Grey Matters VC Issue 8

FEATURING Facing Mythical Fury: The Calamitous Path of Lyssavirus Rabies What’s Porn Got to Do With It? The Role of Empathy in Sexual Violence @greymattersjournalvc greymattersjournalvc.org

SPRING 2024

To Fear or Not to Fear: Exploring Fear Through the Lens of Urbach-Wiethe Disease

TABLE OF CONTENTS 8

LIMITLESS RECOLLECTION: THE PHENOMENON OF HIGHLY SUPERIOR AUTOBIOGRAPHICAL MEMORY

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by Brooke Berbeco/ art by Mischa Landgarten

by Anoushka Bhatt/ art by Anna Bishop

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BEYOND THE BOARD: INSIDE THE BRAIN OF A CHESS MASTER

by Daniel Bader/ art by Maia Su

FROM PLEASURE TO PAIN: THE EFFECTS OF COCAINE USE DISORDER ON THE BRAIN

34 THE ROLE OF EMPATHY IN SEXUAL VIOLENCE FEATURED ARTICLE

by Iona Duncan/ art by Alexandra Adsit FEATURED ARTICLE

THE MYTHICAL FURY: THE 16 FACING CALAMITOUS PATH OF LYSSAVIRUS RABIES

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by Anna Conway/ art by Emily Holtz

FROM BATTLE: THE CONDITIONING 22 BACK OF FEAR IN PTSD

by Elsie McKendry/ art by Katie Hieb

YEARNING FOR YESTERDAY: THE MECHANISMS AND APPLICATIONS OF NOSTALGIA

by Niah Dang/ art by Sneha Das

WARS: THE PAST, PRESENT, AND 45 IMMUNE FUTURE OF MULTIPLE SCLEROSIS RESEARCH

by Daniel Wunschel/ art by Abigail Schoenecker CLUB TO CLINIC: THE TREATMENT 26 FROM OF PTSD WITH MDMA

by Erin Kaufman/ art by Iris Li

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FEATURED ARTICLE

TO FEAR OR NOT TO FEAR: EXPLORING FEAR THROUGH THE LENS OF URBACH-WIETHE DISEASE

by Kristen Carroll/ art by Sarah McDonald

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ISSUE NOTES ON THE COVER

LEARN MORE

Art by Jane Stempien

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

LET US KNOW If you have any questions or comments regarding this Issue 8, please write a letter to the editor at brainstorm.vassar@gmail.com.

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GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 8

PRODUCTION STAFF

SHAWN BABITSKY Editor-in-Chief

FREDERICA VON SIEMENS Senior Editor, General Editing

Co-Senior Managing Editor

FRANK RYAN

Co-Senior Managing Editor & Production Manager

ANSHUMAN DAS

JACLYN NARLESKI

EVE ANDERSEN

JULIA VITALE

AINSLEY SMITH

Treasurer & Senior Editor, Lay Review

IONA DUNCAN

RILEIGH CHINN

Art Executive

Senior Editor, Scientific Review

BROOKE BERBECO Social Media Coordinator

ALEXIS EARP

Outreach Coordinator

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Senior Editor, Scientific Review

MAX FREEDMAN

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EVELYNN BAGADE Assistant Outreach Coordinator

SOPHIA SKLAR

Assistant Layout Executive

DANIELLA LORMAN Graduate Student Executive

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 8

ALEX KAYE

Graduate Student Executive

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ARTISTS

AUTHORS

FACULTY ADVISORS

Alexandra Adsit Anna Bishop Iris Li Mischa Landgarten Katie Hieb Emily Holtz Abigail Schoenecker Sarah McDonald Sneha Das Maia Su Jane Stempien

Kristen Carroll Anna Conway Elsie McKendry Erin Kaufman Iona Duncan Niah Dang Daniel Wunschel Brooke Berbeco Daniel Bader Anoushka Bhatt

Evan Howard PhD Lori Newman PhD Kathleen Susman PhD Bojana Zupan PhD

SCIENTIFIC REVIEW

LAY REVIEW

GENERAL EDITING

Autumn Cullinan Caroline Stewart Chloe Mengden Danielle Schwartz Eden Lanham Evelynn Bagade Harper Navin Jack Matter Jadon-Sean Sobejana Junhyeok Park Kevin Li Lily Brigman Maia Beaudry Matthew Rawson Maxx Martinez Munashe Mupunga Posey Whidden Shira Freilich Talia Roman Jannessa Ya

Alyssa Gu Kate Billow Caris Lee Margot Vaughan Alexis Earp Eli Kanetsky Gordon Zhang Isabel McGuire Alex Astalos Joe Lippman Linnea Zimmer Emily Pouzhyk Emilee Busby

Kyle Benson Duncan Beauchamp Claire Bennett Charlotte Bowman Grace Cabasco Zayn Cheema Quincey Dern Jonathan Eccher-Mullally Zachary Garfinkle James Hatch Mihika Hete Ananya Krishnan Chloe Lucas Karina Mangru Laurel Obermueller Susanna Osborne Emily Pouzhyk Owen Raiche Kaitlin Raskin Shayni Richter Ellis Rubin

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SPECIAL THANKS Olivia Pocat - Layout

GREY MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 8

Neave Rynne Emma San-Fillippo Max Saran Olivia Selby Arden Spehar Grace Speranza Madeleine Stewart Jolie Walker Abigail Wang

EDITOR’S NOTE As we put our pens down and Issue 8 goes to print, I can’t help but reflect on my time with Grey Matters thus far. Less than a year ago I walked into my first meeting as Editor-in-Chief, confident that I knew exactly what was in store. I was well-acquainted with the structure of the journal, the responsibilities of my job, and most importantly, our mission. However, I didn’t yet know just how much I was going to learn from Grey Matters.

Over the last two publication cycles, in addition to learning about engaging neuroscience topics from our authors, I have had the unique privilege to lead an extraordinary team. This group of talented individuals has taught me both how to lead and how to approach effective, accessible science communication. Thank you for following me on this journey of science accessibility. This issue — and all previous Grey Matters issues — would not be possible without our dedicated editors, authors, and artists.

In this issue, we invite you — our reader — to explore the vicious nature of rabies disease in “Facing Mythical Fury: The Calamitous Path of Lyssavirus Rabies,” to dive into the neural underpinnings of a perfect memory in “Limitless Recollection: The Phenomenon of Highly Superior Autobiographical Memory,” and to consider the cognitive benefits of chess in “Beyond the Board: Inside the Brain of a Chess Master.”

And thank you to our readers. Your continuous support not only maintains our journal but also inspires us to explore greater innovations with every issue. All those hours of researching, writing, and revising are worth it so that we can help bring you closer to the wondrous field of neuroscience.

See you all soon,

Shawn Babitsky Editor-in-Chief

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LIMITLESS RECOLLECTION: THE PHENOMENON OF HIGHLY SUPERIOR AUTOBIOGRAPHICAL MEMORY

by Anoushka Bhatt/ art by Anna Bishop THE WOMAN WHO NEVER FORGETS

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e are highly dependent on our memories: they shape our understanding of the past, guide our present decisions, and influence our future aspirations [1]. Yet, our memories are notoriously imperfect. It’s easy for us to forget things, like that essay you have been meaning to finish for weeks, or the name of the person you were just introduced to.

Therefore, it may seem ideal to be able to remember everything. Think back to your first day of school. Do you remember what you ate for breakfast that day?

Or the clothes that you wore? Or what day of the week it was? Jill Price, known from her case study as ‘the woman who never forgets,’ involuntarily remembers each of these minute details with incredible clarity [2]. When provided with a date, Jill could specify what day of the week the date fell on and what she did that day — not due to rote memorization, but because of her exceptional ability to recall her past with remarkable detail and accuracy [2]. Jill is different from most people who have a ‘good memory,’ as she does not rely on techniques like mnemonics or repeated practice to remember information [2]. For Jill, remembering is automatic. Jill has a highly superior autobiographical memory (HSAM), in which innumerable details from the last week, the last year, and even the past few decades of her life indelibly stick in her mind [1]. After HSAM was initially discovered via Jill’s experiences, around 60 additional individuals with this extraordinary ability have been identified, and further exploration into HSAM’s causes has revealed interesting characteristics of the phenomenon [3]. A consideration of the typical memory processing pathways may result in a more comprehensive understanding of the mechanisms of HSAM.

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CONGRATULATIONS, CLASS OF 2024!

Think back to your most memorable birthday, your worst day of middle school, or your high school graduation. These events are all autobiographical memories, recollections of your personal experiences that contain knowledge of the self and personal identity [4, 5]. Autobiographical memories are a type of explicit memory, which require conscious effort to recall [6, 7, 8]. Autobiographical memories are composed of episodic and semantic memories [6, 7]. Episodic memory refers to specific moments of life and includes qualitative details such as when, where, and

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LIMITLESS RECOLLECTION how an event occurred [9, 10]. Recall the example of your high school graduation. Episodic memories of that day might include how hot it felt to sit in a black gown as the sun blazed down, or the moment you looked at your best friend as the class threw their caps into the air. Semantic memories, on the other hand, are made up of general factual and conceptual knowledge, including facts, rules, concepts, and associations [11, 12, 13]. For instance, you might remember your class size or be able to identify the notes playing from the piano on stage during the graduation march. Episodic and semantic memory work together to organize and connect your experiences in order to create rich autobiographical memories [14, 15].

in storing memories — where it is ‘filed’ alongside other associated memories [20, 21]. The sole memory of receiving your diploma when you graduated may bring to mind several other memories in which you experienced similar feelings of excitement, jittery anticipation, or even the anxiety of holding something fragile or important in your hand. Memories are not just linked linearly [22]. Rather, they comprise complex networks in which multiple memories are connected to one another. Each memory is linked to others through different concepts, events, or any other associations that connect them [22]. When the memory is ‘filed,’ a physical change in the brain — known as a memory trace — is formed, allowing the memory to be later accessed [22, 23].

WHAT DID HE CALL ME?

LATTE FOR WHO?

To solidify your life experiences into autobiographical memories, the brain uses a process called encoding [16, 17]. Returning to your high school graduation, when it’s finally time to get your diploma, you hear your principal mispronounce your name. The sound associated with the mispronunciation is then processed in your working memory. While information is held in your working memory, it is in a temporary, malleable state. In the same way you edit files, memories can be changed before they reach the ‘filing cabinet’ in your brain [18, 19]. You are stunned, thinking, ‘what did he call me?’ As your attention shifts, your recollection of the mispronunciation reaches your hippocampus — an area of your brain that plays a large role

Months later, when a barista mispronounces your name in a coffee shop, the memory file of your principal’s similar offense is retrieved by your hippocampus and temporarily returned to your working memory [24, 25]. Memory ​​ retrieval is the activation of a memory trace in response to internal or external cues, thereby triggering the recollection of the memory [22, 26]. Memories may be retrieved through the use of conscious effort, while alternatively, an external cue can trigger memory retrieval spontaneously [26]. In the case of the barista, your feeling of annoyance spontaneously triggers the retrieval of the memory of the absurd way your principal pronounced your name.

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LIMITLESS RECOLLECTION Each time you recall a memory, you reconstruct the original event, reassembling it from memory traces stored throughout the brain [26]. In the same way, you reassemble the memory of your principal’s pronunciation [27]. On the day of your graduation, your principal’s wording may have been only slightly off.

Nonetheless, in your current recollection, his wording becomes exaggerated, morphing into a complete butchering of your name. Your original memory may be molded and reconstructed many times through repeated recollections of your experience [28, 29].

However, not every encoded memory is retrievable.

Often, our memories fade and disappear [30]. One proposed explanation for the fading of memories is the trace and decay theory, which posits that forgetting may be attributed to the automatic decay or fading of memory traces [28]. For a few years after your graduation, the memory of your name being mispronounced — however altered — is still a memory that you can easily recall. Over time, as a memory becomes less recent and revisited, physical changes to the brain due to the formation of memory traces begin to fade until the memory is no longer accessible [28]. By your 25th-year high school reunion, you may not even remember that the incident at your graduation happened at all. As years pass and new memories are formed, old information becomes harder to retrieve, ultimately wearing away [31]. The speed at which memory decay occurs depends on the salience, or personal relevance, of the memory [32]. When a memory is connected to a more intense emotional experience — as is the case with most autobiographical memories — the memory decays at a slower pace, making it less likely to deteriorate entirely [30].

IT’S ALL COMING BACK TO JILL NOW Surprisingly, in some individuals, many memories seem to decay at an even slower rate, and in some cases, they may not even decay at all [28, 33]. Individuals with HSAM can recall minuscule autobiographical details from decades ago, long after these details would have faded in the brains of individuals who do not experience the phenomenon [28]. HSAM is characterized by the ability to accurately recall an exceptional number of experiences and their associated dates from events occurring throughout one’s lifetime [28, 34]. Because remembering is automatic with HSAM, individuals who experience the phenomenon do not need to rehearse information in order to remember all of their autobiographical memories; they are simply unable to forget their memories. [28, 34, 35]. As a person who most likely does not have HSAM, you

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might only remember the most significant parts of your high school graduation, like walking across the stage. But Jill Price can remember what she ate for breakfast that day, the color of her dad’s tie, and the exact time she received her diploma, even decades after the fact: all because of her HSAM. If Jill’s principal had mispronounced her name, she would encode it similarly to someone who does not experience this memory phenomenon [28, 35]. Yet, once it was time for Jill to retrieve that memory, she would likely be able to recall the exact way in which her name was pronounced — as well as numerous other adjacent details — with shocking accuracy, indicating that the process of memory consolidation in Jill’s brain differs from that of people who do not have HSAM [35].

For example, when asked to recall the third time she drove a car, Jill immediately responded, ‘January 10, 1981. Saturday. Teen Auto,’ recalling a memory from when she was fifteen years old as easily as one can remember what they had for dinner last night [36].

Moreover, Jill’s memories very closely resemble her original memories, even after they are retrieved and re-filed multiple times [28, 37].

RECOLLECT AND RECONNECT So what makes the memories of people with HSAM different? One theory asserts that there is a biological difference between the brains of those with and without HSAM [34, 35]. While there are no major anatomical differences in the brain structures of people with and without HSAM, differences in connectivity between brain regions may underlie the phenomenon [38, 39]. Differences in neural connectivity between the frontal lobes and the hippocampus — two brain areas involved in memory processing — are characteristically exhibited by people with HSAM [34, 40, 41]. The hippocampus is involved in encoding autobiographical memories and the frontal lobe is involved in categorizing and classifying these memories, thereby aiding in the consolidation of long-term memories [42, 43]. However, there are mixed findings in the specific changes in connectivity between the hippocampus and frontal lobes observed [34, 40]. Both increased and decreased connectivity between the frontal lobes and hippocampus of people with HSAM have been observed, which calls for investigation into how these differences in connectivity contribute to the memory phenomenon [34, 40]. Increased connectivity between the hippocampus and the frontal lobe may lead to stronger associations between memories that already exist or may suggest that pre-existing memories are receiving new information and therefore being altered [34, 44]. Decreased connectivity

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LIMITLESS RECOLLECTION between the hippocampus and frontal lobes, on the other hand, may suggest that the brain has a reduced capacity to prioritize information, and is, therefore, less selective about what information it stores [40].

When connections between the hippocampus and frontal lobes are compromised, the brain consolidates far more information than it typically would, regardless of the information’s saliency [40]. However, we cannot make assumptions about what changes in connectivity suggest [38, 45]. Alternatively, the unique patterns of connections in a brain with HSAM could also be a result of the memory phenomenon, not the cause of it [38]. The repeated use of connections between the frontal lobe and the hippocampus may reinforce a relationship between the two brain regions, which may induce the aforementioned connectivity differences [38]. Another lesser-explored theory of HSAM suggests that a psychological condition characterized by obsessive thoughts about one’s previous experiences may explain why some individuals can remember autobiographical memories better than others [28]. Regularly thinking about personal events helps strengthen the ability to recall them, thereby allowing individuals with HSAM to more effectively preserve their memories [46]. However, this psychological theory has not been confirmed and would contradict the idea that intentional rehearsal of memory is not necessary to experience HSAM [28]. In any case, some difference in memory mechanisms prevents people with HSAM from forgetting, though further research is required to uncover the precise neurobiological underpinnings of HSAM [28, 34, 40, 46].

