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When age is really just a number

in Featured, Highlight/by Dr. Emily Rogalski

We all age. Some of us age better than others. This is an area of expertise for Dr. Emily Rogalski, professor of neurology at the University of Chicago. Dr. Rogalski heads the school’s brand-new Healthy Aging & Alzheimer’s Research Care (HAARC) Center, which will focus on building deep multidisciplinary expertise and bridging the gap between scientific disciplines to accelerate breakthroughs in cognitive resilience. This focus is increasingly important as the world’s population continues to age—the World Health Organization estimates that one in six people will be aged 60 years or older by 2030. Early in her career, while at Northwestern University, Rogalski operationalized the term “SuperAger” to describe people over the age of 80 whose memory still functions as well as that of someone in their 50s or 60s. That project has received considerable attention, including this piece from CNN. The project also received a $20 million from the National Institute on Aging and the McKnight Brain Research Foundation to establish an international multi-center SuperAging Consortium. BrainWise Managing Editor Matt Villano caught up with Dr. Rogalski before a talk at the recent NAN Conference in Philadelphia to discuss her work, its implications, and where SuperAger research goes from here. What follows is an edited transcript of their chat.

BrainWise: How did you get into this area of neuropsychology?

Dr. Emily Rogalski: I grew up the daughter of a schoolteacher who taught kids with learning challenges. From a very early age I was surrounded by brilliant kids that learned a little bit differently. That’s really where my interest in the brain came from. As a young kid, I had a very naive question: ‘If these kids are so brilliant but they can’t learn in the traditional way that our schools are set up, I wonder if there’s something different about their brains.’ I think I’ve been always attracted by things that are on the outskirts rather than in the main lane, and how those elements can inform both the mainstream, but also help those on the outside. When I was in graduate school, I learned about a really rare dementia called Primary Progressive Aphasia (PPA), where instead of losing memory like we lose in Alzheimer’s dementia, individuals lose language. And not only that, but they lose it at a really young age. They can be in their 50s and 60s, even [in their] 40s sometimes. When this is happening, nobody is thinking it’s dementia. It can take years to get a diagnosis. I was really struck by the lack of research that was going on 20 years ago in this space and thought, ‘This is a real opportunity to explore and help.’ This dementia can be caused by Alzheimer’s disease about 40 percent of the time. And so I found myself in an aging and Alzheimer’s center for my dissertation work.

In the trajectory of aging, you’re constantly told there’s nowhere to go but down. Normally, the first thing that’ll come out of the mouth of anyone who’s giving an aging talk is something like, ‘As we get older, we lose our memory.’ [We’re taught to know] that when you get older, your eyesight changes, your hair gets gray, your skin gets wrinkled, and your memory declines. And while that makes sense in general, I think if we all stop to think about that, it’s not in practice all of the time. We all know the Betty Whites of the world. We know these people who really stick out as being something different. We know them as our neighbors, we know them as our aunts and uncles in our daily lives. And so this thing that we talk about with aging and it being nothing but bad news doesn’t really fit with people’s lived experience of they know at least somebody in this other sphere.

The challenge was that 15 years ago, there were people already studying successful aging. I think that was a great change in something that really [John] Rowe and [Robert Louis] Kahn did a great job of getting that concept out there, that there could be another trajectory called successful aging. But that definition and that concept was general. There was a great review done by [Colin] Depp and [Dilip] Jeste [in 2006] and they looked at definitions of successful aging. What they found was that in 28 studies, there were 29 different definitions. In and of itself, that’s not a problem. They also found that in those studies, the percentage of people who met the criteria for successful aging ranged from 0.9 percent to something like 97 percent. So virtually nobody to virtually everybody. That proved the definitions for successful aging were all over the place. One was you’re over the age of 65, dementia free, and you have good physical health. Another definition was that if you’ve lived to age 90, you’re a successful ager. There also were definitions in between—sometimes requiring good cognition, sometimes requiring good physical health. I started looking into aging and what makes for ‘successful’ aging. That’s when I [coined the phrase], SuperAgers.

BrainWise: What characterizes a SuperAger?

Dr. Rogalski: I operationalized this term SuperAger so it would be very specific. [The paper that established the definition is here.] While it fits under the larger umbrella of a type of successful aging, the goal was really to say we wanted to have both a specific neuropsychological definition and an age criteria. SuperAgers are individuals who are over age 80 who have memory performance at least as good as individuals in their 50s and 60s. Why age 80? Again, kind of back to this idea is everything gets worse when you’re older. And it turns out that merely getting older is the biggest risk factor for Alzheimer’s dementia. It wins. It wins over all other factors right now. By age 80, you’ve reached a point where you’re at great risk for typical or average cognitive decline. You’re at greater risk for Alzheimer’s dementia. If you’ve reached this age and then you have memory performance that’s youthful, that’s unique. If you’ve gone through all of those lived experiences, all that wear and tear, and you’re able to really look like a 50- to 60-year-old, that is, neuropsychologically speaking, quite different.

