Paul Rand: Not long ago, University of Pennsylvania neuroscientist, Nicole Rust, was studying how memory works in the brain, but she couldn't shake an experience that kept happening.

Nicole Rust: There were these calls by the heads of our funding agencies, that there was some sort of disconnect between the things that researchers like myself have been discovering and what society needs from us.

Paul Rand: With all the research into how our brain works, all the MRI scans and studies, why is it that we haven't been able to reliably treat most brain conditions, including depression, schizophrenia, and Alzheimer's?

Nicole Rust: It's been a bit of a mystery. Why haven't we made more progress in understanding and treating those conditions? So that's really what "Elusive Cures" was all about, is trying to figure out what's it gonna take in order to make breakthroughs in that stage.

Paul Rand: "Elusive Cures", her new book, is the culmination of Rust's research into this challenge, and finding answers hasn't been that easy.

Nicole Rust: This book for me was really a process of discovery, trying to tease apart from a very high level and think through this vast literature. And I wrote the book, and I ripped it up a couple times because I wasn't satisfied with the answers that I formulated, but I finally got there. I finally get there. 

Paul Rand: The conclusion that she came to is that for decades, really, researchers and scientists have been thinking about the brain all wrong. They pictured brain conditions almost like a domino chain. Some gene caused some molecule to dysfunction, and if they could just find that one point of failure, well, they thought they could fix it.

Nicole Rust: So that was the idea that there was this one common pathway along which everything worked.

Paul Rand: But if the whole field is built on the wrong startup assumption, everything downstream then naturally collapses. And the brain, Rust argues, is definitely no domino chain. It's more like the weather, a complex system of swirling interactions in which a single shift can ripple unpredictably.

Nicole Rust: Not just what's happening at the level of molecules and cell death, but we're trying to think about big human brain circuits, right? And what's happened, for example, in the mood network in our brains in order to transform experiences into moods and how we are interacting with our environments to shape. What's happening.

Paul Rand: But Rust does see things changing. Researchers and technology are catching up. 

Nicole Rust: 25 years ago when I was in graduate school, we could really only record from a single brain cell at a time, it's neural activity. Today, we can record from one million neurons at the same time in a mouse. The technology is incredible. And so for the first time, we can actually evaluate the brain's activity at this very high resolution, at the resolution of individual brain cells, which is what we need.

Paul Rand: And she hopes her research on why we haven't made progress on brain treatments combined with these advancing technologies will lead to what she calls a new grand plan for brain research.

Nicole Rust: Instead of find the broken domino and fix it. It's something like embrace the complexity, create models of the system to determine their fragility, what's going wrong, and also determine what engineers would call control, but I would call it treatment to shift the brain from disease to health.

Paul Rand: From the University of Chicago podcast network, welcome to Big Brains, the show where we explore the groundbreaking research and discoveries that are transforming our world. I'm your host, Paul Rand. Join me as we meet the minds behind the breakthroughs on today's episode, why neuroscience hasn't solved brain disorders and how we can change that.

Paul Rand: Nicole, I wonder if we can talk a little bit, and the overall premise of your work is that we really haven’t made serious progress in treatment for diseases of the brain. And I wonder if you can just set the stage for us about what you mean by that and why it’s of concern.

Nicole Rust: First, I think we have to be a little bit thoughtful when we use that term disease, because not all of the conditions we’ll be talking about today are diseases. And some of them, we might even not want to call them disorders. So there are legitimate concerns that there are certain classes of conditions-

Paul Rand: We’ll dig into that as well. That’s great. Yep.

Nicole Rust: Yeah. Yeah. Forms of neurodiversity that society maybe has wrongly become intolerant to. So examples of that might be attention deficit hyperactivity disorder, depression, autism spectrum disorder. So when we use this term, we definitely want to be thoughtful about how we’re using it, and really in an empathetic spirit. There are individuals who are diagnosed with conditions and maybe they don’t think of themselves as having a condition. And then there are other individuals who want and need treatment. And it’s really those individuals that we’re talking about today, the ones that want and need treatment, and our treatments are falling short of anything that we have to offer them.

