do not generally show differences between PNES and healthy patients, quantitative EEGs (qEEG) have emerged as a tool to help illuminate the neural underpinnings of PNES via statistical analyses [12, 26] Increasing awareness of this disorder along with advances in modern medicine will help to avoid the frustration of prolonged mistreatment. It’s time to understand PNES distinct from our scientific grasp on epilepsy; only then will PNES patients get the help they need. References on page 59.

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Animal Venom Neurotherapy

ANIMAL VENOM NEUROTHERAPY FORGES THE FUTURE USING THE PAST by Sloane Boukobza art by Sophie Sieckmann

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Animal Venom Neurotherapy Nature’s creations can be both harmful and beneficial in unexpected ways. The ruby red berries that you see on a hike through the woods may be lethally toxic, while the leaves hanging above you could be made into a salve for burns. In the natural world, there exists a stable yet complex equilibrium of heal and harm. As humankind evolved, we learned to harness beneficial features of nature: certain animal bones became our hunting tools, flint and rock became our firestarters, and venom became a therapeutic tool [1, 2]. Despite these origins, more recently we have strayed from using nature’s remedies and instead favor relying on medication synthesized in laboratories. Scientists have spent time and resources creating new cures for pain and disease when venom’s neurotherapeutic solutions may have been already lying at their feet — or rather, between the leaves, under the sea, and flying through the air above. In pharmacies around the country, opiates are one of the most abundant forms of pain medication [3]. However, the societal devastation caused by opiate addiction has driven a search for alternative therapies. Meanwhile, research on neurodegenerative diseases — diseases marked by the deterioration of neural functioning — has plateaued due to the focus on therapeutic over preventative measures [4]. Animal venom research may be a fruitful path in determining pain relief alternatives to opiates and finding a cure for neurodegenerative disorders. Imagine: if wielded correctly, a snake’s sharp fangs may be your friend, a bee’s sting could benefit you, and a painful sea anemone could be much more than a dangerous bundle of tentacles. The venom from our friends of the sky, earth, and water might just be the key to a host of medical advancements.

WHO WILL WIN THE RACE: MORPHINE, SNAKE VENOM, OR PAIN? Over the past 30 years, the addictive quality of opiates and painkillers has spawned an epidemic across the United States. Considering that 98% of patients are prescribed opiates following surgery, it’s no wonder the rate of opiate dependency has skyrocketed [5]. In 2017, the U.S. Department of Health and Human Services declared opiate addiction to be a public health emergency [6]. A five-point strategy was announced in an attempt to end the epidemic: (1) prevent and treat addiction, (2) distribute overdose-reversing drugs, (3) strengthen public data collection, (4) support addiction research, and (5) advance pain management research [6]. Unfortunately, the implementation of this

strategy did little to calm the crisis: the number of overdose deaths by all opioids has increased six-fold from 1999 to 2017 [6]. However, while all eyes were focused on this mostly ineffective tactical plan, a scaly friend slithered into the limelight and bared its fangs to offer a solution.

Snakes of the Elapidae family, such as Indian spitting cobras and black mambas, are known for their potent neurotoxic venom [7]. Neurotoxic venom is composed of peptides (the building blocks of proteins) that disrupt the function of cells in the nervous system by either blocking signals between the brain and body or causing neuron death [8, 9]. As soon as a cobra bites its victim, venom is injected into the bloodstream; this paralyzes the respiratory system and kills the victim through lack of oxygen [10]. Peptides in venom vary between snake species, but thanks to these molecules’ large variation in shape and size, they are remarkably similar to proteins and peptides found in the human body [10]. This molecular overlap allows the venom to target and bind to specific neurotransmitter receptors in the human body [11]. Neurotransmitters are chemical messengers used to propagate chemical signals throughout the nervous system [12]. Similarly, neuropeptides act as signaling molecules that are secreted from neurons that communicate pain, fear, and stress to the body’s response systems; certain neuropeptides play an integral role in the body’s pain response [12, 13]. When we are injured, these proteins initiate a

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Animal Venom Neurotherapy signaling pathway to the vital organ that causes our body to experience subsequent pain: the brain [13]. When venom peptides attach to these receptors, they saturate the receptor sites and prevent the pain-related neuropeptides from binding. With nowhere to bind, the peptides can no longer stimulate the pathways that cause us to feel pain [14]. Neuropeptides and receptors specifically fit each other, and can be thought of as a square block and a square hole. The neuropeptide releases a neural signal after slotting into place, like the sound that the block makes as it falls into the hole. However, when a snake bites down and injects venom into its victim, venom peptides block these neuropeptide receptors by filling the square-shaped hole themselves. Venom peptides act like a large piece of play-doh: molding to and sticking in the receptor site, they obstruct neuropeptides from binding to the receptor [14]. Because venom peptides adapt to obstruct a wide variety of receptors — for example square, circle, or star-shaped blocks — they can overwhelm the body’s large-scale communication pathways and lead to seizures and paralysis [15]. This is why black mamba venom can kill a human in less than 20 minutes [16]. In other words, a black mamba bite will bring death in the time it takes to watch an episode of Friends, but at least you won’t feel anything [16]!