BrainWise: So, neuropsychologically speaking, what do all SuperAgers have in common?

Dr. Rogalski: We require them to have this memory performance that’s at least as good as 50- to 60-year-olds. Then we say other cognitive domains have to be at least average, but we’re going to explore it and then we’re going to look at those as variables to say, well, how much does attention and executive function contribute? When Dr. Amanda Cook Mayer was a graduate student at Northwestern working with me (now she’s faculty at the University of Michigan), we did a study on that to say, what are their other strengths in cognitive function? What we found is there’s not one path to get there, but [SuperAgers] tend to have strengths in attention and executive function, and that there’s some variability that helps to explain some of their memory performance. Some SuperAgers, no matter which cognitive tests you give them, knock it out of the park. They perform like 50- to 60-year-olds or better across all the cognitive domains. In other instances, there’s people where memory is really their strength and other cognitive domains are average. There’s a third trajectory where people of course have great memory, and the other cognitive domains oscillate a little bit. I think this is important because it’s not that the SuperAgers had to get there all the same way. There can be different paths or trajectories that got them here. As we move more toward personalized medicine and precision health, we have an opportunity to understand the contributors to each of those pathways.

BrainWise: How does this translate to your current study?

Dr. Rogalski: Our goal in this study is not to just look at one domain. So some studies are like, ‘I’m a study of sleep.’ That’s very important, but that’s not what we are going for. We really wanted to cover as many domains as possible, do them well, and then look for that integration across the things. So we’re going to look at structural function, but how does that relate to cognitive function? We’re going to look at genetic factors. What’s the interplay between cognition, genetics, neuropathology, and brain structure? What can we detect during life, knowing that in a living person, we can only see with a certain resolution? I liken this to when we first got digital cameras and we were all excited, we didn’t need film anymore, and we could take a bunch of pictures and that seemed great and they looked great on the back of our cameras. And then we printed them out in our home printers, and everybody’s faces looked like little squares. They were pixelated. Well, that’s about the resolution we can see during life. And so this is where someone donating their brain at the time of death gives us that better resolution where we’re at with our iPhones now or better so that we can really look at contributors of cellular and molecular factors.

BrainWise: Can you give us specifics about one of your SuperAgers?

Dr. Rogalski: Our oldest SuperAger is 109. And I was at her house a couple of weeks before her birthday to bring her a present, and we did a little video shoot with her. The day before, she made us strawberry rhubarb jam. She’d never made strawberry rhubarb jam before. She’s still trying new recipes at age 109, and it was delicious. She enrolled [in the SuperAger study] when she was in her early 100s. At that time, she was driving, and I would’ve ridden in the car with her. She only stopped driving because she got gout, and the medicine she was taking messed with her grip strength. She’s sharp as a tack. We ended up doing a three-hour interview [with her]. Her best quotes were at the end of the interview. I mean, everybody was in tears as she was sharing aspects of her life. She was the first Black woman to graduate from Grinnell College in Iowa. She talked about the first time there was a radio in her house, the first time there was a phone. Think about what she’s lived through: two pandemics, World War I, [World War II]. That’s pretty remarkable. She’s seen a lot.

BrainWise: How many people over 100 are participating in the study?

Dr. Rogalski: Fewer than 10, out of about 300 total.

BrainWise: How do I know if I’m a SuperAger, and what can I do to increase my chances to become one?

Dr. Rogalski: We know that diet and exercise are important from [epidemiologic] studies and from other cohort studies. When we look at SuperAgers specifically, we see they have variable diet and exercise. The good news [there] is [that] it’s a good idea to pay attention to your diet and exercise, but all may not be lost if you’ve not paid the closest attention.

We know that SuperAgers range in education from 12 to 20 years. So it’s not just doctors and lawyers that we’ve enrolled. And every time we make a comparison in our study, the IQ of the control group is always in the same range. So that means it’s not just general intelligence or a measure of intelligence that’s differentiating the groups. I’ve worked with cohorts in South America where they have focused on enrolling or identifying SuperAgers that have little to no education, and they’ve been able to find them. We [too] are starting to enroll more diverse samples. It is possible to find SuperAgers who have lower education. We’re not just picking up on extreme levels of education that allow you to maintain good cognition over age 80.

I think one practical thing that we’ve seen, and now we’re trying to quantify it more objectively, is that SuperAgers report having stronger social relationships with others. We don’t know much about those relationships. We don’t know whether they have one best friend that’s a trusted partner, or if they are the social butterflies of their community. I know anecdotally many of them are the social butterflies of their communities.

Until recently all the data we collected on SuperAgers was self-reported. Then in 2020 we had this opportunity to write a grant that expanded the program to make it multi-site and to change the depth and breadth of science that we do. And one of the ways that we changed the depth and breadth of science was to add in wearable sensors. Now we ask the SuperAgers to wear these in their daily lives for about 14 days so we can get measurements of activity and social engagement. Objectively we can get measures of sleep and autonomic function. For all the survey data and the anecdotes that we have collected over the first 15 years, we’re now collecting those data objectively and quantitatively moving forward across five cities in the U.S. and Canada.

