How today’s world is reshaping your brain

Between the COVID-19 pandemic, climate change, constant mass shootings, social injustice, political turmoil, and 24/7 exposure to social media and misinformation, one thing’s for certain: We’re all going through a lot. New terms like “climate anxiety” and “solastalgia” are entering the lexicon to address what we’re experiencing—some even call these events “collective traumas.” If you’re feeling a general sense of stress and anxiety, that makes sense. You’re not alone.

If you’re also feeling a little numb, that makes sense, too. Our brains are powerful places—we know that we can neurally adapt in certain ways, desensitizing our brains to repeated stimuli. But studies also show that these collective traumas, despite their constancy, are taking a toll on us, with long-term consequences for our mental health.

Of course, neither numbness nor anxiety and trauma are ideal. When it comes to absorbing current events, what’s going on in our brains? And how can we healthily cope in today’s world?

Neural adaptation—your brain wants to be smart and efficient

Our brains love forming heuristics—shortcuts to making decisions and predicting patterns. This happens constantly, in both minor ways (is Simone Biles going to outperform Grace McCallum? (You’ve probably heard of Simone, so she’ll likely get your vote) and major ones (would you rather apply for a job at a workplace with one job opening or a dozen? Odds are the one with fewer openings seems more competitive and desirable).

In other words, our brains are always trying to save time and energy, down to the single-cell level, sometimes at the expense of logic—or even our senses. Heuristics, selective attention, going on “autopilot,” the list of ways our brains love efficiency goes on and on.

This energy-saving phenomenon can also be seen in the form of neural adaptation: the gradual decrease over time in responsiveness to a constant stimulus. For most neurotypical individuals, this can be seen nearly every second of every day—did you feel the texture of your chair the moment before you read this sentence? What about the background noise around you that you’re just now noticing? Your brain is making a good argument: If a stimulus keeps occurring and requires no response, why should it waste its time?

But what does the brain do with a near-constant bombardment of negative media exposure? From school shootings to misinformation to climate change, does the brain deem these incessant stimuli as worth less of a response over time? Do we grow numb to the data, or do we grow anxious and stressed? The short answer: As far as we know, it’s both.

Desensitization and stress

Neural adaptation to today’s constant barrage of negative events is a huge, nebulous topic. To demonstrate how it works, Krista Lisdahl, professor of psychology at UW–Milwaukee, starts us off with a narrower, more defined example: alcohol consumption.

“Over time, as the brain gets used to alcohol, receptors and neurotransmitters get downregulated, so they’re less available,” she explains.

With your natural baseline down—in this case, the brain’s GABA (gamma-aminobutyric acid) signaling, which reduces brain activity and provides a sense of calm—you wind up drinking more alcohol to achieve that same dopamine rush. That leads to a whole slew of negative side effects; desensitization, when gone too far, comes with repercussions.

Lisdahl points to a study that’s closer to the topic at hand, where children’s brains neurally adapted in response to adverse events like divorce, abuse, substance use, and natural disasters. At first, she explains, the children demonstrated an increased cortisol response through the hypothalamic-pituitary-adrenal axis (HPA) function—aka stress. Over time, that cortisol response blunted, and the brain’s neuronal structure changed. In this scenario, adaptation resulted in poor emotional control and reduced problem-solving skills.

“In the end,” says Lisdahl, “these things are bad for the brain.”

For more abstract stressors, such as media exposure to climate change and the Covid pandemic, we don’t have as much neural evidence, says Lisdahl—it’s a difficult study to do, never mind the unethical territory of ceaselessly bombarding individuals with triggering events. But a few topical studies do exist: One climate anxiety study found that a moderate level of media exposure was actually ideal, “encouraging people to rethink actions with negative ecological impacts.” Another study found that exposure to stressful information on climate change can be overwhelming, ultimately encouraging actions with negative ecological impacts.

Those sound contradictory, but what we know about stress tells us otherwise: In short, a moderate level of stress is good—it teaches and informs us, and we can eventually desensitize appropriately. We learn new coping strategies, explains Lisdahl, who brings up her 15-year-old learning how to drive. “When he first got behind the wheel, there was a lot of fear and hesitancy,” she says, until he was driving effortlessly on the highway two months later. “That stress increased adaptation and learning, and it was good for him.”

But go too far on either end—imagine a curve shaped like an upside-down U—and the brain either doesn’t mobilize the resources needed to meet a challenge, or it can’t regulate stress and ultimately can’t recover. If too much cortisol lives in your system, says Lisdahl, you might see increased inflammation and oxidative stress, sleep disruption, emotional regulation disruption, and maladaptive neuronal changes. Like we saw in the above children’s study, vital stress counter-regulatory systems can turn off entirely. (The same principle applies for adults, too.) These chronic stressors also have the power to hinder our cognition, with negative effects on critical cognitive functions such as memory and attention.

Clearly, desensitization and stress are a dangerous game, but there’s a wrench in this system: Some studies have found that, when it comes to things like media exposure to traumatic events, we don’t desensitize at all. Instead, we sensitize, a process with similar side effects—but one we have the power to stop.

Negative media exposure and sensitization

The Orlando shooting, the Colorado River disappearing—these are serious stories. What if our brains don’t desensitize to negative media exposure? That’s what E. Alison Holman, professor of nursing science and psychological science at the University of California–Irvine, sees in her research. Instead, negative media exposure initiates a dangerous cycle: Worrying about the future draws an individual to the media, which makes them worry about the future, which draws them to the media, and so on.

“Whether it be a hurricane or mass shooting or terrorist attacks,” Holman says, “people can develop post-traumatic stress-type symptoms, both early and across time.”

In one poignant example, Holman studied the degree of acute stress following the 2013 Boston Marathon bombings in two groups: those present at the event and those exposed through the media. On average, notes Holman, the people who were at the site reported less stress than the people who watched via the media. She attributes this in part to the media’s gravitational pull to the unnecessarily violent and dramatic: In the real world, people got to see the whole picture—an act of terrorism, yes, but also an act of the community coming together.

Holman adds that negative media exposure can compound—it doesn’t have to be one event or topic. In today’s world, from Charlottesville to Canadian wildfires to Ukraine, stressful events are coming clip after clip after clip, which can be overwhelming psychologically—your brain doesn’t get a break to relax and process. “It’s what we call ‘cascading or compounding collective events’,” she describes. “It’s those moments that work together to be very psychologically distressing for many people.”

She points to a study where individuals were given MRIs and exposed to different videos, some traumatic. The ventral occipital cortex (VOC), the part of the brain associated with the development of PTSD and other mental health issues, lit up upon viewing the violent content. Specifically, the study mentioned the VOC was associated with flashbacks, or the intrusive mental re-experiencing of traumatic events. “If we know that these things that we’re looking at are triggering,” she says, “it’s a really good idea for us to stop doing it.”

How to keep your brain healthy and engaged

Both Lisdahl and Holman independently remark that the media isn’t doing society any favors—the news gravitates toward sensational headlines and traumatic imagery to get your attention. It’s part of why the self-care movement is so huge; when it comes to the media, societal self-care doesn’t exist.

“Each person really needs to be very mindful and tuned in with their own mental health and their own stress,” says Lisdahl.

We all have different barometers for stress, and it’s important to stay in that Goldilocks zone of resiliency. Not everyone can be an activist—you have to stay engaged in a way that aligns with your values and with the time or resources that you have available.

Several NAN researchers noted the importance of caring for our physical bodies in how we mediate stress and build resiliency. Some peer-reviewed resources on those subjects are here, here, here, and here.

Holman notes that you can get a lot of knowledge from your body—if you pay attention to it. Notice your breathing, the tension you feel in your core; if you’re having a physiological response, cut it off.

“I wouldn’t even wait to that point,” she adds. “If you’re starting to feel like, ‘Oh my god, this is overwhelming,’ just turn it off.”

Both researchers suggest hard and fast limits on media exposure: 30 minutes or less per day. Both even suggest picking two neutral outlets—like the Associated Press or Reuters—and making your bite-sized news consumption routine. That also limits your exposure to misinformation, which, as other studies show, sways your emotions and opinions.

Lastly, Holman notes how important it is to connect with real people in your social world—to talk about these events, to get the support you need, to create social connections in your community.

“The way things have always been fixed or changed or made for the better,” she says, “is by people coming together and supporting each other. We can do that.”

For additional resources on dealing with climate anxiety, check out this Headspace feature, this book, and, of course, NAN’s brain health brochure.

This article has been factchecked by members of NAN’s Publications Committee. For more about that process, click here.

Music and the brain

Sure, Dr. Eric A. Zillmer is the Carl R. Pacifico Professor of Neuropsychology at Drexel University. Yes, he serves as the school’s athletic director emeritus, and is the director of The Happiness Lab, a Drexel thinktank that investigates the meaning of happiness and its place in our culture. He’s a past president of the National Academy of Neuropsychology (NAN). He’s even a stroke survivor. Dr. Zillmer’s real passion is music. He is an accomplished musician and the current President of the Philadelphia Classical Guitar Society. He also spends much of his free time thinking about the intersection of music and the brain—how we as humans interact with and process music when we hear it. BrainWise Managing Editor Matt Villano recently sat down with Dr. Zillmer to discuss some of these topics. What follows is an edited transcript of their interview.

BrainWise: Generally speaking, what happens in our brains when we hear music?

Dr. Eric Zillmer: When you’re listening to music, it is relaxing, it lowers your blood pressure, it makes you feel good. There are very few things about music that are bad or wrong. If you think about it, [music] is almost a panacea to feeling well and happiness and creativity and just a lot of good things. If you look underneath the hood [of our brains], there’s a lot going on [when we hear music]. The brain contains billions of cells and neurons and an infinite number of possible connections among individual neurons that allow for this amazingly complex information exchange. Music locks you into the brain and into the moment, which is a beautiful, pleasant thing to do, very much like you would when you drive a car or when you engage in art or anything creative that requires you to be present. So that’s what happens.

I think a good way to frame all of this is that everything psychological, everything musical is essentially biological. When people say, ‘I trust my gut,’ or, ‘Let’s play it by ear,’ their behavior and thinking has a little to do with your ear and gut; it has to do with how your brain processes information. For me, as a teacher of how the brain works, I try to make how the brain works come alive, and I try to answer questions that seemingly look simple but may be complicated.

BrainWise: Can you elaborate?

Dr. Zillmer: If you think of the brain as a house that’s being remodeled and has many, many different rooms, there’s music everywhere. This analogy works well because we’ve had this reptilian brain, I would call it the basement, where sleep and breathing and heart rate [happen]. And then you have the first floor, which is the limbic system, the second floor is the cortex. And you have this new structure, this beautiful penthouse. Music enters the brain at the lowest level, we call it the brainstem. Which basically means we are hardwired for music.

From there, music is processed in many different areas of the brain. Even at the lowest level there is crossover. Almost everything that comes from the right side goes to the left side. There’s complexity right away when you’re dealing with music. If you’re a neuroscientist, you might say, ‘Wait a minute, this is interesting. What role does this play in evolution? What role does this play in humanity and making us feel humans?’ You don’t realize this when you put the stylus on the vinyl, you’re just listening to something. Then the brain starts processing. It manages information and then sorts it out and gives it meaning. In psychology, we talk about the difference between sensation, which is basically just realizing there is information out there, and then perception, which is, ‘Oh, this song sounds like Metallica.’

As we get a little bit more complicated, up in the evolutionary ladder of the brain to the first floor, we call that the limbic system, limbic meaning the border to the brain, and it includes several interesting structures that are well-defined. It’s like there’s certain rooms in this house that are well-defined, and one room is the cerebellum, which is an interesting structure in and of itself. Phrenologists thought this was where music was processed, so they would identify people’s skulls to see if they had a larger area in the back of their heads—where the cerebellum resides—and determine if someone might be musical. The cerebellum is a very complicated structure, it’s the brain’s organ of agility, it involves almost all cognitive functions related to music perception and music production. I think of it as a large filing cabinet. Everything gets sequenced there in terms of time and rhythm, and it’s being done automatically without you being aware of it.

So, you’re listening to music, and you don’t have any idea that this supercomputer, your cerebellum, is working all the time, just like when you turn on your car and the engine is running underneath the hood. And this cerebellum is a beautiful little piece of the puzzle because it requires the analysis of music. But when you play music, it also requires you to learn how to phrase a piece of music and then store it in the cerebellum.

BrainWise: The cerebellum plays a big part in how the brain engages with music. What other parts of the brain are important?

Dr. Zillmer: Another one is the hippocampus because it’s associated with memory and emotions. And anybody who thinks about music can relate to that because, if anything, music is emotional. And many times, when I was young, we would give music to a friend, a cassette deck, or we would make up a CD. And you’re thinking, ‘What am I actually giving them?’ Well, you’re giving them an emotion, and you’re presenting them with a potential memory. And that’s because music, as it works its way up to the penthouse, gets tagged emotionally, and then it also gets tagged with a memory. So, a lot of times it can’t be separated. Because it travels through this structure, which looks like a seahorse-shaped brain structure, and it processes conscious memories and explicit memories and implicit memories. There’s a lot going on even before you realize what you’re hearing.

There also is tremendous neuronal connectivity related to the processing of music. And many researchers think music came before language, so it makes sense that the brain has a lot of architecture that is related to understanding music, to identifying it, to appreciating it. (Language is much more localized in the smaller part of the brain.) There’s also a connection between our major sensory sense, which is vision, and this auditory information. In the visual cortex, we associate watching music and hearing music, so there’s a connection there between music and vision. Here one thinks about MTV or going to a Pink Floyd concert and seeing all the visuals and the artists standing in the shadows, or going to an opera and seeing all of this presentation.

Interestingly, in the brain there’s an area in the cortex [that controls] movement and feeling sensation. When music is being processed by your brain, it activates the motor strip and the motor cortex, and that’s why people dance, or they would like to dance to music or move to music. Even when I talk, I would say language is a form of music, [since] I use my hands. And so there is this integration and synchronization between motor behavior and auditory sounds.