THE DOUBLE-EDGED SWORD OF NEVER FORGETTING Forgetting is often a frustrating experience — the answer on the test you know you have read somewhere, the misplaced keys, the word on the tip of your tongue. As such, HSAM may seem like a gift. Wouldn’t it be nice to never forget important details of your life? Unexpectedly, evolution seems to indicate that it’s actually the brain’s job to forget [47]. Forgetting is not indicative of a failure of memory. Rather, it is an intentional and important evolutionary process. The brain needs to prioritize remembering

important information, so it sacrifices storing extraneous information [48, 49, 50]. Some memories can actually be harmful, and memory decay can protect us from experiencing psychological harm [51, 52]. For example, survivors of trauma are sometimes able to heal faster when they forget their traumatic experience, suggesting that forgetting may be important for our well-being [47]. Forgetting also has a physiological advantage, as the process of remembering and retrieving memories requires a lot of effort [53]. Accurately recalling every detail of each autobiographical memory demands significant amounts of energy that the brain could otherwise allocate for other means [53, 54]. When you remember everything, it may also be difficult to differentiate between what is important to you and what is not [50, 54, 55, 56]. Those with HSAM, who cannot forget, often consider their condition as both a gift and a curse [57]. Take Jill Price, who sees daily life in a kind of “split-screen,” with present-day events, songs, smells, and even TV programs causing her to recall detailed memories that she can’t quell [36]. The weight of such memories impacts many aspects of life for those with HSAM and can lead to permanent changes in their emotional arousal, imagination, and sleep quality [58]. However, those with HSAM also value the positives of the phenomenon, appreciating easy access to the happiest memories of their lives [57]. Ultimately, obtaining a stronger understanding of memory and its mechanisms could help those who have trouble remembering things [35, 57]. Further research on the causes of HSAM and the differences exhibited by individuals who possess this unique phenomenon can help build a better understanding of the mechanisms behind memory [1]. Finally, for people with HSAM, further study into the phenomenon may provide useful insights and create avenues for receiving support, regardless of whether they feel as though their heightened ability to remember is a curse or a gift.

References on page 53.

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BEYOND THE BOARD: INSIDE THE BRAIN OF A CHESS MASTER

by Daniel Bader/ art by Maia Su worldwide, there are only about 1,800 grandmasters [1, 2]. Like Rozman, many chess players who dedicate their lives to learning chess theory never earn the title of grandmaster. However, some individuals become grandmasters before they reach adulthood [3, 4, 5].

For example, legendary American chess player Bobby Fischer became the United States chess champion at the age of 14, and he was officially named a grandmaster at 15 [3]. Why can some people strive towards earning the grandmaster title for their entire life while others reach this echelon before they can legally drive? Chess skill can be determined by several factors, including physical alterations to the brain from extensive training, genetic traits associated with cognition, and intuitive memory techniques [6, 7, 8].

Regardless of skill, practicing chess can improve our ability to withstand the cognitive effects of aging by increasing cognitive reserve, which is our brain’s ability to resist damage, solve problems, and cope with challenges [6, 7].

ALL THE RIGHT MOVES: THE IMPORTANCE OF CHUNKING

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rguably, one of the most difficult accomplishments in the world is earning a chess grandmaster title — a prestigious rank reserved for those who have accrued an extremely high rating on online chess platforms and performed exceptionally well in professional tournaments. A chess player named Levy Rozman — famous for his YouTube channel ‘Gotham Chess’ — has dedicated his life to producing online content and books that teach people how to play chess. Despite Rozman’s long career teaching chess and his rank among the top 1% of chess players in the world, he is not considered a grandmaster, which demonstrates how rare the title truly is. Out of the 600 million people who play chess

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Chess is a tactical game in which advantages are obtained from the precise positioning of each piece in relation to the others. Prowess in the game of chess therefore requires strategy and specific methods of analysis. Of particular importance to chess is the brain’s ability to readily access and manipulate certain information for a short period of time, called working memory [8]. Chess experts can enhance their working memory through a technique called chunking, in which items are remembered more easily when they are purposely associated with other objects [9]. Put simply, chunking allows more objects to be recalled in the short term by coupling words or items into larger, more memorable groups. The way phone numbers are divided into three or four number sections is an example of everyday chunking as it allows one to memorize the whole phone number in ‘chunks.’ Additionally, the alphabet song divides the letters into smaller chunks, such as ‘L-M-N-O-P’ and ‘T-U-V,’ making it easier to remember. Chunking allows players to memorize chess positions from previous games more effectively [9].

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BEYOND THE BOARD Developing chunking memory is also key to recognizing familiar positions that help determine the strongest future moves in a game of chess [9]. In a memory task experiment, chess players of varying skill levels were asked to recall the exact position of their pieces at a particular point in a tournament game that they recently played [10]. Chess experts recounted almost the entire board correctly, while chess novices were only able to remember the position of about five pieces on the board [10]. Furthermore, when presented with random positions, grandmasters were able to recall the location of more pieces than novices, including positions that aren’t even technically possible in chess gameplay [10, 11]. Chess experts have also been found to create larger memory ‘chunks,’ that involve more pieces than chunks made by amateur players in both random set-ups and game positions [12]. The fact that grandmasters showed superior performance in memory retention of chess positions supports the notion that grandmasters utilize chunking more effectively than novices [10, 13]. By developing chunking abilities through repeated chess practice, chess experts can retain more information in their working memory, placing them in the optimal position to win [12].

Chunking may also play a role in how expert chess players respond to tasks associated with working memory and spatial recognition compared to non-experts [11]. Expert players respond to an impractical or impossible position in chess the same way that they may respond to a face missing a nose or an eye [11, 14]. When we see a face with distorted features, our prefrontal parietal network — a neural system linked to working memory, attention, and consciousness — demonstrates an increase in activity, since we search for familiar structures to help make sense of the face [14, 15]. An increase in neurological activity in the prefrontal parietal network is also observed when chess experts are introduced to impractical or impossible chess positions [14, 15]. In the same way that people chunk all the structural features of a face together,

chess experts chunk pieces and consequently struggle to make sense of positions in which pieces are laid out in unexpected ways [14, 16]. This similarity in spatial learning-related brain activity demonstrates how chess experts are better able to apply chunking to chess gameplay [14, 17].

WHAT’S THE MOVE? EMPATHIZING WITH THE ENEMY Chess is not just about understanding the board; it also involves knowing your opponent. Along with well-developed chunking strategies, advanced chess players display a greater ability to predict the intentions of their opponents [18]. This phenomenon, known as theory of mind, describes the capacity to understand others’ mental states so as to predict their behavior; in other words, theory of mind is the ability to put yourself in someone else’s shoes [18, 19]. A classic example is a soccer goalie attempting to save a penalty kick; by asking themselves where they would kick the ball as an offensive player, the goalie can choose which side of the net to defend. In the context of chess, theory of mind involves seeing the board from the opponent’s perspective and imagining their thought process in order to predict their strategy [18, 20]. Repeated chess practice is associated with improved theory of mind in cognitive tasks [18]. An exercise recommended by one of the most accomplished chess players — Magnus Carlsen — is to play as both black and white, competing against yourself to improve your understanding of your opponent’s plans and develop a feel for the game [21].

Understanding your opponent’s objective is essential to attaining chess prowess [18]. Advanced theory of mind is associated with chess practice, and it allows expert players to better understand how their opponent might move [20]. In contrast, novice players, who have less developed theory of mind in the context of chess, often play inadequate moves in the hopes of masking their attack from their opponent [20]. Practicing chess improves one’s ability to take perspectives, providing players with a critical advantage in a game where predicting the tactics of their opponent is essential [18].

In addition to theory of mind, chess training can enhance a similar skill: one’s ability to empathize, or understand the thoughts and emotions of others [22]. Regions of the brain associated with chess and theory of mind are also associated with our ability to demonstrate empathy [22]. The temporoparietal junction — an area of the brain responsible for understanding the emotions and intentions of other people — is activated during chess and when experiencing

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BEYOND THE BOARD empathy [22, 23]. Empathizing with a competitor allows a chess player to understand how they would react to a certain play and what they would elect to do next [22]. Therefore, advanced chess training may be associated with an increased ability to empathize, which in turn enhances the ability of expert chess players to predict the motives of their opponents [22, 23, 24].

possible; in the case of the KIBRA T variation, an enhancement in signaling efficiency improves memory and spatial learning [25, 28]. By increasing the volume and metabolic efficiency in the cortex of the brain and hippocampus, expression of the T variation of KIBRA contributes to enhancement of working memory and spatial awareness, both of which are crucial to success in chess [25]. While working memory and spatial awareness can be developed via training, the prevalence of the KIBRA T variation in chess grandmasters demonstrates how inherited traits can provide an innate advantage that separates their skill from other high-level players [25].

WE HAVE A SPECIAL CONNECTION: HOW PRACTICING CHESS PHYSICALLY ALTERS THE BRAIN

IT’S ALL IN THE GENES While everyone can benefit from long-term chess practice, some people may be born with a natural aptitude that originates in their genetics [25]. A specific variation of the KIBRA gene, which contributes to memory-related structures in the brain, is found to be especially prevalent in chess experts. The KIBRA gene has two forms, C and T; elite chess players, especially grandmasters, have a significantly higher frequency of the T form compared to non-elite players [25].

The presence of the T form of the KIBRA protein is associated with increased hippocampal volume [26].

The hippocampus is an area of the brain responsible for memory processing and decision-making, and a larger hippocampal volume may be associated with enhanced working memory [26, 27]. People who express the T form of the KIBRA protein exhibit superior working memory to those with the C form [25, 27].

Additionally, the KIBRA T protein acts as a scaffolding protein in memory and spatial-learning regions of the brain [25]. Scaffolding proteins help regulate cell signaling by making cell communication as efficient as

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Frequent chess gameplay has been correlated with changes in gray matter volume in brain regions associated with chess gameplay [29]. Gray matter is composed of cell bodies, including those of neurons [30]. A reduction of gray matter volume in brain regions that are activated while people play chess has been connected to superior processing of information from neighboring brain regions [31]. Reduced gray matter volume in expert chess players is accompanied by increased connectivity in key regions of the brain, as well as superior control of concentration and improved chess problem-solving ability [31, 32].

Reduced gray matter in the caudate nuclei — which is composed of structures involved in learning and memory— is associated with decreased activity of a brain network called the default mode network (DMN) [32, 33, 34]. The DMN is a group of interconnected brain regions involved with inner monologue, self-reflection, and daydreaming, which are activities that are generally undesirable and distracting in chess [32, 35]. An increase in DMN deactivation is associated with improved concentration alongside other cognitive functions [32, 34]. Chess experts also exhibit a reduction of gray matter volume in the thalamus, which serves as a center for relaying sensory information [36, 37]. A decrease in thalamus volume of chess experts has been associated with increased connectivity from the thalamus to the fronto-parietal network, which is involved in working memory [36, 38]. Increased connectivity between key brain regions marked by reduced gray matter volume is related to the improvement of essential chess skills [32, 36].

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BEYOND THE BOARD

LIFE-LONG REWARDS Playing chess is associated with the stimulation of brain regions that are vulnerable to the deterioration of the brain that is characteristic of dementia, or the progressive loss of cognitive functions such as memory and reasoning [6, 39]. Alzheimer’s disease accounts for about 70% of dementia cases and is responsible for the gradual deterioration of neurons in memory-related regions of the brain such as the hippocampus [6, 40]. Early stages of Alzheimer’s disease also cause a reduction in hippocampal tissue, leading to a loss of connectivity between brain regions and drastically decreasing memory and spatial learning abilities [41]. Engaging in mentally stimulating and challenging activities are often encouraged in an attempt to preserve cognitive functions and a prevention against dementia, suggesting that chess could be effective at promoting cognitive reserve [6].

Though playing chess may not eradicate the possibility of receiving an Alzheimer’s disease diagnosis, people who occasionally play chess may develop the disease later than people who don’t play the game.

In fact, people who frequently play board games like chess may be 35% less likely to develop dementia than those who do not. It is estimated that, between 2000 and 2050, the number of people over 60 years old will double, and the amount of people with neurodegenerative diseases will grow at a similar rate [6].

Chess could become an increasingly viable tool to challenge and stimulate the brain by enhancing cognitive reserve and building resilience to symptoms of dementia [6, 42].

Significant effort has been put into providing the elderly population, who are at the highest risk of developing dementia, with the ability to consistently play chess [43, 44]. Currently, there are chess-playing robots called ‘chessmen’ that each feature a camera and a robotic arm and serve as opposing chess players [44]. The ‘chessmen’ — who often play against elderly populations due to their heightened risk of developing dementia — may be useful in helping the elderly fortify neural connections and preserve cognitive functions [36, 44]. Similarly, a recently developed computer program called the Asynchronous Advantage Actor Critic (A3C) serves as a chess gameplay aid for people with cognitive disabilities [43]. A3C stimulates the brain by offering advice in chess gameplay when a player has not made a move in a long time, or has a low chance of winning the game. A3C promotes the use of cognitive skills by prioritizing learning new

tactics and approaches rather than simply showing players how to win the game [43]. The ‘chessmen’ and A3C are two examples of modern technological applications of chess that are employed to promote cognitive health [43, 44].

HISTORIC GAME, FUTURE APPLICATIONS Chess is a timeless international tradition and can continue to be a useful game for future generations as dementia becomes increasingly prevalent [6]. Practicing chess has been associated with the increased development of chunking, a technique which aids in expanding the boundaries of working memory [9, 45].

Chess gameplay is also connected to the development of theory of mind and empathy, demonstrating the influence of chess practice beyond memory retention [22, 23, 24]. Additionally, long-term chess play is associated with physical changes in memory-related brain regions such as the caudate nuclei and the thalamus [31, 32, 36]. These structures often experience a decrease in gray matter volume, which is associated with greater connectivity between other regions of the brain [31, 32, 36]. Expanding on the alterations correlated with chess gameplay, there is also a genetic component related to chess success: the KIBRA T protein variation is linked with improved performance in the game, although the presence of this gene does not limit the cognitive benefits of playing chess [25]. Not everyone will achieve the level of prowess required to become a chess grandmaster, but there is no denying the usefulness of regular chess gameplay; whether one is playing competitively or recreationally, chess offers competition and mental stimulation [24, 46].

References on page 55.

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FACING THE MYTHICAL FURY

FEATURED

FACING THE MYTHICAL FURY: THE CALAMITOUS PATH OF LYSSAVIRUS RABIES 16 MATTERS JOURNAL AT VASSAR COLLEGE | ISSUE 8

by Anna Conway/ art by EmilyGREY Holtz diagrams by Jane Stempien

FACING THE MYTHICAL FURY

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t is an unseasonably pleasant afternoon in August when Jane Doe and her partner decide to take a weekend camping trip.

They pack their minivan with sleeping bags and sandwiches and set off toward their campsite on a congested Florida highway. Friday and Saturday go off without a hitch. They have lots of fun, but Jane becomes weary from two nights of sleeping on the harsh ground. She decides to pitch a hammock between two tall trees while the early afternoon sun is still high in the sky. Jane then notices a little brown bat flying haphazardly a few yards away, low to the ground. She thinks nothing of the creature as it is minding its own business.

Suddenly, she feels a pinch near her knee, by the lower end of her hamstring. She hurriedly leans down to inspect the source of the pain. The bat had bitten her. The wound is shallow and hardly draws any blood at all. Viewing it as an annoyance more than anything else, Jane — an otherwise healthy thirty-year-old woman— hops into her hammock and enjoys a nap in the sun. However, this is a fatal mistake. A horrifying predator by the name of Lyssavirus rabies has found its way beneath her skin, ready to claim her as its next victim.

Lyssavirus rabies derives its name from Lyssa, the Greek goddess of rage and fury, known for turning dogs mad and against their owners [1]. Lyssavirus rabies, colloquially known as the rabies virus, is responsible for approximately 59,000 deaths per year, with 95% of cases occurring in Asia and Africa [2, 3]. Most frightening of all, the virus is almost always fatal once symptoms have begun. This stage is often referred to as the ‘point of no return,’ where the virus attacks the nervous system, ultimately leaving people as mere shells of their former selves [4, 5, 6]. Let’s turn back to Jane Doe on her camping trip, and examine what exactly happens when a human is infected with the rabies virus.

WHAT IS THE RABIES VIRUS? Composed of a short chain of five proteins, the rabies virus is a considerably simple structure with only two goals: infect and replicate [7, 8, 9]. Completely dependent on its host’s metabolic processes to survive, the rabies virus is a cellular intruder — sapping energy and hijacking cell functioning to transform those cells into centers for replication [9].

