Improving Imaging of the Spinal Cord with Molly Bright, DPhil

Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I am Erin Spain, host of the show. The spinal cord is a complex and fascinating part of the nervous system, but it is also very difficult to study using non-invasive imaging, especially when it comes to imaging blood flow and vascular function. Now, Northwestern Medicine investigators have developed a new functional MRI, or fMRI, based approach to more accurately assess blood flow in the spinal cord with potential to better inform treatment for neurological diseases and injuries. This discovery is detailed in a recent study published in Scientific Reports. We are joined today by its senior author, Molly Bright, to talk about the findings and how this approach may one day help clinicians detect early disease, monitor recovery, and guide treatment decisions in people with spinal cord injuries or diseases. Molly is an assistant professor in the Department of Physical Therapy and Human Movement Sciences at Feinberg and of Biomedical Engineering in the McCormick School of Engineering. Welcome to the show, Molly. 

Molly Bright, DPhil: Thanks for having me. 

Erin Spain, MS: Tell me a little bit about your lab here at Northwestern and what drew you to doing this kind of translational research that can impact human health? 

Molly Bright, DPhil: Sure. My background is in engineering and physics, and so most of my career before coming to Northwestern, I have developed methods, and I have enjoyed that greatly. But with the move to Northwestern, I found myself surrounded by people who had good uses for these new tools that we were coming up with. In particular, I found myself in the Department of Physical Therapy and Human Movement Sciences. And when you are studying movement, you really want to capture not just what the surface of the brain is doing, but actually how that information from the brain gets connected to the rest of the body. And to do that, you need slightly different imaging tools. And I thought that was a very exciting challenge on a worthy target—something to go after. 

Erin Spain, MS: I love that. Tell me a little more about your lab in general. What type of research is your team taking on? 

Molly Bright, DPhil: Yes. So we have several different strategies for making functional MRI, hopefully, a bit more useful. It is a very promising technique. It has a lot of potential because of what it is able to do compared to any other medical imaging technique. It can really see further into deeper structures; it can capture neural activity, vascular function. So there is a group of students in my lab, and they are all engineering students. Every single one of them is trying to figure out a new imaging method, and it is all within MRI or functional MRI. But they are all trying to push this method in a different way, and with that, they have a clinical target in mind. So some of my students are trying to really understand motor control. Some of my students are really trying to understand how we react to different breathing environments. Some of my students are trying to get very precise information in stroke subjects, and then some of my students are trying to understand the spinal cord. And each of these projects means you need to make the imaging a little bit different in order to be successful. 

Erin Spain, MS: And what about the tools at your disposal here at Northwestern, the technology that you have, how does that enable you to do this type of research? 

Molly Bright, DPhil: Yes, we have a fabulous imaging center here. It is the Center for Translational Imaging, and it is divided into more of the cardiac and body imaging and then the neuroimaging side. And as part of the neuroimaging CTI community, we have two top-end MRI scanners that are dedicated for research. So when I came to Northwestern, I started working very closely with the director of that center, Todd Parrish, and he had already been developing some of the spinal cord imaging methods. And I was able to really learn from him and build off of his expertise and kind of push those methods myself. So we have these great scanners and great people who are helping us make the most of them. In many ways, I am trying to use functional MRI to understand the brain’s plumbing—how that blood supply that is actually delivering the nutrients you need, removing the waste, how that vascular system is supporting the central nervous system. I think in many different pathologies, it is actually a vascular problem that causes many neural consequences, or it is circular. And so really being able to capture what both systems are doing is going to be important, and functional MRI is pretty great because it can really capture both sides of that coin. A lot of the research taking place in your lab is on healthy people, a lot of this fMRI research. Why are you looking specifically at healthy people, even though you are studying things like spinal cord injuries and stroke? I think our lab, with this most recent work, we are really the first people to see the things that we are seeing at all inside of people who are alive. And it is all very non-invasive, so we have not interrupted the healthy functioning of the spinal cord. So these measurements that we are making, we are learning quite a bit just about what happens in a healthy spine. How is the spinal cord supported by the vasculature? And that is something where we are learning a lot just by looking in healthy adults. 