So it’s not that we haven’t made progress in anything. So there have been these game-changing drugs, these breakthroughs where big discoveries about the brain lead to a new therapy. In cases of that, are things like the new sleep drugs and new drugs for migraine. But there are classes of disorders that have just been really difficult to understand what causes them and understand how to create new treatments. And so, those three classes are our neurodegenerative conditions, so things like Parkinson’s and Alzheimer’s disease, are neuropsychiatric conditions, so depression, anxiety, psychosis.

And then the intellectual disability, so these are neurodevelopmental disorders like intellectual disability. Another neurodevelopmental disorder is autism spectrum disorder.

Paul Rand: Let’s take maybe one of the conditions as a way of talking about it. Let’s take depression. And when we think about depression as a condition, what have we learned and why do you think it’s not enough?

Nicole Rust: So in some sense, we all know what causes certain cases of depression. We all know someone who has gone through a very traumatic experience, which they didn’t necessarily recover back to full force from, like the death of a loved one. We all know about the role of poverty and trauma, and it’s creating the susceptibility to depression. So those types of causes are ones that live outside the brain. So these are external causes. And so, then there’s a question of, well, what’s happening inside the brain as a consequence of those causes?

And in some cases, it’s also we know that some individuals with depression, you can’t really point to any one external event that happened to them. They just seem to enter or be susceptible or more sensitive to bouts of depression. So one of the big mysteries for a very long time has been what’s been happening inside the brain. Back in the 1960s, there started to be these ideas that maybe depression is about a chemical imbalance of the brain. So we serendipitously discovered this class of drugs that we call the antidepressants. And those were discovered. It was a fascinating story behind that one. The first antidepressant was discovered when they were doing clinical trials for the lung-infecting bacteria, tuberculosis.

And what they found is, the people who took this drug in the clinical trials were dancing around, they were joyous. And so, they said, “Well, maybe this could be mood uplifting.” And so, this was the first clinical trial for an antidepressant. So we’ve had many antidepressants since, and we’ve even learned a lot about how they operate at the chemical level in our brain. So when two brain cells connect together, they release a chemical in order to facilitate that communication. And these antidepressants, they modify how much chemical is released or how long it’s released, and so on. So this led to this idea about the chemical imbalance theory. But fast forward, it doesn’t explain everything.

So for example, some of these antidepressants, they increase the amount of chemical that’s released into the synapse between these two brain cells that are communicating. But that happens pretty quickly after you start taking these drugs. And the drugs themselves in terms of their mood uplifting properties, that doesn’t kick in for weeks or months. So there’s a big question, what’s happening during those weeks and months in order to make antidepressants work? There’s so much we don’t know about the brain and depression. We can’t put someone in a brain scanner and determine whether or not they’re going through a depressive or a psychotic episode, for example.

We can’t look at a brain and determine if it’s depressed. We don’t even really understand how our brains take our experiences and transform them into our moods. So it turns out that emotion research, mood research, it’s a really, really difficult area of neuroscience. And so, while we’re beginning to make some progress in that realm, it’s because we’re starting to think about the brain in a slightly different way. Not as there’s a broken step in a really long chain. And that step is chemicals that might be embracing the brain more and thinking about this new way, embracing more of its complexity. And that’s when I talk about in Elusive Cures.

Paul Rand: Yeah. And so, this in some ways, you talk about this approach is the molecular and neuroscience framework, which to me, helps set up an understanding of how we have historically thought of how the brain is working. Can you expand a little bit more on that for me, please?

Nicole Rust: Yeah. So back in the 1990s, neuroscience really began to adopt this way of thinking about the brain, which in the book I introduced is the molecular neuroscience framework. What it does is, it envisions the brain as a very long sequence of dominoes that are all tied together. So it’s a very satisfying way to think about how anything works. We’ve all done the thing where we set up the dominoes.

Paul Rand: And very logical.

Nicole Rust: We tip the first one and they all fall down. Yes, it’s very logical. It’s about how causes lead to effects. And so, this domino chain was really set up with the emergence of some remarkable technologies, including the ability to sequence genes. And also to image what’s happening in the brain, non-invasively using a technique called MRI that I’m sure many of the listeners have actually had done to themselves. So the way the molecular neuroscience framework works is, it all begins with the genes. So genes then are expressed and that creates a program that’s used to create brain cells.