Beginning its journey from the bite in Jane Doe’s hamstring, the rabies virus silently replicates and infects neighboring cells: a slow yet widespread invasion entirely unbeknownst to Jane [4, 10]. Anxious to return to work on Monday morning, Jane places a band-aid over the inconspicuous wound and resumes her daily life, gradually forgetting about that humid afternoon and the bite on her leg. For a little while, it seemed as though nothing would come of that distant memory. On average, rabies has an incubation period of 15 to 90 days, during which those infected are asymptomatic and remain unaware of the vast internal spread of the virus [3, 10, 11, 12]. Since Jane was bitten on a lower extremity — further from the spinal cord — her incubation period will likely fall closer to 90 days, which is more than enough time for the wound to heal and for the memory of the bite to fade [10, 13].

A PATIENT PREDATOR Under the skin, however, the rabies virus is furiously carrying out the instructions encoded in its genome: replicate and move toward the central nervous system, where it can continue to replicate at an accelerated rate [6, 14]. From its original infection point in Jane Doe’s hamstring, the virus leaps into her peripheral nervous system — that is, all of the nerves outside the brain and spinal cord — via the neuromuscular junction [12, 14, 15]. The neuromuscular junction (NMJ) is a synapse, or bridge for communication, between a neuron and a muscle [16]. The NMJ is vital for movement, relaying signals from the nervous and muscular systems to prompt muscle contractions [16]. Once the virus invades Jane’s peripheral nervous system, it moves toward the next target: the spinal cord [14]. If the rabies virus behaved like other molecules in the body, such as proteins, it would be passed along in the ‘forward’ direction: from the dendrites — the receiving end of the neuron — to the cell body and down the axon toward the axon terminal — the transmitting end of the neuron [17]. While less frequent, molecules can move ‘backward’ via the reverse process, referred to as retrograde transport: moving from the axon terminal, up the axon, and toward the cell body and dendrites. As transport must be quick and efficient no matter the direction, retrograde transport is aided by other protein players, primarily a motor protein called dynein [17].

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FACING THE MYTHICAL FURY

The rabies virus is distinct because it takes advantage of retrograde transport by hijacking dynein proteins [14, 18]. The virus acts as a stowaway, ‘hitching a ride’ on dynein to be transported up the axon via microtubules — a cellular highway — progressing closer to the central nervous system with each neuron it travels on [14, 18]. Eventually, the rabies virus progresses toward Jane Doe’s spinal cord, all the while replicating and taking over more cells on the path to total destruction [12, 14].

However, the rabies virus works to inhibit interferon signaling pathways [19, 22]. Despite the infected cells’ attempt to initiate an antiviral effort via interferons, the virus ensures that cells are rendered unable to produce and deliver interferons outward [19]. Thus, neighboring cells do not erect their antiviral defenses, and are easily invaded by the rabies virus, which can then replicate unchecked within them [3, 19, 23].

Throughout a typical viral invasion, the infected cells produce a substantial amount of chemokines, another type of molecule that acts as an alarm system [24]. Chemokines prompt your immune cells to rush toward the infection site and fight off the virus [19].

However, the rabies virus causes cells to produce only a moderate amount of chemokines. As such, a full-scale immune response is not actualized, and the virus flies under the immune system’s radar [19].

All the while, Jane Doe remains none the wiser. She goes to work, hangs out with her friends, and feels completely healthy while the rabies virus tirelessly progresses toward her central nervous system — specifically the spinal cord. Jane is entirely unaware that soon, it will be too late to alter her fate.

A NEUROLOGICAL NIGHTMARE You might be asking yourself: what is Jane’s immune system doing to fight off the virus? Unfortunately, the answer is very little [8, 19]. Ordinarily, when the body is infected with a foreign pathogen, the immune system acts quickly to destroy the infection and protect healthy cells [19]. The immune response is kickstarted by interferons that act as alarm bells when released by infected cells [20]. Interferons cause both the infected and neighboring cells to produce antiviral proteins, which prevents further viral replication in every cell involved [20, 21]. Interferons can also summon specialized immune cells to the infection site and compound the antiviral effort [21].

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On a cold Tuesday morning, Jane Doe wakes up with a fever. She twists and turns in bed, feeling uncomfortable. She remains oblivious to the fact that the rabies virus has reached its first major destination— the central nervous system [3]. Jane is unaware that her run-of-the-mill fever indicates something far more sinister: that the virus has reached the point of no return, where no current treatment regimen is capable of reversing the inevitable [6, 8, 25]. While there is still a degree of uncertainty regarding exactly what happens once the rabies virus reaches the spinal cord, it is believed that the virus’s introduction to the central nervous system prompts a devastating

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FACING THE MYTHICAL FURY cascade of neuronal dysfunction, ultimately leading to death [3, 12, 25, 26]. Though the virus has previously evaded the immune system, it is the virus’s introduction to the central nervous system that finally triggers a full-scale immune response [8]. Jane lies on her bed, feeling feverish and fatigued, alternating between curling up into her blankets and kicking them off [25, 27]. Jane has entered the early phase of the disease, where she begins displaying non-specific symptoms as a result of her immune system’s early fight against the rabies virus [4, 8]. Unfortunately, the immune system is far too late. The rabies virus has succeeded in infiltrating the central nervous system and now blocks immune cells from clearing the virus by preventing the enhancement of blood-brain barrier permeability [28, 29]. The blood-brain barrier is composed of a tight layer of specialized cells located around the blood vessels in the central nervous system [30]. The blood-brain barrier works to prevent toxins, pathogens, and potentially harmful chemicals from gaining access to the central nervous system [30]. Even though Jane’s immune system has been alerted to the presence of a viral infection, most immune cells are unable to access her brain and spinal cord [29, 31, 32]. Not only are immune cells barred from entry into the central nervous system, but they are also ordered to perform apoptosis: programmed cell death [31]. The immune system is once again hindered as the virus begins to infect Jane’s brain, wreaking fatal havoc in the process [31].

Brain activity is due to action potentials, which are electrical signals sent down the axon that allow for communication between neurons [33]. The successful propagation of neural signals is highly dependent on ion channels within the neuron’s membrane: namely, sodium and potassium channels [34]. The malfunctioning of these channels is closely related to many neurological disorders, such as epilepsy [35]. The rabies virus causes dysfunction in sodium and potassium channels; as a result, action potentials cannot be properly sent down the axon, and communication between neurons is impaired [25, 36]. Once the virus spreads throughout the brain, the neural areas responsible for controlling impulses and aggression become dysfunctional [36]. As a result, Jane begins to yell and punch her bedroom walls in two-minute spells [4]. Her partner — frightened for Jane’s safety — begs and pleads for an explanation for her aggression. Unfortunately, Jane is also experiencing confusion, accompanied by the disorienting effects of a fever [4, 25]. She is unable to properly articulate what is wrong as the virus overtakes her brain, in preparation to fatally ravage the rest of her body [25].

The rabies virus then spreads outward from the central nervous system, descending back into the peripheral nervous system in a process called centrifugal spread [25, 37]. The virus’s next destinations are Jane’s internal organs. Jane’s throat begins to ache, and the previously bitten leg develops a tremor [4, 25, 38]. Her partner offers her a glass of water, hoping to aid in her fever. Jane, however, is beginning to experience a classic symptom of rabies: hydrophobia [4].

It is believed that hydrophobia is caused by infection in the areas of the brainstem that control neurons involved in swallowing. While ordinarily protective, the rabies virus causes our body’s natural choking instinct to become wildly overactive, sometimes occurring anytime water is ingested at all. As the water washes down Jane’s throat, her diaphragm painfully contracts in a horrific spasm that lasts about ten seconds. She vomits the water back up and begins to convulse, refusing any further offers of water. She even trembles in fear at the mere sight of it [4]. However, her self-imposed dehydration does not prevent the ‘foaming of the mouth’ that we commonly associate with rabies, which occurs as the virus infiltrates the salivary glands to provide its host with a method of transmitting the virus to others, via biting [39]. At this point in the virus’s assault, Jane Doe is in pain, thirsty, and deeply confused as to what is happening to her. Just under two weeks after the initial onset of clinical symptoms, the introduction of the virus into the heart causes a defect in the electrical conduction of cardiac impulses [40]. As a complication of the rabies virus, Jane goes into heart failure from myocarditis — or inflammation of the heart — which is listed as her cause of death [40].

HOPE IN RABIES TREATMENT While Jane’s story is harrowing, researchers and policymakers are striving to ensure that rabies is someday eradicated, so that no more stories have to end like Jane’s. Since a common method of rabies transmission is through dog bites, many countries in the Western Hemisphere have rolled out massive vaccination campaigns for domestic dogs and created more stringent guidelines for responsible pet ownership [41]. The goal is herd immunity: maintaining widespread rabies resistance in a large percentage of the canine population. As a result of these measures, strains of the rabies virus are becoming progressively rarer. Cases of human rabies in North America have plummeted to near zero, and have been steadily decreasing throughout the Caribbean and South America [41]. Moreover, extremely efficacious protocols have been implemented for when an individual

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FACING THE MYTHICAL FURY believes that they have been infected with rabies, which aim to address the virus before it reaches the point of no return [42]. An individual would receive a series of purely preventative injections referred to as post-exposure prophylaxis, or PEP. PEP, at its core, relates to the function of antibodies against antigens [42]. Antibodies are proteins produced by immune cells that are specialized to fight against antigens: which are any substances the immune system can respond to [43, 44]. Antigens that are recognized as foreign are subsequently attacked by the immune system, using antibodies [44]. PEP protocol takes a three-pronged approach: carefully washing any wounds potentially involved in rabies transmission, administering a rabies vaccination, and providing rabies immunoglobulin (RIG) [42]. RIG is composed of antibodies from humans that have received the rabies vaccine [45]. Since it often takes upwards of eight days for the average person to begin producing their own rabies-fighting antibodies in response to the vaccination alone, RIG is administered so the body can begin fighting off the virus as soon as possible. Once administered, the virus is unable to hide from the now-enhanced immune system [45]. The World Health Organization estimates that current PEP regimens are nearly 100% effective, and there are very few recorded deaths due to rabies after someone with confirmed rabies exposure undergoes the PEP regimen prior to the onset of clinical symptoms [42].

So, what can be done if someone is experiencing symptoms of a rabies infection? In such cases, doctors have often attempted a regimen called the Milwaukee Protocol. Through this protocol, people are placed into a medically induced coma and are provided with a cocktail of drugs that have antiviral properties in an attempt to slow the neurological destruction caused by the rabies virus [46, 47]. The combination of therapies in the Milwaukee Protocol was inspired by discovered treatments for other diseases, such as cancers and HIV, which respond well to multiple drugs administered simultaneously [46].

In a famous 2004 case study, a fifteen-year-old girl survived the rabies virus with only mild neurological deficits after undergoing the Milwaukee Protocol [48, 49]. However, it is unclear whether the Milwaukee Protocol truly made a difference when it came to her survival [4, 46]. Sadly, there have been numerous documented failures of the Milwaukee Protocol since the case study was published [46, 47, 50]. Due to the Milwaukee protocol’s lack of efficacy, many experts have recommended that the protocol be discontinued as a treatment for rabies [4]. Instead, most medical attention has been placed on preventing the

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FACING THE MYTHICAL FURY spread of the virus and treating it in its early stages to ensure that the rabies infection does not reach the point of no return in infected individuals [46].

While the protocol’s lack of success is discouraging, further research is being conducted to create an effective regimen to treat rabies in its symptomatic stage so that there is a chance of recovery from what is typically the point of no return. Monoclonal antibodies, which are lab-made proteins that are meant to be a clone of one specific antibody, seem to be the key [51, 52]. Once monoclonal antibodies stick to their corresponding antigen, they can assist in destroying other cells that also contain a harmful antigen by marking those infected cells for later immune destruction [51, 52]. When treated with a combination of two monoclonal antibodies, rabid mice who were already in a symptomatic stage were completely cured of the virus [53]. While research on humans has yielded less conclusive results, current research is steadily moving toward a cure for symptomatic rabies — an innovation that would save countless lives, Jane’s included [54].

Greater global attention must be focused on guaranteeing equal access to the PEP regimen across all populations, as well as providing education to ensure that those exposed to the rabies virus seek treatment [60]. Jane’s story might have ended in tragedy, but there is a great deal of hope for a future entirely rid of the rabies virus, sending Lyssa’s wrath back to the myths where it belongs.

References on page 57.

QUELLING LYSSA’S FURY: A PATH TO RABIES ERADICATION While the rabies virus still occupies many people’s worst nightmares, progress is on the horizon [55, 56, 57]. The World Health Organization maintains its goal of eradicating canine-born rabies from 155 countries by 2030 [58]. While nearly 60% of current human rabies cases originate in Asia, many countries such as Thailand and Vietnam are seeing rapid decreases due to increased canine vaccination [55, 56]. Singapore has even been declared rabies-free [55, 56].

A growing focus on community-based public health programs has shown to be majorly effective at both contributing to the eradication of rabies and the maintenance of rabies-free areas, which are becoming progressively wider [56]. Furthermore, the global disease burden — often measured together as both years spent disabled by disease and years lost due to disease-related premature death — caused by rabies has shrunk over the last thirty years. [57, 59]. While improvement is significant and deserves celebration, disease burden due to rabies is still highly correlated to socioeconomic index, with those from middle and low-income countries bearing the vast majority of that burden [57].

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BACK FROM BATTLE: THE CONDITIONING OF FEAR IN PTSD

by Elsie McKendry/ art by Katie Hieb

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veryone has felt afraid before. Maybe you have a fear of heights, spiders, or the dark.

Fear keeps us safe when it warns us of danger.

Now imagine if you frequently felt fear in harmless situations, such as every time you brushed your teeth or heard a plane. An overactive fear response would quickly become disruptive to your daily life. For many people with post-traumatic stress disorder, this imagined scenario is a reality.

Post-traumatic stress disorder (PTSD) is a mental health condition that can arise after a person experiences a traumatic event [1]. A traumatic event can be defined as a frightening or dangerous experience that threatens an individual’s life or physical security [2]. What defines a trauma is complex, but traumatic events can include abuse, natural disasters, bullying, refugee and war experiences, and life-threatening illnesses [2]. Characteristic symptoms of PTSD include re-experiencing and avoidance of a trauma, heightened arousal, and mood disruptions [3]. PTSD is characterized by a heightened fear response in reaction to occurrences that remind an individual of a previous traumatic event, potentially resulting in impairments to well-being, cognition, memory, identity, and relationship formation [2]. Heightened fear responses become a source of dysfunction when they occur frequently enough to interfere with day-to-day life [4].

CLASSICAL CONDITIONING: HOW WE LEARN TO REPSOND Heightened fear responses can be triggered by both threatening and non-threatening stimuli that remind a person of traumatic events [5]. Trauma responses can be explained as a disorder of learning and memory processing, specifically through the lens of classical conditioning: a type of associative learning where two unrelated stimuli are paired, leading to the same response when either stimulus is encountered individually [5]. When most people think about classical conditioning, they recall the scientist Ivan Pavlov and

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his salivating dogs [6]. In Pavlov’s experiment, each time the dogs were fed, a bell was rung right before the delivery of food [7]. Dogs automatically salivate in anticipation of food; accordingly, food is an unconditioned stimulus that triggers an automatic response.

Over time, the dogs began associating the bell sound with food, salivating at its tone [7]. Their salivation indicated that the sound of the bell had become a conditioned stimulus: a stimulus that did not previously evoke an automatic response, but one that the subject learns to react to in a particular manner [8].

We encounter classical conditioning in our everyday lives: hearing a school bell elicits excitement at the end of the school day while hearing a soda can open may elicit thirst.

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BACK FROM BATTLE

HOW IS CLASSICAL CONDITIONING RELATED TO PTSD? The concept of classical conditioning can be applied to fear responses caused by trauma-related cues [6]. Consider a hypothetical war veteran named Phil.

Imagine that Phil spent a few years serving overseas and experienced significant violence firsthand.

During combat, an enemy plane dropped a bomb close to Phil’s station, and he rushed to find shelter. His instinct to run away ended up saving his life.

Throughout the remainder of his service, the sound of planes was frequent. Each time he heard an incoming plane, he feared that it was another enemy plane preparing to drop a bomb, and ran to find cover. After Phil’s initial traumatic experience, he used the sound of planes to predict the dropping of bombs.