The snake’s head must be guided to bite down through a latex film covering a glass vial to collect the venom, and the animal poses a constant threat, regardless of the snake handler’s experience [19]. Research has shifted towards stem cell therapy to replicate venom glands in snakes and address issues of scarcity [20]. Stem cells have the ability to differentiate many kinds of cells, including neurons, liver cells, and everything in between; these cells’ diverse set of potentials makes them incredibly useful in modern research [21]. In fact, when you were a developing embryo in your mother’s uterus, your body was almost entirely made of stem cells, and now you’re you! By culturing stem cells to mimic venom-producing glands, scientists have been able to grow three-dimensional artificial venomous glands to secrete the same toxic proteins as those found in a snake’s mouth [21]. Although it is still in the early stages of research, animal venom production with stem cells introduces the possibility of a safe and nature-derived alternative to the fraught standard of synthetic painkiller use.

SEA ANEMONES ARE NOT OUR ENEMIES: HARNESSING VENOM FOR CHRONIC PAIN RELIEF

NIPPING PAIN IN THE BUD: SNAKE VENOM AS A SAFER ALTERNATIVE PAINKILLER What if the “no pain” factor could be isolated from potent mamba venom without the typical side effects of pain medications? Snake venom works similarly to painkillers, but is perhaps even safer; painkillers block receptors in the brain, but they generate a surplus of chemicals that sit in the brain rather than binding to the receptors [12]. When the painkiller wears off, the brain still feels like it needs to process the buildup of chemicals, causing withdrawal. This problem does not occur with the venom substitute: it specifically targets receptors that only activate select pain signaling pathways, so it doesn’t induce the unwanted side effects that opiates cause, making it a safer alternative [17]. Thus, snake-venom derived painkillers are promising replacements for the opioids that have plagued our society. However, the scarcity of snake venom makes availability and treatment development challenging [18]. Milking venom from a snake is a skilled task that cannot be replaced by machine or assembly line work [19].

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Animal Venom Neurotherapy In addition to acute pain, animal venom has also succeeded in relieving chronic pain. Opiates are commonly prescribed to calm the immediate pain of traumatic accidents, such as car crashes or sports injuries; however, the long-term use of these drugs can unfortunately lead to addiction, overdose, and death [22]. Unlike acute pain, chronic pain is caused by the abnormal, constant firing of pain signals from nervous system receptors which occur for weeks, months or years on end [23]. Over 60% of adults will experience chronic back pain throughout their lives, but a non-addictive drug treatment for the condition has yet to be developed [24]. This lack of advancement has once again driven us to creatively explore the medicinal applications of nature. Perhaps to alleviate your chronic pain, you go for a swim in the ocean, admiring the seafloor as the buoyancy of the water takes away some of the pressure in your back. Looking down, you see hundreds of sea anemone tentacles wave with the current. It may seem hard to imagine that one of these sea anemones could be used to ease the limp in your step or the pain in your neck. However, out of the sea anemone Telmatactis stephensoni’s 84 different venom peptides, one dubbed U-Tstx-1 has the ability to block pain receptors. Much like snake venom, this peptide has the ability to relieve the exhaustive perpetual activation of neurons related to pain perception [25]. It does so by interfering with receptor binding: when a cell is stimulated by something binding to its receptor, it reaches a certain voltage threshold, then sends out an electrical signal to communicate. By blocking pain receptors, U-Tstx-1 makes it so the cell can’t reach a high enough voltage to fire, preventing pain signals from being processed in the brain [13]. Weaving between the toxic tentacles of the anemone during your swim, you see a lazy marine cone snail slowly making its way across the seafloor. These slow-moving snails also have potential applications to relieve chronic pain: they possess neurotoxic peptides called conotoxins, which have developed in many organisms to target specific parts of the muscular system controlled by your brain [26, 27]. The cone snail’s venom consists of thousands of different combinations of peptides; because we can isolate each peptide and mix and match them for different purposes, this feature leads to great versatility in its research applications [26]. To mimic the complex composition of the venom, scientists choose a few conotoxin peptides to target specific receptors within the nervous system. To scientists, conotoxin venom is like a box of

10,000 lego bricks. If they put the bricks together by following the instruction manual the snail used, they create a highly dangerous venom. But if scientists ignore the snail’s manual and build other things with the bricks, they can create a plethora of other things that aren’t dangerous, and may even be helpful. Currently, there are nine conotoxins in clinical evaluation for medicinal treatment. One FDA approved conotoxin, Prialt, has been made commercially available for severe chronic pain [28]. Prialt is injected into the spinal cord, where it blocks a specific pain-transmitting receptor and pain signals to provide significant pain relief [28]. As a non-narcotic pain reliever, Prialt creates no dependence, and is especially useful for patients with a tolerance to opiates like morphine [28]. Both sea anemone and cone snail venom peptides offer a plausible alternative to narcotic pain relief for the many Americans who will experience chronic pain in their adult life [25, 29].

