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Oby Ukadike: 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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On the last episode of ThinkResearch, we re-aired Dr. Alexander Lin's podcast about his research into brain injuries, specifically looking at the effects of concussions on NFL athletes throughout their career. Listen as Dr. Lin updates us on the shift in focus of his research. Enjoy the update.

Alexander Lin: Thank you very much for inviting me back to give an update on our current state of research. Last time I was here was in 2019, where we were talking about our brain injury research. So I just wanted to follow up on where things have gone there and things that continue to inspire us, influence the work that we do within the field.

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The last time we spoke, we had focused a bit on the work that we were doing in the NFL and looking at the effect of concussion on those athletes through their professional career. Those studies are now largely completed. We were part of a large U01 study with Boston University. And there's over-- been a dozen papers published from that study, and so very exciting to move that forward.

Where things have evolved a little bit for me has been really my focus, which I mentioned a bit in the last podcast, looking more at the gender differences in concussion. And so we had an RO1 funded with Inga Koerte, looking at sex differences in concussion in Harvard athletes. And that study is just about wrapping up.

We've published a few papers from there. It's very interesting and exciting to see that some of the things we were hypothesizing in the previous podcast are now things that we've been able to publish on and demonstrate that, indeed, there are gender differences between men and women in concussion.

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We spoke last time as well about our focus on intimate partner violence and looking at neuroimaging methods to explore that further. And I'm very happy to report that we have two NIH-funded RO1 grants that have now explored that topic in much more detail. With Eve Valera and [inaudible] and MGH, we have a local study looking at the impact of intimate partner violence on neuroimaging, in particular, NMR spectroscopy.

And then we also have another RO1 funded by NIH, which is a multicenter study, led by Carrie Esopenko at Mount Sinai; David Tate, at Utah University; and Frank Girard, at Penn State; and myself, as co-PIs of a study looking at much larger group of women undergoing neuroimaging studies, to better understand intimate partner violence. And so we're very excited to be able to really push that forward. And it has allowed us to really better understand the different aspects of intimate partner violence, that really differ a lot from what we saw in terms of CTE, or Chronic Traumatic Encephalopathy, in our football players.

As you can imagine, the situations are much more complex. There is the impact of not just the brain injury in these women, but the post-traumatic stress, as well as near-fatal strangulation. And those are factors that really differ in the brain injury that's experienced with intimate partner violence, that we are really beginning just to better understand.

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I think last time, I also alluded to some of the impacts of hormones as a factor that guides a lot of this research. And so for recent collaborations that we've established, we've really moved a lot more into that area. I'm very excited to report that we're working with now, Pamela Mahon, Jessica Busler, and Hadine Joffe in the psychiatry department here at Brigham Women. We have multiple studies ongoing there.

For example, the CD study, which is looking at stress response in aging women, the Rosa study, looking at eplerenone and its effect on perimenopausal depression, so really trying to get a much better understanding of the impact of hormones on brain and brain metabolism. We have a couple preliminary papers that have published from there, and really excited to keep that moving forward, to get a better understanding of what's going on with this.

So based on the research that we've been doing and understanding the impact of hormones on the brain, there is one area that I think is going to be really important for us to understand, is that of our transgender studies, where these individuals are taking a number of different hormones. And if they get a concussion or if there's a domestic violence thing that occurs in their life, which, sadly, occurs often within the transgender population, we really need to understand the impacts of these kind of things and hopefully, help them with the transition, to be able to better understand, What are the impacts of the hormones? and then subsequently, what are the impacts of the injury upon their brain?

And I think that's an area that it's a double whammy. It's going to have both effects. And we really need to understand those things better. And so I think that's a really important area of research that is completely neglected in this day and age.

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There is a very broad range of impacts that occur with concussion. Everyone suffers from it differently. And it's really been key to understand, what are the individual differences that are occurring that help us predict whether or not someone is going to suffer or not suffer from the long-term effects? It's much more on an individual basis.

From the research standpoint, that's pushed us to look at things like blood biomarkers in conjunction with the neuropsych and other measures that we were typically thinking of as symptomologic findings and now, really tying it to potential biomarkers. It has moved our research into a more biomarker identification phase that's, hopefully, going to be very helpful in the future, and that provides them targets for treatments, so that we can say, OK, if you're suffering from this problem, we can measure these biomarkers and then see if those treatments, then, subsequently, decrease them or increase them, whatever state, and allow us to track and be able to help improve that.