Erin Spain, MS: I want to talk more about that because the spinal cord has been very difficult to image in the past compared to the brain. And as you said, you are charting unknown territory here. Tell me about that first. Why is the spinal cord so much more difficult to image than the brain? 

Molly Bright, DPhil: Yes, so the brain—it is not that big, but it is pretty big by our standards. It is about the size of a grapefruit, and our imaging resolution is, let's say, about 2 millimeters. And this grapefruit brain, it moves a little bit. But we are able to do a lot to correct for that, and we have gotten very good at it. And methods over the last 20 or 30 years have all focused on getting better and better at imaging the brain. As soon as you go a little bit down, as soon as you go into the brainstem or into the spinal cord, everything gets harder because, first of all, now we are talking about a very, very small anatomy, and our resolution is now just at the border of being sufficient. It is also surrounded by cerebral spinal fluid. So you have this liquid that is flowing and pulsing and creating a lot of artifacts in the data. The person you are imaging is breathing, and so you have movement of their chest that is creating a lot of artifacts in the data, and the lungs as they fill with air—that creates additional artifacts that make it look like the spinal cord is wiggling. If you have a living, breathing human being in the scanner, which hopefully you do, all of that is pretty disastrous for data quality. So you have to just, on many fronts, try to tackle each one of those problems in order to really see the cord and make sense of it. 

Erin Spain, MS: So in this recent paper in Scientific Reports, you introduce a new way to map spinal cord vascular reactivity using the fMRI. Take me back to the start of this study. What question were you trying to answer? 

Molly Bright, DPhil: I can take you back all the way to the start of my career. The very first measurement I ever made was vascular reactivity. It was in the brain. Functional MRI, I think, almost anybody who knows about it peripherally thinks of it as a tool to study neural activity. You see it in popular TV shows—you can make a map of where in the brain is active when people see these pictures or do this task. But functional MRI does not measure neural activity. It actually measures vascular changes. It measures changes in blood flow and blood oxygenation. So it is a vascular imaging method just being used as an indirect measure for brain activity. But in my doctorate, way back when, I started using it as a vascular tool and trying to understand how vessels can respond. You need your vessels to be able to dilate and increase blood flow at times in order to support the healthy function of the tissue. And so this measure of vascular reactivity—it has really taken off in the brain because it is a great way to say how healthy is the blood supply, how resilient is it? If the vessels cannot respond, maybe the tissue might be at risk. We have gotten this measurement pretty well sorted in the brain. It is starting to enter clinical practice a little bit. But in terms of being able to measure other parts of the body where it is equally important that you have that very responsive blood flow, that had not been done. So I found myself at Northwestern where spinal cord imaging was becoming possible. I had all of these techniques in my back pocket of how we can use functional MRI to capture these vascular changes. And then, with some very clever work from my graduate student, we put it together and just thought this is a very important unknown thing of how that blood supply is actually regulated. Because it is likely to go wrong in several different patient groups, and that would be a helpful measurement. 

Erin Spain, MS: You are talking about these kind of clever ways that you designed it. So in this study, instead of a more invasive approach, like injections or contrast dyes, your team used this breath holding task on the subjects to trigger blood vessel dilation. Tell me about this. What did you have these folks do when they were inside the scanner? 

Molly Bright, DPhil:  Everybody listening could practice. You breathe in, you breathe out at a nice paced rate, and then at some point you are asked to just hold your breath—about 15 to 18 seconds—and then breathe normally. And just that short of a breath hold increases how much carbon dioxide is in your blood, and that then causes vasodilation. Your blood vessels everywhere dilate, and that dilation—the increase in blood flow that it causes—that is what we can pick up with the functional MRI. 

Erin Spain, MS: Had this been used before in the literature? This technique? 

