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Oby Ukadike-oyer: From the campus of Harvard Medical School, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Oby, your host. ThinkResearch is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center, and by NCATS, the National Center for Advancing Translational Sciences.

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We are continuing our journey through the archives, revisiting conversations with some of our previous guests and catching up with them to hear what they are up to now. Today, we are re-airing an episode from the summer of 2020 featuring Dr. Alex Lin, the director of the Center for Clinical Spectroscopy at Brigham and Women's Hospital and associate professor of radiology at Harvard Medical School. Tune in next month for an update on where Dr. Lin's work has taken him since we last spoke.

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Speaker: From Pop Warner youth football leagues to collegiate hockey and the NFL, brain injury and the implications of repetitive concussions are a growing concern. With modern MRI technologies, researchers are able to detect important structural changes in the brain that result from these injuries. Dr. Alex Lin and his colleagues at Brigham and Women's Hospital are expanding their patient population and their technologies to see a clearer picture.

Using functional magnetic resonance spectroscopy, they hope to better understand brain chemistry while also examining the effects of traumatic brain injury on populations of vulnerable individuals that have gone under-studied. Dr. Alex Lin is an assistant professor of radiology at Harvard Medical School and director of the Center for Clinical Spectroscopy in the Department of Radiology at Brigham and Women's Hospital. Dr. Lin, welcome. Thank you for joining us.

Alex Lin: Thank you for having me.

Speaker: So you've been on the show before. And for listeners that didn't hear your first episode, maybe you could just refresh our memory and explain briefly what your work centers around.

Alex Lin: Sure. So I'm the director of the Center for Clinical Spectroscopy at Brigham and Women's Hospital in the Department of Radiology. And our focus is looking at measuring brain chemistry using a method called magnetic resonance spectroscopy, or what I like calling a virtual biopsy because it gives us an ability to noninvasively examine chemistry in the brain without having to do any kind of surgical intervention or anything along those lines. And so we've focused this method primarily on traumatic brain injury.

So we've been studying NFL players, soccer players, ice hockey players, and all sorts of different types of sports to try to better understand what are the effects of concussion or repetitive concussion on the brain. We've published quite a few papers in the area of the Football Players Health Study, mainly looking at the results coming back from what we call the 'Detect' study. It was an NIH-funded RO1 study with Boston University that looked at about 100 football players.

And so the results of that study are now becoming published by nature of our publications. So we just recently just had a paper accepted looking at some of the biochemical changes that occur in those football players. And we're seeing certainly different patterns of injury that are emerging as a result of that. And I think one of the things we're starting to understand is that CTE, or Chronic Traumatic Encephalopathy is definitely a complicated issue.

It's not just as simple as you get head injuries and you're going to develop this disease. And so we're trying to better understand what is it that goes to developing this disease. And also, the presentation of the disease is not something that is simple either. I think people typically think of it as a disease where it's neurodegenerative, you get memory loss, problems with anger management, those kind of things. But what we're finding is that there's actually many different components to it.

There's both a mood behavior component as well as a more neurocognitive, neurodegenerative kind of component. And that's one of the things we're studying now is, can we get a better way of using the brain chemistry to better understand these differences, even amongst the CTE population itself? So we're using machine learning methods there to try to better understand what are the correlations between brain chemistry and these different functions of CTE as a disease.

And so we're definitely moving that further to better understand things. We also have ongoing studies now looking at trying to expand this study into other areas where we have some new technology. So one of the biggest things that we've had at Brigham recently is the advent of a new 7-Tesla MRI machine. So typically, most MRI machines are around 3-Tesla. So this is more than double the field strength. And what that offers us is a way to improve the resolution of our images as well as the resolution that we get with spectroscopy. And so we can look at a number of different aspects of chemistry that we weren't able to look at before.

I think one of the really exciting things that we've done recently is developing what we call a functional spectroscopy method. So you've probably heard of functional MRI, where you have different areas of the brain that light up as a result of different processes that one will study. And that's mostly what we call a bold effect or blood related effect. And what we're really interested in is trying to see, do those things activate different chemical changes now in the brain? And so that's one of the new things that we've developed to advance that field.