There is a neurological reason that’s connected to the auditory processing system. Even when people sit still, there’s research that shows that the brain is activated in those areas, and there must be other areas in the brain that superimposed the inhibition of that activation, almost like you’re at war with yourself sitting still while listening to a rock concert, that’s why people want to get up and move. This idea of sitting quietly and processing music is somewhat incompatible with how the brain works. It’s much more compatible in terms of getting up and moving around.

BrainWise: You mentioned the ‘penthouse’ of the brain. What is that and what did you mean?

Dr. Zillmer: The penthouse of the brain is, of course, the frontal lobe, the most recently evolved structure. And it is so interesting because it allows free will, the idea that you can play music or that you can turn it off, and that you prefer different genres. Yet if you look at jazz and classical music and pop and R&B and electronic dance music, I do think the brain doesn’t differentiate between them. (See this article for more about this phenomenon.) What the brain kind of senses is beats per minute. If you’re a DJ, you know what that means because you’re locking into the synchronization of how your brain works.

The frontal lobe would allow you to make those kinds of selections. We have these genres, but I think you’re just dialing into the mood of how you want to consume this music. And that is interesting because most people want to listen to music to feel good or feel sad or feel reflective. And there’s these great mysteries why a minor chord would make people feel sad, and why a major chord would make them feel happy. But if you understand it within the idea that music is being traced through memories and through emotions, and then you can make that choice, it makes more sense.

BrainWise: A recent study out of New York University determined we can tell within the first five seconds of listening to a song whether it’s going to be a song that resonates with us. Why does this happen?

Dr. Zillmer: We are very good at reducing complex information into its units. Our brains are so good at sequencing information that we’re paying so much attention to the timing and synchronization of information that we don’t even think about. This leads to other mysteries. How is it possible that people who are blind, like Joaquín Rodrigo, a famous Spanish composer, can compose music? I bring him up because in the second movement of the Concierto de Aranjuez, he has three notes that Santana plays, Miles Davis plays, and probably 20 other artists have played them in pop culture. What is he tapping into? How is it possible that these three notes make so much sense?

BrainWise: Why and how do our brains affix music to certain memories?

Dr. Zillmer: Music is not that concrete, and it’s much more abstract. It’s almost like an inkblot test—an auditory inkblot. Almost everything we listen to is an ink blood test, it’s abstract, and we attach meaning to it because our frontal lobes are always on. I personally think it’s bad because we’re always trying to figure things out. We’re always on social media inside our own brains. I wish we would have a switch and we just turn it off, and we’re not trying to explain everything. Of course, then it becomes important to have the memory be filed away. But most of the time it is just an offer and a suggestion. That’s why music is played in bars, in food stores, in the elevator, and certainly when you’re performing gymnastics or figure skating. In these settings, music is evoking the potential, opening the door for a projection or a memory to occur. It might be an abstract memory, it could be it makes me feel sad, or it makes me feel good, or it makes me feel like being around people. But there’s a connection.

BrainWise: So why can we remember every word from a song we learned 30 years ago, while many of us can’t even remember what we ate for lunch yesterday?

Dr. Zillmer: Words are music, too. We rarely talk without intonation or rhythm, like the computer in ‘2001: A Space Odyssey.’ All this intonation and rhythm in speech is music. When you’re having auditory information coming into your brain, you are having a narrative that’s much deeper and complex because of the abstract nature. It has an opportunity to resonate in different ways, in different areas of the brain. Like I just said earlier, there are so many architectural geographical areas in the brain where music gets managed. It could be having a visual association, it could have a memory association, it could have no association. That is the beauty of it. More than half of all Nobel Peace Prize winners play an instrument, which means they’ve tapped into this conversation with themselves about creativity, opportunity, and hope. It’s much more complicated than language, and it also leaves the door open for growth and for self-actualization and creativity.

BrainWise: What is it about music that makes our brains—and bodies—react viscerally?

Dr. Zillmer: I’m a sports psychologist, and I’ve recently also worked with musicians because I really think of them as athletes. If you look at their personality profiles, the way they attack a problem and solve a problem, they’re very similar to athletes because it’s difficult to perform music. I think at the top of this food chain are vocalists. But if you think of a guitar solo like by David Gilmour or by Carlos Santana, they’re talking. And there are sections where they’re playing, and then there are sections where they are breathing, so to speak. It sounds like he’s talking, and I think that’s how they conceive music, they’re using, not their vocal cords, but they’re using the guitar. The most famous vocal groups like The Beatles and Crosby, Stills, Nash & Young, and the Bee Gees, have these incredible harmonies. And you could even argue that the Bee Gees have the best harmonies because they’re all from the same biological source because they’re brothers.

When you study the longest living people in the country, cultures, so for example, you go to Sardinia where the longest living men live, one out of 10 men live to the age of 90, healthy, you see a lot of different things. And, of course, people will focus on nutrition, but it’s also the lifestyle, how they eat and how they physically exercise. And that they do everything in moderation, including drinking, even though they make wine, and they make good wine. But something else they do is sing together. And really nobody talks about that. They look at the Mediterranean diet, but these people also sing together. And they have these beautiful groups of four men singing together in harmonies.

When we sing in harmony, we have a lot of neuronal circuitry that is dedicated to understanding the pitch and harmonies of a melody. When you’re singing like this with other performers, you’re simply activating more connections in your brain, thereby making it more interesting to listen to. And if it’s done well, and that’s what harmonies are, it must resonate with the architecture of the brain in the way we process information. The end effect is, ‘This is beautiful.’ You don’t even know what’s happening. You just think, ‘This is really pleasant and it’s really uplifting.’ What we also are learning from Sardinia is that also this idea that a culture does this suggests a form of socialization at the highest level, a form of bonding. There’s a connection not only between the music and the sounds, but also in terms of us humans doing this together that makes it very magical and special, makes those people happy, makes them feel like they’re connected. If you study happiness, the No. 1 key is social relationships. You’re doing something together, but you’re also doing something together that’s synchronized in a very complicated way by using your body as an instrument and having that come together in the auditory sense.

BrainWise: What happens in the brain when a musician engages in improvisation?

Dr. Zillmer: When you think of most of the music that we play, it’s concrete. The piano is like a typewriter, there are not that many keys. There are more keys than there are notes or on the guitar frets. But even on a guitar, there are 12 bars, six strings, and a bunch of frets. You can bend the string like some artists do to create a different kind of note. Even though it sounds infinitely difficult to understand music, especially in the Western hemisphere and the Western civilization, music has been very concrete. If you go to a normal orchestra concert, they play from a sheet of music and they’re playing something that was composed potentially 200, 300 years ago by, maybe Joan Sebastian Bach. The only modification is how they’re interpreting this piece of music. There’s no improv at all, it’s all being played from the source that the composer created. Most music is played like that.

Well, once musicians really work hard at what they’re doing, and like I already said earlier, they file everything into a filing cabinet, they must make everything automatic because the complexity of music is such that you can’t process and synthesize it at the same time. You must have it already stored. That’s why you need 10,000 hours of practice to become a professional musician. And if you are blessed with more talent and more perseverance and discipline, you become a virtuoso. These musicians look like they’re performing on the fly, as if they’re improvising. But if you think of what true improvisation would look like, it would look like randomness; it would be just random numbers, random notes. We don’t like that either, even improv needs to be within the context of the music.

What I’ve learned from the jazz guitar is, for example, that there’s quite a lot of structure within a jazz piece. The structure comes in key and chords. What jazz artists are very good at is changing the key with the chord, which is hard to do because you must have in your head all of the scales that go with a specific chord. You might change from A minor to E major within two beats, and you’re changing your solo, which jazz artists do. This sounds like improvisation. It’s very difficult and it’s very automatic, and it may even feel to them like improvisation, but they’re just playing scales. And so, I think there’s less improvisation to it than people might think, but I don’t think it takes anything away from it because it just looks like it.

BrainWise: Where will your research into music and the brain go next? What are the next big questions you plan to ask?

Dr. Zillmer: The first question is why is there music there to begin with? It’s also interesting to look at what makes music, music?  With AI everywhere these days, it seems like a computer could create this kind of pop song that could hit the Top 10. I mean, computers can beat humans in chess! But so far, no computer can compose music that we would consider novel and satisfactory or even celebrate. There are some other mysteries. One I already mentioned is this idea that music can sound sad, but also can sound happy. That is interesting—the connection between music and emotions. The moment you hear a piece in D major, it’s going to be uplifting and it has some hope. And then the movement changes to B minor and it’s all gloom and desperation, like the world is coming to an end. How’s that possible? That’s how composers composed it. Did they know this, or is this just something essentially how we live our lives?

Then there are interesting questions surrounding dancing to music. I don’t think we’ve really understood how that all happens there. There’s an interesting neuropsychological event that’s called synesthesia, which is where people hear music and sounds at the same time. Unfortunately, I don’t have that. I think I would love that. It’d be like a Pink Floyd concert in my head all day. How is that possible? The final question is what door does music open to our understanding of us as humans? That is ultimately the biggest question. When we send an object into space to represent humanity, I would send a piece of music. I think it captures us best and represents us as a people. There’s nothing to regret about ever putting on a record. It’s almost universally positive.

Editor’s note: Dr. Zillmer has contributed several panels about the intersection of music and brain science to an exhibit at the Paul Peck Gallery and Bossone Research Center at Drexel University in Philadelphia. The exhibit is titled, “Electrified: 50 Years of Electric Factory,” and will run through December 2023.

What happens when you treat depression with ketamine

It was a Wednesday afternoon. March 27, 2019. The out-of-office notification popped up on the team calendar at my corporate job. I told everyone I had a “doctor’s appointment” – technically accurate, yet spiritually a lie. I wasn’t going to the doctor’s; I was going to space.

Okay, not actual space–a ketamine clinic just a block or so away from the University of Texas at Austin. I answered a few clipboards full of questions. They sat me in a chair, read my blood pressure, and asked me “What is your intention for today’s infusion?” I do not recall my answer.

Then the infusionist hooked me up to an EKG and poked a vein. The machine beeped and the bag began to drip. The next hour was the weirdest of my entire life–I was about to go into a K-hole to treat a depression I’d been battling for years.

Why I chose ketamine

I received my first official diagnosis of major depressive disorder in the spring of 2001. I was a freshman at Syracuse University, struggling with being a working-class kid from the Rust Belt at a prestigious private school that was a popular magnet for the types of kids we’d call “nepo-babies” in today’s parlance. I was not taking great care of myself. I exercised but forgot to eat. I made friends but not as quickly as I lost them. Occasionally, I even went to class. I got good grades but felt like a misfit.

For treatment, I tried Zoloft. I saw a social worker for counseling. I can’t say either worked. This began a years-long journey on therapists’ couches and doctors’ pills, trying to understand why I felt so sad, anxious, and broken – and, hopefully, feel better. My mental health waxed and waned, but in late 2018 I was low enough (and well-off enough) to try new alternatives.

When my counselor first suggested ketamine infusion therapy after my latest 90-day course of Lexapro yielded unremarkable results, I recoiled. I was never a fan of “drugs.” Too scary. Too much can go wrong. I saw kids put powdered ketamine up their noses in college, sink back in their chairs, and fall out of touch with reality. I thought to myself, “That looks like no fun at all and I’m never going to do that.”

Never say never, I guess. My counselor assured me I would be safe. “I can refer you. I’m good friends with the woman who runs the clinic and her husband’s the doctor there. They’ll take good care of you.” Eventually, I acquiesced. Weeks later, there I was in the chair: determined and pot-committed. I paid $500 to be there (and $3,000 for the initial course of treatment) and put my faith in this Y2K-era club drug. I had some good research on my side.

How ketamine works

Developed in 1962 as a dissociative anesthetic, chemists created the novel compound to be a safer and less hallucinogenic alternative to phencyclidine (PCP). At anesthetic doses, ketamine provides pain relief, sedation, and amnesia. Breathing function is preserved, your blood pressure rises, and your pulse ticks upward. It’s short-acting and quickly metabolized, providing relief within seconds and acute effects that last for an hour or less. It’s antidepressant potential was first noted in 1975.

Unlike conventional antidepressants, which target monoamines, ketamine acts upon the glutamate system of the brain as an N-methyl-d-aspartate (NMDA) receptor antagonist, mediating activity of GABA and glutamate neurotransmitters. Glutamate plays an important role in modulating responsive synaptic changes related to experiences associated with learning and memory.

If how ketamine works is unusual, how fast ketamine works is genuinely unprecedented. Recipients notice an improvement in mood within hours–improvements that can last over a week on their own and, when coupled with integrative therapies and proper care pre- and post-infusion, can last for months if not years.

Researchers at the University of British Columbia conclude, “[Ketamine’s] effects may ‘reset the system’ by counteracting the synaptic deficits, neuronal atrophy, and loss of connectivity in depression.” If you think of the brain as a computer–ketamine appears to perform a soft reboot, a quick start, a system restore, a hard-drive cleanup, and defragmentation all in one.

Ketamine’s ace in the hole is the way it appears to actually “rewire the brain” by increasing neuroplasticity. The brain can heal itself more easily by allowing new neural pathways to develop. Theodora Blanchfield, AMFT, a Los Angeles-based ketamine therapist posits that “the new neural pathways—think of them as new roads in your brain—allow you to create more positive thoughts and, therefore, behaviors. This is compared to traditional antidepressants, which only work as long as they are in your system.”

We can even observe this rewiring visually. In 2022, University of Pennsylvania researchers reported that ketamine switches off specific neurons involved in normal awake brain function and switches on an entirely different and previously inactive set of cells – believed to be a network of cells that enable “dreams, hypnosis, or some type of unconscious state”.

In an interview with Harvard Gazette, anesthesia researcher Fangyun Tian, Ph.D., summarized her own research by drilling down even further, reporting “high-frequency gamma oscillations in the prefrontal cortex and the hippocampus known to be involved in ketamine’s antidepressant effects from other studies.” Additionally, the researchers “found a three-hertz oscillation in the posteromedial cortex that another study showed might be related to ketamine’s dissociative effects.”