Phil’s learned response to the sound of planes is an example of classical conditioning [6]. The unconditioned stimulus is the bomb, since a fear response to a bombing is natural. Conversely, plane sounds are a conditioned stimulus for Phil, because they do not typically evoke fear. He began to associate the sound of planes with danger through repeated recall of his previous traumatic bombing experience each time a plane flew overhead. While his instinct to run from the sound of planes was initially life-saving, it became maladaptive after his service ended [9].

THE EXPANSION OF FEAR THROUGH STIMULUS GENERALIZATION Phil’s inability to process non threatening stimuli, even in a different context, contributed to his disrupted fear response. After his return home, Phil found himself having intense fear reactions to plane sounds and other harmless noises that sounded similar, such as lawnmowers and vacuums [9]. For instance, when Phil was awoken by the sound of an electric mixer on a Sunday morning, he immediately jumped out of bed and dove into his closet. After a sweet smell wafted through the closet door, Phil realized that his wife was using the kitchen mixer to make blueberry muffins, as she occasionally did on the weekends.

Phil’s reaction is consistent with the finding that people with PTSD have difficulty differentiating between safety and danger cues [9, 10]. Even though Phil consciously knew he was safe in his home, he reacted to the sound as if he was in danger and found it difficult to calm himself [9, 11]. In classical conditioning, a tendency to respond to neutral stimuli that bear similarities to a conditioned stimulus is known as stimulus generalization [9]. Generalization typically serves

as an adaptive process to help people respond to new situations based on prior experiences. However, it can become harmful when it occurs too frequently [9]. It’s possible that overgeneralization in those with PTSD may be attributed to deficiency in the dentate gyrus, a brain region involved in the encoding of similar events as distinct based on specific, oftentimes minute details that differ between the two events [12]. This process is known as pattern separation, and its impairment has been theorized to contribute to stimulus generalization [12]. In Phil’s case, he responded to the sound of the mixer similarly to how he would respond to the original conditioned stimulus — the sound of the plane [6, 9]. However, once Phil returned to civilian life, his learned reaction no longer protected him; instead, it caused him unnecessary distress [9, 10].

FIGHT OR FLIGHT: OUR FEAR RESPONSE When learned fear becomes overwhelming and is no longer protective, it may be not only unhelpful, but harmful [9, 10]. As Phil hid in his bedroom closet, his hands shook, his lungs constricted, and his heart raced. Phil exhibited dilated pupils, slowed digestion, and an adrenaline rush [4, 13]. The sensations that Phil was experiencing are products of an active sympathetic nervous system: the part of the nervous system best known for its role in triggering the fight-or-flight response [14]. Notably, the sympathetic nervous system works alongside the hypothalamic-pituitary-adrenal (HPA) axis: a system responsible for releasing hormones that activate the fight or flight response [13, 14, 15]. One of these hormones, known as adrenaline, triggers physiological changes to help respond to frightening stimuli. Adrenaline release leads to increased blood flow that encourages muscle activation, while an increase in blood glucose concentration allows the body to make use

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BACK FROM BATTLE of energy reserves [16]. Essentially, the sympathetic nervous system works to maximize survival in stressful or dangerous situations by activating bodily responses that improve our ability to react to threats [17]. However, when the sympathetic nervous system is chronically activated, such as in individuals with PTSD, health consequences that affect a person for the rest of their life may occur [2]. When the HPA axis becomes dysregulated in response to chronic stress, a person faces possible damage to these crucial systems. Cortisol, another hormone released during HPA activation, particularly contributes to the ‘wear and tear’ of these regulatory systems, which can lead to the impairment of cognitive functions such as memory and behavioral regulation [2]. Altogether, strain of the sympathetic nervous system due to fear responses in those with PTSD can impose an array of debilitating symptoms.

MEMORY STORAGE GONE WRONG: WHY PTSD FLASHBACKS FEEL SO REAL In addition to physiological responses, those with PTSD often experience intrusive memories related to a traumatic event. Such flashbacks can occur even years after the traumatic event has passed [5]. When experiencing these memories, it can be difficult to differentiate between the past and present. Let’s return to Phil. When he first heard the sound of his wife’s electric mixer, he was reminded of the enemy planes that dropped bombs near his station. Even though that event took place overseas many years ago, Phil had difficulty remembering he was in the safety of his home and not at war, causing his flashback to feel real. Disruptions with contextualizing familiar stimuli in different environments is partly attributed to dysfunction of the hippocampus, which is a brain structure that regulates our learned fear responses, learning, and memory [5, 6]. The hippocampus — along with other brain regions — is involved in identifying whether a stimulus is safe or dangerous based on the context of the situation, and stores this information for later use [6, 18]. Although the mechanism by which the storing of information is debated, unpleasant emotional arousal — such as Phil’s experience during the bombing — disrupts hippocampal memory processing. Disrupted hippocampal functioning makes contextualizing information surrounding a stimulus difficult [19, 20]. If a person incorrectly associates a previous context with a stimulus, they can experience flashbacks and stimulus generalization similar to what Phil experienced [19].

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WHY IS EXTINCTION IMPAIRED IN PEOPLE WITH PTSD? While dysregulated fear conditioning and stimulus generalization can cause major disruptions to a person’s life, it is possible to unlearn these harmful associations [5]. The suppression of a conditioned fear response is referred to as extinction. In classical conditioning, conditioned responses fade once the conditioned stimulus is no longer associated with the unconditioned stimulus that originally prompted a response. While extinction may resemble forgetting, extinction is more so a form of new, inhibitory learning that competes with the previously learned fear response. For instance, if Phil was continuously exposed to plane-like noises that were unaccompanied by bombs, he could eventually learn that those sounds do not predict danger and would stop having adverse reactions to the sound. If Phil’s conditioned fear of planes became extinct, he would no longer panic and jump into his closet at the sound of an electric mixer. In this instance, a stimulus that originally elicited fear would begin to elicit a new response as a new outcome is learned.

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BACK FROM BATTLE However, because the fear memory is not erased during the extinction process — but is overwritten during the extinction process instead — efforts to unlearn traumatic associations can be reversed in a process called reinstatement. In reinstatement, a fear response returns when the unconditioned stimulus reappears, such as in the event of another bombing [5]. In people with PTSD, fear extinction impairment may be attributed to decreased activation of the prefrontal cortex, a brain area involved in executive functions such as decision making and behavioral flexibility [21, 23]. A decrease in activation of the prefrontal cortex reduces its ability to regulate brain areas such as the amygdala, a brain region that plays a key role in reacting to danger and eliciting fear responses [6]. When the prefrontal cortex is inactive, its inhibitory power over the amygdala weakens, causing individuals with PTSD to experience an exaggerated fear response [6, 24]. The possibility of fear extinction impairment contributes to the persistent and debilitating nature of PTSD [5, 6, 24].

THE ROAD TO RECOVERY: AN ARRAY OF PTSD TREATMENT OPTIONS Though the difficulty of unlearning fear responses can result in persistent symptoms, new therapeutic techniques offer hope for people with PTSD [25]. Phil eventually sought out treatment for his PTSD and found a therapist that specializes in Eye Movement Desensitization and Reprocessing (EMDR). Phil’s therapist began by having him visualize the bombing he experienced, and then had him discuss his emotions and beliefs surrounding the event [26]. In the next phase of treatment, Phil was asked to focus on the traumatic event as he simultaneously tracked a bilaterally moving stimulus with his eyes. By working through these revisited memories with his therapist, he was able to positively reframe negative associations of his trauma and practice calming himself during moments of high arousal [27]. Though EMDR is effective, little is known about its underlying mechanisms [27]. Specific medications, such as selective serotonin inhibitors (SSRIs), can also be effective in treating PTSD; combining psychotherapy and medication can maximize the benefits of treatment [25]. Furthermore, there have been recent investigations into treatment plans involving the use of psychedelic drugs instead of SSRIs [28, 29].

For example, the clinical administration of MDMA in combination with psychotherapy is more effective in reducing PTSD symptoms than dual therapy-SSRI treatment plans. Fortunately, evolving treatments — such as those utilizing MDMA — show promise in reversing maladaptive fear triggers to non-threatening stimuli [28, 29]. As research progresses, PTSD treatment could continue to improve the quality of life for people with PTSD. References on page 60.

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FROM CLUB TO CLINIC: THE TREATMENT OF PTSD WITH MDMA

by Erin Kaufman/ art by Iris Li

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ifficult experiences are universal. However, in extreme cases, past traumas can resurface, interrupting daily life. Post traumatic stress disorder, or PTSD, is a psychiatric disorder that can lead to a variety of emotional and physical symptoms in response to a singular or repeated extreme traumatic event [1, 2]. While not everyone who experiences a traumatic event will develop PTSD, those who do may not present with the disorder in the same way and may respond to treatment differently [3, 4].

Due to the individuality of PTSD diagnoses, there is not one specific treatment plan to alleviate PTSD symptoms [5, 6]. While current medication paired with therapy may relieve symptoms for some, just under half of people diagnosed with PTSD experience treatment resistance [7]. In response to the prevalence of treatment-resistant PTSD, investigations have begun into new methods of treatment, particularly in first responders and military personnel [8]. MDMA, more commonly known as ecstasy, is a promising option for an alternative treatment avenue [9, 10].

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SYSTEMS AND SYMPTOMS: PTSD AND ITS TREATMENTS PTSD is often associated with a persistent negative emotional state and feelings of anxiety and depression, but because of the case-specific nature of the diagnosis, the range of symptoms will vary [1, 5, 6, 11].

Diagnostic criteria also include intrusive and disturbing memories, flashbacks, and physiological reactions, such as a rapid heartbeat, dizziness, and insomnia [1, 11]. An individual diagnosed with PTSD will likely express two main kinds of symptoms [1, 2]. These two types are categorized as hyperarousal symptoms — anxiety, hypervigilance, re-experiencing the traumatic event — and avoidance symptoms — withdrawal and emotional numbness [1, 2]. These symptoms can lead to months or even years of suffering [2].

PTSD develops through the disruption of fear memory systems in the brain [12]. Given the duration and repetitive nature of PTSD, exploring its connections to both fear and memory is essential to battling people’s

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FROM CLUB TO CLINIC physiological and psychological symptoms [2, 13]. Fear is encoded in neurological circuits of a brain structure called the amygdala, which is intricately involved in emotional processing and is the master coordinator of fear memory [14, 15, 16]. Dopamine and serotonin are neurotransmitters, or signaling molecules, that help create strong fear memories when released in the amygdala [17, 18]. Although fear memory allows people to differentiate between what is harmful and what is safe, dysregulation of this system can lead to the maladaptive responses seen in PTSD [12, 19].

People with PTSD currently have only two medication options available to help combat emotional duress and resulting maladaptive responses, both of which alter serotonin activity in the brain [20, 21]. Serotonin is a versatile neurotransmitter that regulates systems such as those for mood and sleep [22]. A process called reuptake halts serotonin signaling by bringing serotonin molecules out of the synapse — the space between brain cells — and back into the cell [23]. The medications for PTSD treatment are selective serotonin reuptake inhibitors (SSRIs), which act by preventing reuptake, therefore keeping serotonin in the synapse and prolonging its effects [24]. SSRIs paired with psychotherapy can help reduce the frequency and severity of symptoms for some people with PTSD [13, 25, 26]. However, this combined treatment is not effective for every person; over one-third of people suffering from PTSD fail to see improvement in their symptoms with prescribed SSRIs and psychotherapy [13, 25, 26].

THE ECSTATIC BRAIN: NEURAL EFFECTS OF MDMA In response to the prevalence of treatment-resistant PTSD, an alternative substance has become the focus of treatment studies: MDMA [20, 26]. MDMA is a widely used illicit substance in the U.S. [27]. It has both hallucinogenic and stimulant properties, giving people who use it a combination of dissociative, out-of-body feelings and increased mental alertness and energy [9]. The combination of these effects in MDMA goes beyond improving the internal experience of the user; the drug has unique prosocial behavioral effects, such as increased sociability and enhanced feelings of trust, openness, and closeness with others [28, 29]. Therefore, MDMA has been considered as a new method of treatment for patients with PTSD as it can help them better process their trauma during talk therapy [4, 7, 9, 10, 13, 30].

Another reason MDMA-assisted therapy has been explored as an alternative PTSD treatment is because of its effect on dopamine and serotonin pathways, particularly in the amygdala [4, 13, 31]. Like SSRIs, MDMA reduces serotonin reuptake, but it also has a secondary effect on dopamine reuptake [28, 32]. MDMA affects serotonin and dopamine packaging before the neurotransmitters leave the cell, allowing them to be packed and released in higher quantities [28, 32].

When dopamine levels are increased people report an increase in awareness and motivation to engage in psychotherapy [9, 25]. Increased serotonin and dopamine levels contribute to increased self-confidence, reduced amygdala fear response, and greater compassion and empathy for oneself and others [25].

MDMA also has unique effects on the brain because it is thought to promote the release of oxytocin [1, 33].

Oxytocin is a molecule often associated with love and social bonding, and it is involved in feelings of safety, sociability, and sexual arousal [34]. For instance, hugging a friend or loved one can increase oxytocin levels [35]. Beyond its prosocial effects, oxytocin can help people cope with stress while navigating traumatic situations [34, 35]. When an individual is under the influence of MDMA, their increased sociability is theorized to be related to an excessive release of oxytocin [33, 36, 37]. High oxytocin levels can increase awareness of both positive and negative social experiences [33]. On the other hand, MDMA increases awareness of positive social experiences and limits awareness of negative social experiences [33]. While the prosocial effects of MDMA may be related to oxytocin levels, it is the complexity of the drug’s neurochemical effects that causes a beneficial prosocial experience in therapy [37, 38, 39].

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FROM CLUB TO CLINIC MDMA use also significantly affects the hippocampus, a brain structure primarily involved in memory retention, reactivation, and reconsolidation [30, 40]. The hippocampus contributes to the memory component of the fear memory circuits that also route through the amygdala [30, 40, 41, 42, 43]. During memory reconsolidation, memories are reaccessed, reformed, and stored differently than before [42, 44, 45]. When a person revisits the memory of a traumatic event in therapy they are able to think about it in a new way, forming a less emotionally volatile version of that memory [40]. MDMA affects hippocampal activity in fear memory circuits, potentially allowing a person to reform the traumatic memory with less emotional weight [30, 40]. Therefore, people in therapy under the influence of MDMA are able to discuss their traumatic memories with fewer physiological and psychological pains [13].

someone, MDMA acts as a key to making people more emotionally and cognitively receptive toward treatment [7, 13]. During a therapy session, a person receives a controlled dosage of MDMA in a supervised clinical setting and meets with psychiatrists and psychologists to access the traumatic memory [4, 7, 10, 23]. The doctors help those receiving treatment recount memories that would normally trigger severe PTSD symptoms while ensuring that they feel safe under the influence of MDMA. As MDMA can inhibit fear systems in the amygdala and provide people with a heightened sense of self-awareness, doctors can probe traumatic memories without triggering the person receiving treatment [7, 13]. MDMA alone is not known to treat any neurological disorder, but it can provide people with a greater sense of trust and security to process distressing events during psychotherapy [7, 13].

Although MDMA can be beneficial in a clinical setting, cell death that results from the abuse of MDMA can cause damage to major memory circuits [30, 46].

MDMA abuse can cause damage to overactive serotonin receptors in the brain and serotonin-sensitive nerve endings in the hippocampus [43].

This potential danger seen in chronic use has led to the neglect of MDMA as a potential therapeutic [30]. Consequently, MDMA is legally classified as a Schedule 1 drug: a drug with no current accepted medical use in the United States and a high potential for abuse [47]. However, a controlled dosage of MDMA taken in a medical setting is significantly less likely to cause permanent damage to the brain and has a variety of possible benefits [4]. MDMA-assisted therapy is now in the process of getting approved by the Food and Drug Administration (FDA) for medicinal use [48].

If FDA approved, MDMA would no longer be considered a Schedule 1 drug and could be implemented for treatment in controlled environments [47].