BrainWise: To what extent could a SuperAger potentially have issues with eyesight or have some physical disability, and where does that come into play with your research?

Dr. Rogalski: I was very intentional in not requiring super agers to have good physical health. We know from the larger body of research that good physical health tends to be associated with good cognitive health. And this makes sense for a lot of reasons. However, if you make that an entry barrier, now you’re kind of penalizing people who were able to maintain great cognitive health, but they might need a wheelchair or a walker. Their physical aging or their physical brain age may outpace their cognitive brain age, and I didn’t want to have that penalty. Instead, I wanted to be able to look and say, ‘How many people do we find that are using wheelchairs or walkers?’ So our SuperAgers vary. Some of them are riding their bikes hundreds of miles a week or in the pool doing exercises and weightlifting in the pool. Others are leading a chair stretching class. There also are several who are like, ‘I don’t exercise and I don’t plan to start exercising.’

What we do see in our super agers is that their brain integrity and brain structure looks different. They tend to look more like 50- to 60-year-olds in brain structure than they look like 80-year-olds. In this instance, we’re talking about cortical thickness. That’s the outer layer of your brain where your brain cells live—we can measure that thickness and it gives us a proxy measure of the health of the brain. Generally speaking, thinner is worse and thicker is better. When we compare our average 50-year olds to our average 80-year olds, we see that same thing that others have shown: cortical thinning across the cortex of the brain. When we compare our super agers to the average 50-year olds, we don’t see any significant cortical thinning. In fact, we see a region in the anterior cingulate cortex that’s thicker in super agers than it is in the 50-year olds. This has spurred some of our investigations pathologically to make sure we’re paying close attention to this anterior cingulate region.

BrainWise: Where do biomarkers fit into this research? At what point do you hope we can begin to apply some of these lessons you’ve learned to say 40- and 50-year-olds to maybe help them get a sense of whether or not they will become a SuperAger?

Dr. Rogalski: The larger body of research tells us social isolation and loneliness are bad. There are studies that have shown those who are socially engaged and have Alzheimer’s dementia tend to have slower trajectories of decline and tend to fare better cognitively. Our data fit with that. The practical implication is that if you’re going to go home today and on your commute home, you’re thinking about calling your best friend, call them, talk to them, stay socially engaged. Why might that be important from a brain health standpoint? Conversation is hard. I don’t know exactly what you’re going to say next, but you’re going to ask me a question. And then I have to think really quickly on my feet to say, ‘Okay, how am I going to answer that?’ Our brain likes new and challenging things, and social engagement creates that newness all the time to keep you on your toes, so to speak.

Finding the thicker anterior cingulate, that was serendipitous and it led us to other research questions. Under the microscope, it turns out we see a greater density of a special type of neuron called Von Economo neurons. These are neurons that have only been described in two regions of the brain, the anterior cingulate [cortex] and the frontal insular cortex. They seem to have something to do with social behaviors and social function, and they tend to be abnormal in Alzheimer’s dementia, frontotemporal dementia, autism, schizophrenia, bipolar disorder. They also tend to only be present in higher order species like [humans and] whales and elephants. We can now look cellularly, molecularly, genetically at these neurons to say, what role are they playing? This [part of our research] isn’t going to have an actionable endpoint tomorrow, but we need to be looking at all of these different levels. And so that’s kind of the beauty of the design that we have, is that some things kind of glean more actionable things to think about today, where others might lead to whole new directions and protective factors that might take a little bit longer to get there.

[To speak to the issue of biomarkers], we are looking at blood-based biomarkers. Some of the SuperAgers have been getting amyloid PET and tau PET scans so that we can measure aspects of Alzheimer’s disease during life, and then also measure it at the time of death when they pass away. As I’ve mentioned, one thing about SuperAgers is that they tend to be healthier, so I always joke that I do better in my side of the study that’s on the living side than my colleagues who have to wait until they pass away because they keep living.

BrainWise: Which questions will you be asking in your research next?

Dr. Rogalski: I lead what’s called the SuperAging Research Initiative, which now has five sites across the U.S. and Canada. My particular expertise is in the cognitive aspects, the neuroimaging aspects, and in some of the social function and other survey data that we give. My partners in this are geneticists, neuropathologists, neuroanatomists, [and others]. I’m kind of fluent in many of these things, but they’re the primary leaders, and that’s the goal, to bring together these scientists with these different expertise so that we can really dig a little bit deeper. And so now we’ve got these partners across the U.S. and Canada, and we’ve got the SuperAgers.

Another goal is to diversify our sample, make sure we’re identifying SuperAgers in different communities, both regionally across the U.S. and Canada, but also racially and ethnically. We’re working hard to make sure we’ve got strong community partnerships and trusted relationships, and we’re not just coming in and saying, ‘Sign up for research!’ We want to make sure we’re intentionally there and building partnerships because these folks are with us for life. When they sign up, they’re coming back year after year after year. It’s a relationship we’re starting with them. It’s not a study where they come in for one blood draw, and we never see them again. This is longer term.