These gamma oscillations appear to promote the profound changes in cognition and perception that permeate the psychedelic experience–and also appear to aid in shaking the brain out of the “default mode network,” allowing people to more easily experience mental health breakthroughs and behavioral shifts.

Research into the potential applications yields buzzy headlines and buzzier results, suggesting ketamine-powered neuroplasticity improvements can aid in everything from OCD to PTSD to smoking cessation to alcohol use disorder to learning to tolerate tropical house music.

If this all sounds a bit bullish, it doesn’t come without risks or unknowns. While generally (and often exceptionally) safe, especially in short-term clinical settings, adverse side-effects among long-term clinical ketamine recipients include impairments in memory, executive functioning, self-awareness, and increases in emotional blunting and reward processing. Additionally, a 2022 review published in Frontiers in Neuroanatomy proposes that long-term recreational ketamine use was “associated with lower gray matter volume and less white matter integrity, lower functional thalamocortical and corticocortical connectivity.”

How a therapeutic K-Hole actually feels

My ketamine infusion treatment course consisted of six doses over three weeks. I received progressively increasing amounts, starting at 50mg and ending at 200mg. While no two infusions were alike, they were similar enough to be able to speak about them in broad strokes. Each infusion took about an hour. They started slowly, gradually warmed up, peaked, then waxed and waned in their cognitive distortions until the last drop. The emotional whiplash was sudden, frequent, random, and severe. I laughed, cried, and screamed – sometimes all at once. All the while, I felt a warm glow, a genuine sense of awe-struck wonder, and a slight tinge of dread that this could all go very wrong at any given moment.

Immediately after each dose, I journaled my thoughts in an attempt to remember as much of what I had just experienced as I could. I described the infusions as a “solo space flight,” the Antoine de Saint-Exupéry novella “La Petit Prince,” a journey into “the operating system” of reality to modify the UI and UX, “a wafer-thin atmosphere buffering a sort of meta-reality, enveloped by a dark abyss of nothingness, monitored by scientists in lab coats,” the “minus world” video game glitch in the original Super Mario Bros., and “the flume ride in the Mexico installation at Disney’s EPCOT theme park.” By the final infusion, I started coining terms like “soul meridian” and comparing myself to Simba from The Lion King and the Manchurian Candidate.

Other common ketamine experiences for me included: speaking in perfect French with my dead Papa as a young man at a Parisian cafe, faceless people performing heavy industrial work, feeling as though I’m hanging from the ceiling, feeling watched by MK Ultra-era government medical observers, staring in the direction of a precipice that never quite arrives, and a procession of formless deep blues and greens that wash into each other.

One frequent recurring experience was what I call the “coffin moment.” Approximately two-thirds of the way through most of the infusions, the chair in which I was sitting in folded into a coffin that rose from below the floor and onto a stage where people passed and pay respects. Then I levitated and floated toward a bright light on a well-lit path (think: Rainbow Road from Super Mario Kart). My life fast-forwarded like the climax of a montage that ended in silence and white stillness. I walked to a white door. That was when I heard a voice whisper “not yet,” and I dropped back into my body. I didn’t always make it all the way through that progression–sometimes I ended at the rising coffin–but the moment always played out the same: I was dead and I shouldn’t have been. Then the ketamine subsided.

For as insane as “pretend death” sounds, it’s not uncommon in a psychedelic context. In fact, ketamine is so adept at simulating near-death experiences that there’s peer-reviewed literature detailing the phenomenon. People taking clinical doses of ketamine report experiencing these sensations with uncanny levels of accuracy and consistency.

Not all of my ketamine infusions were pleasant; on two occasions out of the roughly 40 (including boosters) I’ve received, my hallucinations were so painful and intense that I had to cut the infusion short. On a handful of other occasions, my blood pressure spiked to levels that caused clinicians to draw the same dosage out over 75 or even 90 minutes instead of 60.

Still, at doses that cause full dissociation–approaching anesthesia–I progressed through states of curiosity, childlike immersion, omniscient appraisal of life and reality, existential dread, death, rebirth, and newfound confidence. Just about always in that order.

How it feels when it works (and when it doesn’t)

In my experience, there’s been no correlation between how an infusion feels and how successful it is. I’ve had profoundly meaningful and pleasant infusions that did next to nothing; I’ve had frightening and elegiac infusions that changed me in lasting ways.

Post-infusion care and integration are every bit as vital to neural rewiring as the ketamine itself.

My gameplan for what I call the “afterburn” (the 24 hours post-infusion) is to drink plenty of water, eat plenty of food, get plenty of sleep, and avoid all of the following: calls, work, driving, decision-making, the news, deep thought, stress, alcohol, and tobacco.

While most infusions register some improvement, a handful have not–usually due to something sabotaging the post-infusion window. Booze. Bad sleep. Dehydration. Stress. The Buffalo Bills losing to the Kansas City Chiefs in the playoffs.

When ketamine works–and I was usually able to tell by day No. 2, if not sooner–it was obvious. I started incorporating healthier habits. I felt myself become kinder and more empathetic, clearer in thought and morality, more courageous and self-assured, more compassionate toward myself, and less reactive to slights or mistakes. I laughed often and more easily.

Most noticeably, I became more curious. Ketamine may not be a wonder drug, per se, but my elementary understanding of neuronal function and limited experience with other psychotropic medication has convinced me to believe that there may be no other substance that sparks wonder so subtly or effectively.

It’s the curiosity and wonder that have led me to believe that this is the “rewiring” in action. I was often reminded of the Overview Effect–a cognitive shift experienced by astronauts upon seeing the Earth in full from space for the first time. When they return from orbit, they report increased feelings of cooperation and collectivism and a kind of self-transcendence. They become more appreciative, empathetic, and kind. They change the way they show up.

So … does it work?

It’s been four years since I first explored ketamine treatment for my depression. Since then, we’ve endured a deadly global pandemic and a distressing decline in our social and political climates. There’s not enough ketamine in the world to cure what ails us collectively. There’s so much of that noise in the data – plus unrelated work, home, and life stressors – that I can’t tell you whether I’m “still depressed” or if the infusions were worth it.

In short, I think it was worth trying, but it also was no magic bullet.

What I can tell you is this: Ketamine made me a marginally better person. Clearer, kinder, more curious, and occasionally happier. At the same time, I recognized that ketamine is just one part of a bigger picture. Improving your mood requires diligent self-care and self-inquiry, the absence of significant personal and systemic challenges, robust relationships with people close to you, and the curiosity and enthusiasm required to keep learning and growing. Ketamine helps facilitate that final piece and only that final piece.

If that feels like an underwhelming appraisal of something that repeatedly simulates near-death experiences for $500 per hour, let me close with this anecdote. In 2019, I collected my ketamine notes into a 10,000-word essay I published on Medium. It became my most popular and critically lauded written work and earned me enough money and professional and public service opportunities – including writing this very article – to radically change my life. It wasn’t the chemical that changed me; it was what I did with the opportunity it granted me that did. I’ve learned, grown, changed, and evolved – maybe that’s all we can do. Maybe that’s the best we can do. I’ll take it.

Running through a diagnosis of dementia

Toughness might as well be Tom White’s middle name.

He served nearly five years in the U.S. Marine Corps. In 33 years with the Jacksonville (Florida) Sheriff’s Office, he worked his way up from patrolman to detective. He learned SCUBA rescue. When he retired from that gig, he spent 10 years working in other law enforcement posts, mostly as a fire marshal. Tom always has served the public, always given back.

In his spare time, Tom is an avid runner. About 10 years ago, he and his wife Becky challenged each other to run road and trail races in every state. They were well on their way until 2022, when Tom received a dementia diagnosis that rocked his world. Tom wasn’t about to let the disease derail his goal. So, with the blessing of his doctor, the dynamic duo kept on running.

As of this writing (early September 2023), the Amelia Island, Florida-based couple has completed races of varying lengths in 33 states. They recently wrapped a race in Alaska, under the midnight sun. They’re registered for races in Oregon and Washington before October begins.

“We’ll keep going until we can’t go anymore,” the 74-year-old Tom tells BrainWise. “I don’t care what the doctor tells me. There’s no way I’m giving up on life.”

Becky, 71, agrees.

“We may not be as fast as either one of us was years ago, but we’re still competing, still participating, and still finishing these races as best [as] we can,” she says.

Love of culture

Sure, Tom loves the endorphin rush of running a race. In his earlier days, that and a competitive spirit would propel him through marathons several times a year. As Tom aged, his interests matured, and he became less focused on the race itself and more focused on the culture that racing inspires.

One year—2003, to be exact—Tom came up with an idea of racing with a camera and taking pictures of what runners see from the course. These images captured fellow runners in grief and agony, spectators cheering on loved ones, and more. According to Becky, he became known as “the runner with the camera,” and everybody knew his name.

“People get pictures of the finish line, but they don’t ever get images of what’s going on during the race,” says Becky, who worked for years as a photographer for the Jacksonville Times-Union herself. “Once Tom started taking these pictures, everybody loved it because it was different and unique.”

Tom’s photos were published in Becky’s newspaper. Later, the local news station spotlighted his work.

Feedback on the photos was overwhelmingly positive. In subsequent races, runners and spectators would cheer for Tom every time he strode by.

Love of travel

Tom still races with his camera, though he isn’t taking many pictures anymore, and the race distances have shortened from full marathons (26.2 miles) to halves (13.1). Now he also has other priorities, such as maintaining his balance on the course and finishing each race so he can cross more states off his list.

He and Becky both say they love the new challenge because it enables them to see the world.

“It’s not so much about staying in shape as it is about being together and seeing all of these new and exciting places we’ve never seen,” Becky says. She adds that her personal objective every time they book a new race is to plan the trip so they can get out and see interesting attractions in or around the race destination.

To find sights to see, Becky investigates websites such as Atlas Obscura and Roadside America.

When they traveled to Illinois for a marathon, for instance, Becky discovered the race was near a tiny town named Metropolis, which was inspiration for the home of Superman. When they traveled to the western United States, they saw the Grand Canyon and Mt. Rushmore.

“Every place we go we find something unique and memorable,” Tom says.

Love of storytelling

Upon returning home, Becky prints out pictures and puts together photo books as mementos of their trips. Becky decorates each book to reflect something from the trip.

For example, on the front of the book from a trip to Louisiana is a picture of a crawfish.

Becky notes that the books serve two purposes: To tell stories of the couple’s adventures and to collect memories so Tom can access them easily if he needs to. She adds that the books are symbols of their love, too.

“There aren’t a whole lot of husbands and wives who do this together,” she says with a tremble in her voice. “We always do it together, at the same pace, which means he’s usually going slower for me. There’s no competition. Instead, there’s cooperation. We’ll say, ‘Give me a hand’ or ‘I’ll pull you up.’ We enjoy it more because we do it together. There’s no pressure that way.”

What’s next

Tom and Becky say they’ll keep running races as long as they can.

Becky says the two of them probably shouldn’t be running half-marathons any more, but they’re still doing it for now. She says she envisions a time in the near future where the duo might downgrade to 10- or 5-kilometer races instead. She adds that the distance doesn’t matter.

“Tom and I always say, ‘It’s you and me from here on out,’” Becky notes. “It’s important to nurture that, I think. I will always be here for Tom and he will always be here for me, no matter what. We treat each other with respect and dignity. We support each other. Really, that’s all you can ask for from a partner in this life.”

Tom agrees. He adds that once he and Becky hit all 50 states, they plan to start visiting the home nations of their ancestors, which include several countries in Europe.

“There’s nobody I’d rather be doing this with,” he says. “Nobody in the world.”

Cutting through the (brain) fog

More than three years after the start of the Covid-19 pandemic, neuropsychologists and neurologists are learning more about one of the scariest symptoms: brain fog. Dr. Gabriel de Erausquin is one of the experts leading the charge. The bespectacled de Erausquin is director of the Laboratory of Brain Development, Modulation, and Repair at The Glenn Biggs Institute of Alzheimer’s and Neurodegenerative Disorders. He also serves as professor of neurology and radiological science in the Joe and Teresa Long School of Medicine at the University of Texas Health San Antonio. Since 2020, de Erausquin has been researching brain fog and its similarities to what happens in the brains of patients with dementia. BrainWise Managing Editor Matt Villano recently sat down with him to learn more.

BrainWise: What is brain fog?

Dr. Gabriel De Erausquin: It is not a medical term, but a phrase people use to describe a range of symptoms including poor concentration, confusion, thinking more slowly than usual, fuzzy thoughts and slower-than-usual short-term memory. In most cases it is temporary or improves over time.

BrainWise: How did your research into this area begin?

Dr. de Erausquin: When the pandemic began, in January and February of 2020, of the things that caught my attention was that people were complaining of impairment in recognizing smells, a symptom that doctors referred to as anosmia. The reason that caught our attention is that anosmia, or lack of ability to recognize smells, is a very common early symptom in several progressive diseases of the brain—specifically Parkinson’s disease, Alzheimer’s disease, and other forms of dementia. That suggested the possibility that the virus was affecting the brain in one way or another. So, we set out to lay the groundwork to collaborate long-term on [researching] the possible consequences of the virus on brain performance and brain function. To do this, we used the platform of a collaborative group within the World Health Organization: Experts Advisory Committee on SCANs. SCAN is an instrument, an assessment instrument, called Schedules of Clinical Assessment in Neuropsychiatry. It’s been around for 30 years, and it’s considered the gold standard as an assessment instrument for neuropsychiatric symptoms, meaning behavioral changes and subjective complaints, including memory complaints, including changes in motor performance and such. This group was meeting in February 2020 in New Delhi. This happened just at the time India was about to close for COVID restrictions, and we had the opportunity to discuss this thing at the very outset and start planning long-term studies. A few months later, the Alzheimer’s Association came on board and brought a significant additional network of people. The consortium exploded, basically, to include something like 100 different institutions in 39 or 40 different countries. That has continued to work with different fluctuating participation over the past several years.