The brain cells are wired together into these brain circuits. And it’s the activation of those brain circuits that leads to all of our functions and dysfunctions. So everything that we do, seeing, hearing, remembering, deciding, imagining. And the idea then is that, if there’s a type of dysfunction like maybe Alzheimer’s disease or perhaps psychosis, that is reflected in our patterns of brain activity. Now, there’s a single feedback loop in this idea such that our environments, what we experience actually shapes how our brains are wired up. And that happens via feedback or we input these experiences through our senses, and then that reshapes these brain circuits by changing how the genes are expressed.

And that was the molecular neuroscience framework. It caused a lot of brain researchers, including myself, to focus on how causes lead to effects in the brain. How the expression of a gene leads to one of these brain circuits, or how activity leads to behavior. And so, that was really the agenda of that era, was to map these cause-effect chains and under the presumption that dysfunction follows from a broken domino in the chain. The goal is to pinpoint the broken domino, and we can go in and target it for a fix. 

Paul Rand: And that applies to any type of condition. Is that right?

Nicole Rust: Yes, absolutely.

Paul Rand: Yep. Now, the implications of this level of understanding has had some pretty big restrictions. Not only in terms, it sounds like in your mind, of how we have come to understand these different conditions, but arguably even how drug companies are choosing or not choosing to invest in continuing to look for answers.

Nicole Rust: Absolutely. So with this idea that it’s singular broken dominoes in the chain that are causing individuals’ disorders, there was a hunt for finding the broken dominoes and then targeting them for a fix. And in the case of something that had to do with the molecular level, like the gene that was expressed, maybe a genetic variation or mutation, the idea was be that we would target that level with a drug.

And so, the pharmaceutical industry was very interested in trying to target those broken dominoes with exquisite selectivity. There were lots of mottos of that era, one disease, one drug, one molecule type of mottos.

Paul Rand: And so, in terms of this whole idea when the human genome sequence, it just didn’t lead to those solutions. And so, when was the realization that this approach was not delivering what the expected and hoped for outcome was going to be?

Nicole Rust: Yeah, it happened gradually. It unfolded across decades. In some cases, you will get a disorder that can actually be linked directly to the mutation of an individual gene. One example of that is cystic fibrosis, is always the mutation of a single gene. There are other types of disorders that are weakly linked to maybe one or a handful of genes. Alzheimer’s is an interesting case for many individuals.

If you inherit a variant of Alzheimer’s, it will increase your risk for getting Alzheimer’s, but it won’t ensure it. And then there are other classes of disorders that are linked to hundreds of genes, very, very weakly. And this is the example of some of the psychiatric conditions. So depression, anxiety, autism, schizophrenia. If you inherit these variants, it will increase your risk, but really, there’s a weak link between the disorder and the genes that you inherit. Not one of these strong links for particular genes.

Paul Rand: Which leads us to this idea as you’re promoting in your book, about it’s time for lack of a better word, of a new grand plan. And I wonder what you mean by that, and how is that message beginning to be received?

Nicole Rust: The way that researchers have been approaching the brain, it was technology limited and it was in fact, useful. It set a foundation for what we need to know, but it isn’t sufficient. And the problem is, we’ve been massively oversimplifying the brain. The brain is held up as the most complex thing in the entire universe. And so, you can ask the question, what’s so complicated about it?

A domino chain, maybe it has many levels, but domino chains ultimately aren’t really that complicated. So what’s so complicated about the brain? The brain is full of these feedback loops, so causes that lead to effects that feed back on themselves as causes. And we know a lot about systems like these.

Paul Rand: It’s not linear.

Nicole Rust: They’re called complex dynamical systems. It’s not linear. It’s a highly nonlinear system. It’s much more like the weather ecosystems, nuclear reactors. We know that these types of systems have special properties, and it’s because their parts interact in interesting ways. They’re often called emergent properties because they’re so surprising when they happen.

And we also know that in these types of systems, when you try to intervene or perturb, work with them, these small changes that you introduce can have big unpredictable effects. And the weather is a great example of that. As we all know, we cannot control the weather. and it’s not because we haven’t tried, it’s not because we’re energy limited, it’s because of what’s called the butterfly effect. So a small perturbation to the weather can lead to a big unpredictable effect later on. And so, that’s what I realized when writing this book.