Molly Bright, DPhil: In the brain for sure. I think one or two other groups used it to try to validate other models. But we are the first to try to really map this and capitalize on it to get sort of a characterization of how the blood vessels in the spinal cord are responding. 

Erin Spain, MS: When you asked people to hold their breath, you expected to see blood flow increase across the spinal cord, but what you found was definitely more nuanced. 

Molly Bright, DPhil: Yes. And we did not know to look for this going in, so this is all post-hoc and very interesting. But we saw one thing we can measure is not just how much the blood vessels dilate, but also when they dilate. So we saw that part of the cord responded a bit sooner and part of the cord responded a bit later. And this sort of aligns with what we know from hand-drawn figures and old textbooks of the vascular supply that you have two different maybe arterial supply regions, these vascular territories, and that maybe these different regions respond at a different time, and our method is sensitive to that kind of difference. The idea would be not only can we say how healthy are these vessels, how much can they respond, but the different parts of your sort of vasculature, are they supporting the regions they should, or is something atypical happening in a given person? 

Erin Spain, MS: So why is this kind of information important or matter so much in spinal cord disease or injury? 

Molly Bright, DPhil: I think that probably this is going to be important in a few different fronts, some of which are maybe more feasible targets than others. The target that I am most interested in, the application that I am most interested in, is going to be people with non-traumatic spinal cord injury. These individuals, usually something age-related degeneration of their spinal discs. But something is causing compression of the spinal cord. And it is to the point where if you get an MRI scan and you are over age 50 or 60, many of us will have compression of our spinal cord. And many of us are fine, but some of us are not. Some of us start to have this progressive neurodegeneration that occurs because of that compression, and it can get worse over time and you can get a lot of symptoms, you can have weakness, and this is degenerative cervical myelopathy. What we know now is that the compression of the cord—this is what we know from animal models—compression of the cord is causing problems in the blood supply. The small vessels within the spinal cord are compromised, and over time that can lead to some neurodegeneration. So if we are able to capture whether or not the vascular supply in a compressed spinal cord is affected, we might be able to identify which patients are probably going to get this progressive condition, and who we might want to monitor and who we might want to treat sooner. 

Erin Spain, MS: Okay, because there are treatments available right now for this type of condition? 

Molly Bright, DPhil: Usually it is surgical, and it is usually not done until the symptoms are more severe, and it does not always reverse the symptoms, but it can stop the progression. So ideally, if we identify the higher risk patients sooner, then we could intervene sooner and just stop everything happening at an earlier time point. 

Erin Spain, MS: You were talking about the artifacts and the noise that kind of makes it difficult to interpret what is happening with some of these images. How were you able to solve for that in this study? 

Molly Bright, DPhil: This research, it really is not glamorous or fortuitous. You know, we did not stumble into a discovery. It really is just a lot of hard work and engineering and putting these pieces together in a slightly different way, trying another slightly different way, and it all builds. So I think my graduate student who did this project, I think she had nothing for a while, and then still nothing. And then by the end of her PhD, it just took off, because finally we had gotten the pieces in the right order. Some of the things we had to do involve how we acquire the data. The scanner needs to be very carefully set up to image the spinal cord. We try to avoid getting any artifacts from the things around it. There are tricks we can play. It requires a lot of extra data processing, so how do we record physiological signals about the cardiac pulsations, the breathing, and how can we model that and get rid of it? Because that is not what we are interested in. We are interested in that dilation effect. So there is a lot of post-processing and signal modeling that happens. And then ultimately what we also saw is that if you want to make a really nice picture in one person, you just need a lot of data. So we scanned some of these healthy individuals many times. We scan them for 2.5 hours, with breaks, of course. Lots of breaks, but that is a direction that the field is going in for research. It is precision imaging where you get a lot of data in one person. Now it is very successful; it helps us be really sensitive and really see an individual person’s anatomy and function, but it is obviously not ready for clinical primetime. You are not going to scan a patient for three hours in order to get this, but this is how it all starts. I think with every advance with medical imaging, it starts off a little slow, a little blurry, a little noisy, and then things do just keep improving. Particularly in this age of AI, machine learning, radiology is just a ripe target for that. Once you get this kind of first study where you demonstrate we can see something and we can understand it, then it is almost inevitable that it will get faster and better over time. So the hope is that we can get that single subject mapping to really help specific individual patients, but it is not going to happen tomorrow. 