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

What brain imaging can tell us about brain conditions

in Featured, Highlight/by Dr. Marek Marsel Mesulam

Attendees at the annual NAN Conference in Philadelphia last month were treated to a keynote speech from Marek Marsel Mesulam, MD, the Ruth Dunbar Davee Professor of Neuroscience and Founding Director Emeritus of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University. Dr. Mesulam’s talk spotlighted what happens in the temporal pole, the very tip of the temporal lobe. Dr. Mesulam is a neurologist, and his textbook, Principles of Behavioral and Cognitive Neurology, has been part of training programs in neurology, psychiatry, neuropsychology and cognitive neuroscience. Dr. Mesulam’s current research focuses on the functional imaging of neurocognitive networks, the factors that promote memory preservation in advanced age, and treatment of dementia. After Dr. Mesulam’s talk at the NAN Conference, BrainWise Managing Editor Matt Villano caught up with him to ask him about the intersection between brain imaging and neuropsychology, and how 50 years of experience in the field has informed his perspectives today. Their chat was the latest in a series of interviews Dr. Mesulam has given on this subject (for another good one, click here). What follows is an edited transcript of the conversation.

BrainWise: You’ve been researching brains for more than 50 years. How has brain imaging evolved in that time?

Dr. Marek Marsel Mesulam: Until the 1970s, all we had were traditional X-Ray films of the skull. At that time, it was difficult to localize regions of the brain. If you had a patient and they showed certain deficits and you wanted to find out what part of the brain was causing that deficit, it was almost impossible. There were a few instances where arteriograms were done and that helped to find out which vessel was impacted. That might provide information about where a lesion might be, but that was it. It is important to realize that for the first 100 years of neuropsychology, the brain lesion correlation has been central to understanding brain function. Logic says that if you lose certain function and there’s a lesion in the brain, that was the part of the brain critical for that function.

There was revolution in imaging in the 1970s. We had the first CAT scan. Then we had the MRI, which was far more powerful. These are structural methods. They show you where a stroke is or where you have loss of substance. They helped establish an important distinction between stroke and the sudden death of a whole bunch of neurons in a specific part of brain, like where there is atrophy that could be the result of degenerative disease. Then we had another revolution in the structural/functional relationship. This first came in the form of PET scans where blood flow was scanned. Later we had single-photon emission computerized tomography (SPECT) scans. This allowed us to see where function was lost in the brain physiologically. For instance, when a part of the brain doesn’t work it doesn’t draw blood.

The last layer in the revolution has been to use PET scan and MRI to do something called functional imaging. In the initial paradigm, when you lose function, you look at part of brain that’s injured either by stroke or atrophy and you correlate the two. With functional imaging—with PET and MRI—we have the ability to ask the converse question or complimentary question: If you do a function, which part of the brain shows activation? That is a different paradigm.

By the time the 90s were over, we had all these tools in place. That means the past 20 years they have kept getting refined. Temporal resolution got better. Spatial resolution got better. Computational methods for analyzing data became better. Right now, we’re still reaping the benefits of these various technologies. The downside is that this is not something you just take off the shelf. You have to be pretty sophisticated in order to make sense of this. What I’m saying here is that images don’t come with labels. Interpretations can vary because the methods are so noisy. There is sometimes a lot of fantasy in interpreting results. By and large, compared to the 70s, where it was just a desert in terms of imaging, right now it’s really like being in a toy store. I think there will be continuous improvement.

BrainWise: From a research and clinical perspective, what do these new techniques offer?

Dr. Mesulam: They enable us to address impairment, for one. Where is the structural change in the brain? That gives you clues to identify the disease that is causing the problem. There are certain regenerative diseases that impair primarily the hippocampus. One other advantage, in addition to the scientific question of where in the brain is such-and-such a function, is to be able to understand what the underlying disease might be.

There are now dozens of different techniques. You can search for structural imaging of volume. Or structural imaging according to thickness. You can look at fibers. You can look at a resting state connectivity analysis. With PET scans alone, the options are multiplying. There are now metabolic PET scans, scans that show the number of synapses. We can also go in and look at amyloid distribution, tau distribution. Like I said earlier, there’s no such thing as ordering an image and getting an answer. The data provides information for a continuous hypothesis. As a doctor you start and try to make do with the least possible disruption and expense to the patient. If your initial imaging doesn’t give you an answer, then you keep getting deeper and deeper.

BrainWise: How does cognitive measurement assist imaging in getting a full picture of someone’s brain functioning?

Dr. Mesulam: People don’t come to you and say, ‘Doctor, I have atrophy in my frontal lobe.’ They come and say, ‘I have difficulty with x, y, and z.’ What people say and what really is there are two different things. People are not neuropsychologists. Many times, when we have patients coming in and saying, ‘My memory is not the way it should be,’ you have a have big differential. What do they mean by memory? Do they mean they can’t find words? Do they mean they can’t see faces from the past? Does it mean they can’t remember things from childhood? From yesterday? Does it mean they can’t hold someone’s phone number. Each one of these is a different kind of memory and each one of them has a different relationship to the brain. The job of neuropsychologist is to translate the lay language of patient into a language that can be correlated into what imaging shows. [For a systematic review of work on this subject, read this peer-reviewed article from the Archives of Clinical Neuropsychology.]