REPTILES, ANEMONES, BEES… AND ALZHEIMER’S DISEASE? The experience of chronic pain is often coupled with aging and neurodegeneration [30]. Neurological diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease all exhibit illness-specific tangles in the brain [31]. Tangles are accumulated over time, and these lumps of proteins begin to act like neurotoxic knots, decreasing neuronal signaling and function in a process known as neurodegeneration [31, 32]. They work like a knot in a hose, blocking the flow of water. When the knot prevents water from reaching the sprinklers and watering the plants, they start to wither — just like how tangles affect neurons in the brain. In 2021, Aduhelm was introduced by the FDA as the first approved Alzheimer’s drug, and it claimed to deplete levels of the protein responsible for accumulation of tangles and neurodegeneration, amyloid beta [33]. Although the FDA gave accelerated, tentative approval for human use, the drug failed to replicate the striking clinical results produced in either of its two initial trial phases, sparking immense controversy [33]. Because of Aduhelm’s inefficacy and $100,000 annual cost per patient, researchers are now trying to find more successful, affordable alternatives to treat neurodegenerative disease. While drugs like Aduhelm work to treat existing protein buildup in the brain, a better approach may be to prevent it altogether [34]. Some diseases, including Alzheimer’s, are caused by irregular compounds binding to neuronal receptors. Animal venom peptides can

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Animal Venom Neurotherapy selectively bind to these targeted neuronal receptor sites before these disease-causing compounds can, ultimately preventing deterioration. You can think of this as similar to how your foot should slip perfectly into a new shoe, but won’t if the shoe still has cardboard inserts inside. These venom peptides act as “inserts” to fill the bonding site, which prevents the disease (your foot) from accessing it. Venom peptides could prevent the onset of Alzheimer’s instead of just slowing its progression [34]. Slowed glucose metabolism in the brain is another strong indicator of Alzheimer’s disease, and just like with protein tangles, animal venom may provide a solution [35]. Glucose metabolism levels indicate how much energy the brain uses at a given moment; about a quarter of the body’s total glucose is consumed by brain activity [36]. Previous attempts at preventing Alzheimer’s development by maintaining these metabolic levels have been unsuccessful due to neuroinflammation, which occurs when the brain attempts to protect itself from perceived harm, but hurts itself instead. The brain’s first line of defense (white-blood cells) misrecognize the metabolic treatment as dangerous and attempt to eradicate it, causing significant harm to the brain’s own tissue in the process. This inflammatory response can be detrimental to the brain by increasing the tangled and knotted proteins that cause Alzheimer’s – speeding up the progression of the disease [37]. There has yet to be a synthetic drug created to raise lowered glucose metabolism from Alzheimer’s, but nature can again provide a preventative approach through the maintenance of brain metabolism levels using bee venom [38]. This time, scientists used a protein found in bee venom that speeds up chemical reactions called bee venom phospholipase. Mice with mutations associated with Alzheimer’s disease that were administered bee venom phospholipase demonstrated better brain glucose uptake than those given a placebo of the venom — without the adverse inflammatory responses seen in past trials [38].

SCORPIONS DON’T JUST STING: THEY PREVENT NEURODEGENERATION, TOO Accumulated misfolded protein tangles not only block signaling between neurons, but also launch a brainwide immune response [37]. Misfolded proteins are treated similarly to potentially harmful material, and support cells in the brain warn the immune system of possible infection [39]. However, when immune cells release toxic chemicals in an effort to protect the brain, many neurons also get caught in the crossfire.

Neurons in the area die off and are not able to be replaced due to their low rates of division, causing long-term, sometimes permanent, d a m a g e [39]. The natural world offers a potential solution to neuroinflammation, which occurs in diseases like Alzheimer’s. Venom from the scorpion Buthus martensii Karsch (BmK) has been able to reduce neuroinflammation after brain injuries, so the venom’s peptides could also have an anti-inflammatory effect on the brain during Alzheimer’s [40]. A peptide from BmK scorpion venom can prevent microglia from sending out the alarm signals that cause neuroinflammation during Alzheimer’s disease — without killing them [40]. Once again, nature provides, and our venomous friends present a solution. Nature’s biochemical complexity can help drive human scientific innovation in stagnant areas of research. As we learn more about the vast ecological systems and organisms inhabiting our planet, we can better harness and re-purpose the vicious powers of nature in the pursuit of healing. It’s becoming clear that the venom of snakes, sea anemones, and cone snails can help to eradicate opiate addiction from the treatment of chronic pain. Even age and its accompanying neurodegeneration, both seemingly inevitable, can be prevented by scorpion and bee venom. Neurotherapies derived from animal venom have given us the ability to explore the curative resources that nature has to offer and treat a variety of life-altering diseases. All we have to do is learn from our slithering, buzzing, and slimy friends. References on page 60.

