Issue 5

FEATURING

A Trip to the Therapeutic World of Psychedelic Mushrooms A Little-Known Side Effect of Chemotherapy: ChemotherapyInduced Peripheral Neuropathy

Taking New Leaps Into Treatment for Parkinson’s Disease

RUNNING UP THAT HILL: THE STRANGER THINGS ABOUT LISTENING TO MUSIC

by Jadon-Sean Sobejana / art by Iris Li

LOST IN MIGRATION: EXPLORING THE ROOTS OF GREY MATTER HETEROTOPIA

by Dimple Kangriwala / art by Stuart Heintz

36

FEATURED ARTICLE TAKING NEW LEAPS INTO TREATMENT FOR PARKINSON’S DISEASE

by Maia Beaudry and Talia Roman / art by Mingjia Ni

41

THE FUTURE OF TBI THERAPY STEMS FROM STEM CELLS

NOW YOU SEE ME, NOW YOU DON’T: THE MYSTERIOUS PHENOMENON OF PHANTOM PREGNANCY

by Kalina Rashkov and Sudiksha Miglani / art by Elsie McKendry

44

by Shawn Babitsky / art by Anna Bishop

TOXOPLASMA GONDII: THE BEAST LURKING IN THE LITTER BOX

by Sufana Noorwez / art by Abigail Schoenecker

49

ISSUE NOTES

ON THE COVER

Art by Nikita Sidoryk

LET US KNOW

If you have any questions or comments regarding this Issue 5, please write a letter to the editor at brainstorm.vassar@gmail.com.

REFERENCES

LEARN MORE

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

PRODUCTION STAFF

LUCAS ANGLES Editor-in-Chief

LUCY VOLINO Senior Managing Editor

OLIVIA GOTSCH Senior Editor, General Editing

NANAKO KUROSU Senior Editor, General Editing

ANJALI KRISHNA Senior Editor, Lay Review

JULIA VITALE Senior Editor, Lay Review

AMBER HUANG Senior Editor, Scientific Review

AINSLEY SMITH Senior Editor, Scientific Review

YUCHEN

ANSHUMAN DAS

Manager

SHAWN BABITSKY

TALIA MAYERSON Graduate Student Executive

CLEM DOUCETTE Graduate Student Executive

DANIELLA LORMAN Graduate Student Executive

ARTISTS

Anna Bishop Iona Duncan Ayane Garrison Stuart Heintz Ella Larson Iris Li Elsie McKendry Mingjia Ni Anna-Kate Pittman Abigail Schoenecker Nikita Sidoryk Hanqi Wu

AUTHORS

Shawn Babitsky Maia Beaudry Cherrie Chang Gage Haden Dimple Kangriwala Riley Lipman

Sudiksha Miglani Sufana Noorwez Kalina Rashkov Talia Roman Jadon-Sean Sobejana Rory Thompson

SCIENTIFIC REVIEW

Evelynn Bagade Avery Bauman Eamon BenSlama-McKinley Hailey Brigger Jess Camacho Rileigh Chinn Anshuman Das Jade Hsin Jas Kaur Alex Kaye Jordan Klembczyk Hannah Koolpe Ninamma Rai Dhriti Seth Monika Sweeney Victoria Tager-Geffner

LAY REVIEW

Eve Andersen Evan Banning Hadley Boyle Alexis Earp Alyssa Gu Caris Lee Lilah Lichtman Nandini Likki Frank Ryan Caitlin Shi

GENERAL EDITING

Nehal Ajmal Zayn Cheema Anna Conway Madeline Galian Juliana Ishimine Claire Karlin Alex Kaye Lilah Lichtman Jaya Moorjani Jaclyn Narleski Susie Osborne Isabella Sagman Martine Schwan Nico Silverman-Lloyd Anna Terry Jolie Walker Freddie von Siemens

EDITOR’S NOTE

As the excitement of editing concludes and the fifth issue of Grey Matters at Vassar College goes to print, I find myself reflecting on the team’s continued effort and enthusiastic dedication. To my team: my deepest thanks go to the editors, authors, and artists who have been with us for years, and to our fresh-eyed newcomers for accompanying me on this wonderful journey. To our readers: I hope this issue will make you laugh, reflect, and, most of all, learn.

As I step into my new role as editor-in-chief of Grey Matters, being a part of this remarkable publication has taken on a new meaning altogether. Not only do I value the ability to collaborate with and mentor undergraduates in their scientific writing, but the opportunity to learn from my team myself is something I will treasure for a long time. Every day, I discover something new, be it the puzzling dilemma of a phantom pregnancy, or the incredibly complex world surrounding our neurons — all delivered in simple, digestible prose.

This issue of Grey Matters offers new perspectives on well-known aspects of brain science, as well as introductions to topics that will become the future of key research in the field. Discover the extraordinary healing effect that music can have on our brains in “Running Up That Hill: The Stranger Things About Listening to Music,” examine a new, exciting treatment modality for addiction, depression, and anxiety in “A Trip to the Therapeutic World of Psychedelic Mushrooms,” or dip your toes into the physiological underpinnings of those who stutter in “When Words Get Stuck: The Complex Causes Behind Stuttering.” We hope these pieces will serve as both an introduction and an exploration into the world of science for readers from a vast array of academic backgrounds.

We wholeheartedly invite you to join us in this semester’s exploration of the human brain.

See you all again soon,

Lucas Angles Editor in Chief

WHEN WORDS GET STUCK: THE COMPLEX CAUSES BEHIND STUTTERING

by Cherrie Chang / art by Iona Duncan

Aking sits before a microphone, moments before addressing his entire nation. Despite his position and power, anxiety ripples through him. Sweat soaks through his suit and into the cushioning of his chair. He starts to speak: “Through the…” He falters, then continues, “…wireless… one of the marvels of…” Seated close to him, his father raises an eyebrow and ad vises him to take his time. The man hesitates, suf focated by fear and the tightness of his necktie. He tries to go on, “…m-modern… science…” Every word is a struggle. “Just try it!” His father barks at him in anger. The king tries to continue, but the words only form a lump in his throat. Disappointed, his father walks away.

This is how the film The King’s Speech depicts King George VI stuttering through his Christmas day speech. From his exchange with his father, we can see the overwhelming stress that many stutterers experience. While it may be tempting to ease the

anxiety of a stutterer by saying “take your time, relax, you’ll get it out,” these kinds of respons es misunderstand the com plex mechanisms that actually drive a person’s stutter. John Hendrickson, a stutterer and senior editor at The Atlantic, explains that contrary to popular be lief, stuttering is a neurological condition caused by many factors, and is not solely anxiety-induced [1]. In fact, anxiety usually follows stuttering, especially when the stutterer is being pressured by the listener through aggressive prompting like “just try it!” [2, 3]

To become truly compassionate listeners to an indi vidual who stutters, it is important to understand the neurological mechanisms underlying stuttering and how they interact with the vast network of genetic, developmental and other factors that shape a stut terer’s unique speech pattern.

WHAT IS STUTTERING?

Stuttering, also known as stammering, is a speech disorder where an individual’s flow of speech is dis rupted by irregular features like repeated sounds, prolonged words, and long pauses. Historically, stut tering has been primarily treated as a uniform disor der without any further subdivisions. Despite the di versity of causes behind each person’s stutter, there is currently no official classification of stuttering into subtypes in the U.S. [4, 5, 6]. In many attempts at classification, stuttering has been grouped by behav ior, brain activity, and other factors [7, 8].

While classifications differ, stuttering is often divided into three subtypes: developmental, neurogenic, and psychogenic [9]. Developmental stuttering refers to the repetition of words and phrases by young children when first learning a language — imagine a flustered 4-year-old with balled up fists, howling “I-I-think-I think you’re lying!” This type of stuttering is not seen as a disorder, but simply typical in language acquisi tion, and it usually subsides when the child reach es the age of five [10, 11]. However, stuttering that persists beyond this age becomes a cause for con cern and leads physicians to look for deeper caus es. Neurogenic stuttering characterizes cases where the stutter stems from injury, disease, or dysfunction of the brain, while psychogenic stuttering is usually used to classify cases caused by psychological stress or trauma [9, 12].

A perfect classification is difficult for most stutter ing cases, however, because of the complexity of its causes. For instance, it is nearly impossible to distinguish neurogenic and developmental stuttering based only on how someone speaks [13]. Case reports have also complicated classification further by showing that neurogenic stuttering can involve damage to al most any brain region, from areas associated with movement to those that process auditory informa tion [7]. Due to the distinct nature of the damage, many clinicians treat stuttering on a case-by-case basis, customizing treatment plans for each individ ual [13, 14]. Some patients benefit from therapy that focuses on cultivating their in-the-moment aware ness during speech; some find physical training like breathing exercises more helpful; and others develop speech strategies like circumlocution, where they re place difficult words with longer but easier sentenc es on the go [15]. The in dividualization of stutter ing treatment stems from the diversity of stuttering causes. Therefore, while it is imperative to explore the neurological mecha nisms behind stuttering, we should also recognize that these three categories are tentative and overlap ping, demonstrating the complex nature of stutter ing’s causes.

THE NEUROLOGICAL MECHANISMS OF STUTTERING

The irregularities in a stutterer’s speech can be char acterized into three types — repetitions, prolonga tions and blocks. Repetitions refer to stutters where sounds, syllables or words get repeated, like “this-this st-stutter.” Prolongations involve extending sounds or syllables in speech, like in “pro-looooooooongation” instead of “prolongation.” Blocks indicate long gaps in speech, usually occurring between the beginnings of words. In a New York Times interview about his ex perience with stuttering, John Hendrickson demon strates these stuttering patterns, tripping over his description of stuttering itself: “right after a really long painful block,” he starts, “is momentary relief and exhaustion, you typically have a large… exhale.” Here, he blocks before “exhale” [1].

Several attempts have been made to determine the neurological mechanisms behind each stutter type. One highly utilized approach is to identify the areas of the brain involved in stuttering by analyzing neu roimaging data from individual patients. The findings between these cases and neuroimaging data does not always line up: there was a Vietnam War soldier who acquired stuttering after missile wounds to both sides of their brain, a 68-year old man who devel oped a stutter following damage to a large area in the middle of his brain, and several stroke patients who had begun to stutter after suffering cell death in a wide range of brain areas [16, 17, 18]. Stuttering, therefore, can arise from damage to almost any site in the brain [17, 19, 20]. Recently, however, more findings have shown stuttering to be more strong

ly correlated with damage to two brain areas — the thalamus and the basal ganglia — which are both im portant components of the brain’s motor pathways for producing voluntary movements [21, 22]. The con nection between stuttering, the thalamus, and the basal ganglia offers a promising start to uncovering the mechanisms behind stuttering. By examining the roles played by the thalamus and the basal ganglia, we can analyze how damage to these regions could disrupt the flow of speech.

THE STEPS OF A STUTTER

One important function of the thalamus is to relay signals between brain structures involved in motor coordination. Imagine saying the word “prolongation:” first, the sequence of motor movements involved in saying “prolongation” has to be planned. This plan ning is done by the motor areas of your cerebral cor tex, the neurons in the wrinkly outer layer of the brain that performs sophisticated cognitive functions, like decision-making and movement-planning [23]. Af ter the motor areas of the cerebral cortex create the blueprint for a movement, they send signals to the brain structures that coordinate the sequential movements of all the muscles involved in speech, from contracting your diaphragm to pressing your lips together for the “p.” The thalamus mediates commu nication in this pathway by regulating how signals are relayed between the cerebral cortex and the lower structures [23]. When there is damage to your thala mus, the normal flow from planning to say “prolonga tion” to actually saying it is disrupted. In other words, you experience a block in speech.

Another theory of stuttering’s origin in the brain fo cuses on the basal ganglia and its role in controlling the sequence of motor movements in speech [21, 24]. When you try to say “prolongation,” you are not just trying to create a single motion that results in the entire pronunciation of “prolongation.” Rather, you are making a series of correctly timed move

ments to utter each syllable — “pro-lon-ga-tion” — smoothly and sequentially. To time pronunciation correctly, your basal ganglia generates an internal timing cue after each syllable, signaling the next one to be pronounced. If your basal ganglia could speak in your ear, it would almost sound like an in-ear monitor cueing each syllable you utter with “1, 2, 3, go!” Now imagine this is occurring rapidly in between each syl lable: “pro”— 1, 2, 3, go! — “lon” — 1, 2, 3, go! — “ga”... and so on. Damage to the basal ganglia impairs the brain’s ability to provide these cues and leads you to repeat the previous syllable like a broken record [21, 24]. “Pro-” you start, but your basal ganglia fails to cue for the “-lon.” “Pro-pro-prolo…” your brain fails to find the cue for “ga,” so you are stuck “prolonging” this syllable. “Prolooooooon…gation,” you finish. To gether, these two theories propose explanations for the variety of stutter types in terms of impairments to the motor pathways leading to speech. However, the wide range of brain regions that could result in stut tering when damaged suggests that not only is there room for many more explanations, but that looking at neurological explanations alone may not be enough to understand the causes of a stutter. Instead, we must understand how the neurological mechanisms of stuttering interact with its larger network of other causal factors.

