Grey Matters VC Isuue 8

@greymattersjournalvc

SPRING 2024

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

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

LIMITLESS RECOLLECTION: THE PHENOMENON OF HIGHLY SUPERIOR AUTOBIOGRAPHICAL MEMORY

by Anoushka Bhatt/ art by Anna Bishop

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

by Brooke Berbeco/ art by Mischa Landgarten

BEYOND THE BOARD: INSIDE THE BRAIN OF A CHESS MASTER

by Daniel Bader/ art by Maia Su

FEATURED ARTICLE

THE ROLE OF EMPATHY IN SEXUAL VIOLENCE

by Iona Duncan/ art by Alexandra Adsit

FEATURED ARTICLE

FACING THE MYTHICAL FURY: THE CALAMITOUS PATH OF LYSSAVIRUS RABIES

by Anna Conway/ art by Emily Holtz

BACK FROM BATTLE: THE CONDITIONING OF FEAR IN PTSD

by Elsie McKendry/ art by Katie Hieb

FROM CLUB TO CLINIC: THE TREATMENT OF PTSD WITH MDMA

by Erin Kaufman/ art by Iris Li

YEARNING FOR YESTERDAY: THE MECHANISMS AND APPLICATIONS OF NOSTALGIA

by Niah Dang/ art by Sneha Das IMMUNE

by Daniel Wunschel/ art by Abigail Schoenecker

FEATURED

by Kristen Carroll/ art by Sarah McDonald 49

ISSUE NOTES

ON THE COVER

Art by Jane Stempien

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

LEARN MORE

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

PRODUCTION STAFF

ARTISTS

Alexandra Adsit

Anna Bishop

Iris Li

Mischa Landgarten

Katie Hieb

Emily Holtz

Abigail Schoenecker

Sarah McDonald

Sneha Das

Maia Su

Jane Stempien

SCIENTIFIC REVIEW

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

AUTHORS

Kristen Carroll

Anna Conway

Elsie McKendry

Erin Kaufman

Iona Duncan

Niah Dang

Daniel Wunschel

Brooke Berbeco

Daniel Bader

Anoushka Bhatt

FACULTY ADVISORS

Evan Howard PhD

Lori Newman PhD

Kathleen Susman PhD

Bojana Zupan PhD

SPECIAL THANKS

Olivia Pocat - Layout

LAY REVIEW

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

GENERAL EDITING

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

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

LIMITLESS RECOLLECTION: THE PHENOMENON OF HIGHLY SUPERIOR AUTOBIOGRAPHICAL MEMORY

by Anoushka Bhatt/ art by Anna Bishop

THE WOMAN WHO NEVER FORGETS

We 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.

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

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].

WHAT DID HE CALL ME?

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

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].

LATTE FOR WHO?

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.

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

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

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.

BEYOND THE BOARD: INSIDE THE BRAIN OF A CHESS MASTER

by Daniel Bader/ art by Maia Su

Arguably, 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

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

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].

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

BEYOND

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].

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

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

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].

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.

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

by Anna Conway/ art by Emily Holtz

It 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.

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

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].

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].

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].

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].

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

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

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

believes that they have been infected with rabies,

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].

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].

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.

BACK FROM BATTLE: THE CONDITIONING OF FEAR IN PTSD

by Elsie McKendry/ art by Katie Hieb

Everyone 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

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.

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

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. 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].

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.

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.

FROM CLUB TO CLINIC: THE TREATMENT OF PTSD WITH MDMA

by Erin Kaufman/ art by Iris Li

Difficult 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].

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

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].

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].

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].

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].

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

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].

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.

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

by Brooke Berbeco/ art by Mischa Landgarten

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?

Yet 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

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

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

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

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 facil itates communication between the left and right hemispheres of the brain [33, 34, 35, 36]. Dis rupting communication between hemispheres of the brain is associ ated with a reduced ability to prob lem-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 in tegrity [33, 34].

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

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.

FEATURED

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

by Iona Duncan/ art by Alexandra Adsit

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

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

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

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].

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].

WHAT'S PORN GOT TO DO WITH IT?

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 coun-

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

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

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

WHAT'S PORN GOT TO DO WITH IT?

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].

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].

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].

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.

YEARNING FOR YESTERDAY: THE MECHANISMS AND APPLICATIONS OF NOSTALGIA

by Niah Dang/ art by Sneha Das

THE ENDURING MAGIC OF MEMORIES

Remember 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

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

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

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

YEARNING FOR YESTERDAY

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

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

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

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.

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.

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.

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

by Daniel Wunschel/ art by Abigail Schoenecker

EPISODE I: THE PHANTOM DISORDER

For 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

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

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, investiga tions continue to explore the relationship between the immune and nervous

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].

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.

References on Page 76.

FEATURED

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

by Kristen Carroll/ art by Sarah McDonald

You’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

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.

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 reg ulates 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 amyg dala 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].

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].

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

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

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].

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.

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.

REFERENCES

LIMITLESS RECOLLECTION: THE PHENOMENON OF HIGHLY SUPERIOR AUTOBIOGRAPHICAL MEMORY

1. Ally, B. A., Hussey, E. P., & Donahue, M. J. (2013). A case of hyperthymesia: Rethinking the role of the amygdala in autobiographical memory. Neurocase, 19(2), 166–181. doi:10.1080/13554794.2011. 654225

2. Parker, E. S., Cahill, L., & McGaugh, J. L. (2006). A case of unusual autobiographical remembering. Neurocase, 12(1), 35–49. doi:10.1080/13554790500473680

3. Ford, L., Shaw, T. B., Mattingley, J. B., & Robinson, G. A. (2022). Enhanced semantic memory in a case of highly superior autobiographical memory. Cortex, 151, 1–14. doi:10.1016/j.cortex.2022.02.007

4. Vranić, A., Jelić, M., & Tonković, M. (2018). Functions of autobiographical memory in younger and older adults. Frontiers in Psychology, 9. doi:10.3389/ fpsyg.2018.00219

5. Lambert, H. K., & McLaughlin, K. A. (2019). Impaired hippocampus-dependent associative learning as a mechanism underlying PTSD: A meta-analysis. Neuroscience & Biobehavioral Reviews, 107, 729–749. doi:10.1016/j.neubiorev.2019.09.024

6. Jawabri, K. H., & Cascella, M. (2020). Physiology, explicit memory. In StatPearls. StatPearls Publishing. PMID:32119438

7. Simons, J. S., & Johnsrude, I. S. (2014). Temporal lobes. Encyclopedia of the Neurological Sciences, 2, 401–408. doi:10.1016/b978-0-12-3851574.01180-5

8. Schendan, H. (2017). Implicit Memory. Reference Module in Neuroscience and Biobehavioral Psychology. doi: 10.1016/b978-0-12-809324-5.064592

9. Moscovitch, M., Cabeza, R., Winocur, G., & Nadel, L. (2016). Episodic memory and beyond: The hippocampus and neocortex in transformation. Annual Review of Psychology, 67(1), 105–134. doi:10.1146/annurev-psych-113011-143733

10. Pitel, A. L., H. Beaunieux, Desgranges, B., Sullivan, E. V., & Eustache, F. (2017). Memory disorders in alcohol use disorder without clinically-detectable neurological complication. Encyclopedia of Behavioral Neuroscience, 2, 447–454. doi:10.1016/ b978-0-12-809324-5.00358-8

11. Brown, T. I., Rissman, J., Chow, T. E., Uncapher, M. R., & Wagner, A. D. (2018). Differential medial temporal lobe and parietal cortical contributions to real-world autobiographical episodic and autobiographical semantic memory. Scientific Reports, 8(1). doi:10.1038/s41598-018-24549-y

12. Schendan, H. E. (2012). Semantic memory. Encyclopedia of Human Behavior, 2, 350–358. doi:10.1016/b978-0-12-375000-6.00315-3

13. Richmond, L. L., & Burnett, L. K. (2022). Characterizing older adults’ real world memory function using ecologically valid approaches. Psychology of Learning and Motivation, 77, 193–232. doi:10.1016/ bs.plm.2022.07.004

14. Wilson, A., & Ross, M. (2003). The identity function of autobiographical memory: Time is on our side. Memory, 11(2), 137–149. doi:10.1080/741938210

15. Meléndez, J. C., & Satorres, E. (2021). Autobiographical memory as a diagnostic tool in aging. Elsevier EBooks, 305–314. doi:10.1016/b978-0-12818000-6.00028-7

16. Kapsetaki, M. E., Militaru, I. E., Sanguino, I., Boccanera, M., Zaara, N., Zaman, A., Loreto, F., Malhotra, P. A., & Russell, C. (2021). Type of encoded material and age modulate the relationship between episodic recall of visual perspective and autobiographical memory. Journal of Cognitive Psychology, 34(1), 142–159. doi:10.1080/20445911.2 021.1922417

17. Bauer, P. J. (2020). Amnesia, Infantile. Elsevier EBooks, 2, 45–55. doi:10.1016/b978-0-12-8093245.21207-8

18. Kaiser, J. (2015). Dynamics of auditory working memory. Frontiers in Psychology, 6. doi:10.3389/ fpsyg.2015.00613

19. Cowan, N. (2017). The many faces of working memory and short-term storage. Psychonomic Bulletin & Review, 24(4), 1158–1170. doi:10.3758/ s13423-016-1191-6

20. Dhikav, V., & Anand, K. S. (2012). Hippocampus in health and disease: An overview. Annals of Indian Academy of Neurology, 15(4), 239–246. doi:10.4103/0972-2327.104323

21. Capone, C., Pastorelli, E., Golosio, B., & Paolucci, P. S. (2019). Sleep-like slow oscillations improve visual classification through synaptic homeostasis and memory association in a thalamo-cortical model. Scientific Reports, 9(1). doi:10.1038/ s41598-019-45525-0

22. Feld, G. B., & Born, J. (2019). Neurochemical mechanisms for memory processing during sleep: basic findings in humans and neuropsychiatric implications. Neuropsychopharmacology, 45(1), 31–44. doi:10.1038/s41386-019-0490-9

23. Fields, R. D. (2011). Imaging learning: The search for a memory trace. The Neuroscientist, 17(2), 185–196. doi:10.1177/1073858410383696

24. Jiang, L., & Rao, R. (2024). Dynamic predictive coding: A model of hierarchical sequence learning and prediction in the neocortex. PLoS Computational Biology, 20(2), e1011801–e1011801. doi:10.1371/journal.pcbi.1011801

25. Sheldon, S., Fenerci, C., & Gurguryan, L. (2019). A neurocognitive perspective on the forms and functions of autobiographical memory retrieval. Frontiers in Systems Neuroscience, 13. doi:10.3389/ fnsys.2019.00004

26. Frankland, P. W., Josselyn, S. A., & Köhler, S. (2019). The neurobiological foundation of memory retrieval. Nature Neuroscience, 22(10), 1576–1585. doi:10.1038/s41593-019-0493-1

27. McCarroll, C. J. (2020). Remembering the personal past: Beyond the boundaries of imagination. Frontiers in Psychology, 11. doi:10.3389/ fpsyg.2020.585352

28. Ricker, T. J., Vergauwe, E., & Cowan, N. (2016). Decay theory of immediate memory: From Brown (1958) to today (2014). Quarterly Journal of Experimental Psychology, 69(10), 1969–1995. doi:10.1080 /17470218.2014.914546

29. Josselyn, S. A., & Tonegawa, S. (2020). Memory engrams: Recalling the past and imagining the future. Science, 367(6473). doi:10.1126/science. aaw4325

30. Cooper, R. A., Kensinger, E. A., & Ritchey, M. (2019). Memories fade: The relationship between memory vividness and remembered visual salience. Psychological Science, 30(5), 657–668. doi:10.1177/0956797619836093

31. Walker, W. R., Skowronski, J. J., Gibbons, J. A., Vogl, R. J., & Ritchie, T. D. (2009). Why people rehearse their memories: Frequency of use and relations to the intensity of emotions associated with autobiographical memories. Memory, 17(7), 760–773. doi:10.1080/09658210903107846

32. Santangelo, V. (2015). Forced to remember: When memory is biased by salient information. Behavioural Brain Research, 283, 1–10. doi:10.1016/j. bbr.2015.01.013

33. Santangelo, V., Pedale, T., Colucci, P., Giulietti, G., Macrì, S., & Campolongo, P. (2021). Highly superior autobiographical memory in aging: A single case study. Cortex, 143, 267–280. doi: 10.1016/j. cortex.2021.05.011

34. Santangelo, V., Cavallina, C., Colucci, P., Santori, A., Macrì, S., McGaugh, J. L., & Campolongo, P. (2018). Enhanced brain activity associated with memory access in highly superior autobiographical memory. Proceedings of the National Academy of Sciences, 115(30), 7795–7800. doi:10.1073/ pnas.1802730115

35. Talbot, J., Convertino, G., Matteo De Marco, Venneri, A., & Mazzoni, G. (2024). Highly Superior Autobiographical Memory (HSAM): A systematic review. Neuropsychology Review. doi:10.1007/s11065-02409632-8

36. Rodriguez McRobbie, L. (2017, February 8). Total recall: the people who never forget. The Guardian; The Guardian.

37. Patihis, L., Frenda, S., LePort, A., Petersen, N., Nichols, R., Stark, C., McGaugh, J., & Loftus, E. (2013). False memories in highly superior autobiographical memory individuals. Proceedings of the National Academy of Sciences, 110(52), 20947–20952. doi:10.1073/pnas.1314373110

38. LePort, A. K. R., Mattfeld, A. T., Dickinson-Anson, H., Fallon, J. H., Stark, C. E. L., Kruggel, F., Cahill, L., & McGaugh, J. L. (2012). Behavioral and neuroanatomical investigation of Highly Superior Autobiographical Memory (HSAM). Neurobiology of Learning and Memory, 98(1), 78–92. doi:10.1016/j. nlm.2012.05.002

39. Brandt, J., & Bakker, A. (2018). Neuropsychological investigation of “The amazing memory man”.. Neuropsychology, 32(3), 304–316. doi:10.1037/ neu0000410

40. Daviddi, S., Pedale, T., Serra, L., Macrì, S., Campolongo, P., & Santangelo, V. (2022). Altered hippocampal resting-state functional connectivity in highly superior autobiographical memory. Neuroscience, 480, 1–8. doi:10.1016/j.neuroscience.2021.11.004

41. Anderson, M. C., & Hulbert, J. C. (2020). Active Forgetting: Adaptation of Memory by Prefrontal Control. Annual Review of Psychology, 72(1). doi:10.1146/annurev-psych-072720-094140

42. Barry, D. N., Clark, I. A., & Maguire, E. A. (2020). The relationship between hippocampal subfield volumes and autobiographical memory persistence. Hippocampus, 31(4), 362–374. doi:10.1002/ hipo.23293

43. Jamjoom, A., Gallo, P., Kandasamy, J., Phillips, J., & Sokol, D. (2017). Autobiographical memory loss following a right prefrontal lobe tumour resection: A case report and review of the literature. Childs Nervous System, 33(7), 1221–1223. doi:10.1007/ s00381-017-3380-7

REFERENCES

44. Eichenbaum, H. (2017). Prefrontal–hippocampal interactions in episodic memory. Nature Reviews Neuroscience, 18(9), 547–558. doi:10.1038/ nrn.2017.74

45. Mazzoni, G., Clark, A., De Bartolo, A., Guerrini, C., Nahouli, Z., Duzzi, D., De Marco, M., McGeown, W., & Venneri, A. (2019). Brain activation in highly superior autobiographical memory: The role of the precuneus in the autobiographical memory retrieval network. Cortex, 120, 588–602. doi:10.1016/j. cortex.2019.02.020

46. Fawcett, J. M., Benoit, R. G., Gagnepain, P., Salman, A., Bartholdy, S., Bradley, C., Chan, D. K.-Y. ., Roche, A., Brewin, C. R., & Anderson, M. C. (2015). The origins of repetitive thought in rumination: Separating cognitive style from deficits in inhibitory control over memory. Journal of Behavior Therapy and Experimental Psychiatry, 47, 1–8. doi:10.1016/j. jbtep.2014.10.009

47. Nørby, S. (2015). Why forget? On the adaptive value of memory loss. Perspectives on Psychological Science, 10(5), 551–578. doi:10.1177/1745691615596787

48. Gruber, M., Ritchey, M., Wang, S., Doss, M. K., & Charan Ranganath. (2016). Post-learning Hippocampal Dynamics Promote Preferential Retention of Rewarding Events. Neuron, 89(5), 1110–1120. doi:10.1016/j.neuron.2016.01.017

49. Braun, E.K., Wimmer, G.E. & Shohamy, D. (2018) Retroactive and graded prioritization of memory by reward. Nature Communications, 9. doi:10.1038/ s41467-018-07280-0

50. Murphy, D. H., & Castel, A. D. (2021). Responsible remembering and forgetting as contributors to memory for important information. Memory & Cognition, 49. doi:10.3758/s13421-021-01139-4

51. Brewin, C. R. (2018). Memory and forgetting. Current Psychiatry Reports, 20(10). doi:10.1007/ s11920-018-0950-7

52. Strange, D., & Takarangi, M. K. T. (2015). Memory distortion for traumatic events: The role of mental imagery. Frontiers in Psychiatry, 6(27). doi:10.3389/ fpsyt.2015.00027

53. Li, H. L., & van Rossum, M. C. (2020). Energy efficient synaptic plasticity. ELife, 9. doi:10.7554/ elife.50804

54. Kluge, A., & Gronau, N. (2018). Intentional forgetting in organizations: The importance of eliminating retrieval cues for implementing new routines. Frontiers in Psychology, 9. doi:10.3389/ fpsyg.2018.00051

55. Basu, R. (2022). The importance of forgetting. Episteme, 1–20. doi:10.1017/epi.2022.36

56. Ray, D. G., Gomillion, S., Pintea, A. I., & Hamlin, I. (2019). On being forgotten: Memory and forgetting serve as signals of interpersonal importance. Journal of Personality and Social Psychology, 116(2), 259–276. doi:10.1037/pspi0000145

57. MacMillan, A. (2017). The Downside of Having an Almost Perfect Memory. Time. https://time. com/5045521/highly-superior-autobiographical-memory-hsam/

58. Patihis, L. (2015). Individual differences and correlates of highly superior autobiographical memory. Memory, 24(7), 961–978. doi:10.1080/0965821 1.2015.1061011

BEYOND THE BOARD: INSIDE THE BRAIN OF A CHESS MASTER

1. Lu, Y., Li, W., Li, W. (2023). Official international mahjong: A new playground for AI research. Algorithms, 16(5), 235. doi:10.3390/a16050235

2. International Chess Federation (2024). FIDE ratings and statistics. Retrieved March 31, 2024 from https://ratings.fide.com/

3. Fernandez-Egea, E., Robbins, T. (2022). Bobby Fischer and the Delusions of a King in Logic. Brain, 145(5), 1570-1573. doi:10.1093/brain/awac140

4. Gobet, F., & Ereku, M. H. (2014). Checkmate to deliberate practice: The case of Magnus Carlsen. Frontiers in Psychology, 5. doi:10.3389/ fpsyg.2014.00878

5. Campitelli, G. (2015). Answering research questions without calculating the mean. Frontiers in Psychology, 6. doi:10.3389/fpsyg.2015.01379

6. Lillo-Crespo, M., Forner-Ruiz, M., Riquelme-Galindo, J., Ruiz-Fernández, D., & García-Sanjuan, S. (2019). Chess practice as a protective factor in dementia. International Journal of Environmental Research and Public Health, 16(12), 2116. doi:10.3390/ijerph16122116