Due to long-term exposure to military combat, terrorism, violent crime, and death, military veterans are especially likely to be diagnosed with PTSD [4]. Veterans can receive MDMA-assisted therapy to treat these wounds and provide a sense of emotional and social comfort, allowing them to speak about their trauma without experiencing PTSD symptoms [4, 7, 10, 13]. During MDMA-assisted therapy, memory reconsolidation can help people address their PTSD and trauma responses [47]. When veterans suffering from PTSD are able to speak about traumatic events in a secure setting under the prosocial and mood-boosting effects of MDMA, they can reconsolidate their memory of traumas into memories that do not provoke the same PTSD symptoms [7, 13]. In a recent phase three clinical trial for MDMA-assisted therapy as a treatment for PTSD, about two-thirds of veterans participating in the trial no longer met the eligibility criteria for PTSD after three sessions of MDMA therapy, compared to less than half of veterans who did not receive MDMA [4]. Although there is individual variability in the reactions to and efficacy of MDMA-assisted therapy for PTSD, the overall potential of MDMA treatment offers the exciting prospect of a safe and effective treatment plan [4, 7, 10, 13].

UNLOCKING THE GATE: MDMA’S ROLE IN CLINICAL TREATMENT Think of PTSD as a locked gate, with the recollection of traumatic memories lying behind that gate. By providing access to those memories in the brain in a way that does not physically or emotionally harm

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FROM CLUB TO CLINIC While the first studies of MDMA-assisted therapy focused on PTSD treatment for military veterans and first responders, more recent studies show that MDMA-assisted therapy has been effective in people who have experienced vastly different traumas [7, 13]. For example, historically underrepresented populations in PTSD clinical trials — including survivors of chronic sexual violence, transgender individuals, and ethnoracial minorities — have been shown to experience an alleviation of PTSD symptoms after MDMA-assisted therapy [13]. Despite the uniqueness of each diagnosis, MDMA-assisted therapy is beginning to open the door to reliable treatment for people from a broad range of backgrounds who are living with PTSD [4, 7, 10, 13].

A SHIFT IN CULTURE: THE RISE OF ALTERNATIVE TREATMENTS MDMA-related treatment results for PTSD have only come to light in recent years [8]. Due to the stigma against substances and the anti-drug movements of the 1970s, avenues for MDMA treatment have been prohibited and ignored [49]. However, as cultural perspectives on drugs have shifted over the years, new perspectives have suggested MDMA and its benefits as a potential treatment for PTSD [21, 25]. For the first time since the 1960s, the government is funding research on MDMA for treatment of PTSD in military veterans and first responders [20, 50]. In December 2023, MDMA-assisted therapy was brought to the FDA to obtain approval for medicinal use outside of clinical studies [47]. If approved, MDMA could become an alternative treatment to SSRIs and give people with PTSD a chance to live without the constraints of their past traumas [50].

References on page 62.

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FROM PLEASURE TO PAIN: THE EFFECTS OF COCAINE USE DISORDER ON THE BRAIN

by Brooke Berbeco/ art by Mischa Landgarten diagrams by Jane Stempien

Disclaimer: The following article discusses Cocaine Use Disorder and contains detailed descriptions of drug use, overdose, and its effects. If you or someone you know is struggling with addiction, you can call the SAMHSA National Helpline at 800-662-HELP (4357) to find treatment options near you.

WELCOME TO THE PARTY... OR NOT?

Y

et another party scene flashes across your screen: people dancing and laughing, colorful lights illuminating the room, and thin white lines of powder are being cut across a table with an Amex Black credit card. There’s no question that cocaine use is glamorized in the media — for instance, in images of Jordan Belfort’s rich and wild lifestyle in The Wolf

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Wall Street, or the characters of Saltburn at the Cattons’ parties in their luxurious old-money mansion [1, 2]. Throughout these staged moments, cocaine is often portrayed as an exciting party drug that makes people who use it feel like they are on top of the world [1]. Yet, this glamorous representation of cocaine shrouds an opposite reality: cocaine profoundly impacts the human body, particularly the intricate workings of the nervous system [3, 4, 5]. While indigenous communities around the world have valued the coca plant — or cocaine in its natural state — for its stimulating effects for centuries, modern extraction and refinement processes produce cocaine at unprecedentedly high concentrations [6]. As a result, cocaine’s effects are amplified, subjecting those who chronically use cocaine to consequences that manifest in their brain and the rest of their body [6].

Cocaine use may cause a diverse array of behavioral changes, ranging from heightened energy levels or irritability to persistent paranoia and anxiety [7]. Behavioral changes manifest due to cocaine’s ability to disrupt chemical balances in certain brain structures that coordinate our motivational state, known as the reward circuitry; this may lead to Cocaine Use Disorder (CUD) [8]. CUD is a chronic condition marked by compulsive cocaine seeking and usage despite negative emotional, social, or health effects [8]. Understanding the psychological and physiological mechanisms that cocaine targets is key to understanding the origins of CUD and its associated health risks [8, 9].

I’M GETTING ‘NERVOUS’ The nervous system serves as the body’s primary form of communication by transmitting signals through the specialized cells, called neurons, throughout the body [10]. These signals are responsible for

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transmitting sensory information, coordinating responses to stimuli, and regulating bodily functions.

The nervous system consists of the central nervous system — made up of the brain and spinal cord — and the peripheral nervous system, a network of neurons that connects the central nervous system to the rest of the body. Two important subdivisions of the peripheral nervous system are the sympathetic and parasympathetic systems, which work together to maintain bodily equilibrium by regulating involuntary functions such as heart rate and blood pressure [10].

When a person faces perceived threats and stressors, the sympathetic nervous system activates the rapid fight-or-flight response, increasing heart rate, alertness, and breathing [10, 11]. Cocaine also has theability to activate the sympathetic nervous system, inducing an undue fight-or-flight response [7, 12]. On the other hand, the parasympathetic nervous system — often referred to as the body’s ‘rest and digest’ system — counterbalances the sympathetic nervous system [13]. Communication in nervous systems begins with the production of signals within individual neurons, a process called synaptic signaling [14]. As signals travel down a neuron, they trigger the release of chemicals — known as neurotransmitters — into the synapse or the space between neurons [14]. Once neurotransmitters flow into the synapse, they bind to receptors on an adjacent cell, activating the cell through a cascade of signals [15]. To ensure precise control over synaptic transmission, neurotransmitter signaling must be tightly regulated [16]. One regulatory mechanism of neurotransmitter signaling is reuptake, during which specialized transporter proteins ‘vacuum up’ neurotransmitters from the synapse back into the presynaptic cell that produced them, reducing the neurotransmitter’s ability to bind to adjacent cells and cause downstream effects [16]. But what happens when cocaine, a molecule that inhibits neurotransmitter reuptake, comes into play?

DOWN TO THE POWDER: COCAINE AT THE SYNAPTIC LEVEL Cocaine interferes with neurotransmission, particularly in the brain’s pleasure-inducing reward circuitry [3, 7]. Generally, dopamine reuptake transporters in the reward circuitry carry dopamine — a neurotransmitter implicated in pleasure and motivation — back into the presynaptic neuron. However, cocaine disrupts neurotransmission by inhibiting the reuptake of dopamine from the synapse [7, 17, 18]. By preventing the reuptake of dopamine, cocaine prolongs the neurotransmitter’s signaling effect [7]. Cocaine also accelerates the firing rate of dopaminergic neurons that originate at the ventral tegmental area (VTA) — a brain region that plays a role in reward processing and stress regulation — and project to the nucleus accumbens — the ‘pleasure center’ of the brain [4, 5, 19, 20]. An increase in firing rate of dopaminergic neurons induces a surge in dopamine levels within the nucleus accumbens, creating an immediate and overwhelming sense of euphoria in people who use cocaine [7, 21, 22]. When cocaine is used repeatedly, physical changes occur at the synapse between neurons, which further reinforces drug-seeking behavior in people who use the drug [7, 20, 21, 22, 23, 24]. In part, physical changes at the synapse are due to an increase in the signaling of glutamate, which is a neurotransmitter that plays an important role in learning, memory, and behavior [23, 25].

Long-term cocaine use results in abnormally high glutamate levels in various regions of the brain, including the VTA [26]. An increase in glutamate activity increases the firing rate of dopaminergic neurons in the VTA that ultimately extend into the nucleus accumbens, driving drug-seeking behavior [20, 26].

An increase in glutamate signaling also reduces the sensitivity of dopaminergic receptors in the nucleus

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COCAINE USE DISORDER accumbens through a process known as downregulation, altering reward processing [20, 27]. By reducing the sensitivity of dopamine receptors, cocaine subsequently reduces affinity to natural, non-drug related rewards [20]. Downregulation of dopamine receptors therefore serves as a central mechanism in reinforcing addiction, as downregulation compels individuals to compensate for reduced pleasure from other sources by seeking out more of the drug instead [20].

WARNING: DANGER AHEAD! Frequent and extended periods of cocaine use develop an individual’s tolerance to the drug [7]. People who chronically use cocaine require progressively larger drug doses to achieve the same desired effects, potentially driving cocaine dependence. With continued use, individuals may struggle to function without the drug and experience intensified withdrawal symptoms that worsen over time [7]. Of the two million Americans who frequently use cocaine, 1.5 million fit the diagnostic criteria for CUD, or the chronic use of cocaine despite psychological, social, or physical harm [8] For individuals who chronically use cocaine, abruptly stopping cocaine use causes intense withdrawal symptoms such as depression, anxiety, slowed thoughts and movements, as well as paranoia [8, 28]. Detrimental consequences of stopping cocaine use may lead people with CUD to continue seeking cocaine, hoping to avoid the mental and physical anguish of withdrawal [8]. As a result, one’s initial goal of obtaining pleasure becomes

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replaced with the goal of avoiding a painful withdrawal episode [8, 28]. In addition to tolerance and dependence, chronic cocaine use is associated with chemical and physical alterations to the brain and body [7, 20].

In the case of CUD, prolonged cocaine use can damage the orbitofrontal cortex — a region essential for decision-making and self-awareness [8, 9]. Damage to the orbitofrontal cortex can cloud an individual’s assessment of the consequences of drug use; more broadly, damage to this area can reduce one’s capacity for rational thinking [9]. Individuals with CUD also exhibit a decrease in white matter integrity, which is a measure of the structural health of white matter fibers [29, 30]. White matter mainly consists of nerve fibers coated with an insulating substance called myelin [29]. Myelin coating allows signals to travel quickly across neurons, facilitating rapid communication between cells [29]. Greater white matter integrity is generally associated with increased efficiency of communication in the brain [31]. People with CUD often exhibit a reduction in white matter integrity, possibly due to the way cocaine constricts blood vessels and reduces blood volume in tissues [29, 30, 32, 33, 34, 35]. For people with CUD, reduction in white matter integrity is observed in their corpus callosum, a brain region that facilitates communication between the left and right hemispheres of the brain [33, 34, 35, 36]. Disrupting communication between hemispheres of the brain is associated with a reduced ability to problem-solve and reason effectively [36].

Additionally, cognitive impairments, such as difficulties in decision-making and working memory, are observed in people with CUD who exhibit a lower white matter integrity [33, 34].

Outside of the brain, CUD causes long-term, adverse, and potentially life-threatening

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effects on the body, particularly to the cardiovascular and respiratory systems [7]. By repeatedly activating an individual’s fight-or-flight response, chronic cocaine use strains our blood vessels, significantly increasing risks of developing heart disease and circulatory damage [12]. In the respiratory system, snorting cocaine can chemically damage cells in the nose and lungs, causing bleeding, infection, and tissue death [7]. Overall, chronic cocaine use wreaks havoc on the brain and body and warrants effective methods of diagnosis and treatment [7].

TREATING THE MENTAL AND PHYSICAL EFFECTS OF CUD People suffering from CUD often face significant barriers to accessing treatment; unfortunately, many individuals with CUD never receive the help they require [8, 37]. Despite an urgent need for effective CUD care, there are currently no FDA-approved pharmacological treatments for CUD [8]. However, various psychosocial treatments have effectively been utilized in CUD treatment, and include counseling, cognitive behavioral therapy, and motivational interviewing [38]. Another psychosocial treatment called contingency management stands out as particularly effective. Contingency management involves rewarding people as they achieve treatment goals by giving them vouchers, which can then be redeemed for goods and services; these vouchers can be exchanged for incentives that may motivate people who use cocaine to abstain from drug use. Additionally, intensive outpatient therapy offers a cost-effective treatment plan that can be uniquely adapted to patient needs, and has been found to be as effective as more expensive inpatient treatments for CUD. Unfortunately, some people do not respond to aforementioned

standard addiction treatments, which is reflected in high dropout rates from studies. Promising treatment options for CUD — such as contingency management and cognitive behavioral therapy — underscore the importance of tailored interventions to address the diverse needs of individuals with CUD [38].

While there are ample psychosocial treatment options available for people with CUD, pharmacological interventions may also effectively treat the disorder [38]. Topiramate, a medication commonly prescribed for epilepsy and migraine prevention, has emerged as a promising candidate for treating CUD. Topiramate inhibits glutamate transmission, targeting an underlying neurochemical process involved in cocaine addiction. Clinical trials investigating topiramate’s effectiveness in treating CUD have yielded encouraging results: topiramate significantly reduces both cocaine use frequency and cravings in people with CUD. Moreover, many individuals treated with topiramate have reported that they were able to remain abstinent from cocaine for longer periods of time than they were previously able to. When combined with psychosocial interventions such as cognitive behavioral therapy, topiramate demonstrates increased effects, enhancing treatment outcomes. Although further research is needed to refine dosing strategies and assess long-term efficacy, topiramate offers renewed hope for recovery through integrated approaches to addiction treatment [38]. Through these novel addiction treatments, people struggling with CUD have a chance to move past their addiction.

References on page 65.

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FEATURED

WHAT’S PORN GOT TO DO WITH IT? THE ROLE OF EMPATHY IN SEXUAL VIOLENCE

by Iona Duncan/ art by Alexandra Adsit 34

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WHAT'S PORN GOT TO DO WITH IT? Disclaimer: The following article is not meant to shame or reprimand people who use, make, or produce pornography or those who have behavioral addictions, but instead to raise awareness about a topic with profound sociological implications.

‘

Rule 34’ is the colloquial internet term for the idea that ‘if it exists, there’s porn of it’ — and indeed, you will be hard-pressed to find a fictional character, famous individual, or even company mascot that hasn’t been depicted in a sexually compromising situation, providing a perfect example of the increasingly pervasive role porn has in society [1, 2, 3, 4].

Pornography and its influence on social interactions and interpersonal relationships has been a topic of psychological and neurological research for decades [5]. The rise of the Internet as the primary mode for accessing porn has further underscored these investigations, as the web provides a near-infinite library of any type of porn [5, 6]. Research has focused on heterosexual male viewers of pornography since they typically watch more porn than women [7, 8, 9]. Particular attention is paid to the potential effects of violent pornography and its relationship with empathy, as violent porn may perpetuate harmful sexual scripts where women are expected to be hesitant and coy during sex while men are expected to behave aggressively [10, 11, 12]. Violent porn can be defined as material portraying overtly non-consensual, coercive, or physically aggressive sex [13]. In contrast, non-violent porn lacks clear instances of aggression, coercion, or explicit statements of non-consent — though the implication of unequal power dynamics remains common in pornography as a whole [11, 14, 15]. Mainstream pornography tends to feature a fair amount of casual violence against women [13, 14, 16].

An estimated 45% of videos on Pornhub.com include physical aggression, (in most instances, men hitting and choking women), potentially normalizing acts of violence against women during sex without their explicit verbal consent [17]. The titles of porn videos alone also consistently feature violent themes; as many as one in eight videos suggested to first-time users on porn sites have titles describing acts of sexual violence, such as simulated rape, incest, abuse, coercion, and physical assault [11, 14].

If empathy can be thought of as the capacity to identify, understand, and relate to the emotions of others, where does it fit in with the desire to watch women be degraded and physically abused in porn [18]? Frequently viewing pornography, especially violent porn, is correlated with reduced empathy in sexual contexts, which is in turn associated with an increased

likelihood of perpetrating acts of sexual violence [19, 20, 21, 22, 23, 24]. So, does watching violent or degrading porn cause empathy deficits? Or do pre-existing empathy deficits lead to the regular consumption of violent porn? It’s difficult to establish causative effect and directionality, but the absence of a direct causal relationship doesn’t necessarily rule out the existence of any relationship between pornography and empathy [25, 26]. The very existence of violent pornography necessitates that women on camera are subjected to actual violence, which the viewer justifies by objectifying the woman and rationalizing her seemingly positive response to being subjected to aggression [12, 17, 27]. Considering the potential effects of porn consumption on empathetic processing in the brain, is there a correlation between the viewer’s desire to watch violent porn and a desire to execute sexual violence?