GETTING TO THE ROOTS OF A STUTTER

The complexity of the causes behind stuttering is best illustrated by stuttering that begins at a young age and persists beyond the age of five, which often involves not only a neurological component, but genetic, developmental and social components as well [25, 26, 27]. For instance, mapping the family heritage of real developmental stuttering cases has revealed patterns in stuttering’s inheritance: stuttering is more likely to be passed from a parent onto their child of the opposite sex, boys in particular. Compared to a boy with a stuttering father, a boy with a stuttering mother is more likely to develop and not recover from stuttering, and is also more likely to stutter than his sister [27, 28]. Behind this pattern are four genes that determine the process by which molecules are packaged and transported between structures within each cell, which is called intracellu lar transportation [29]. A mutation in one or more of these four genes affects the normal functioning of a cell [29]. This mutation can damage the intracellular transportation of many cells at once, so if this damage is concentrated in a particular brain region,

the malfunctioning in its composite cells will im pair the region’s overall function [30]. When this region is one involved in stuttering, such as the thalamus or basal gan glia, speech production will be compromised [21, 31]. By integrating this genetic explanation and neurological mech anisms, we may achieve a more comprehensive understanding of the causes behind stutter ing.

While genetic mutations may kickstart stuttering, a stutterer’s individual developmental pro cess plays a large role in shaping their stutter [32]. Twin studies show that shared environ mental variables — such as excessive parental concern about imper fect speech, compet itive families and per fectionistic household cultures — can cause stuttering to persist or make it difficult to overcome [32]. As doc umented in The King’s Speech, King George VI was raised under the immense pressure of being a royal, and his fa ther’s high expectations and pronounced disap pointment had always been constants in his life [33]. If we imagine that the king had an identical twin living in a less stressful household, with parents who did not pressure him for smooth speech, perhaps that twin could have grown up to have a milder stutter or even none at all. Even if a stutterer carries the rel evant genetic mutations for stuttering, how strongly these mutations are expressed to affect the person’s speech-production is heavily influenced by the envi ronmental factors surrounding their childhood [32].

STUTTERING UNDER STRESS

One final important contributor to a stutter is the moment-to-moment emotional state of the person. When a stutterer is faced with a stressful situation, they may anticipate that they will stutter through their words and subsequently feel anxious [34]. This freezes some of their vocal muscles in what is called an involuntary stress response, making it even more difficult for them to speak [35]. In The King’s Speech, King George VI stutters through most of his sentenc

When Words Get Stuck

es, but he struggles the most during public speeches, or whenever he is under father’s piercing gaze [33]. His stutter pattern echoes evidence suggesting that stuttering occurs more frequently when the stutter er faces increased difficulty in their linguistic task or emotional stress, especially when they are treated with impatience from their audience [2, 24, 36]. King George VI, for instance, stumbles over the long and convoluted speeches he has to give in front of thou sands of people, but manages to consistently speak eloquently to his speech therapist [33].

In fact, handling stress during speech is one of many highly successful techniques stutterers use to man age stuttering [37]. Some stutterers report feeling in tense urgency and fear during conversations, as they feel the need to respond to their audience in a time ly manner, while predicting that they will need more time to speak without stuttering. To manage this, they try to resist the urge to respond immediately, allowing themselves to slow their rate of speech, resulting in slower, but much more fluent speech. To be able to employ this strategy in conversations on the spot, stutterers often train themselves in their own time by learning to take a broader perspective on their stutter, distancing their sense of self-worth from their self-criticism of their stuttering [37, 38]. These reports affirm the significant effect stress has on stuttering, in the form of immediate pressure during conversations but also as a pervasive anxiety stutterers face every day when their self-confidence is harmed by their disdain towards their own stutter.

HOW CAN WE SUPPORT STUTTERERS?

A stutterer’s speech is continually shaped from birth to death, with genes and environmental factors inter acting to mold how their nervous system produces speech. Even within a single moment, a stutterer’s speech patterns fluctuate according to the difficulty of the subsequent word and stress. Because of the constant variation in stutter patterns, people study ing stuttering are moving towards analyzing stutter ing as a dynamic system of interacting causal factors [39]. Recognizing the complexity behind stuttering is crucial to correct any misconceptions of it. By pa tiently listening to those who stutter, we may be able to shatter the unwarranted stigma surrounding stut tering.

References on page 49.

A TRIP TO THE THERAPEUTIC WORLD OF PSYCHEDELIC MUSHROOMS

by Rory Thompson / art by Ayane Garrison

Psychedelic Mushrooms

saw a liquor bottle in the middle of a desert … all of a sudden it disintegrates into the sand. And I thought that was pretty obvious symbolism for my alcoholism leaving me… At that point, I, kind of, felt free from my addiction,” reflects Jon Kostas, con templating his experience taking psychedelic mush rooms [1]. Kostas struggled with alcoholism since he was a teen, and it got to the point where he had “nothing to lose” except for his life. After three doses of the psychedelic compound psilocybin, along with psychotherapy, Kostas began his journey into seven years of sobriety, emphasizing how he had “no words to explain how crazy and shocking this is.” Kostas is just one of many individuals whose drinking was re duced long-term after receiving psilocybin-assisted therapy [2].

What is this drug that has succeeded in treating psychiatric disorders where modern Western medi cine has historically failed [1]? Psilocybin is a nat ural psychedelic compound produced by fungi colloquially termed “magic mushrooms.” Humans have ingested psilocybin for millions of years; in fact, psi locybin-containing mushrooms are present across all major habitable regions of Earth [3]. In Cuenca, Spain, the Selva Pascuala mural of rock art thought to be from 4000 B.C.E. — portrays mushroom figures [4]. Further, in 1910, anthropologists found rock carvings in the Tas sili caves in the south of Algeria depicting dancing figures with mushroom heads holding mush room-like objects [5]. Lines carved from the objects to the heads of the dancers are thought to reflect the states of con sciousness induced by psychedelic mushrooms, while the postures of the figures depict the associat ed ritual dances. These carv ings suggest that psilocybin use has been widespread in Afri ca and the Middle East since ancient times [6].

Psilocybin was often ingested in religious practic es for healing purposes [5, 7]. In many parts of the world, including ancient Europe and Asia, shamanis tic practices incorporated the use of hallucinogenic mushrooms to enhance healing abilities by connect-

ing shamans with the spiritual world [5, 7]. Psilocybin allows shamans to “see” the causes of illness, and healing is assisted by spirits, referred to as “power animals,” “guardians,” or “helpers” [8]. Hindu practic es may have also incorporated the use of psilocybin. Soma, a drink that was believed to be consumed by the Hindu gods and their ancient priests, has been theorized to originate from hallucinogenic mush rooms [9, 10]. Its consumption was thought to heal illness, promote positive emotions, and bring humans closer to the divine.

Given psilocybin’s use in healing by indigenous com munities for thousands of years, researchers today are investigating its ability to treat psychiatric dis orders. Psilocybin-assisted therapy has been identi fied as a potential treatment option for conditions including major depressive disorder, generalized anx iety disorder, and addiction [11]. Unfortunately, the use of psychedelics as therapeutics is often met with controversy because of their complex and politicized past [12, 13]. As a result, much is still un known about how psilocybin acts on the brain to produce healing effects. Dismantling the negative stigmati zation surrounding psilocybin has the potential to make alterna tive treatments for debilitat ing psychological disorders more accessible.

A TRIP TO THE PAST: OVERCOMING HISTORICAL STIGMAS SURROUNDING PSYCHEDELICS

The indigenous peoples of Mesoamerica consumed psychedelic mushrooms during therapeutic and reli gious rituals for many cen turies before the arrival of Christopher Columbus [14]. Spanish missionary Fray Ber nardino de Sahagún first men tioned these practices in an account from 1530: “The first thing they ate in a feast, were some black mushrooms… that make you drunk and make you see visions” [15]. How ever, many indigenous groups were forced to stop consuming mushrooms during the colonial era due to laws imposed by Christian missionaries which for-

“I

bade the use of psilocybin, even for medicinal and religious purposes [14]. Christians believed that us ing hallucinogens allowed individuals to communi cate with the devil [16]. They associated mind-alter ing substances with supernatural forces they feared, such as witches and the demonically possessed [17]. Prohibition began with Columbus’s presence in Me soamerica and continued until the 20th century, as Catholic and Evangelical Protestant missionaries dis couraged the use of hallucinogenic mushrooms in re ligious rituals.

In the 1960s, scientific and popular interest in psy chedelic compounds resurged [18]. Unfortunately, the increased interest exacerbated preexisting neg ative biases towards these substances within law enforcement and scientific institutions. Initially, the renewed use of psychedelics prompted hundreds of studies on hallucinogenic substances worldwide. At the same time, the distribution of illicitly manufac tured psychedelics led to use in uncontrolled settings and increased reports of “bad trips,” or psychedelic experiences involving overwhelming anxiety that can turn into panic, anger, and depression with suicidal thoughts. The rare but highly publicized suicide cases following these kinds of psychedelic experiences led to social backlash, resulting in the discontinuation of research on psilocybin [18]. The use of psychedelics by anti-Vietnam War activists also led government officials to associate psychedelic use with anti-war sentiment [19]. The stigma surrounding psychedel ics contributed to the commencement of the War on Drugs and the enactment of the Controlled Sub stances Act of 1970, formally classifying these sub stances as dangerous drugs with a high potential for abuse [20].

Despite these efforts to vilify psilocybin, its use is gradually becoming more accepted. In November 2022, a vote by Denver, Colorado resulted in the de criminalization of psilocybin for recreational use [21]. Additionally, four in ten adults surveyed in the United States feel that psilocybin should be legal, at least under some circumstances [22]. This change in per spective can be attributed to new evidence demon strating that psilocybin has many therapeutic bene fits and little potential for abuse or dependence; in healthy participants, the short-term and long-term effects of psilocybin are safe and tolerable [23, 24, 25]. These findings challenge negative stigma around psilocybin created by colonial leaders, religious fig ures, and pro-Vietnam war advocates, demonstrat ing that psychedelics are safe and medically effective drugs.

A TRIP INTO THE BRAIN: HOW DOES PSILOCYBIN TREATMENT WORK?

The War on Drugs and the resulting halt in psilocybin research have limited our understanding of how this psychedelic acts on the brain [26]. One widely ac cepted theory for the brain mechanisms underlying psilocybin’s effects is that they occur largely through the stimulation of serotonin receptors [26]. Serotonin is a chemical in our brains known to modulate mood, cognition, reward, learning, and memory [27]. Psilo cybin’s chemical structure is similar to that of sero tonin, allowing it to activate serotonin receptors [28]. Let us imagine the serotonin receptor as a baseball player catching a baseball, the serotonin molecule. The shape of the player’s glove is created specifically to catch a baseball. If a basketball were thrown at the player, they would not be able to catch it with the glove. However, if a ball that is similar in structure to the baseball is thrown, such as a softball, the glove would be able to catch it equally as well. Like the similar shapes and sizes of the softball and baseball, psilocybin and serotonin can both be “caught” by se rotonin receptors [26].

Why is it important to understand psilocybin’s un derlying mechanisms? Psilocybin may be a viable treatment option for mental health disorders [11]. Especially effective in tandem with psychothera py, psilocybin can help individuals with alcohol de pendence reduce their alcohol consumption [2, 29]. Similar positive results were found for persons ex periencing tobacco addiction—psilocybin treatment led to greater rates of smoking cessation than other behavioral therapies such as nicotine replacement therapy [30, 31]. Psilocybin doesn’t just counteract a specific drug dependency but may interrupt the neu rological pathways of addiction by improving a per son’s ability to change ingrained behaviors [32]. This can support their agency to alter drug-use behaviors, but more research into this topic needs to be done [33, 34, 35]. Individuals with substance dependence also have impairments in their emotional processes controlled by the amygdala, the brain area involved in memory, decision making, and emotional responses [36]. Hyperactivity and a disturbed balance in serotonin receptors in the amygdala have been thought to contribute to emotional distress seen in substance use disorder [28]. Psilocybin’s actions on serotonin receptors decrease amygdala activity, which can be useful in treating emotional dysregulation found in drug users [37].

Psychedelic Mushrooms

Along with psilocybin’s positive effects on substance use disor ders, it holds large therapeutic potential in treating major depres sive disorder and generalized anxiety disorder [38, 39, 40]. Psilocybin leads to rapid and long-term antidepressant effects [39]. Similarly to substance dependence, these positive effects appear to be mediated by a decrease in amygdala activity [41]. Additional ly, individuals with depression often demonstrate increased communi cation between the hippocampus, a brain region important for memory encoding and retrieval, and the pre frontal cortex — an area involved in high-order cognitive processes such as decision making, reasoning, per sonality expression, and social cog nition. After psilocybin treatment, communication between these regions decreases [41]. Major depressive disorder, gen eralized anxiety disorder, and substance use disorder are all associated with increased connectivity be tween brain regions in a large-scale network that is active when the brain is at rest [11]. The network is primarily composed of the dorsal medial prefrontal cortex, posterior cingulate cortex, and angular gyrus [42]. When completing a cognitive task, this network is typically inactive, but increased connectivity be tween the brain regions involved renders the network overactive, which can impair cognitive performance [43]. Psilocybin appears to disrupt this impaired neu ral network by decreasing communication between brain areas after its consumption [11, 44]. Psilocybin demonstrates high therapeutic potential in treating these psychiatric disorders, but because it is still classified as a dangerous drug according to legisla tion, it cannot be prescribed for treatment until it is reclassified as a medication [20].

A TRIP TO THE FUTURE: THE GROWING ACCEPTANCE OF PSILOCYBIN THERAPY

Although psilocybin demonstrates potential efficacy in treating mental health disorders, negative stigma tization continues to impact the amount of psyche delic research being conducted [12, 13]. In Australia and New Zealand, for example, psychedelics are still viewed as addictive and dangerous with no therapeu tic applications, so academic institutions are hesitant

to become involved in this field of research. These countries are top leaders in medical research and could contribute to the advances being made psychedelic therapy, but due to the con tinued perception of these drugs as harmful substances, they are falling behind in psychedelic research [12, 13]. Many other countries are adopt ing the use of psychedelics in therapy, and now, there are hundreds of ongo ing psychedelic research trials [45]. The Netherlands, in particular, has legalized psychedelics and is home to worldclass psychedelic therapy centers, embracing them as a medical treatment [46]. Examples of le galization, such as the case in the Netherlands, may provide a potential avenue for other coun tries to follow suit.