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The Brat With a Bat

THE BRAT WITH A BAT: EXPLORING THE DARK PSYCHOLOGY OF SATOSHI KON’S PARANOIA AGENT by Cherrie Chang / art by Cherrie Chang

“It’s not me!” yells thirteen-year-old Ichi as he tries to escape the bullies accusing him of being the infamous “Bat Boy” [1]. It seems that all of Musashino, Tokyo, is being tormented by the thought of this cryptic attacker. On one side of the city, a middle school teacher has hallucinations of Bat Boy every night. On the other side, beneath hundreds of pink balloons lauding a cartoon dog [2], housewives gossip about the mysterious assailant in inconspicuous voices. Everyone wants to know:“have you heard about the baby born holding a bat?” [3]. hese scenes from Satoshi Kon’s Paranoia Agent Ta large demonstrate mass hysteria, a phenomenon in which group of individuals simultaneously express ir-

rational anxiety and paranoia [4]. Paranoia Agent is an anime television series that follows the city of Mu44

sashino and its obsession with “Bat Boy,” a fictional assailant who attacks people with his bat. As the city’s gossip magnifies the threat of Bat Boy, the citizens of Musashino spiral into hysteria, becoming irrationally suspicious of each other and terrified of the fictional Bat Boy. To escape from their distressing reality, they fanatically worship Maromi, a cute cartoon dog. Both Bat Boy and Maromi are born from the imagination of Tsukiko Sagi, a character designer who accidentally killed her dog as a child. Unable to face her trauma, Tsukiko suppressed her memory and made up the fictional Bat Boy as the culprit in her place. She designs the cartoon character Maromi in her dog’s image to pretend it still lives [2]. As you watch Paranoia Agent unfold, you begin to see Bat Boy and Maromi rule over citizens’ minds with paranoia and fanaticism. But how is it possible that one woman’s suppression of a mem-

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The Brat With a Bat ory caused mass hysteria to spread across a city? Using Paranoia Agent as our guide, let’s explore the neuroscience underlying these phenomena and figure out what really goes on in the brain when we use fiction to escape our real-life troubles.

MY DOG ATE MY MEMORIES: HOW BAD MEMORIES ARE SUPPRESSED To some degree, our brains are able to control what memories we recall, especially when it comes to negative memories we do not wish to remember. In Paranoia Agent, this is demonstrated by Tsukiko, who suppresses memories of the role she played in her dog’s death. Our brains’ ability to control memory retrieval allows us to reduce mental stress by consciously choosing which memories to recall [5]. This two-step process is characterized first by the direct suppression of the negative memory; then, the troubling recollection is substituted with a different, alternative memory [6, 7]. For example, not wishing to remember the guilt of killing her dog, Tsukiko suppresses her memory by refusing to acknowledge it. Instead, she substitutes it with a fabricated memory in which Bat Boy killed her dog. After years of suppression, Tsukiko genuinely believes she is not to blame for her dog’s death. But how was Tsukiko able to control her memory retrieval [8]? Contrary to what you might know or expect of memory suppression, we actually do have some control over which memories we retrieve. Experiments following the Think/No Think (TNT) paradigm are prime examples of memory retrieval control [9]. If you were a participant in one of these experiments, you would first be given two sets of word pairs, like “AFRICA HIPPO” and “ALASKA PENGUIN.” The first set of words is the “Think” set. For this set, you should try to think about the second word

in each pair after being prompted with the first. For example, if “AFRICA HIPPO” is in the “Think” set, “HIPPO” should come to mind when I say “AFRICA.” Then, you would be given the second set of words, which is the “No Think” set. For this set, you should try not to think about the second word in each pair after being prompted with the first. If “ALASKA PENGUIN” is in the “No Think” set, you should not think about “PENGUIN” when I say “ALASKA.” After many rounds of practice with each set, you will find yourself getting better at remembering and saying “HIPPO” when I say “AFRICA,” but getting worse at remembering and saying “PENGUIN” when I say “ALASKA’’ [9]. It turns out you do have some conscious control over what memories you keep — the more you try to remember a memory, the faster you can do so when given a cue. Conversely, the more you actively suppress one, the slower you remember it.