7. Stern, Y., Arenaza-Urquijo, E., Bartrés-Faz, D., Belleville, S., Cantilon, M., Chetelat, G., Ewers, M., Franzmeier, N., Kempermann, G., Kremen, W., Okonkwo, O., Scarmeas, N., Soldan, A., Udeh-Momoh, C., Valenzuela, M., Vemuri, P., Vuoksimaa, E. (2020). Whitepaper: defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimer’s & Dementia, 16(9), 1305–1311. doi: 10.1016/j.jalz.2018.07.219

8. Cowan, N. (2017). The many faces of working memory and short-term storage. Psychonomic Bulletin and Review, 24(4), 1158-1170. doi: 10.3758/ s13423-016-1191-6

9. Krivec, J., Bratko, I., Guid, M. (2021). Identification and conceptualization of procedural chunks in chess. Cognitive Systems Research, 69, 22-40. doi:10.1016/j.cogsys.2021.05.001

10. Sala, G., Gobet, F. (2016). Experts memory superiority for domain-specific random material generalizes across fields of expertise: A meta-analysis. Memory and Cognition, 45, 183-193. doi:10.3758/ s13421-016-0663-2

11. Smith, E., Bartlett, J., Krawczyk, D., Basak, C. (2021). Are the advantages of chess expertise on visuo-spatial working-memory capacity domain or domain general. Memory and Cognition, 49, 1600-1616. doi:10.3758/s13421-021-01184-z

12. Gong, Y., Ericsson, K., Moxley, J. (2015). Recall of briefly presented chess positions and its relation to chess skill. PLoS 10(3). doi:10.1371/journal. pone.0118756

13. Gobet, F., Lane, P. C. R., Croker, S., Chang, P. C. H., Jones, G., Oliver, I., & Pine, J. M. (2001). Chunking mechanisms in human learning. Trends in Cognitive Sciences. 5 (6), 236-243. doi:10.1016/S13646613(00)01662-4

14. Bartlett, J. C., Boggan, A. L., & Krawczyk, D. C. (2013). Expertise and processing distorted structure in chess. Frontiers in Human Neuroscience, 7. doi:10.3389/fnhum.2013.00825

15. Pereira, T., Castro, M., Villafaina, S., Santos, A., Fuentes-Garcia, J. (2020). Dynamics of the prefrontal cortex during chess-based problem-solving tasks in competition-experienced chess players: An fNIR study. Sensors (Basel), 20(14), 3917. doi:10.3390/s20143917

16. Jenkin, Z. (2022). Perceptual learning and reasons-responsiveness. Noûs, 57(2), 481-508. doi:10.1111/nous.12425

17. Küchelmann, T., Velentzas, K., Essig, K., Koester, D., Schack, T. (2022). Expertise-dependent perceptual performance in chess tasks with varying complexity. Frontiers in Psychology, 13. doi:10.3389/ fpsyg.2022.986787

18. Gao, Q., Chen, W., Wang, Z., & Lin, D. (2019). Secret of the masters: Young chess players show advanced visual perspective taking. Frontiers in psychology, 10, 2407. doi:10.3389/fpsyg.2019.02407

19. Schurz, M., Radua, J., Aichhorn, M., Richlan, F., & Perner, J. (2014). Fractionating theory of mind: A meta-analysis of functional brain imaging studies. Neuroscience & Biobehavioral Reviews, 42, 9-34. doi:10.1016/j.neurobiorev.2014.01.009

20. Weimer, A. A., Cortez, N., & Razo, N. (2022). Does chess-playing relate to theory of mind? An examination of the interrelations among theory of mind, perspective-taking, and empathic concern in chess-players. Studies in Psychology, 43(2), 389-413. doi:10.1080/02109396.2022.2058266

21. Carlsen, M. (2014). Magnus Carlsen gives his top 13 chess tips + Bloopers. YouTube. https://www. youtube.com/watch?v=FMaaHd7aFIs

22. Powell, J. L., Grossi, D., Corcoran, R., Gobet, F., & García-Fiñana, M. (2017) The neural correlates of theory of mind and their role during empathy and the game of chess: A functional magnetic resonance imaging study. Neuroscience, 355, 149-160. doi:10.1016/j.neuroscience.2017.04.042

23. Krall, S. C., Rottschy, C., Oberwelland, E., Bzdok, D., Fox, P. T., Eickhoff, S. B., Fink, G. R., & Konrad, K. (2014). The role of the right temporoparietal junction in attention and social interaction as revealed by ALE meta-analysis. Brain Structure & Function, 220(2), 587-604. doi:10.1007/s00429-014-0803-z

24. Nanu, C. C., Coman, C., Bularca, M. C., MesesanSchmitz, L., Gotea, M., Atudorei, I., Turcu, I., & Negrila, I. (2023). The role of chess in the development of children - parents’ perspectives. Frontiers in Psychology, 14. doi:10.3389/fpsyg.2023.1210917

25. Ahmetov, I. I., Valeeva, E. V., Yerdenova, M. B., Datkhabayeva, G. K., Bouzid, A., Bhamidimarri, P. M., Sharafetdinova, L. M., Egorova, E. S., Semenova, E. A., Gabdrakhmanova, L. J., Yusupov, R. A., Larin, A. K., Kulemin, N. A., Generozov, E. V., Hamoudi, R., Kustubayeva, A. M., & Rees, T. (2023). KIBRA gene variant is associated with ability in chess and science. Genes, 14(1), 204. doi:10.3390/ genes14010204

26. Fogwe, L. A., Reddy, V., & Mesfin, F. S. (2023). Neuroanatomy, hippocampus. In StatPearls. StatPearls Publishing. PMID:29489273

27. Witte, A. V., Köbe, T., Kerti, L., Rujescu, D., & Flöel, A. (2015). Impact of KIBRA polymorphism on memory function and the hippocampus in older adults. Neuropsychopharmacology, 41, 781-790. doi:10.1038/npp.2015.203

28. Su, Z., Dhusia, K., & Wu, Y. (2020). Understand the functions of scaffold proteins in cell signaling by a mesoscopic simulation method. Biophysical Journal, 119(10), 2116-2126. doi:10.1016/j.bpj.2020.10.002

29. RaviPrakash, H., Anwar, S. M., Biassou, N. M., & Bagci, U. (2021). Morphometric and functional brain connectivity differentiates chess masters from amateur players. Frontiers in neuroscience, 15, 629478. doi:10.3389/fnins.2021.629478

REFERENCES

30. Mercadante, A. A., & Tadi, P. (2023). Neuroanatomy, gray matter. In StatPearls. StatPearls Publishing. PMID:31990494

31. Hänggi, J., Brütsch , K., Siegel, A. M., Jäncke, (2014). The architecture of the chess player’s brain. Neuropsychologia. 6, 152-162. doi:10.1016/j.neuropsychologia.2014.07.019

32. Duan, X., Liao, W., Liang, D., Qiu, L., Gao, Q., Liu, C, Gong, Q., & Chen, H. (2012). Large-scale brain networks in board game experts: Insights from a domain-related task and task-free resting state. PLoS ONE, 7(3). doi:10.1371/journal.pone.0032532

33. Driscoll, M., Bollu, P., Tadi, P. (2023). Neuroanatomy, Nucleus Caudate. In StatPearls. StatPearls Publishing. PMID:32491339

34. Premi, E., Gazzina, S., Diano, M., Girellia, A., Calhoun, V., Iraji, A., Gong, Q., Li, K., Cauda, F., Gasparotti, R., Padovani, A., Borroni, B., Magoni, M. (2020). Scientific Reports, 10. doi:10.1038/s41598-02063984-8

35. Raichle, M. E. (2015). The brain’s default mode network. Annual Review of Neuroscience, 38, 433447. doi:10.1146/annurev-neuro-071013-014030

36. Wang, Y., Zuo, C., Wang, D., Tao, S., Hao, L. (2020). Reduced thalamus volume and enhanced thalamus and fronto-parietal network integration in the chess experts. Cerebral Cortex, 30 (10), 55605569. doi:10.1093/cercor/bhaa140

37. Torrico, T. J., & Munakomi, S. (2023). Neuroanatomy, thalamus. In StatPearls. StatPearls Publishing. PMID:31194341

38. Wallis, G., Stokes, M., Cousijn, H., Woolrich, M., & Nobre, A. C. (2015). Frontoparietal and cingulo-opercular networks play dissociable roles in control of working memory. doi: 10.1162/ jocn_a_00838

39. Arvanitakis, Z., & Bennett, D. A. (2019). What is dementia? JAMA, 322(17), 1728. doi:10.1001/ jama.2019.11653

40. Breijyeh, Z., & Karaman, R. (2020). Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules, 25(24), 5789. doi:10.3390/molecules25245789

41. Rao, Y. L., Ganaraja, B., Murlimanju, B. V., Joy, T., Krishnamurthy, A., & Agrawal, A. (2022). Hippocampus and its involvement in Alzheimer’s disease: A review. 3 Biotech, 12(2). doi:10.1007/ s13205-022-03123-4

42. World Health Organization (2023). Dementia. Retrieved March 13, 2024 from https://www.who.int/ news-room/fact-sheets/detail/dementia

43. Joypriyanka, M., & Surendran, R. (2023). Chess game to improve the mental ability of Alzheimer’s patients using A3C. 2023 Fifth International Conference on Electrical, Computer, and Communication Technologies, 1-6. doi:10.1109/ICECCT56650.2023.10179809

44. Chen, P.-J., Yang, S.-Y., Wang, C.-S., Muslikin, M., & Wang, M.-S. (2020). Development of a Chinese chess robotic system for the elderly using convolutional neural networks. Scopus. 12 (10), 3980. doi:10.3390/su12103980

45. Huang, L., Awh, E. (2018). Chunking in working memory via content-free labels. Scientific Reports, 8, 23. doi: 10.1038/s41598-017-18157-5

46. Eather, N., Wade, L., Pankowiak, A., Eime, R. (2023). The impact of sports participation on mental health and social outcomes in adults: A systematic review and the ‘Mental Health through Sport’’ conceptual model. Systematic Reviews, 12 (1), 102. doi:10.1186/s13643-023-02264-8

FEATURED

FACING THE MYTHICAL FURY: THE CALAMITOUS PATH OF LYSSAVIRUS RABIES

1. Centers for Disease Control and Prevention. (2012). Etymologia: Rabies. Emerging Infectious Diseases, 18(7), 1169. doi:10.3201/eid1807.et1807

2. World Health Organization. (2023). Rabies. Retrieved April 1, 2024 from https://www.who.int/ news-room/fact-sheets/detail/rabies

3. Bastos, V., Pacheco, V., Rodrigues, E.D.L., Moraes, C.N.S, Nóbile, A. L., Fonseca, D.L.M., Souza, K.B.S, do Vale, F.Y.N., Filgueiras, I.S., Schimke, L.F., Giil, L.M., Moll, G., Cabral-Miranda, G., Ochs, H.D., da Costa Vasconcelos, P., de Melo, G.D., Bourhy, H., Casseb, L.M.N., Cabral-Marques, O. (2023). Neuroimmunology of rabies: new insights in an ancient disease. Journal of Medical Virology, 95(10). doi:10.1002/jmv.29042

4. Jackson, A.C. (2018). Rabies: a medical perspective. Revue Scientifique et Technique, 37(2), 569580. doi:10.20506/rst.37.2.2825

5. Liu, C., Cahill, J.D. (2020). Epidemiology of rabies and current US vaccine guidelines. RI Medical Journal, 103(6), 51-53. PMID: 32752569

6. Fooks, A.R., Cliquet, F., Finke, S., Freuling, C., Hemachudha, T., Mani, R.S., Müller, T., Nadin-Davis, S., Picard-Meyer, E., Wilde, H., Barnyard, A.C. (2017). Rabies. Nature Reviews Disease Primers, 3. doi:10.1038/nrdp.2017.91

7. Guo, Y., Duan, M., Wang, X., Gao, J., Guan, Z., Xhang, M. (2019). Early events in rabies virus infection — attachment, entry, and intracellular trafficking. Virus Research, 263, 217-225. doi:10.1016/j.virusres.2019.02.006

8. Katz, I.S.S., Guedes, F., Fernandes, E.R., dos Ramos Silva, S. (2017). Immunological aspects of rabies: a literature review. Archives of Virology, 162, 3251-3268. doi:10.1007/s00705-017-3484-0

9. Taylor, M. W. (2014). What is a virus? Viruses and Man: A History of Interactions, 23–40. doi:10.1007/978-3-319-07758-1_2

10. Shankar, S., Mahadevan, A., Sapico, S., Ghodkirekar, M. S., Pinto, R. G., & Madhusudana, S. (2012). Rabies viral encephalitis with probable 25 year incubation period! Annals of Indian Academy of Neurology, 15(3), 221. doi:10.4103/0972-2327.99728

11. Singh, R., Singh, K.P., Cherian, S., Saminathan, M., Kapoor, S., Manjunatha Reddy, G.B., Panda, S., Dhama, K. (2017). Rabies - epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review. Veterinary Quarterly, 37(1). doi:10.1080/01652176.2 017.1343516

12. Scott, T. P., & Nel, L. H. (2021). Lyssaviruses and the fatal encephalitic disease rabies. Frontiers in Immunology, 12. doi: 10.3389/fimmu.2021.786953

13. Dutta, T.K. (2014). Rabies - an overview. International Journal of Advanced Medical and Health Research, 1(2). doi:10.4103/2349-4220.147998

14. Davis, B. M., Rall, G. F., & Schnell, M. J. (2015). Everything you always wanted to know about rabies virus (but were afraid to ask). Annual Review of Virology, 2(1), 451–471. doi:10.1146/annurev-virology-100114-055157

15. Murtazina, A., Adameyko, I. (2023). The peripheral nervous system. Development, 150(9). doi:10.1242/ dev.201164

16. Rodriguez Cruz, P.M., Cossins, J., Beeson, D., Vincent, A. (2020). The neuromuscular junction in health and disease: molecular mechanisms governing synaptic formation and homeostasis. Frontiers in Molecular Neuroscience, 13, 1-22. doi:10.3389/fnmol.2020.610964

17. Maday, S., Twelvetrees, A.E., Moughamian, A.J., Holzbaur, E.L.F. (2014). Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron, 84(2), 292-309. doi:10.1016/j.neuron.2014.10.019

18. Liu, X., Nawaz, Z., Guo, C., Ali, S., Naeem, M.A., Jamil, T., Ahmad, W., Siddiq, M.U., Ahmed, S., Ahmed, S., Idrees, M.A., Ahmad, A. (2022). Rabies virus exploits cytoskeleton network to cause early disease progression and cellular dysfunction. Frontiers Veterinary Science, 9. doi:10.3389/ fvets.2022.889873

19. Ito, N., Moseley, G.W., Sugiyama, M. (2016). The importance of immune evasion in the pathogenesis of rabies virus. Journal of Veterinary Medical Science, 78(7), 1089-1098. doi: doi:10.1292/jvms.160092

20. Taylor, M.W. (2014). Interferons. Viruses and Man: A History of Interactions, 101-119. doi:10.1007/9783-319-07758-1_7

21. Dalskov, L., Gad, H.H., Hartmann, R. (2023). Viral recognition and the antiviral interferon response. The EMBO Journal, 42(14). doi: 10.15252/ embj.2022112907

22. Zhang, H., Huang, J., Song, Y., Liu, X., Qian, M., Huang, P., Li, Y., Zhao, L., Wang, H. (2022). Regulation of innate immune response by rabies virus. Animal Models and Experimental Medicine 5(5), 418-429. doi:10.1002/ame2.12273

23. Rieder, M. and Conzelmann, K.K. (2011). Chapter 6 - Interferon in rabies virus infection. Advances in Virus Research 79, 91-114. doi:10.1016/B978-0-12387040-7.00006-8

24. Sokol, C.L. and Luster, A.D. (2015). The chemokine system in innate immunity. Cold Spring Harbor Perspectives in Biology, 7. doi:10.1101/cshperspect. a016303

25. Jackson, A. (2011). Update on rabies. Research and Reports in Tropical Medicine, 31. doi:10.2147/ rrtm.s16013

26. Li, X., Sarmento, L., & Fu, Z. F. (2005). Degeneration of neuronal processes after infection with pathogenic, but not attenuated, rabies viruses. Journal of Virology, 79(15), 10063–10068. doi:10.1128/ jvi.79.15.10063-10068.2005

27. Soler-Rangel, S., Jiménez-Restrepo, N., Nariño, D., Rosselli, D. (2020). Rabies encephalitis and extra-neural manifestation in a patient bitten by a domestic cat. Revista do Instituto de Medicina Tropical 62(1). doi:10.1590/S1678-9946202062001

28. Feige, L., Zaeck, L.M., Sehl-Ewert, J., Finke, S., Bourhy, H. (2021). Innate immune signaling and role of glial cells in herpes simplex virus- and rabies virus-induced encephalitis. Viruses, 13(12). doi:10.3390/v13122364

REFERENCES

29. Chai, Q., He, W.Q., Zhou, M., Lu, H., Fu, Z. Z. (2014). Enhancement of blood-brain barrier permeability and reduction of tight junction protein expression are modulated by chemokines/cytokines induced by rabies virus infection. Journal of Virology, 88. doi: doi:10.1128/jvi.03149-13

30. Daneman, R. and Prat, A. (2015). The blood-brain barrier. Cold Spring Harbor Perspectives in Biology, 7(1). doi:10.1101/cshperspect.a020412

31. Scott, T.P. and Nel, L.H. (2016). Subversion of the immune response by rabies virus. Viruses, 8(8), 231. doi:10.3390/v8080231

32. Roy, A., Phares, T.W., Koprowski, H., Hooper, D.C. (2007). Failure to open the blood-brain barrier and deliver immune effectors to central nervous system tissues leads to lethal outcome of silver-haired bat rabies virus infection. Journal of Virology, 81(3), 1110-1118. doi:10.1128/JVI.01964-06

33. Grider, M.H., Jessu, R., Kabir, R. (2019). Physiology, action potential. In StatPearls. Statpearls Publishing. PMID: 30844170

34. Barbieri, R., Nizzari, M., Zanardi, I., Pusch, M., Gavasso, P. (2023). Voltage-gated sodium channel dysfunctions in neurological disorders. Life 13(5). doi:10.3390/life13051191

35. Wang, J., Ou, S., Wang, Y. (2017) Distribution and function of voltage-gated sodium channels in the nervous system. Channels, 11(6), 534-554. doi:10.1 080/19336950.2017.1380758

36. Mahadevan, A., Suja, M.S., Mani, R.S., Shankar., S.K. (2016). Perspectives in diagnosis and treatment of rabies viral encephalitis: Insight from pathogenesis. Neurotherapeutics 13(3), 477-492. doi:10.1007/s13311-016-0452-4

37. Mostraccio, K.E., Huaman, C., Warrilow, D., Smith, G.A., Criag, S.B., Weir, D.L., Laing, E.D., Smith, I.L., Broder, C.C., Schaefer, B.C. (2020). Establishment of longitudinal pre-clinical model of lyssavirus infection. Journal of Virological Methods, 281. doi:10.1016/j.jviromet.2020.113882

38. Udow, S.J., Marrie, R.A., Jackson, A.C. (2013). Clinical features of dog- and bat-acquired rabies in humans. Clinical Infectious Diseases 57(5), 689696. doi:10.1093/cid/cit372

39. Guo, X., Zhang, M., Feng, Y., Liu, X., Wang, C., Zhang, Y., Wang, Z., Zhang, D., Guo, Y. (2024). Transcriptome analysis of salivary glands of rabies-virus-infected mice. Frontiers in Microbiology, 15. doi:10.3389/fmicb.2024.1354936