While results on psilocybin-as sisted therapy are promising, it is important to note many of these stud ies report small sample sizes [38]. Large sample siz es are a necessity if we want to more closely ap proximate how the larger population would react to this type of treatment [47]. Since psychedelics are becoming increasingly accepted around the world, a greater number of studies with larger sample sizes have been conducted. For example, a recent study on treatment-resistant depression had 230 participants, the largest population in a psychedelic study to date, and reported a concrete reduction in depressive symptoms [48]. With a large sample size like this one, we can better predict the effects on a range of peo ple, as well as check for any adverse symptoms that may have not been present in smaller groups [48]. If more studies with larger sample sizes are conduct ed, we may be able to see a future where psilocybin is accepted as a medical treatment. Individuals who are suffering from mental illnesses could experience a life-changing moment like Jon Kostas did when he realized, after only his second psilocybin session, that he was “killing off the addiction, the alcoholism and starting with a clean slate” [1].

References on page 50.

NATURE’S SCAFFOLDING: THE EXTRACELLULAR MATRIX

by Gage Haden / art by Hanqi Wu

Imagine walking through New York City, neck craning as you stare, agape, at the giant skyscrapers and buildings at every turn. Now, focus your attention on the buildings still under construction and the pro tected walkways between buildings. The city itself is supported and reinforced by lattices of metal piping, a steel exoskeleton of scaffolding, often overlooked, yet essential to the construction and safety of citi zens. The scale of this scaffolding is enormous, but the principle is universal. Scaffolding supports every thing from the largest skyscrapers to the minuscule cells of our bodies. Hidden between the 37 trillion in

dividual cells of our bodies is another essential struc ture for life: the extracellular matrix (ECM). The ECM is a complex, variable biological scaffolding that sur rounds each of our cells, giving them structure and keeping reserves of important messenger molecules [1, 2]. In the central nervous system (CNS), made up of our brain and spinal cord, the ECM plays an important role in fortifying neurons. The central nervous system is our command center, receiving, interpreting, and sending information to direct the actions of the rest of our bodies. This information is passed as electrical signals from one neuron to the next in pathways that

generate specific commands. Thousands of these pathways exist in the human brain, all connecting and branching to create neuronal networks responsi ble for more coordinated information processing and command issuing. Surrounding these networks is the ECM, hard at work stabilizing the neural connections and stabilizing the structure of the CNS.

THE BUILDING BLOCKS OF THE ECM

The ECM in the central nervous system works to maintain healthy brain function through a variety of mechanisms, including establishing structure [3]. This neuronal scaffolding consists mostly of proteins and carbohydrates bound together, designed to support brain function by allowing an increase in the rigidity of the structure [4]. The ECM makes up roughly 1020% of the total volume of the brain and is composed of three distinguishable components: the basement membrane, perineuronal nets (PNNs), and the inter stitial matrix [5]. The basement membrane is aptly named; similar to a basement separating a building from its foundation, the basement membrane sep arates the main parts of the brain from their sur roundings [6]. Perineuronal nets, like bearing walls in a building, surround the cell bodies of neurons and provide structural solidity to neuronal networks [3]. PNNs are imperative for regulating the adaptability of our brains as well as developmental growth. Finally, the interstitial matrix, made up of all other ECM mol ecules dispersed throughout the CNS, provides stor age for important molecules in the CNS [1].

MODELING THE BRAIN: THE ECM IN DEVELOPMENT

As the nervous system matures, a person’s interac tion with their environment alters the formation and reinforcement of frequently used neural networks [7]. The networks in our brains are specific to the ways we live; for example, people who are born deaf have different neural networks for language than those who are born with hearing [8]. People born without hearing require less auditory interpretation and con sequently, the networks specific to this function will not develop the same as in a person born with their hearing [8]. As the brain develops, certain networks are built up and others removed as specific environmental conditions narrow down what functions are more important for the survival of an individual [9].

Imagine this process like the remodeling of a house: contractors take out unwanted walls while fixing up the walls still important to the house’s structure. The ability of the nervous system to remodel its networks

in this way is reliant on the principle of plasticity — the malleability of the brain and its ability to rewire neural pathways [9].

The brain’s capacity for this rewiring changes throughout development; plasticity is not constant in the CNS. During development, there are specific time periods in which plasticity is dramatically in creased, known as critical periods [7]. Critical periods are important for the development and refinement of complex functional networks; the brain’s increased flexibility allows for more rapid growth and develop ment [9]. Following these critical periods, plasticity is then decreased by building up structural compo nents, such as perineural nets, which bind the intact networks that have been formed and refined during the critical period [10, 11]. Neural plasticity changes throughout development and is driven by the forma tion and movement of various ECM components [7]. Plasticity and structure are opposing forces in the brain, and without a delicate balance between them, the nervous system is left vulnerable.

DISRUPTING THE BALANCE: ECM ABNORMALITIES IN ILLNESS

Neurological disorders often affect the ECM in the brain. Abnormalities in the human ECM are associ ated with schizophrenia, a chronic psychotic disor der, and Alzheimer’s disease, an aggressive form of dementia [12, 13]. Soon after these associations were found, scientists corroborated the results by exper imentally disrupting the ECM in mice, leading to sig nificant alterations in schizophrenia-related neural

networks [14]. The ECM disruptions most commonly found in individuals with schizophrenia are the loss of functional perineural nets and altered expression of ECM molecules within neuron support cells [14].

expression of ECM-related molecules, while others increase expression, indicating that the ECM must be kept in a delicate balance [13, 17].

ADDING INSULT TO INJURY: THE ECM IN BRAIN INJURY

These support cells, called glial cells, protect and re inforce neurons as well as provide them with essen tial oxygen and nutrients [15, 16]. Without the ECM, glial cells cannot properly support the function of neurons [14]. An increase in neural plasticity, caused by lower levels of ECM, is correlated with schizophre nia; the decreased structure results in the break down of essential neural networks [12, 13]. Plasticity benefits the growth and learning of the brain during development, but once the brain is mature, it leaves functional neural networks without support from the ECM. Therefore, these networks are vulnerable to degradation.

Alzheimer’s disease, a degenerative and progressive neurological disorder associated with the buildup of plaques in the brain, is associated with a differ ent disruption in the ECM [12]. The plaques clog up the brain, similar to how a blood clot obstructs a blood vessel, and studies linking Alzheimer’s to the ECM found structural components of the neural ECM within the plaque build-ups [17]. More research is needed to reveal the entirety of the role these mol ecules have in the cause and effects of the disorder, but it is clear that Alzheimer’s is using ECM building blocks in ways they were not evolutionarily intended. The disruption of the ECM is involved in a wide va riety of neurological disorders, each with a different mechanism of action [12, 14]. Certain disorders lower

When an injury occurs in the central nervous sys tem, cells that increase the production of ECM components are activat ed, thus increasing the structural rigidity surrounding the area of injury [18, 19]. Immediately prior to reinforcement of the injured CNS, a new crit ical period opens, when plasticity has not yet de creased, and recovery po tential is at its highest [20, 12]. This is why a speedy response to brain injury is important for good longterm outcomes: it is crucial to take action before plasticity is obstructed by the ECM [20]. Similar to how the expression of ECM components is related to mental disorders, the fluctuating ECM-propelled balance of rigidity and plasticity poses benefits and vulnerabilities following traumatic injury [18].

Similar to cuts and wounds forming scars as they heal, scar tissue also forms around injured areas of the brain and spinal cord [22]. This scar tissue is made of neuron-supporting glial cells, neuroimmune cells, and ECM components, blocking the spontaneous re generation of neurons and their networks. While at other times, the increase of ECM components is ben eficial, in this case, it hinders the recovery of dam aged neural networks [22]. Plasticity is a powerful tool of the nervous system, both in development and recovery. Without the proper regulation of ECM com ponents, however, plasticity is either over-heightened or lowered, causing issues in health and recovery po tential.

MATRIX MEDICINE: CLINICAL APPLICATIONS OF THE ECM

The extracellular matrix is an essential component of the CNS and works to keep our body’s command centers in a healthy equilibrium. The ECM balances the brain’s inherent plasticity with an equally import

ant need for structure. Based on these character istics, the ECM has emerged as a potential clinical target for the treatment of numerous neurological issues [23]. There are two basic approaches to clini cal treatments with the ECM: increasing structure by stimulating the formation of ECM components, or im planting synthetic copies and conversely increasing plasticity by dissolving the present ECM [23]. These opposing approaches, increasing either structure or plasticity, are applied in many different ways.

Attempting to increase the structure and stability of neural pathways is effective in improving nerve transplantation techniques [24, 25]. When implant ing cells intended for regeneration, or intact nerves as a transplant, synthetic ECM substitutes increase the benefits and success rate [24, 25, 26]. This tech nique works similarly to vines of ivy climbing a trellis. Without the trellis, the vines grow jumbled on the ground and are less healthy. With the trellis or our synthetic ECM, the nerves or stem cells have a path and structure to grow on, resulting in healthier grafts growing in precise, specified directions. These same regenerative benefits can be achieved by stimulating cells that naturally create and release ECM compo nents or by implanting extracted brain-derived ECM components [27, 28, 29].

Other treatments seem to contradict the idea of the structural “trellis” and instead focus on dissolving the ECM to allow for enhanced mobility and growth of neural cells [30, 31]. Depending on the abundance and location of ECM components in the CNS, they can either act as a trellis or an impenetrable wall. PNNs, especially, seem to aggregate at traumatic brain inju ry or neurodegeneration sites, providing structure for

the scar tissue that forms in the space and leaving no room for our “vines’’ to regrow [32, 33]. Enzymes can dissolve these ECM components, allowing dam aged neurons to heal their appendages and restore disrupted neural networks [30, 31].

CONCLUSION

Therapeutic approaches to the ECM seem to be two sides of the same coin, one increases structure and decreases plasticity, and the other does the opposite, showing the great complexity of ECM interactions in the CNS. Both approaches have been shown to be beneficial in medicine when used properly and at the right time point following damage to the CNS. Tar geting the neural ECM has great potential as a clin ical approach but is similar to balancing on a dou ble-edged sword; leaning too far in either direction is dangerous. Much more research on neural ECM inter actions in disease and injury is needed to improve the potential clinical solutions. Because of this, we are only beginning this grand scientific journey.

References on page 52.

A LITTLE-KNOWN SIDE EFFECT OF CHEMOTHERAPY: CHEMOTHERAPYINDUCED PERIPHERAL NEUROPATHY

by Riley Lipman / art by Anna-Kate Pittman

Throughout our lifetimes, many of us will feel the life-altering effects of cancer in one way or an other. Even if we have not experienced the disease firsthand, it is likely that someone close to us has. An estimated 19.3 million people worldwide were di agnosed with cancer in 2020, and this already dis turbingly large number is expected to grow by 47% to 28.4 million people by 2040 [1]. Given how common cancer is, many people are at least somewhat famil iar with chemotherapy, a medical regimen that uses powerful drugs to target fast-growing cells in your body [2]. Unfortunately, this life-saving cancer treat ment is a double-edged sword — while effective in fighting several forms of cancer, many of the drugs used for chemotherapy treatment can simultaneous ly have damaging large-scale effects on a person’s nervous system. These unintended consequences of chemotherapy can have detrimental effects on a can cer patient’s quality of life [3]. While the severity of side effects varies from person to person, symptoms often take a physical toll [4]. Those who undergo che motherapy often feel weak and frail due to treatment [5, 6]. When people think of chemotherapy, they often think of the more visible side effects caused by the treatment, such as vomiting and hair loss. One of the overlooked side effects is the development of an un derstudied side effect called Chemotherapy-Induced Peripheral Neuropathy (CIPN).

WHAT IS CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY?

When chemotherapy treatment tampers with biologi cal mechanisms vital for nervous system functioning, it has debilitating effects that impact basic human

function on a broad scale, from holding a pencil or tying shoelaces. People with CIPN experience symp toms caused by damage to the nerves that control sensation and movement in the arms, legs, hands, and feet. A person receiving chemotherapy described CIPN as “not one of those high profile things that you think about when you think about chemotherapy, like the nausea, the vomiting, the hair loss” [5, 7]. Yet, for nearly 70% of people undergoing chemotherapy, the symptoms of CIPN take the biggest toll on both their physical and mental health out of all the chemother apy-induced symptoms they experience [8, 9, 10]. Broadly, these symptoms include pain, extreme sen sitivity to temperature, and numbness in the hands and feet, all of which significantly impact even the most basic functions [11, 12]. Tasks such as writing your name, brushing your teeth, fastening buttons, or taking a bite of food can become difficult. People often have difficulty with manipulating small objects, like pencils, particularly if not looking directly at them [12]. One person described their loss of sensation in their hands when eating food: “sometimes, when I was holding a bowl, the bowl would suddenly drop…. My [hands] had no strength at all” [13]. Another per son described a similar sensation when trying to write their name and said that their “handwriting became very ugly… [they] could not even sign properly.” CIPN can also affect a person’s ability to stand up and stay balanced, especially in poorly lit environments. Nearly a year after completing chemotherapy treatment, one person continued to experience pain in their legs and had “no strength to walk,” even to the bathroom [13]. Some state that CIPN is even “worse than having cancer because it changed [their] lifestyle” more than the disease itself [7]. People can begin to experience

Chemotherapy-Induced Peripheral Neuropathy

symptoms of CIPN during chemotherapy treatment, and some symptoms, such as numbness and tingling, can persist for years to come [14]. CIPN occurs in ap proximately 68% of individuals within the first month of completing chemotherapy, and continues to affect 30% of people 6 months after they finish treatment [12].