The big formidable challenge that we’re up against in our quest to create treatments for these conditions, is that small perturbations into the brain can also have big unpredictable effects. That’s the side effects of all of our drugs, for example, and it’s because the brain is one of these complex systems with so many parts that are interacting. Now, I have a lot of hope that we’ll be able to create treatments to shift the brain from unhealthy to healthy states, but it’s not going to be as simple as targeting a broken domino for a fix. It’s going to be something much more complicated than that, and that’s the formidable challenge that we’re up against.

Paul Rand: Yeah. As I hear you talk about this, we’re still very much of course, talking about the physicality of the brain. And there’s a whole other level that I’m not sure what a comparative would be, but that’s where the mind fits into this. How do you think about, and maybe there’s a better word than physicality of the brain, but how do you think about that and where the mind, whatever that is, fits into this equation as we’re looking to solve some of these conditions?

Nicole Rust: This is one that I’m deeply and profoundly interested in, and it is a very, very tricky question at many levels. For example, that what you’re talking about, the problem of subjective experience we often call it, is one of the big things holding back progress in psychiatric conditions.

Paul Rand: Tell me what you mean by subjective experience?

Nicole Rust: Yeah. One of the things that makes studying emotions really hard is there is no objective ground truth to emotion. So let’s just compare emotion to memory. If I want to study memory, I can create a memory task. For example, I can show you pictures and I can ask you, have you seen this picture before? And there’s an objective right or wrong answer, you have or you haven’t. In comparison, I can ask you, how happy are you right now, Paul? There’s no objective answer to that. Only how happy you are, and there’s no right answer to how happy you should be. I can’t create an objective test in order to study it. And so, that makes emotions very difficult to study.

We’re very limited to studying them, for example, in humans that can actually make subjective reports. And sometimes it’s even hard for us to tap into our feelings, but it’s very difficult to ask, for example, an animal how they feel. So it takes a lot of the types of research that we typically use in neuroscience to make progress off the table, or makes it more complicated, I should say. We have to work around it. So you have that problem of experience and how does the brain give rise to the mind? And what can we access about the mind? What can we access about the brain? It’s a hugely challenging problem.

So before I wrote Elusive Cures, I used to study memory, scene and memory. And then I zoomed out and got a big bird’s eye perspective on all of brain mind research. And then when I asked myself, where do I want to dive back in as a researcher to make progress? Where do we need to make progress? I decided to dive back in with mood. So that’s my line of research. I study mood now, taking on directly this problem of subjective experience. We have to get through the bottleneck that’s holding back our understanding of emotions and moods in comparison to these other brain functions.

Paul Rand: Do I need to understand the mind at some foundational level in order to be able to understand how mood is part of that, or are they understood together, or do you think of them together?

Nicole Rust: Typically, when I think about the mind, I think about the psychological level. So there’s the brain levels. So that’s questions about what’s happening in the brain. And that can happen at the level of molecules or the level of brain activity. And then there’s the mind. One example of the difference and why I think it’s sometimes easy to think about the level of the mind, is one I use in Elusive Cures, the phrase insomnia causes fatigue. Now, if you think about who’s causing who, insomnia and fatigue are phenomena at the level of the mind. We’re not pointing to brain networks in the brain.

What’s really happening is the absence of sleep is causing certain things to happen in the brain, which then manifests with certain symptoms that may cause fatigue. So that’s actually happening. Who’s causing who? There’s these brain states that are causing other brain states. There’s nothing really physically in the world called insomnia that causes something called fatigue outside what’s happening in the brain. That said, it makes a lot of sense to use that phrase, insomnia causes fatigue. We want to talk about the mind at that causal level. If you’re having insomnia... or I can say it differently. If you’re having fatigue, you might wonder, well, what’s causing it? Well, it’s caused by insomnia. And then in turn it’s like, well, how am I going to get more sleep?