LOOKING FOR ALASKA: THE COGNITIVE MECHANISMS OF SUPPRESSION We know that we have some conscious control over what memories we retrieve, but what cognitive mechanisms do we actually employ to control what we remember? Inhibitory control is a mechanism where we consciously prevent activating our negative memories by blocking our access to them [10]. In general, a memory gets activated by external cues. Any stimulus — from visual cues like photographs to verbal cues like the sound of someone’s name — can activate and target specific memories for retrieval [8]. The more closely related a cue is to the memory, the more likely the memory is to be activated. In Paranoia Agent, each sentence in the investigator’s interrogation serves as a verbal retrieval cue for Tsukiko [2]: “There was never an attacker,” he accuses. “You got distracted and… Maromi ran into a passing car and died!” By forcing her to think about Maromi’s death, the investigator provides Tsukiko with stronger and stronger retrieval cues, shaking her faith in her fabricated memory. Eventually, the strength of these cues forces Tsukiko to remember killing Maromi. As in the interrogation scene, there may be several cues that cause a memory to be retrieved. Likewise, a single cue can retrieve several different memories [9]. When I say “ALASKA,” you may remember its experimental partner “PENGUIN,” but you may also think of “SALMON,” or “ICE,” or “SNOW” [9, 10]. When given one cue, several memories may return at once — but you’ll only remember the one that is retrieved most quickly, which is the memory most strongly related to the giv-

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The Brat With a Bat en cue. As a result, memories “race” each other to be remembered first, with the fastest memory becoming the only one we recall consciously. In our Think/No Think experiment above, this is likely “PENGUIN” since you were very recently reintroduced to its relationship with “ALASKA.” To suppress memory in the long term, we put conscious effort into inhibiting the negative memory’s retrieval, even if it is the one most strongly associated with the given set of retrieval cues [9]. By discouraging yourself from thinking about “PENGUIN” after “ALASKA,” you inhibit your retrieval of “PENGUIN” [9,10]. Inhibitory control of memory retrieval thus allows us to exert some conscious control over what we remember by suppressing a negative memory.

HIPPOS OR HIPPOCAMPUS? THE NEUROSCIENCE OF SUPPRESSION Like a biased referee pulling a fast runner off of a base, suppression pulls out the negative memory most strongly associated with the retrieval cue and prevents it from finishing the memory race. Where is this memory race taking place, and what parts of the brain play the role of this biased referee? To find out, we can use functional Magnetic Resonance Imaging (fMRI) to observe brain activity regions during memory recall tasks [12]. When a brain region is activated by a cognitive task, the increased neural activity in that region requires it to use more energy, which causes an increase in oxygen flow to the given brain region. As a result, the blood flow to that region also increases in order to supply oxygen in support of this uptick in activity [11]. Using fMRI to measure the blood flow in the brains of each Think/No-Think paradigm demonstrated that the hippocampus and the prefrontal cortex are the key players in memory retrieval and suppression, as increased blood flow during TNT studies was observed extensively in these two regions [12]. Seated near the center of our brains, the hippocampus is

essential for forming declarative memory, or memories of things that can be stated explicitly, like names, dates, or events [13]. Increased activation in the hippocampus is associated with the experience of consciously remembering a declarative memory [14]. As such, the hippocampus is where the memory retrieval “race” occurs and determines which declarative memory is recalled. For Tsukiko, the declarative memory may have been that she accidentally let go of Maromi’s leash and caused her death. If Tsukiko consistently recalled this memory, there would be an increase in the activation of her hippocampus. The hippocampus’s functioning is subject to interference from the prefrontal cortex, which is the “biased referee” lying right beneath our foreheads. The prefrontal cortex helps to override many of the brain’s tasks, like controlling extreme behavior caused by emotional fluctuation and, in this case, inhibiting retrieval of a negative memory [15]. Inhibitory control occurs when the prefrontal cortex (i.e., the biased referee) is recruited to override the hippocampus’s default activity and thereby suppress the retrieval of the negative memory [10]. By consciously willing herself not to think of her negative memory, Tsukiko used her prefrontal cortex’s executive control to interfere with the hippocampus’s memory retrieval process, stopping herself from recalling killing her dog. Similarly, as a hypothetical TNT participant, you override your hippocampus’s memory retrieval of “PENGUIN” following “ALASKA” by activating your prefrontal cortex. By leveraging the executive control of our prefrontal cortex, we gain conscious control over the memories that our hippocampus retrieves. We may then allow ourselves to retrieve a weaker activated memory like “SALMON” or, in Tsukiko’s case, fabricate an alternative one altogether. [2, 10].

