While a flexible body may be helpful for physical health, a flexible brain — or the ability to break out of cycles of negative thoughts, behaviors and actions — is key to mental health.
A new study conducted by a team of researchers from the University of Minnesota Medical School’s Department of Psychiatry and Behavioral Sciences and published in the journal “Science Translational Medicine” has found that deep brain stimulation (DBS), a surgical procedure that uses electrical impulses to treat neurological disorders, can enhance psychological flexibility in people with depression, anxiety or obsessive-compulsive disorder (OCD). This enhanced mental flexibility was shown to help people move away from behavioral cycles that have left them feeling “stuck” in their mental illnesses.
Frustrated by relatively slow progress in the development of new psychiatric treatments for mental illness, the University of Minnesota team decided to take a new approach to their research. Instead of beginning development of this treatment in the traditional way — through animal trials — they instead started by treating human subjects with depression, OCD and anxiety with DBS and then interviewing them about the treatment’s impact on their symptoms.
After study subjects reported that DBS treatment helped them break free of the limiting cycles of their mental illnesses, researchers launched a clinical trial in rodents in which rats who had learned to complete a task for a reward in a specific way were given DBS-like stimulation and then required to find a different way to complete that task. The research team found they were able to replicate the human results in rodents, that the rats that had been treated with DBS showed mental flexibility and an ability to adapt to new behavioral requirements.
Recently, I spoke with Alik Widge, associate professor of psychiatry and behavioral sciences and one of the study’s lead authors. He told me that his team’s results — aided by the innovative way it conducted its research — demonstrate DBS’ great potential as a treatment for significant mental illness. “This could help change the way we treat mental illness,” he said. But, he added, mainstream use of the practice is still far off on the horizon. “The field is still grinding through and will be for some time to figure out how to make this work.”
This interview has been edited for length and clarity.
MinnPost: I’m intrigued that you started this research with humans and then replicated your results in rodents. Isn’t that the reverse of the usual order?
Alik Widge: My lab does human and rodent research. We do this with the idea that we have these treatments that have very complex brain effects, but we don’t know exactly how they work and it is very difficult to study those mechanisms in humans. That’s true, whether it is drugs, brain stimulation, any of it, because the tools we have to measure humans in terms of behavior and brain activity are not what we can do in animal models. You can make an animal do something over and over and over again. But you can’t do that with a human because they will get bored and walk away. Humans also have a negative reaction when you ask, “How will you feel if we put a bunch of wires in your brain?” whereas animals don’t get to say that.
MP: So animals aren’t as difficult to deal with as humans?
AW: If you want to study stroke, you can give an animal a stroke. If you want to study cancer, you can give an animal cancer. But that only goes so far. If you want to study anxiety, you can ask a rat, “How are you feeling?” They will answer, “Squeak.”
MP: That doesn’t sound very helpful.
AW: What we’ve been wrestling with for decades is, “How do we build an animal model that we can use in people to modulate the disease process?” Unless you have an animal model that lines up with what you’ve been doing in humans, that model is scientifically useless. It is very limited, unless you can prove your animal model lines up with something that happens in humans.
That’s what led to this study. Nearly 10 years ago now, I started thinking about the question of, “What if we flipped that script a little bit? What if we found a treatment that is replicable in people and build an animal model where that same intervention does the same thing? What if you find something that lines up and you could use it for a platform or a toehold to do really good science and modeling?”
This is where we centered on the model that we call “cognitive flexibility.” I found data that shows that when you do DBS in people, one of the things it does is improve their cognitive flexibility. It helps people shift away from the mindset that they are “stuck” in their mental illness into one that is more adaptive.
MP: How does making the brain of a person with, say, depression or OCD more flexible help them to recover from their mental illness?
AW: There is a whole pile of [mental health] disorders where people say, “I’m stuck. I don’t want to do this thing but I seem to always end up doing it in the moment.” What we discovered in the initial human papers is if you do DBS in the right way you can get people unstuck so they can break free from this cycle. It’s kind of like a circuit override.
MP: How did your patients describe the experience of being unstuck?
AW: I gave a dean’s lecture about a month ago that was meant to be accessible to the general public. It included a video where patients talk about their experience of having their cognitive function enhanced and becoming more flexible. They say things like, “Whatever was weighing me down just can’t get to me.” Another patient says, “Now, the OCD is behind the door. It is pounding on it and trying to get to me, but it is on the other side of the door.”
MP: With depression, for instance, is it the feeling of being stuck like when a person is so depressed they can’t get out of bed?
AW: In depression, the classic loop I describe is what Aaron Beck talked about when he was developing cognitive behavioral therapy: You wake up and you feel miserable. You have an option: You could do something. You could go to the coffee shop. You could apply for a job. You could message your friends. You know you could do something, but depression is a cancer waiting to perpetuate itself. It is a parasite.