BrainWise: What were the first steps?

Dr. de Erausquin: One of the first questions was, ‘How do you compare?’ Put differently, what do you do to compare cognitive performance across all these different samples in a way that makes sense to include the different levels of cultural, not culture, but rather educational attainment, so different levels of average school participation or literacy, as well as different cultural environments? It’s not the same if you are reading Chinese or Japanese symbols or if you are reading Latin-style characters, or if you’re not reading at all, if your language is spoken, as is the case in the Quechua language, for instance, in the mountains of South America. We had all these different possibilities and we had to come up with recommendations on how to test cognitive change across all these different samples. So that was the outset of the neuropsychological expertise group within the consortium that spent the better part of 2020 and early 2021 working out the consensus. We had some interaction at the time with the International Neuropsychological Society. They had their own vision of how to do things, so it didn’t coalesce into a single effort, but we had some conversations about what they thought was important or ideal. Eventually, the whole thing coalesced into a set of recommendations that were part of a much larger research publication, with the harmonization of the consortia groups on how to test cognitive assessment. A separate grant from the National Academy of Neuropsychology and the Alzheimer’s Association, was intended to create a tool, an app, or a series of apps, that were to be deployed on Android devices, because they are much more prevalent worldwide than iOS devices, and that contained the minimum cognitive assessment that we had all across the world agreed that was necessary for this task. So that was done, that tool is done, is completed, and it’s being tested now.

BrainWise: What are some of the questions you answered after that?

Dr. de Erausquin: In parallel with the deployment of the cognitive assessment on the tablet, we started collecting data, and there are two different efforts that were done in that direction. One of them was a so-called pooled analysis and meta-analysis of cognitive data across the entire consortium that was recently completed, as well. The results were presented in Amsterdam at the Alzheimer’s Association International Conference, and that included a data analysis of cognitive impairment post-COVID in individuals from samples in India, Chile, Argentina, Russia, the UK, Canada, and I’m forgetting a couple of countries. Anyway, it was a large sample, with several thousand people from multiple different cultures. We found there was confirmation, really, of something that we already thought was present, which is a combination of two different types of consequences to COVID. There seems to be two different syndromes. One of them that happens in younger people tends to affect more commonly women than men and, if you will, is less severe. That’s what’s typically described as ‘brain fog.’ This seems to be somewhat reversible or at least less severely chronic. It tends to affect primarily sustained attention, a little bit of the ability to organize tasks, and executive function. And it’s related to lack of stamina, mental stamina, physical stamina on the one hand, and also related to preexisting mood or anxiety symptoms.

This is very different from a second syndrome that is seen primarily in people older, who are 60 years of age, and that is equally frequent in males and females, no distinction there, and that appears to be much closer to what you expect to see in a person with early Alzheimer’s disease. These folks have clear memory impairment, particularly short-term memory impairment, the episodic type. They also hey have much more prominent language impairment. In more severe cases, they have trouble with putting together practical tasks. This second syndrome looks to be very much like an early Alzheimer’s-type of clinical picture. It’s also associated with changes in brain volume. We were not the first ones to report that. That had been reported by the Brain Bank in the UK, but we confirmed it in a larger sample. And we also have found that—perhaps not entirely surprisingly—it’s also affected by your genes. So the risk of having cognitive decline after COVID appears to be inherited, at least in part.

BrainWise: Can you please elaborate on the differences between the two syndromes?

Dr. de Erausquin: The first syndrome is clearly different in that it doesn’t affect memory. It affects primarily attention and concentration and mental stamina, and physical stamina. The two studies that looked at this specifically found that it tends to improve over time. It doesn’t improve on everybody, but it tends to improve over time. And so there is some hint that, at least for a proportion of the people who complain of these symptoms, it is reversible or improving over the first year after the infection. The picture of these younger folks who have it, as I said, are mostly women, younger, often with a history of affective or anxiety symptoms prior to the infection. In some cases, it has looked like this is more akin to the picture of chronic fatigue syndrome, fibromyalgia, postviral encephalomyelitis and other postviral and chronic presentations that are not particularly specific to COVID. This is all very different from the picture of the memory decline that you see in older folks. Those symptoms were clearly Alzheimer’s-like, in the sense that it doesn’t seem to reverse. It seems to be progressive. It doesn’t distinguish male or female and it doesn’t require any preexisting disease or symptoms of neuropsychiatric type as in the case of the brain fog. These folks often don’t have any history of any impairment before. They just present with memory impairment.

BrainWise: What happens in the brain to cause these syndromes?

Dr. de Erausquin: It’s another very important question and one that we don’t have a definitive answer yet. There are several changes in the brain that have been associated with COVID, particularly with acute COVID, and those are mostly vascular, microbleeds, microhemorrhages, and changes in white matter that are consistent with ischemic changes. None of the early data supports the possibility of direct viral effects on the brain. If it did happen at all, it was rare. What seems to have happened is either one of the two things: either the inflammatory changes that were triggered by the virus caused persistent changes in the brain and that’s the so-called vascular hypothesis, or the invasion by the virus of the olfactory bulb, which is the initial brain stop of the olfactory system, was enough to cause what’s called transneuronal or distant effects of the presence of the virus in those neurons. It may be that all that was needed was the presence of the virus in the olfactory bulb for a period, and then several remote effects of that presence followed, changing function in the brain or perhaps structure in the brain in the connections of the olfactory bulb, the so-called extended olfactory network. Both these things seem to happen, but they don’t necessarily represent the same disease process. In fact, they may happen in different people with different susceptibilities and that may account for the fact that we are finding an interaction between memory loss and the genes. To put it differently, it may well be that only susceptible people who have a particular genetic makeup are the ones who got the severe loss of smell and the remote changes in the olfactory network over time and those are the ones who are picking up as Alzheimer’s-like or memory decline in the older folks. Whereas the nonspecific inflammatory postviral changes may be what accounts for the more common syndrome of brain fog in younger folks. This is entirely hypothetical on my part. I don’t have data to support any of what I just said. I mean, accepting directly what I just mentioned, that we know that there is a link between anosmia and memory loss, that we have shown very clearly, and others have. We know that that link is also associated with specific changes in the size of the structures of the brain that are associated with the olfactory function. And we know that there is some form of genetic predisposition that increases the risk of having those problems. And so, we can reasonably hypothesize that it’s one explanation for memory loss. The other, the inflammatory pathway associated with chronic fatigue and brain fog, that’s much less established on the data, much less supported by the data. It is speculative on my part.

BrainWise: What are the next questions you’ll ask? Where does the research go from here?

Dr. de Erasquin: The crucial questions now are: What are the genetic contributions to this? What are the biological mechanisms underlying it? Do we have any targets to prevent it or reverse it? The data we’re collecting include whole-genome sequencing scans of all these folks in very different settings, with and without infection, with documented vaccines and without vaccines, vaccinated before and after having COVID. We know what variants of COVID they were infected by. And we have blood-based biomarkers of neurodegenerative processes, Alzheimer’s-like, and of inflammatory processes. And we have brain imaging, both functional and structural brain imaging data. We will do that longitudinally, so we’ll be able to assess trajectories and assess the impact of all these variables on functional brain imaging, on structural brain imaging, on cognition, of course, and assess the predictive value of the specific gene variations or specific genes on all these things.

NAN and the Alzheimer’s Association partnered in 2021 to offer eight grants totaling $800,000 for research focusing on the impact of COVID-19 — including cognition, behavior and overall functioning — in older adults from health disparity populations. Some of that funding was routed to research cited in this piece. For more information about the grants, click here and here.

Life without a mind’s eye

The first time I realized that the way I visualized was different from other people, I was 27 years old and taking part in a month-long yoga teacher training in south India.

Lying down on my mat in savasana, with my eyes closed, I listened intently to my teacher’s gentle voice guiding the class through its final meditation of the day. He urged us to visualize each limb relaxing, beginning at the feet and slowly working our way up the body, towards the neck and head. I tried to follow his instructions, but all I could perceive was a disconcerting darkness.

Despite repeated attempts at visualization and subsequently listening to various guided imagery exercises on Headspace, I’ve continued to meditate in pitch blackness. My mind’s eye has remained an impenetrable black void, unable to create the vibrant mental images that seem so natural to others.

And, as it turns out, I’m not the only one.

This lack of mental visual imagery is a cognitive condition known as aphantasia. Dr. Adam Zeman, professor of cognitive and behavioral neurology at the Univeristy of Exeter in the United Kingdom, has studied aphantasia extensively in the last two decades. “It’s a kind of absence of wakeful imagery, both deliberate and involuntary,” he said.

Zeman continued: “When most people think of an apple, for example, they will be able to call to mind the appearance of an apple. They’ll have an experience that is somewhat visual. But people who have aphantasia can’t do that; they are unable to summon imagery to mind in that kind of deliberate fashion.”

One of the first to describe the phenomenon of having no mind’s eye was Sir Francis Galton in 1880, who, during a statistical study on mental imagery, discovered that not everybody could conjure up mental images.

Fast forward to more than a century later and research now indicates that people with aphantasia, known as aphants, make up approximately three to four percent of the population — and Zeman has spoken to more than 17,000 of them.

Aphantasia doesn’t also just apply to visual imagery; Zeman explains that for some people, it can be a multisensory experience as well. Many people with aphantasia can also lack in other senses, including the mind’s ear and the mind’s fingertip.

The history of aphantasia

Today, a quick search for the term “aphantasia” on Facebook yields several active groups that offer varying levels of support and awareness for this relatively understudied cognitive phenomenon. The r/aphantasia subreddit alone has more than 57,000 members, making it one of Reddit’s largest communities.

But this wasn’t always the case.

While records of people having no mind’s eye date as far back as the 19th Century, research and interest in aphantasia are still relatively new. It wasn’t until the early aughts that pioneering researchers like Zeman started diving into why this cognitive condition even occurred.

After his original study on patient MX, who lost the ability to visualize after an angioplasty, was published in Discover magazine in 2010, Zeman began to receive messages from people with similar experiences. “We studied these folks by sending them questionnaires and found that they were reporting a consistent experience,” he says. “But there wasn’t a catchy name for it.” In 2015, Zeman coined the term aphantasia, basing it on the Greek word phantasia, which Aristotle used to describe imagination and the mind’s eye.

The VVIQ, or Vividness of Visual Imagery Questionnaire is one way to determine if you have aphantasia. First developed in 1973 by British psychologist David Marks, the test asks you to visualize 16 different scenes, rating each of them from one to five — one means you don’t see anything, you’re just thinking about it, while five means your visual imagery is as vivid as reality. “I think, on the whole, that test is pretty reliable,” says Zeman. “If you score one or the other extreme, that’s likely to be a meaningful answer.”

When the Mind’s Eye is Blank

Explaining what it’s like to have aphantasia is hard because it feels different for everyone. It’s also one of the main reasons why many aphants go most of their lives unaware they even have it. Facebook groups like the Aphantasia Support Group provide a wealth of information for aphants like elementary school teacher Stephanie Kawamoto and music composer Jamie Kowalski, who often comment and share their unique experiences and methods of coping with the condition.

Kawamoto was first made aware of her lack of visualization skills during an undergraduate class on teaching reading and listening skills in 2011. She recalls learning about how one of the characteristics of being a good reader lies in a person’s ability to visualize and perceive what’s going on in the text.

“I put my hand up and said that I was an avid reader but had never been able to visualize,” Kawamoto says. “And my professor joked that there must be something wrong with me.” A few years later, Kawamoto’s brother enrolled in the very same course, leading her to rehash her pointed classroom experience. “I got curious and ended up googling ‘inability to visualize,'” she says. “This led me to stumble upon aphantasia.”

Some aphants like Kowalski, who found out he had aphantasia in his 50s, have never felt that the condition affected their ability to work. “I had suspected something was different with me for a few years, but I couldn’t articulate it,” he explains. “Then I happened upon a YouTube video about aphantasia, and everything suddenly made sense.”

However, others like Kawamoto report that having a blank mind’s eye can sometimes hinder their ability to work. “Aphantasia mostly affects me at work when I have to organize things visually,” Kawamoto explains of her inability to make seating plans or organize the classroom just by looking at the space alone. “I have to either physically place things in my classroom to see if I like the setup, or I have to make models on paper or on the computer to try to figure out where things should go.”

Aphantasia and Art

Zeman notes that while there’s a slightly higher likelihood for aphants to work in STEM fields that don’t require the need for visualization, there are exceptions to the rule. He is quick to make it clear that people with aphantasia are far from unimaginative. “The lack of the ability to visualize does not imply a lack of the ability to be imaginative in creative and artistic ways,” he says.

Zeman’s research over the years has led to the surprising discovery of several highly successful and creative people that range from artists and authors to Pixar co-founder and Turing Award winner Ed Catmull, who realized he had a blind mind’s eye after being unable to visualize a simple sphere during a Tibetan meditation session.

J. Craig Venter, the scientist responsible for mapping the human genome, told 60 Minutes in 2010 that having aphantasia was his most extraordinary talent. “I have an unusual type of thinking. I have no visual memory whatsoever,” he said. “Everything is conceptual to me. So I think that’s part of it. I see things differently.”

Aphantasia and Memory

According to Zeman’s research, a small subgroup of people with aphantasia may also be autistic. It’s a phenomenon that mental health clinician and fellow aphant Monica Villar sees quite often in her practice. “Many of my autistic clients find it hard to create visual imagery. Some can, but they describe it as very faint outlines,” she says. “I know my mind’s eye has some spatial awareness in memory, but I really can’t create an image in my mind unless I try really hard.”

Casey E. Ovella Davis’ personal experience with aphantasia fuels her work as an archivist, oral historian, and memory worker, making her more attuned to the fragility of recollection. “We all have personal motivations and emotional attachments to different aspects of our past,” Davis says. “But we may not always have the ability to retain or access those memories as clearly as we would like.”