CAN PEOPLE BE ‘ADDICTED’ TO PORN?

“I knew [porn] was bad for me, it had a very big negative effect on my life, but I just couldn’t stop it. That’s clearly in my eyes a sign of addictive behavior.”

Transcribed from an interview with an individual diagnosed with Problematic Pornography Use (PPU) [29].

While colloquial terms like sex ‘addict’ or nymphomania are familiar, the clinical facets of hypersexuality may not be as well-known [28]. Compulsive Sexual Behavior Disorder (CSBD) is characterized by frequent, uncontrollable, and repetitive sexual behaviors, harming psychological well-being and interfering with personal and occupational functioning [28].

Some examples of sexual behaviors that can become ‘addictive’ include visiting strip clubs, masturbating, and watching pornography, all of which can be an escape from loneliness, anxiety, or depression [29, 30, 31]. These behaviors persist even when they have serious negative consequences, like marital strain or STD transmission, characterizing the compulsive aspect of CSBD [29, 32, 33]. CSBD also has an impulsive aspect: the tendency to act rashly and without foresight, which is associated with an increased occurrence of sexual fantasies, urges, and behaviors [34, 35]. Research commonly groups CSBD with

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WHAT'S PORN GOT TO DO WITH IT? ‘behavioral addictions’ like gambling disorder and food addiction, and so this term will be used hereafter [36, 37, 38]. Within the umbrella category of CSBD, frequent and uncontrollable pornography consumption is labeled as Problematic Pornography Use (PPU) [39]. PPU is characterized by the frequency of porn use and by levels of compulsivity and impulsivity comparable to symptoms of substance abuse [40, 41, 42]. In addition to behavioral similarities, ‘addictions’ like PPU also exhibit neurobiological processes similar to substance addiction, like the activation of the brain’s reward pathways responsible for motivation, reward-seeking, and reinforcement [33, 43, 34, 44, 45, 46, 47, 48, 49]. One of the molecules involved in these reward pathways, dopamine, acts as a messenger between the cells in the reward system [49].

When someone engages in rewarding behavior like using drugs or viewing pornography, neurons release dopamine and activate surrounding neurons, further propagating the signal along the reward circuit [50, 47, 32].

It’s a common misconception that dopamine is involved in the associated pleasure or ‘liking’ of a reward, but scientific understanding actually considers it to characterize the motivational component of reward learning: the ‘wanting’ of a reward [51, 52, 53]. It may seem that liking and wanting a reward are too intertwined to be separate processes — isn’t it true that we want things because we like them? The difference can be exemplified by junk food. At one point or another, everyone wants to eat chips in bed at 9 p.m., but about halfway through the bag, the classic consequences of late-night chip consumption become apparent. Even after crossing the line from feeling full to gross, getting crumbs all over the

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sheets, and not really tasting the chips themselves anymore, we continue reaching into the bag and grabbing another chip. For some reason, we still want to eat ‘just one more’ chip, even though we don’t actually like eating them anymore. In this sense, we can distinguish liking and wanting something — whether it’s chips or pornography — as two distinct processes [51, 52, 53]. In people without addiction, the liking and wanting processes are typically proportionate, but in individuals with CSBD or substance use disorder, the disparity between liking and wanting is felt more intensely because they experience significantly different dopamine activity in response to rewarding experiences [54, 55, 56].

Despite their addictive patterns of increased reward anticipation, individuals with PPU experience decreased enjoyment of sexual stimuli over time [57, 58, 44]. When anticipating the sexually rewarding experience of viewing an erotic picture, men with PPU want to see the image more than their non-addicted peers, showing higher corresponding activation of brain areas involved in the dopamine reward pathway [57, 58]. However, upon seeing the sexual photograph, men with PPU do not actually show higher rates of enjoyment than men without PPU [57, 58, 59]. The additional dopamine release during anticipation distorts how pleasurable the reward itself will be; people with addictions end up chasing an unachievable high, leading to a desire for new and different types of rewards after they find that their preferred type is no longer meeting expectations [55, 60, 61, 62, 63].

One man with PPU recounted watching increasingly extreme and violent pornography categories as his addiction progressed, explaining that “…you’re just, like, stimulating yourself with so much intense material your brain takes more and more hardcore material in order to get off” [29]. This pattern of escalating pornographic content is not only confined to individuals with PPU [64]. The changing course of porn consumption can also be seen in a sample of college students without PPU, 46% of whom reported switching to a new genre of porn after consistent porn use, and 32% of whom reported requiring more violent material to achieve sexual gratification [64]. Indeed, exposure to any unfamiliar stimuli is generally associated with a high level of dopamine release in the reward pathway in individuals with and without PPU alike [65, 66, 67].

However, men that excessively use pornography as an escape from negative emotions — as is seen in PPU — show a higher preference for novel porn than their non-addicted counterparts [62]. For example, repeated exposure to the same pornographic material leads to a significantly lower sexual interest in individuals

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WHAT'S PORN GOT TO DO WITH IT? the recurrent stimulus is dampened [61]. Unable to achieve the high they anticipated, individuals with PPU may chase more shocking or taboo material, even turning to content with high levels of violence, despite the guilt and disgust associated with using such content for sexual gratification [29].

CAN YOU HAVE EMPATHY FOR AN OBJECT? THE ROLE OF EMPATHY IN SEXUALIZATION

“Yeah, I started to prefer a woman’s physique more than who she really was.”

Transcribed from an interview with an individual diagnosed with Problematic Pornography Use (PPU) [29].

How does PPU impact individuals in real sexual contexts? Like most people with PPU, individuals who frequently watch porn tend to objectify others [68, 69, 27, 20, 19]. Furthermore, people who frequently watch porn tend to engage in pornography-like sexual behavior; both men and women who watch more porn report having engaged in the degrading or aggressive acts seen in pornography more often [70, 71].

Generally, enjoying sex is positively correlated with the empathy levels of a sexual partner, presumably because empathetic individuals are more responsive to a partner’s needs and desires [72, 73]. In sexual contexts, lower measures of empathy are associated with a higher likelihood of perpetuating sexual assault, demonstrating the critical importance of empathy for healthy and positive sexual relationships [22, 74].

Consequently, an individual with higher oxytocin levels is more willing to help a stranger in need, possibly due to oxytocin enhancing empathetic processes, like taking the emotional perspective of another person [80, 82].

Emotional perspective taking, or the ability to emotionally ‘put yourself in another person’s shoes,’ is one of the several distinct processes that make up empathy [83]. However, when individuals direct empathy-related processes toward sexualized women, empathy appears to be both neurologically and behaviorally suppressed [21, 84, 25]. A sexually objectified person is viewed as lacking mental and emotional experiences, so is then evaluated solely on their appearance and sexual role [27, 85, 21, 25]. Once objectified, a person is no longer a person but rather an instrument or tool for another’s use and consumption [85, 25, 86]. Since watching porn is associated with higher levels of objectification, empathy via emotional perspective-taking may be hindered as you can’t take the emotional perspective of an object [87, 19, 20, 27]. Taking the emotional perspective of others during sex is a critical component of empathy because it can facilitate concern, potentially counteracting pre-existing attitudes and behaviors associated with sexual violence and consequently influencing how much people tend to harm others in sexual contexts [88, 89, 74].

Empathy is considered to be the ability to understand and relate one’s feelings, needs, and desires to those of another person, processes that are thought to rely on hormones like oxytocin and vasopressin [18, 25].

Vasopressin and oxytocin’s regulation of empathy are integrated together in the brain pathways associated with social engagement, indicating that these hormones work together to shape social behavior in different contexts [75, 76]. Vasopressin and oxytocin typically play dichotomous roles in social behavior: while vasopressin is involved in interactions related to fear and aggression, oxytocin is considered a ‘social bonding hormone,’ as it’s thought to be involved in social interactions and sexual desire [77, 75, 78, 79]. When people are administered oxytocin, they perceive victims of criminal offenses to have experienced more harm compared to people not administered oxytocin [80, 81]. An increase in oxytocin is therefore thought to facilitate important feelings of sympathy, compassion, and concern for others [28].

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WHAT'S PORN GOT TO DO WITH IT? In a similar vein to emotional perspective-taking, another critical empathetic process is vicarious pain, or pain empathy [90]. The sensory pathway in the brain called the ‘pain matrix’ is activated not only when an individual feels pain first-hand but also when they witness another person in pain, suggesting that vicarious pain may rely on a simulation of how others feel, grounded in personal experience [91, 92, 93, 90].

However, even individuals with typical levels of empathy seem to be impaired in feeling vicarious pain for sexualized women [84]. Regardless of their individual empathy levels, people tend to believe that sexualized women feel less pain than nonsexualized women, even when both women are exposed to the same painful stimulus, showing that empathy is directly related to how much the other person is sexualized [84]. In porn, the individuals on-screen are defined almost entirely by their appearance and the sexual services they can provide to each other and, subsequently, the viewer; they become objects for the viewer’s sexual gratification [69]. Thus, pornography use and the resulting increased levels of objectification are associated with the denial of others’ mental and sensory experiences [68, 20, 84]. The denial of internal states essentially prevents empathy via emotional perspective-taking and vicarious pain, leading to the decreased empathy for sexualized women [68, 69, 20, 27, 85, 21, 84].

IS EMPATHY LOWER IN FREQUENT PORN VIEWERS? It remains unknown whether low empathy or frequent porn use presents first. What is known is that the two factors are linked in a detrimental relationship, such that higher porn use is correlated with lower empathy, depending on the content and frequency of the pornography watched [69, 94, 20]. When exposed to videos of degrading pornography, men tend to objectify the woman in the clip more and generate stronger hostile sexist beliefs toward her, both of which are correlated with low empathy [94, 95]. Additionally, people who often consume porn and other objectifying media are more likely to generally objectify women, exhibit attitudes supporting violence against women, and show less empathy towards victims of sexual assault [19, 20]. Specifically, men who frequently watch porn exhibit a clear association between porn, objectification, and low empathy in their cognitive processing and behavior [19, 20, 29, 63, 64, 69, 94, 95]. But does this unempathetic behavior also correlate with neurological measures of empathy? As expected, oxytocin and vasopressin hormones appear dysregulated in men with PPU [25]. As previously

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discussed, oxytocin levels are correlated with empathy, such that higher oxytocin is associated with higher empathy [82]. Vasopressin levels, implicated in aggressive behavior and lower measures of empathy, appear to be abnormally high in men with PPU, much higher than their oxytocin levels [25]. An imbalanced ratio of vasopressin dominating over oxytocin is associated with increased stress and social hostility [25, 96]. Since both neurological and behavioral measures of empathy are reduced in men with PPU, does this mean that these individuals are more likely to perpetrate sexual aggression [25]?

HOW DOES WATCHING VIOLENT PORN RELATE TO THE PERPETRATION OF SEXUAL VIOLENCE?

“I think [porn] changed my mindset. Put me in a more deviant mindset. I mean it could be easier to reoffend. Because of the degradation of women. Calling them names, slapping them, objectifying.”

Transcribed from an interview with an individual convicted of a sexual offense [112].

Considering the association between porn use, reduced empathy and, consequently, sexual aggression, does frequently watching porn increase the likelihood of committing acts of sexual violence [19, 20, 25]?

Unfortunately, there is no simple yes or no answer to this question; instead, there are many caveats. Several factors contribute to the relationship between frequent porn use and sexual aggression, including the type of pornographic content viewed, someone’s age at their first exposure to porn, their perception of porn as realistic, and especially their empathetic traits [24, 26, 97, 98, 99]. While there is evidence for a general association between pornography consumption and increased sexually aggressive behavior, the consumption of violent porn seems to enhance this association [97, 100, 101, 102]. The objectification and subsequent dehumanization of women are strongly associated with committing acts of sexual violence, such as sexual assault via intoxication, coercion, and threat of physical force [20, 22].

Given the prevalence of sexual aggression in internet porn and the young age at which people are typically first exposed to porn — 13 and 15 years old for boys and girls, respectively — access to the internet could have a significant psychological impact during critical periods of development, shaping sexual preferences [15, 29, 103, 104, 105, 106]. One facet of early

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WHAT'S PORN GOT TO DO WITH IT? exposure to violent porn can be seen in teen dating violence — adolescent boys who have seen violent pornography are two to three times more likely to report having been physically violent during sex compared to their peers [100]. This association could be linked to adolescents’ porn-driven expectations that real-life sexual interactions should mirror what they see in pornography [15, 107]. The adolescent belief that porn is authentic is especially significant given that men who perceive pornography as realistic have an increased risk of pressuring another person into having sex, even after an explicit declaration of

nonconsent — likely due to the harmful sexual scripts perpetuated by mainstream porn [98]. There is also the possibility that the age of first exposure to porn is associated with a higher incidence of sexist attitudes, such as the desire to have power over women, which may translate to harmful sexual behavior [15, 108].

Additionally, when sex offenders are first exposed to porn at a younger age, they inflict more severe physical injury on their victims [105, 109, 110, 111]. Overall, the pornographic content consumed by sex offenders often reflects the real-world crimes that they commit [15, 26, 101, 110, 112].

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WHAT'S PORN GOT TO DO WITH IT? Generally, it appears that pornography reinforces men’s tendency to be sexually aggressive toward female sexual partners, especially if men already lack empathetic traits [24, 25, 113, 114, 115, 116]. Men who exhibit animosity and low empathy toward women are thought to be high in ‘hostile masculinity,’ a mindset composed of concepts like sexual dominance and acceptance of using interpersonal violence to gain compliance within relationships [117, 118]. For instance, men who have inappropriate emotional responses — like feeling pleasure at another’s pain — have difficulty empathizing with sexual partners during sexual interactions and are significantly more likely to use aggressive strategies like lying, coercion, manipulation, and physical force to pressure someone into having sex with them [22, 23]. Men high in hostile masculinity are thought to be more likely to enact sexual violence due to their insecurity and defensiveness, which manifest in higher levels of anger and resentment toward women and a propensity to seek sexual gratification by exerting power and control over women [115, 119]. These attitudes are reflected in a higher frequency of porn consumption and the pornographic content consumed — men high in hostile masculinity are more likely to watch extreme, violent, and male-dominant porn which includes content featuring rape depictions, child pornography and sex with animals — indicating that men at high risk of sexual aggression typically consume more violent and degrading porn than low-risk men [24, 115, 116, 120]. Hostile masculinity in itself predicts a higher likelihood of perpetuating sexual aggression, but when paired with the consumption of violent porn, these characteristics are associated with a significantly increased frequency of recent physical sexual aggression [14, 113, 114, 117]. One focus of sexual assault prevention programs is to identify the men and boys at high risk for perpetrating sexual assault by assessing their pornography use [113, 121, 117].

Again, this is not to say that the act of watching porn in itself increases the likelihood of committing sexual violence, but rather that we should approach sexually explicit media with a critical lens [112]. Media literacy education focusing on improving critical thinking skills surrounding sexual health topics, such as sexual violence and unrealistic expectations about sex, has shown to be much more effective in remedying harmful sexual attitudes than shaming or demonizing the consumption of porn [112, 124, 125]. Improved empathetic processing, awareness, and self-reflection may be the most powerful tools in our arsenal for combating sexual violence and the negative impacts of porn consumption [22, 112, 124, 125, 126].

References on page 67.

CONCLUSION The objectifying attitudes and subsequent empathy deficits associated with frequent porn use bear significant real-world consequences on people’s likelihood to enact sexual violence, the nature of supportive services offered to sexual assault victims, and the legal ramifications for their assaulters [20, 21, 22, 27, 68, 74, 84, 85, 122, 123]. Though a direct causative link between porn and empathy — and subsequently between porn and sexual violence — has not been proven, it is clear that pornography plays a significant part in the sexual fantasies, attitudes, and behavior of those who watch it [19, 20, 25, 26].