Erin Spain, MS: Did you use machine learning or AI at all in this study? 

Molly Bright, DPhil: Not yet. No. I am going to have to find a very knowledgeable collaborator here at Feinberg who can help us boost that. But no, we have not started that yet. This is all without any of those bells and whistles. 

Erin Spain, MS: The goal, as you said, is translational medicine. So how are you pursuing the next steps after this study? 

Molly Bright, DPhil: Right now we are trying to get the first precision maps in patients. Because we need to make sure that we are sufficiently sensitive. If you have a compressed spinal cord, can we see the changes in the vascular physiology there? So that is the immediate step now. I also, I do not want to lose sight of this dual nature of functional MRI. The fact that right now we are talking about it as a vascular tool, but I can also capture neural activity with this imaging as well. So I think another goal is to bring that side back in so that for a lot of these patients, maybe there is this vascular driving factor involved, but fundamentally their symptoms are neurological. So being able to monitor both neural and vascular function, I think, will be important long-term if this is going to be some sort of monitoring strategy. 

Erin Spain, MS: So you are sitting between two schools, the School of Engineering and the School of Medicine at Northwestern, and this is a really exciting intersection. There is so much happening right now. What is that like for you to go between these two schools and combine your expertise and use the resources of both to do this kind of research? 

Molly Bright, DPhil:I think this research does not happen without that interface and blurring that. So all of my students are in biomedical engineering, and we all sit down here in the med school surrounded by people more attuned to the application. And so far, I have found that very fruitful. I suppose also personally, I have never had formal training in neuroscience or anatomy or any clinical experience myself. If I were to just develop imaging methods in isolation, I feel like there is some metaphor about hammers and nails and screws and whatnot, that it is probably not a great idea to develop these techniques without really understanding what the goal of them would be. So I do not have to guess at that because I am surrounded by people who have questions and who know what physiological factors are important or what would actually influence treatment or decision making. And so I have all of these reference points that kind of keep me going in a direction where at the end of the day, if what I am trying to do works, we already know that it is going to be helpful. 

Erin Spain, MS: It is not just spinal cord injuries and diseases that you are interested in. Tell me about some of the other diseases that you are working on and that you are using imaging to find some more discoveries. 

Molly Bright, DPhil:  I will talk about two areas that have been particularly fruitful lately. Both are in collaboration with people who have more of a physical therapy slant and rehabilitation emphasis. One direction is we are trying this precision imaging approach in chronic stroke. A lot of my collaborators here in the Department of Physical Therapy and Human Movement Sciences have been working with many different modalities—with robotics, with EEG, with pharmacological modulations—trying to understand why some people have the motor impairments that they do following stroke. And there are certain patterns that come out, and they have, over the years, developed hypotheses about which motor systems become upregulated and cause some of these patterns that we observe. The thing is, a lot of these motor pathways involve very deep brain structures such as the brain stem, and so really functional MRI would be the way to understand if that really is what is happening and what that might mean for rehabilitation for these patients. So I have been trying to take a lot of the precision imaging methods and bring that into this sort of chronic stroke environment to say in that person, are they using this part of the cortex, this part of the brainstem, this part of the cerebellum? And we can do that now. That involves a lot of engineering. So we build a lot of things that go in the scanner. Our experiments are not simple; they are a bit complicated, but they are also really fun. The other direction that we have been focusing on is multiple sclerosis. So this is in collaboration with Milap Sandhu at the Shirley Ryan AbilityLab. And there we have just finished a really exciting clinical trial where we have been giving this hypoxia intervention called acute intermittent hypoxia to improve motor function in people with MS. So this therapy involves breathing gases, a little bit like what I was doing with breath holding and things, and you kind of alternate between low oxygen and normal air back and forth every minute or so for about half an hour. And it creates this window where function is improved and the potential for neuroplasticity is enhanced. So we tried this out for the first time in multiple sclerosis with this clinical trial. Previously it had been used in spinal cord injury for the most part, and in this trial we did see proof of concept that we can improve function with this therapy. And the really exciting thing is we brought in neuroimaging. All of these participants in the trial did a lower limb motor task during functional MRI, and we identified that there are changes in how some of the deep brain structures are activated during this movement. There are some changes in that because of this therapy, and so now we are trying to pursue how to use that information to maybe select which patients are most suited for this therapy or to personalize it so they get the right dose, that kind of thing. 