40. Alexander, B., Lopez-Lopez, J.P., Saldarriaga, C., Ponte-Negretti, C.I., Lopez-Santi, R., Perez, G.E., del Sueldo, M., Lanas, F., Liblik, K., Baranchuk, A. (2021). Rabies and the heart. Cardiology Research, 12(2), 53-59. doi:10.14740/cr1216

41. Velasco-Villa, A., Escobar, L. E., Sanchez, A., Shi, M., Streicker, D. G., Gallardo-Romero, N. F., Vargas-Pino, F., Gutierrez-Cedillo, V., Damon, I., & Emerson, G. (2017). Successful strategies implemented towards the elimination of canine rabies in the Western Hemisphere. Antiviral Research, 143, 1–12. doi:10.1016/j.antiviral.2017.03.023

42. Tarantola, A., Tejiokem, M.C., Briggs, D.J. (2019). Evaluating new rabies post-exposure prophylaxis (PEP) regimens or vaccines. Vaccine, 37, A88-A93. doi:10.1016/j.vaccine.2018.10.103

43. Aziz, M., Iheanacho, F., Hashmi, M.F. (2023). Physiology, antibody. In StatPearls. StatPearls Publishing. From https://www.ncbi.nlm.nih.gov/books/ NBK546670/

44. Dean, L. (2005). Blood group antigens are surface markers on the red blood cell membrane. National Center for Biotechnology Information. From https://www.ncbi.nlm.nih.gov/books/NBK2264/

45. Briggs, D.J., Moore, S.M. (2020). Chapter 16 - Public health management of humans at risk. Rabies: Scientific Basis of the Disease and its Management, 527-545. doi:10.1016/B978-0-12-8187050.00016-9

46. Jackson, A.C. (2013). Current and future approaches to the therapy of human rabies. Antiviral Research, 99(1), 61-67. doi:10.1016/j.antiviral.2013.01.003

47. Lacy, M., Phasuk, N., Scholand, S.J. (2024). Human rabies treatment — from palliation to promise. Viruses, 16(1), 160. doi:10.3390/v16010160

48. Hu, W.T., Willoughby, R.E., Dhonau, H., Mack, K.J. (2007). Long-term follow-up after treatment of rabies by induction of coma. The New England Journal of Medicine, 357(9), 945-946. doi:10.1056/ NEJMc062479

49. Jackson, A.C. (2016). Human rabies: a 2016 update. Current Infectious Disease Reports, 18. doi:10.1007/s11908-016-0540-y

50. Lampejo, T., Bruce, M., Teall, A., Dall’Antonia, M., Crawley-Boevy, E., Grant, P., Polhill, S., Pillay, D., Brown, D., Brown, M., Nastouli, E. (2017). Caring for a patient with rabies: implications of the Milwaukee protocol for infection control and public health measures. Journal of Hospital Infection 96(4), 385-391. doi:10.1016/j.jhin.2017.04.018

51. Monoclonal antibody. National Cancer Institute. From https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monoclonal-antibody

52. Malik, B., Ghatol, A. (2023). Understanding How Monoclonal Antibodies Work. In StatPearls. StatPearls Publishing. From https://www.ncbi.nlm.nih. gov/books/NBK572118/

53. Dias de Melo, G., Sonthonnax, F., Lepousez, G., Jouvion, G., Minola, A., Zatta, F., Larrous, F., Kergoat, L., Mazo, C., Moigneu C., Aiello, R., Salomoni, A., Brisebard, E., De Benedictis, P., Corti, D., Bourhy, H. (2020). A combination of two human monoclonal antibodies cures symptomatic rabies. EMBO Molecular Medicine, 12. doi:10.15252/ emmm.202012628

54. Zorzan, M., Castellan M., Gasparotto, M., Dias de Melo, G., Zecchin, B., Leopardi, S., Chen, A., Rosato, A., Angelini, A., Bourhy, H., Corti, D., Cendron, L., De Benedictis, P. (2023). Antiviral mechanisms of two broad-spectrum monoclonal antibodies for rabies prophylaxis and therapy. Frontiers in Immunology, 14. doi: https://doi.org/10.3389/fimmu.2023.1186063

55. Ling, M.Y.J., Halim, A.F.N.A, Ahmad, D., Ramly, N., Hassan, M.R., Rahim, S.S.S.A., Jeffree, M.S., Omar, A., Hidrus, A. (2023). Rabies in Southeast Asia: a systematic review of its incidence, risk factors, and mortality. BMJ Open 13(5). PMID: 37164462

56. Miranda, M.E.G., Miranda, N.L.J. (2020). Rabies prevention in Asia: institutionalizing implementation capacities. Rabies and Rabies Vaccines, 103116. doi:10.1007/978-3-030-21084-7_6

57. Gan, H., Hou, X., Wang, Y., Xu, G., Huang, Z., Zhang, T., Lin, R., Xue, M., Hu, H., Liu, M., Cheng, Z. J., Zhu, Z., & Sun, B. (2023). Global burden of rabies in 204 countries and territories, from 1990 to 2019: Results from the global burden of disease study 2019. International Journal of Infectious Diseases, 126, 136–144. doi:10.1016/j.ijid.2022.10.046

58. World Health Organization. Validation of elimination of dog-mediated human rabies as a public health problem. Retrieved April 6, 2024, from https://www.who.int/teams/control-of-neglected-tropical-diseases/rabies/elimination-of-rabies-as-a-public-health-problem#:~:text=WHO%27s%20road%20map%20for%20 neglected,or%20%E2%80%9CZero%20 by%20 30%E2%80%9D

59. World Health Organization. Disability-adjusted life years (DALYs). Retrieved April 6, 2024, from https://www.who.int/data/gho/indicator-metadata-registry/imr-details/158#:~:text=DALYs%20 for%20a%20disease%20or,health%20condition%20in%20a%20population

60. Castillo-Neyra, R., Buttenheim, A.M., Brown, J., Ferrara, J.F., Arevalo-Nieto, C., Borrini-Mayon, K., Levy, M.Z., Becerra, V., Paz-Soldan, V.A. (2020). Behavioral and structural barriers to accessing human post-exposure prophylaxis and other preventive practices in Arequipa, Peru, during a canine rabies epidemic. PLOS Neglected Tropical Diseases, 14(7). PMI: 32692739

BACK FROM BATTLE: THE CONDITIONING OF FEAR IN PTSD

1. Duncan, L. E., Cooper, B. N., & Shen, H. (2018a). Robust findings from 25 years of PTSD genetics research. Current Psychiatry Reports, 20(12). doi:10.1007/s11920-018-0980-1

2. Laricchiuta, D., Panuccio, A., Picerni, E., Biondo, D., Genovesi, B., & Petrosini, L. (2023). The body keeps the score: The neurobiological profile of traumatized adolescents. Neuroscience & Biobehavioral Reviews, 145, 105033. doi:10.1016/j.neubiorev.2023.105033

3. National Institute of Mental Health (2023). Post-Traumatic Stress Disorder. Retrieved April 13, 2024 from https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd

4. American Psychiatric Association. (2013). [Trauma- and Stressor-Related Disorders]. In Diagnostic and statistical manual of mental disorders (5th ed.). doi:10.1176/appi.books.9780890425596

5. Careaga, M. B., Girardi, C. E., & Suchecki, D. (2016). Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. Neuroscience & Biobehavioral Reviews, 71, 48–57. doi:10.1016/j.neubiorev.2016.08.023

6. VanElzakker, M. B., Kathryn Dahlgren, M., Caroline Davis, F., Dubois, S., & Shin, L. M. (2014). From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, and anxiety disorders. Neurobiology of Learning and Memory, 113, 3–18. doi:10.1016/j.nlm.2013.11.014

7. Pavlov P. I. (2010). Conditioned reflexes: An investigation of the physiological activity of the cerebral cortex. Annals of neurosciences, 17(3), 136–141. doi:10.5214/ans.0972-7531.1017309

8. Rehman, Ibraheem., Mahabadi, Navid., Sanvictores, Terrence., l. Rehman, Chaudhry. (2023). Classical Conditioning. In StatPearls. StatPearls Publishing. PMID:29262194

REFERENCES

9. Lis, S., Thome, J., Kleindienst, N., Mueller-Engelmann, M., Steil, R., Priebe, K., Schmahl, C., Hermans, D., & Bohus, M. (2019). Generalization of fear in post-traumatic stress disorder. Psychophysiology, 57(1). doi:10.1111/psyp.13422

10. Dymond, S., Dunsmoor, J. E., Vervliet, B., Roche, B., & Hermans, D. (2014). Fear generalization in humans: Systematic review and implications for anxiety disorder research. Behavior Therapy, 46(5), 561-582. doi:10.1016/j.beth.2014.10.001

11. Besnard, A., & Sahay, A. (2016). Adult Hippocampal Neurogenesis, Fear Generalization, and Stress. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(1), 24–44. doi:10.1038/npp.2015.167

12. Hayes, J. P., Hayes, S., Miller, D. R., Lafleche, G., Logue, M. W., & Verfaellie, M. (2017). Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume. Journal of Psychiatric Research, 95, 247–252. doi:10.1016/j.jpsychires.2017.09.007

13. Park, J., Marvar, P. J., Liao, P., Kankam, M. L., Norrholm, S. D., Downey, R. M., McCullough, S. A., Le, N. A., & Rothbaum, B. O. (2017). Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder. The Journal of physiology, 595(14), 4893–4908. doi:10.1113/JP274269

14. Rotenberg, S., & McGrath, J. J. (2016). Inter-relation between autonomic and HPA axis activity in children and adolescents. Biological psychology, 117, 16–25. doi:10.1016/j.biopsycho.2016.01.015

15. Dunlop, B. W., & Wong, A. (2019). The hypothalamic-pituitary-adrenal axis in PTSD: Pathophysiology and treatment interventions. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 89, 361–379. doi:10.1016/j.pnpbp.2018.10.010

16. Chu, Brianna., Marwaha, Komal., Sanvictores, Terrence., Ayers, Derek. (2022). Physiology, stress reaction. In StatPearls. StatPearls Publishing. PMID:31082164

17. Beutler, S., Mertens, Y. L., Ladner, L., Schellong, J., Croy, I., & Daniels, J. K. (2022). Trauma-related dissociation and the autonomic nervous system: A systematic literature review of psychophysiological correlates of dissociative experiencing in PTSD patients. European Journal of Psychotraumatology, 13(2). doi:10.1080/20008066.2022.21325 99

18. Sangha, S., Diehl, M. M., Bergstrom, H. C., & Drew, M. R. (2020). Know safety, no fear. Neuroscience & Biobehavioral Reviews, 108, 218–230. doi: 10.1016/j.neubiorev.2019.11.006

19. Damis, L. F. (2022). The role of implicit memory in the development and recovery from trauma-related disorders. NeuroSci, 3(1), 63–88. doi:10.3390/ neurosci3010005

20. van Rooij, S. J. H., Stevens, J. S., Ely, T. D., Hinrichs, R., Michopoulos, V., Winters, S. J., Ogbonmwan, Y. E., Shin, J., Nugent, N. R., Hudak, L. A., Rothbaum, B. O., Ressler, K. J., & Jovanovic, T. (2018). The role of the hippocampus in predicting future posttraumatic stress disorder symptoms in recently traumatized civilians. Biological Psychiatry, 84(2), 106–115. doi:10.1016/j.biopsych.2017.09.005

21. Joshi, S. A., Duval, E. R., Kubat, B., Liberzon, I. (2020). A review of hippocampal activation in post-traumatic stress disorder. Psychophysiology, 57. doi:10.1111/psyp.13357

22. Hathaway, W. R., Newton, B. W. (2023). Neuroanatomy, prefrontal cortex. In StatPearls. StatPearls Publishing. PMID:29763094

23. Jiao, X., Beck, K. D., Myers, C. E., Servatius, R. J., & Pang, K. C. H. (2015). Altered activity of the medial prefrontal cortex and amygdala during acquisition and extinction of an active avoidance task. Frontiers in Behavioral Neuroscience, 9. doi:10.3389/ fnbeh.2015.00249

24. Schrader, C., & Ross, A. (2021). A review of PTSD and current treatment strategies. Missouri Medicine, 118(6), 546–551. PMID:34924624

25. Gainer, D., Alam, S., Alam, H., & Redding, H. (2020). A FLASH OF HOPE: Eye Movement Desensitization and Reprocessing (EMDR) Therapy. Innovations in clinical neuroscience, 17(7-9), 12–20. PMID:33520399

26. Landin-Romero, R., Moreno-Alcazar, A., Pagani, M., & Amann, B. L. (2018). How does eye movement desensitization and reprocessing therapy work? A systematic review on suggested mechanisms of action. Frontiers in Psychology, 9. doi:10.3389/ fpsyg.2018.01395

27. Mitchell, J.M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., Ot’alora G., M., Garas, W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells G., Klaire, S.S., van der Kolk, B., Tzarfaty, K., Amiaz, R., Worthy, R., Shannon, S., Woolley, J.D., Marta, C., Gelfand, Y., Hapke, E., Amar, S., Wallach, Y., Brown, R., Hamilton, S., Wang, J.B., Coker, A., Matthews, R., de Boer, A., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2021). MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 27, 1025-1033. doi:10.1038/s41591-021-01336-3

28. Mithoefer, M. C., Mithoefer, A. T., Feduccia, A. A., Jerome, L., Wagner, M., Wymer, J., Holland, J., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2018) 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: A randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry, 5(6), 486-497. doi:10.1016/ S2215-0366(18)30135-4

FROM CLUB TO CLINIC: THE TREATMENT OF PSD WITH MDMA

1. Riaz K, Suneel S, Hamza Bin Abdul Malik M, Kashif T, Ullah I, Waris A, Di Nicola M, Mazza M, Sani G, Martinotti G, & De Berardis D. (2023) MDMA-based psychotherapy in treatment-resistant post-traumatic stress disorder (PTSD): A brief narrative overview of current evidence. Diseases, 11(4), 159. doi:10.3390/diseases11040159

2. Kessler, R.C., Aguilar-Gaxiola, S., Alonso, J. Benjet, C., Bromet, E.J., Cardoso, G., Degenhardt, L., de Girolamo, G., Dinolova, R.V., Ferry, F., Florescu, S., Gureje, O., Haro, J.M., Huang, Y., Karan, E.G., Kawakami, N., Lee, S., Lepine, J., Levinson, D., Navarro-Mateu, F., Pennell, B., Piazza, M., Posada-Villa, J., Scott, K.M., Stein, D.J., Have, M.T., Torres, Y., Viana, M.C., Petukhova, M.V., Sampson, N.A., Zaslavsky, A.M., & Koenen, K.C. (2017). Trauma and PTSD in the WHO Mental Health surveys. European Journal of Psychotraumatology, 8. doi:10.1080/ 20008198.2017.1353383

3. Krystal, J.H., Davis, L.L., Neylan, T.C., Raskin, M.A., Schnurr, P.P., Stein, M.B., Vessicchio, J., Shiner, B., Gleason, T.D., & Huang, G.D. (2017). It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: A consensus statement of the PTSD psychopharmacology working group. Biological Psychiatry, 82(7), e51-e59. doi:10.1016/j. biopsych.2017.03.007

4. Mithoefer, M.C., Mithoefer, A.T., Feduccia, A.A., Jerome, L., Wagner, M., Wymer, J., Holland, J., Hamilton, S., Yazar-Klosinki, B., Emerson, A., & Doblin, R. (2018). 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: A randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry, 5(6), 486-497. doi:10.1016/ s2215-0366(18)30135-4

5. Elklit, A., Hyland, P., & Shevlin, M. (2014). Evidence of symptom profiles consistent with posttraumatic stress disorder and complex posttraumatic stress disorder in different trauma samples. European Journal of Psychotraumatology, 5(1). doi:10.3402/ejpt.v5.24221

6. Fried, E.I., Eidhof, M.B., Palic, S., Costantini, G., Huisman-van Dijk, H.M., Bockting, C.L.H., Engelhard, I., Armour, C., Nielsen, A.B.S., & Karstoft, K.I. (2018). Replicability and generalizability of posttraumatic stress disorder (PTSD) networks: A cross-cultural multisite study of PTSD symptoms in four trauma patient samples. Clinical Psychological Science, 6(3). doi:10.1177/2167702617745092

7. Mitchell, J.M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., Ot’alora G., M., Garas, W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells G., Klaire, S.S., van der Kolk, B., Tzarfaty, K., Amiaz, R., Worthy, R., Shannon, S., Woolley, J.D., Marta, C., Gelfand, Y., Hapke, E., Amar, S., Wallach, Y., Brown, R., Hamilton, S., Wang, J.B., Coker, A., Matthews, R., de Boer, A., Yazar-Klosinski, B., Emerson, A., & Doblin, R. (2021). MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 27, 1025-1033. doi:10.1038/s41591-021-01336-3

8. Feduccia, A.A., Mithoefer, M.C., Jerome, L., Holland, J., Emerson, A., & Doblin, R. (2018). Response to the consensus statement of the PTSD psychopharmacology working group. Biological Psychiatry, 84(2), e21-e22. doi:10.1016/j.biopsych.2017.11.023

9. Garcia-Romeu, A., Kersgaard, B., & Addy, P.H. (2016). Clinical applications of hallucinogens: A review. Experimental Clinical Psychopharmacology, 24(4), 229-268. doi:10.1037%2Fpha0000084

10. van der Kolk, B.A., Wang, J.B., Yehuda, R., Bedorsian, L., Coker, A.R., Harrison, C., Mithoefer, M., Yazar-Klosinki, B., Emerson, A., & Doblin, R. (2024). Effects of MDMA-assisted therapy for PTSD on self-experience. PLOS ONE. doi:10.1371/journal. pone.0295926

11. American Psychiatric Association. (2022). Traumaand Stressor-Related Disorders. Diagnostic and Statistical Manual of Mental Disorders (5th ed., text revision). doi:10.1176/appi.books.9780890425787. x07_Trauma_and_Stressor_Related_Disorders

12. Iqbal, J., Huang, G., Xue, Y., Yang, M., & Jia, X. (2023). The neural circuits and molecular mechanisms underlying fear dysregulation in posttraumatic stress disorder. Frontiers in Neuroscience, 17. doi:10.3389/fnins.2023.1281401

REFERENCES

13. Mitchell, J.M., Ot’alora G., M., van der Kolk, B., Shannon, S., Bogenschutz, M., Gelfand, Y., Paleos, C., Nicholas, C.R., Quevedo, S., Balliett, B., Hamilton, S., Mithoefer, M., Kleiman, S., Parker-Guilbert, K., Tzarfaty, K., Harrison, C., de Boer, Al., Doblin, R., Yazar-Klosinski, B., & MAPP2 Study Collaborator Group. (2023). MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nature Medicine, 29, 24732480. doi:10.1038/s41591-023-02565-4

14. Maddox, S.A., Hartmann, J., Ross, R.A., & Ressler, K.J. (2019). Deconstructing the gestalt: Mechanisms of fear, threat, and trauma memory encoding. Neuron, 102. doi:10.1016/j.neuron.2019.03.017

15. Haubrich, J., Crestani, A.P., Cassini, L.F., Santana, F., Sierra, R.O., de O Alvares, L., & Quillfeldt, J.A. (2015). Reconsolidation allows fear memory to be updated to a less aversive level through the incorporation of appetitive information. Neuropsychopharmacology, 40(2), 315-326. doi:10.1038/ npp.2014.174

