Welcome to the Electome: An Interview with Rainbo Hultman

By Lincoln Tracy | March 7, 2024 | Posted in

“A fundamental goal [of my research] is to understand what is different in people who are more susceptible to either a depressive or migraine phenotype across brain networks, neural circuits, cells, and molecules, and what makes someone else resilient. I’m also interested in whether there are any differences in the brain prior to experiencing the stressor, and if these differences can predict the outcome. And we are finding some interesting predictors of outcomes, especially with electrical brain networks.” – Rainbo Hultman

Rainbo Hultman, PhD, is an assistant professor at the Iowa Neuroscience Institute in the Carver College of Medicine, University of Iowa, Iowa City, US. Her research focuses on promoting the development of precision medicine for brain disorders such as migraine and major depressive disorder by identifying therapeutic targets that promote healthy electrical network activity in the brain.

In this Migraine Science Collaborative interview, she chats with Lincoln Tracy, PhD, a researcher and writer from Melbourne, Australia, to discuss what inspired her to become a neuroscientist, her research on depression and migraine, and much more. The interview has been edited for clarity and length.

What was your path to becoming a neuroscientist?

I came across an old journal recently from when I was in second or third grade, and it made me realize my dream of becoming a scientist started a lot earlier than I had previously thought. My grandfather had Parkinson’s disease, and seeing that started to make me ask questions like, How does the brain work? How does perception work? What’s happening in someone’s head or brain when things aren’t what they seem?

As I got through high school and early college, I became fascinated with chemistry and physics – the physical forces that drive biology. I felt I had to understand these fundamental forces underlying biology before I could really understand the brain and move forward. I started with the very microscale of biophysics and expanded gradually throughout each stage of my career, majoring in biochemistry at the University of Iowa and studying the thermodynamics of protein function during undergrad and early grad school, and then molecular neuroscience during my PhD. Then, when I did my postdoc, I started uniting these concepts I had thought about way back in elementary school and connecting how the neurons I studied in grad school connect to one another across the brain to form networks, and how these brain-wide networks can manifest in behavior.

Rainbo Hultman

Rainbo Hultman

And is that what sparked your interest in exploring the relationship between the electrical activity of the brain and behavior?

Yes. I’m always thinking about behavior and brain disease across multiple levels at any given time. I’m thinking about the manifestation of electrical networks across the brain, or what we call electome factors, but am also aware these networks are driven by very precise physical connections between specific cell types in each of the different brain regions. This is happening because the underlying genes are being expressed in different ways in response to environmental cues. It all comes together in this big picture of multiple things happening across different levels.

What are the main aims of your research?

Understanding how stressors impact the brain across each of these levels is a huge part of what I do, as stress is a major component in the onset and exacerbation of brain disorders such as depression and migraine. We know somewhat more about the mechanisms by which stressors impact the brain in depression than we do in the migraine world, but I think we’re getting closer to understanding this concept of resilience and susceptibility to various kinds of stress in the context of migraine. People can go through the same experience and have very different responses to it.

A fundamental goal is to understand what is different in people who are more susceptible to either a depressive or migraine phenotype across brain networks, neural circuits, cells, and molecules, and what makes someone else resilient. I’m also interested in whether there are any differences in the brain prior to experiencing the stressor, and if these differences can predict the outcome. And we are finding some interesting predictors of outcomes, especially with electrical brain networks.

Are there a lot of similarities between the underlying mechanisms of depression and migraine?

Stress seems to play an important role in both disorders, but there are some other interesting intersections. The Brainstorm Consortium published a nice article several years back showing that migraine is the only neurological disorder sharing genetic heritability with psychiatric disorders, and major depressive disorder is the most significant one it intersects with. And we know a lot about the neuromodulatory circuitry involved in both disorders; serotonin, dopamine, and norepinephrine pathways seem to be involved in both migraine and depression.

But there’s a lot we don’t know, and I obviously wouldn’t be in business if we completely understood the etiology of either disorder. What fascinates me are the studies in both migraine and depression showing that multiple brain regions are involved, and that the communication between different brain regions is very important in both disorders. Going after brain networks is so important because there is evidence suggesting this will help identify differences in individual susceptibility to disease. Ideally, we could get to a place where we can do some brain scans to identify which therapeutic is the best target for you as an individual and eliminate the whole process of guessing what will work for one person versus what will work for another.

You presented research at last year’s American Headache Society Annual Scientific Meeting that involved a calcitonin gene-related peptide (CGRP) mouse model of migraine. What were some of the key learnings from this work?

We started using these models to understand the electrical brain networks across multiple brain regions involved in migraine and emotional or affective disorders. We took in vivo neurophysiology recordings from a wide range of brain regions – more than most people would bother with – and we’ve begun to find networks that are predictive of whether or not an animal is in a CGRP-induced migraine-like state based on the connectivity between these networks. We’ve identified one network connecting the thalamus with the parabrachial nuclei, and then another that seems to be more amygdala driven. We are now starting to look at migraine-like and depression-like activity in the same networks of the same animals at the same time.

You’ve received several awards in recent years, including the McKnight Neurobiology of Brain Disorders Award, as well as the NIH Director’s New Innovator Award. What does winning awards such as these mean to you and for your career?