BrainWise: Looking forward, based on the decades of experience you have, how do you think artificial intelligence can help impact the way we read brain images?

Dr. Mesulam: Artificial intelligence (AI) is one of these totally ambiguous terms to me. Of course, we’re using artificial intelligence in interpreting images. We have powerful computers that are chewing out the data and comparing it to controls and giving us incredible and sophisticated information based on whatever thresholds we want. If one wants to call this artificial intelligence, they can suit themselves. To me the word is meaningless. We like to play with toys, and that’s what this is. If AI can find out the handedness of a patient, the developmental history, whether they had dyslexia in the past, that would be significant. If you assume that all the data in the world someday will be in some kind of computers, I suppose there eventually will be something slightly better, but right now it’s not as if we’re screaming out for some artificial thing doing something we can’t do.

BrainWise: So what does the future hold, Dr. Mesulam? How will better brain imaging make for better and more efficient neuropsychology?

Dr. Mesulam: We’ll get better inventions and statistics, better special resolution. We’ll invent new things that will show different chemicals in the brain. By 2028, I don’t think there will be much conceptual change. In 200 years, I don’t know. If we had a chance to introduce an electrode into each of the 40 billion neurons in the head, what questions would we ask? We don’t have a theory of brain function yet. Could we develop one? Data is a dime a dozen, and you need to interpret it to the best of your ability. We do our best and still even for the most seasoned clinicians there are surprises. Ultimately a clinician must believe the results of a clinical exam over imaging. That’s what the patient is experiencing. For people who take care of patients, at least as of now, that remains the primary source of data and therefore the primary part of the experience.

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

Music and the brain

in Featured, Highlight/by Matt Villano

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 Johann 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

in Featured, Highlight/by John Gorman

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.

Cutting through the (brain) fog

in Featured, Highlight/by Matt Villano

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

in Featured, Highlight/by Christabel Lobo

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.

5 ways to manage symptoms of Multiple Sclerosis

in Blog/by Matt Villano

Multiple sclerosis (MS) is an unpredictable disease of the central nervous system that disrupts the flow of information within the brain, and between the brain and body.

The exact cause of MS is unknown, but experts do know that something triggers the immune system to attack the central nervous system. The resulting damage to myelin, the protective layer insulating nerve fibers, as well as damage to neurons themselves, can derail signals to and from the brain. This interruption of communication signals causes unpredictable symptoms such as numbness, tingling, mood changes, memory problems, pain, fatigue, blindness and/or paralysis.

In short, neuronal damage can cause lots of problems and discomfort. And at this point, there’s no cure for MS.

Everyone’s experience with MS is different and these losses may be temporary or long lasting. According to two neuropsychologists who have studied MS for decades, this is why it’s so important for MS patients to manage their symptoms.

The experts—Dr. Peter Arnett and Dr. John DeLuca, both past presidents of the National Academy of Neuropsychology—said many MS symptoms revolve around cognition, which comprises perception, attention, information processing, and memory. Statistics from the National MS Society support this claim: Data from that group indicates up to 65 percent of people with MS will experience some changes in cognitive functioning, most related to speed of information processing, memory, and attention.

Here, then, are five tips for managing some of the cognitive symptoms of the disease.

Get by with a little help from friends

Friendships and social support also can go a long way toward helping a patient with MS manage symptoms. Several researchers including Dr. DeLuca, senior vice president of research and training at the Kessler Foundation, recently published an article about it in the October 2023 issue of Multiple Sclerosis and Related Disorders.

The study found that greater perceived social support is associated with better performance on processing speed and executive functioning measures among persons with MS.

Put differently, DeLuca said maintaining a strong social support network may be an important factor in optimizing cognitive health in MS.

“We are social creatures,” said DeLuca, who also serves as professor in the departments of Physical Medicine & Rehabilitation and Neurology at Rutgers-New Jersey Medical School. “It should come as no surprise that being around other people can be extremely beneficial.”

Stay on top of depression

Dr. Arnett, professor of psychology at Penn State University, has spent years investigating the link between depression and MS. A snapshot of his findings suggests that, anywhere from 25-30 percent of MS patients can experience significant depression. This is a serious uptick from statistics revealing that depression is prevalent in about 15 percent of the general population. It also offers hope for MS patients, as depression is treatable.

A recent study in Lancet Digital Health indicates that, compared with a waitlist control group, those patients who were randomly assigned to an online cognitive behavioral therapy (CBT) treatment showed improved quality of life and a substantial decline in depression scores.

“People who are depressed certainly don’t have to stay that way,” Arnett said.