As founder and co-lead of the Autistic Voices Oral History Project, Davis aims to capture stories and lived experiences across the spectrum of the Autistic experience using video, audio, and text. “The fact I am an aphant and autistic has made me even more aware of the fleeting nature of our memories,” she explains. “While others may have vivid visual or sensory recall, I rely more on other forms of memory cues, such as facts and contextual information.”

Much like myself, Davis is also unable to relive past memories. It’s a condition known as Severely Deficient Autobiographical Memory (SDAM), and it’s often interlinked with aphantasia. Having a blank mind’s eye doesn’t just diminish the ability to visualize; it can also affect how the brain processes memory and imagination.

It’s not uncommon for aphants to have a less rich recollection of their personal past. “Many people with aphantasia also experience a reasonably consistent reduction in the richness of autobiographical memory,” says Zeman.

In fact, a 2022 study published in Cognition found a marked difference in how aphants recollect past experiences and imagine future ones. Participants that lacked visual imagery showed lowered capacities for remembering episodic memories and were also less likely to create future scenarios.

Despite having a blank mind’s eye, my visual aphantasia has never affected my ability to create art and write. Since I’m entirely unable to visualize, I rely on reference images when illustrating and painting. When it comes to writing, I use outlines to guide my stories; looking at reference pictures also helps me write better descriptions of food and travel sights.

It’s been six years since I first discovered my lack of mental visual imagery while lying on my yoga mat, and I’ve learned so much about how aphantasia has helped shape who I am today. It’s easier for me to be present, a characteristic that Zeman says he often observes in people with aphantasia as they tend to be less prone to emotions that are driven by imagery, such as regret, longing, and craving.

And, because aphantasia doesn’t keep me from being creative, I view the condition as more of a quirk in my psychological makeup rather than a disability — a fact that often surprises people who have the ability to visualize because they simply cannot imagine a life without an active mind’s eye.

Aphantasia might keep some of us from “seeing” in our minds, but it shows just how different and unique our brains can be, proving there’s no one-size-fits-all way to think or dream.

Christabel Lobo is a freelance writer and illustrator based between Washington, DC and the UAE. Her writing has been published in Time, Insider, Lonely Planet, AllRecipes, Verywell Fit, Healthline, webMD, and more. You can find her on Instagram @whereschristabel.

The truth about Parkinson’s Disease

Parkinson’s Disease is a brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. For the better part of the last 30 years, Dr. Alexander Troster has been studying this condition to learn more about what causes it, what happens when people have it, and what treatments seem to work best. Today Dr. Troster is professor of neuropsychology and chair of the Department of Neuropsychology at Barrow Neurological Institute at Dignity Health St. Joseph’s Hospital and Medical Center in Phoenix. His current investigations include the assessment, definition, and neural bases of mild cognitive impairment in Parkinson’s disease, and the evaluation and prediction of neurobehavioral outcomes of deep brain stimulation for a variety of neurological and psychiatric conditions. BrainWise Managing Editor Matt Villano recently sat down with Dr. Troster to learn more about his research and his perspective on Parkinson’s Disease. What follows is an edited transcript of their interview.

BrainWise: How is Parkinson’s Disease diagnosed?

Dr. Troster: There is no one diagnostic test for Parkinson’s Disease. One of the things that’s true of Parkinson’s Disease is that the symptoms with which this disease begins is quite variable. If we look at the most common forms, people either begin with having a tremor, which is probably about two thirds of all cases of Parkinson’s disease, and one third who tend to have more difficulty with walking, slowing and stiffness. What’s important to point out is that before Parkinson’s disease is even diagnosed, this is a disease with a long prodromal period. What that means is that the changes in the brain underlying Parkinson’s disease have been occurring for a long, long time. And the estimates are anywhere from 15 to as long as 30 years before diagnosis.

In general, people have difficulties with movement, they’re slower to move. They may shake, especially at rest. But it’s very hard in the individual case to draw a straight line and say, ‘This is going to be the progression, this is the symptom you’re going to have next.’ Symptoms declare themselves slowly, gradually, and with great variability.

One of the things that’s been noticed is that people with Parkinson’s Disease often have depression, even before they get diagnosed with Parkinson’s Disease. They also tend to have something known as REM sleep behavior disorder. During sleep, the muscles are usually paralyzed and then REM sleep behavior disorder, that paralysis doesn’t occur. When people have dreams, they start to act out their dreams, they talk in their sleep, they might start to thrash, they might start falling out of bed. And these are things that one wants to look for. These are all what we call prodromal things. And one of the things that people also have is a loss of smell, which is very common. When you ask people, they often have before the motor symptoms began a loss of smell many years before that.

BrainWise: Do we know what causes Parkinson’s Disease?

Dr. Troster: No, we don’t. I mean, we can talk about how people with Parkinson’s Disease get a misfold of protein that aggregates in the brain cells, then Lewy bodies and Lewy neurites form, but even with that explanation, you can keep on saying, ‘What causes this?’ The truth is that we don’t really know what causes the disease.

Parkinsonism is not the same as Parkinson’s disease. Parkinsonism is the core symptoms involving, for example, tremor, slowness, stiffness, imbalanced difficulties. But those can be produced by literally well over 100 conditions. And some of those are reversible and some are not. Some are just mimics of Parkinson’s disease. This can be frustrating for patients sometimes because they’ll go in and say, ‘I’ve got a tremor,’ and neurologists often are not going to give a diagnosis of Parkinson’s Disease until some of the other symptoms declare themselves and some of the other tests are done.

BrainWise: Is Parkinson’s Disease congenital?

Dr. Troster: If we think genetically, in terms of Mendelian genetics where either one or both parents have the condition, you’re going to get the condition potentially. There are genes associated with it. One is known as LRRK2, leucine-rich kinase repeating, a protein or what’s also called dardarin. And there’s a gene coating for alpha-synuclein, which is the core protein that accumulates and misfolds and forms Lewy bodies. And there’s two types of genes that are both autosomal dominant genes, meaning if one parent has that and you inherit that gene from that parent, that you’re going to get the disease.

What we don’t know at this point is whether there are minor mutations or polymorphisms either individually or in several forms and number can produce something like Parkinson’s Disease. It is likely that some genetic factors might predispose to environmental factors that can then trigger the disease as well. We know environmental factors like exposure to fertilizers, pesticides, well water, for example, can increase risk for Parkinson’s Disease.

BrainWise: What do people often get wrong about Parkinson’s Disease?

Dr. Alexander Troster: I think some of the misconceptions that people held maybe 10, 15 years ago are no longer the misconceptions they hold now generally. I think the biggest things are still a lack of realization that Parkinson’s disease is more than a movement disorder. Most people still think of it as it affects my movement. Some people mistakenly think it paralyzes them. So, I think over the past 10 years, more and more work has been done on the non-motor symptoms in Parkinson’s disease, and I think patients have become aware of non-motor symptoms as the disease has progressed.

Number two is that Parkinson’s is rapidly progressive. It’s much more [dependent on] when one develops the disease and the symptoms that impact the disease course. People with young onset Parkinson’s very often take a long time to progress. Several studies suggest that if you develop things like a dementia or global cognitive impairment, people with young onset Parkinson’s still develop it in their seventies, just like people tend to with regular onset Parkinson’s disease, for want of a better word. So, I’ve seen plenty of patients with Parkinson’s disease for 25 and 30 years.

I think the other misconception is that there’s little one can do. While it’s true that there’s no treatment or even a disease-modifying therapy at this point, a lot of the symptoms can be treated either pharmacologically or by ancillary therapies like speech therapy, physical therapy, occupational therapy. And more recently there’s been much more effort made at trying to study some methods of cognitive rehabilitation and remediation in patients with Parkinson’s disease.

BrainWise: To what extent do cases of Parkinson’s Disease incorporate dementia? Does the former always lead to the latter?

Dr. Troster: To my knowledge there’s only one good longitudinal study and that’s one from Australia, which I think followed people for up to 40 years. And obviously, that shows that pretty much 95 percent of people with Parkinson’s, if you survive that long, are going to develop a dementia. But of course, many people pass away with secondary things, not necessarily Parkinson’s disease, but for example, aspiration pneumonia, heart disease, regular old age. People pass away and never develop dementia. But yes, obviously most people, if they live long enough, will develop dementia. Far more common than previously thought is what’s known as mild cognitive impairment. Some people have called mild cognitive impairment (MCI) as an intermediate state between normal cognition and dementia. There are cases of mild cognitive impairment that are related to factors such as medications, depression, anxiety and so on. So, if you look at studies of Parkinson’s disease with MCI, probably over three-year period, somewhere between five and 10 percent of cases of MCI revert.

BrainWise: How should a person change their lives after receiving a diagnosis of Parkinson’s Disease?

Dr. Troster: One must start looking for new hobbies, new ways to express one’s creativity. I think it’s very important for people to remain socially engaged. People with Parkinson’s Disease sometimes tend to feel stigmatized or become embarrassed by these symptoms. You also see people with Parkinson’s often try to hide it by putting their hand in their pocket or they sit on their hand. Actor Michael J. Fox himself talked about how long he hid it, and I think it took him eight or nine years before he came out and told people that he had Parkinson’s disease.

I think things are less stigmatizing than they were in the past. I think some people’s reactions to mental health conditions often come from a poor understanding of what the condition is and sometimes a fear or a sense of threat that one may suffer a similar fate. But persons with Parkinson’s Disease are very adapt. We’ve looked at coping strategies. They use coping strategies just like healthy people. They’re quite capable of adapting to the disease, the diagnosis, of keeping on going. Many people with Parkinson’s disease continue to work, they continue to find pleasure in social activities.

I cannot overemphasize, quality of life can be very good in Parkinson’s disease for a long time, despite these changes. And I think people have to hear that.

BrainWise: Once someone is diagnosed with Parkinson’s Disease, is there a uniform course of symptoms?

Dr. Troster: Not really. Not everybody has cognitive impairment—again, look at Michael J. Fox. Cognitive impairment and MCI tend to be especially rare in young onset. Some patients also react differently to medications, develop dyskinesias, or erratic movements, in response to medications sooner, which is unusual. But there are alternative therapies available too, such as deep-brain stimulation.

BrainWise: What is deep-brain stimulation and how can it help?

Dr. Troster: Surgical treatment is usually way down in the armamentarium of treatments. It’s not the first thing one considers. It’s usually when people have side effects from medications or intolerable side effects from them, or the diseases become less responsive, some of the symptoms, or they have complications as they’re from the treatment like dyskinesias or they can’t tolerate doses of medication. Then it’s a good time to consider alternative therapies. Deep-brain stimulation (DBS) is one of those alternatives.

It’s been around 30 years now. The devices have become much smaller, much more sophisticated, so you can steer currents to very small parts of the brain and shape the electrical field with which you’re stimulating the brain. With DBS it becomes easier to control specific symptoms and avoid side effects with the therapy. These devices last [a relatively long time]. Some people choose to have devices with batteries in them that need to be replaced every few years. Some people prefer a rechargeable device, so they don’t have to worry about replacing a battery. Again, it’s not a first line therapy, but it’s a therapy down the road for people who have complications or an unusual course if they’re young and develop some of these symptoms early.

BrainWise: How does this treatment work?

Dr. Troster: It’s pretty much like a pacemaker. The treatment is ongoing, it’s continuous. The device needs to be programmed by a neurologist and the programming tends to take a little more time initially. You’ll have more visits with your neurologist immediately after surgery, probably every four weeks or every two months. Once it’s programmed, you’re probably going to see your neurologist just like every other patient, probably every six to 12 months. The therapeutic benefit lasts a long time. Typically, what people tell you is that the very best you are with medicine is probably the very best you’re going to be with the device. It evens out the effect, so you don’t have the fluctuations. If somebody’s got balance problems or gait disturbance because of balance problems, it’s not going to help for that. It’s not a therapy for everything. People ask whether a person with Parkinson’s disease a candidate for surgery, and I’ve always preferred to turn it the other way around and say, ‘Is this an appropriate therapy for the person with Parkinson’s disease?’

Patients also are very different in their risk tolerance. I’ve seen persons where they see the neurologist and the neurologist says, ‘Well, you’ll have some benefit from DBS.’ And the person says, ‘I don’t care. I want surgery anyway.’ In one example I’ll remember forever, a patient told me, ‘I don’t care. I’m retired. All I want to be able to do is tee up the golf ball.’ My response: ‘Well, who knows,’ sort of jokingly. ‘If it affects your memory, your golf score will get better too because you won’t remember the number of strokes you’ve taken.’

BrainWise: What does the future of Parkinson’s Disease treatment look like?

Dr. Troster: Let me get out the crystal ball here. There’s an amazing amount of research going on in therapies, in terms of molecular biology, genetics, gene therapy, medications, and identifying what causes some of the misfolding of protein. As you know, some advances have lately been made with medications for Alzheimer’s disease. Will there be a similar thing for Parkinson’s disease? One hopes so. I think ancillary therapies are going to continue to get better. [Researchers] have never looked at cognitive rehabilitation in Parkinson’s disease, but now there are people looking at that. [Researchers] also are looking at transcranial stimulation, be that direct current, alternating current or magnetic stimulation. And what’s exciting to some extent is there’s some findings from studies in Italy that suggest with [this treatment] you might make persons more receptive when you do cognitive rehabilitation.

[Other researchers] are trying to find biomarkers. I think that’s one of the things that’s going to be imperative. If we can find these biomarkers and put them together with other markers, we can predict what the course of the disease is going to be. Then we can determine what treatment needs to be given. I think in future, maybe five or 10 years from now, doctors are going to say, ‘We need to treat you fairly aggressively; this is going to be a progressive quick form of Parkinson’s,’ or, ‘This is going to be relatively benign. You’re going to develop this at that stage, and we’ll treat you at that time for this [one] symptom.’ So I think with treatment tailored for individual symptoms rather than trying to hit all symptoms with one drug or two drugs, that will be the way things go down the road.