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YEARNING FOR YESTERDAY: THE MECHANISMS AND APPLICATIONS OF NOSTALGIA

by Niah Dang/ art by Sneha Das THE ENDURING MAGIC OF MEMORIES

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emember that perfect summer day, when the sun warmed your skin and the wind rustled through your hair? Envision your childhood best friend, the person you grew up with who is a part of your fondest memories. Recall those early days spent laughing so hard your stomach hurt on the elementary school playground and, much later, crying on their shoulder after losing your first love. Memories can elicit this feeling of nostalgia, which is often categorized as wistful affection and sentimental yearning for the past [1]. Nostalgia can evoke both positive and negative emotions; remembering can induce a wave of happiness that is quickly followed by a bittersweet or melancholic longing [2]. Nostalgia is generally prompted by meaningful memories, past close relationships, and childhood experiences, with sensory stimuli being a common trigger [3]. For some, the smell of freshly cut grass may bring back memories of playing outside on their childhood home’s front lawn, promoting a yearning for the past [4]. For others, it’s the taste of their grandmother’s golden pie that ‘tastes like home’ [5]. Whether nostalgia is prompted by past social ties, smells, tastes, music, or nature, most of us are familiar with its ambivalent experience [1].

UNLOCKING THE MEMORY VAULT: THE INTRICACIES OF SEMANTIC AND EPISODIC MEMORIES Before examining what makes a memory nostalgic, let’s consider how our ‘normal’ memories function.

The memory of general concepts — usually separated from personal experience — is known as semantic memory [6]. Think of semantic memory as an

encyclopedia of knowledge or facts [7]. These are things you learned in school, such as the days of the week [6]. On the other hand, episodic memories are attached to personal experiences that occurred at a specific time and place [7]. How did you spend your childhood birthdays? What’s the happiest memory you have of the past year? Maybe you have a vivid

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YEARNING FOR YESTERDAY memory of the cotton candy machine at your fifth birthday party or when you went on a big trip to the waterpark with your entire family. Such memories are a recollection of personal experiences through an autobiographical lens [7]. When semantic or episodic memories are encoded in the brain, they form a physical unit called an engram [8]. During engram formation, your brain takes in information about a situation — sights, sounds, smells, tastes, emotions, and language — and assigns value to whatever you perceive or pay attention to [9]. Your brain then weaves together all the neural activity occurring at this time to form a pattern of associated connections, also known as a neural circuit, and stores it as an engram [10].

Notably, the more important or personally significant the information from the situation is, the stronger the engram will be and the easier the memory will be to recall as a result [11]. Later — whether that be the next day or years down the line — when a familiar stimulus reactivates the engram, an electrical signal is produced by the neurons that compose the engram, allowing you to recall stored information [8].

Engrams allow short-term memories to be encoded into stable long-term memories that you retain far in the future [9].

Although engrams represent both semantic and episodic memories in the brain, remembering your amazing algebra teacher is quite different from remembering the Pythagorean theorem. Because of the personal significance of episodic memories, they are easier to recall than general knowledge, such as facts and theorems [12]. Different brain structures are responsible for the processing of different types of memories: the hippocampus mediates the storage of episodic memories, while the neocortex manages the storage of semantic memories [13]. When it comes to memory storage, the hippocampus is comparable to a filing cabinet, which stores and organizes individual experiences in memory [14]. In fact, the hippocampus plays a key role in encoding the patterns of neural firing that occur as memories are formed, distributing and integrating information throughout the network of neurons that are involved in the recollection of that experience [7]. When the hippocampus encodes episodic memories, it stores the details of personal experiences [15]. On the other hand, the neocortex can be thought of as a textbook and is involved in processes such as cognition, language, and consciousness [16]. The neocortex is useful in gathering representations of structured knowledge, such as the rules of a game [15]. But how do we go about daunting tasks like studying for a test or trying to memorize large amounts of information? Most of us

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know that repetition is key in encoding and storing large amounts of information: reading something once probably won’t result in a comprehensiveunderstanding of the material [17]. We need repetition because the neocortex is known to be a ‘slow learner,’ where many encodings of the same information are necessary to achieve long-term storage, substantiating its role in semantic memory [17]. In essence, the intricate roles of the hippocampus and the neocortex underscore the dynamic nature of memory formation and storage in the human brain.

A MENTAL PHOTO ALBUM: NOSTALGIC MEMORIES IN THE BRAIN The aforementioned processes are how all memories are encoded: semantic, episodic, and nostalgic [8].

Though a nostalgic memory has many of the same characteristics as an episodic memory — since it too originates from personal experiences and carries an emotional component — nostalgic memories can be thought of as a unique form of episodic memory [1].

Consider a memory that is solely episodic, such as a typical day sitting through your boring class lecture. There isn’t a huge emotional component to this memory; however, that could change. Imagine that years down the line, you begin to reminisce about your formative college years. You feel nostalgic for the crazy adventures with your friends in addition to the mundane days spent in class daydreaming about the future. Your once largely episodic memory has now morphed to include a nostalgic component. Interestingly, this may have to do with the time period in which the memory takes place, as memories from adolescence and early adulthood are more strongly encoded and prone to becoming nostalgic [18]. Nostalgic memories uniquely draw a co-occurrence of positive and negative emotions when the memories are recalled, often with more positive than negative feelings — a complex mix of emotions not elicited by episodic memories [19, 20]. Nostalgia includes feelings of happiness and pleasure, but more importantly, involves a melancholy component of longing for a time that has since passed [19, 20, 21]. Furthermore, nostalgia comprises more than just a general recall of the details of important life events; it also involves ‘mental time travel,’ where detailed imagery associated with the event is recalled as if you are re-experiencing the event for the first time again [21, 22]. Imagine walking past the park where you used to watch the sunset every night of the summer with your best friend. You spot the rock you used to sit on, the fond location of many deep conversations, and begin to reminisce about your youth. Through a

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YEARNING FOR YESTERDAY process called pattern completion, the sight of the place where you spent so much of your childhood reactivates the same pattern of neural activity that was triggered when the memory was first encoded [15].

In that moment, you experience a brief escape from reality in which you return to the joy experienced in the past. The hippocampal circuits that were created when the memory was first formed are reactivated alongside the ventral striatum. The ventral striatum is a brain structure responsible for releasing dopamine, a molecule that is highly involved in the body’s reward system [23, 24]. The memory-reward system is dependent on the hippocampus and ventral striatum being largely intertwined [23]. When nostalgic stimuli engage the ventral striatum, dopamine is released, strengthening the relevance and significance of these memories and making them more accessible in the future [19]. The hippocampal connections with the ventral striatum are thought to aid in the recall of these memories, forming an intricate network that contributes to nostalgia’s uniqueness [19].

Interestingly, the co-activation of the hippocampus and ventral striatum can explain why the experience of nostalgia often includes viewing past experiences through ‘rose-colored glasses’ [25]. When thinking of certain cherished memories, the negative aspects of the event can be overshadowed by the positive aspects, which contribute to the overall positive experience of nostalgia [25]. Each time you recall a nostalgic memory, dopamine reinforces the memory and the positive emotion associated with it, making it easier to recall in the future and inducing an increasingly rewarding feeling as the nostalgic memory is further re-encoded and re-stored [19]. Nostalgia stems from

this recalling, where the engram, as well as the emotion and reward centers that are associated with the memory, are activated [10]. However, with these rewarding feelings and memories, a yearning for that specific time period follows [21]. Essentially, the positive feelings stemming from mental time travel are accompanied by the sadness or wistfulness due to the realization that things have since changed [26].

Interestingly, nostalgic emotions are experienced in an an ‘ebb and flow’ style, where neither the positive nor the negative feeling is gone, but rather one feeling is emphasized at a time [26]. For instance, when you’re back at the rock watching the sunset, you are reminded of your best friend who is no longer a part of your life and reminisce about memories the two of you once shared. For a moment, your happiness becomes overshadowed by longing for the past, before returning once again.

HOW THE PAST FUELS THE FUTURE: THE MOTIVATIONAL POWER OF NOSTALGIA The unique characteristics of nostalgia allow sentimental memories to benefit our everyday lives [27].

For instance, nostalgia can be a remarkable source of motivation [27, 28, 29]. Nostalgia has the ability to enhance our self-perceived meaning of life and solidify our intentions to pursue our most important goals [27]. Meaning in life is necessary for well-being and adaptability [30]. In fact, nostalgia therapy, which includes 45 to 60-minute weekly meetings, during which patients are instructed to think about memories that foster nostalgia, has been shown to improve the quality of life for elderly people living with

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YEARNING FOR YESTERDAY depression, suggesting that nostalgia leads people to feelings of emotional safety and a higher appreciation for life [31]. Nostalgic narratives may include reflecting on important personal memories that include family and friends, and this act of remember ing helps increase feelings of social connectedness [30]. Strengthening social ties further contributes to greater fulfillment in life and helps us assign priority on what is most important to us [32]. Individuals are shown to be more successful when focusing mental resources towards a singular goal [27]. Nostalgia helps to set personal priorities, which in turn motivates attributes such as optimism, creativity, and the pursuit of one’s goals [27]. Nostalgia can also increase perseverance by placing significance upon past memories and reinforcing one’s identity and reasons for working towards their aims [33]. Lastly, ‘anticipatory nostalgia,’ where one predicts the future experience of feeling nostalgic following an event that has not yet occurred, acts as a motivating factor for new experiences [34]. Consider traveling: you might look forward to seeing beautiful sites — like the view from the mountaintop you saw online — and the nostalgic feeling of longing you will feel after you have returned back to your everyday routine [35]. Though you have not yet partaken in your journey, anticipatory nostalgia can push you to book a flight and visit that new vacation spot [35]. The multifaceted influence of nostalgia on life’s meaning, reinforcement of identity, and anticipatory emotions underscores its role as a motivational force, shaping our pursuit of significant goals and inspiring action.

FRIENDSHIP’S NOSTALGIC ECHO: REVIVING BONDS AND FOSTERING CONNECTIONS Think about how many of your friendships have changed throughout your life. Inevitably, some of your close friends faded away as life got busy, or perhaps you had an unfortunate falling-out. Nonetheless, do you remember how they listened to your problems and gave their best advice? Whether you stay in touch or not, it’s easy to reminisce on the time spent together, and doing so can function as a way to sustain the camaraderie that is lost alongside the deterioration of that friendship [1]. When friendships break apart, those involved may attempt to repair the relationship [1]. However, when rekindling the relationship is not possible, individuals can rely on nostalgic memories of the relationship to still feel socially connected to that person [34]. In fact, nostalgia can actually be triggered by a psychological threat — such as feelings of loneliness — and acts as a buffer against unpleasant emotions [31]. Through conjuring a feeling of

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relationships from their past, nostalgic narratives can act as a unique resource to those feeling unstable in their relationships [31]. Additionally, nostalgic memories may bring to mind past examples of relationship stability and trust, motivating conflict resolution in moments of strife with our close friends and family [38]. However, nostalgia does not only aid in relationship repair; it also motivates maintenance of sustained relationships to create more positive experiences than we have had in the past [36]. When reflecting on nostalgic experiences that are shared with other members of a group, members are more strongly bonded with each other through companionship [39].

Nostalgia can even motivate positive intentions and behaviors toward others, ranging from providing emotional support to performing charitable actions [40].

After experiencing nostalgia for past relationships, people demonstrate a larger desire to foster connections with others, such as via making new friends, repairing broken friendships, or strengthening

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current relationships [36]. Additionally, nostalgia amplifies the optimism one holds for forming interpersonal relationships and inspires confidence in one’s social skills [38]. By returning to a version of one’s idealized past, perceptions of one’s self-esteem and self-conception are improved [1]. Lastly, the brain often treats past experiences as predictive of what can be expected in the future. Recalling close relationships from the past through a positive nostalgic lens leads to optimistic predictions for future relationships [1]. Perhaps the next time you experience a fading friendship, instead of parting ways, take a moment to consider your shared history. As feelings come rushing back to you, nostalgia may drive your desire to reach out and rekindle past connections.

Nostalgia can serve as a comforting refuge and reminder of the past, grasping memories and weaving them into the future. Through a unique lens, we can reconnect with the cherished moments and people of our past, reliving memories with a bittersweet fondness that continues to impact our present and future experiences. In fact, the next time you see a sunset that reminds you of the many you once watched with your best friend, pull out your phone to give them a call and reminisce together about the good old days.

References on page 74.

LOOKING AHEAD BY LOOKING BACK Nostalgia has a checkered history — it was once regarded as an emotion of great melancholy and sadness, and is now frequently perceived to be a positive emotion, one so instinctual that most of us experience it in our everyday lives [41]. When considering who has impacted your life, nostalgia can emphasize the importance of these relationships as well as your personal ambitions. Continued research in nostalgia has reframed how we perceive it as an emotion; nostalgia is often recognized as a motivating force and a way to reexamine social relationships.

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IMMUNE WARS: THE PAST, PRESENT, AND FUTURE OF MULTIPLE SCLEROSIS RESEARCH

by Daniel Wunschel/ art by Abigail Schoenecker diagrams by Jane Stempien

EPISODE I: THE PHANTOM DISORDER

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or most, hopping out of bed and brushing your teeth are tasks done with ease. Once you decide to get up, your muscles spring into action and you find yourself standing in no time. In the bathroom, you quickly squeeze toothpaste on your brush and get to cleaning your teeth. Now imagine yourself back in bed: despite your best efforts, your muscles can not enact what your brain asks them to do. Once you finally make it to the bathroom, your shaking hands struggle to remove the cap and squeeze the tube before the paste misses the brush and falls into the sink. No matter how hard you try, the movements of your muscles never match what your brain is dictating. For people living with multiple sclerosis (MS), daily tasks — such as getting out of bed and brushing your teeth — can become overwhelmingly difficult. Multiple sclerosis is the most common neurological disease in people of ages 20 to 40, and the disease typically presents through muscle weakness, visual impairment, and a loss of coordination and control over bodily movements [1, 2]. MS can vary over a person’s lifetime, causing those affected to experience phases of relapse and recovery [1].

While we know how MS manifests, the disorder remains a neurological puzzle with many missing pieces [3]. Many of these missing pieces rely on understanding the biology behind the cause of the disease and its progression [3]. Although the specific cause of MS is unknown, some associated factors have been identified, including low levels of vitamin D, tobacco smoking, and certain viruses [2, 4, 5]. Of these potential causes, the Epstein-Barr virus (EBV) has drawn significant interest amongst researchers [6, 7]. EBV is the most common cause of mononucleosis — commonly known as ‘mono’ — and is associated with a 32-fold increased risk of developing MS [6, 7]. While nearly everyone with MS is infected

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IMMUNE WARS with EBV, there are many more individuals infected with EBV that do not develop MS, creating a cloud of uncertainty surrounding the relationship between EBV and MS [7]. Nonetheless, belief in the connection between EBV and MS has guided research for decades [8, 9].

EPISODE II: ATTACK OF THE T-CELLS Despite the uncertainty surrounding the causes of MS, we know MS is an autoimmune disease in which the immune system attacks its own body’s tissues [10, 11, 12]. Normally, the immune system targets disease-causing bacteria or viruses called pathogens, but a malfunctioning immune system may also mistakenly attack healthy cells or tissues like myelin [13, 14, 15]. Dysfunctional immune activation sometimes causes immune cells to migrate into the brain and inadvertently target oligodendrocytes — cells that produce insulation called myelin — as well as myelin itself [14, 16]. Myelin is a fat and protein-rich insulation that wraps around the axons of neurons in the brain, forming a layer called the myelin sheath [17, 18]. Like the coating on electrical wires protecting the transmission of electric current, myelin helps to transmit signals between neurons [17, 19]. The loss of myelin, called demyelination, is followed by axon degradation, which diminishes the ability of neurons to transmit crucial signals [17]. In addition, the destruction of oligodendrocytes reduces the brain’s ability to produce new insulation [17]. While the cause of the initial immune response in MS which damages oligodendrocytes and myelin is unknown, demyelination is believed to be perpetuated by the dysfunctional activation of the immune system, leading to neuroinflammation [20, 21].

Neuroinflammation is the activation of the brain’s immune system in response to infection or injuries [22]. In MS, neuroinflammation becomes harmful to the body when T-cells — a type of immune cell that normally kills infected cells — go into overdrive and attack healthy tissue [23, 24, 25].

In conjunction with neuroinflammation, immune attacks on oligodendrocytes and myelin result in the formation of lesions, or localized damage to the brain or spinal cord [26, 27]. Depending on the site and severity of lesions, people with MS experience different symptoms [1]. Lesions along the optic nerve cause visual impairment, a common symptom of early-stage MS. [1, 17, 28]. Lesions on muscle-stimulating nerve fibers may cause difficulty walking by preventing muscles from receiving signals from the central nervous system, leading to reduced control over body movements [29, 30, 31].