Arnett added that if a person experiences depression and they get treated, they may be less likely to experience it in the future. He noted online versions of CBT will become available and will help broaden access to depression treatment.

Build a cognitive reserve

DeLuca also studies the importance of building a cognitive reserve—that is, how our lifetime of intellectually stimulating activity (e.g., music, reading, art, education, etc.) can build a brain that’s more resistant to the expression of a disease such as cognitive decline.

As he explains, people with high cognitive reserve are “much less likely to experience cognitive decline than people with low” cognitive reserve. DeLuca and several other authors published an article about this in a 2016 edition of the Journal of Neurology. Their takeaway: Reserve can be built and maintained over time based on ongoing participation in cognitively stimulating activities.

Of note, there is also evidence that cognitive reserve may provide a buffer against depression, as shown in a study published in the Archives of Clinical Neuropsychology by Arnett’s lab in 2018.

“It’s easy to do,” DeLuca said. “Join a reading club. something like that. Play cards with friends. There are any number of things you can do to get involved and build a cognitive reserve. So long as you’re stimulating your brain, you’re doing a good job with brain health.”

Seek rehab (if necessary)

Some people who have MS experience cognitive impairment; thankfully data indicate there are cognitive rehab programs that might be able to help.

DeLuca was among the authors of a 2020 study in Neurology that addressed this point. The takeaway: Neurologists and neuropsychologists can perform cognitive screenings to assess cognition, and treatments are available for those patients presenting with a certain amount of impairment.

“Treatment is available if cognition is suffering,” DeLuca said. “Talk to your healthcare provider about how to get assessed for cognitive issues and how to find professionals who can provide cognitive rehabilitation services.”

Experts call many of these treatments Disease Modifying Treatments, or DMTs. They are designed to reduce inflammatory disease activity and slow worsening disability.

Eat well

Finally, of course, is diet.

Eating right—particularly a plant-based and anti-inflammatory diet—can help maximize brain health for everyone, regardless of age, condition, or diagnosis.

While a Mediterranean diet comprising vegetables, fruits, and whole grains generally is the best for promoting brain wellness overall, Arnett said it also is a great choice for managing many symptoms of MS.

According to a 2017 study in Neurotherapeutics, there is evidence to suggest potential roles for vitamin D supplementation, tobacco smoking cessation, routine exercise, a plant-based, anti-inflammatory diet, and maintenance of emotional well-being as adjunct therapies to disease modifying therapies. Subsequent studies have shined further light on these approaches.

The take-home message: Become engaged and active in your own symptoms of MS. Ask questions and seek answers, as there are many things within your control to experiment with.

Understanding GBM

in Blog/by Matt Villano

Today, July 19, is Glioblastoma Multiforme (GBM) Awareness Day—a day dedicated to raising awareness about the most dangerous type of cancerous brain tumor there is.

GBM is one of the most complex, deadly, and treatment-resistant cancers. It accounts for 14.2 percent of all tumors and just over 50 percent of all primary malignant brain tumors in the United States at any given time. More than 14,490 Americans are expected to receive a GBM diagnosis in 2023, up from 12,000 cases annually just a few years ago.

Currently, there is no cure for this condition.

According to the National Brain Tumor Society (NBTS), the five-year relative survival rate of GBM is only 6.9 percent, and the median survival is only 8 months. At the same time, for patients with malignant brain tumors, the five-year relative survival rate following diagnosis is 35.7 percent.

Some can survive for years after a GBM diagnosis. Dr. Tresa Roebuck Spencer, former president of the National Academy of Neuropsychology and a lifelong advocate for neuropsychology, received a GBM diagnosis nearly three years ago and is still fighting—be sure to read our Q&A with Dr. Spencer.

The NBTS has put together some interesting data points about GBM to commemorate GBM Awareness Day. Here are some of those data:

An estimated 1 million Americans are living with a primary brain tumor.
Approximately 81.7 percent of all primary brain tumors occur in the adult population.
An estimated 94,390 people will receive a new primary brain tumor diagnosis in 2023.
Brain tumors are the seventh most common tumor type overall and the sixth most common cause of cancer related death among people over age 40.
GBM is the second most common (16.4 percent) type of brain tumor, but meningiomas are nearly three times more prevalent (46.1 percent).
Brain cancer is estimated to be the 10th leading cause of cancer death in 2023 for both males and females in all age groups.

For more information about GBM, please visit the NBTS or the American Brain Tumor Association.

Understanding Conditions of Aging, Frontotemporal Dementia

in Featured/by Dr. Andrew Budson

When actor Bruce Willis was diagnosed with Frontotemporal Dementia (FTD) earlier this year, it thrust the degenerative neurological condition into the national spotlight. Many people learned about FTD for the first time. The stories served as a sobering reminder of how our brains change as we age. Dr. Andrew Budson, chief of cognitive and behavioral neurology and director of the Center for Translational Cognitive Neuroscience at the Veterans Affairs Boston Healthcare System, is an expert on that subject. Dr. Budson has co-authored several books, including a new work titled, “Seven Steps to Managing Your Aging Memory: What’s Normal, What’s Not, and What to Do About It.” BrainWise managing editor Matt Villano recently sat down with Dr. Budson to discuss the conditions of aging and how we can better understand what happens to our brains as we mature. What follows is an edited transcript of their conversation.

