Why are brain disorders so mind-boggling? When we know so much about what a healthy brain looks like, why do we still not have cures for neurodegenerative diseases such as Parkinson’s and Alzheimer’s? Why do current drugs for anxiety, depression and psychosis not work for a third of people? Why can’t we fix some brains to make them work like healthy ones, in the same way other drugs and treatments can cure physical disease?
Neuroscientist Nicole Rust, a professor of psychology at the University of Pennsylvania, is hooked on understanding how a healthy brain works to guide clinicians in seeking cures and treatments for brain disorders. She uses the analogy of a car: you can only understand how to fix a car if you know how a car works.
That sounds good in theory. But on a video call with the Listener, Rust talks about how she became frustrated that decades of brain research have not translated into new treatments and cures, while neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease continue to baffle neuroscientists.
In her new book Elusive Cures, Rust considers the mysteries that continue to elude scientists concerning brain diseases. The book is a personal journey to understand the community she is working within, and why we’re little closer to understanding or solving Alzheimer’s disease, for example, than we were several decades ago.
Dominoes discredited
Her theory for this puzzling lack of progress in brain drugs and treatments is that neuroscientists and brain researchers have focused too much on a chain reaction of cause and effect: for instance, that lack of activity in the prefrontal cortex is linked to depression and mood disorders, or amyloid build-up in the brain causes Alzheimer’s disease.
With this approach, the idea is that you “find the broken domino and fix it’’, or “find a brain area with aberrant brain activity and stimulate it’’.
Rust argues the brain is like a complex, chaotic weather system, with many influences. Treating a brain disorder should therefore be like “redirecting a hurricane rather than fixing a domino chain of cause and effect’’.
This kind of thinking isn’t entirely new in scientific circles, but Rust sees it as the central lens through which to view brain disorders and dysfunction.
“The most significant thing holding back new treatments is that, for the most part, we have not yet learnt the right things about the brain, and so we still don’t know what causes brain dysfunction.’’
She notes new drugs introduced to treat brain disorders are not as novel as drug companies would like us to imagine, and are often reworked old ones. “I also assumed that new drugs followed from novel discoveries about the brain more than they do,’’ she writes.
Environmental impact
Rust’s book explains that until the 1990s, molecular neuroscience guided brain research and treatments: everything going wrong in the brain could be pinpointed to genes, proteins, neurons and other molecules.
But the molecular neuroscience approach was too simplistic, she says. To understand what is happening in the brain, we also need to know what is going on in the mind, especially with mental health disorders, and how a person lives: their social, environmental and economic conditions.
She points to brain disorders that continue to puzzle doctors and neuroscientists: Alzheimer’s, Huntington’s, Parkinson’s, multiple sclerosis, epilepsy, depression, schizophrenia and many more. The first three are diseases “where we know the brain has degenerated but we’re not sure what has caused that. Though we have ways of mitigating the effects of these disorders, we cannot cure any of them.’’
Then there are mental health conditions and neurodevelopmental disorders such as intellectual disabilities and some forms of autism. “These are the classes of disorders we’ve really had a hard time understanding, and for some of them really developing effective treatments.”
Her book traces the history of Alzheimer’s, which for decades was thought to be caused by viruses or environmental toxins. British woman Carol Jennings changed the course of study in the mid-1980s when she asked Alzheimer’s researchers why her father and his siblings had been diagnosed in their 40s and 50s. The scientists switched to thinking a gene mutation causes amyloid clumps to form in the brain and lead to neurodegeneration.
“The amyloid hypothesis fits within this framework, with its emphasis on a domino-chain cascade of events that begins with a mutated gene that produces a protein (amyloid) and ends in cognitive impairment,” says Rust.
Dementia affects about 1 in 20 New Zealanders aged over-65 and one in five over the age of 80. But after 30 years of looking at genes – the APOE4 gene variant is one that’s implicated in Alzheimer’s – neuroscientists and drug companies are no closer to finding a drug that can cure the disease or slow it down.
Rust says amyloid-clearing drugs – aducanumab and lecanemab, introduced in the US in 2021 and 2023 – aren’t the answer, as they clear amyloid from the brain but delay the disease only by an average eight or nine months.
“It’s not stopping the disease in its tracks, which is what we really want for Alzheimer’s. So now, everyone is asking the question: why not? What’s gone on? What kind of thing might Alzheimer’s be? And I don’t think this has a simple answer, but one possibility is that in families like Carol Jennings’, amyloid triggers something to happen. Then, once that starts to happen, you can’t just stop it by clearing amyloid from the brain.’’
Brain disorders cost a staggering $1.5 trillion, or 9% of GDP, in the US, according to a 2016 study.