BrainWise: Finally, Dr. Troster, what’s the next big research question for you?

Dr. Troster: The big question is, ‘Can we predict who’s going to develop dementia with Parkinson’s disease and how quickly?’ Because these are the folks we really want to spend more time on. We want to repair families, make these changes earlier, and hopefully predict these things sooner. And I’m not hopeful that our neuropsychological tests are necessarily the best for this right now. About 25 years ago, when I started focusing on this, a Parkinson’s Disease expert who will remain nameless said to me, ‘Why are you doing neuropsychology in Parkinson’s disease? It’s a movement disorder.’ That’s a big [hurdle to overcome.]

Non-motor symptoms are the big challenge in Parkinson’s Disease today. These are things that lead to caregiver burden. These are the things that lead to institutionalization, and loss of independence. I think we’ve made huge strides in the last 10 years. I think we also have a long way to go. We’ve come to realize a lot of what some of the issues are, whether they’re impulsive and compulsive behaviors that people can develop, cognitive changes, depression, anxiety, psychosis, other non-motor features, like some patients develop pain, sleep disturbances. How do we cope with those? How do we best treat those? And I think we’ve come to recognize them at least, and able to diagnose them a little better. Now what we have to do is get better treatments for these things.

From expert to patient

Dr. Tresa Roebuck Spencer has spent most of her life as an expert in and national advocate for neuropsychology. The Houston-based doctor is a board-certified clinical neuropsychologist who has worked in Texas, Louisiana, Florida, and Washington, D.C. She is a past president of the National Academy of Neuropsychology. She has published more than 70 peer-reviewed publications and book chapters in the areas of traumatic brain injury, rehabilitation, and computerized neuropsychological testing. For the last few years, however, Dr. Spencer has also been a patient. In October 2020, Dr. Spencer was diagnosed with glioblastoma multiforme (GBM), a fast-growing and aggressive cancerous brain tumor. Since then, she has managed the roller coaster of treatment (including four brain surgeries, three clinical trials, two rounds of radiation and chemotherapy), as well as the ups and downs that have come with transitioning from expert to patient. In advance of Glioblastoma Awareness Day on July 19, BrainWise Managing Editor Matt Villano sat down with Dr. Spencer to interview her about her experiences. What follows is an edited transcript of that conversation.

BrainWise: Take us back to the beginning. How did your experience with GBM begin?

Dr. Tresa Spencer: On October 13, 2020, I was in my office working, and I started to feel funny. I had no symptoms or problems prior to that point, I was just living my everyday normal life, as a working mom, traveling frequently while establishing my fast-growing private practice. I’m a bit of an over-achiever, so it was not uncommon for me to start my day with a Camp Gladiator workout and then fall asleep with my laptop in my lap writing reports. So, I was in my office, and I started to feel funny. I had the wherewithal to call my neighbor who lives right down the street and say, ‘Can you come check on me? Something’s not right.’ I was dropping things out of my left hand and kept mistyping my passwords. I started thinking, ‘Am I having a stroke? What’s happening to me?’  When my neighbor arrived, I was walking around my office, doing a neurological exam on myself. I was raising my eyebrows, sticking out my tongue, and having her look at my pupils. I was walking back and forth to test my balance. I knew something was wrong but didn’t know what. It was a surreal experience, as you might imagine. We called our other neighbor who’s a physician, for her advice, because I was starting to feel dizzy at that point. Then we went to the ER.  I made sure to take my work bag, thinking I’d be home within a few hours. As we were driving to the ER, my voice sounded strange, and I continued to assess myself, trying to make sense of what was happening to me.  I instructed my neighbor what to tell the ER triage nurse, because I knew if I got there within a certain amount of time, they could give me [tissue plasminogen activator, or TPA,] a particular medication that helps lessen the effect of stroke. So, I told her, ‘Tell them my symptoms started at 10:00 a.m., and that we’re getting here within an hour. They can still give me TPA.’ I wasn’t only assessing myself, but I also was thinking about how to give an accurate history, and what my treatment plan would be. When we got to the ER, I started to explain my symptoms, and I passed out.

BrainWise: What happened next?

Dr. Spencer: My next memory is of waking up in an exam room and my neighbor staring at me with the biggest eyes I’ve ever seen. I asked, ‘What’s going on?’ At that point, I was confused. And she looked at me and said, ‘Tresa, you just had a seizure.’ And I said, ‘Well, what kind of seizure?’ I immediately went back into clinician mode. And she said, ‘How do I know what kind of seizure?’ So again, being a clinician, I said, ‘Well, describe it to me,’ because that’s what I would say to a patient. And she said, ‘I can’t describe it. It was a seizure.’ She left to ask the doctor. When she came back, she said, ‘They told me to tell you that you had a generalized tonic-clonic seizure.’ At that point, everything stopped. I thought, ‘How could I have a seizure? I’ve never had a neurologic problem or seizure in my life.’ Fast-forward from there, they put me in a CT scan, and they saw a tumor. They decided to send me to the hospital for more tests. I was in the hospital for three days, where they ran tests including continuous EEG monitoring and functional MRIs, all the things I knew about from my work as a neuropsychologist, treating people with brain disorders. None of it seemed real. Luckily, I had my laptop and lots of friends on speed dial to support me. Finally, they gave me a diagnosis. They told me it was a brain tumor. And that, given the characteristics, it was most likely a GBM, a, glioblastoma, which I knew to be the worst of the worst. None of it made sense. I thought, ‘brain tumors are rare and happen to other people, not me.’

BrainWise: What was the initial plan of treatment?

Dr. Spencer: I was able to get myself registered as a patient at MD Anderson Cancer Center at the University of Texas within 48 hours. In that respect, I felt incredibly lucky, because most people would not have had that opportunity. It all felt very surreal. I kept thinking, ‘I am the luckiest, unlucky person ever.’ It was hard to even conceive that something was wrong because I had no symptoms other than [being] in a complete state of shock. I had brain surgery two weeks later to remove the tumor. When the anesthesiologist, who assisted the surgery, asked me in pre-op, “Is this your first brain surgery?” I waited a good 10 seconds to respond because I thought he was joking and was waiting for him to laugh. ‘Who has more than one brain surgery?’ I thought. Now I know it is common for patients with GBM to have multiple surgeries. Luckily, I had an amazing neurosurgeon who was able to remove all the tumor from my right parietal lobe with no residual effects on my functioning other than intermittent numbness in my left hand.  I then went on with my normal life. I started chemotherapy and radiation treatment. I continued to run my private practice and volunteer in the professional arena. I continued to see patients, even some patients with brain tumors who needed help with cognitive issues. It was a bit surreal to be a clinician and patient at the same time. I also gave a few talks on the emotional and cognitive effects of brain tumors and volunteered to be a mentor for other patients. This all happened during Covid-19, which added a layer of anxiety, since I was worried about getting sick.

A brain scan of Tresa Spencer's brain shows exactly where her GBM was located.

BrainWise: How did the experience change over time?

Dr. Spencer: I was fatigued, as you can imagine, because I was going through chemo and radiation treatment. Then I [joined] a clinical trial, which was another form of chemo. I was always scared of having another seizure. After about nine months and following a mountain climbing trip with my family, I started to have some problems again with my left hand. My doctors thought I might be having a tumor recurrence. So, I went back in for a second surgery. It turned out that I did not have a recurrence; I was having necrosis, or damage from the prior radiation treatment. I fortunately went through that surgery well and with no residual problems. My good luck continued. I’m not sure if being a neuropsychologist helped or hindered my situation. I knew what to watch for and all the ways to keep my brain healthy. Over time, the radiation effects continued leading to headaches and a third surgery. I then went on medication to control the radiation necrosis that essentially caused me to have a small stroke, proving that the treatments can be as bad as the disease. I was lucky that my cognition and personality stayed intact, but I suffered sensory changes and weakness on the left side of my body I started going to physical and occupational therapy; [coincidentally] I did those treatments in the same place where I had completed my fellowship 20 years before.

BrainWise: What have the last six months been like?

Dr. Spencer: A few months ago, I started to have some problems with my vision, and I decided it was time to stop working, because I didn’t want to risk making a mistake. Since then, I’ve focused on my rehabilitation therapies. As you might imagine, I’m not the typical patient. As a neuropsychologist who has worked in rehab hospitals for 20 years, I am constantly pushing myself and thinking of ways to use the intact parts of my brain to compensate for my areas of weakness. I work closely with my therapists to set goals and make it a priority to stay active in my home and community. I love a challenge and urge my therapists to set harder goals for me. Over the last six months I’ve been doing volunteer and advocacy work for the National Brain Tumor Society and the American Brain Tumor Association. I serve as a mentor for other patients with GBM.  I also serve as a patient advocate for research and clinical initiatives. That work has been incredibly fulfilling to me, and I hope it makes a difference for other patients on this crazy journey.

Medically, I just participated in a phase-one clinical trial, but I had to stop due to adverse side effects. There is no cure for GBM, so treatment is ongoing. Despite my feeling good, my last MRI was worrisome. So, my treatment team recommended a second round of radiation. From a functional standpoint, I still have problems with my left side. I can walk with a cane, but in the community, or for longer distances, I use a wheelchair, I have a home physical therapy program and participate in an open gym neurorecovery program to make sure I stay as strong and active as I can. Rehab has been my saving grace.

BrainWise: What have been the biggest challenges for you in enduring this disease?

Dr. Spencer: It’s been a unique experience going through this with the knowledge of a neuropsychologist. I have assessed myself through this entire journey. In the beginning, I gave myself the grooved pegboard test to [evaluate] fine motor dexterity in my hands, because my symptoms started in my left hand. Over time, I’ve been acutely aware of my memory and problem-solving skills to make sure my decision making is still sound. Each time I had surgery, I woke up and gave myself a memory test, which my neurosurgeon found humorous and advised me to stop doing. Now, I continue to stay focused on my cognition, but I also try to take care of my mental health because the ups and downs of this disease can be discouraging.  I make sure to follow the counsel I gave my patients in the past about [getting] rest, cultivating mindfulness, and appreciating the little joys in life. I also try to keep a good sense of humor and frequently make jokes about how brain tumors mess with your head or how we should give our non-dominant hand more credit. After all, we need [those non-dominant hands] to scratch itches and hold our phone while texting!

Rehabilitation has been my passion in neuropsychology; the question I’ve asked for years is, ‘How do we help people with brain injuries get to as close to their everyday lives as possible, and help them integrate back into their communities, and their family roles?’ The difficult part of GBM is that the symptoms fluctuate. Just when you think you’re getting better, something else comes and pulls the rug out from under you. I’ve had to fight every step of the way. Something sets me back. Then I get better. Then something new happens. That has been a big challenge. Each time I’ve had a setback, I ask myself, ‘What can I do to get my brain working the way I want it to work again?’ In many ways I think of my journey like Sisyphus and his boulder—every time I think I’ve pushed the boulder to the top of the mountain, it falls back down, and I need to start over again.

Dr. Tresa Roebuck Spencer, who served as president of NAN, stands at the podium at the NAN annual meeting.

BrainWise: How do you wrap your conscious mind around what you’ve been through?

Dr. Spencer: I’ve spent 20 years working with patients in my situation, so sometimes I’m my own therapist. In dark moments I tell myself, ‘What do you now need to do? You need to stay socially, cognitively, and physically active.’ I still want to live a meaningful life. And so, I have practiced what I preached to my patients for all those years. Even on the days when I feel discouraged or don’t want to do anything, I make myself reach out to friends, and make sure I’m doing things I care about, because I know that is the best thing that [one] can do for recovery and for the brain. I also still want to be part of the world. I am not sure what the alternative would be. I love hiking, so we bought a trail-friendly wheelchair. I love music, so I try not to miss my favorite bands when they’re in town for concerts.

BrainWise: How has your family responded to this diagnosis and the situation?

Dr. Spencer: My husband works from home now, and we have two teenage daughters. I don’t want to be a burden on my family. I want to be present and remain an active part of my family. At first, we just went through life as normal. We told [our girls] what was happening with me medically. For a long time, I didn’t say the word, ‘Glioblastoma,’ because I didn’t want them to look it up. Eventually, the stress of surgeries and treatments built. I encouraged them to ask questions, and I answered them. This is a shared experience. It isn’t something that is happening just to me. It is happening to the whole family. Like I said, we try to keep life as normal as possible, and I think they have adjusted well. Less than 24 hours after I got home from one of my surgeries, my daughter came down and asked me to order her stuff off Amazon. It was like, ‘Okay, I’m going to take that as a sign that they’re normal teenagers through this whole thing.’ We’re not hiding anything. Because there’s no way that you can. We’re going back and forth to the hospital all the time. We make sure they have support, that sure they spend time with their friends, and we keep the communication open.

BrainWise: How has the experience changed you as a neuropsychologist?

Dr. Spencer: I feel like I understand better when someone is sharing their experience as a brain injury patient. [Neuropsychologists are big on test scores, but] A person’s experience is more than just a test score. As a neuropsychologist, I was very focused on how our services improved patients’ lives, not just neuropsychology as a field, but where is the value that we bring to healthcare? And I think the value that we bring is this: How do we make patients’ lives still full and meaningful in the face of cognitive impairment?  Because GBM affects the brain, it can affect the core of who you are and how you cope. As a neuropsychologist [now going through this as a patient], I worry, ‘What if this disease takes that away from me?’ It terrifies me to think, ‘What if I start to have significant cognitive impairment or personality changes?’ I’ve seen these changes in my patients and worked with their families.