16. Björkstrand, J., Agren, T., Frick, A., Engman, J., Larsson, E., Furmark, T., & Fredrikson, M. (2015). Disruption of memory reconsolidation erases a fear memory trace in the human amygdala: An 18 month follow-up. PLOS One, 10(7). doi:10.1371/ journal.pone.0129393

17. Tang, W., Kochubey, O., Kintscher, M., & Schneggenburger, R. (2020). A VTA to basal amygdala dopamine projection contributes to signal salient somatosensory events during fear learning. Journal of Neuroscience, 40(20), 3969-3980. doi:10.1523/JNEUROSCI.1796-19.2020

18. Bocchio, M., McHugh, S.B., Bannerman, D.M., Sharp, T., & Capogna, M. (2016). Serotonin, amygdala and fear: Assembling the puzzle. Frontiers in Neural Circuits, 10. doi:10.3389/fncir.2016.00024

19. Clancy, K.J., Devignes, Q., Ren, B., Pollmann, Y., Nielsen, S.R., Howell, K., Kumar, P., Belleau, E.L., Rosso, I.M. (2024). Spatiotemporal dynamics of hippocampal-cortical networks underlying the unique phenomenological properties of trauma-related intrusive memories. Molecular Psychiatry. doi:10.1038/s41380-024-02486-9

20. Feduccia, A.A., Jerome, L., Yazar-Klosinski, B., Emerson, A., Mithoefer, M.C., & Doblin, R. (2019). Breakthrough for trauma treatment: Safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline. Frontiers in Psychiatry, 10. doi:10.3389/fpsyt.2019.00650

21. Haycraft, A.L. (2023). The future for psychedelic agents in the treatment of posttraumatic stress disorder. The Journal for Nurse Practitioners, 19(5). doi:10.1016/j.nurpra.2023.104586

22. Bamalan, O.A., Moore, M.J., Khalili, Y.A. (2023). Physiology, serotonin. In StatPearls. StatPearls Publishing. PMID:31424752

23. Shelton, R.C. (2018). Serotonin and norepinephrine reuptake inhibitors. In: Macaluso, M., Preskorn, S. (eds). Antidepressants. Handbook of Experimental Pharmacology, 250, 145-180. Springer. doi:10.1007/164_2018_164

24. MacNamara, A., Rabinak, C.A., Kennedy, A.E., Fitzgerald, D.A., Liberzon, I., Stein, M.B., Phan, K.L. (2016). Emotion regulatory brain function and SSRI treatment in PTSD: neural correlates and predictors of change. Neuropsychopharmacology, 41, 611-618. doi:10.1038/npp.2015.190

25. Sessa, B., (2017). MDMA and PTSD treatment: “PTSD: From novel pathophysiology to innovative therapeutics.” Neuroscience Letters, 649, 176-180. doi:10.1016/j.neulet.2016.07.004

26. Williams, T., Phillips, N.J., Stein, D.J., Ipser, J.C. (2022). Pharmacotherapy for post traumatic stress disorder (PTSD). The Cochrane Database of Systematic Reviews, 3(3). doi:10.1002/14651858. cd002795.pub3

27. National Institute on Drug Abuse. (2022). Who is using MDMA? Retrieved March 28, 2024 from https://nida.nih.gov/publications/research-reports/mdma-ecstasy-abuse/who-is-using-mdma

28. Costa, G. & Gołembiowska, K. (2022). Neurotoxicity of MDMA: Main effects and mechanisms. Experimental Neurology, 347. doi:10.1016/j.expneurol.2021.113894

29. Sottile, J.E., Macia, K.S., Wickham, R.E., & Haug, N.A. (2023). Development and initial validation of an MDMA/Ecstasy motives assessment. Addictive Behaviors, 136. doi:10.1016/j.addbeh.2022.107494

30. Mustafa, N. S., Bakar, N. H. A., Mohamad, N., Adnan, L. H. M., Fauzi, N. F. A. M., Thoarlim, A., Omar, S. H. S., Hamzah, M. S., Yusoff, Z., Jufri, M., & Ahmad R. (2020). MDMA and the brain: A short review on the role of neurotransmitters in neurotoxicity. Basic and Clinical Neuroscience, 11(4), 381-388. doi:10.32598/bcn.9.10.485

31. Carhart-Harris, R.L., Murphy, K., Leech, R., Erritzoe, D., Wall, M.B., Ferguson, B., Williams, L.T.J., Roseman, L., Brugger, S., De Meer, I., Tanner, M., Tyacke, R., Wolff, K., Sethi, A., Bloomfield, M.A.P., Williams, T.M., Bolstridge, M., Stewart, L., Morgan, C., Newbould, R.D., Feilding, A., Curran, H.V., & Nutt, D.J. (2015). The effects of acutely administered 3,4-methylenedioxymethamphetamine on spontaneous brain function in healthy volunteers measured with arterial spin labeling and blood oxygen level-dependent resting state functional connectivity. Biological Psychiatry, 78(8), 554-562. doi:10.1016%2Fj.biopsych.2013.12.015

32. Lizarraga, L.C., Cholaniana, A.B., Phan, A.V., Herndon, J.M., Lau, S.S., & Monks, T.J. (2015). Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine. Toxicological Sciences, 143(1), 209-219. doi:10.1093/toxsci/kfu222

33. Kirkpatrick, M.G., Lee, R., Wardle, M.C., Jacob, S., & de Wit, H. (2014). Effects of MDMA and intranasal oxytocin on social and emotional processing. Neuropsychopharmacology, 39, 1654-1663. doi:10.1038/npp.2014.12

34. Carter, C.S. (2022). Oxytocin and love: Myths, metaphors and mysteries. Comprehensive Psychoneuroendocrinology, 9. doi:10.1016/j.cpnec.2021.100107

35. Morrison, I. (2016). Keep calm and cuddle on: Social touch as a stress buffer. Adaptive Human Behavior and Physiology, 2, 344–362. doi:10.1007/ s40750-016-0052-x

36. Vizeli, P. & Liechti, M.E. (2018). Oxytocin receptor gene variations and socio-emotional effects of MDMA: A pooled analysis of controlled studies in healthy subjects. PLOS ONE, 13(6). doi:10.1371/ journal.pone.0199384

37. Molla, H., Lee, R., Lyubomirsky, S., & de Wit, H. (2023). Drug-induced social connection: Both MDMA and methamphetamine increase feelings of connectedness during controlled dyadic conversations. Scientific Reports, 13. doi:10.1038/ s41598-023-43156-0

38. Ramos, L., Hicks, C., Caminer, A., Goodwin, J., & McGregor, I.S. (2015). Oxytocin and MDMA (‘ecstasy’) enhance social reward in rats. Psychopharmacology, 232, 2631-2641. doi:10.1007/s00213015-3899-9

39. Kamilar-Britt, P. & Bedi, G. (2015). The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals. Neuroscience and Biobehavioral Reviews, 57, 433-446. doi:10.1016/j.neubiorev.2015.08.016

40. Sottile, R.J. & Vida, T. (2022). A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy. Frontiers in Psychiatry, 13. doi:10.3389/fpsyt.2022.991753

41. Dai, Z., Xu, X., Chen, W., Nie, L., Liu, Y., Sui, N., & Liang, J. (2022). The role of hippocampus in memory reactivation: An implication for a therapeutic target against opioid use disorder. Current Addiction Reports, 9(2), 67-79. doi:10.1007%2Fs40429022-00407-w

42. Molitor, R.J., Sherrill, K.R., Morton, N.W., Miller, A.A., & Preston, A.R. (2021). Memory reactivation during learning simultaneously promotes dentate gyrus/ CA2,3 pattern differentiation and CA1 memory integration. Journal of Neuroscience, 41(4), 726-738. doi:10.1523%2FJNEUROSCI.0394-20.2020

43. Wunderli, M.D., Vonmoos, M., Fürst, M., Schädelin, K., Kraemer, T., Baumgartner, M.R., Seifritz, E., & Quednow, B.B. (2017). Discrete memory impairments in largely pure chronic users of MDMA. European Neuropsychopharmacology, 27(10), 987999. doi:10.1016/j.euroneuro.2017.08.425

44. Lee, J.L.C., Nader, K., & Schiller, D. (2017). An update on memory reconsolidation updating. Trends in Cognitive Sciences, 21(7), 531-545. 10.1016/j. tics.2017.04.006

45. Schwabe, L., Nader, K., & Pruessner, J.C. (2014). Reconsolidation of human memory: Brain mechanisms and clinical relevance. Biological Psychiatry, 76(4), 274-280. doi:10.1016/j.biopsych.2014.03.008

46. Costa, G., Morelli, M., & Simola, N. (2017). Progression and persistence of neurotoxicity induced by MDMA in dopaminergic regions of the mouse brain and association with noradrenergic, GABAergic, and serotonergic damage. Neurotoxicity Research, 32, 563-574. doi:10.1007/s12640-017-9761-6

47. Multidisciplinary Association for Psychedelic Studies. (2023, December 13). MAPS celebrates submission of new drug application to FDA for MDMA-assisted therapy for PTSD. Globe Newswire. Retrieved March 31, 2024 from https://www.globenewswire.com/news-release/2023/12/13/2795925/0/en/MAPS-Celebrates-Submission-of-New-Drug-Application-toFDA-for-MDMA-Assisted-Therapy-for-PTSD.html

48. Feduccia, A.A. & Mithoefer, M.C. (2018). MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? Progress in Neuro-Psychopharmacology and Biological Psychiatry, 84, 221-228. doi:10.1016/j.pnpbp.2018.03.003

49. Hall, W. (2022). Why was early therapeutic research on psychedelic drugs abandoned? Psychological Medicine, 52(1), 26-31. doi:10.1017/ S0033291721004207

50. U.S. Department of Veterans Affairs. (2024, January 5). To improve care for Veterans, VA to fund studies on new therapies for treating mental health conditions [Press release]. Retrieved from https://news.va.gov/press-room/to-improvecare-for-veterans-va-to-fund-studies-on-newtherapies-for-treating-mental-health-conditions/

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

1. Ghosh, A., Naskar, C., Sharma, N., Fazl-e-Roub, Choudhury, S., Basu, A., Pillai, R. R., Basu, D., & Mattoo, S. K. (2022). Does online newsmedia portrayal of substance use and persons with Substance Misuse Endorse Stigma? A qualitative study from India. International Journal of Mental Health and Addiction, 20(6), 3460–3478. doi:10.1007/s11469022-00859-1

2. Denham, B., Cacciatore, S., & Caves, M. (2021). Bleeding borders and enemies within: How newsmagazine covers portrayed drugs of abuse, 1979–2019. Contemporary Drug Problems, 48(1), 3–18. doi:10.1177/0091450921993835

3. Clare, K., Pan, C., Kim, G., Park, K., Zhao, J., Volkow, N. D., Lin, Z., & Du, C. (2021). Cocaine reduces the neuronal population while upregulating dopamine D2-receptor-expressing neurons in brain reward regions: Sex-effects. Frontiers in Pharmacology, 12. doi:10.3389/fphar.2021.624127

4. Creed, M., Kaufling, J., Fois, G. R., Jalabert, M., Yuan, T., Lüscher, C., Georges, F., & Bellone, C. (2016). Cocaine exposure enhances the activity of ventral tegmental area dopamine neurons via calcium-impermeable NMDARs. The Journal of Neuroscience, 36(42), 10759–10768. doi:10.1523/ jneurosci.1703-16.2016

5. Gerth, A. I., Alhadeff, A. L., Grill, H. J., & Roitman, M. F. (2017). Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem. Brain Research, 1655, 252–260. doi:10.1016/j.brainres.2016.10.022

6. Biondich, A. S., & Joslin, J. D. (2016). Coca: The history and medical significance of an ancient Andean tradition. Emergency Medicine International, 2016, 1–5. doi:10.1155/2016/4048764

7. Roque Bravo, R., Faria, A. C., Brito-da-Costa, A. M., Carmo, H., Mladěnka, P., Dias da Silva, D., & Remião, F. (2022). Cocaine: An updated overview on chemistry, detection, biokinetics, and pharmacotoxicological aspects including abuse pattern. Toxins, 14(4), 278. doi:10.3390/toxins14040278

8. Schwartz, E. K., Wolkowicz, N. R., De Aquino, J. P., MacLean, R. R., & Sofuoglu, M. (2022). Cocaine use disorder (CUD): Current clinical perspectives. Substance Abuse and Rehabilitation, 13, 25–46. doi:10.2147/sar.s337338

9. Schoenbaum, G., Chang, C.-Y., Lucantonio, F., & Takahashi, Y. K. (2016). Thinking outside the box: Orbitofrontal cortex, imagination, and how we can treat addiction. Neuropsychopharmacology, 41(13), 2966–2976. doi:10.1038/npp.2016.147

10. Waxenbaum, J. A. (2023). Anatomy, autonomic nervous system. In StatPearls. StatPearls Publishing. PMID:30969667

11. Bennett, J. M., Reeves, G., Billman, G. E., & Sturmberg, J. P. (2018). Inflammation–nature’s way to efficiently respond to all types of challenges: Implications for understanding and managing “the epidemic” of chronic diseases. Frontiers in Medicine, 5. doi:10.3389/fmed.2018.00316

12. Kim, S., & Park, T. (2019). Acute and chronic effects of cocaine on cardiovascular health. International Journal of Molecular Sciences, 20(3), 584. doi:10.3390/ijms20030584

13. Tindle, J. (2022). Neuroanatomy, parasympathetic nervous system. In StatPearls. StatPearls Publishing. PMID:31985934

14. Südhof, T. C. (2021). The cell biology of synapse formation. Journal of Cell Biology, 220(7). doi:10.1083/jcb.202103052

15. Faber, D. S., & Pereda, A. E. (2018). Two forms of electrical transmission between neurons. Frontiers in Molecular Neuroscience, 11. doi:10.3389/ fnmol.2018.00427

16. Niello, M., Gradisch, R., Loland, C. J., Stockner, T., & Sitte, H. H. (2020). Allosteric modulation of neurotransmitter transporters as a therapeutic strategy. Trends in Pharmacological Sciences, 41(7), 446–463. doi:10.1016/j.tips.2020.04.006

17. Verma, V. (2015). Classic studies on the interaction of cocaine and the dopamine transporter. Clinical Psychopharmacology and Neuroscience, 13(3), 227–238. doi:10.9758/cpn.2015.13.3.227

18. Heal, D. J., Gosden, J., & Smith, S. L. (2014). Dopamine reuptake transporter (DAT) “inverse agonism” – a novel hypothesis to explain the enigmatic pharmacology of cocaine. Neuropharmacology, 87, 19–40. doi:10.1016/j.neuropharm.2014.06.012

19. Cai, J., & Tong, Q. (2022). Anatomy and function of ventral tegmental area glutamate neurons. Frontiers in Neural Circuits, 16. doi:10.3389/fncir.2022.867053

20. Volkow, N. D., & Morales, M. (2015). The brain on drugs: From reward to addiction. Cell, 162(4), 712–725. doi:10.1016/j.cell.2015.07.046

21. Poisson, C. L., Engel, L., & Saunders, B. T. (2021). Dopamine circuit mechanisms of addiction-like behaviors. Frontiers in Neural Circuits, 15. doi:10.3389/fncir.2021.752420

22. Samaha, A.-N., Khoo, S. Y.-S., Ferrario, C. R., & Robinson, T. E. (2021). Dopamine ‘ups and downs’ in addiction revisited. Trends in Neurosciences, 44(7), 516–526. doi:10.1016/j.tins.2021.03.003

23. Chiamulera, C., Piva, A., & Abraham, W. C. (2021). Glutamate receptors and metaplasticity in addiction. Current Opinion in Pharmacology, 56, 39–45. doi:10.1016/j.coph.2020.09.005

24. Moulin, T. C., & Schiöth, H. B. (2020). Excitability, synaptic balance, and addiction: The homeostatic dynamics of ionotropic glutamatergic receptors in VTA after cocaine exposure. Behavioral and Brain Functions, 16(1). doi:10.1186/s12993-020-00168-4

25. Pal, M. M. (2021). Glutamate: The master neurotransmitter and its implications in chronic stress and mood disorders. Frontiers in Human Neuroscience, 15. doi:10.3389/fnhum.2021.722323

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

27. Gong, S., Fayette, N., Heinsbroek, J. A., & Ford, C. P. (2021). Cocaine shifts dopamine D2 receptor sensitivity to gate conditioned behaviors. Neuron, 109(21). doi:10.1016/j.neuron.2021.08.012

28. Volkow, N. D., Michaelides, M., & Baler, R. (2019). The neuroscience of drug reward and addiction. Physiological Reviews, 99(4), 2115–2140. doi:10.1152/physrev.00014.2018

29. Sampaio-Baptista, C., & Johansen-Berg, H. (2017). White matter plasticity in the adult brain. Neuron, 96(6), 1239–1251. doi:10.1016/j.neuron.2017.11.026

30. Hampton, W. H., Hanik, I. M., & Olson, I. R. (2019). Substance abuse and white matter: Findings, limitations, and future of Diffusion Tensor Imaging Research. Drug and Alcohol Dependence, 197, 288–298. doi:10.1016/j.drugalcdep.2019.02.005

31. Li, X., Salami, A., Avelar-Pereira, B., Bäckman, L., & Persson, J. (2022). White-matter integrity and working memory: Links to aging and dopamine-related genes. Eneuro, 9(2). doi:10.1523/ eneuro.0413-21.2022

32. Desai, R. A., Davies, A. L., Tachrount, M., Kasti, M., Laulund, F., Golay, X., & Smith, K. J. (2016). Cause and prevention of demyelination in a model multiple sclerosis lesion. Annals of Neurology, 79(4), 591–604. doi:10.1002/ana.24607

33. Ma, L., Steinberg, J. L., Wang, Q., Schmitz, J. M., Boone, E. L., Narayana, P. A., & Moeller, F. G. (2017). A preliminary longitudinal study of white matter alteration in cocaine use disorder subjects. Drug and Alcohol Dependence, 173, 39–46. doi:10.1016/j. drugalcdep.2016.12.016

34. Tondo, L. P., Viola, T. W., Fries, G. R., Kluwe-Schiavon, B., Rothmann, L. M., Cupertino, R., Ferreira, P., Franco, A. R., Lane, S. D., Stertz, L., Zhao, Z., Hu, R., Meyer, T., Schmitz, J. M., Walss-Bass, C., & Grassi-Oliveira, R. (2021). White matter deficits in cocaine use disorder: Convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomic analysis. Translational Psychiatry, 11(1). doi:10.1038/s41398-021-01367-x

35. Alballa, T., Boone, E. L., Ma, L., Snyder, A., & Moeller, F. G. (2021). Exploring the relationship between white matter integrity, cocaine use and gad polymorphisms using Bayesian model averaging. PLOS ONE, 16(7). doi:10.1371/journal.pone.0254776

36. Maxfield, M., Cooper, M. S., Kavanagh, A., Devine, A., & Gill Atkinson, L. (2021). On The outside looking in: A phenomenological study of the lived experience of Australian adults with a disorder of the corpus callosum. Orphanet Journal of Rare Diseases, 16(1). doi:10.1186/s13023-021-02140-5

37. Farhoudian, A., Razaghi, E., Hooshyari, Z., Noroozi, A., Pilevari, A., Mokri, A., Mohammadi, M. R., Malekinejad, M. (2022). Barriers and facilitators to substance use disorder treatment: An overview of systemic reviews. Substance Abuse: Research and Treatment, 16. doi:10.1177/11782218221118462