FAKE BATS AND FICTIONAL BUGS: HOW INDIVIDUAL SUPPRESSION LEADS TO MASS HYSTERIA When a well-known individual substitutes their suppressed memory with a fabricated one that they later publicize, this fictional memory may become a widely believed story, causing their society to spiral into mass hysteria. After becoming a household name for creating the cartoon character Maromi, Tsukiko begins to face immense pressure from her employers to create the company’s next cash cow [16]. While walking home after a grueling day of work, Tsukiko trips and falls. As she breaks down and sobs into the ground, Bat Boy “appears” from behind and hits her with his bat. Word

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The Brat With a Bat of Tsukiko’s violent “assault” quickly makes headline news, and the city, consumed by paranoia over the fictional assailant, descends into mass hysteria [16]. While a citywide descent into mass hysteria may seem like the stuff of fiction, similar phenomena have occurred in the real world: in the 1962 “June Bug” mass hysteria outbreak in a Montana mill, large swaths of the mill’s workers suddenly reported feeling nauseous and dizzy, some even fainting [17]. Many claimed their illnesses were caused by a bug bite, hence the name “June Bug,” but despite a team of entomologists’ best efforts, no one could find the responsible bug [17].

YOUR SMILE IS MY REFLECTION: THE NEURAL CORRELATES OF MASS HYSTERIA Unlike other epidemics, mass hysteria spreads rapidly through a group while lacking an obvious physical contagion [4]. Instead, mass hysteria is spread via emotional contagion, the process through which we observe others’ emotional states through their behavior and mirror them [18]. As humans, we are naturally inclined to share the emotional state of another person [18]. Each episode of Paranoia Agent demonstrates this in action: as visible fear and distress spread through Musashino’s residents, everyone becomes paranoid of Bat Boy one by one, and the city itself succumbs to mass hysteria. But what neural processes in our brain are responsible for this “copycat” phenomenon? The answer to this is the aptly-named mirror neuron system, a group of specialized neurons that synchronize an individual’s actions and sensations with those observed in another person [19]. One group of mirror neurons spans both the brain’s parietal cortex — responsible for sensing touch — and the premotor cortex, which is responsible for integrating sensory and motor information. This group of mirror neurons is responsible for synchronizing actions between individuals. When four housewives stand in a circle to gossip about Bat Boy, their body language often appears synchronized: they all fearfully touch and cup their faces, covering their mouths in horror [3]. As the first housewife cups her face, the second housewife sees this and mirrors the first housewife by touching her cheek, immediately followed by the third doing the same. As the housewives’ mirror neuron systems are activated, they begin to unknowingly copy each other’s actions, and so the face-touching action “bounces” in a circle from one housewife to the next [20]. Emotional contagion is also enabled by the mirror

neuron system in the somatosensory cortex of the brain, a region responsible for synchronizing physical sensations [21]. As the housewives touch their faces simultaneously, their sensations also become synchronized: they all feel their biceps contracting and their warm hands on their faces. Combined with the synchrony of their actions, their mirror neuron systems enable them to feel and share similar emotions. When the body performs an action that corresponds to a particular emotion, the brain assumes that the emotional state is actually being felt and sends signals to produce such a feeling. For example, if you smile, your brain can be tricked into thinking you’re happier [22]. So when the housewives mirror each others’ actions of concern (like the fa c e -t o u c h i n g ) , their paranoia becomes contagious. As the threatening presence of Bat Boy looms large over Musashino, this emotional contagion effect snowballs to spread hysteria across the city [23]. Trading stories of Bat Boy becomes the norm in Musashino, allowing citizens to indulge in this urban horror fantasy instead of the troubles in their real lives.

FROM BAT BOY TO BEATLEMANIA: COMFORT FICTION FANATICISM AS MASS HYSTERIA From fainting mill workers to exaggerated gossip, our understanding of mass hysteria is characterized by extreme behavior, isolating this phenomenon from the norms of daily life. But what if a form of mass hysteria is arguably happening right now, across every consumerist country? In Paranoia Agent, the cartoon dog Maromi appears as an adorable and harmless character, providing Musashino citizens with comfort as they live in paranoia under the threat of Bat Boy. However, Maromi’s fans slip into a dangerous and disruptive obsession: they report not being able to sleep “without it,” and news reports show the fandom’s behavior becoming extreme, from robberies of Maromi vendors to violent fights between fans. The report ends ominously: “Maromi is dangerous” [2]. The news reports argue that Bat Boy and Maromi are two sides of the same

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The Brat With a Bat coin: much like how Bat Boy’s malicious presence provides the citizens of Musashino with an external threat to focus on, Maromi’s cuteness also provides an unrealistic fantasy used by its fans to escape from their real-life troubles. In our consumerist society, viral cultural phenomena like Maromi are littered across every country. This makes Paranoia Agent a poignant warning for how mass hysteria could spread in our society: could a fandom’s fanatic behavior be a form of mass hysteria? When does a fan become a fanatic? A 1964 Beatles concert saw “Beatlemaniacs” excessively screaming and breaching police lines to reach the stage, and news reporters criticized the band for generating mass hysteria. In response, a study on the same concert compared the fans’ behavior against psychometric measures and concluded that they did not meet the mass hysteria criteria then [24]. However, when the study was revisited half a century later, the authors warned against our still-vague definition of mass hysteria and the lack of rigorous investigation [25]. A clear and deep understanding of mass hysteria has yet to be developed, but the possibility of fanaticism being a mutated form of mass hysteria takes the phenomenon further out of the screen and into real life. As seen in Paranoia Agent, our high-stress and consumerist culture often pushes us to fantasize about suppressing our memory of real-life troubles, whether it is a sensational urban legend, like Bat Boy, or a comforting character, like Maromi [2]. As an increasing number of stressed individuals become over-reliant on the same fiction, fanatic behavior can quickly spread across our societies. By showing how the citizens of Musashino obsess over Bat Boy and Maromi, Paranoia Agent provides us with a cautionary tale of how one person’s suppression of a bad memory could have the capacity to send society into hysterics. References on page 62.