When I talk with my doctors about my treatment plan, I’m always focused on those issues. I’ll ask them, ‘Okay, what is this going to do to my cognition?’ I always tell my neurosurgeon, ‘Thank you for sparing my frontal lobes, because that means I can now bug you with lots of questions.’  We regularly talk about brain regions and what my preferences are. I think that’s probably different from other patients, who may not be able to speak at that level of specificity. When I’m looking at my MRIs, I might say, ‘Oh, there’s the place where I lost my motor function,’ or, ‘I don’t want [the tumor] to move over here, because then it may affect my personality.’ Overall, my neuropsychology background allows me to advocate for myself in ways that other patients might not. It also makes the situation more terrifying because I know things that other patients may not know. Sometimes I think awareness is a blessing and a curse. Funny enough, the location of my tumor often affects people’s awareness, so they may not fully understand or be aware of their deficits. But my awareness has been quite good. There are some days that I ask, ‘Is [awareness] a good thing?’ Maybe it would be better to be a little bit blissfully ignorant.

Tresa Spencer laying in a hospital bed with "fiducials," or special surgical markers, on her head to help guide brain surgeons for brain surgery.

BrainWise: What have you learned as a patient that you didn’t know before?

Dr. Spencer: Doctors need to see their patients as people. They shouldn’t make assumptions. Some doctors and health care providers treat you differently when they see you in a wheelchair and they see your diagnosis. They make assumptions. When you’re a clinician, you’re living in a bubble. I miss that bubble. I really do.  I look at my doctors and my therapists, and I know they’re in a bubble. Being outside of that bubble, I often think about when I was in that bubble. I [think] I was a compassionate clinician. I remember many of my patients vividly. I wish I could be with some of them now. I would do some things differently. When I reflect, I really feel like I understand their experience better, having now gone through something similar myself.

BrainWise: As uncomfortable as it might be to discuss this, what is your prognosis?

Dr. Spencer: Generally, when people are diagnosed with a GBM, the average [prognosis] is eight to 12 months. For me, I’m close to 3 years since my diagnosis. It hasn’t been an easy three years but I’m here and continuing to find new meaning in life every day. I still think I’m one of the luckiest unlucky people ever. I’ve already thought, ‘If I start to have some deficits, how am I going to handle that?’ My answer: I’ll continue to work hard in rehab. And I’ll work through the fatigue. I’ll stay active and keep doing what I’ve been doing. I’ll just keep pushing the boulder, no matter how many times it might come back down the hill.

A stroke survivor’s story

Most people know Dr. Eric Zillmer as professor of neuropsychology at Drexel University, a licensed clinical psychologist, president of the Philadelphia Classical Guitar Society, former athletic director at Drexel University, and past President of the National Academy of Neuropsychology. As he explains in this personal essay, it is time people know him as something else, as well. Dr. Zillmer shared this essay with Managing Editor Matt Villano as the two were discussing a forthcoming feature on music and the brain. The publication of this essay marks the first time Dr. Zillmer is sharing the story publicly.  

My name is Eric Zillmer, and I am a stroke survivor.

At the age of 19, I experienced a hemorrhagic stroke. It left me with some residual disabilities. But, because of the stigma of a stroke “victim,” I have kept this information to myself.

Until now and this is my story.

I grew up in Garmisch-Partenkirchen, Germany, as an “Army brat,” a term reserved for those who grew up in U.S. military families. We “brats” wear the name as a badge of honor because the moves, stressors, and various cultural experiences have made us more resilient. I was born in Tokyo, Japan, but my family later moved to Europe, where I was enrolled in German-speaking schools, first “Volksschule” (elementary school) and later Gymnasium (grade 5 through 13). During my senior year of Gymnasium and at the age of 19, I became dizzy during a high-school basketball championship game. After the contest, I started to feel sick, became disoriented and aphasic, but rather than going to the emergency room I walked home. I did not trust myself to drive, I knew something was wrong, but I thought I could sleep it off.

On the way home, I collapsed and had a series of grand mal seizures. I was unconscious, so I don’t remember being taken to the hospital, where I was in a coma for several days. Unbeknownst to everyone, I had experienced a major cardiovascular event. A relatively large structure in the brain, an arteriovenous malformation, ruptured. It was probably starting to bleed during the basketball game, where I first experienced symptoms, perhaps due to the cardiovascular stress associated with extreme physical activity.

I stayed in the hospital for a week, but this was one year before CT scans were widely available in Germany, and so I was not diagnosed correctly. I was subjected to unnecessary medical tests, including a liver biopsy, and ultimately it was thought that the diagnosis may have been related to metabolic irregularities. “Eat less ice cream,” I was told upon discharge. Subsequent EEG studies at the Max-Planck Institute in Munich, Germany, and additional medical studies in the United States later that year did not shed any additional light on my medical event. Because of my young age nobody suspected that I had suffered a stroke.

Since then, I have remained mildly aphasic, and I experience mild verbal problems. I have difficulty with spelling, the correct pronunciations of words, and to this day vowels completely confuse me. I am terrible at crossword puzzles and acronyms. Learning a foreign language seems beyond reach. I often invert words much to the delight of those around me. I certainly would have benefitted from a neuropsychological workup as well as occupational and speech therapy at the time of my stroke, but this occurred in the 1970s, before neuropsychology became a clinical specialty.

I did not know it at the time, but I was a teenage stroke survivor.

Instinctively, I was drawn to anything that required non-verbal problem solving. I was comfortable with music, sports, photography, and art, which came natural to me and did not require as much verbal-comprehension or verbal expression. When I had to engage in something complicated in the verbal modality, it took me a long time. I learned to write like an architect builds a house. I formed ideas of what the structure would look like and then I would try to find words to populate that structure. I would edit my drafts dozens of times. It was tedious but it worked. I always had someone proofread my verbal material and was consistently shocked by how much better it sounded after someone else’s edits. I read books very slowly. I absorb information best via learning by doing. I became an excellent cook, not by reading cookbooks but by watching YouTube. When I was listening to other people speak, I try to figure out the context, how people were saying it rather than what they were saying. If I would not understand, I made a note and would look it up later.

My father, a U.S. Military Academy West Point alum, also had earned a master’s degree in German language from the University of Heidelberg. He was a gifted expert in languages. When I attended college in the United States, I lived at home, and Dad would help me write and rewrite my reports. I was ambitious and I had persistence. I was functional in speech in everyday life, but I was not competitive in college. I would try my best in an English writing class, and even though I worked harder than any of my classmates, I could not do any better than a C. A passing grade but not good enough for graduate school, where my aspirations lie. Organic chemistry, forget it. The terminology was very confusing to me. Honestly, those classes felt like a nightmare. I received Fs and flunked out of college.

My mother insisted that I make an appointment with the dean of students to see if I was allowed back in, on probation. I did and I switched my major from biology to psychology and everything fell into place. Even though psychology is highly verbal, it is also highly conceptual and creative, areas I was good at. 

I later became interested in clinical psychology and then in clinical neuropsychology, mostly related to my fascination with human behavior, mental illness, and the psychobiology of the brain. For that, however, I needed to go to grad school. But my verbal GRE was terrible – in the second percentile; 98 percent of other applicants scored higher than me. I blamed it on being bilingual, as my mother is Austrian. But I knew all languages were a challenge for me.

I personally knew that I was verbally disabled, but I would not tell anyone. As I learned later, this is a common misperception about individuals with stroke, their disability is most noticeable to themselves but not to others.  

Personally, I just sucked it up, like I would do in the athletic arena when encountering adversity. I was very resilient, and the disability made me even more so. I was lucky to get into a graduate school where someone on the admissions committee saw my potential in other aspects of cognition than GRE scores, in areas where I showed high, even superior, intelligence. For example, as a young adult, I was a first responder in the Austrian alps as a member of the National Ski Patrol, leading medical evacuations at high altitudes and extreme conditions. I also was the captain of my tennis team at the University of Rutgers-Camden, and I was creative. Leadership and organizational skills came easy to me. And, what became an advantage for me, I was not dependent on linear problem solving. I figured out problems differently than others. Often better.

Music and especially rhythmic music, the timing, managing and synchronization of events, mostly by the brain’s right hemisphere, were easy for me, and I compensated for my verbal disabilities by relying on my emotional IQ and a preponderance for non-verbal problem solving. I played guitar and drums every day, and I loved sports, the angles of the ball, the creativity. I excelled at photography, I can frame a picture, a slice of the world, and my pics have been used in magazines and on an album cover. I love poetry. I am good at organizing things, even large complex systems, big data, that others are intimidated by. And I am competitive, ambitious yet collaborative, an effective team player but also a leader.

Even though I had a disability I worked around it. I managed and even excelled.

The cover of the textbook that changed everything for Dr. Eric Zillmer

Decades later, I wrote the second edition of my textbook “Principles of Neuropsychology.” To avoid copyright issues, I was planning on using pictures of my own brain on the cover. I had friends in imaging among one of the local hospitals in Philadelphia, and they informed me that I could get a “free” MRI study in the early morning hours as part of a research study. Before I settled in for the exam, they gave me the standard warning about a brain imaging study, that is, “one never knows what one might find.” Sure thing, there was a “hole” in my brain 1.5 cm diameter in size located in the left posterior frontal lobe.

I could not believe it! I immediately made an appointment with the chief of neurosurgery.

Naturally, I was nervous. I brought my MRI images to the neurosurgeon, and it was comforting to know that he knew of my neuropsychology textbook and that one of my coauthors extended neuropsychological services to his son. The doctor was the nicest guy and took a lot of time to study my brain images.

Then he turned to me and asked me if I ever had been unconscious. I told him no; it seemed the furthest thing from my mind that what occurred to me as a 19-year-old was related to why I was sitting there as an adult. He asked me whether I have or had speech or language impairments. Then, things started to come into focus.

The doctor told me that he was 100 percent certain that this left-hemisphere lesion in my brain was the result of an old stroke, a ruptured Arteriovenous Malformation (AVM). Of course, I knew exactly what that was. I had an entire section written on it in my neuropsychology textbook:

Arteriovenous malformations (AVMs) represent direct and essentially useless communications between arteries and veins without an intervening capillary network. AVMs are typically congenital collections of abnormal vessels that result in abnormal blood flow. Because they are inherently weak, AVMs may lead to stroke or to inadequate distribution of blood in the regions surrounding the vessels. Rupture of AVMs may produce intracerebral and subarachnoid bleeding.” (Zillmer et al., 2008)

AVMs occur in less than 1 percent of the population and are more common in males than in females. They are congenital, meaning that they are present from birth on. I also knew that most of the damage of a ruptured AVM came from the hemorrhagic stroke associated with it, that is the bleeding, literally the escape of blood from the vessels. When blood spills out of the artery and into brain plasma, many toxins in the blood can interfere with normal brain metabolism. In an intact vascular system, the blood–brain barrier protects the surrounding tissue from any toxic properties contained in blood, but exposed blood outside of the artery irritates brain tissue, hence the seizures. And the additional volume of the blood can create life-threatening increases in intracranial pressure, coma and even death.

After all these years of compensating I had the answer why. I was a left hemisphere stroke survivor. Ironically, I am now a neuropsychologist and I have published and presented many papers on the cognitive functioning of stroke survivors. As a neuropsychologist and as an athlete, perhaps it became second nature for me to adapt, because I knew how. Because of my clinical knowledge and my personality, I learned how to compensate and how to move forward. In many ways I saw the world musically. I use anything nonverbal like music, sports, politics, visuospatial processing, or creativity to compensate for my deficits. The invention of the word processor, as well as the computer spelling and grammar check, was an absolute blessing to me.

“Should I be worried,” I asked the neurosurgeon. He said, “no, you are obviously doing fine,” but noted that I should get an imaging procedure known as an angiogram that examines the integrity of the cerebral arterial network of vessels, just to make sure I didn’t have any more of these “time-bombs” in my brain. I did get an angiogram. Thankfully, it came out negative.

I donate money to the American Heart Association, a leader in stroke research, every year. But I can’t wrap my arms around the fact that I am a stroke survivor and almost died as the result of a stroke. I am worried about the stigma associated with a stroke survivor and have told literarily no one. I am 6’5” tall, successful, strong, and healthy. I fear others would look at me as impaired.

The literature on strokes confirms exactly that. That others treat stroke survivors either as victims (“Are you feeling better now?”) or as if nothing happened (“Gee, you don’t look like you had a stroke”). Also, there is a bias that strokes only happen to the elderly, even though 25 percent of all strokes occur under the age of 60. This stigma suggests that many younger survivors suffer a delayed diagnosis, like I did. As a result, appropriate stroke services and interventions are not implemented to deal with the challenges confronted by having a stroke at a young age.

As a clinical neuropsychologist I know that I have used compensatory tactics that we as a profession do research on and write about. It has absolutely worked for me and may have even given me an edge. The “advantage of disadvantage,” that Malcom Gladwell writes about so elegantly in his book “Outliers.”

That is right, it can be an advantage to be neurodiverse.

I am now sharing this fact about myself to perhaps inspire others to think of a path forward on how neuropsychology can assist. Perhaps to touch other stroke survivors to come forward and talk about themselves and about how others can support them.

A stroke is always a major health event. It is usually traumatic and life changing. I know first-hand that the invisible consequences of a stroke can be equally as devastating as the ones everybody can see. But most stroke survivors can do most of what they once did, with some form of management. I am living proof of this.

A deficit in one area can become a strength in another area. For example, in the classroom I teach the same way I process information personally, visually. By using PowerPoint, metaphors, analogies, humor, poetry, discussion, field trips, and music. For my final exams, I don’t ask my students to write 20-page papers, but to present 3-minute TED-style talks. I also focus on conceptual courses; I teach courses like Happiness, Sport Psychology, the Psychology of Music, and my favorite, General Psychology. My students seem to love it and I have received many teaching awards, the most recent one in 2019 for outstanding teaching from the Pennoni Honors College at Drexel University. I am very grateful to the science of neuropsychology and rehabilitation psychology.

I lived through all the fears of having a neurological event define me; but ultimately it did not.

The future of Alzheimer’s Disease drugs

Few people in the world know more than Dr. Jeffrey Cummings about treating Alzheimer’s Disease. Dr. Cummings is a research professor in the department of brain health at the University of Nevada, Las Vegas. He’s also director of the Chambers-Grundy Center for Transformative Neuroscience at UNLV. Every year Dr. Cummings publishes a report about the number of trials for new drugs to treat Alzheimer’s Disease. This means he has his finger on the pulse of Alzheimer’s Disease treatment approaches. BrainWise Contributing Editor Matt Villano recently sat down with Dr. Cummings to discuss 2023 data and the future of Alzheimer’s Disease treatment overall. This transcript of their conversation has been edited for clarity.