Speaker: And so using spectroscopy, you're measuring the level of different chemicals as opposed to MRI, which can't see chemical. It measures more structural.

Alex Lin: That's correct. Absolutely right. Yeah. And I think they're very highly complementary to one another. The structural changes that one sees. For example, in some of the early studies we published, changes something called cavum septum pellucidum, where there's a splitting of the membranes by the ventricles to the diffusion tensor imaging changes where you see different patterns of fractional anisotropy and the fiber tracts that are within the brain that certainly show differences. And I think what the spectroscopy does to try to complement that is to also examine some of the pathophysiological changes that are driving these structural changes. So the chemistry hopefully will help inform the imaging.

Speaker: So right now, how much is understood about how much chemistry impacts structure?

Alex Lin: I think it's-- definitely, it's still in the process of trying to better understand what's going on. We are just now starting to correlate the two. And those are ongoing studies that we're still working on the data. But we're certainly, for example, seeing changes in neuroinflammation that I mentioned earlier that seem to correlate with the changes that we see in the imaging. And there's an early study that we showed at the International Brain Injury Association where we find the DTI changes are very much correlated with some of the spectroscopy changes. And that tells us that the structural changes that we're seeing are a result of some of the underlying pathophysiology.

Speaker: And with that information, as you start to learn more about the pathophysiology and how that impacts structure, what could you see down the road? Or what do you imagine for treatments that could possibly intervene?

Alex Lin: That's a great question. I think that's one of the-- certainly the next big area that the brain injury research needs to go is exactly fine. Once we can identify some of these changes, we can then use these as biomarkers for treatment and monitoring treatment. So I think one of the areas that we really would love to explore is now that we identified some of these potential markers, what can we now use in terms of drug treatments to look at them?

Speaker: And the studies that you've done, have they-- I want to talk about the work you're doing with traumatic brain injury and gender difference because I think it's really interesting and an area that you don't hear a lot about. I think a lot of the studies focus on men. But you are looking at women and the difference in traumatic brain injuries between men and women. Could you tell us about that?

Alex Lin: Yeah, absolutely. So unfortunately with the football player style study, we're just looking at men, right? It's really primarily a men's sport. And so when we started looking at other sports, for example, collegiate ice hockey, we suddenly had access to a population that was both men and women. And we had the data that allowed us to examine that. And so we just recently last year published a paper looking at some of the differences in brain chemistry between men and women.

And what we're finding are that there are certain similarities. So for example, both preseason and post-season, we see similar changes in men and women when it comes to changes in what I mentioned earlier, N-acetylaspartate, which is a neuronal marker. So that tells us and confirms some of the previous findings that during the season of play, there's definitely some kind of subconcussive injuries that are occurring that's driving that.

But when we looked at other chemicals, for example, glutamate, which is an excitatory neurotransmitter, in men, preseason to post-season, it increased. That's something that we've known for a number of different studies that glutamate increases as a result of brain injury or exposure to brain injury. But in women, it actually decreased. And what we also found was that women also had a starting higher level of glutamate than men did. And so clearly, there's a different impact on the brain depending on gender specificity.

And with that pilot data, we then applied for an NIH grant where we're looking at Harvard College athletes. And that grant completely focuses now on the gender differences. So the whole idea is to recruit men and women and particularly in sports where the similarities are better. So for example, in collegiate ice hockey, there are differences in the way that ice hockey is played, whether it's playing male or female, particularly with checking.

And so there, you don't know, OK, is it because there's a difference in play that we're seeing some of these differences, or is it truly gender differences? Whereas you have other games like soccer where I think male and female participation is much similar or more similar. And so we can therefore now start really getting at some of the gender differences that are occurring there.

Speaker: And the chemical you mentioned, glutamate, you said it's an excitatory neurotransmitter. What function does that perform in the brain? And why do you think that there's differences in levels between men and women?

Alex Lin: Yeah, so it's one of probably the most predominant excitatory neurotransmitters that's available in the brain. Much of the body's metabolism goes to supporting that process. And the differences that we see in men and women, we think-- and we're still working on the studies to prove this-- might be governed more by hormonal differences and changes in the body. And that eventually obviously affects the brain as well.