CIPN involves severe damage to the nerves outside of the brain and spinal cord, which comprise the pe ripheral nervous system [15]. The peripheral nervous system is a two-way highway: it carries signals and sensations to the brain, and also transports signals of movement to our extremities, such as our arms and legs. When anticancer drugs block this highway, com munication between the brain and body is severed; sensory input can no longer reach the brain, and mo tor output from the brain can no longer reach the rest of the body. This disruption causes symptoms including mild tingling and numbness in fingers and toes, sensitivity to temperatures, burning sensations, and sharp, stabbing pain. Damage to the peripher al nervous system can even inhibit individuals from performing daily tasks like eating, writing, or walking. Many patients persist through the challenging side effects of CIPN, continuing their painful cancer treat ment in the hopes of increasing their chances of survival. Doctors have reported that some patients resist suggestions to stop or reduce their dose of chemotherapy, even when their CIPN becomes hard to manage [7]. Nonetheless, CIPN is a very common reason that patients cite when asked what caused them to stop their chemotherapy treatment before its conclusion [7, 16, 17, 18]. Today, when an individual experiences these difficult side effects of CIPN, the predominant approach by doctors is to delay, reduce, or discontinue chemotherapy altogether, giving their symptoms the opportunity to improve with time. However, preemptively halting one’s cancer treat ment to alleviate the debilitating symptoms of CIPN can also jeopardize their journey to being cancer-free [18].

HOW DOES CIPN ATTACK THE NERVOUS SYSTEM?

Our body’s nervous system is divided into the central nervous system (CNS) — the brain and spinal cord — and the peripheral nervous system (PNS). These two divisions of our nervous systems are protected from pathogens and toxins by specialized biological barriers. The blood vessels that line our brain, which make up the blood-brain barrier (BBB), selectively

regulate what substances enter and exit [19]. Think of the BBB as a strong, tall, castle wall that is tightly guarded. This castle wall has a gate that only opens to let certain things pass. The BBB only lets certain particles and molecules through. Without this tight layer of protection around the brain, unwanted mole cules and cells would easily be able to pass through and affect cognitive function. The tight regulation of the BBB’s gates keeps toxic chemotherapy drugs from directly damaging our brain and spinal cord. Howev er, the blood vessels that line our peripheral nervous system, which make up the blood nerve barrier (BNB), are less protected than the BBB. The BNB has less tightly regulated gates with fewer guards fortifying its barrier, and its gates can easily be swung open, allowing more to pass through. Because the walls of the BNB are not as fortified as the strong walls of the BBB, it is easier for potential toxins to enter the pe ripheral nervous system as opposed to the brain [20]. As such, dangerous intruders, such as toxic chem icals, are able to accumulate in peripheral nerves. When chemicals interfere with the functioning of cells in that area it can potentially cause nerve death. The degeneration of peripheral nerves due to the loss of the cells that comprise these nerves is thought to be the underlying mechanism of CIPN [21].

A DEEPER LOOK INTO THE DESTRUCTIVE MECHANISMS OF CIPN

Neurologists continue to investigate the mechanisms underlying the development of CIPN in hopes of bet ter combating its debilitating effects. Many different components of the cells within the peripheral ner vous system are at risk of harm from various anti cancer drugs, such as the mitochondria, which facili tate energy production and metabolic processes [22]. Think of the mitochondria as a power plant. A pow er plant produces energy for a city, but also releas es greenhouse gasses that pollute the air. Similarly, when mitochondria pump out energy to be used by neurons, one of the nasty byproducts they release are reactive oxygen species (ROS), which are dangerous

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ISSUE 5

to the cell in large quantities [23]. Antioxidants, like the ones plentiful in the fruits and vegetables that we eat, can help clean up excess ROS and act as the air filters of the power plant [23]. They are the cells’ normal maintenance system for clearing out unwant ed byproducts of energy production. When ROS levels are steady and controlled, mitochondria are able to produce energy efficiently and the antioxidants can easily play their role, allowing the power plant to run smoothly. But when the power plant of the city is not functioning properly, the city as a whole can no lon ger sustain itself.

This cycle of energy production in the mitochondria of neurons is thrown out of balance when chemo therapeutic drugs interfere [18]. When chemothera peutic drugs are administered, they disrupt the ener gy production system of the cell. ROS levels increase and antioxidants can no longer keep up with filtering and clearing away harmful byproducts; therefore, mi tochondria are flooded with an excess of ROS and begin to break down [18]. This puts cells in a harmful state called oxidative stress [22]. Neurons are heavi ly dependent on mitochondria for energy production, which are utilized to power a variety of neuronal pro cesses. When the major energy producing machines are disrupted, the neuron’s ability to function is simi larly disrupted. Neurons impacted by oxidative stress are no longer able to produce the energy required to function and communicate with each other properly, so they die [24]. The death of neurons responsible for sending sensory information to the brain prevents the peripheral system from carrying these signals. This dysfunction plays a direct role in the develop ment of CIPN [25].

OXALIPLATIN: A DOUBLE-EDGED SWORD

There are a wide range of chemotherapeutic drugs frequently administered to treat cancer. The physio logical side effects vary between different classes of drugs due to their chemical properties — ranging from acute and fleeting pain to permanent and potentially irreversible neuronal damage. While different chemo therapeutic agents may impact the mitochondria of neurons in different ways, many chemotherapeutic drugs disrupt neuronal energy production, causing neuronal death. Some of the most neurotox ic chemotherapy drugs are platinum-based drugs, such as Oxaliplatin, which causes CIPN in 70% to 100% of all people the drug is administered to [26, 27]. Oxaliplatin can damage peoples’ sensory systems with

Chemotherapy-Induced Peripheral Neuropathy

in hours of treatment, with the effects sometimes persisting long after their therapy is complete [28]. At a cellular level, Oxaliplatin damages the mitochondria of neurons, leading to a buildup of harmful reactive oxygen species, and eventual neuronal death [29].

Because of the aggregation of damaged mitochondria in the sensory nerves of individuals taking Oxaliplatin, this drug may cause the aforementioned symptoms [30]. At the beginning of treatment, people taking Ox aliplatin describe feelings of numbness and tingling in their hands and feet, though they often find it diffi

GREY MATTERS JOURNAL AT VASSAR COLLEGE |

Chemotherapy-Induced Peripheral Neuropathy

ing oxidative stress and the damage it can cause in mitochondria [33]. Antioxidant drugs have been associated with a significant decrease in oxidative stress and may be promising candidates for further study to treat CIPN, due to their restorative effects within the nervous system [33, 34].

The lack of standardization in tools used for clinical assessment, evaluation, and diagnosis of CIPN has significantly hindered the ability to address symptoms at their onset [20]. While there are a number of tools available for assessing CIPN, there is current ly no universally-accepted approach for diagnosis of the disorder [35]. Determining whether an individual is experiencing CIPN requires more than a routine blood test; verbal reports from the individual on their experience are paramount to diagnosing CIPN symp toms. Doctors usually assess pain by asking a person to rate their pain on a scale of 1-10 [36]. This ap proach may be ineffective because pain is subjective and pain tolerance varies between people, so doctors may have a hard time understanding the severity of one’s discomfort. Further, the way in which people describe their pain to their physician may vary. Many chemotherapy patients say that it is nearly impossi ble to be able to describe the sensations caused by CIPN to their doctors; it is something that someone would have to experience themselves in order to un derstand. In an attempt to express their symptoms verbally, people with CIPN often utilize analogies. They use phrases such as “moving insects” when de scribing numbness on their skin and compare sensa tions to jellyfish stings [7]. Abstract descriptions such as these show just how difficult it is to standardize and treat CIPN.

Fortunately, recent studies are beginning to explore ways to standardize CIPN diagnosis, such as by using quantitative sensory testing (QST). QST counts neu rons in images of the peripheral nervous system to

evaluate neuron death in a quantifiable manner [37]. This approach is promising because it removes the subjectivity of verbal pain descriptions. Medical practitioners using QST can theoretically cus tomize treatment plans based on a person’s unique level of nerve degeneration. However, the implementation of QST is still in its initial stages — today, there are still no assessment tools that have proven to be clinically effec tive. As a result, there is no standardized ap proved way to go about diagnosing or analyz ing individual cases of CIPN [38]. The creation and utilization of instruments to quantify symptomatology of CIPN will allow clinicians to learn more about the causes of CIPN, in order to determine how to best diagnose and treat it.

CONCLUSION

Even though CIPN is one of the most debilitating side effects of chemotherapy, many patients tend to be more aware of the common side effects of chemo therapy such as hair loss and fatigue and don’t con sider CIPN [7]. However, CIPN presents a significant issue for the treatment of cancer patients because it can compromise one’s quality of life and ability to continue treatment. Because of CIPN’s complex ity, it has been difficult to find preventive strategies or effective treatments for the disease. Defining the mechanisms underlying the pain symptoms of CIPN is crucial to developing preventive measures and treat ment strategies, as well as quality of life for individ uals battling cancer.

References on page 54.

RUNNING UP THAT HILL: THE STRANGER THINGS ABOUT LISTENING TO MUSIC

by Jadon-Sean Sobejana / art by Iris Li

The interior of Max Mayfield’s mind is treacherous. She is trapped, plagued by her inner struggles, and drowning in a flood of vivid, harrowing memories. All seems hopeless. Suddenly, a beam of light splin ters through the darkness and illuminates an escape route. Running Up That Hill by Kate Bush — Max’s fa vorite song — echoes through the shadows. The music sparks her memories of happi ness, friends, family, and love. Now armed with renewed strength, Max overpowers her inner demons and manages to narrowly es cape the danger in her own mind. In this scene from the beloved TV series Stranger Things, we can clearly see a de piction of the emotional and behavioral sig nificance of music [1]. While we may think of listening to music as a mere pleasure or hobby, it has another peculiar power: the potential for therapeutic value. Music ther apy can, in fact, be used as a non-invasive approach to treat a variety of mental ill nesses and disorders [1]. Listening to music activates a wide range of brain structures involved in modulating cognitive, motor, emotional, and motivational processes, making it a good candidate for therapy [2]. In order to grasp music therapy’s power as an effective alternative remedy to pharma cological interventions, it is first important to understand how sounds enter and interact with the brain.

MUSIC TO OUR EARS

While the process of listening to music may seem instantaneous, there are many complex interactions between the ear and brain that occur as we listen to our favor

ite songs. Every sound we hear is made up of waves [3]. Imagine plucking the strings of a guitar and watching as the cords wa ver back and forth; vibra tions emanate from where the strings are plucked and create the waves that we interpret as the sounds we hear. Next, they travel through the ear canal until they reach the inner ear, where they interact with a spiral structure called the cochlea and transform them into electrical sig nals. Within the cochlea, the vibrations cause small hair cells to oscillate back and forth, like palm trees swaying in the wind. The physical and alternating movement of these cells back and forth generates electrical energy, which travels through the auditory nerves into the brain. This conversion step is cru cial, as the brain can only understand these signals as electrical impulses, and not vibrations.

Running Up That Hill

Once auditory information passes through the ear, it begins to traverse the brain. Think of this process like a game of connect-the-dots, where each dot represents a part of the brain that the signal passes through. The electrical signals pass through the first dot, the auditory nerves in the back of your brain. Here, differences in auditory timing and intensity are combined to help you discern where the sounds are in your environment [4]. The next dot is a large fiber of nerves in the middle of your brain, where distinct au ditory centers help you identify the source of sounds and combine many different auditory signals. The following stop on the path of dots is the thalamus, a specialized area that evaluates auditory informa tion – determining a sound’s direction and location [4]. The final dot represents an area of the cerebral cortex, dubbed A1, which participates in the more

specific processing of music [5]. Similar to the image revealed when you complete connect-the-dots, the auditory information processed in the A1 reveals to your brain the nature of the sound [6]. Only in the A1 can your brain separate the different components of auditory stimuli by frequency. For example, imagine all the different components of your favorite piece of music: the throbbing bass, the belting sopranos, and the strumming guitars. Each of these sounds is made of many different frequencies. The A1 isolates these frequencies for analysis and thoroughly processes components of the sound signal, such as pitch, qual ity, tone, and intensity [6]. In order to fully experi ence music, we need our A1 to combine all of these components together [7]. On the way to the A1, the same electrical signals that allow us to experience music also pass through and affect regions associat ed with emotions and memory [8]. This stimulation can have a pro found impact on the way in which we experience music. Think about how music can influence our feel ings and our moods — just putting on a certain song can make us feel a whole host of complex emo tions! When music has reached the brain, we are able to connect our reaction to the music to the experience of listening, revealing our sentiments not only towards the song itself, but also towards what music reminds us of.

ESCAPING FROM THE UPSIDE DOWN: HOW MUSIC CAN LIFT YOUR SPIRITS

Do you ever play a certain song to hype yourself up before do ing something difficult? Or, does a specific playlist ever bring back vivid memories you made with a certain someone? Whatever rea son you have for listening to mu sic, many complex emotional re sponses can be evoked by the songs you hear. These responses are regulated by the region of the brain involved in the processing and controlling of your emotions and memory, known as the lim bic system [8]. The limbic system, composed of the nucleus ac cumbens, amygdala, and hippo

campus, receives sound input from the A1, and makes associations between emotions, memories and the music we listen to [9].