I’m certainly very honored that people can see the benefit of the work I do. I took off in a different direction pursuing the migraine work when I started my lab back in 2019; I had previously studied stress, affect, and emotion, so it was a risk to take the work in a different direction. But I thought the field was ripe for this, and that we could really make a big difference in the world of migraine research. The biggest thing about receiving those awards was knowing there are other people out there who are with me, see the vision, and who see the hope that this could be game-changing work.

It’s also exciting. When I first started the lab, it was very hard to get students enthused about the migraine work; everyone still wanted to do the depression work. Now we’re at the stage where new students who come into the lab just want to work on migraine. It’s very exciting to see the work become established enough to get other people excited about it and wanting to put their time and energy into it as well.

What are some newer projects you and your team are currently working on?

We’ve previously looked at differences in resilient and susceptible brain activity, and used a machine learning model to identify six different networks that could distinguish some aspects of stress, even if they only made a small contribution. Now we’re starting to explore different kinds of environmental stressors. For example, when a mouse is rearing pups and you remove some of the environmental enrichment, how does it impact these networks?

We have animals that have received or not received this kind of stress in the early postpartum stages as a way of looking at postpartum depression, which seems to be a very different condition than major depressive disorder. We’re starting to investigate whether these electrical brain networks are related to stress in some way to see if they can predict postpartum depression.

We’re also looking at the sensory component of migraine, and the sensory component of depression and other psychiatric disorders, with respect to how manipulating different sensory inputs changes and rewires the brain. We’re collaborating with Ishmail Abdus-Saboor, a researcher at Columbia University, to see how animals that lose their ability to detect sensitive, social touch have different levels of resiliency to stress. You can see there is some rewiring of these brain networks, showing us there is a definite yet complex link between sensory perception and stress resilience.

Something that has been pointed out in medical and scientific research is that mice aren’t just fuzzy little humans. How do you think about this issue, in terms of how the animal work relates to what we see in people?

I think there are lessons we can learn about this from both the migraine and depression worlds. Mice are not little humans, and we’ve certainly had deficits in both fields from thinking of them as little people. It’s important not to look at the work we do as “Step 1 – mice, step 2 – humans,” but instead be constantly taking observations from humans and doing our best to model some aspect of what we see in humans in mice, and then take that information back to people, in a cyclical effort.

One exciting thing from our depression work was that, when we looked at what neuroscientists were doing with fMRI and deep brain stimulation in people, we saw that the electrical networks we were finding in mice mapped up with what people were finding in humans.

But, on the other hand, certain behavioral models used to study depression or identify new treatments have mostly found serotonin targets. This might mean that we’re not actually looking at depression in mice by looking at these behaviors, but rather we’re looking at serotonergic neural circuits. And while those circuits are involved in depression in humans, it doesn’t give us a lot of new targets to build on, as there is much more to depression than serotonin. I think that’s a cautionary tale for the migraine world to think about – we need to go deeper and think critically about whether we’re evaluating the same things in mice and humans if we want to inform the development of better therapeutics.

What’s something in your area of research we don’t currently know or understand but that you hope we will have an answer to, in five or 10 years?

I hope we can start to integrate a person’s genes, environment, habits, and diet to come to understand what they need, in an efficient way. And it might not just be giving them one drug for the rest of their lives; it might be a process. For example, you might need a month of a drug, and then six months of a certain diet and exercise regimen.

If you think about migraine, one of the best preventative tools is exercise, but exercise is also a common trigger for migraine. But perhaps there’s a way – a medication or a diet – that can get a person to a place where exercise is beneficial rather than harmful. A similar thing happens when I think about medication-overuse headache and migraine. Patients constantly have to think about when they took their last medication, and whether taking another one will put them in a worse position than where they are currently.

But the reality is that what works for one person doesn’t necessarily work for another person. So we can make recommendations to patients, like you can only take this medication so many times a month, and then hope it will work, but we really don’t know. I think having more precise guidelines on an individual basis would go a long way to helping patients.

If you could have a dinner party with anyone from history, dead or alive, who would you want to invite and why?

On a personal level, I would do anything to have one more dinner with my Granny. She was a very special inspiration to me – a family member with no blood relation – who really helped raise me. She was one of the most creative, kind, and amazing people I will probably ever meet.

On a more scientific level, I felt very understood when I read Walter Isaacson’s biography of Einstein. I related to so much of how Einstein thought. People think things like “scientists are so smart; you must think extremely quickly.” But I actually think really slowly and meticulously. When I heard he was also a unique thinker on this level – he attributed his slow, careful thinking of his visualized thought experiments as leading to some of his most important discoveries – that was a massive revelation for me. I really related to that.

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on X (formerly Twitter) @lincolntracy

Image credit: 123RF Stock Photo.

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Dr. Lincoln Tracy is a researcher and freelance writer from Melbourne, Australia. As a researcher, he uses data from an international clinical quality registry to explore burn injuries in Australia and New Zealand. As a freelance writer, he turns basic, translational, and clinical research into high-quality news, features, interviews, meeting reports, and podcasts. As a person, he is one half of one of two sets of twins in his family. Follow him on Twitter @lincolntracy.

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