And what we've always thought of glutamate before from an energy perspective was that we know that with each hit, glutamate increases. But then it goes back down. But then with more subsequent hits, that glutamate level seems to rise. And then it becomes to a point where when you have too much glutamate in the brain, it becomes neurotoxic and starts killing off brain cells. And that's something we saw in our football players as a pattern. But in women, obviously, there's something very different.

And what we think is that there are the different hormonal processes, and people have studied this in other areas, where the female hormones can potentially be neuroprotective and benefit them. There's also other stages in which in women, the hormones actually might be more damaging. And so one of the things we're studying in our current study is depending on what stage of the menstrual cycle, the hormone levels are obviously going to differ.

If that injury occurs during the luteal stage or in other stages of the menstrual cycle, those hormone levels will change. And that could potentially be the reason why some women are more impacted than others. And there have been some other studies that have supported this kind of theory.

Speaker: So a lot of the studies you've talked about focus on athletes, but I know you're also looking at other ways that people suffer brain injuries. And one of them is domestic violence. Could you talk about that?

Alex Lin: Absolutely. Yeah. I think one of the things that once we started transitioning over from sports and then to gender differences, we quickly realized that the-- it's really a very unexplored area. And it really was an eye opener to look at domestic violence and the incidence of brain injury in women that-- it's known that one in about one in three women experience some type of intimate partner violence. So the populations we're looking at now are much, much larger than what we're seeing in sports-related head injury.

And the prevalence of brain injury in these women is devastating. One of the studies, recent studies that have been published, looking at a very select population of intimate partner violence is looking at trafficked women and the reports in that study of one woman reporting over 100 concussions that she suffered during that period of her life. And that made me realize that we're studying the same type of things. We're looking at repetitive concussion.

But we've never looked at it in the case of intimate partner violence. And that's an area that we literally just got funded by the Women's Brain Initiative over at Brigham to start studying this population. And I think it'll be really interesting to explore this and see how the changes we're seeing that we mentioned earlier in football players might either resemble or maybe not resemble what's going on in domestic violence.

And will it inform us whether or not these women, for example, might be at risk for developing chronic traumatic encephalopathy as a result of all these head injuries? I think those are things that people don't think about. And sadly, I think we're just beginning to realize now the high incidence of this and the prevalence of the concussions that could potentially play into this.

Speaker: Talk more about the lack of awareness about these injuries, if you can. You said that you had seen previous published studies. But how recent are those studies?

Alex Lin: Yeah, no. I think all those studies are very, very recent, over the past year or two. And there are more and more studies coming out now that are beginning to better characterize what's going on in intimate partner violence. Looking at it from the perspective of someone who came in the traumatic brain injury field, you first think of traumatic brain injury mostly as motor vehicle accidents, those kind of things. And then you think about sports.

But domestic violence was never something that ever really came up before. And I have to say, I was introduced to it largely because I was involved in an organization called PINK Concussions, which is a organization that really tries to bring prominence to the fate of concussions in women. And they, too, when we first started the conferences, did focus a lot on military brain injury or sports-related brain injury.

And just more recently, they've been bringing in IPV as one of the major areas that needs to be studied. And I think a lot of brain injury researchers are suddenly realizing, holy cow, this is an area we've completely missed. If you look at the literature, there's virtually maybe two papers out there that have looked at neuroimaging in IPV. And so clearly, this is very, very much understudied compared to say sports-related head injury where now there's hundreds of papers.

Speaker: You mentioned PINK Concussions. Could you talk more about that?

Alex Lin: Yeah, PINK Concussions is a group started by Katherine Snedeker probably about six or seven years ago. I remember going to their first conference where I was invited to speak. And she's really been the driving force behind me. Just incredible, bringing in people from all aspects of brain injury, whether it be, like I said, sports, military or IPV, and getting them together at all the major brain injury conferences to look at what's going on in women.

And I think first, she really brought awareness to the fact that all these sports studies that we were looking at were all in men and never in women. And so that was the next part where she brought in a lot of women to be involved in these brain injury studies. And that, I think, brought a lot of prominence to it, and then, as I mentioned recently, more transitioning to things like domestic violence and bringing those topics into play.