So we don’t need to have that understand a lot of neuroscience in order to know we need to get more sleep. It’s a way to very pragmatically and effectively think through the problem. So that’s I think one example of the difference between thinking through the mind versus thinking through the brain, and thinking through causality. But I hope this example also highlights how one can easily get confused by taking for granted that word cause because things in the mind aren’t actually causing other things in the mind in that simple way.

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So you are now focused on mood, and I wonder if we can start with a definition of how you think about what mood is, and why do you think it is compelling enough to make it your new direction of your studies?

Nicole Rust: So mood is often differentiated from emotion, and I think it’s an important difference. So our emotions are typically thought of as being triggered by something. So if I see a tiger, I’ll become afraid. Our moods tend to be more diffuse and slowly changing. And so, then the question is, well, why is that? One of the things that we know about moods is that they are an integration over many experiences. They’re not just triggered by one. So a lot of our behavioral research suggests that there’s something like a running average of the goodness and badness of things that have happened to you lately.

So big questions in mood research are things like, well, how is the brain doing that averaging over recent events? Another big question in mood is, it’s the ultimate kind of loopy system in terms of these feedback loops that I’ve been talking about, and that’s one of the reason I selected it to study it. So we know that our moods are this average of the things that have happened to us. But we also know that our percepts of how good and bad things are depends on our moods. So if something happens to you and you’re in a good mood, you’ll perceive it as better than it actually is. And if you’re in a bad mood, you’ll perceive it as worse.

So now we have this big loopy system where our moods are the average of our percepts of how good things are that have happened to us, but our percepts in term impact our moods. So there are big questions about how is it that we don’t just have five bad things in a row happen to us and we spiral down into a depression? Or how is it that five good things happen to us and we don’t spiral up into mania? So we have all these mechanisms that presumably reside in our brain in order to keep mood within a normal range. And one of the questions is, when someone is getting out of that normal range, what about those mechanisms are going awry? So those are some of the classic questions that we’re after in mood neuroscience.

Another question that we’re after is the question of, what bits of the brain are actually taking in your experience, and then transforming them into mood? And we’re really interested in creating big models of how that works. So we can hand those models off to our clinicians who do things like stimulate the brain, noninvasively, you can stimulate the brain with magnets. And that’s one treatment for depression actually, that you can target TMS it’s called, transcranial magnetic stimulation. But it doesn’t work for everyone. And so, maybe for some individuals that’s the wrong treatment, it’s the wrong brain area.

So we want to give them big maps of the mood network and what each bit of it is doing, so they can then transform these maps into clinical treatments.

Paul Rand: As you now look to switch your research, is there a fundamental question or two that you feel like you really have to answer about mood to understand it even to a greater degree?

Nicole Rust: Yeah. So for me, the one that we’re really trying to... I’ve hinted at some of the questions we’re trying to approach out of the gate. But the way we approach mood is, it turns out that a really terrific mood induction paradigm, is to have individuals play gambling games. When you play a gambling game, when you win, it makes you happier. And when you lose, you become less happy. And what’s really nice about these is, we can have individuals play many trials of this. And we can ask them every few trials, how happy are you right now? How happy are you right now? And then we can see what their mood depends on in the gambling game.

And so, the types of things that we learn are individuals, their happiness doesn’t just depend on what happened on the last trial. Their happiness depends on many trials and this running average I was talking about. And there are some more subtle things that we can extract as principles. For example, you get to choose in these gambling where you want to win some money for certain, or you want to take a gamble. And if you win because you took a gamble, it makes you happier than if you win if you took the money for certain. So we really like surprising things. Winning makes us happy, but surprising winning makes us even happier.

And then once we have these, well, they’re actually models that we can use to predict how anyone’s happiness will fluctuate. And as they play these games, we can then go into the brain and we can ask, where in the brain is processing the events you won or lost? And where in the brain is converting that experience of winning and losing into this running average called mood? So we’re trying to create these big loopy dynamical systems maps that I was talking about, that we can then hand to our clinical colleagues who are trying to design new therapies for transcranial magnetic stimulation and in order to create clinical therapeutics. That’s one way. That’s one class of questions really interested in.

But I also want to emphasize that part of this research that I do, it’s really just trying to understand the nuts and bolts, and we have no idea where it will lead. So looking into the brain and trying to understand how the brain does this. We were talking about this loopy loop. How does the brain stop the system from spiraling out of control either into depression or up to mania? Those principles might give us insights in how to create new behavioral therapies that have nothing to do with the brain at all.