BrainWise: What are the most common misconceptions about Frontotemporal Dementia (FTD) and what separates it from dementia more generally?

Dr. Budson: Dementia is a general term that we use when people’s thinking and memory have gone downhill and deteriorated to the point that it interferes with day-to-day function. Alzheimer’s disease is one type or one cause of dementia and frontotemporal dementia, abbreviated as FTD, is another type or cause of dementia. FTD basically comes in two types: language variants and behavior variants. The language variants are off in their own world; we now call them primary progressive aphasias. When Bruce Willis was initially diagnosed with aphasia, I would say what that means is he had primary progressive aphasia. The causes of aphasia could be a stroke, a brain tumor, a traumatic brain injury, or it could be a neurodegenerative disease like a frontotemporal dementia variant. FTD affects the temporal lobes. That’s why it tends to affect language, because our store of knowledge and our ability to speak are both close to the temporal lobes. The temporal lobe is our storehouse of words. Names of people, names of animals, names of tools—they’re all in there. People with disruptions to those parts of the temporal lobes may not recognize a word and forget what something is all together. I had one patient with FTD, and this person had lost the words for many body parts. I asked him, ‘What’s an elbow?’ And he was like, “Elbow. I know the word elbow, but I don’t know what it means.” This person also didn’t know what a knee was. Or a foot. It was very interesting.

BrainWise: So with primary progressive aphasia, the word itself doesn’t disappear, but rather the connection between the word and the definition?

Dr. Budson: That’s right. People can lose what a fork is for or something like that. They may be like Ariel in ‘The Little Mermaid,’ who comes across a fork and thinks it’s used to twirl her hair or something like that. It’s like if you grew up in a culture that just didn’t have forks, so you’d never seen one before. You had no idea what to do with it. Those sorts of things can happen. There are other types of language variants of frontotemporal dementia. People can have trouble getting the words out. They may know exactly what they want to say. They haven’t lost the words, but they have trouble getting the words out.

Behavioral variant frontotemporal dementia is when the frontal lobe is deteriorating, and patients began struggling with everyday life. In some cases, patients will have trouble completing complicate tasks or they’ll just become apathetic—they’ll just sit there like a bump on a log. In these cases, the deterioration is impacting the top and outer part of the frontal lobe, also known as the dorsolateral. In cases where the damage to the frontal lobe is on the bottom or the middle—the ventral medial—people become uninhibited, and they can’t control their urges. They may act or say or do whatever comes to mind without any filter. Of course, this can lead to aggression if the person’s asked to do something they don’t want to do. All these situations are difficult to endure as a patient and difficult to watch as a family member. They’re all variations of FTD.

BrainWise: So back to the Willis case for a moment. Is it safe to say that aphasia is a symptom of the language variant of FTD, or is aphasia its own genre of FTD?

Dr. Budson: It’s almost both, and the reason I say it like that is when people first present, when they first come to the doctor with problems speaking that have come on gradually and an evaluation is done, that would always include an MRI scan and some type of language cognitive testing. If they’re not having any behavior problems, we would assume it is primary progressive aphasia. Now, as the frontotemporal dementia progresses, so what happens is more and more of the brain becomes involved. Basically, what I’m saying is that people who start with primary progressive aphasia, especially if it’s due to frontotemporal dementia, will experience spread and will begin to have behavior problems too.

I have never met Bruce Willis. I have certainly never examined him, but I would speculate that because we are first told he had aphasia, which I thought from the start must be primary progressive aphasia. Then later we’re told he has FTD, he has frontotemporal dementia. My speculation is that it was always a form of frontotemporal dementia that began with the temporal lobes being involved, causing language problems. It then spread to the frontal lobes causing behavior problems as well, and that’s when we heard on the news it was FTD.

BrainWise: How common is FTD? How prevalent is this in a population of people over age 65?

Dr. Budson: In a population of 65-plus, I would estimate it’s probably somewhere around 50 times less common than Alzheimer’s.

BrainWise: And what is that number?

Dr. Budson: By the time people reach the age of 85, approximately 40% of those 85 and older have Alzheimer’s. The dementias do become more common as people get older. One of the interesting things about frontotemporal dementia is although approximately a quarter of patients do present above age 65, three-quarters of them present younger than age 65. It’s a more common cause of dementia in younger people. The ages of patients there usually fall into the 45 to 65 range.

BrainWise: Why is there a link between age and brain development over time and memory loss?