38. Kampman, K. M. (2019). The treatment of cocaine use disorder. Science Advances, 5(10). doi:10.1126/ sciadv.aax1532

FEATURED

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

1. Berstein, S., Warburton, W., Bussey, K., & Sweller, N. (2021). “Rule 34: If it exists, there is porn of it...” Insights into the content choices, viewing reasons and attitudinal impact of internet pornography among young adults. Sexual Health & Compulsivity, 28(1-2), 1-28. doi:10.1080/26929953.2021.1986 763

2. Tyler, M., & Quek, K. (2016). Conceptualizing pornographication: A lack of clarity and problems for feminist analysis. Sexualization, Media, & Society, 2(2). doi:10.1177/2374623816643281

3. Bridges, A. J., Condit, D. M., Dines, G., Johnson, J. A., & West, C. M. (2015). Introducing sexualization, media, & society. Sexualization, Media, & Society, 1(1). doi:10.1177/2374623815588763

4. Ward, L. M. (2016). Media and sexualization: State of empirical research, 1995–2015. The Journal of Sex Research, 53(4–5), 560–577. doi:10.1080/0022 4499.2016.1142496

5. Peter, J., & Valkenburg, P. M. (2016). Adolescents and pornography: A review of 20 years of research. The Journal of Sex Research, 53(4–5), 509–531. doi:10.1080/00224499.2016.1143441

6. Fisher, W. A., & Kohut, T. (2019). Reading pornography: Methodological considerations in evaluating pornography research. The Journal of Sexual Medicine, 17(2), 195–209. doi:10.1016/j.jsxm.2019.11.257

7. Chapman, M., Dammeyer, J., Strizzi, J. M., & Hald, G. M. (2023). Using pornography, paying for sex, and violence: A Danish national survey study. The Journal of Sex Research, 1–12. doi:10.1080/002244 99.2023.2280965

8. Richters, J., de Visser, R. O., Badcock, P. B., Smith, A. M., Rissel, C., Simpson, J. M., & Grulich, A. E. (2014). Masturbation, paying for sex, and other sexual activities: The Second Australian Study of health and relationships. Sexual Health, 11(5), 461–471. doi:10.1071/sh14116

9. Carroll, J. S., Busby, D. M., Willoughby, B. J., & Brown, C. C. (2016). The porn gap: Differences in men’s and women’s pornography patterns in couple relationships. Journal of Couple & Relationship Therapy, 16(2), 146–163. doi:10.1080/1533269 1.2016.1238796

10. Marshall, E. A., & Miller, H. A. (2022). The role of sexual scripts in the relationship between pornography use and sexual coercion. Journal of Interpersonal Violence, 38(7–8), 5519–5541. doi:10.1177/08862605221123291

11. Vera-Gray, F., McGlynn, C., Kureshi, I., & Butterby, K. (2021). Sexual violence as a sexual script in mainstream online pornography. The British Journal of Criminology, 61(5), 1243–1260. doi:10.1093/ bjc/azab035

12. Foubert, J. D., & Bridges, A. J. (2016). What is the attraction? Pornography use motives in relation to bystander intervention. Journal of Interpersonal Violence, 32(20), 3071–3089. doi:10.1177/0886260515596538

13. Hald, G. M., & Malamuth, N. N. (2014). Experimental effects of exposure to pornography: The moderating effect of personality and mediating effect of sexual arousal. Archives of Sexual Behavior, 44(1), 99–109. doi:10.1007/s10508-014-0291-5

14. Shor, E. (2021). Who seeks aggression in pornography? findings from interviews with viewers. Archives of Sexual Behavior, 51, 1237–1255. doi:10.1007/s10508-021-02053-1

15. Biota, I., Dosil-Santamaria, M., Mondragon, N. I., & Ozamiz-Etxebarria, N. (2022). Analyzing university students’ perceptions regarding mainstream pornography and its link to SDG5. International Journal of Environmental Research and Public Health, 19(13), 8055. doi:10.3390/ijerph19138055

16. Herbitter, C., Norris, A. L., Nelson, K. M., & Orchowski, L. M. (2021). Understanding associations between exposure to violent pornography and teen dating violence among female sexual minority high school students. Journal of Interpersonal Violence, 37(17–18). doi:10.1177/08862605211028314

17. Fritz, N., Malic, V., Paul, B., & Zhou, Y. (2020). A descriptive analysis of the types, targets, and relative frequency of aggression in mainstream pornography. Archives of Sexual Behavior, 49(8), 3041–3053. doi:10.1007/s10508-020-01773-0

18. Marsh, A. A. (2018). The neuroscience of empathy. Current Opinion in Behavioral Sciences, 19, 110–115. doi:10.1016/j.cobeha.2017.12.016

19. Wright, P. J., & Tokunaga, R. S. (2015). Men’s objectifying media consumption, objectification of women, and attitudes supportive of violence against women. Archives of Sexual Behavior, 45(4), 955–964. doi:10.1007/s10508-015-0644-8

20. Zhou, Y., Liu, T., Yan, (Harry) Yaojun, & Paul, B. (2021). Pornography use, two forms of dehumanization, and sexual aggression: Attitudes vs. behaviors. Journal of Sex & Marital Therapy, 47(6), 571–590. doi:10.1080/0092623X.2021.1923598

21. Cogoni, C., Carnaghi, A., & Silani, G. (2021). Reduced shared emotional representations toward women revealing more skin. Cognition and Emotion, 35(2), 225–240. doi:10.1080/02699931.2020.1 826409

22. Levitan, J. A., & Vachon, D. D. (2021). The nuanced association between deficient empathy and sexual aggression. Personality and Individual Differences, 177, 110812. doi:10.1016/j.paid.2021.110812

23. Štulhofer, A. (2020). Is male adolescents’ sexual aggressiveness better explained by prior pornography use or callousness? A Brief Report. Sexual Abuse, 33(3), 361–373. doi:10.1177/1079063220952777

24. Baer, J. L., Kohut, T., & Fisher, W. A. (2015). Is pornography use associated with anti-woman sexual aggression? Re-examining the confluence model with third variable considerations. The Canadian Journal of Human Sexuality, 24(2), 160–173. doi:10.3138/cjhs.242-A6

25. Kor, A., Djalovski, A., Potenza, M. N., Zagoory-Sharon, O., & Feldman, R. (2022). Alterations in oxytocin and vasopressin in men with problematic pornography use: The role of empathy. Journal of Behavioral Addictions, 11(1), 116–127. doi:10.1556/2006.2021.00089

26. Johnson, S. A. (2015). The role of pornography in sexual offenses: Information for law enforcement & forensic psychologists. International Journal of Mental Health and Human Resilience, 17, 239-242.

27. Tranchese, A., & Sugiura, L. (2021). “I don’t hate all women, just those stuck-up bitches”: How incels and mainstream pornography speak the same extreme language of misogyny. Violence Against Women, 27(14), 2709–2734. doi:10.1177/1077801221996453

28. Kraus, S. W., Krueger, R. B., Briken, P., First, M. B., Stein, D. J., Kaplan, M. S., Voon, V., Abdo, C. H. N., Grant, J. E., Atalla, E., & Reed, G. M. (2018). Compulsive sexual behaviour disorder in the ICD11. World Psychiatry, 17(1), 109–110. doi:10.1002/ wps.20499

29. Hanseder, S., & Dantas, J. A. (2023). Males’ lived experience with self-perceived pornography addiction: A qualitative study of problematic porn use. International Journal of Environmental Research and Public Health, 20(2), 1497. doi:10.3390/ ijerph20021497

30. Cardoso, J., Ramos, C., Brito, J., & Almeida, T. C. (2023). Difficulties in emotion regulation and problematic pornography use: The mediating role of loneliness. International Journal of Sexual Health, 35(3), 481–493. doi:10.1080/19317611.2023.2224807

31. Levi, G., Cohen, C., Kaliche, S., Sharaabi, S., Cohen, K., Tzur-Bitan, D., & Weinstein, A. (2020). Sexual addiction, compulsivity, and impulsivity among a predominantly female sample of adults who use the internet for sex. Journal of Behavioral Addictions, 9(1), 83–92. doi:10.1556/2006.2020.00007

32. Antons, S., Engel, J., Briken, P., Krüger, T. H. C., Brand, M., & Stark, R. (2022). Treatments and interventions for compulsive sexual behavior disorder with a focus on problematic pornography use: A preregistered systematic review. Journal of Behavioral Addictions, 11(3), 643–666. doi:10.1556/2006.2022.00061

33. Lee, R. S., Hoppenbrouwers, S., & Franken, I. (2019). A systematic meta-review of impulsivity and compulsivity in addictive behaviors. Neuropsychology Review, 29, 14–26. doi:10.1007/s11065019-09402-x

34. Antons, S., & Brand, M. (2018). Trait and state impulsivity in males with tendency towards Internet-pornography-use disorder. Addictive Behaviors, 79, 171–177. doi:10.1016/j.addbeh.2017.12.029

35. Bőthe, B., Tóth-Király, I., Potenza, M. N., Griffiths, M. D., Orosz, G., & Demetrovics, Z. (2019). Revisiting the role of impulsivity and compulsivity in problematic sexual behaviors. The Journal of Sex Research, 56(2), 166–179. doi:10.1080/00224499.2 018.1480744

36. Rumpf, H.-J., & Montag, C. (2022). Where to put compulsive sexual behavior disorder (CSBD)? phenomenology matters. Journal of Behavioral Addictions, 11(2), 230–233. doi:10.1556/2006.2022.00039

37. Brand, M., & Potenza, M. N. (2023). Behavioral addictions in the ICD-11: An important debate that is anticipated to continue for some time. Journal of Behavioral Addictions, 12(3), 585–589. doi:10.1556/2006.2023.00042

38. Adams, R. C., Sedgmond, J., Maizey, L., Chambers, C. D., & Lawrence, N. S. (2019). Food addiction: Implications for the diagnosis and treatment of overeating. Nutrients, 11(9), 2086. doi:10.3390/ nu11092086

39. Ince, C., Yücel, M., Albertella, L., & Fontenelle, L. F. (2020). Exploring the clinical profile of problematic pornography use. CNS Spectrums, 26(6), 648–657. doi:10.1017/S1092852920001686

40. Grubbs, J. B., Exline, J. J., Pargament, K. I., Hook, J. N., & Carlisle, R. D. (2014). Transgression as addiction: Religiosity and moral disapproval as predictors of perceived addiction to pornography. Archives of Sexual Behavior, 44(1), 125–136. doi:10.1007/s10508-013-0257-z

41. Mennig, M., Tennie, S., & Barke, A. (2022). Self-perceived problematic use of online pornography is linked to clinically relevant levels of psychological distress and psychopathological symptoms. Archives of Sexual Behavior, 51(2), 1313–1321. doi:10.1007/s10508-021-02101-w

42. Christensen, E., Albertella, L., Chamberlain, S. R., Brydevall, M., Suo, C., Grant, J. E., Yücel, M., & Lee, R. S. C. (2024). The neurocognitive correlates of non-substance addictive behaviors. Addictive Behaviors, 150, 107904. doi:10.1016/j. addbeh.2023.107904

43. Perales, J. C., King, D. L., Navas, J. F., Schimmenti, A., Sescousse, G., Starcevic, V., van Holst, R. J., & Billieux, J. (2020). Learning to lose control: A process-based account of behavioral addiction. Neuroscience & Biobehavioral Reviews, 108, 771–780. doi:10.1016/j.neubiorev.2019.12.025

44. Noori, H. R., Cosa Linan, A., & Spanagel, R. (2016). Largely overlapping neuronal substrates of reactivity to drug, gambling, food and sexual cues: A comprehensive meta-analysis. European Neuropsychopharmacology, 26(9), 1419–1430. doi:10.1016/j.euroneuro.2016.06.013

45. Blinka, L., Ševčíková, A., Dreier, M., Škařupová, K., & Wölfling, K. (2022). Online sex addiction: A qualitative analysis of symptoms in treatment-seeking men. Frontiers in Psychiatry, 13, 907549. doi:10.3389/fpsyt.2022.907549

46. Demetrovics, Z., Van Den Brink, W., Paksi, B., Horváth, Z., & Maraz, A. (2022). Relating compulsivity and impulsivity with severity of behavioral addictions: A dynamic interpretation of large-scale cross-sectional findings. Frontiers in Psychiatry, 13, 831992. doi:10.3389/fpsyt.2022.831992

47. Cai, J., & Tong, Q. (2022). Anatomy and function of ventral tegmental area glutamate neurons. Frontiers in Neural Circuits, 16, 867053. doi:10.3389/ fncir.2022.867053

48. Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C., Roberts-Wolfe, D., & Kalivas, P. W. (2016). The nucleus accumbens: Mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacological Reviews, 68(3), 816–871. doi:10.1124/pr.116.012484

49. Love, T. M. (2014). Oxytocin, motivation and the role of dopamine. Pharmacology Biochemistry and Behavior, 119, 49–60. doi:10.1016/j.pbb.2013.06.011

50. Nestler, E. J., & Lüscher, C. (2019). The molecular basis of drug addiction: Linking epigenetic to synaptic and circuit mechanisms. Neuron, 102(1), 48–59. doi:10.1016/j.neuron.2019.01.016

51. Olney, J. J., Warlow, S. M., Naffziger, E. E., & Berridge, K. C. (2018). Current perspectives on incentive salience and applications to clinical disorders. Current Opinion in Behavioral Sciences, 22, 59–69. doi:10.1016/j.cobeha.2018.01.007

52. Kowalewska, E., Grubbs, J. B., Potenza, M. N., Gola, M., Draps, M., & Kraus, S. W. (2018). Neurocognitive mechanisms in compulsive sexual behavior disorder. Current Sexual Health Reports, 10(4), 255–264. doi:10.1007/s11930-018-0176-z

53. Becker, S., Bräscher, A.-K., Bannister, S., Bensafi, M., Calma-Birling, D., Chan, R. C. K., Eerola, T., Ellingsen, D.-M., Ferdenzi, C., Hanson, J. L., Joffily, M., Lidhar, N. K., Lowe, L. J., Martin, L. J., Musser, E. D., Noll-Hussong, M., Olino, T. M., Pintos Lobo, R., & Wang, Y. (2019). The role of hedonics in the human affectome. Neuroscience & Biobehavioral Reviews, 102, 221–241. doi:10.1016/j.neubiorev.2019.05.003

54. Grigutsch, L. A., Lewe, G., Rothermund, K., & Koranyi, N. (2019). Implicit ‘wanting’ without implicit ‘liking’: A test of incentive-sensitization-theory in the context of smoking addiction using the wanting-implicit-association-test (W-IAT). Journal of Behavior Therapy and Experimental Psychiatry, 64, 9–14. doi:10.1016/j.jbtep.2019.01.002

55. Linnet, J. (2014). Neurobiological underpinnings of reward anticipation and outcome evaluation in gambling disorder. Frontiers in Behavioral Neuroscience, 8. doi:10.3389/fnbeh.2014.00100

56. Antons, S., Brand, M., & Potenza, M. N. (2020). Neurobiology of cue-reactivity, craving, and inhibitory control in non-substance addictive behaviors. Journal of the Neurological Sciences, 415, 116952. doi:10.1016/j.jns.2020.116952

57. Gola, M., Wordecha, M., Sescousse, G., Lew-Starowicz, M., Kossowski, B., Wypych, M., Makeig, S., Potenza, M. N., & Marchewka, A. (2017). Can pornography be addictive? An fMRI study of men seeking treatment for problematic pornography Use. Neuropsychopharmacology, 42(10), 2021–2031. doi:10.1038/npp.2017.78

58. Voon, V., Mole, T. B., Banca, P., Porter, L., Morris, L., Mitchell, S., Lapa, T. R., Karr, J., Harrison, N. A., Potenza, M. N., & Irvine, M. (2014). Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours. PLOS ONE, 9(7), e102419. doi:10.1371/journal.pone.0102419

59. Christensen, E., Albertella, L., Chamberlain, S. R., Brydevall, M., Suo, C., Grant, J. E., Yücel, M., & Lee, R. S. C. (2024). The neurocognitive correlates of non-substance addictive behaviors. Addictive Behaviors, 150, 107904. doi:10.1016/j. addbeh.2023.107904

60. Bornstein, A. M., & Pickard, H. (2020). “Chasing the first high”: Memory sampling in drug choice. Neuropsychopharmacology, 45(6), 907–915. doi:10.1038/s41386-019-0594-2

61. Banca, P., Morris, L. S., Mitchell, S., Harrison, N. A., Potenza, M. N., & Voon, V. (2016). Novelty, conditioning and attentional bias to sexual rewards. Journal of Psychiatric Research, 72, 91–101. doi:10.1016/j.jpsychires.2015.10.017

62. Wang, J., Chen, Y., & Zhang, H. (2022). Electrophysiological evidence of enhanced processing of novel pornographic images in individuals with tendencies toward problematic internet pornography use. Frontiers in Human Neuroscience, 16, 897536. doi:10.3389/fnhum.2022.897536

63. Kühn, S., & Gallinat, J. (2014). Brain structure and functional connectivity associated with pornography consumption. JAMA Psychiatry, 71(7), 827–834. doi:10.1001/jamapsychiatry.2014.93

64. Dwulit, A. D., & Rzymski, P. (2019). Prevalence, patterns and self-perceived effects of pornography consumption in Polish university students: A cross-sectional study. International Journal of Environmental Research and Public Health, 16(10), 1861. doi:10.3390/ijerph16101861

65. Egecioglu, E., Prieto-Garcia, L., Studer, E., Westberg, L., & Jerlhag, E. (2016). The role of ghrelin signalling for sexual behaviour in male mice. Addiction Biology, 21(2), 348–359. doi:10.1111/adb.12202

66. Park, B., Wilson, G., Berger, J., Christman, M., Reina, B., Bishop, F., Klam, W., & Doan, A. (2016). Is internet pornography causing sexual dysfunctions?