THALAMUS

of her negative emotions. Listening to music can be considered one of the most stimulating and reward ing human experiences, and this functional need is reflected structurally in our brains, with music expo sure being correlated to increased dopamine levels in the NAc [14].

LOBE

One particularly intense version of this process be comes apparent when watching horror movies. For instance, have you ever noticed that the most terrifying part of a scary movie may be its loud and exaggerated sound effects? This fear can be attributed to activity in the brain’s amygdala, a structure primarily responsi ble for connecting emotional re sponses to specific stimuli and regulating feelings such as fear [10]. If tense mu sic starts to play be fore a scary scene, your amygdala may prompt you to look away as fear builds and your heart rate quickens. However, regu lating responses in distressing situations is not the amygdala’s only strength. Think back to a time when you first listened to your favor ite song. Did you get goosebumps when the chorus started to play? Did you feel a slight shiver in your body when the melody began? These pleasurable feelings in response to music are also associated with your amygdala. In fact, the experience of feeling chills when you reach an emotional moment in a song is correlated with decreased blood flow to the amyg dala [11]. Conversely, in disorders like depression and anxiety, symptoms are associated with an increase in blood flow to the amygdala. Therefore, using music therapy to decrease blood flow could be beneficial to counteracting these symptoms and treating different affective disorders. [12].

When you listen to music that evokes joy, your pos itive emotions are managed by the amygdala’s com munication with a nearby area in the brain called the nucleus accumbens (NAc) [10]. Associated with moti vation and emotion, the NAc is regarded as the most important pleasure center of the brain [10]. Activation of the NAc releases a chemical known as dopamine, involved in the production of pleasure and satisfac tion [13]. Perhaps this is the mechanism behind Max’s use of music to regulate her emotions in Stranger Things, as she frequently listens to music as a means of escape from feelings of regret and anger. Accord ingly, Max’s constant interaction with music seemed to enhance her self-esteem and lessen the severity

NERVE

COCHLEA

CANAL OSSICLES

However, the song itself is not always the sole reason we experience emotion when listening to music; sometimes music recalls certain memories, which then evoke emotions specific to those experiences [8]. Most of us have certain songs that remind us of the good times of summer. Some of us even have that one song that always reminds us of a significant other. A region in your brain called the hippocampus enables you to recognize happy or sad memories through stimuli such as music [10]. Generally, the hippocampus is known to contribute to emotions and memory [9]. Unlike the amygdala and NAc, the hippocampus is associated with more pos itive emotions that are closely related to the music listening experience, like tenderness, peace, and joy. In addition, the hippocampus’s involvement in our positive emotions is connected with reductions in emotional stress [10]. Another distinguishing function of the hippocampus is its ability to create, maintain, or strengthen social attachments, which are the feel ings of love, joy, or happiness we feel toward other things or people [10]. Stranger Things alluded to this concept when Max associated memories of friend ship and love with her favorite song. Because music is capable of engaging our social attachments, along with various emotions and memories in the limbic system, music therapy is a viable option for alleviat ing and treating mental distresses that relate to such social and emotional functions [2].

HOW MUSIC CAN KEEP YOU IN TUNE

“Music reaches parts of the brain words can’t,” says Max’s friend, Robin. This statement encompasses the basis for music therapy: the idea that music and lan guage have always been two sides of the same coin, different mechanisms for communicating the same emotions [15]. Since musical stimuli can activate the limbic system and the rest of the brain, music thera py can harness its power o to potentially reduce the severity of neurological diseases or mental disorders

TEMPORAL

EAR

Running Up That Hill

such as depression and anxiety [1].

In practice, there are two types of music therapies that clinicians currently use: passive and active [1]. Passive music therapy includes patients listening carefully and sincerely to the music with the goal of genuinely connecting with the emotions of the song. It provides patients with a non-invasive therapeutic approach in which they can choose music on their own accord and honor their preferences [2]. Active music therapy, on the other hand, engages patients in music through singing, dancing, or the use of musical instruments [1]. Though both are beneficial in treating mental health symptoms, passive listening has been the most commonly used [2].

In recent years, more attention and resources have been focused on mental illness care due to the in crease in diagnoses of anxiety and depression [16]. Depression is a common disorder that impairs social functioning and quality of life, and increases mortality [17]. The limbic structures have been shown to function irregularly in those with depressive symp toms [2]. Because music can activate and engage these structures, cognition, social function, and pos itive emotion can be better engaged in patients that have affective disorders [2]. Remember how playing music for a patient can reduce the blood flow to their amygdala? Increased blood flow to the amygdala is associated with increased symptoms of depression or anxiety, so by reducing blood flow, the effect of these symptoms can be lessened. Though music treatment has resulted in positive effects as a potential treat ment for depression, it is important to note that more trials are needed to fully establish the neuroscientific basis for the therapeutic effects of music [9].

Think about the last time you were nervous. Now mul tiply that feeling times ten. Anxiety disorders cause this high level of intensity to occur even in situations that don’t warrant it [18]. The amygdala and hippo campus display increased activity when people listen to music [11]. Just as music therapy helps reduce symptoms of depression, it can result in decreased anxiety [2]. Mood, depression, and anxiety are all connect ed, which is why it is not surprising that music can affect them similarly [1]. Cur rently, music therapy is a growing field. It holds exciting promise in alleviating and treating symptoms of disorders that affect the way we feel [11].

ENDING ON THE RIGHT NOTE

In Stranger Things, what would have happened if Max didn’t hear her music? Confined in the abyss of her mind, overwhelmed by the ghosts of her past, she wouldn’t have survived without her favorite song. Stranger Things magnified how music can retrieve memories as music’s effect on the brain has been shown to have extreme therapeutic value. Music is accessible to everyone as a simple pastime, a stress reliever, or as some benign background noise, and formal music therapy exhibits significant potential as a treatment for mental health issues. The next time you hear your favorite song, or your least favorite song, consider how you feel—it might just give you some insight into the stranger things of your mind.

References on page 56.

LOST IN MIGRATION: EXPLORING THE ROOTS OF GREY MATTER HETEROTOPIA

by Dimple Kangriwala / art by Stuart Heintz

Have you ever lost a package in the mail? If you have, it was probably at the most inconvenient moment possible. Maybe it was a textbook you need ed to study for an upcoming exam, or a prop neces sary for a play you were putting on. You might have checked the UPS tracking constantly, refreshing and refreshing, waiting for it to arrive. When delivery day finally arrived, you sat by the window, invented rea sons to walk by the door, and peered outside your home at every rumble of an approaching car. But no luck: it just never showed up. Little did you know, your package had been delivered to another doorstep — all the way across the city. Say this package was a bunch of neurons you needed to construct an area of your brain. Without these cells, your brain would not be able to function properly. This misplace ment of neurons within the brain is known as grey matter hetero topia (GMH), with heterotopia trans lating to “out of place.” Simply put, during neu ral development, neurons may not migrate to their predetermined des tination and instead end up in an area where they do not belong [1].

THE TRIALS AND TRIBULATIONS OF NEURAL DEVELOPMENT

Grey matter gets its name from the many grey-colored neurons in the outermost layer of the brain, known as the cerebral cortex. These cells are vital components of the brain, playing a major role in cognition, memo ry, emotion, and behavior [2]. Grey matter cells in the cerebral cortex interact with other parts of the brain to aid in higher-level processing, which includes de cision-making and analysis of sensory input. Changes to these cells and their organization can disrupt neural activity and communication, hindering the overall functioning of the brain [3]. Grey matter heterotopia (GMH) is one such change to the organization of these grey matter cells, where neurons end up in the wrong place during neural development.

Normal neural development can be broken down into three steps: neural proliferation, cell migration, and cell differentiation. During neural proliferation, neural precursor cells, which are destined to develop into a specific type of neural cell (in this case, grey mat ter neurons), prepare to begin their journey across the brain [2]. Think of these precursor cells as cars on a highway. Just as drivers are guided by signs on a highway, precursor cells are guided by the projec tions of supporting cells to help them reach their fi nal destination [4]. Every driver has their own map to follow, and every precursor cell has genetic program ming that directs it to a specific location in the brain. Genetic programming also tells the cell to take on a characteristic appearance that corresponds to that

specific neu ron’s location and function, a process called differentiation [2]. Differentiation can occur well before the precursor cell reaches its final destination, meaning these cells know what kind of neural cells they will become be fore their journey comes to an end [2]. Though the cells aren’t fully differentiated when they’re migrat ing, they have already been prepared to become a certain type of neuron — neurons designated for the cerebral cortex are akin to vacationers prepared for a warm beach villa. These vacationers may have brought nothing but swimming trunks and flip-flops for their journey, so if they take a wrong turn on their road trip and end up at a freezing ski resort, they would be woefully unprepared. In the same way, grey matter neurons that end up in the wrong place in the brain can cause disastrous effects. In GMH, where migration goes awry, neural precursors fail to reach their destination, resulting in neurons differentiat ing in unintended areas. This is a problem, because if a differentiated neuron is in an area where it is not

supposed to be, it cannot function properly in its new environment, leading to neural communication er

WRINKLES: A PERSON’S FEAR, THE BRAIN’S FRONTIER

During migration, a neuron receives instructions from its genes, like a map that instructs it on how to reach its intended destination [5]. Some vital information on this map can be missing, like in a genet ic condition called DiGeorge’s Syndrome (DGS), which is one cause of grey matter heteroto pia. In DGS, some of the direc tions on the genetic map are deleted, causing the neuron to migrate to an undesignated lo cation. This faulty migration can have a staggering impact on brain development, causing grey matter heterotopia and resulting in a range of the physical and psychological symptoms associated with DGS [5]. Since DGS causes a large amount of grey matter cells to end up in the wrong location, it not only limits migra tion, but also the process of gyrification — the process where the brain creates its wrinkly pattern of bumps and grooves [6]. These folds are important because they increase the surface area of the cerebral cortex, enabling a great er number of neurons to interact. Reduced folding hinders short range neuronal connectivity, which may result in the development of ADHD, seizures, or anx iety disorders [7, 8]. In short, DGS can lead to grey matter heterotopia, which in turn lowers cerebral cortex volume, resulting in changes to brain structure and function due to improper distribution of neurons [9–12].

THE REALITY OF IT ALL: GMH AND SCHIZOPHRENIA

If a neuron is misdirected by a deletion on its genetic “map,” the consequences can also be psychological, not just structural. One well-studied psychiatric dis order that occurs alongside GMH is schizophrenia, a mental disorder that is characterized by delusions, hallucinations, and disturbances in thoughts and perception [13, 14]. The causes of schizophrenia vary, and may include genetic factors and abnormalities in

neurotransmission, though in some cases the exact cause cannot be explained [15, 16, 17]. Many stud ies have investigated genetic components, namely DiGeorge’s Syndrome, to explore this correlation be tween GMH and schizophrenia [5, 8, 18, 19, 5]. DGS is present in 1–2% of schizophrenia cases, despite be ing present in less than 0.1% of the entire population, suggesting a causal relationship between the two conditions [20, 21, 5]. Moreover, people with schizo phrenia, whether they’re born with or without DGS, show lower grey matter volume than people without schizophrenia [22, 23, 20]. This disparity implies that reduced amounts of grey matter is indeed a charac teristic of schizophrenia, thereby demonstrating the connection between the disorder and GMH. Reduc tions in grey matter impact neural connectivity, which can also contribute to symptoms of schizophrenia [24].

A CRASH COURSE IN COURSE CORRECTION

The abnormal migrations of grey matter neurons sug gest a startling connection to schizophrenia. The connection between GMH and schizophre nia can open new avenues for research, paving the way for novel therapies tar geting these disorders. As of now, there is no clear treatment for GMH itself, but there are treat ments for the disorders and symptoms produced by GMH [25, 26]. By treating schizo phrenia with a variety of medications and thera-

pies, doctors can reduce symptoms, but they cannot target the underlying cause [27]. Targeting GMH as an underlying contributor could lead to progress in the discovery of new treatments for schizophrenia [27]. Further research is needed to establish a better un derstanding of GMH and its connection to genetics, as it can open new doors to gene therapy research and techniques. New treatments could give these beach-bound neurons a corrected map to follow so that they can reach their sunny destination and have the relaxing vacation they prepared for.

References on page 57.

NOW YOU SEE ME, NOW YOU DON’T: THE MYSTERIOUS PHENOMENON OF PHANTOM PREGNANCY

by Kalina Rashkov and Sudiksha Miglani / art by Elsie McKendry

On September 3rd, 1554, news that Queen Mary I was expecting a child swept through Britain [1]. England would finally have an heir to the throne, prompting celebrations throughout the country. For quite some time, Mary had been experiencing symptoms of preg nancy: her stomach was swollen and expanded, she experienced morning sickness, and even reported feeling the baby moving beneath her abdo men. However, the royal infant never appeared. Several years after this in cident, Mary believed she was expect ing yet again. However, this was not the case, leaving physicians baffled by her inexplicable condition for a sec ond time. While medical practitioners in the Tudor Era could not determine the cause of the monarch’s suffering, historians consider Queen Mary I to be the first recorded case of pseudocye sis, also known as phantom or hyster ical pregnancy [1].

THE TANGIBLE SYMPTOMS OF PSEUDOCYESIS

Pseudocyesis occurs when a woman believes she is pregnant and shows physical signs of pregnancy despite not carrying a child [2]. Among the most common physical symptoms in women

This article uses female-gendered language to refer to pregnant people and those who menstruate. This choice was made because cited literature on the subject focuses on only female-identifying patients. The editors wish to recognize that pregnancy and menstruation are independent of gender identity.

who experience pseudocyesis are irregular menstru ation and changes in breast size and shape; other reported symptoms include abdominal swelling, the sensation of fetal movement, lactation, weight gain, nausea, and vomiting [3]. Queen Mary’s experience with these symptoms is not as uncommon as we might predict; medical literature has recorded around 550 cases of pseudocyesis in individuals whose ages ranged from 6 to 79, with a frequency of around 1 in 10,000 pregnancies in the Western world [4].