Erin Spain, MS: This is very exciting. This really is, as you said, laying the groundwork for personalized medicine using fMRI technology. And you are opening new doors potentially for your colleagues and peers. What is that like? Like to be the first to really find something, discover it, and publish it? 

Molly Bright, DPhil:  It is very exciting. It is very fun. But I think when doing this work, you have to be a skeptic, and when you are the very first to see something, it certainly for me, it made me question everything, and my poor student had to really go back and convince me of each interim step and all of the conclusions. And we did so many sanity checks, and we really had to convince ourselves more than anyone else before I really had the confidence to put it out there because it was new, and that is exciting, but it comes with a great responsibility in making sure you are putting out new information that is meaningful long-term. It sounds like things are moving really fast right now. There are these new methods, better technology, there is AI that you are talking about possibly using in the future. Where would you like to see your research go in the next decade? It is an excellent question. I think there is still this huge barrier to getting the methods we are doing just across the road into the hospital. I see in my mind very clearly the next 10 years of doing research at our imaging center and how I will advance that. That is all within reach; it has so much support. There is so much exciting work we can do there. But I do think that the next 10 years is probably a good horizon to be trying for real translation. Where we do finally get out of the basement research facility and into the hospital radiology suite. That is certainly happening for all of my colleagues doing advanced methods, imaging, other parts of the body. But there is something about studying the central nervous system that it is just a little more difficult, in particular because we are asking people to do things while they are in the scanner. You know, we are asking them to do a task, hold their breath, move their limbs, something like that. And so all of that, it is just that much harder, I think, to translate it into the real hospital system. So it is something that I would like to really push ahead with over the next decade. The work we are doing now, I would say, it is pretty much 50-50 on how much we are using this method to look at the vasculature and how much we are using it to look at neural activity. And my goal is to increasingly integrate the two in stroke, in multiple sclerosis, in this degenerative cervical myelopathy. Pretty much across the board you are going to see both systems are implicated, and so I think that is another direction that I really want to pursue. It is making sure that when we are capturing the physiology of one specific patient that we are sensitive to both of those systems. And right now I feel like a lot of our studies are going after one or the other, and so harmonizing that would also be something for the future. 

Erin Spain, MS: Why is this the type of research that could really only happen at Northwestern? 

Molly Bright, DPhil: We have all the expertise in place. We have the imaging center with the expertise in how to specifically capture a function of the spinal cord. We have my group’s addition to that, which is refining that to look at the vascular function in the cord with that method. We have several people here across the med school who are pushing this precision imaging, and a lot of us talk to each other and try to enhance each other’s methods. And so we are really making grounds on that front. And then we have the amazing clinicians who see these patients who really want this information. And so I am working now to connect that last little element so we can work on translation. 

Erin Spain, MS: Molly Bright, thank you so much for coming on the show and talking about your breakthrough research. It was very exciting to hear about everything happening in your lab. Thank you for your time today. 

Molly Bright, DPhil: Thanks for having me. 

Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media @NUFeinbergMed to stay up to date with our latest research findings. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Molly Bright, DPhil, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.