EPISODE III: REVENGE OF THE STATISTICS Research into EBV as a potential causal factor of MS stems from a seemingly monumental statistic: almost everyone diagnosed with MS tests positive for EBV [1, 7, 32]. The overlap in EBV and MS has fueled research into the potential causal link between MS and EBV, in which EBV possibly triggers the dysfunctional immune response and associated neuroinflammation in MS [33, 34]. Active EBV infections are thought to be characterized by an increase in the number and

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IMMUNE WARS reactivity of EBV-attacking T-cells, which contributes to neuroinflammation [33, 35]. Another way EBV may trigger neuroinflammation is by mimicking myelin proteins, which hold together the layers of myelin sheaths [34, 36, 37]. When EBV infects the body, the immune system responds by sending T-cells to attack foreign pathogens [34, 36]. When attempting to kill EBV, the virus’s structural resemblance to myelin may cause the immune system to attack myelin proteins instead, leading to further neuroinflammation [6, 34, 38]. Additionally, the risk of MS increases with the degree of EBV infection, suggesting a connection between severity of EBV and MS symptoms [34, 35, 39].

Despite a multitude of discoveries suggesting an EBVMS connection, we cannot conclude that EBV alone causes the development of the autoimmune disorder [6, 33, 40]. As is the case with many other viruses, EBV may remain in the body in a latent state even after an infected individual has recovered from their initial symptoms [41, 42]. Since nearly everyone with MS has EBV, one might think that EBV causes MS, however, this connection has not been established [44, 45].

People who are diagnosed with MS also test positive for hundreds of other viruses, suggesting that viral presence in individuals with MS is not unique to EBV [46]. Many people with MS present with general autoimmune dysfunction and receive autoimmune diagnoses outside of MS [47, 48, 49]. For example, a number of people who test positive for MS and EBV are also diagnosed with inflammatory bowel disease — an autoimmune disorder affecting the digestive tract — or Hashimoto’s disease — an autoimmune disease that affects the thyroid [50, 51, 52].

While EBV is not a definitive cause of MS, research into EBV’s connection to MS has helped expand our understanding of the role of neuroinflammation in people living with MS [6, 34].

EPISODE IV: A NEUROLOGICAL HOPE While the connections between EBV and MS are unclear, investigations continue to explore the relationship between the immune and nervous

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systems, primarily focusing on the role of neuroinflammation in the immune system’s response [8, 53, 54]. By improving our understanding of the connection between MS and neuroimmunology — the combined study of neuroscience and the immune system — personalized treatments can be built for people living with MS [55]. In order to improve the efficacy of MS treatments and construct individualized treatment plans, it’s crucial to map gene activity and examine what proteins are implicated in the development of MS [56, 57, 58]. Mapping genes and proteins involved in MS can reveal characteristics unique to each person living with the disease and be used to develop individualized drug therapy treatments [59, 60, 61, 62].

One leading MS treatment strategy involves modifying genes involved in the immune response of people with MS, in order to dampen autoimmune effects experienced by people living with the disease [62].

Novel techniques, such as RNA sequencing, provide a detailed picture of the biological processes altered

by MS, allowing us to further understand the contributing factors to disease development by locating and targeting related genes and proteins in treatment [63, 64, 65].

In recent years, additional treatment methods for MS that directly target components of neuroinflammation have improved the quality of life for people with the disease [9, 66]. Novel methods include disease-modifying treatments (DMTs), which reduce the immune response in the brain and aim to limit demyelination and disease progression as a whole [67].

Currently, 20 DMTs are approved for MS in the United States, each one targeting a different component of the overactive immune system [42, 68]. For example, one type of DMT, Fingolimod, reduces the ability of immune cells to engage with the CNS by preventing the circulation of lymphocytes: immune cells made in bone marrow, including T-cells [68, 69, 70]. Fingolimod is also suspected to lessen attacks on myelin, which in turn decreases neuroinflammation by reducing the amount of inflammation-promoting molecules [42, 68, 71].

In clinical trials, Fingolimod has successfully reduced relapse rates and significantly decreased disability progression, lesion activity, and brain volume loss in people with MS [72].

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IMMUNE WARS In addition to DMTs, medications that encourage remyelination — the process of forming new myelin sheaths around axons — are promising [73, 74, 75].

Some of these medications enhance the differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes [76]. One way medications do this is by altering the local environment to become more hospitable to OPCs created within the brain [76].

OPCs are prevalent in MS lesions, but the microenvironments of lesions prevent OPCs from becoming oligodendrocytes [42, 77]. Medications that encourage the transformation of OPCs into oligodendrocytes aid in the formation of new myelin, which prevents axon degradation and improves MS symptoms [76, 78]. Two FDA-approved drugs that have improved remyelination are miconazole and clobetasol [79]. Miconazole, an antifungal medication, encourages the development of oligodendrocytes by promoting OPC differentiation into oligodendrocytes, aiding remyelination without causing damage to the immune system [79, 80]. Clobetasol, a widely-used eczema medication, is an immunosuppressant that also helps with remyelination. [79, 80]. Clobetasol increases the differentiation of oligodendrocytes in lesions and promotes the signaling of anti-inflammatory molecules, reducing inflammation and promoting remyelination [81].

Drugs with both similar and different mechanisms of action are being developed today [82].

EPISODE V: THE CLINICAL TRIALS STRIKE BACK While it may seem that time spent looking into a connection between EBV and MS was wasted due to no definitive links between the virus and the disease being uncovered, the treatments of today and tomorrow are founded on information uncovered due to this research [9, 55, 56]. Neuroinflammation in MS may not originate from EBV, but EBV is still thought to play an important role in the disease [7, 8, 9]. As we continue to search for the missing pieces of the MS puzzle, several ongoing clinical trials that focus on neuroinflammatory correlates of MS hold promise [82].

Clinical trials that target dysfunction in myelination and immune suppression may improve the quality of life for people with MS. Over the next few years, several clinical trials are expected to reach completion, adding to the arsenal of treatments against MS [82]. By aiming to slow down disease progression and improve shortcomings of current treatments, clinical trials can make common tasks like brushing your teeth and getting out of bed more achievable for people with multiple sclerosis.

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FEATURED

TO FEAR OR NOT TO FEAR: EXPLORING FEAR THROUGH THE LENS OF URBACH-WIETHE DISEASE

by Kristen Carroll/ art by Sarah McDonald diagrams by Jane Stempien

Y

ou’re standing in line for a haunted house. As you inch closer to the entrance, anticipation builds and you shudder. Upon reaching the entrance, you try to convince yourself that there’s nothing to fear.

After all, if haunted houses were truly scary, wouldn’t people not find them fun? With that thought, you have reassured yourself enough to make it to the front of the line. Once it’s finally your turn to enter the house of horror, your body tenses. Glaring strobe

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lights force you to squint, and blasting fog machines further cloud your vision. As you swat off cobwebs from your clothing, a shadowed figure starts creeping towards you. Your breathing quickens and your heart begins to pound. Suddenly, an actor in a Ghostface mask jumps out from behind you. You scream and run, wishing you had never entered the house in the first place.

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TO FEAR OR NOT TO FEAR This hypothetical haunted house experience demonstrates the mechanisms and processing of fear. In the haunted house, the appearance of fearful stimuli, like Ghostface, led you to experience physiological changes that caused the well-known ‘fight-or-flight’ response. Ghostface triggered a hormone-release cascade that induced physiological changes typical of fear, such as increased heart rate and rapid breathing [1, 2]. Seeing Ghostface also induced cognitive recognition of fear, meaning that alongside sweaty palms and fast heart rate, you also became aware that you were experiencing fear [3]. While feeling fear may seem like a universal aspect of the human experience, there are, in fact, people who do not experience fear [4]. These individuals have a rare genetic disorder called Urbach-Wiethe Disease (UWD), which can inhibit the ‘fight-or-flight’ fear response [4, 5]. A woman diagnosed with UWD, known as S.M., has been a topic of interest for researchers due to her unusual reactions to typically fearful stimuli [6, 7, 8, 9]. To assess the physiological and behavioral components of fear, S.M. was observed in an experiment where she wandered through a haunted house with what was considered “scary” conditions [8]. Walking through the house, S.M. did not experience physiological changes, such as increased heart rate and rapid breathing, and did not cognitively interpret the house’s stimuli as frightening [8, 9]. This extremely rare disorder is fascinating but can put someone — such as S.M. — into dangerous and avoidable situations [6, 8]. In addition to being a nuanced topic in its own right, UWD and related research can teach us more about the physiological and cognitive responses involving fear [5, 6, 7, 9].

PANIC! IN THE LIMBIC SYSTEM In order to defend the body against potentially harmful stimuli, the limbic system regulates emotional responses that are essential for survival [10].

The key players of the limbic system include the amygdala, the hypothalamus, and the hippocampus; together, these three brain regions process and react to threatening stimuli [10, 11]. Say a child sees a snake and reaches to pick it up.

Reacting to her movement, the snake bites her. The painful sensation triggers the child’s amygdala to perform various fear-processing

functions, which recognize the snake as a harmful stimulus [7]. The amygdala then sends signals to the hypothalamus and other key brain regions involved in regulating the physiological components of fear [7, 10, 12, 13, 14]. Then, her hypothalamus — a structure that regulates bodily functions by releasing hormones — causes her breathing and heart rate to quicken [10].

Simultaneously, the hippocampus, playing a major role in memory and learning, stores the association between snakes and fear to memory [11]. The next time the child encounters a snake, she is reminded of the painful bite, and experiences the same quickened heart rate and breathing [10, 11]. Reacting to her body’s stress-filled response, she immediately flees [10, 11]. Her limbic system processes her second encounter with a snake in a chain reaction: her hippocampus retrieves the memory of her original encounter, then her amygdala connects that memory to the feeling of fear, causing the hypothalamus to trigger a physiological response [10, 11, 15]. With its rapid response time and ability to learn from past experiences, the limbic system is incredibly important in helping us develop behaviors to avoid subsequent harm [16, 17].

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TO FEAR OR NOT TO FEAR

FEAR NOT, IT’S IMPORTANT! Despite being an uncomfortable emotion, fear is essential to one’s survival. However, there is debate surrounding how fear is processed in the brain [18, 19]. Much discussion revolves around three predominant theories about how emotions operate: the James-Lange theory, the Cannon-Bard theory, and the Schacter-Singer theory [20]. The James-Lange theory suggests that harmful stimuli trigger a distinct physiological response that we then associate with a specific emotion, such as fear [3, 20]. Thinking back to the snake, imagine the child on a hike, where a snake begins slithering toward her. When she sees the snake, she might begin to sweat, breathe heavily, and feel her heart beating out of her chest [20]. According to the James-Lange theory, the cognitive recognition of these specific physiological changes induces the emotion we know as fear. Alternatively, the Cannon-Bard theory proposes that a harmful stimulus causes us to experience physiological and cognitive reactions simultaneously, leading to the perception of fear. Applying the Cannon-Bard theory, when the child sees the snake, she feels frightened while experiencing an increased heart rate, heavy breathing, and her body shaking. Her physical response alone doesn’t generate her fear; rather, the simultaneous cognitive recognition in conjunction with physiological changes causes her to fear the snake [20]. Finally, the more recent Schacter-Singer theory postulates that we have the same physiological responses to a myriad of stimuli, but the cognitive response to each stimulus is interpreted differently based on the situational context [3, 20, 21, 22, 23]. When the child recognizes the snake, her nervous system prepares her body to either fight or flee the scene [20]. After determining that the situation poses a threat to her safety, her brain labels the physiological response as fear and causes her to flee the snake [20]. However, if someone can’t react to a threatening stimulus or cognitively label it as ‘fear,’ they may behave recklessly when facing the stimulus in the future [24, 25].

glycoprotein [4]. Glycoproteins play a variety of roles in the body, such as preventing infection and facilitating cell signaling [28, 29, 30, 31]. In general, the ECM1 gene allows for controlled production of a subset of glycoproteins in the body that primarily contribute to skin integrity [30]. Consequently, a mutation in the ECM1 gene can lead to a build-up of glycoproteins in the skin, larynx, and brain [27]. A surplus of these glycoproteins forms a pale, glassy cartilage known as hyaline [32, 33]. Overproduction of hyaline results in the formation of calcified lesions, a type of abnormal tissue, in the brain and body [4, 34]. Over time, the calcified lesions of the amygdala can cause neural degeneration, significantly reducing fear-processing abilities [4, 5].

FEARLESS (S.M.’S VERSION) Loss of function of the ECM1 gene can lead to the calcification of brain areas including the amygdala, as observed in S.M. [4, 7, 30]. S.M. was born with the ECM1 mutation, which provoked the development of calcified lesions on her amygdala [8]. S.M. recalls experiencing fear as a child but lost the ability to feel fear as the lesions on her amygdala developed over time [35]. Due to the rarity of her condition, S.M. is the subject of many case studies pertaining to UWD and the amygdala’s function in relation to fear [6]. In most cases, S.M. is unresponsive to harmful stimuli that would typically elicit a fearful response and S.M. even has trouble identifying fear in others [7].

When presented with several faces projecting different emotions, S.M. was unable to discern which faces exhibited fearful expressions, thus demonstrating her unresponsiveness to visual expressions of fear [7, 35, 6]. Furthermore, due to her difficulty detecting

BIOLOGICAL BASIS OF URBACH-WIETHE DISEASE Now imagine another scenario where another child doesn’t associate the dangerous snake with fear; she continues towards it and attempts to pick it up [8]!

This child may have UWD, a genetic disorder associated with excess calcium build-up in the skin, larynx, and central nervous system, a process called calcification [4, 26, 27]. UWD is caused by mutations in the ECM1 gene, which encodes for a specific type of

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TO FEAR OR NOT TO FEAR threats, S.M. reported that she has often found herself in dangerous or even life-threatening situations, such as being held at gunpoint [8]. S.M. claimed that she felt no fear during these traumatic situations; rather, she felt upset and angry [8].

Despite her seeming inability to recognize and experience fear, one study successfully caused S.M. to report the feeling of fear and present with standard physiological responses to a potentially life-threatening stimulus [35]. To study whether someone could feel fear with impaired amygdala function, S.M. and two other participants were given high concentrations of carbon dioxide gas to inhale while under observation [35, 36]. Because inhalation of abnormally high carbon dioxide levels increases breathing and heart rates, and can also induce panic in those inhaling it, this experiment could possibly indicate whether S.M. had any capacity to feel fear [35]. After inhaling an extremely high level of carbon dioxide, S.M. experienced both a panic attack and fear for the first time since childhood. Her experience in the carbon dioxide study was important to our understanding of the amygdala; while the amygdala is critical for triggering the fear response, it did not play a role in the specific type of fear the carbon dioxide triggered in S.M. [35]. During the study, S.M. did not respond to fear that is normally processed through visual or auditory pathways that project to the amygdala [35, 37]. Instead, the carbon dioxide may have been able to trigger S.M.’s fear response by acting on brain structures outside of the impaired amygdala [35, 37]. CO2 inhalation can provoke physiological changes — such as an increase in breathing and heart rate — that are characteristic of experiencing fear [37]. Although S.M. was unable to have a physiological response to visually fearful stimuli — like haunted houses or snakes — she was able to exhibit a fear response when triggered by carbon dioxide inhalation, which appears to bypass the amygdala altogether and seems to be processed through a different pathway [6, 8, 35, 37]. As a result, we now know that some people with UWD can experience intense fear despite a damaged amygdala [35].

Although we no longer have to frequently fend off bears, our world is still a perilous one. Due to complications from UWD, individuals like S.M. have found themselves in multiple life-threatening situations because of their inability to connect harmful stimuli with the emotion of fear [6, 8]. As the tissue in S.M.’s amygdala calcifies, it loses its ability to function, leading to changes in the way S.M. experiences stimuli [35, 37]. Since there is still no unified definition of what fear is or how it operates on a universal scale, studying unusual reactions to fearful stimuli can help us better understand the amygdala and other brain regions involved in the fear response pathway. Doing so can lead to new discoveries, such as the pathway that triggers physiological changes and alternative pathways for fear processing [35, 37].

References on page 80.

GOT FEAR? When you find yourself in safe, yet frightening situations —such as haunted house attractions — you may desire a life free from the unpleasant emotion of fear. However, through years of evolution, the fightor-flight response associated with fear has helped protect us from danger [1, 22]. When cavemen returned home to find a sleeping bear, instantaneous decision-making proved vital for their survival.

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