In pseudocyesis, a woman’s intense psychological desire for a child accompanies these physical symp toms. In many cases, women experiencing pseudo cyesis want children and have a history of infertility or miscarriages. Clinicians have proposed that the psychological and social pressure to have children can influence physical changes in the body [3, 5]. Because of this psychological component, pseudo cyesis is commonly confused with delusional preg nancy, when women falsely believe they are pregnant without physical symptoms [6]. Physical symptoms that mimic pregnancy distinguish pseudocyesis from delusional pregnancy, which is entirely psychological [6]. As such, pseudocyesis is most easily recognized by characteristics like morning sickness, lactation, and irregular periods [6]. Although scientists are still unsure of the root causes of pseudocyesis, the effort to uncover the biological and psychological underpin nings of this debilitating illness is ongoing [7].

HOW THE BODY PREPARES FOR A PHANTOM BABY

Patients who experience pseudocyesis do not fall un der one specific medical profile and may exhibit a wide range of hormonal interactions [8]. However, many of the first physical signs of pseudocyesis are related to the imbalance of essential hormones associated with pregnancy and the regulation of the ovulatory cycle [3]. Hormones are chemical messengers secret ed by glands to communicate with cells throughout the body. Critical hormones involved in pregnancy are released and regulated by a gland at the base of the brain called the anterior pituitary gland. These hor mones bind to receptors, causing physical changes in regions of the body associated with pregnancy, such as the breasts, ovaries, and uterus [9].

Estrogen and progesterone are hormones involved in initiating and sustaining pregnancy through every trimester [10]. During pregnancy, estrogen and pro gesterone are responsible for building and maintain ing the lining of the uterus so that the developing embryo is supported in its growth period [10]. The

ovaries and other glands produce these crucial hor mones. The ovaries produce estrogen in response to signals mediated by the anterior pituitary gland. Cli nicians have frequently observed high levels of estro gen and progesterone in women with pseudocyesis [11]. These high hormonal levels often lead to symp toms that can be confused with pregnancy in women who are not pregnant, such as irregular periods, ten der breasts, mood swings, bloating of the stomach, and symptoms of morning sickness, including nau sea and vomiting. The abdominal growth commonly associated with pseudocye sis is due to the presence of estrogen and proges terone, which promotes the development of uterine tissue and increases blood flow to the uterus [11].

Another pregnancy hormone involved in pseudocyesis is prolactin, produced by the anterior pituitary gland [12]. In pregnant and breastfeeding women, high lev els of prolactin aid in breast milk production and lac tation. The hormone travels through the bloodstream to stimulate the mammary glands’ growth, which ac tivates the synthesis and release of breast milk [13]. High prolactin levels have been observed in several cases of pseudocyesis [12]. They are recognized as the cause of some pregnancy-like symptoms, such as enlarged breasts, in women who are not pregnant [12]. These high prolactin concentrations signal to the body that a baby is on the way, stimulating breast milk production. The breasts of individuals with pseudocyesis subsequently swell and can produce milk like those with a typical pregnancy [3, 5]. These individuals often have high prolactin levels due to the dysregulation of the anterior pituitary, as well as a va riety of biological and psychological factors [12]. The imbalances in estrogen, progesterone, and prolac tin concentrations mimic the physical conditions of pregnancy, essentially tricking the body into believing it is pregnant [8, 14].

Factors that dysregulate the anterior pituitary, caus ing hormonal imbalances, vary from case to case. But they are often caused by specific medications and the patient’s mental state [8]. Antipsychotic medica tions, typically prescribed to treat certain mental ill nesses, can dysregulate the anterior pituitary, caus-

ing the overproduction of prolactin in the body [15]. A specific mental illness typically treated with anti psychotics is schizophrenia, a psychotic disorder [16]. Individuals diagnosed with schizophrenia maintained normal levels of prolactin before receiving antipsy chotic drugs to treat the disorder. After treatment, they showed five times the normal levels of prolac tin [16]. Schizophrenic patients with pseudocyesis are also prone to experiencing illusions and hallu cinations involving children [4]. Mental illness, like schizophrenia, coalescing with medication-induced hormonal imbalances can create the perfect storm for pseudocyesis.

While there is a clear correlation between the abil ity of antipsychotic medications to alter the anteri or pituitary gland and the production of prolactin, it is important to consider that the known causes of pseudocyesis are complex. A dysregulated anterior pituitary gland and pseudocyesis are not always a re action to antipsychotic medications, and the effects of antipsychotics on hormone levels and the body are highly variable based on factors including age, meno pause, and stress levels [17]. Not every woman who takes antipsychotics experiences pseudocyesis, and not every woman with pseudocyesis takes antipsy-

chotics; the interaction between the psychological state of wanting to be pregnant and bodily changes caused by hormones causes pseudocyesis. The pow er of a person’s psychological state on their physical response cannot be understated [18]. When you are anxious about taking an exam, your body releases stress hormones to physically prepare you for a dan gerous situation [19]. Your breath quickens, and your heart beats faster to pre pare your body to run away from something frightening, even though there is noth ing inherently dangerous about your situation. The same concept applies to pseudocyesis; psychologi cal stress can cause phys ical changes in your body, like the pregnancy symp toms we see in women with pseudocyesis [18]. The ability of psychological stress to physically influence the body is a common expla nation for why pseudocye sis seems to have a higher chance of occurring in cer tain populations [7].

WHEN LIFE INTERVENES

While it is known that neu roendocrine changes are involved in pseudocyesis, it is crucial to consider the importance of certain so ciocultural factors that make women more likely to initially experience these hormone changes and psy chological stressors [8]. The link between sociocul tural factors and the manifestation of pseudocyesis is not entirely understood; however, women with fewer socioeconomic opportunities are more like ly to develop pseudocyesis [3]. In these cases, chil dren may be considered necessary to these women, as they could support the struggling household when they are older [7]. Other factors that increase the likelihood of women experiencing this phenomenon include relationship instability and recurrent partner abuse [3].

Women whose cultures value childbearing and em phasize the need to have children to continue certain traditions or preserve the family line can be more vul

nerable to experiencing pseudocyesis [7]. The cultur al pressure to have children and continue the lineage can be an environmental stressor triggering physical changes in women [7]. Women’s psychological stress due to the social expectation to bear children occurs in several reported cases of pseudocyesis, including Mary I of England [1]. As the Queen, Mary was under immense pressure to produce an heir to the throne. It was seen as a duty to Great Britain, and her failure to have a child would paint her as an unsuccessful monarch in the eyes of her subjects [20]. Like many other women, Queen Mary had previously struggled with fertility issues and miscarriages [1]. This previous struggle could increase the stress she felt to become pregnant and contribute to her case of pseudocyesis.

Due to sociocultural influences disparately impacting the development of pseudocyesis, women in distinct regions are affected differently. Pseudocyesis is more common in countries with less access to prenatal testing throughout pregnancy [8]. This pattern is primarily attributable to the psychological aspect of the disorder; women with pseudocyesis often convince themselves they are pregnant, and in some cases, the most effective treatment is to provide the individual with irrefutable evidence that they are not [21]. This evidence usually comes in the form of an ultrasound. When women have access to ultrasounds, they can see no evidence of a fetus in their womb, which gen erally resolves pregnancy-related hormone imbal ances and related pregnancy symptoms [21]. With the assistance of these technological advancements, those who may be at risk for pseudocyesis, and even those experiencing mild symptoms, may resolve their case before their symptoms give cause for concern [8]. However, even after absence of pregnancy is con firmed by an ultrasound or blood test, some individ uals continue to experience the physical and psycho logical symptoms of pseudocyesis [5]. Since the exact hormonal and psychosocial causes of pseudocyesis remain unknown, a blanket treatment plan for these cases is still unavailable [8]. Some patients receive hormone therapy to correct imbalances in hormone levels, while others are treated with behavioral ther apy focused on problem solving to challenge false beliefs of pregnancy [3]. This psychologically-focused approach harnesses the intense mind-body connec tion that was a key factor in the development of the symptoms in the first place [3]. On the other hand, not all individuals have access to these treatment options, and pseudocyesis may resolve itself without their aid [3]. Regardless of treatment options, access to a robust support system is vital for complex and effective care both before and after the individual is

able to accept the absence of a pregnancy [22]. While addressing the symptoms of pseudocyesis and sup porting those affected by the disorder is important, understanding the interplay between the psycholog ical, biological, and sociocultural components is cru cial in treating the root cause [3].

References on page 58.

by Maia Beaudry and Talia Roman / art by Mingjia Ni

It’s a Saturday night and you’re sprawled out on the couch, ready to watch your favorite Olympic athletes compete. The first performers that pop up on the screen twirl and leap across the mat, demonstrat ing an incredible ability to pull off a complex routine. Watching in awe, you start to wonder how they coor dinate each movement so effortlessly. The event soon ends and a relay race begins: runners whiz along a track, passing a baton from person to person as they frantically dart to reach the finish line first. Though you may not realize it, there are countless relay rac es happening this instant in your brain, contributing to the exact coordination you were admiring in the gymnast moments before. The runners in this race are neurons, the fundamental units of our nervous system, while the signaling molecules passed be tween them act as the baton. One of the main “batons” responsible for your movement is a chemical called dopamine. In a healthy brain, dopaminergic neurons pass the chemical between each oth er to help coordinate the flow of information between the brain and muscles. If someone sudden ly drops the baton, the whole line of communication within the team stops, and it becomes impossible to complete the relay. Without these dopamine handoffs, we would have trouble performing voluntary movements and our bodies could not correctly regulate mood, pleasure, or motivation. If a team of neurons fails to complete a race, it can have drastic conse quences in the brain: this lessened communication between neurons can manifest as the symptoms of Parkinson’s disease (PD) [1]. PD is a neurodegenera tive disorder — a type of disease that occurs when neurons in the brain stop working or die — which makes it more difficult for people to execute simple movements, let alone perform the complex routines you saw the Olympic athlete perform [1, 2, 3].

Reductions in dopamine and neural communication, which are both associated with Parkinson’s disease, manifest in the body as a lack of control over vol untary movements [1]. This loss of control typical ly involves shaky movements (tremors), and slowed movement due to muscle rigidity is also common: one’s joints and muscles may begin to feel stiff and tight, the ground less stable, and movements slow and lethargic, almost like walking through water.

Most people with Parkinson’s experience physical in stability on a daily basis, and it can uproot their nor mal lives and routines [1]. PD often causes people to develop secondary symptoms in addition to these motor changes [2]. They may become socially isolated — oftentimes leading to depression, anxiety, and oth er cognitive issues — or develop chronic pain due to the rigidity of their bodies. As neurons and connec tions deteriorate, cognitive functioning, in addition to motor operation, becomes increasingly impaired [3]. The damage results in symptoms that can often ac company Parkinson’s disease, like dementia [1].

WHEN TREATMENTS TANGO: PHARMACEUTICALS AND COMBINATION THERAPY

Many common types of drug therapies help preserve and ef ficiently use the dopamine “ba tons” that still remain. Combina tion therapy makes use of two or more treatments working along side each other to treat PD more effectively than a single drug [4]. The most commonly prescribed drug for PD, called Levodopa, is oftentimes prescribed alongside another class of drugs, called MAO-B inhibitors [5]. Levodopa supplies the brain with synthet ic “batons” that can be converted into dopamine so the neurons can still pass them along and eventually finish their “race” [4]. Unfortunately, medi cations like Levodopa can have negative side effects, particularly increased muscle spasms that occur as the medication wears off. Because Parkinson’s al ready causes motor difficulties, involuntary muscle contractions compound the issue [1]. MAO-B inhib itors help this issue by prolonging the effectiveness of dopamine already present either naturally or as a result of Levodopa, and are quickly growing in popu larity due to their ability to rapidly improve PD symp toms [5]. These inhibitors have fewer detrimental side effects than Levodopa, so when both medications are used in conjunction, a smaller dose of Levodopa is needed, which decreases overall negative side effects [4].

To alleviate the side effects of pharmaceutical treat ments, doctors have recently been exploring the use of holistic medicine: a treatment philosophy that col lectively focuses on treating the psychological and

Taking New Leaps

physical symptoms of a disease [6]. Treatments can include dance, yoga, or other forms of exercise, as well as therapies such as mindfulness meditation, massage, and acupuncture [7]. Because of its success in treating a wide spectrum of health issues includ ing PD, holistic medicine has become more popular in the past few years [6]. Holistic treatments for PD often focus on modes of self-expression, such as dance therapy, because they target and treat phys ical and mental symptoms in tandem [7].

THE DOPAMINE JIVE: DANCE THERAPY FOR PARKINSON’S DISEASE

You may have heard someone rave about the rush they felt after an exhausting workout at the gym. Though their muscles are fatigued and their energy is depleted, some irrational part of them wants to keep going. Why is this? The impulse to continue exercis ing is associated with the release of dopamine, and our brains form a connection between dopamine and pleasure that motivates us to exercise more in the future [8]. Dancing, a widely enjoyed form of exer cise, promotes the release of dopamine in the brain [9]. The neurological benefits of dancing have made it a commonly used holistic treatment for a variety of mental illnesses [10].