A review with clinical reports. Behavioral Sciences, 6(3), 17. doi:10.3390/bs6030017

67. Costa, V. D., Tran, V. L., Turchi, J., & Averbeck, B. B. (2014). Dopamine modulates novelty seeking behavior during decision making. Behavioral Neuroscience, 128(5), 556–566. doi:10.1037/a0037128

68. Mikorski, R., & Szymanski, D. M. (2017). Masculine norms, peer group, pornography, Facebook, and men’s sexual objectification of women. Psychology of Men & Masculinity, 18(4), 257–267. doi:10.1037/ men0000058

69. Bridges, A. J., Willis, M., Ezzell, M. B., Sun, C.F., Johnson, J. A., & Wright, P. J. (2024). Pornography use and sexual objectification of others. Violence Against Women, 30(1), 228–248. doi:10.1177/10778012231207041

70. Ezzell, M. B., Johnson, J. A., Bridges, A. J., & Sun, C. F. (2020). I (dis)like it like that: Gender, pornography, and liking sex. Journal of Sex & Marital Therapy, 46(5), 460–473. doi:10.1080/009262 3X.2020.1758860

71. Bridges, A. J., Sun, C. F., Ezzell, M. B., & Johnson, J. (2016). Sexual scripts and the sexual behavior of men and women who use pornography. Sexualization, Media, & Society, 2(4). doi:10.1177/2374623816668275

72. Impett, E. A., Muise, A., & Rosen, N. O. (2015). Is it good to be giving in the bedroom? A prosocial perspective on sexual health and well-being in romantic relationships. Current Sexual Health Re-

ports, 7, 180–190. doi:10.1007/s11930-015-0055-9

73. Acevedo, B. P., Poulin, M. J., Geher, G., Grafton, S., & Brown, L. L. (2019). The neural and genetic correlates of satisfying sexual activity in heterosexual pair-bonds. Brain and Behavior, 9(6). doi:10.1002/ brb3.1289

74. Hudson-Flege, M. D., Grover, H. M., Meçe, M. H., Ramos, A. K., & Thompson, M. P. (2020). Empathy as a moderator of sexual violence perpetration risk factors among college men. Journal of American College Health, 68(2), 139–147. doi:10.1080/07

448481.2018.1536055

75. Carter, C. S. (2017). The oxytocin–vasopressin pathway in the context of love and fear. Frontiers in Endocrinology, 8. doi:10.3389/fendo.2017.00356

76. de Jong, T. R., & Neumann, I. D. (2017). Oxytocin and aggression. Behavioral Pharmacology of Neuropeptides: Oxytocin, 175–192. doi:10.1007/7854_2017_13

77. Sparapani, S., Millet-Boureima, C., Oliver, J., Mu, K., Hadavi, P., Kalostian, T., Ali, N., Avelar, C. M., Bardies, M., Barrow, B., Benedikt, M., Biancardi, G., Bindra, R., Bui, L., Chihab, Z., Cossitt, A., Costa, J., Daigneault, T., Dault, J., Davidson, I., Dias, J., Dufour, E., El-Khoury, S., Farhangdoost, N., Forget, A., Fox, A., Gebrael, M., Gentile, M.C., Geraci, O., Gnanapragasam, A., Gomah, E., Haber, E., Hamel, C., Iyanker, T., Kalantzis, C., Kamali, S., Kassardjian, E., Kontos, H.K., Uven Le. T.B., LoScerbo, D., Low, Y.F., Mac Rae, D., Maurer, F., Mazhar, S., Nguyen, A., Nguyen-Duong, K., Osborne-Laroche, C., Park, H.W., Parolin, E., Paul-Cole, K., Peer, L.S., Philippon, M., Plaisir, C., Marroquin, J.P., Prasad, Simran., Ramsarun, R., Razzaq, S., Rhainds, S., Robin, D., Scartozzi, R., Davindra, S., Fard, S.S., Soroko, M., Motlagh, N.S., Stern, K., Toro, L., Toure, M.W., Tran-Huynh, S., Trépanier-Chicoine, S., Waddingham, C., Weekes, A.J., Wisniewski, A., Gamberi, C. (2021). The biology of vasopressin. Biomedicines, 9(1), 89. doi:10.3390/biomedicines9010089

78. Feldman, R. (2017). The Neurobiology of Human Attachments. Trends in Cognitive Sciences, 21(2), 80–99. doi:10.1016/j.tics.2016.11.007

79. Cera, N., Vargas-Cáceres, S., Oliveira, C., Monteiro, J., Branco, D., Pignatelli, D., & Rebelo, S. (2021). How relevant is the systemic oxytocin concentration for human sexual behavior? A systematic review. Sexual Medicine, 9(4), 100370–100370. https://doi.org/10.1016/j.esxm.2021.100370

80. Stallen, M., Rossi, F., Heijne, A., Smidts, A., De Dreu, C. K. W., & Sanfey, A. G. (2018). Neurobiological mechanisms of responding to injustice. The Journal of Neuroscience, 38(12), 2944–2954. https://doi.org/10.1523/JNEUROSCI.1242-17.2018

81. Krueger, F., Parasuraman, R., Moody, L., Twieg, P., de Visser, E., McCabe, K., O’Hara, M., & Lee, M. R. (2012). Oxytocin selectively increases perceptions of harm for victims but not the desire to punish offenders of criminal offenses. Social Cognitive and Affective Neuroscience, 8(5), 494–498. doi:10.1093/scan/nss026

82. Hu, Y., Scheele, D., Becker, B., Voos, G., David, B., Hurlemann, R., & Weber, B. (2016). The effect of oxytocin on third-party altruistic decisions in unfair situations: An fmri study. Scientific Reports, 6(1). doi:10.1038/srep20236

83. Jääskeläinen, I. P., & Kosonogov, V. (2023). Perspective taking in the human brain: complementary evidence from neuroimaging studies with media-based naturalistic stimuli and artificial controlled paradigms. Frontiers in Human Neuroscience, 17. doi:10.3389/fnhum.2023.1051934

84. Cogoni, C., Monachesi, B., Mazza, V., Grecucci, A., & Vaes, J. (2023). Neural dynamics of vicarious physical pain processing reflect impaired empathy toward sexually objectified versus non‐sexually objectified women. Psychophysiology, 60(12), e14400. doi:10.1111/psyp.14400

85. Morris, K. L., Goldenberg, J., & Boyd, P. (2018). Women as animals, women as objects: Evidence for two forms of objectification. Personality and Social Psychology Bulletin, 44(9), 1302–1314. doi:10.1177/0146167218765739

86. Cogoni, C., Carnaghi, A., & Silani, G. (2018). Reduced empathic responses for sexually objectified women: An fMRI investigation. Cortex, 99, 258–272. https://doi.org/10.1016/j.cortex.2017.11.020

87. Braithwaite, S. R., Coulson, G., Keddington, K., & Fincham, F. D. (2014). The influence of pornography on sexual scripts and hooking up among emerging adults in college. Archives of Sexual Behavior, 44(1), 111–123. doi:10.1007/s10508-0140351-x

88. Stietz, J., Jauk, E., Krach, S., & Kanske, P. (2019). Dissociating empathy from perspective-taking: Evidence from intra- and inter-individual differences research. Frontiers in Psychiatry, 10, 126. https://doi.org/10.3389/fpsyt.2019.00126

89. Davis, A. N., Martin-Cuellar, A., & Luce, H. (2019). Life events and prosocial behaviors among young adults: Considering the roles of perspective taking and empathic concern. The Journal of Genetic Psychology, 180(4–5), 205–216. doi:10.1080/002213 25.2019.1632785

90. Riečanský, I., & Lamm, C. (2019). The role of sensorimotor processes in pain empathy. Brain Topography, 32(6), 965–976. doi:10.1007/s10548-01900738-4

91. Orenius, T. I., Raij, T. T., Nuortimo, A., Näätänen, P., Lipsanen, J., & Karlsson, H. (2017). The interaction of emotion and pain in the insula and secondary somatosensory cortex. Neuroscience, 349, 185–194. doi:10.1016/j.neuroscience.2017.02.047

92. Rütgen, M., Seidel, E.-M., Silani, G., Riečanský, I., Hummer, A., Windischberger, C., Petrovic, P., & Lamm, C. (2015). Placebo analgesia and its opioidergic regulation suggest that empathy for pain is grounded in self pain. Proceedings of the National Academy of Sciences, 112(41), 5638–5646. doi:10.1073/pnas.1511269112

93. Namkung, H., Kim, S.-H., & Sawa, A. (2017). The insula: An underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends in Neurosciences, 40(4), 200–207. doi:10.1016/j. tins.2017.02.002

94. Skorska, M. N., Hodson, G., & Hoffarth, M. R. (2018). Experimental effects of degrading versus erotic pornography exposure in men on reactions toward women (objectification, sexism, discrimination). The Canadian Journal of Human Sexuality, 27(3), 261–276. doi:10.3138/cjhs.2018-0001

95. Garaigordobil, M. (2014). Sexism and empathy: Differences as a function of sociodemographic variables and relations between both constructs. In Advances in Psychology Research (Vol. 100, pp. 59–80). Nova Science Publishers. ISBN: 978-163321-482-8.

96. Rosell, D. R., & Siever, L. J. (2015). The neurobiology of aggression and violence. CNS Spectrums, 20(3), 254–279. doi:10.1017/s109285291500019x

97. Wright, P. J., Tokunaga, R. S., & Kraus, A. (2015). A meta-analysis of pornography consumption and actual acts of sexual aggression in general population studies: Pornography and sexual aggression. Journal of Communication, 66(1), 183–205. doi:10.1111/jcom.12201

98. Wright, P. J., Paul, B., & Herbenick, D. (2021). Preliminary insights from a U.S. probability sample on adolescents’ pornography exposure, media psychology, and sexual aggression. Journal of Health Communication, 26(1), 39–46. doi:10.1080/1081073 0.2021.1887980

99. Marshall, E. A., & Miller, H. A. (2019). Consistently inconsistent: A systematic review of the measurement of pornography use. Aggression and Violent Behavior, 48, 169–179. https://doi.org/10.1016/j. avb.2019.08.019

100. Rostad, W. L., Gittins-Stone, D., Huntington, C., Rizzo, C. J., Pearlman, D., & Orchowski, L. (2019). The association between exposure to violent pornography and teen dating violence in grade 10 high school students. Archives of Sexual Behavior, 48(7), 2137–2147. doi:10.1007/s10508-019-1435-4

101. Johnson, S. A. (2014). Pornography and the violent offender: Importance of finding the offender’s pornography stash. Journal of Forensic Research, 5(3), 229. doi:10.4172/2157-7145.1000229

102. Brem, M. J., Garner, A. R., Grigorian, H., Florimbio, A. R., Wolford-Clevenger, C., Shorey, R. C., & Stuart, G. L. (2018). Problematic pornography use and physical and sexual intimate partner violence perpetration among men in Batterer Intervention Programs. Journal of Interpersonal Violence, 36(11–12), 6085–6105. doi:10.1177/0886260518812806

103. Sharpe, M., & Mead, D. (2021). Problematic pornography use: Legal and health policy considerations. Current Addiction Reports, 8, 556–567. doi:10.1007/s40429-021-00390-8

104. Huntington, C., Willoughby, B., & Rhoades, G. (2022). Associations of adolescents’ pornography viewing with their romantic relationship skills and behaviors. The Journal of Sex Research, 61(1), 80–91. doi:10.1080/00224499.2022.2096844

105. Marshall, E. A., & Miller, H. A. (2023). Age and type of first exposure to pornography: It matters for girls and boys. Deviant Behavior, 45(3), 377–393. doi:10.1080/01639625.2023.2248338

106. Harper, C., & Hodgins, D. C. (2016). Examining correlates of problematic internet pornography use among university students. Journal of Behavioral Addictions, 5(2), 179–191. doi:10.1556/2006.5.2016.022

107. Jhe, G. B., Addison, J., Lin, J., & Pluhar, E. (2023). Pornography use among adolescents and the role of primary care. Family Medicine and Community Health, 11(1). doi:10.1136/fmch-2022-001776

108. Gutierrez, B. C., & Leaper, C. (2023). Linking ambivalent sexism to violence-against-women attitudes and behaviors: A three-level meta-analytic review. Sexuality & Culture, 28(2), 851–882. doi:10.1007/s12119-023-10127-6

109. Mancini, C., Reckdenwald, A., & Beauregard, E. (2012). Pornographic exposure over the life course and the severity of sexual offenses: Imitation and cathartic effects. Journal of Criminal Justice, 40(1), 21–30. doi:10.1016/j.jcrimjus.2011.11.004

110. Mancini, C., Reckdenwald, A., Beauregard, E., & Levenson, J. S. (2014). Sex industry exposure over the life course on the onset and frequency of sex offending. Journal of Criminal Justice, 42(6), 507–516. doi:10.1016/j.jcrimjus.2014.09.002

111. Pathmendra, P., Raggatt, M., Lim, M. S., Marino, J. L., & Skinner, S. R. (2023). Exposure to pornography and adolescent sexual behavior: Systematic review. Journal of Medical Internet Research, 25, e43116. https://doi.org/10.2196/43116

112. Holt, K., Kissinger, J., Spickler, C., & Roush, V. (2021). Pornography use and sexual offending: An examination of perceptions of role and risk. International Journal of Offender Therapy and Comparative Criminology. doi:10.1177/0306624x211049183

113. Huntington, C., Pearlman, D. N., & Orchowski, L. (2020). The confluence model of sexual aggression: An application with adolescent males. Journal of Interpersonal Violence, 37(1–2), 623–643. doi:10.1177/0886260520915550

114. Malamuth, N. M. (2018). “Adding fuel to the fire”? Does exposure to non-consenting adult or to child pornography increase risk of sexual aggression? Aggression and Violent Behavior, 41, 74–89. doi:10.1016/j.avb.2018.02.013

115. Malamuth, N. M., Lamade, R. V., Koss, M. P., Lopez, E., Seaman, C., & Prentky, R. (2021). Factors predictive of sexual violence: Testing the four pillars of the confluence model in a large diverse sample of college men. Aggressive Behavior, 47(4), 405–420. doi:10.1002/ab.21960

116. Saqib, S., & Davidson, M. (2023). The confluence model of sexual aggression: The role of pornography as a secondary risk factor. Sexual Offending: Theory, Research, and Prevention, 18, e13005. doi:10.5964/sotrap.13005

117. Ray, T. N., & Parkhill, M. R. (2023). Components of hostile masculinity and their associations with male-perpetrated sexual aggression toward women: A systematic review. Trauma, Violence, & Abuse, 24(2), 355–368. doi:10.1177/15248380211030224

118. Burt, M. R. (1980). Cultural myths and supports for rape. Journal of Personality and Social Psychology, 38(2), 217–230. doi:10.1037//0022-3514.38.2.217

119. Hales, S. T. (2023). Hostile masculinity (HM): Confluence model of sexual aggression. Encyclopedia of Sexual Psychology and Behavior, 1–4. doi:10.1007/978-3-031-08956-5_1136-1

120. de Heer, B. A., Prior, S., & Hoegh, G. (2020). Pornography, masculinity, and sexual aggression on college campuses. Journal of Interpersonal Violence, 36(23–24), 13582–13605. doi:10.1177/0886260520906186

REFERENCES

121. Orchowski, L. M., Oesterle, D. W., Berry-Cabán, C. S., Borsari, B., Kahler, C. W., Kazemi, D. M., & Berkowitz, A. D. (2023). An application of the confluence model of sexual aggression among young adult male soldiers. Journal of Interpersonal Violence, 38(13-14), 8263-8285. https://doi. org/10.1177/08862605231153895

122. Ferrer-Perez, V. A., Bosch-Fiol, E., Ferreiro-Basurto, V., Delgado-Alvarez, C., & Sánchez-Prada, A. (2020). Comparing implicit and explicit attitudes toward intimate partner violence against women. Frontiers in Psychology, 11. doi:10.3389/ fpsyg.2020.02147

123. Willis, M., Bridges, A.J. & Sun, C. Pornography use, gender, and sexual objectification: a multinational study. Sexuality & Culture 26, 1298–1313 (2022). https://doi.org/10.1007/s12119-022-09943-z

124. Dawson, K., Gabhainn, S. N., MacNeela, P. (2020). Toward a model of porn literacy: Core concepts, rationales, and approaches. The Journal of Sex Research, 57(1), 1-15. doi:10.1080/00224499.2 018.1556238

125. Austin, E. W., Pinkleton, B. E., Chen, Y. C., & Austin, B. W. (2015). Processing of sexual media messages improves due to media literacy effects on perceived message desirability. Mass Communication and Society, 18(4), 399-421. doi:10.1080/1 5205436.2014.1001909

126. Sousa, M., Cunha, O., Gonçalves, R.A. et al. To Be or Not to Be Empathic: the Role of Empathy in Child Sexual Offending. Eur J Crim Policy Res (2023). https://doi.org/10.1007/s10610-023-095675

YEARNING FOR YESTERDAY: THE MECHANISMS AND APPLICATIONS OF NOSTALGIA

1. Sedikides, C., Wildschut, T., Routledge, C., Arndt, J., Hepper, E. G., & Zhou, X. (2015). Chapter Five—To Nostalgize: Mixing Memory with Affect and Desire (J. M. Olson & M. P. Zanna, Eds.; Vol. 51, pp. 189–273). Academic Press; doi:10.1016/ bs.aesp.2014.10.001

2. Fetterman, A. K., & Evans, N. D. (2023). Remembering our first date brings back those fuzzy feelings: The role of romantic nostalgia in relationship functioning. Current Opinion in Psychology, 49; doi:10.1016/j.copsyc.2022.101524

3. Hepper, E. G., Sedikides, C., Wildschut, T., Cheung, W. Y., Abakoumkin, G., Arikan, G., ... & Zengel, B. (2024). Pancultural nostalgia in action: Prevalence, triggers, and psychological functions of nostalgia across cultures. Journal of Experimental Psychology: General; doi:10.1037/xge0001521

4. Green, J. D., Reid, C. A., Kneuer, M. A., & Hedgebeth, M. V. (2023). The Proust effect: Scents, food, and nostalgia. Current Opinion in Psychology, 50; doi:10.1016/j.copsyc.2023.101562

5. Reid, C. A., Green, J. D., Buchmaier, S., McSween, D. K., Wildschut, T., & Sedikides, C. (2022). Foodevoked nostalgia. Cognition and Emotion, 37(1), 1–15; doi:10.1080/02699931.2022.2142525

6. Ralph, M. A. L., Jefferies, E., Patterson, K., & Rogers, T. T. (2017). The neural and computational bases of semantic cognition. Nature reviews neuroscience, 18(1), 42-55; doi:10.1038/nrn.2016.150

7. Renoult, L., Irish, M., Moscovitch, M., & Rugg, M. D. (2019). From knowing to remembering: the semantic–episodic distinction. Trends in cognitive sciences, 23(12), 1041-1057; doi:10.1016/j. tics.2019.09.008

8. Josselyn, S. A., & Tonegawa, S. (2020). Memory engrams: Recalling the past and imagining the future. Science, 367(6473); doi:10.1126/science. aaw4325

9. Ortega-de San Luis, C., & Ryan, T. J. (2022). Understanding the physical basis of memory: molecular mechanisms of the engram. Journal of Biological Chemistry, 298(5); doi:10.1016/j.jbc.2022.101866

10. Poo, M. M., Pignatelli, M., Ryan, T. J., Tonegawa, S., Bonhoeffer, T., Martin, K. C., ... & Stevens, C. (2016). What is memory? The present state of the engram. BMC biology, 14, 1-18; doi:10.1186/s12915016-0261-6

11. Leake, J., Zinn, R., Corbit, L. H., Fanselow, M. S., & Vissel, B. (2021). Engram size varies with learning and reflects memory content and precision. Journal of Neuroscience, 41(18), 4120-4130; doi:10.1523/ JNEUROSCI.2786-20.2021

12. Tanguay, A. F., Palombo, D. J., Love, B., Glikstein, R., Davidson, P. S., & Renoult, L. (2023). The shared and unique neural correlates of personal semantic, general semantic, and episodic memory. ELife, 12; doi:10.7554/eLife.83645

13. Kronrod, A., Gordeliy, I., & Lee, J. K. (2022). Been There, Done That: How Episodic and Semantic Memory Affects the Language of Authentic and Fictitious Reviews. Journal of Consumer Research; doi:10.1093/jcr/ucac056

14. Eichenbaum, H. (2017). The role of the hippocampus in navigation is memory. Journal of neurophysiology, 117(4), 1785-1796; doi:10.1152/jn.00005.2017

15. Kumaran, D., Hassabis, D., & McClelland, J. L. (2016). What learning systems do intelligent agents need? Complementary learning systems theory updated. Trends in cognitive sciences, 20(7), 512-534; doi:10.1016/j.tics.2016.05.004

16. Heuer, K., & Toro, R. (2019). Role of mechanical morphogenesis in the development and evolution of the neocortex. Physics of life reviews, 31, 233239; doi:10.1016/j.plrev.2019.01.012

17. Brodt, S., & Gais, S. (2021). Memory engrams in the neocortex. The Neuroscientist, 27(4), 427-444; doi:10.1177/1073858420941528

18. Renwick, J., & Woolhouse, M. H. (2023). Reminiscence bump invariance with respect to genre, age, and country. Psychology of Music, 51(4), 13491365; doi:10.1177/03057356221141735