Depression tells you that things aren’t going to turn out well, so why should you bother doing anything? You are stuck. You spend the day stuck in that loop, and then you look at the clock and say, “I had so many things I wanted to do today. I didn’t do them. I am a useless piece of humanity.” The next day, you wake up feeling much worse. That cycle is one of the classic perpetuators of depression and anxiety.
MP: And the circuit override caused by DBS can help patients step out of that cyle?
AW: The idea is that if you can just do something a little bit outside of that pattern, if you can get just a little bit outside of the path, even if you fill out the job application and don’t hit submit, maybe tomorrow you will hit submit. You’ll never get there until you start. The classic proverb is, “The journey of a thousand miles begins with one step.” All you have to do is take one step. If you take one step, you start tomorrow one step closer to your goal.
With DBS, we can make it easier to take one small step. That was something we saw in people. The question then was, “Could we do it in an animal model?”
MP: Do rats change their behavior patterns after they experience DBS-like treatment?
AW: Yes. Rats in our study learn to adapt to the demands. If we change the demands that are on them, they adapt their behavior. We’ve been able to show that DBS makes humans’ brains more adaptable. We were able to show that we could use similar technology to make rats adapt in the same way.
After doing about a year and a half of math, we were able to say, “These are the computation processes that happen when a rat gets better at doing this task.” The cool thing is, we said, “OK. What if we went back to our old human data and ask, ‘Does that model accurately fit and predict what happens in humans?’” The answer is yes.
We have evidence of human cognitive enhancement. We managed to make the same cognitive enhancement happen in rats. In the rats, we identified a mechanism. Then we went back to the human data and showed that the rat data explained what happens in humans. It is a truly translational model. It goes back and forth between humans and animals.
MP: Is this “humans-first” approach part of what makes your study stand out?
AW: Doing this type of reverse translational human-to-animal approach to build a model is really rare. I don’t think it’s ever been done before. That’s why I think it’s so powerful because now something lines up. Now we have a platform for therapeutics discovery because we understand what we need to do to the brain. This is why that paper ended up in a big, fancy journal.
MP: Do you think this approach will catch on? How do you think a reliance on animal trials limits advancement in psychiatric treatment?
AW: Many of us in the field, we believe that’s one of the biggest problems in psychiatry. So many drugs look promising in animal studies. They succeed in phase one and phase two studies, then fail in phase three studies. Psychiatry is a valley of death for drug development. Developing new drugs has been hard because scientists start with the animals, do some stuff, see value, then advance the work to humans and see it is not a reliable indicator of effectiveness in humans.
This is a new approach. It was first talked about 10 years ago as a means of study. It is one thing to say theoretically, “We should start with the human brain and then build animal models.” It is another thing to actually say, “This is how we are going to do this.” Clearly, there are still a lot of details that need to be worked out.
MP: Is one of the goals of this approach to research being able to develop treatments that target areas of the brain to treat specific mental illnesses? Right now, the psychiatric treatments available don’t seem to have that kind of specificity.
AW: In cancer treatment, there are more options. Doctors can genotype your tumor to identify if it is sensitive to one of these new categories of drugs. Then they will target your treatment to that type of tumor, and you will have way less nausea, less hair falling out. If you are unlucky, you might have a mutation of a tumor that doesn’t respond to these new drugs, and doctors are still going to have to carpet bomb you with chemo — but that’s where all the new cancer drugs are heading.
The approach we used in this study is a gateway to being able to do similar things in psychiatry, to be able to say, “I know exactly what I need to do to change your brain to make you healthier. I’m going to adjust your treatments until I see that I have caused that change.”
If you go to a doctor right now and say, “I’ve got depression,” they will say, “Why don’t you try this drug? I’ve tried this with a lot of my patients. It works pretty often.” If a patient asks, “How does this SSRI treat my depression?” a doctor might say, “We don’t really know.” With DBS, I can say to a patient, “Because you told me that a lot of your problem is you are getting stuck in this negative pattern, I know a way to get you unstuck.”
MP: If this research continues, it feels like you’re one step closer to one day being able to say, “I’ve taken a scan of your brain. Here is your depression. This is the way I will treat it.” That makes mental illness somehow seem more identifiable and understandable to others. What’s next?
AW: A colleague at Stanford has developed a brain scan that can tell if someone has a deficit in cognitive systems that she can treat. We are working together to pair these things with my research. We want to do a trial of my brain stimulation for people who are positive for her biomarker.
It is a big, bold claim. We haven’t been able to get the money for this trial yet. If we do get the money, we will eventually have the ability to say, “I brain-scanned you. You have this problem. I know the specific treatment for this problem. I’m going to give it to you, just like I would if you had cancer.”
Andy Steiner
Andy Steiner is a Twin Cities-based writer and editor. Before becoming a full-time freelancer, she worked as senior editor at Utne Reader and editor of the Minnesota Women’s Press. Email her at asteiner@minnpost.com.