We're moving more-- further away from, What are we seeing? to, how can we use this to better monitor and treat these patients? I think we're really at the cusp now of finding new treatments for these patients in concussion. Before, it was, go lie in a dark room and relax. And there's really not much more that one can do.

I think as we've increased our understanding of what's going on with concussion and brain injury in general, there are now a number of different therapies that become available to try to help treat that. Also, when it comes to, say, intimate partner violence, where we see this conjunction of brain injury plus post-traumatic stress, there are therapies that can be tailored, then, to those individuals that allow them to get a better success rate of treatment.

Because we understand now that it's not just about the brain injury. It's also you have to treat the post-traumatic stress aspects, or you have to treat the strangulation aspects, that we identified in our initial studies.

A lot of the biomarkers that we're looking at, particularly with MR spectroscopy, in some of the initial data we were showing, were a lot of neurodegenerative changes. So we have a chemical called n-acetylaspartate that measures the neuronal health. And we were seeing that was decreased in people after concussions.

The problem with that is that it's almost like Alzheimer's disease, where there's damage already occurring. There's not a whole lot one can do about it. So I think what we're really focusing now on are on some of the earlier biomarkers that are part of the neuroinflammatory process. So there are chemicals like glutathione, glutamate, myo-inositol, that are all involved in different aspects of inflammation in the brain.

We're finding that, as one always knows, with neuroinflammation, it's a double-edged sword. It's something that helps the brain heal when it's injured. But also, too much of it can drive things further and make it worse.

And so using these biomarkers, we can get a better understanding of what's going on in the brain. And, can we dampen the neuroinflammatory effects so it doesn't go on to lead to things like the tauopathy, that develops in chronic traumatic encephalopathy, or some of the other subsequent effects? For example, in post-traumatic stress, we've shown that there are changes in these inflammatory markers.

So if you have both a brain injury and a traumatic stress, now you have double the kind of inflammation. And that is why things get worsened later on. And so having biomarkers for these inflammatory changes is going to be really key, I think, to understanding the treatment effects on these patients.

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In looking ahead, our future goals with this research is, obviously, to continue doing this. And this podcast, I thought, would be an excellent opportunity to just emphasize the importance of these studies, looking at the impact of hormones on the brain, looking at gender differences and concussion. And really being able to explore that in greater detail and continue these studies is so critically important for us to move forward on. And so I think the focus of our research will really be in that area.

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In terms of the real-world applications, I think one of the most exciting developments in my career has been the spin-off of a company called BrainSpec from our lab. BrainSpec is a software company. It automates the processing of spectroscopy data and reporting of the data. And so it really takes it from something that is, in the scientific world, used often, into the clinical world. And that's been our goal, to really take a lot of these findings that we have in the research world and translate it now into clinical practice.

BrainSpec was formed initially out of a kind of hackathon that was thrown together by Brigham Women's Hospital, where they brought together people from Harvard Business School, obviously, Harvard Medical School, MIT. And then what was really interesting, actually, some students from Mass Arts, working with those artists, we were able to mock up a sort of initial design for the software that really ends up being pretty much what we're using today.

It was a wonderful experience that allowed us to do a prototype for the software. And then from there on, we were able to expand out and form a company with Alex Zimmerman as the CEO. She's a Harvard Business School graduate. And it's been a really great experience being able to take these experiences and research and translate it and see how it can impact our patients.

The company just received FDA approval of the software last year. And so we're now moving forward to getting it established at many local hospitals here. We're working with some great collaborators, Ellen Grant, over at Beth Israel, as well as Tufts University. And certainly, at the Brigham, we use it on a regular basis and in the future, hopefully seeing it spread and really help promote the use of MR spectroscopy and the ability for other sites to be able to measure these chemicals in ways that will be able to further both the research side of things, as well as the clinical side of things.

So we'd love to see it being used and then, hopefully, expand it out across the nation and perhaps internationally. With that, we received a breakthrough designation from the FDA for the use of it in brain cancer. And so we're really excited to move that forward in this new era of artificial intelligence and in radiology. I think this is really one of the great applications in which we can really garner the resources that are developed out of the research world and apply them to clinical practice that allows us to hopefully, impact patient management.

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Oby Ukadike: Thank you for listening. 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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