So they’re a whole suite of therapies that are quite effective for some individuals at treating depression and anxiety, but they don’t work for everyone. And so, everyone is always on the hunt for new ideas about how these systems work that we can then use to design new therapies.

Paul Rand: Help me understand, if you are optimistic about how advancing technologies and this understanding of the broken link or a domino not working as it should is a good one. Because the explanation is, it’s an entire processes. You can’t just go in and replace the broken fuse, you have to think of it collectively.

How is the research and the technology advancing that will help us understand that processes? And part of it is to your example of, it can’t be self-reported only because that limits it. How do you see the technology evolving to help figure out where in the flow something is not working as it’s intended to work?

Nicole Rust: Yeah. I think the key insight is that when you get these big feedback loops, it’s really hard to think through how these systems work just in your mind. And that’s where these mathematical models come in, just like the weather. It would be very hard for someone to take look at the weather data and then predict what the weather is going to be five days from now. It’s just the system is just too complicated. And likewise for the brain. We can build these models that tell us how the system works. We can then incorporate what our observations about what’s going array. And even more, we can use these models in order to figure out how to shift the system from disease to health.

There’s a new example of a Parkinson’s drug, which is great. It’s in clinical trial, so we don’t know yet if it will work. So Parkinson’s is one of these disorders that is weakly tied to genes and certain individuals, it’s tied to a gene called GBA1, which codes for an enzyme that does some cleaning up in our cells to get rid of the gunk. So upon discovering that, a pharmaceutical company designed a drug that would target this system with some pretty simple ideas about how this enzyme works.

So it’s two fatty molecules. One enzyme transforms A to B, the other transforms B to A back again. And so, they were thinking about this in a very domino-chainy-type way. The clinical trials failed. In fact, the drug actually made individuals worse. So that was a failure. So then a second generation of researchers goes in and says, “No, we have to model this entire system.” One thing goes to another and there’s this big feedback loop as a complex dynamical system, a bit like you would model the weather. And they realized, one, why that first drug didn’t work. And they realized exactly what they should do to make it right.

And based on those models, which are very hard to think through, if you’re just thinking through things simply, they were able to develop this new drug, which is in its second phase of clinical trials. So all fingers are crossed. And this is the new generation of how drugs will be a developed. It’s by modeling the system and figuring out from those models how to shift the system to help.

Paul Rand: Awesome. Awesome. And if we were to come back to the beginning part of the physicality of what we’re doing, tell me if we come back in five years, and is the world embracing your observation or your insight here? And recognizing, it sounds like it is, like for example, in your Parkinson’s example, that the world is catching up and you’ve done a great job conceptualizing this and putting some words to it. Is research caught up to you in that level of thinking at this point across the board?

Nicole Rust: Yeah. I do want to emphasize, when I wrote Elusive Cures, my intent wasn’t to swoop in as the genius who was going to tell and boss everybody around. I’m a scientist, and as scientists, we’re all in the weeds. It was to zoom out and look around and see what the genius of our era was. So that’s really what this book was about. And so, I was channeling the genius of our era and trying to write it down and synthesize it. So I was really acting as much more of a curator. So yes, the book is channeling the ethos of a community who is very eager and embracing these ideas. I’ll also say that there are some who are a little bit more skeptical. They do wonder if this is the path forward.

And they worry about things like, we cannot control the weather. Therefore, maybe taking on all of this complexity is just too complicated of an approach. Maybe that’s not the most efficient way to go about things. And I also highlight that there are many paths to the end goal of what society really needs for us. And some of those will embrace all of the complexity, model the system at all its detail, throw a bunch of AI at it, figure it out. And then others will build up an intuition, a suspicion for how the system might work, and then try it out. Individuals are suffering. We can’t wait till we understand everything until we try to create new treatments.

And the history of therapeutic interventions has a long history of success with, let’s just try. We have some intuition, let’s try take safe conservative steps, but let’s try to creative a therapy around this and see if it works. And so, I think there are these two paths to the end goal, and it’s really all hands on deck.