BrainWise: When we look at the landscape of Alzheimer’s drugs treatments today, what would you say characterizes a lot of them and what specifically are these medications addressing?

Dr. Jeffrey Cummings: We’re in an enormously fast-moving portion of Alzheimer’s disease research and therapeutic development. From 2003 to 2020 with no approvals of new medications. During that time, the pharmaceutical industry by itself spent $40 billion on Alzheimer’s disease clinical trials. In 2021, we had the approval of aducanumab, and then in 2023 the approval of lecanemab, both of those by accelerated pathways. Now, we think that within the next probably two months, we will have standard approval of lecanemab and likely standard approval of donanemab.

Soon there will be three monoclonal antibodies on the market. A critical step in that is the review of them to determine whether they will be reimbursed, because people will take the medication only if it’s reimbursed, and they can benefit from the medication only if they take it. We must establish that link in order for Alzheimer’s patients with early Alzheimer’s disease to benefit from this research advance. To emphasize a few of those areas, these are complicated drugs, monoclonal antibodies administered intravenously, and with a side effect called ARIA that must be carefully monitored and managed. On the other hand, they are the first disease-modifying therapies for Alzheimer’s disease and almost the first disease-modifying therapies for any neurodegenerative disease. Only ALS has some disease-modifying agents, nothing for Parkinson’s disease, frontotemporal dementia, any of the other late onset neurodegenerative diseases. This is a breakthrough. It’s truly a breakthrough, because it’s turning a corner on disease modification and our ability to impact the underlying biology of the processes that lead to neurodegeneration.

The clinical benefit is modest. There’s been some criticism about this. It’s about 30% slowing of cognition, about 40 percent slowing of function. I think that’s fantastic. If I had MCI, which lasts about three years, and I could make my cognitive integrity last another year during that period before I became fully demented, I would want it. I think that’s the human question that is worth asking. What is the value of human cognition towards the end of life? I find these worthwhile drugs, but I acknowledge the complexity that they bring, for sure.

I regard them also as a preliminary, almost proof-of-concept, advance. They show us that amyloid is a reasonable target. They’re not the drugs that we want ultimately, right? We want drugs that are more efficacious. We would like them to be more convenient. We would like them to be safer. All those things are goals to be realized in the next steps in therapeutics.

There are other drugs in the pipeline, some close to coming to the end of their trials. They have reasonable hypotheses. We have evidence for these monoclonal antibody approaches. We also have, I think, pretty strong evidence for the anti-tau ASO, a drug which must be administered directly into the spinal canal. The effect of that [in trials has been] unbelievable. Again, I see real excitement in the field all around our ability to manipulate the biology.

BrainWise: You just raised a fascinating ethical question. What is the value of human cognition later in life? How do you think a family should address that when a loved one has Alzheimer’s Disease?

Dr. Cummings: This is a question I want my patients to answer. I don’t want Medicare to answer it for them. I want them to be able to say, ‘Yes, I want to go in for an infusion every other week with lecanemab,’ or, ‘Yes, I want to have those MRIs that are required to make sure that I don’t get ARIA,’ or ‘I’m 92 and I want to live out my life now without these medical complications.’ I think those are all defensible positions and I want my patients to be able to make them.

One of the things I am trying to help achieve is the availability of the drugs so that my patients can make educated choices. We’re going to have to educate patients and caregivers and the world about these drugs and hopefully we’re going to get simpler. There are already subcutaneous equivalents in clinical trials and there are already blood tests that look pretty good in terms of being able to replace the PET scan and the lumbar puncture to establish the diagnosis. But once we can identify the patient with a blood test and treat them with a subcutaneous injection, we’re in a different world of the inconvenience that these drugs currently represent.

That’s coming fast. We need to accept that we don’t know what the future will bring, so we need to deal with what we have now. But if you had to forecast, how long will we be here in this space? I think we’d say a short period of time, because the subcutaneous injections look very good, and the blood biomarkers look very good.

BrainWise: What are the most important questions for drug researchers to be asking at this point, as we look to future development?

Dr. Cummings: I would say we’re looking forward to combination therapies. Improvement of 30 or 40 percent is not enough. So, what do we want? Well, we would like essentially to arrest the disease progression. We’d like a combination of therapies that would come close to that. We also want to improve cognition. We want to restore them to as close to a normal level of function as we can. Only 11 percent of the pipeline is currently devoted to cognitive enhancers. Those are drugs that would improve cognition. And 78 percent of the pipeline is currently devoted to disease-modifying therapies, drugs that would slow the progression. So, one of the things I’d like to bring back into the drug development world is more emphasis on cognitive enhancement.

Other questions pertain to how we’re approaching this. Recruitment is horribly slow. It’s the major reason that we’re not getting drugs through each phase quickly enough. The diversity of recruitment is terrible. We’re not reaching diverse populations and we have no idea whether these drugs are equally efficacious across racial and ethnic groups, yet we’re going to sell them across racial and ethnic groups.

BrainWise: To what extent are there currently trials in place that incorporate a more diverse subject group?

Dr. Cummings: One example is the Global Alzheimer Platform, which did a biomarker trial. They achieved, I think, 22 percent racial and ethnic minority representation in that study. That’s pretty good. I think we’re kind of pretending right now that we’re going to have an answer regarding treatment in minorities if we include a representative number [of minorities in trials]. We will not.

BrainWise: What’s the current landscape of trials?

Dr. Cummings: This year—the 2023 data just came out—we had 178 trials and 141 unique agents in clinical trials on the index date of the study. Most of them are not viable. When we last calculated, there was a 99 percent failure rate of Alzheimer’s disease therapeutics. I think it’s less severe than that now but I’m sure it’s at least 80 percent. Most of them still will not be viable. One of the correctable reasons that drugs fail is because they’re in poorly designed trials. We want to make sure that when a drug fails, it’s because the drug didn’t work, not because the trial didn’t test it adequately. This is a solvable problem over here. We can make those trials be great. We should require it. We can’t predict which target will work, that’s why we have a whole bunch of targets.

BrainWise: What trends are you seeing?

Dr. Cummings: More trials; the 2022 numbers weren’t as high. Another trend that is obvious is that the type of drug is changing. A biologic is a big molecule that must be given intravenously or subcutaneously or intrathecally (which means, into the spinal canal). Those are all called biologics. The drugs that are given by mouth are called small molecules. What you see in the pipeline over the past five years is the growth of the biologics. It’s interesting. It’s gone from 40 in the pipeline to 60 in the pipeline, which is about a third of the pipeline.

This is important because that’s what the doctor is going to offer the patient. It also means the doctors must begin thinking about what their practices are going to look like. They’re going to have to have infusion chairs, they’re going to have to anticipate subcutaneous administration. Alzheimer’s Disease treatment likely will become much more like cancer therapy. Practice patterns are going to have to change. Healthcare systems are going to have to change. And that’s part of the stress that we are going through right now: How do we change a whole system when we get an unprecedented compound that is effective but makes [real] demands on the system?

One position that I’m taking in some of the things I write is that this is the first step. The march of science is no doubt going to yield more medications, and we [must] have social and healthcare systems that can absorb the advances in science. We haven’t had much success before, so we haven’t had to do much of that before. But we should see this almost like a test case. How do we begin thinking about having a system which is sufficiently flexible; [a system into which] we can introduce new medications without there being a lot of hurdles? By the way, the pharmaceutical companies must be partners here. If they make the prices very high, that’s just another hurdle. But if this is a kind of collaborative arrangement so that we can get these drugs in without too much cost, then the system is likely to have the flexibility to be able to do it.

BrainWise: Tactically, what aspects of the landscape of the brain will be the targets of the next generation of Alzheimer’s Disease drugs?

Dr. Cummings: I think amyloid will continue to be a target. Tau looks like a good target. The two most active areas in the pipeline are inflammation and synaptic function. We’re going to see a lot of emphasis on trying to decrease the inflammatory aspect of Alzheimer’s disease. There are roughly 20 drugs against inflammation in the pipeline right now. No two of them have the same target within inflammation. Is one of these more manipulable than another, in a way that we can see a therapeutic benefit or early on a biomarker benefit? Is there a combination that looks like it might work together because both have small effects?

The fact that we have so many targets within a given process is going to be highly informative. The same is true of the synaptic function. Of the roughly 15 drugs addressing the synapse, only two have the same mechanism, so it is interesting to see how diversified the mechanisms are within a single target area.

BrainWise: Five years from now, what do you think Alzheimer’s Disease treatment looks like?

Dr. Cummings: It’ll still be dominated by biologics, but I do believe [some treatments will] be given subcutaneously or maybe at longer intervals. We might be able to extend this so that we could give a drug, say, every three months after an initiation period where it’s given every month. That’d be a great outcome so that the patient doesn’t have a lifelong commitment to infusions every other week or every month as they are now, depending on the drug.

With donanemab, when [patients] get the amyloid levels to undetectable, they stop. That’s interesting because, of course, that’s a lot cheaper drug than the drug that must be given continuously. Already, we’re seeing vastly different strategies within this therapeutic category. So, I think we will continue with biologics. I also think these blood tests are going to be so great that we’re going to be able to use them very effectively, both to choose who needs the therapy, to follow that therapy, and maybe when therapy is interrupted, to decide when to introduce it. I think the blood tests are going to help us in a whole variety of ways.

BrainWise: Where does stem-cell development fit into this overall puzzle?

Dr. Cummings: There’s a lot of excitement about stem cells. There are six stem cell trials in play right now. Five years is a short time horizon for that, because the FDA is very conservative in terms of stem cell trials. Often, they [administer] stem cells and then watch for a year to see what happens. [It ends up being] 18 months or two years to recruit the trial, and then it’s a year after the last patient in before you get the last patient out. Now, you’re talking about three years already.

I don’t think we’ll have stem cell therapy [for this] figured out in five years, but I think that’s a worthy pathway to keep working on. Can we make sure they’re safe? That they do what they’re supposed to do once we introduce them into the body? What’s the magnitude of the response and what’s the durability of the response? These are the things that must be answered, and they’ll be answered, I think, more slowly for stem cells than they are for biologics or small molecules, because the trials are more difficult to do.

BrainWise: How likely is it that we’ll see combinations of different treatments?

Dr. Cummings: I think it’s very likely, even necessary. I think manipulating one target is almost certainly not going to be enough to halt or seriously slow complex disease. At the same time, combinations are tough, because a company [would need] to have two agents at the same level that could be put into the same trial, and they almost never have that. [The way it is] now, you got to have one company with one agent and another company with the other agent, and those two companies [must] work together. These are just operational complexities that keep us from doing what we want to do.

The trials are hard, and the developmental process is hard, but we absolutely must do it. This is where, I think, federal funding is critical, because you could get two repurposed agents and put them in the same trial at the same time, and at least see whether manipulating those two pathways looks beneficial. If so, you have a whole range of ways to exploit it. But there are complexities that you don’t ordinarily think of, like a company must have two drugs in order to do the trial of combinations, and it’s a rare event in the company. They usually have one asset that they’re advancing in Alzheimer’s disease and then a bunch more that they’re advancing in cancer, so they don’t have two assets that they can put into the same trial.

BrainWise: As we look to the distant future, to what extent do you envision super drugs that might be able to treat Alzheimer’s Disease and other forms of dementia?

Dr. Cummings: What I want is the AIDS discovery. You have the virus, put your person on combination therapy, and they’re able to live, really, without manifestations of the infection for many years. Magic Johnson, right? The classical example of this. That’s what we want. Do your blood test every year. When your PTAL 217 starts to rise, you’re getting amyloid in the brain. You get put on a combination therapy and you stay on that for the rest of your life, and you follow your PTAL 217 to know whether you have ameliorated the acceleration of the neuronal processes in the brain. That’s a kind of future scenario that, I think, is realistic. I think that could be done and looking forward to having it be done.

BrainWise: What other mysteries do we need to solve about Alzheimer’s Disease?

Dr. Cummings: There’s a part of Alzheimer’s Disease that is driven by aging, and aging is pretty hard to fix. I’m not forecasting a cure, but I do foresee a time when we could prevent the disease through early detection or maybe through risk stratification of people in their fifties. Amyloid starts in the fifties, and then people become symptomatic 20 years later in their seventies. We could start testing very early. By then, maybe we will have small molecules that could be taken, so it would not be an inconvenience and we could prevent the onset of illness.

BrainWise: What are the next big questions you’ll be asking in your research?

Dr. Cummings: How can we accelerate biomarkers to allow us to do great drug development? That’s a huge one. Because it turns out that biomarkers have been the key to our success, That’s why we have monoclonal antibodies. We also have what’s called the Amyloid Tau Neurodegeneration framework, or ATN. We have biomarkers for all three of those. We need more biomarkers so we can be more informed about the impact of therapy and who should be on therapy. We also need biomarkers of health. The biomarker expansion is critical, both for the disease and also to begin to understand the biomarkers that would signal good health in individuals, because it’s ultimately some sort of algebra between the brain health and the brain disease that determines who becomes symptomatic.

BrainWise: What do you want people to know about Alzheimer’s Disease?

Dr. Cummings: If I had to simplify the message, I would say great progress is being made and hope is there. We’re going to be able to help people. We’re going to see who needs help early on. We’re going to keep people at a more dignified level of function during their aging years.

At the same time, while there has been a good increase in funding for Alzheimer’s disease, we need more. Alzheimer’s disease has a greater negative impact now in the country than cancer does, and yet we’re far behind funding in terms of cancer. We need money because we need to grow more centers. We need more outreach to minority communities. We need more outreach to rural communities. We’ve got to get everybody on this wagon. We’ve got to make sure we’re helping everybody, and that costs a lot of money.