She had a conference just several months ago where she brought in victims of intimate partner violence to describe the kind of just horrendous situations being in. And it makes you realize as a TBI researcher that there's so much more that needs to be explored and understood here. These women need to be studied. We need to get a better understanding. We talk about underreporting in football play, right? These guys who are macho and don't want to say, hey, I got a concussion and be taken out of field of play.

This is a completely different kind of underreporting where women are just terrified to report any kind of injury. And with brain injury being called the invisible injury, this becomes even a greater problem because unlike broken bones, or bruises, or things that may be a little bit more indicative of what's going on in domestic violence, brain injury is not something you see. And that's to be able to bring some light to that and hopefully use these more advanced neuroimaging methods to better understand what's going on or to be able to characterize that I think will be really important.

Speaker: And you said earlier that you became interested in the gender differences when you started looking at hockey players. What role did your colleague bringing these people in to conferences and giving this issue a spotlight-- what role did that play in making people aware of these issues?

Alex Lin: Certainly. In my life, it was an eye opener. When I went to that first PINK Concussion conference, I sat there and realized, whoa, this is an area that I just had not explored before. And to be honest, it brought personal relevance to it too. I've got two daughters. They both are involved in sports activities. And it made me realize that here I am studying all these male football players. And I could speak nothing to whether or not-- if they have a concussion, what would happen with them?

There was a number of different incidences that really helped drive me towards that. I think certainly, PINK Concussions was one large part of it. But I do remember a case over at Children's Hospital where we scanned one of the sports related concussions in a young girl. And she was a soccer player, ran into another soccer player head on, was concussed. And it was incredible. She was an A student who now couldn't even concentrate for more than half an hour.

And having met her in person, she was desperate to try to get back into school. And the opposite of what you think of most students. Most students will be like, hey, if I can skip school for a couple of months, great. So much better. But she was really struggling to really try to get back into things. And it made me realize that there are differences in the way people recover from TBIs and--

Speaker: From just person to person?

Alex Lin: From person to person, and then after exploring the literature, realizing that in many ways, girls actually take much longer than boys to recover from brain injury. There's also the prevalence that girls report more injury than boys do. And so it makes it a little bit different to try to understand this population, all these different factors that you really need to take gender into consideration. If you were to just group them all together, it really wouldn't make sense. You have to really separate them out and be able to better understand what's going on specifically in women that's different from men.

Speaker: So how long would, say, a student who is an athlete, gets injured, concussed, how long does that recovery process typically take?

Alex Lin: It takes anywhere from a couple weeks to about three months. Most concussions recover by about the three-month period. And what they were finding was that in girls, that was much was a bit more extended than that. It would take sometimes four months, sometimes up to six months for full recovery [inaudible].

Speaker: That's half a school year.

Alex Lin: Exactly. Yeah. And you don't think about that. To a kid, that's a really big part of their life.

Speaker: Yeah, like, 10% of their life.

Alex Lin: Exactly. So yeah, it was really incredible that-- we didn't realize that there was this difference in how much of an impact it can make.

Speaker: Looking forward, you've received a grant to study intimate partner violence. Where do you hope that you can take this work in the future?

Alex Lin: Yeah, that's a great question. I think for one, being able to use-- once we identify, again, those appropriate biomarkers for brain injury in IPV, using that to potentially use that as a diagnostic test because of the big problem with IPV is that you don't know whether these women have concussions or not. And I think that would be something I could see in the future would be really valuable as someone who undergoes-- has an experience with IPV that one can then utilize this technique to see, OK, well, what's the extent of this brain injury?

And sometimes-- it's not to say that it's unreported, but a lot of times, women-- or people in general don't realize that these concussions have such a major impact. Getting a better understanding of what's going on in the brain as a result of this will help better understand those processes.

Speaker: Dr. Lin, thank you for coming in. It's a pleasure to have this conversation with you.

Alex Lin: Great. Thank you very much for having me.

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Oby Ukadike-oyer: Thank you for listening. If you enjoyed this episode, please rate us on iTunes, and help us spread the word about the amazing research taking place across the Harvard community and beyond. We are always looking to connect and collaborate with the research community and would like to hear from you. Please feel free to email us at onlineeducation.catalyst.harvard.edu to inquire about being a guest on the podcast.

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