A Full Slate of Migraine Research: An Interview with Tally Largent-Milnes

“The big thing is that this isn’t just about the science for me – this is about patients and quality of life. There are always interesting questions that can be asked on the basic science front, but it’s really important to me that we’re doing something that has the potential to make a difference, whether that’s a new drug or a better understanding of what you’re experiencing, and creating an environment where you feel like you can talk about it.” – Tally Largent-Milnes

Dr. Tally Largent-Milnes, PhD, is an associate professor at the University of Arizona in Tucson, US, where she is also the director of graduate studies in the Medical Pharmacology graduate program. A behavioral neuropharmacologist by training, Dr. Largent-Milnes has a broad range of interests in migraine and headache research, using behavioral and molecular approaches in animal and human studies. In this Migraine Science Collaborative interview, she speaks with Neil Andrews, a science journalist and the executive editor of MSC, to discuss how she got into the headache field, ongoing projects in her lab, the role of cortical spreading depression in migraine, and much more. The interview has been edited for clarity and length.

What was your path to headache research?

I trained in neuropathic pain, and that is where I first started my PhD projects. During my postdoc, I moved from spinal and sciatic-type pain into corneal and dental pain, looking at the trigeminal circuitry in the brainstem. My first foray in headache research was to look at the blood-brain barrier in the context of migraine. Since I had worked on that and had a background in basic trigeminal physiology, when I started my lab I said, “Let’s do that.” Also, I have migraine myself, and many in my family also have migraine, so that clearly is a motivator for me to study it as well.

Can you tell me a little bit about your lab? What are the questions you’re most interested in? How are you addressing those questions in terms of the types of studies you’re doing and the methods that you’re using?

The overall approach of the lab is that if we can understand normal physiology, then that gives us the foundation to understand what’s happening with pathophysiology. We use migraine and medication overuse models to answer the big question: What is migraine, and what puts people at risk for developing it? And if we can understand all of that, can we then develop a therapeutic that targets migraine across the lifespan and as disease progression occurs?

There are several ways that we’re approaching this. Our primary outcome measure is behavioral – I’m a behavioral neuropharmacologist by training; pharmacology is my passion, and neuroscience is the path. The behavioral work encompasses traditional pain outcome behaviors like periorbital allodynia. In one of our earlier studies, we identified a different behavior called head tucking, which is akin to pressing your head when you have a headache.

We also use molecular approaches. One of the more nuanced things that we do is look at the total proteome [the full set of proteins expressed in particular tissues or cells], as well as the phosphoproteome [the collection of proteins that contain a phosphate group]. We want to understand what those look like in different brain regions over time, between the sexes and across models, to find if there are aspects that are unique to each type of headache. With animal models, we’re looking at headache-like behaviors, because migraine is very nuanced, but are there symptoms that can be correlated more with human migraine compared to other headache types, particularly in the context of the timing of headache?

Tally Largent-Milnes

What are some other projects you are working on?

We have taken serum samples from migraine patients versus healthy controls and measured their total proteome and their phosphoproteome. In this small pilot cohort, we were able to identify unique protein signatures, in both the total proteome and phosphoproteome, for episodic or chronic migraine and for migraine with aura versus migraine without aura.

We’re also part of a National Eye Institute consortium that is focused on the anterior eye and the cornea, and what the corneal nerve fibers are doing. Dry eye can elicit headache, and headache can elicit eye pain – where are those overlaps coming from? A lot of the people in this consortium also do migraine work.

One of your interests is cortical spreading depression (CSD). What is the current state of knowledge about CSD as it relates to migraine? Are there still fundamental discoveries to be made?

There’s a huge amount to learn. There are not a lot of groups who are still working on CSD, and those who are work in TBI [traumatic brain injury] research. We have focused a lot on the general characteristics of a CSD, when it is happening and how it happens relative to the pain. There are people who induce single CSDs; a lot of the time in my lab we’re doing that in awake, freely moving animals so that we can observe the behavior. Some people do CSD recordings [in animals] under anesthesia, and other groups will do continuous CSD induction.

So there’s a lot of disjointedness in the field, which makes it difficult to make concrete conclusions aside from knowing that CSD happens, and that it happens a lot in some patients. For example, everybody has CSDs, but in some patients they cause symptoms, and in others they don’t. So I think that there are still discoveries to be made.

Some of my colleagues here would argue that you need 30 cells that are disrupted to cause symptoms. The analogy that we have come up with together is very colloquial: It’s a needle in a haystack, so you’re looking for something hard to find, but one bad apple ruins the bunch; you don’t need many cells to have a problem. That’s going to be the direction that I see the field going for people who want to come back into this realm.

Also, it’s really important to be careful about terminology. My students struggle with the concept that a CSD is not a headache, but CSD can elicit headache-like behaviors. And so it’s about distinguishing the two phenomenologies from each other.

There was a recent MRI study that raised the question of whether CSD causes headache or instead is just a symptom or epiphenomenon [see MSC related news story]. What are your thoughts about that?

I don’t think CSD is causing headache. I do think that it’s a co-occurring phenomenology, and CSD can prime the system to be ready to go, whatever the headache inducer is. When you look at those MRIs – and I’ve looked, and I’ve looked at other data from patients as well as animal models – you definitely see changes in blood flow in a distinct pattern cortically. But I don’t think that it’s sufficient to solely have the cortical activation to generate the collective symptoms for what we call migraine.