19. Yang, Z., Wildschut, T., Izuma, K., Gu, R., Luo, Y. L. L., Cai, H., & Sedikides, C. (2022). Patterns of brain activity associated with nostalgia: a social-cognitive neuroscience perspective. Social cognitive and affective neuroscience, 17(12), 1131–1144; doi:10.1093/scan/nsac036

20. Li, B., Zhu, Q., Li, A., & Cui, R. (2023). Can good memories of the past instill happiness? nostalgia improves subjective well-being by increasing gratitude. Journal of Happiness Studies, 24(2), 699-715; doi:10.1007/s10902-022-00616-0

21. Evans, N. D., Reyes, J., Wildschut, T., Sedikides, C., & Fetterman, A. K. (2021). Mental transportation mediates nostalgia’s psychological benefits. Cognition and Emotion, 35(1), 84-95; doi:10.1080/0269 9931.2020.1806788

22. Stephan, E., & Sedikides, C. (2023). Mental time travel as self-affirmation. Personality and Social Psychology Review; doi:10.1177/10888683231203143

23. Oba, K., Noriuchi, M., Atomi, T., Moriguchi, Y., & Kikuchi, Y. (2016). Memory and reward systems coproduce ‘nostalgic’ experiences in the brain. Social cognitive and affective neuroscience, 11(7), 1069-1077; doi:10.1093/scan/nsv073

24. Gomes, F. V. (2022). Altered Ventral Striatum–Hippocampus connectivity during reward processing as an Endophenotype for Psychosis. Biological Psychiatry, 91(2), e7-e9; doi:10.1016/j. biopsych.2021.10.019

25. Mallory, A. B., Spencer, C. M., Kimmes, J. G., & Pollitt, A. M. (2018). Remembering the good times: The influence of relationship nostalgia on relationship satisfaction across time. Journal of marital and family therapy, 44(4), 561-574; doi:10.1111/ jmft.12311

26. Vaccaro, A. G., Kaplan, J. T., & Damasio, A. (2020). Bittersweet: the neuroscience of ambivalent affect. Perspectives on Psychological Science, 15(5), 1187-1199; doi:10.1177/1745691620927708

27. Sedikides, C., Cheung, W.-Y., Wildschut, T., Hepper, E. G., Baldursson, E., & Pedersen, B. (2017). Nostalgia motivates pursuit of important goals by increasing meaning in life. European Journal of Social Psychology, 48(2), 209–216; doi:10.1002/ ejsp.2318

28. Sedikides, C., & Wildschut, T. (2020). The motivational potency of nostalgia: The future is called yesterday. Advances in Motivation Science, 7, 75–111. doi:10.1016/bs.adms.2019.05.001

29. Abeyta, A. A., Routledge, C., Roylance, C., Wildschut, T., & Sedikides, C. (2015). Attachment-related avoidance and the social and agentic content of nostalgic memories. Journal of Social and Personal Relationships, 32(3), 406-413; doi:10.1177/0265407514533770

30. Abeyta, A. A., & Pillarisetty, S. (2023). Nostalgia supports a meaningful life. Current Opinion in Psychology, 49; doi:0.1016/j.copsyc.2022.101520

31. Huang, Y., Liao, X., & Cai, F. (2023). A Clinical Study on the Effect of Group Nostalgia Therapy on Quality of Life and Cognitive Function in Elderly Patients with Depression. International Journal of Mental Health Production, 25(12); doi:10.32604/ ijmhp.2023.030558

32. King, L. A., Heintzelman, S. J., & Ward, S. J. (2016). Beyond the search for meaning: A contemporary science of the experience of meaning in life. Current Directions in Psychological Science, 25(4), 211-216; doi:10.1177/0963721416656354

33. Batcho, K. I. (2018). The role of nostalgia in resistance: A psychological perspective. Qualitative Research in Psychology; doi:10.1080/14780887.201 8.1499835

34. Batcho, K. I., & Shikh, S. (2016). Anticipatory nostalgia: Missing the present before it’s gone. Personality and Individual Differences, 98, 75–84; doi:10.1016/j.paid.2016.03.088

35. Wang, J. F. (2023). Nostalgia in tourism. Current Opinion in Psychology, 49; doi:10.1016/j.copsyc.2022.101552

36. Juhl, J., & Biskas, M. (2023). Nostalgia: An impactful social emotion. Current Opinion in Psychology, 49; doi:10.1016/j.copsyc.2022.101545

37. Abeyta, A. A., Routledge, C., & Juhl, J. (2015). Looking back to move forward: Nostalgia as a psychological resource for promoting relationship goals and overcoming relationship challenges. Journal of Personality and Social Psychology, 109(6), 1029; doi:10.1037/pspi0000036

REFERENCES

38. Wildschut, T., Bruder, M., Robertson, S., van Tilburg, W. A., & Sedikides, C. (2014). Collective nostalgia: A group-level emotion that confers unique benefits on the group. Journal of Personality and Social Psychology, 107(5), 844; doi:10.1037/ a0037760

39. Green, J. D., Cairo, A. H., Wildschut, T., & Sedikides, C. (2021). The ties that bind: University nostalgia fosters relational and collective university engagement. Frontiers in Psychology, 11; doi:10.3389/ fpsyg.2020.580731

40. Dodman, T. (2023). Nostalgia, and what it used to be. Current Opinion in Psychology, 49; doi:10.1016/j. copsyc.2022.101536

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

EPISODE VI: RETURN OF THE REFERENCES

1. Ghasemi, N., Razavi, S., & Nikzad, E. (2017). Multiple sclerosis: Pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J (Yakhteh), 19(1). doi:10.22074/cellj.2016.4867

2. Wallin, M. T., Culpepper, W. J., Campbell, J. D., Nelson, L. M., Langer-Gould, A., Marrie, R. A., Cutter, G. R., Kaye, W. E., Wagner, L., Tremlett, H., Buka, S. L., Dilokthornsakul, P., Topol, B., Chen, L. H., & LaRocca, N. G. (2019). The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology, 92(10). doi:10.1212/ WNL.0000000000007035

3. Kamm, C. P., Uitdehaag, B. M., & Polman, C. H. (2014). Multiple sclerosis: Current knowledge and future outlook. European Neurology, 72(3–4), 132–141. doi:10.1159/000360528

4. McGinley, M. P., Goldschmidt, C. H., & Rae-Grant, A. D. (2021). Diagnosis and treatment of multiple sclerosis: A review. JAMA, 325(8), 765. doi:10.1001/ jama.2020.26858

5. Waubant, E., Lucas, R., Mowry, E., Graves, J., Olsson, T., Alfredsson, L., & Langer-Gould, A. (2019). Environmental and genetic risk factors for MS: An integrated review. Annals of Clinical and Translational Neurology, 6(9), 1905–1922. doi:10.1002/ acn3.50862

6. Bjornevik, K., Cortese, M., Healy, B. C., Kuhle, J., Mina, M. J., Leng, Y., Elledge, S. J., Niebuhr, D. W., Scher, A. I., Munger, K. L., & Ascherio, A. (2022). Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 375(6578), 296–301. doi:10.1126/ science.abj8222

7. Robinson, W. H., & Steinman, L. (2022a). Epstein-Barr virus and multiple sclerosis. Science, 375(6578), 264–265. doi:10.1126/science.abm7930

8. Pachner, A. R. (2022). The neuroimmunology of multiple sclerosis: Fictions and facts. Frontiers in Neurology, 12. doi:10.3389/fneur.2021.796378

9. Hollen, C. W., Paz Soldán, M. M., Rinker, J. R., 2nd, & Spain, R. I. (2020). The Future of Progressive Multiple Sclerosis Therapies. Federal Practitioner, 37(Suppl 1), S43–S49. PMID:32341636

10. Leray, E., Moreau, T., Fromont, A., & Edan, G. (2016). Epidemiology of multiple sclerosis. Revue Neurologique, 172(1), 3–13. doi:10.1016/j.neurol.2015.10.006

11. Ruprecht, K. (2020). The role of Epstein-Barr virus in the etiology of multiple sclerosis: A current review. Expert Review of Clinical Immunology, 16(12), 1143–1157. doi: 10.1080/1744666x.2021.1847642

12. Dobson, R., & Giovannoni, G. (2019). Multiple sclerosis – a review. European Journal of Neurology, 26(1), 27–40. doi:10.1111/ene.13819

13. Hejrati, A., Rafiei, A., Soltanshahi, M., Hosseinzadeh, S., Dabiri, M., Taghadosi, M., Taghiloo, S., Bashash, D., Khorshidi, F., & Zafari, P. (2020). Innate immune response in systemic autoimmune diseases: A potential target of therapy. Inflammopharmacology, 28(6), 1421–1438. doi:10.1007/ s10787-020-00762-y

14. Rodríguez Murúa, S., Farez, M. F., & Quintana, F. J. (2022). The immune response in multiple sclerosis. Annual Review of Pathology: Mechanisms of Disease, 17(1), 121–139. doi:10.1146/annurev-pathol-052920-040318

15. Riedhammer, C., & Weissert, R. (2015). Antigen presentation, autoantigens, and immune regulation in multiple sclerosis and other autoimmune diseases. Frontiers in Immunology, 6. doi:10.3389/ fimmu.2015.00322

16. López-Muguruza, E., & Matute, C. (2023). Alterations of oligodendrocyte and myelin energy metabolism in multiple sclerosis. International Journal of Molecular Sciences, 24(16), 12912. doi:10.3390/ijms241612912

17. Al-Badri, G., & Castorina, A. (2018). Insights into the role of neuroinflammation in the pathogenesis of multiple sclerosis. Journal of Functional Morphology and Kinesiology, 3(1), 13. doi:10.3390/ jfmk3010013

18. Poitelon, Y., Kopec, A., & Belin, S. (2020). Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism. Cells, 9(4). doi:10.3390/cells9040812.

19. Haase, S., & Linker, R. A. (2021). Inflammation in multiple sclerosis. Therapeutic Advances in Neurological Disorders, 14. doi:10.1177/17562864211007687

20. Stys, P. K. (2010). Multiple sclerosis: Autoimmune disease or autoimmune reaction? Canadian Journal of Neurological Sciences / Journal Canadien Des Sciences Neurologiques, 37(S2). doi: 10.1017/ s0317167100022393

21. Falcão, A. M., van Bruggen, D., Marques, S., Meijer, M., Jäkel, S., Agirre, E., Samudyata, Floriddia, E. M., Vanichkina, D. P., ffrench-Constant, C., Williams, A., Guerreiro-Cacais, A. O., & Castelo-Branco, G. (2018). Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nature Medicine, 24(12), 1837–1844. doi: 10.1038/s41591-018-0236-y

22. DiSabato, D. J., Quan, N., & Godbout, J. P. (2016). Neuroinflammation: The devil is in the details. Journal of Neurochemistry, 139(S2), 136–153. doi:10.1111/jnc.13607

23. Ludwin, S. K., Rao, V. T., Moore, C. S., & Antel, J. P. (2016). Astrocytes in multiple sclerosis. Multiple Sclerosis Journal, 22(9), 1114–1124. doi:10.1177/1352458516643396

24. Papiri, G., D’Andreamatteo, G., Cacchiò, G., Alia, S., Silvestrini, M., Paci, C., Luzzi, S., & Vignini, A. (2023). Multiple sclerosis: Inflammatory and neuroglial aspects. Current Issues in Molecular Biology, 45(2), 1443–1470. doi:10.3390/cimb45020094

25. Pegoretti, V., Swanson, K. A., Bethea, J. R., Probert, L., Eisel, U. L. M., & Fischer, R. (2020). Inflammation and oxidative stress in multiple sclerosis: Consequences for therapy development. Oxidative Medicine and Cellular Longevity, 2020, 1–19. doi:10.1155/2020/7191080

26. Lassmann, H. (2018). Multiple sclerosis pathology. Cold Spring Harbor Perspectives in Medicine, 8(3), a028936. doi:10.1101/cshperspect.a028936

27. Desai, R. A., Davies, A. L., Tachrount, M., Kasti, M., Laulund, F., Golay, X., & Smith, K. J. (2016). Cause and prevention of demyelination in a model multiple sclerosis lesion. Annals of Neurology, 79(4), 591–604. doi:10.1002/ana.24607

28. Kale, N. (2016). Optic neuritis as an early sign of multiple sclerosis. Eye and Brain, 8, 195–202. doi:10.2147/EB.S54131

29. Kamma, E., Lasisi, W., Libner, C., Ng, H. S., & Plemel, J. R. (2022). Central nervous system macrophages in progressive multiple sclerosis: Relationship to neurodegeneration and therapeutics. Journal of Neuroinflammation, 19(1), 45. doi:10.1186/s12974022-02408-y

30. Gelfand, J. M. (2014). Multiple sclerosis: Diagnosis, differential diagnosis, and clinical presentation. In Handbook of Clinical Neurology, 122 269–290. Elsevier. doi:10.1016/B978-0-444-52001-2.00011-X

31. Kumari, A., Dybus, A., Purcell, M., & Vuckovic, A. (2024). Motor Priming to Enhance the Effect of Physical Therapy in People with Spinal Cord Injury. The Journal of Spinal Cord Medicine, doi:10.1080/1 0790268.2024.2317011.

32. Barukčić, K., & Barukčić, I. (2016). Epstein barr virus—The cause of multiple sclerosis. Journal of Applied Mathematics and Physics, 4(6), 1042–1053. doi:10.4236/jamp.2016.46109

33. Morandi, E., Jagessar, S. A., ‘t Hart, B. A., & Gran, B. (2017). EBV infection empowers human B cells for autoimmunity: Role of autophagy and relevance to multiple sclerosis. The Journal of Immunology, 199(2), 435–448. doi:10.4049/jimmunol.1700178

34. Soldan, S. S., & Lieberman, P. M. (2023). Epstein–Barr virus and multiple sclerosis. Nature Reviews Microbiology, 21(1), 51–64. doi:10.1038/s41579022-00770-5

35. Guan, Y., Jakimovski, D., Ramanathan, M., Weinstock-Guttman, B., & Zivadinov, R. (2019). The role of Epstein-Barr virus in multiple sclerosis: From molecular pathophysiology to in vivo imaging. Neural Regeneration Research, 14(3), 373. doi:10.4103/1673-5374.245462

36. Wang, J., Jelcic, I., Mühlenbruch, L., Haunerdinger, V., Toussaint, N. C., Zhao, Y., Cruciani, C., Faigle, W., Naghavian, R., Foege, M., Binder, T. M. C., Eiermann, T., Opitz, L., Fuentes-Font, L., Reynolds, R., Kwok, W. W., Nguyen, J. T., Lee, J.-H., Lutterotti, A., Münz, C., Rammensee, H., Hauri-Hohl, M., Sospedra, M., Stevanovic, S., & Martin, R. (2020). HLADR15 molecules jointly shape an autoreactive T cell repertoire in multiple sclerosis. Cell, 183(5), 1264-1281.e20. doi:10.1016/j.cell.2020.09.054

37. Martinsen, V., & Kursula, P. (2022). Multiple sclerosis and myelin basic protein: Insights into protein disorder and disease. Amino Acids, 54(1), 99–109. doi:10.1007/s00726-021-03111-7

38. Yim, A., Smith, C., & Brown, A. M. (2022). Osteopontin/secreted phosphoprotein-1 harnesses glial-, immune-, and neuronal cell ligand-receptor interactions to sense and regulate acute and chronic neuroinflammation. Immunological Reviews, 311(1), 224–233. doi: 10.1111/imr.13081

39. Zhang, N., Zuo, Y., Jiang, L., Peng, Y., Huang, X., & Zuo, L. (2022). Epstein-Barr virus and neurological diseases. Frontiers in Molecular Biosciences, 8. doi: 10.3389/fmolb.2021.816098

REFERENCES

40. Houen, G., Trier, N. H., & Frederiksen, J. L. (2020). Epstein-barr virus and multiple sclerosis. Frontiers in Immunology, 11. doi:10.3389/fimmu.2020.587078

41. Smatti, M. K., Al-Sadeq, D. W., Ali, N. H., Pintus, G., Abou-Saleh, H., & Nasrallah, G. K. (2018). Epstein–barr virus epidemiology, serology, and genetic variability of LMP-1 oncogene among healthy population: An update. Frontiers in Oncology, 8, 211. doi:10.3389/fonc.2018.00211

42. Amin, M., & Hersh, C. M. (2023). Updates and advances in multiple sclerosis neurotherapeutics. Neurodegenerative Disease Management, 13(1), 47–70. doi:10.2217/nmt-2021-0058

43. Sausen, D., Bhutta, M., Gallo, E., Dahari, H., & Borenstein, R. (2021). Stress-induced epstein-barr virus reactivation. Biomolecules, 11(9), 1380. doi:10.3390/biom11091380

44. Bar-Or, A., Pender, M. P., Khanna, R., Steinman, L., Hartung, H.-P., Maniar, T., Croze, E., Aftab, B. T., Giovannoni, G., & Joshi, M. A. (2020). Epstein–barr virus in multiple sclerosis: Theory and emerging immunotherapies. Trends in Molecular Medicine, 26(3), 296–310. doi:10.1016/j.molmed.2019.11.003

45. Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J.-S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G.-S., Bartley, C. M., Schubert, R. D., Hawes, I. A., Vazquez, S. E., Iyer, M., Zuchero, J. B., Teegen, B., Dunn, J. E., Lock, C. B., Kipp, L. B., Cotham, V. C., Ueberheide, B. M., Aftab, B. T., Anderson, M. S., DeRisi, J. L., Wilson, M. R., Bashford-Rogers, R. J. M., Platten, M., Garcia, K. C., Steinman, L., & Robinson, W. H. (2022). Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature, 603(7900), 321–327. doi:10.1038/s41586-022-04432-7

46. Oskari Virtanen, J., & Jacobson, S. (2012). Viruses and multiple sclerosis. CNS & Neurological Disorders - Drug Targets, 11(5), 528–544. doi: 10.2174/187152712801661220

47. Marrie, R. A., Reider, N., Cohen, J., Stuve, O., Sorensen, P. S., Cutter, G., Reingold, S. C., & Trojano, M. (2014). A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. Multiple Sclerosis Journal, 21(3), 282–293. doi: 10.1177/1352458514564490

48. Magyari, M., Koch-Henriksen, N., Pfleger, C. C., & Sørensen, P. S. (2014). Gender and autoimmune comorbidity in multiple sclerosis. Multiple Sclerosis Journal, 20(9), 1244–1251. doi:10.1177/1352458514521515

49. Magyari, M., & Sorensen, P. S. (2020). Comorbidity in multiple sclerosis. Frontiers in Neurology, 11, 851. doi:10.3389/fneur.2020.00851

50. Nociti, V., & Romozzi, M. (2022). Multiple sclerosis and autoimmune comorbidities. Journal of Personalized Medicine, 12(11), 1828. doi:10.3390/ jpm12111828

51. Janegova, A., Janega, P., Rychly, B., Kuracinova, K., & Babal, P. (2015). Rola infekcji wirusem Epstein-Barr’a w rozwoju autoimmunologicznych chorób tarczycy. Endokrynologia Polska, 66(2), 132–136. doi:10.5603/EP.2015.0020

52. Assaad, S. N., Meheissen, M. A., Elsayed, E. T., Alnakhal, S. N., & Salem, T. M. (2020). Study of Epstein–Barr virus serological profile in Egyptian patients with Hashimoto’s thyroiditis: A case-control study. Journal of Clinical & Translational Endocrinology, 20, 100222. doi:10.1016/j.jcte.2020.100222