Dance therapy is gaining popularity as a therapeu tic approach to treat Parkinson’s disease because of its ability to improve one’s range of movement and address the secondary symptoms that can accom pany a loss of motor control [11]. Motor symptoms are generally shown to improve for a short period of time when undergoing dance therapy, while non-mo tor symptoms are improved long-term [11]. One or ganization that promotes the use of dance therapy for this condition, Dance for Parkinson’s Disease, is a world-renowned dance therapy program that has helped to popularize the use of dance therapy in Parkinson’s treatments starting in 2001 [12]. Classes taught by professional dancers in styles ranging from ballet to traditional folk dance are offered for individ

uals with PD, and are designed to address physical symptoms by promoting balance and coordination [13, 12]. These classes utilize techniques such as imagery, repe tition, rhythm, and imitation of movement to help those with PD focus on the con nection between their mind and body [13]. The awareness of one’s bodily position and movements is known as kinesthesia. Par kinson’s disease is known to correlate with a weakened sense of kinesthesia, likely due to the lack of dopamine inhibiting com munication between the muscles and the brain [14]. Studies performed in conjunc tion with Dance for PD also consistently show improvements in motor symptoms after dance classes: individuals with PD had fewer tremors and their walking pace became more even [12]. Additionally, dance therapy improved the symmetry of their walking movements and posture more than standard physical therapy exercises [11].

The phenomenon of self-efficacy describes how you are only able to grow when you believe in your po tential for success [15]. Take an athlete, for example: if a soccer player does not believe in their own ability to score more goals, they will lose the motivation to improve, and consequently remain stuck at the same skill level. When people with PD have trouble execut ing basic tasks, they may lose motivation to attempt those tasks, which further decreases their quality of life [15]. Those living with chronic illnesses such as Parkinson’s may begin to question their identity and purpose when faced with major life disruptions [16]. Here is where the expressive nature of dance therapy comes into play: the participants have the opportu nity in class to creatively discover their capabilities beyond their physical restrictions [15]. After taking a class, those with PD have expressed feeling “cou rageous” and “optimistic,” demonstrating how the classes greatly improve both their mood and outlook on life [13]. Through dance, participants are able to form connections with others who struggle with the same limitations, allowing them to overcome the so cial isolation that can be a byproduct of PD [12, 17]. Volunteers are also present to help assist individuals with PD who may have trouble balancing or standing on their own, further fostering a sense of belonging and community [13]. The various social connections created in a classroom environment encourage par ticipants to seek meaningful interaction beyond the studio [17]. Purely enjoying these classes for the artis tic and social opportunities they offer creates a pos-

itive feedback loop: the brain is stimulated to pro duce more dopamine “batons,” pushing participants to come to class more frequently [17].

The confidence gained from social interactions helps individuals to improve their perception of their beauty and identity as well. Changes caused by Parkinson’s disease extend beyond just function, and frequently involve altered appearance of the body [17]. As a re sult, people with PD may experience a decrease in self-esteem and can struggle to find beauty when looking in the mirror [18]. This altered perception of self is compounded by neurological conditions, such as dementia, that typically accompany PD, further ing the mismatch between one’s sense of self and their actual appearance [1]. The graceful movements of dance that push them to experiment with more fluid textures of movement help people with PD to view themselves in a more positive light [18]. The pathway between motor control and emotional pro cessing is central to expressive movements, allowing dance to help people improve their motor awareness and remain in-touch with their emotions [19]. In or der to achieve the full potential of expressive move ment, classes help them to work on their kinesthetic awareness. Kinesthesia originates in sensory organs known as proprioceptors that send feedback to the brain about which areas are stretching and relaxing in movement [14]. Having the freedom to move in new ways, the dancers grow to not only believe in their own abilities, but cease to define themselves only by their disease. As they move through space, the danc ers have the opportunity to become one with their movements, uniting a sense of beauty with their own identity [17].

TOEING THE LINE BETWEEN BALLET AND MEDICINE

Ballet is a popular type of dance therapy used to treat Parkinson’s [17]. If you were to observe a PD ballet class, you would notice the swift brush of people’s feet along the floor and elegant gestures of their arms as they glide and twirl through the studio. Bal let classes specifically designed to treat PD combine simple ballet steps in various sequences with the intention of improving one’s coordination, balance, and stability [13, 20]. Parkinson’s disease is often de scribed as “draw[ing] people inwards” — muscles be come tense, the gaze becomes fixed, and movements slow down [18]. These physical changes can deplete feelings of self-worth and potential that become components of a greater negative internalized mind set. In contrast, classical ballet focuses on projecting

energy outwards by learning to lead with your chest and extending the limbs to create length in your body [17]. By practicing dynamic ballet movements, people with PD can counteract their negative internalized mindset which increases their confidence [17, 18, 20].

While participating in ballet classes organized and taught by a trained Parkinson’s dance therapist is in credibly beneficial, the high cost and low availability of these resources limits who can access them [21]. An alternative to dance therapy courses are regular dance classes, which can be found in a multitude of styles in nearly every community. Dance sessions have been found to improve mobility and coordina tion, even when not focused on treating Parkinson’s [21]. The effects of improvements like these extend beyond the classroom: when individuals with PD are able to engage in everyday movements, they gain more independence and are able to participate in daily tasks and activities that bring them joy.

CHOREOGRAPHING A COMPREHENSIVE TREATMENT

Dance is just the tip of the iceberg when it comes to holistic treatments for neurodegenerative disor ders such as PD. Holistic medicine can be particularly useful in treating neurodegenerative diseases when used in tandem with pharmaceuticals [6]. While drug therapies seek to mimic the action of dopamine and to mask symptoms, they don’t actually slow the pro gression of the disease, and instead act as a band-aid solution for secondary symptoms [1]. In contrast, ho listic therapy acts just as a training session for an ath lete does. A soccer player, for example, must practice shooting drills consistently to keep up their skills. If they were to stop training suddenly, they would find it more difficult to score goals. Like the muscles you continue to build when playing soccer, damaged connections in the nervous system can gradually be rebuilt if they are used on a regular basis because the brain will recognize their importance and divert more energy into strengthening them [22]. Physical therapies that emphasize the mind-body connection, such as dance or yoga, are widely regarded as safe and non-invasive, and therefore supplement drug therapies well [7]. Beyond dance or physical thera py, holistic therapies can take many forms — ranging from acupuncture to music therapy — that have the potential to ease the burden of symptoms affecting

people with Parkinson’s [7].

Such holistic therapies can be used to treat more than just PD, creating new treatment options for a wide range of illnesses. Though the effects of holistic medicine are just beginning to be explored, similar therapies rooted in cultural traditions such as mas sage and herbal medicine have been used system atically for thousands of years [23]. By investigating these options in greater depth, treatments can be designed to address each person’s unique sympto mology. Increasing education on the importance of holistic medicines for both health professionals and the general public could inspire more research in this area and further popularize holistic therapies [7]. A Parkinson’s diagnosis can turn one’s world upside down. Holistic medicine treats health beyond just physical wellness, so an upside down world can feel a little more right-side-up. While holistic therapies such as dancing don’t necessarily present a cure for Parkinson’s, they offer promising and effective new dimensions to treatment.

References on page 59.

THE FUTURE OF TBI THERAPY STEMS FROM STEM CELLS

by Shawn Babitsky / art by Anna Bishop

You’re watching an episode of Wile E. Coyote and the Road Runner and an anvil falls out of the sky. It lands hard on Wile E. Coyote’s head and he collaps es to the ground. The coyote must be dead––right? But no, a moment later he jumps back to his feet, unaffected aside from a few stars orbiting his head. Although in the cartoon Wile E. Coyote may appear healthy, in reality he would have suffered a type of severe head wound called a traumatic brain injury. Traumatic brain injury (TBI) is severe damage to the brain resulting from an outside force. TBI can fall into two categories: penetrative trauma or blunt trauma [1]. Penetrative trauma occurs when an object pierces the skull and directly damages the brain. Blunt trau ma usually results from events such as falls, abuse, motor vehicle accidents, or anvils falling out of the sky, and includes any head injury that does not pen etrate the skull. These blows to the head rattle the brain inside the skull, damaging brain tissue [1]. The brain is severely damaged during either type of trau ma; however, the effects of the injury do not end at impact.

AFTER THE ANVIL: THE BODY’S RESPONSE TO TBI

When a person sustains a traumatic brain injury, their body initiates two responses: the primary response and secondary injury cascade. The primary response is the direct result of the initial head injury, occurring within minutes or even seconds. This can manifest as tearing, bruising, and severe bleeding in the brain, all of which can be detrimental to brain function [1]. Tis sue death is one of the main components of the pri mary response. For example, if someone is shot in the head in an event of penetrative trauma, blood vessels

burst as the bullet tears through them, preventing proper blood flow to the brain. Our cells need to be constantly supplied with oxygen-rich blood in order to function properly, so the disruption of blood flow from the burst blood vessels causes tissue death [1, 2, 3].

In the hours and days following an injury such as a gunshot, the body also responds with a series of dev astating complications called the secondary injury cascade [1, 4]. During the cascade, the brain releases cytokines — proteins secreted from immune cells — which, in the case of TBI, cause inflammation of brain tissue. Neurons within the inflamed areas of the brain become dysfunctional and degrade until they even tually die [4, 5, 6]. The release of cytokines also in flames the blood-brain barrier, a sieve-like structure surrounding the brain that controls which substances are allowed to enter [7]. As cytokines are released, they tear holes in this delicate barrier, decreasing its ability to regulate what substances can pass through and therefore allowing excess fluids to enter the brain [7]. This fluid builds up and floods the tight space between the brain and the skull, putting pressure on the brain. This pressure on the brain invites potential health complications, such as blindness, abnormal

INFLAMMATION OF INJURED LOCATION

breathing, and further lack of blood flow [4, 8]. The series of events resulting from the release of cyto kines during the secondary injury cascade inflames the brain and causes severe damage to neurons and the blood-brain barrier [8]. This degree of damage done by TBI requires intensive medical treatment to minimize the effects of such an injury.

Current treatments for traumatic brain injuries fo cus exclusively on alleviating symptoms; there are no treatment options to regenerate damaged brain mat ter [8, 9]. One current treatment involves elevat ing the head to decrease pressure on the brain [9]. When the head is elevated, the force of gravity works to drain excess fluid out of the skull. While this approach is somewhat effec tive at relieving pressure, the brain lacks the ability to regenerate neurons on its own, so only minimal healing can occur [9]. Neurons are responsible for communication within the brain: they act as telephone lines, sending and receiving messages that keep us alive [10]. When neurons die due to inflammation, these lines of communication are severed and messages cannot go through, which can negatively affect a person’s men tal and physical abilities [10]. If doctors are not able to regenerate these neu rons, the effects of the brain injury will persist [8, 9].

STEM CELLS: BIOLOGY’S NATURAL TRANSFORMERS

Although current TBI therapies are unable to restore damaged brain tissue, stem cell therapy provides hope that regeneration may soon be possible [11, 12, 13]. Most of the cells in our bodies are assigned to perform a specific job. For instance, the cells in our heart muscle are programmed to help the heart pump blood through the body, and fat cells are designed to store energy [14]. Stem cells, on the other hand, are a spe cial type of unprogrammed cell, meaning they are not specialized for any particular job. They can be manually programmed to become any type of cell through a process called differentiation, acting like the blank Scrabble tiles of the body [8, 11]. The blank tiles stand in as whatever letter the player needs them to be. Once the blank tile is assigned to a letter, however, the tile becomes that letter until the end of the game. Stem cells work within our bodies in a similar way—they can be assigned to serve as different types of cells; however, once they are assigned to a job, they cannot be reassigned to a different one. The ability of stem cells to evolve into specialized cells, like neurons, has the poten tial to be revolutionary in the treatment of traumatic brain injury [11, 15]. When stem cells differentiate into neurons, they can form new connections between brain structures, potentially restoring the cognitive and motor functions damaged by TBI [10].

REPAIR, REGENERATE, REPEAT

Although several types of stem cells have the ability to differentiate into neurons, TBI research typically involves mesenchymal stem cells (MSCs), which are mainly extracted from bone marrow [3]. Once extracted they must be reprogrammed in order to differentiate into neurons, a process which takes place outside of the body, in a pe tri dish or test tube [15]. During this process, the genes that prevent differentiation are man ually “turned off” while the genes that promote differentiation are “turned on” [15]. Reprogram ming is repeated until the cell has been modi fied to fully differentiate into a neuron [16]. The reprogrammed MSCs, now functioning as neurons, can be injected into an individu al’s vein [17]. When MSCs travel to the brain via the bloodstream, they are ordinarily pre vented from crossing the blood brain barrier. Following a TBI, however, the holes created in

SEVERE NEURONAL DAMAGE

FLUID ENTRY INTO THE BRAIN

INFLAMMATION OF BLOOD-BRAIN BARRIER

the BBB during the secondary injury cascade allow the MSCs to slip through the barrier and migrate to the injury site [17, 18].

Once MSCs reach injured tissue, they behave as neu rons and form new connections, replacing those that have been damaged during the secondary injury cas cade. In addition to neuron replacement, MSCs can address the other consequences of the secondary injury cascade: inflammation and blood-brain barrier damage. They produce proteins that inhibit cytokine production, preventing further inflammation in the brain [3, 5, 11]. MSCs also activate specific genes that are responsible for the permeability of the bloodbrain barrier [19]. When activated, these genes enable proteins to be released that counteract the damage done by cytokines, repair the structural integrity of the barrier, and regenerate some of the tissue dam aged by the TBI [19].

