‘Elusive Cures: Why Neuroscience Hasn’t Solved Brain Disorders—and How We Can Change That’
The first book from psychology professor Nicole Rust of the School of Arts & Sciences dives into why research on conditions like Alzheimer’s and depression hasn’t translated more effectively into better treatments.
Tackling brain conditions, says psychology professor Nicole Rust, requires thinking about the brain not as a domino chain but as a complex dynamical system with feedback loops.
In the late 1980s, researchers identified a rare genetic mutation that leads to Alzheimer’s disease, and yet drugs developed in response haven’t slowed Alzheimer’s progression nearly to the degree researchers had hoped. In the 1990s, scientists dreamed of biological tests—such as brain scans or blood tests—to diagnose psychiatric conditions like depression, and yet diagnoses are still based on symptoms alone.
In her new book, “Elusive Cures: Why Neuroscience Hasn’t Solved Brain Disorders—and How We Can Change That,” University of Pennsylvania psychology professor Nicole Rust tackles the history and future of these types of disconnects in bringing treatment from “bench to bedside.”
“Our brains are designed to adapt to change—that’s really their superpower—but that adaptability also makes them fragile. The idea is that that’s what’s is leading to brain and mental conditions,” Rust says. Tackling these conditions, she says, requires thinking about the brain not as a domino chain but as a complex dynamical system with feedback loops. Rust has seen this kind of mindset shift happen fields such as ecology and cellular biology, and she is optimistic that advances in technology will make it easier for neuroscientists to also look at the whole picture.
Rust says the process of writing the book also inspired her to shift her research program from studying memory to studying mood. She received the Simons Foundation Pivot Fellowship, which is designed to help researchers apply their expertise to a new discipline, and she will spend a year embedded in the lab of Princeton University neuroscientist Yael Niv starting July 1.
Rust talked to Penn Today about the genesis of her book, hopes for the field, and what’s next for her.
What inspired you to write this book?
I’ve been a brain researcher for decades, and I did not know the answer to the following question: Why is it that we have been learning so much about the brain for so long, but our ability to treat certain types of brain and mental conditions is so frustrated? I couldn’t explain what the problem was and how we were going to attack it, and I wanted to understand where this disconnect might be. Moreover, I wanted to understand what we as a community of brain researchers could do about it.
I knew that this question was much bigger than me or my research program. The answers to this question are relevant not only to brain research, but all of humanity. I think nearly everyone is either afflicted with a brain or mental condition or has a loved one who is.
You refer to the current approach to developing treatments and cures as the ‘molecular neuroscience framework.’ What is this, and what are the issues with it?
Starting in the 1990s, researchers began to think about the brain as a very complicated and long domino chain of causes that lead to effects. When they were thinking about the brain’s dysfunction, they were trying to pinpoint the broken domino in the chain that was causing the problem so they could target it for a fix. That might be a gene that, if mutated, you might target with a drug, or it might be a region of the brain that has abnormal activity that you could repair with brain stimulation.
There are three problems with thinking about the brain this way. First and foremost, it’s a massive oversimplification of the type of thing that the brain is. We know that the brain is not just a domino chain; it’s chock-full of feedback loops. For example, if part A of the brain sends information to part B, part B sends information back again to part A. Systems like that can go awry in ways that can’t be described as ‘broken dominoes.’
The second problem is that when you oversimplify the brain this way and target broken dominoes for a fix, even if that’s the problem, the fix may not be as simple as targeting that domino in a chain, because of complex interactions between the dominoes that can lead to things like drug side effects. The third problem is that it’s incomplete. When the molecular neuroscience framework was first proposed, there were certain dominoes in the chain that were proposed as big unanswered questions, and one of those was the question of how the brain gives rise to the mind.
What are some alternative approaches to thinking about the relationship between the brain and the mind—and to thinking about therapeutic approaches?
Once you begin to embrace the idea that the brain is chock-full of these big feedback loops—a system where causes lead to effects that then feed back on themselves as causes—you begin to think about a whole different type of system. Systems like that include weather, ecosystems, and nuclear reactors. They are complex dynamical systems, and when you shift to thinking about the brain this way, everything about how you approach studying it changes. To understand them, you have to study all their parts at the same time as opposed to one at a time, because their special properties follow from interactions between those parts.
I hope that brain researchers will continue to embrace more of this complexity to fill in some of the big missing blanks. One example is creating biological tests, like brain scans, to diagnose psychiatric conditions like depression. That requires that we understand something about how happiness and sadness are reflected in the brain, and we still don’t know the answer to that. There are good reasons to think that what’s happening in the brain to produce emotions is in fact a complex dynamical system.
You write that your book was inspired by your growing pessimism about the path forward for brain research, but now you’re optimistic. How did writing this book make you optimistic?
We’ve had new breakthroughs in our technology—including new ways to measure the brain and its activity—as well as AI, which is helping us wrap our heads around all that data. That has enabled us to really tackle the complexity of the brain in ways we’ve never been able to do before.
Writing the book was a transformation for me—it transformed what I think we need to know about the brain and, in turn, my research program. In terms of the most important unanswered questions, the one I’m jumping into is the question of how emotions are reflected in the brain. I used to work on memory, and now I’m redirecting my entire research program to study mood. If I ask you the question, ‘How happy are you right now?’ what in your brain is driving your sense of that? How do our brains transform our experiences into moods?
Mood is harder to study than memory because it is a subjective experience. To study your memory, I can give you a memory test, and there’s an objective ground truth to whether you get the answers right or wrong. In comparison, there’s no test like that for mood because there's no right answer on a mood test—no one knows how happy you are but you. That’s what makes studying mood difficult.
While mood is more challenging, my approach to it will be informed by my approach to memory. There’s no question that our understanding of how the brain gives rise to memory is more advanced than our understanding of how the brain gives rise to mood. I hope to take some of those insights about how we got there as a community, combined with insights from writing ‘Elusive Cures,’ and apply them to emotion research.
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