53. Eva, L., Pleș, H., Covache-Busuioc, R.-A., Glavan, L. A., Bratu, B.-G., Bordeianu, A., Dumitrascu, D.-I., Corlatescu, A. D., & Ciurea, A. V. (2023). A comprehensive review on neuroimmunology: Insights from multiple sclerosis to future therapeutic developments. Biomedicines, 11(9), 2489. doi:10.3390/biomedicines11092489

54. Ellwardt, E., & Zipp, F. (2014). Molecular mechanisms linking neuroinflammation and neurodegeneration in MS. Experimental Neurology, 262, 8–17. doi:10.1016/j.expneurol.2014.02.006

55. Callegari, I., Derfuss, T., & Galli, E. (2021). Update on treatment in multiple sclerosis. La Presse Médicale, 50(2), 104068. doi:10.1016/j.lpm.2021.104068

56. Dargahi, N., Katsara, M., Tselios, T., Androutsou, M.-E., De Courten, M., Matsoukas, J., & Apostolopoulos, V. (2017). Multiple sclerosis: Immunopathology and treatment update. Brain Sciences, 7(12), 78. doi:10.3390/brainsci7070078

57. Carlström, K. E., Ewing, E., Granqvist, M., Gyllenberg, A., Aeinehband, S., Enoksson, S. L., Checa, A., Badam, T. V. S., Huang, J., Gomez-Cabrero, D., Gustafsson, M., Al Nimer, F., Wheelock, C. E., Kockum, I., Olsson, T., Jagodic, M., & Piehl, F. (2019). Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nature Communications, 10(1), 3081. doi:10.1038/s41467-01911139-3

58. Correale, J., Gaitán, M. I., Ysrraelit, M. C., & Fiol, M. P. (2016). Progressive multiple sclerosis: From pathogenic mechanisms to treatment. Brain, 140(3), 527-546. doi:10.1093/brain/aww258

59. Chiricosta, L., Blando, S., D’Angiolini, S., Gugliandolo, A., & Mazzon, E. (2023). A comprehensive exploration of the transcriptomic landscape in multiple sclerosis: A systematic review. International Journal of Molecular Sciences, 24(2), 1448. doi:10.3390/ijms24021448

60. Sandi, D., Kokas, Z., Biernacki, T., Bencsik, K., Klivényi, P., & Vécsei, L. (2022). Proteomics in multiple sclerosis: The perspective of the clinician. International Journal of Molecular Sciences, 23(9), 5162. doi:10.3390/ijms23095162

61. Gadani, S. P., Singh, S., Kim, S., Smith, M. D., Calabresi, P. A., & Bhargava, P. (2023). Spatial transcriptomics of meningeal inflammation reveals variable penetrance of inflammatory gene signatures into adjacent brain parenchyma. eLife, 12. doi:10.7554/eLife.88414.1

62. Lin, J., Zhou, J., & Xu, Y. (2023). Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis. Brain, 146(8), 3364–3372. doi:10.1093/brain/awad070

63. Fyfe, I. (2022). Insights into the molecular pathways of progressive multiple sclerosis. Nature Reviews Neurology, 18(8), 453–453. doi:10.1038/ s41582-022-00695-w

64. Åkesson, J., Hojjati, S., Hellberg, S., Raffetseder, J., Khademi, M., Rynkowski, R., Kockum, I., Altafini, C., Lubovac-Pilav, Z., Mellergård, J., Jenmalm, M. C., Piehl, F., Olsson, T., Ernerudh, J., & Gustafsson, M. (2023). Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis. Nature Communications, 14(1). doi: 10.1038/s41467-023-42682-9

65. Kihara, Y., Zhu, Y., Jonnalagadda, D., Romanow, W., Palmer, C., Siddoway, B., Rivera, R., Dutta, R., Trapp, B. D., & Chun, J. (2022). Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis: Implications for the efficacy of fingolimod. Frontiers in Cellular Neuroscience, 16, 918041. doi:10.3389/fncel.2022.918041

66. Cocco, E., Sardu, C., Spinicci, G., Musu, L., Massa, R., Frau, J., Lorefice, L., Fenu, G., Coghe, G., Massole, S., Maioli, M. A., Piras, R., Melis, M., Porcu, G., Mamusa, E., Carboni, N., Contu, P., & Marrosu, M. G. (2015). Influence of treatments in multiple sclerosis disability: A cohort study. Multiple Sclerosis Journal, 21(4), 433–441. doi:10.1177/1352458514546788

67. Claflin, S. B., Broadley, S., & Taylor, B. V. (2019). The effect of disease modifying therapies on disability progression in multiple sclerosis: A systematic overview of meta-analyses. Frontiers in Neurology, 9, 1150. doi:10.3389/fneur.2018.01150

68. Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B., & Ciccarelli, O. (2018). Multiple sclerosis. The Lancet, 391(10130), 1622–1636. doi:10.1016/ S0140-6736(18)30481-1

69. Tuulasvaara, A., Kurdo, G., Martola, J., & Laakso, S. M. (2024). Cervical lymph node diameter reflects disease progression in multiple sclerosis. Multiple Sclerosis and Related Disorders, 84, 105496. doi:10.1016/j.msard.2024.105496

70. Chun, J., Kihara, Y., Jonnalagadda, D., & Blaho, V. A. (2019). Fingolimod: Lessons learned and new opportunities for treating multiple sclerosis and other disorders. Annual Review of Pharmacology and Toxicology, 59(1), 149–170. doi:10.1146/annurev-pharmtox-010818-021358

71. Pournajaf, S., Dargahi, L., Javan, M., & Pourgholami, M. H. (2022). Molecular pharmacology and novel potential therapeutic applications of fingolimod. Frontiers in Pharmacology, 13, 807639. doi:10.3389/fphar.2022.807639

72. Kappos, L., O’Connor, P., Radue, E.-W., Polman, C., Hohlfeld, R., Selmaj, K., Ritter, S., Schlosshauer, R., Von Rosenstiel, P., Zhang-Auberson, L., & Francis, G. (2015). Long-term effects of fingolimod in multiple sclerosis: The randomized FREEDOMS extension trial. Neurology, 84(15), 1582–1591. doi:10.1212/WNL.0000000000001462

73. Tepavčević, V., & Lubetzki, C. (2022). Oligodendrocyte progenitor cell recruitment and remyelination in multiple sclerosis: The more, the merrier? Brain, 145(12), 4178–4192. doi:10.1093/brain/ awac307

74. Bebo, B. F., Allegretta, M., Landsman, D., Zackowski, K. M., Brabazon, F., Kostich, W. A., Coetzee, T., Ng, A. V., Marrie, R. A., Monk, K. R., BarOr, A., & Whitacre, C. C. (2022). Pathways to cures for multiple sclerosis: A research roadmap. Multiple Sclerosis Journal, 28(3), 331–345. doi:10.1177/13524585221075990

75. Skaper, S. D. (2019). Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases. In Progress in Brain Research, 245, 119144. Elsevier. doi:10.1016/bs.pbr.2019.03.013

76. Harlow, D. E., Honce, J. M., & Miravalle, A. A. (2015). Remyelination therapy in multiple sclerosis. Frontiers in Neurology, 6. doi:10.3389/fneur.2015.00257

77. Mahad, D. H., Trapp, B. D., & Lassmann, H. (2015). Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology, 14(2), 183–193. doi:10.1016/S1474-4422(14)70256-X

78. Mei, F., Lehmann-Horn, K., Shen, Y.-A. A., Rankin, K. A., Stebbins, K. J., Lorrain, D. S., Pekarek, K., A Sagan, S., Xiao, L., Teuscher, C., Von Büdingen, H.C., Wess, J., Lawrence, J. J., Green, A. J., Fancy, S. P., Zamvil, S. S., & Chan, J. R. (2016). Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. eLife, 5. doi:10.7554/eLife.18246

REFERENCES

79. Najm, F. J., Madhavan, M., Zaremba, A., Shick, E., Karl, R. T., Factor, D. C., Miller, T. E., Nevin, Z. S., Kantor, C., Sargent, A., Quick, K. L., Schlatzer, D. M., Tang, H., Papoian, R., Brimacombe, K. R., Shen, M., Boxer, M. B., Jadhav, A., Robinson, A. P., Podojil, J. R., Miller, S. D., Miller, R. H., & Tesar, P. J. (2015). Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature, 522(7555), 216–220. doi:10.1038/nature14335

80. Su, X., Tang, W., Luan, Z., Yang, Y., Wang, Z., Zhang, Y., Wang, Q., Suo, L., Huang, Z., Wang, X., & Yuan, H. (2018). Protective effect of miconazole on rat myelin sheaths following premature infant cerebral white matter injury. Experimental and Therapeutic Medicine. doi:10.3892/etm.2018.5717

81. Yao, X., Su, T., & Verkman, A. S. (2016). Clobetasol promotes remyelination in a mouse model of neuromyelitis optica. Acta Neuropathologica Communications, 4(1), 42. doi:10.1186/s40478-016-0309-4

82. Chataway, J., Williams, T., Li, V., Marrie, R. A., Ontaneda, D., & Fox, R. J. (2024). Clinical trials for progressive multiple sclerosis: Progress, new lessons learned, and remaining challenges. The Lancet Neurology, 23(3), 277–301. doi:10.1016/S14744422(24)00027-9

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

1. Chu, B., Marwaha, K., Sanvictores, T., & Ayers, D. (2022). Physiology, stress reaction. In StatPearls. StatPearls Publishing. PMID:31082164

2. Scott-Solomon, E., Boehm, E. & Kuruvilla, R. The sympathetic nervous system in development and disease. (2021). Nature Reviews Neuroscience, 22, 685–702. doi:10.1038/s41583-021-00523-y

3. Dror, O. E. (2016). Deconstructing the “two factors”: The historical origins of the Schachter–Singer theory of emotions. Emotion Review, 9(1), 7–16. doi:10.1177/1754073916639663

4. Koen, N., Fourie, J., Terburg, D., Stoop, R., Morgan, B., Stein, D. J., & van Honk, J. (2016). Translational neuroscience of basolateral amygdala lesions: Studies of Urbach-Wiethe disease. Journal of Neuroscience Research, 94(6), 504–512. doi:10.1002/jnr.23731

5. Markowitsch, H. J., Staniloiu, A., & Wahl-Kordon, A. (2023). Urbach-Wiethe disease in a young patient without apparent amygdala calcification. Neuropsychologia, 183, 108505. doi:10.1016/j.neuropsychologia.2023.108505

6. Barrett, 11. L. F. (2018). Seeing fear: It’s all in the eyes? Trends in Neurosciences, 41(9), 559–563. doi:10.1016/j.tins.2018.06.009

7. Šimić, G., Tkalčić, M., Vukić, V., Mulc, D., Španić, E., Šagud, M., Olucha-Bordonau, F. E., Vukšić, M., & R. Hof, P. (2021). Understanding emotions: Origins and roles of the amygdala. Biomolecules, 11(6), 823. doi:10.3390/biom11060823

8. Feinstein, J. S., Adolphs, R., Damasio, A., & Tranel, D. (2011). The human amygdala and the induction and experience of fear. Current Biology, 21(1), 34–38. doi:10.1016/j.cub.2010.11.042

9. Adolphs, R., Tranel, D., Damasio, H., Damasio, A. R. (1995) Fear and the human amygdala. Journal of Neuroscience, 15(9), 5879-5891. doi:10.1523/JNEUROSCI.15-09-05879.1995

10. Lee, H., & Kaang, B.-K. (2023). How engram mediates learning, extinction, and relapse. Current Opinion in Neurobiology, 81, 102723. doi:10.1016/j. conb.2023.102723

11. Rolls, E. T. (2019). The cingulate cortex and limbic systems for action, emotion, and memory. Handbook of Clinical Neurology, 166, 23–37. doi:10.1016/ b978-0-444-64196-0.00002-9

12. Smith, D. M., & Torregrossa, M. M. (2021). Valence encoding in the amygdala influences motivated behavior. Behavioural Brain Research, 411, 113370. doi:10.1016/j.bbr.2021.113370

13. Herman, J. P., Nawreen, N., Smail, M. A., & Cotella, E. M. (2020). Brain mechanisms of HPA axis regulation: Neurocircuitry and feedback in context Richard Kvetnansky lecture. Stress, 23(6), 617–632. doi:10.1080/10253890.2020.1859475

14. Barry, T. J., Murray, L., Fearon, P., Moutsiana, C., Johnstone, T., & Halligan, S. L. (2017). Amygdala volume and hypothalamic-pituitary-adrenal axis reactivity to social stress. Psychoneuroendocrinology, 85, 96–99. doi:10.1016/j.psyneuen.2017.07.487

15. Keifer, O. P., Hurt, R. C., Ressler, K. J., & Marvar, P. J. (2015). The physiology of fear: Reconceptualizing the role of the central amygdala in fear learning. Physiology, 30(5), 389–401. doi:10.1152/physiol.00058.2014

16. Kim, W. B., & Cho, J.-H. (2020). Encoding of contextual fear memory in hippocampal–amygdala circuit. Nature Communications, 11(1). doi:10.1038/ s41467-020-15121-2

17. Kamali, A., Milosavljevic, S., Gandhi, A., Lano, K. R., Shobeiri, P., Sherbaf, F. G., Sair, H. I., Riascos, R. F., & Hasan, K. M. (2023). The cortico-limbo-thalamo-cortical circuits: An update to the original Papez Circuit of the human limbic system. Brain Topography, 36(3), 371–389. doi:10.1007/s10548023-00955-y

18. Mobbs, D., Adolphs, R., Fanselow, M. S., Barrett, L. F., LeDoux, J. E., Ressler, K., & Tye, K. M. (2019). Viewpoints: Approaches to defining and investigating fear. Nature Neuroscience, 22(8), 1205–1216. doi:10.1038/s41593-019-0456-6

19. Raber, J., Arzy, S., Bertolus, J. B., Depue, B., Haas, H. E., Hofmann, S. G., Kangas, M., Kensinger, E., Lowry, C. A., Marusak, H. A., Minnier, J., Mouly, A.M., Mühlberger, A., Norrholm, S. D., Peltonen, K., Pinna, G., Rabinak, C., Shiban, Y., Soreq, H., van de Kooij, M. A., Lowe, L., Weingast, L. T., Yamashita, P., & Boutros, S. W. (2019). Current understanding of fear learning and memory in humans and animal models and the value of a linguistic approach for analyzing fear learning and memory in humans. Neuroscience & Biobehavioral Reviews, 105, 136–177. doi:10.1016/j.neubiorev.2019.03.015

20. Reddy, R. P., Korde, S. P., Kanungo, S., Thamodharan, A., Rajeswaran, J., Bharath, R. D., Upadhya, N., Panda, R., & Rao, S. L. (2014). Neural correlates of emotion: Acquisition versus innate view point. Indian Journal of Psychological Medicine, 36(4), 385–391. doi:10.4103/0253-7176.140720

21. Reisenzein, R. (2016). The legacy of cognition-arousal theory: Introduction to a special section of Emotion Review. Emotion Review, 9(1), 3–6. doi:10.1177/1754073916662551

22. Adolphs, R. (2014). The Biology of Fear. Current Biology, 23(2). https://doi.org/10.1016/j.cub.2012.11.055

23. Schachter, S., & Singer, J. (1962). Cognitive, social, and physiological determinants of emotional state. Psychological Review, 69(5), 379–399. doi:10.1037/h0046234

24. Beckers, T., Hermans, D., Lange, I., Luyten, L., Scheveneels, S., & Vervliet, B. (2023). Understanding clinical fear and anxiety through the lens of human fear conditioning. Nature Reviews Psychology, 2(4), 233–245. doi:10.1038/s44159-023-00156-1

25. Cardinale, E. M., Reber, J., O’Connell, K., Turkeltaub, P. E., Tranel, D., Buchanan, T. W., & Marsh, A. A. (2021). Bilateral amygdala damage linked to impaired ability to predict others’ fear but preserved moral judgements about causing others fear. Proceedings of the Royal Society B: Biological Sciences, 288(1943), 20202651. doi:10.1098/ rspb.2020.2651

26. Chatterjee, A., Viswanathan, L., Nagappa, M., & Sinha, S. (2021). Lipoid proteinosis (Urbach-Wiethe disease): A rare genodermatosis with characteristic dermatological and neuroimaging findings. Annals of Indian Academy of Neurology, 24(5), 761. doi:10.4103/aian.aian_1049_20

27. Parida, J. R., Misra, D. P., & Agarwal, V. (2015). Urbach-Wiethe syndrome. BMJ Case Reports. doi:10.1136/bcr-2015-212443

28. Ceciliani, F., & Lecchi, C. (2019). The immune functions of 1-acid glycoprotein. Current Protein & Peptide Science, 20(6), 505–524. doi:10.2174/1389 203720666190405101138

29. Banerjee, N., Mukhopadhyay, S. (2016). Viral glycoproteins: Biological role and application in diagnosis. VirusDisease, 27, 1–11. doi:10.1007/s13337015-0293-5

30. Li, M., Fischer, J., Safwat, S., Shoman, W., Chazli, Y. E., Alter, S., Has, C., & Abdalla, E. (2022). Lipoid proteinosis: Novel ECM1 pathogenic variants and intrafamilial variability in four unrelated Arab families. Pediatric Dermatology, 40(1), 113–119. doi:10.1111/pde.15105

31. Schjoldager, K. T., Narimatsu, Y., Joshi, H. J., & Clausen, H. (2020). Global view of human protein glycosylation pathways and functions. Nature Reviews Molecular Cell Biology, 21(12), 729–749. doi:/10.1038/s41580-020-00294-x

32. Swain, S. K., Sahu, M. C., & Kavita, M. (2017). A comprehensive review on lipoid proteinosis with emphasis on ECM1 gene mutation. Apollo Medicine, 14(2), 105–112. doi:10.1016/j.apme.2017.05.002

33. Yu, L., Lin, Y.-L., Yan, M., Li, T., Wu, E. Y., Zimmel, K., Qureshi, O., Falck, A., Sherman, K. M., Huggins, S. S., Hurtado, D. O., Suva, L. J., Gaddy, D., Cai, J., Brunauer, R., Dawson, L. A., & Muneoka, K. (2022). Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine. Development, 149(2). doi:10.1242/dev.200249

34. Augustine, D., Rao, R. S., & Patil, S. (2021). Hyalinization as a histomorphological risk predictor in oral pathological lesions. Journal of Oral Biology and Craniofacial Research, 11(3), 415–422. doi:10.1016/j.jobcr.2021.05.002

35. Feinstein, J. S., Buzza, C., Hurlemann, R., Follmer, R. L., Dahdaleh, N. S., Coryell, W. H., Welsh, M. J., Tranel, D., & Wemmie, J. A. (2013). Fear and panic in humans with bilateral amygdala damage. Nature Neuroscience, 16(3), 270–272. doi:10.1038/ nn.3323

36. Savulich, G., Hezemans, F. H., van Ghesel Grothe, S., Dafflon, J., Schulten, N., Brühl, A. B., Sahakian, B. J., & Robbins, T. W. (2019). Acute anxiety and autonomic arousal induced by CO2 inhalation impairs prefrontal executive functions in healthy humans. Translational Psychiatry, 9(1). doi:10.1038/ s41398-019-0634-z

REFERENCES

37. Khalsa, S. S., Feinstein, J. S., Li, W., Feusner, J. D., Adolphs, R., & Hurlemann, R. (2016). Panic anxiety in humans with bilateral amygdala lesions: Pharmacological induction via cardiorespiratory interoceptive pathways. The Journal of Neuroscience, 36(12), 3559–3566. doi:10.1523/jneurosci.4109-15.2016