THE FUTURE OF TBI IS TBD

From their efficiency at reducing inflammation in brain tissue to their impressive ability to replace damaged neurons, mesenchymal stem cells have the potential to be at the forefront of TBI therapy [3, 5]! Despite the hope surrounding stem cells, experts are hesitant to give their use the green light. One of the fears that has prevented stem cell therapy from being widely applied is accidental tumor development [3]. If stem cells are implanted before they are properly repro grammed and differentiated, they have the potential to form tumors within the body. Recently, however, specialists have begun implementing drug therapies during the reprogramming process to ensure proper differentiation, reducing the risk of tumor development and making stem cell therapy safer [3, 16]. Fur

The Future of TBI Therapy

ther research can maximize the ability of stem cells to treat TBI while minimizing the associated health complications, subsequently improving the lives of everyone who has suffered a traumatic brain injury [3, 20]. So the next time an anvil falls and crushes Wile E. Coyote, he would be the ideal candidate for a stem cell clinical trial.

References on page 60.

TOXOPLASMA GONDII: THE BEAST LURKING IN THE LITTER BOX

by Sufana Noorwez / art by Abigail Schoenecker

You are a parasite, drifting through the world with no objective other than to infect. You need nutri ents, and you need them quickly, so what do you do? You can’t produce them yourself; it takes too much energy. Why would you waste time hunting and kill ing when you could just attach yourself to another organism and sap them of their energy and nutrients instead? First, you find yourself inside of a mouse. It seems to have picked you up from your previous home in some rotting meat. How lucky! The mouse is good; it will take you far, and quickly too. But you can’t live here forever, so you’ll need to copy yourself and find as many new hosts as possible. You send a message to the mouse’s brain: get me as close as possible to a cat. And like a puppet under your control, the mouse loses its fear of cats, gets a little close, and — GULP! Now, this is more like it. Inside a cat, you have room to grow and you’re able to reproduce as much as you want. There are millions and millions of cats in this world, all living snugly inside the homes of humans [1, 2]. When their humans pick the cats up and cuddle them — BAM! Now you’re inside the human, too. You wiggle your way to the most delicious part of these strange, two-legged creatures: the brain. Finally, the ultimate feast begins. Your name? Toxoplasma gondii.

THE TINY MONSTER INSIDE YOUR CAT

Toxoplasmosis is a deadly disease capable of ravag ing the human body, caused by a parasite so small that the human eye cannot perceive it: Toxoplasma gondii. Parasites thrive by exploiting another organ ism called a host [3]. Leeches are an example of a common parasite; these vampiric creatures attach to warm-blooded mammals and suck on their skin to draw blood, benefiting the parasite but harming the host, who loses dangerous amounts of blood [4]. T. gondii is far smaller and less bloodthirsty than a leech, but still has the ability to cause great harm to

humans [5]. When T. gondii infects any organ ism, it first multiplies into millions of cop ies [6]. These copies officially set up camp in the host organism within small tissue capsules known as cysts. Then, if T. gondii is lucky enough to come in contact with its preferred host, the cat, it produces eggs that are released in cat feces. T. gondii benefits the most when expelled through cat feces, which comes into contact with a wide vari ety of organisms, such as humans [7]. By multiplying and forming cysts, T. gondii reproduces and thrives in humans, an excellent and readily available source of nutrients [6].

THE SECRET LIFE OF A WORLDWIDE PARASITE

For T. gondii to thrive, it must seek new hosts to ex ploit, and it is extremely successful in doing so. An estimated 30-50% of the world’s human population is infected with T. gondii, many of whom are without

symptoms [8]. One of the main strategies the parasite uses to spread itself so widely is to live in envi ronments frequented by both cats and humans. T. gondii is commonly found in raw or under cooked meat, which cats and humans often handle and eat [9]. Despite its small size, the parasite is estimated to be one of the top leading causes of death from foodborne illness in the United States [9]. Because of its ubiquity in raw, spoiled food, it can come into close contact with vermin, such as mice, who are then infect ed [2]. The parasite has an uncanny ability to exert a zombie-like influence on rodents, remov ing their innate aversion to the smell of cat urine and their fear of the animals themselves [1]. This change in their senses causes rodents to acciden tally wander right in the path of their predator, and the parasite is able to jump into cats — their favorite host [1, 2]. Now that it has infected humans, cats, and mice, T. gondii can continue its journey to the human brain.

YOUR BRAIN ON T. GONDII

T. gondii takes up residence in both our nervous sys tem and muscles, but exerts its most unique effects on the central component of the nervous system: the brain [12]. The brain is an incredibly sensitive organ responsible for processing sensations, organizing vol untary and involuntary movements, and carrying out necessary daily behaviors. Pathogens that invade the brain can wreak havoc on this fragile tissue. To guard against unwanted entry, the human brain is surrounded by a thick network of blood vessels called the blood-brain barrier, which regulates all of the sub stances that move between the blood into the brain [10]. T. gondii’s small size allows it to slip through this barrier easily, leading it to permanently establish it self in the form of cysts — round, raised bumps with protective walls that harbor millions of copies of the parasite. Under certain conditions, these cysts can rupture and widely distribute copies of the parasite, ready to make even more cysts [6]. When the cysts burst open, the parasite’s proteins can cause the death of neurons, the brain’s primary communication cells [11]. The simple presence of T. gondii can also trigger the immune system, which causes the brain to swell [12]. Although this swelling is often an effective way to stop infection, it can actually harm the brain; in some cases, swelling in structures of the brain that are crucial for normal function can cause permanent tissue damage [13, 14]. All of these disruptions to

the central nervous system prevent the brain from functioning properly, producing se vere neurologi cal damage.

WHEN SIGNALS DON’T STOP: YOUR BRAIN WITHOUT TRAFFIC CONTROL

Although most people are not severely impacted by T. gondii, some develop an acute version of the infection, meaning the parasite suddenly and dramatically im pacts their health [15]. Acute infections can interfere with neurotransmission, the process that allows us to sense and react to our surroundings [12]. Neurons, the workhorses of neurotransmission, pass chemical signals from one cell to the next. T. gondii blocks a particularly important signal called glutamate. When glutamate is present in the gaps between neurons, it gives neurons the green light to fire and pass the chemical signal along to the next cell [16, 17]. Neurons are repeatedly stimulated when glutamate remains in the space between neurons for a long period of time. To prevent signals from being transmitted, the brain needs to vacuum up the glutamate from this neuronal gap. T. gondii prevents the brain from doing this, resulting in a buildup in the levels of glutamate between neurons. This buildup causes neurons to fire continuously — the glutamate light is stuck on green forever. Like cars zooming through an intersection with nothing to stop them, the neuron is repeated ly activated, increasing neurotransmission to a dan gerously high frequency. This constant stimulation overwhelms neurons and releases toxic compounds that can lead to cell death [12]. Further, an excess of glutamate in the space between neurons is strongly correlated to the onset and progression of various neurodegenerative diseases [18, 19].

T. gondii also impacts another important signaling chemical, GABA. GABA inhibits signaling in neurons, acting as a kind of stop sign [12]. Because of this, GABA and glutamate have opposite functions: GABA prevents neurons from being excited. T. gondii con sumes GABA from between neurons rather than al

lowing it to build up, and the subsequent lack of this chemical causes neurotransmission to speed up once again — perhaps similar to if someone were to steal all the stop signs on a busy road . The combination of increasing glutamate levels and decreasing GABA levels gives rise to imbalanced neurotransmission, leading to a variety of dangerous symptoms in those afflicted. For example, seizures can occur due to this heightened activity in the brain [12]. While these symptoms are uncommon in most healthy individu als, people who contract an acute infection may ex perience some of these more extreme consequences of infection with T. gondii [20].

EN GARDE! RAISING AN IMMUNE RESPONSE TO T. GONDII

While the most debilitating symptoms of toxoplas mosis usually occur in immunocompromised individ uals, a small fraction of people with functioning im mune systems may contract acute infections with T. gondii, displaying symptoms similar to those of a bad case of the flu [20]. In rare cases, people may even suffer from more serious symptoms, such as swelling in their brain [12]. The majority of cases in non-immu nocompromised people are harmless — they devel

op the characteristic cysts, but these cysts generally go undetected. However, even asymptomatic toxo plasmosis is correlated with an increased chance of developing certain behaviors and conditions, includ ing suicidal ideation, schizophrenia, and personality changes [21, 22, 23, 24]. One potential explanation for this phenomenon is that T. gondii primarily targets structures of the brain responsible for emotions, sen sory processing, and thought processing [25]. Similar patterns of damage are also observed in other neu rological diseases and disorders, such as post-trau matic stress disorder (PTSD), which may explain why the symptoms of toxoplasmosis mirror those of other conditions [25, 26]. Strangely, high levels of T. gondii in the blood also are correlated with a higher prob ability of being in traffic incidents [27]. Since this field of study is relatively new, however, these results don’t necessarily indicate causation, and many of the mechanisms behind T. gondii’s behavioral symptoms remain unknown [12].

For the vast majority of people with healthy immune systems, their bodies are able to easily fight off infec tion by T. gondii [28]. When T. gondii enters a healthy individual, the body produces immune cells that hunt down the parasite and neutralize it, preventing it from replicating [28]. However, illnesses like cancer and HIV/AIDS can disrupt and incapacitate these im mune cells, leaving the body vulnerable to infection [29, 30]. Around 10 million adults in the United States have suppressed immune systems, meaning they may be unable to fight off even relatively common infec tions, such as the common cold or the flu [31]. With out the body’s natural warriors, pathogens are likely to run rampant, developing into more serious dis eases that may even cause death. For immunocom promised individuals, T. gondii is a particularly tricky adversary. When the parasite enters the brain and be gins to develop cysts, compromised immune systems are unable to detect it and mount a response [32]. An unchecked T. gondii infection can trigger a range of devastating neurological issues, anywhere from seizures to paralysis to death [32]. Immunocompro mised people who experience neuronal death and brain lesions can begin to exhibit some behavioral changes associated with schizophrenia and bipolar disorder [33]. However, these symptoms often man ifest very shortly before death, so they are relatively unstudied [34]. These behavioral symptoms are also seen in individuals without immune deficiencies who aren’t suffering from acute infections [25, 35].

PARASITES, PLACENTAS, AND PREGNANCY

Immunocompromised people are not the only popu lation at risk for infection by T. gondii. Pregnant peo ple are also particularly at risk of developing severe symptoms when infected by T. gondii, as are their fetuses [36]. The risk of parasite transmission from the parent to the child increases because these fe tuses are entirely dependent upon their pregnant parent for nutrients through the blood. Therefore, when a pregnant individual is infected, the parasite can be passed on to the fetus through a phenome non known as congenital toxoplasmosis [37]. In the same way that the parasite can sneak through the blood-brain barrier in an adult host, it can also travel through the placenta, which provides nutrients and oxygen straight to the fetus [36]. The rate at which the parasite is passed to a fetus is dependent on when the pregnant person is infected [38]. In latestage pregnancies, transmission rates can climb up to 65%. Fetuses do not have a developed and strong immune system, so they can have trouble fighting off the parasite. Infection without a mature immune system can severely impede the fetus’ development and lead to neurological damage, often impacting the eyes. However, the effects of fetal infection may not even manifest until the second or third decade of life. At this point, cysts formed while a person was in the womb may rupture and cause blindness in both eyes [38]. The severity of these symptoms and their effects on young children point to a need for effective prevention and treatment of the infection.

TAMING THE BEAST

Although the symptoms of toxoplasmosis are fright ening, there are a multitude of ways to prevent and treat the disease. Avoiding places where T. gondii may be found is the first step in preventing infection [39]. This includes staying away from untreated water, wearing gloves when coming into contact with soil, and avoiding consumption of raw or undercooked meat. High-risk populations, such as those who are immunocompromised or pregnant, should also avoid contact with cat feces or their litter. While this kind of physical prevention is the best way to avoid a T. gon dii infection, for some high-risk individuals, there are drugs called prophylactics that can prevent T. gondii from forming cysts [40, 41]. These prophylactics work by stopping the life cycle of T. gondii upon the ini tial exposure, but will not work for individuals already experiencing active infection. Post-infection, a range of drugs can be used to mitigate the symptoms of

toxoplasmosis. Many factors determine the type of drug that works best for an individual, such as the symptoms they experience, pregnancy status, and the state of their immune system [39]. Some antimi crobial drugs are available to help the body fight off T. gondii infection before it spreads out of ruptured cysts, but there are currently no known drugs that can remove cysts from the brain [40, 42]. Additionally, some strains of T. gondii are developing resistance to drugs traditionally used to treat the disease [43]. Another possible treatment for toxoplasmosis is the administration of antipsychotic drugs, which have the potential to reverse the behavioral changes associat ed with infection, though their mechanisms are not well understood [44]. Physically preventing the par asite from entering the brain by reducing exposure may be the best way of ensuring that infection does not occur.

Toxoplasma gondii is an extremely efficient para site, able to spread itself far and wide by utilizing an extremely ubiquitous host, the domestic cat [8]. It moves about in a constant cycle of transmission —

Toxoplasma Gondii

from contaminated food, to a mouse, to a cat, to a human. While the average infected person will carry on with their lives, completely unaware of the pres ence of this foreign invader in their brain, toxoplas mosis presents a particularly unique threat to others [45]. The human immune system can fail to keep the parasite in check, leading to a whole host of devas tating symptoms [32]. Modern medicine has provided a range of solutions to this issue, from prophylactics to antimicrobial drugs, but preventing the parasite from entering your body in the first place is always the best way to ensure that you remain uninfect ed [39]. Something to think about the next time you clean your furry friend’s litter box!

References on page 61.

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A LITTLE-KNOWN SIDE EFFECT OF CHEMOTHERAPY: CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

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TOXOPLASMA GONDII: THE BEAST LURKING IN THE LITTER BOX

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