Dr. Budson: We don’t fully know the answer as to why these different disorders of thinking and memory develop. With Alzheimer’s, there are two collections of proteins. One of them is outside the cell and it’s called amyloid or sometimes beta-amyloid. Then there’s another collection of proteins inside the cell, and that is known as tau. Together, especially things go wrong, they can be very problematic. Again, with Alzehimer’s, problems start with the deposition of these amyloid proteins where the amyloid clusters and clumps together to form plaques. The plaques get bigger and bigger. They start to interfere with neighboring brain cells. There’s an inflammatory reaction, that causes the tau to be released inside the cells which forms long chains. The chains get tangled up. Eventually, these tangles kill the cells.

Why does this happen when people get older? There is a school of thought that I’m a believer in, that the normal function of amyloid in the brain is to help fight off brain infections. Bacteria, virus, fungi, things like that. We all make a little bit of amyloid every day, and we normally clear it away while we’re sleeping, which is one of many reasons why it’s important to get a good night’s rest. Well with Alzheimer’s patients, there either be too much amyloid being made, or not enough of it being cleared away. Tau tangles also can self-propagate. They can essentially move from one brain cell to another through the connections that brain cells have, and it can cause the tau to get tangled up in another brain region. Once this process starts, it can spread.

In terms of frontotemporal dementia, some of the proteins are the same. Unlike Alzheimer’s Disease which we think is a single pathology, in frontotemporal dementia, there’s like a family of maybe up to a dozen different pathologies, and roughly a dozen different abnormal proteins. The two that are most common are the tau and another protein that is called TDP-43. The 43 is how much it weighs in molecular weight, and the TDP stands for transactive DNA-binding protein. TDP-43 can affect people when they’re young and cause frontotemporal dementia for them in their 40s, 50s and 60s.

BrainWise: To what extent can these tau proteins help or contribute to the growth of someone’s brain?

Dr. Budson: The normal function of the tau is to help stabilize these very small tubes called microtubules inside neurons. Neurons have these long processes like long arms that reach out to touch other neurons, and that’s how the brain cells communicate with one another. In order to pass information and substances like proteins from one part of the neuron to another, neurons send them through these tiny microtubules.

BrainWise: Right now, how can people put themselves in a position to live longer and maybe stave off catastrophic memory loss?

Dr. Budson: We’ve really made tremendous strides over the last hundred years in understanding what causes memory loss, what causes dementia. We now understand the brain structures that are involved. We understand many of the abnormal proteins that are doing the damage. We are the furthest along on Alzheimer’s. There’s FDA-approved medications that can help to improve memory function among Alzheimer’s patients equivalent to turning the clock back on the memory loss. For people with FTDs, the main class of medications that can help these individuals if they have behavior problems are the Prozac family of medications, or selective serotonin re-uptake inhibitors. My personal two favorites in this class are Sertraline (Zoloft) and Escitalopram (Lexapro). Those I think work quite well in patients that are having behavioral problems, and there’s good evidence to show that these types of medications are helpful for them.

That’s just medicine. It’s important to engage in aerobic exercise, which releases growth factors from the brain that help us to grow new brain cells—no matter how old we are. Eating right is also important, and people should do their best to stay away from highly processed foods. Sleep is critical, and you want to try to get the right amount of sleep for you. That could be seven hours or nine hours, but I know it’s not five hours. Nobody’s right amount of sleep is five hours. People that try and sleep five hours or less not only have an increased risk of Alzheimer’s or other types of dementia, but they also have an increased risk of death. Other things that have been shown to be beneficial are staying socially active and engaging in novel, cognitively stimulating activities. There’s even a benefit from music.

BrainWise: What questions will you ask in your research next?

Dr. Budson: I am working on developing new strategies and memory aids that can help people to remember things better in day-to-day life without medications (or in addition to medications). Basically, I’m looking to extend the mild-memory phase of Alzheimer’s Disease. I’m also trying to understand the biological basis of thinking and memory and consciousness. I wrote a 30,000-word scientific article that was published in the December 2022 issue of Cognitive Behavioral Neurology. The article explains what I think is the relationship between memory and consciousness and about how if we understand this relationship, not only can we understand memory better, but we can also understand consciousness better. I’m excited about where it will lead.

BrainWise: Why did you choose to study this area of brain science in particular?

Dr. Budson: I’m particularly interested in memory and thinking. As early as high school, I really wanted to understand what are the biological bases of thinking, memory, and consciousness? I’ve maintained that interest throughout my career. Along the way a fascinating thing has happened. As soon as I started to care for patients, I found tremendous satisfaction at being able to help them with memory problems. I have been able to do that a little bit through medications, a little bit through strategies. The other thing that I found is that there’s a lot of neurodegenerative diseases, a lot of different types of dementias that we don’t have effective treatments for. With Alzheimer’s, we can do something, we can’t do everything. Frontotemporal dementia, we can do even less. I realized there’s a lot of good that can be done by just helping families understand what’s going on, helping individuals understand what’s going on with their thinking and memory or language or other types of things. I’ve always wanted to really understand what’s going on at a very deep level so that I can help individuals and their loved ones understand these things too.

If you’ve been diagnosed with FTD or you have a loved one who has been diagnosed, and want to understand more, please reach out to a NAN neuropsychologist or a neurologist for more information.

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