Rust writes many treatments were developed when we didn’t understand the brain the way we do now. Some drugs were discovered by accident: the first anti-anxiety drug, iproniazid, was stumbled upon in 1951 during trials for a tuberculosis drug. Methylphenidate (Ritalin) to treat ADHD was created in 1944 as a “try it and see” drug.
“[Many] of the drugs we have today are actually not new drugs, but rather refinements of old drugs created before 1960. And, while we now better understand how the old (and new) drugs work, many of the newer drugs operate in the same ways as the original ones,” she writes.
Worldwide, 970 million people are living with a mental disorder such as depression, anxiety or psychosis, but medications don’t work for many of them. In New Zealand, antidepressants are still the standard treatment for mood disorders – nearly 12% of New Zealanders, 632,346 patients, were prescribed antidepressants last year, according to Pharmac.
Rust writes: “Like many brain drugs, we know antidepressants work but not how. The most obvious route toward understanding them better begins with understanding how the disorders that these therapies are used to treat – depression and psychosis – manifest in the brain.’’
She tells the Listener, “We are with depression where we were with understanding weather in the 17th century.” But better understanding of the weather brought an acceptance that it was all but uncontrollable.
Mood swings
Rust has recently switched her university research from studying memories and how these are formed in the brain to mood – what’s happening in the brain which puts us in a good or bad mood. It’s an example of her challenging process: refusing to provide falsely optimistic hope in the form of unrealistic claims, while at the same time insisting that clarity around what is really going on in the brain will be the first step on the path to solving the big problems.
She doesn’t have all the answers, but she thinks she might finally have figured out the right questions. She describes psychiatric disorders as the most complex and mysterious in medicine – there is no biological test for them.
She’s not a fan of medicalising all mental illness and mood disorders and thinks cognitive behavioural therapy and mindfulness can be as effective as drugs or an important counterpart to drug treatment.
We are with depression where we were with understanding weather in the 17th century.
She says our moods are “a running average of recent events. And those events can be real or imagined. If you just keep ruminating on something bad that happens, that can affect your mood. I’m saying things that probably everyone knows, but this leads to a whole suite of behavioural strategies.”
On that note, another puzzle she wants to understand is this: “What are the protective mechanisms which switch on when someone has a chain of events that puts them in a bad mood? Our moods depend on the average of things that have happened to us, but our perception of the things that have happened to us depends on our moods. One of the big questions we’re trying to understand is how is this system possibly set up so it doesn’t spiral out of control? It’s one of the big loops.’’
As she said on science podcast The Transmitter: “There might be some cases where we also just throw up our hands and say this might be uncontrollable in a brain-based therapeutic way. That’s where the mood disorders come in in certain cases. It might be that some classes of depression are just a brain that has become entrenched in a maladaptive state because it’s just learnt its way in there. The only therapy to fix this is a benevolent reprogramming of the brain.”
One possibility: “Psychedelic therapies are starting to gain some traction. The idea behind those is you just want to trigger plasticity in the brain and you want to combine that with talk therapy … so it can wiggle itself back to health. It really informs how we should be going about it, if true.”
If that sounds mildly concerning, she added: “We only want to do something as dramatic as is required.” After all, “Talk therapies, where a patient is reliving their trauma, that can just reinforce the trauma and actually make it worse, not better. It’s really important that we proceed cautiously and ethically.”
AI, inevitably
Her book would make depressing reading if it wasn’t for the glimmer of hope at the end. Artificial intelligence and biotechnology should – if all goes to plan – allow us to develop models to get a better glimpse of what is happening in the brain – genes, brain activity and lived experience – when it becomes diseased or disordered.
As Rust says, “I could have written a book about neuro AI. It’s just exploding, It’s hard to keep up. You don’t even want to write that book because it’s going to be out of date in two months.”
But beyond that, she argues we should nourish our brains to make them healthier in the same way we nourish our bodies. She’s an advocate of healthy living to reduce the risk of developing a neurodegenerative condition, and exercise is No 1.
Sleep allows our brains to repair, although, again, it’s not clear why. “We don’t really understand well what’s happening in the brain during sleep. What we do know is that brains that sleep a normal number of hours are healthier.’’
As she has written elsewhere: “There is a gap between what we’re learning and actual, impactful treatment. The most profound insight, I think, that follows from thinking about the brain in this new way is how hard the end goal of treatments really is.”
If Rust has one key message about treating brain disorders it could be summed up as “let’s get real”. As with our thinking about the weather, she believes we will “control” the brain when we shift to “thinking about it as a complex dynamical system … In a complex system, you’re not going to have a single cause.”
Elusive Cures: Why Neuroscience Hasn’t Solved Brain Disorders – and How We Can Change That, by Nicole Rust (Princeton University Press, $46.40)