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Exercising Neurons

EXERCISING NEURONS: HOW WORKING OUT CAN IMPROVE MEMORY & NEURODEGENERATION by Lucas Angles art by Natalie Bielat

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Exercising Neurons s you reach the final climb of your morning run, Aa mental you realize it’s happening again: you’re approaching and physical limit. Your legs are turning to

lead, moving slower and slower each time they hit the pavement. Your vision is clouding and your mind is completely overwhelmed by the notion of completing the path while so fatigued. Just before you give in to the prospect of relief, something strange happens. Suddenly, you begin to pick up pace. Almost magically, your vision clears, your exhaustion subsides, and you’re overcome with a sense of euphoria entering the final stretch of your route. Familiar to many, runner’s high is an excellent example of how physical activity can alter our mental and emotional states. It may seem counterintuitive that exercising can modify something as abstract as consciousness. However, working out doesn’t just build up our abs and biceps — it is also instrumental to the growth and development of our brains. During exercise, your body releases endocannabinoids, biochemical substances similar to cannabis, that travel to the brain and bring about a sense of calm and improved mood [1]. While this phenomenon creates a tangible sensation — euphoria — other cognitive effects of exercise can be more difficult to grasp. Improvements in memory are not often noticed by individuals themselves, but are still very much present in those who exercise [1]. Through the substantial change in brain physiology during and after physical activity, working out can help strengthen neural communication and may offer a useful therapeutic approach to combating degenerative memory loss in the near future.

children who had suffered from an early traumatic brain injury exhibited the detrimental effects long into adulthood [2]. In recent years, however, improvements in microscopic technology revealed that the brain is actually much more malleable than previously thought [3]. Using technologically advanced microscopes we can track the minute changes in neural tissue, including the generation of new neurons, regardless of age. One of the primary locations of this neural production, or neurogenesis, is in the dentate gyrus of the hippocampus. Considering that this brain region is the primary site for memory formation, neurogenesis here allows memory to be elastic; as we take in novel information and experiences, our new neurons quickly incorporate this material into our memories [3]. Thus, our memory can be modified by the growth and maintenance of new brain cells.

SCULPTED ABS, SCULPTED BRAIN: EXERCISE AND NEUROGENESIS

While this neural development occurs throughout one’s lifespan, exercise, in particular, triggers the brain to generate new cells. Physical activity causes the brain to release a variety of molecules which act as the primary initiators for the generation of neurons and the expansion of brain tissue in the hippocampus [4]. These growth factors are used by the body to tell neurons and other cells within the brain to start growing and dividing [4]. Similar to the connections we make as people, these new neurons merge with other neurons with their own linkages, eventually expanding the entire neural network. When you exercise, these new connections can be integrated especially quickly. This transformation is observed most readily in the growth of neural networks in elderly people who undergo a regimen of moderate daily exercise [5]. In fact, aging individuals who exercised weekly for just one year exhibited significant increases in neuron count; this effect contributed to significantly improved scores on memory assessments [5].

For a good portion of the 20th century, the brain was considered to be an entirely static organ [1]. Because the brain’s general size, shape, and weight seemed to remain relatively constant throughout life, scientists believed that neurons — the cells responsible for transmitting and organizing our thoughts and perceptions — were unable to divide or multiply like other cells in the body. Imagine getting a paper cut and never being able to regrow the skin cells needed to close the hole: you would still be able to see the wound even years later. This is how clinicians understood patients’ difficulty in recovering from brain injuries; by conceptualizing the brain as “fixed,” neuroscientists could explain why

Exercise not only develops and multiplies the neurons in our brain but also transforms the brain cells that support neurons: the glia [6, 7]. Glial cells, often overlooked and underappreciated, actually serve an important role in the brain; they support and modify neurons to improve neural

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Exercising Neurons communication as well as overall brain function. Much like an executive assistant, glia are constantly working; these important helper cells cushion the brain, ward off pathogens, and can even help neurons signal faster. Exercise seems to have a particularly useful effect on astrocytes, a type of glial cells that provide nutrients to neurons and regulate the growth and creation of neural connections. The space where direct communication occurs between neurons is referred to as the synapse. Synapses are important in the formation and maintenance of memory in the hippocampus [6]. Regular exercise has been linked to increases in astrocyte proliferation, size, and maintenance of neuronal synapses –– all of which serve to improve cognition and memory [7]. In other words, when we have more astrocytes to help neurons signal and grow, it becomes easier for us to retain and recall memories [7].