You’ve discovered some sex differences in CSD, and you had a recent paper showing sex differences in terms of photophobic behaviors after CSD in rats. Do you think one of the reasons the prevalence of migraine is higher in women compared to men might be because of sex differences in the response to CSD?

The easy answer to that question is yes. The more complex answer is that it’s related to hormone levels; for sex differences in the context of CSD, there is definitely a hormonal component, and I think it has more to do with locally synthesized hormone levels in the brain and their actions within the CNS.

You have identified some of the molecular players involved with CSD, including NHE1, a pH regulator, and endocannabinoids. Can you tell me about some of these players?

NHE1 is a sodium-proton exchanger, and its job is to maintain brain pH. We know that in most injured states, pH changes. I don’t think it’s inciting CSD, but I think it’s a marker of where damage has occurred. So pH definitely plays a role, and I think that it can be taken advantage of pharmacologically.

The endocannabinoid system is my true love. Because so many of the comorbidities of migraine are regulated by the endocannabinoid system, it made sense for me to be working there. I initially got into this area in collaboration with my department chair in the context of cancer bone pain. Later, in my lab, we moved into the endocannabinoid system as it relates to headache and co-occurring phenomena and it just made sense to ask what was happening in the brain.

We looked at a lot of different regions, including the visual cortex, where CSDs typically start. We consistently saw changes in endocannabinoids in both the cortex and the periaqueductal gray [PAG], which is a subcortical region within the pain descending modulatory network; I’ve had a side love of the PAG for a long time, so it was always on the back burner and we were able to move into that. Using multiple models, we have consistently found that endocannabinoid lipid tone for 2-AG [2-Arachidonoylglycerol] is decreased in the PAG across models, including in CSD, and there are changes in anandamide [another endocannabinoid] in the cortex. This really suggests that there’s some type of change in the cortical-to-PAG circuit during CSD.

In the context of the literature, in a number of models, when you look at MRIs, only one subcortical region shows changes in blood flow after CSD is induced, and that’s the PAG, and the blood flow is changed bilaterally. So I felt confident that what we were seeing was real.

Then we started thinking about different strategies that could be employed to manipulate and target the endocannabinoid system, and that really came back to regulation of endocannabinoid synthesis and degradation. It made sense because migraine is associated with elevated inflammation, especially during the ictal phase, and many of the comorbidities are characterized by high inflammation. So we thought that if we could target this loss of endocannabinoid tone by blocking the degradation of 2-AG, we could also mitigate neuroinflammation that may be happening during migraine.

Looking ahead, what are the most pressing questions that you’d love to know the answer to, and can you tell me about any ongoing studies that you’re doing to address those questions?

One of the pressing questions is what the common threads are between different types of medication overuse headache. There’s really no treatment for it, aside from drug cessation or rotation, and rotation often is within a drug class. We’ve expanded beyond headache abortives, like the triptans, to other drugs that cause headache. We’ve looked at formoterol [a β₂-adrenergic receptor agonist], and we’re going to be looking at some environmental toxins to see what they do alone and in combination with other drugs.

In terms of photophobia, we’re still trying to figure out what cells are involved. There’s been a lot of focus on trigeminal ganglion cells and neurons in the visual circuits, but the corneal afferents have been overlooked. With these tissue-selective afferents, I think the other components of the eye may be involved – not necessarily the retina, but perhaps changes in the iris or in the control of the facial nerve and lid closure. There seems to be some clear communication between structures of the eye and pain-sensing neurons, and so we’re trying to understand that, and we’re working on a paper now.

For other work we’re doing in the photophobia space, there’s some clinical evidence that the gepants will work for photophobia, so we’re asking if we can see that in animal models. We had a poster at [the 2024] Society for Neuroscience meeting, and we didn’t see any effects of the gepants on photophobic behaviors associated with CSD induction in a rat model of migraine with aura.

We’re also looking at the role of hormones in migraine – what is it about hormones, and the hormonal milieu over time, that increases risk? We are doing [other] work on environmental toxins, as I think it’s important to look at how headache and migraine prevalence have increased over time, and so we’re looking at the environmental factors that are playing a role in susceptibility. And we’re continuing our work on the endocannabinoid system.

Most of my work is driven by my students’ interest, so I’m kind of all over the place because my students are kind of all over the place! That’s what makes the research fun and cutting edge.

It’s a full slate!

It is a very full slate, and I get to learn a lot.

Is there anything else you would like readers of Migraine Science Collaborative to know about your research, or is there anything I didn’t ask you that you’d like them to know?

The big thing is that this isn’t just about the science for me – this is about patients and quality of life. There are always interesting questions that can be asked on the basic science front, but it’s really important to me that we’re doing something that has the potential to make a difference, whether that’s a new drug or a better understanding of what you’re experiencing, and creating an environment where you feel like you can talk about it.

The last thing I’ll say – and this is not yet related to migraine but it will be – is about the idea that neurological diseases are invisible, and by the time they’re visible on an image, it’s too late. And so I have a totally different project that is using EEGs, but it’s using EEGs from people with Alzheimer’s since those are the data that are available. We’ve actually turned the EEGs into a musical composition so that you can hear what a brain sounds like in a healthy control versus an Alzheimer’s patient in a proof-of-concept installation with the School of Music. Our goal, ultimately, is to take that to other disease states and across the country to give a voice to these patients, diseases, and research.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

Image credit: liudmilachernetska/123RF Stock Photo.