STRENGTHENING NEURAL PATHWAYS WHILE STRENGTHENING MUSCLES Exercise further aids in the strengthening of memory through its lasting effects on the long-term potentiation (LTP) between neurons. LTP explains why the increased practice of a task, or repeated exposure to an experience, causes concrete neurological changes that can reinforce a memory. When your brain experiences an event, the respective pathway of neurons fires in order to process the incident through both sensory or emotional contexts. For example, suppose you read a page of a book many times over. Your interpretation of the letters on the page and your subsequent emotional reaction to the text’s content will consistently activate the same pathways of neurons. When firing along these pathways is increased by frequent engagement with the same page, receptors –– or small biological structures lining the outside of neurons –– activate and initiate LTP. In fact, LTP actually affects the shape and function of neuronal dendrites and axons. Dendrites are like the roots of the neuron; they branch from the body of the cell and receive signals from surrounding neurons. An axon is like the trunk of a tree: it emerges from the cell body and connects to neurons further down the pathway. During LTP, dendrites increase their branching, which allows them to receive more information [8]. LTP also induces branching from the axon, allowing one neuron to reach more neurons, or form repeated neural connections; this greatly improves neural communication within a particular pathway [9]. These rapid changes promote the

fast formation of new memories, as improvements in communication between neurons solidify and consolidate information for future recall [10]. For instance, if you read and re-read the Harry Potter series dozens of times as a child, you can probably recall numerous scenes from the books with ease; the constant re-reading solidifies your memories of these stories. During exercise, the brain repeatedly activates the receptors related to LTP, allowing for increased neuron complexity to develop both during and after exercise [11, 12]. These adaptations bolster memory by forming new connections and strengthening existing ones [13]. Although the cognitive benefits of exercise have been observed for decades, the precise biological mechanisms underlying how exactly exercise can stimulate cell growth and LTP has yet to be identified. Just a few years ago, however, the discovery of a hormone called irisin offered some explanation for the neurological changes generated by exercise [14]. Produced during periods of moderate to vigorous exercise, irisin is released by muscle cells after repeated contractions [15]. The hormone stimulates cells to make more energy so that you can work harder for a longer period of time. Increased production of irisin stimulates the release of growth factors that generate new neurons while maturing ones that are already present. Irisin has also been found to increase the brain’s ability to initiate LTP when administered, most notably in the hippocampus, providing substantial evidence of exercise’s beneficial effect on memory [16].

PUMPING IRON PROPS UP MEMORY The impact of exercise on cellular proliferation and LTP also contributes to the body’s fight against neurodegeneration and age-related cognitive decline. While neurogenesis adds batteries to the brain’s original “circuitry,” LTP strengthens existing wires and creates new ones to enrich the circuit’s complex system of connections. When exercise creates new neurons, it

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Exercising Neurons also maintains and even strengthens memory; this effect is particularly useful for individuals dealing with neurodegenerative diseases which disrupt the ability to recollect information [17]. Many symptoms of such diseases, like memory loss or depression, are primarily the result of cell death; thus, cell growth can counteract any noticeable deficits caused by cell degeneration [17]. The proliferation of astrocytes can help regulate the brain’s immune response against damage and disease, as these cells help to fight off foreign invaders [18]. In neurodegenerative diseases like Alzheimer’s or Parkinson’s, it is the body’s selfdefense response — not the disease itself — that causes cell death. While attempting to destroy foreign substances that may cause the body harm, immune cells release toxic chemicals that not only destroy the offending agent, but the neurons in the surrounding area as well. When new astrocytes are generated as a result of exercise, the brain is able to initiate specific immune attacks to prohibit the destruction of healthy neurons, thereby aiding in the fight against these diseases [18].

occasional exercise, we have the power to modify our neural circuitry, optimizing our minds and bodies and protecting them from the threat of neurodegeneration. References on page 63.

As we age, our brain slowly becomes less malleable. Older brains are no longer able to support LTP and plasticity, or the processes that allow us to incorporate and utilize valuable information instantaneously. With consistent exercise, however, we can reinvigorate our brains and the LTP necessary to improve neural communication [19]. These modifications help individuals build a foundation to stave off neurodegeneration and age-related decline, simply by exerting themselves for a few minutes a day [19]. Just walking for 90 minutes a week can increase brain volume at ages when the brain typically shrinks [5]. Exploration of this phenomenon has opened new doors to a method of accessible, affordable preventative treatments in a world where healthcare costs are rising exponentially [20]. The astounding manner our bodies can affect our brains and vice versa allows us to become the electricians of our own brains. Even by just practicing

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