New Insights from Inside the Brain with Rodrigo Braga, PhD

[00:00:00][Music] The brain is the most complex and mysterious organ in the human body.

[00:00:08]Despite being at the center of everything we do, from managing memory and attention to navigating social interactions, it's not fully understood.

[00:00:18]But here at Northwestern Medicine, advances in neuroscience and imaging are helping to shed light on how our brains function. and recent discoveries could lead to new ways to treat a variety of neuro and psychiatric disorders. Today I'm joined by Dr. Rodrigo Brega, an assistant professor of neurology in the Kin and Ruth Davyy Department of Neurology at Vineberg. He is using precision functional MRI technology to better understand how the brain is organized. He recently discovered new insights into the brain's social cognitive network, areas of the brain that allow us to think about and understand others thoughts and feelings.

[00:00:56]Today, we're going to talk with Dr. Brega about this research and other research in his lab, how quickly the field of neuroscience is moving ahead and possible therapies that could one day come from his recent discoveries.

[00:01:08]Welcome to the show. Thank you for having me. It's a pleasure to be here.

[00:01:12]Well, let's start by hearing a little bit more about you. I know that you joined Northwestern over four years ago, but I want to know a little bit more about your path to neuroscience. I heard this isn't exactly what you set out to do in life. I originally wanted to be a musician, and so I went to college to join a band and start a band and do music, but I thought, well, I have to get a degree in something. So, I'll do stuff that something that I find fascinating, which is the mind. I was always curious about the nature of the mind and how it is that we can create worlds in our minds and experience those almost as if you know perceiving something in the real world.

[00:01:52]And so I was always curious about that and I decided to study it and I initially started studying philosophy and psychology. But then when I studied psychology I realized oh the neuroscience component is what really fascinates me and it was I related more to that way of thinking about the mind.

[00:02:09]You came here to Northwestern in 2020 to set up your lab. Tell me about the draw here to Northwestern and Northwestern Medicine. Well, Northwestern's yeah a very exciting place to be. Um we have access to some really exciting opportunities. My lab we focus on epilepsy patients uh which are being monitored intraraanally for their seizures and so that gives us an opportunity to study the brain directly through intraraanial recordings. We have excellent imaging facilities here at the center for translational imaging. So I knew that we'd be able to accomplish our MRI goals. So for many reasons, it was a a good move. You mentioned epilepsy.

[00:02:50]That's just one of the diseases that you are studying in your lab. Tell me a little bit more about how you use this fMRI technology to help explore and understand epilepsy and other conditions. A lot of our work focuses on epilepsy. the breadth of studies, they're they're all centered around this idea that you can map brain networks within individuals using functional magnetic resonance imaging or fMRI. And so what we do is we start from that point and then we see what what can what populations can we apply this to? What different questions can we tackle with this technique. One of them is to do that within epilepsy patients because we can take those brain network maps and then do intraraanial recordings to sample the brain at high frequency and look at different signatures that you can't see in an MRI scanner. But also being able to map brain networks within individuals gives us a way to study neurodeenerative disease for instance in Alzheimer's.

[00:03:43]The idea being that if you can map exactly which parts of the brain are involved in things like language or recollection, then you can look at how the pattern of atrophy, which is which means brain shrinking in those patients in those specific brain areas, relates to dysfunction. And so those are the two main arms. We're currently starting a project in the stroke division where we're looking at the same thing. take the network maps in people that have had strokes that affect language. So they have a fasia and we're trying to track them over time to see how these networks are changing as someone recovers language ability following stroke. So this mapping of brain networks is what leads us to the study that we're talking about today that was recently published in science advances. And in this study, you focused on the brain's social cognition network to better understand how humans evolve to be so skillful at thinking about what's happening in other people's minds. This is something called the theory of mind network. So let's dig into this a little bit. Tell me about this theory of mind network. And what motivated you to look into this? Yeah.

[00:04:51]So, this is a really interesting thing that we can do as as humans is you can put yourself in someone else's mind and imagine what they must be thinking.

[00:04:59]Classic example, everybody experiences this. You go, you're in a coffee shop, you're paying for something and the cashier seems grumpy or or happy or something is going on with them that you think, I wonder what's happening in their minds. And so, that's just a an example of something that we do all the time. We're always thinking, I wonder how this person is going to react to what I say, how I should approach this, etc. And it turns out that the regions that are involved, the cortical, the regions of the cerebral cortex that are involved in that type of thinking are in parts of the brain that have really expanded in our recent evolution. And that implies that it's something that we have recently become better at doing or somehow are advanced because of that brain expansion. And so that's in itself fascinating. These regions are also part of something called the default network, which is a really interesting set of brain regions that increase their activity when you're left to mind wonder. You know, it's usually in the periods in between a task. You'll be doing your task in the scanner and then when you're waiting for the task to start up again, this network will become active. And and what are you doing in that time? You're probably thinking about what am I going to do tomorrow?

[00:06:12]what what happened to me yesterday what was the this person thinking etc so the default network's involved in this kind of creative selfgenerated type of thought and so that's again something I'm I've always been interested in and my work during my postto showed that actually within this canonical default network we can tease apart two distinct networks when we define networks within the individual brain that these two networks are adjacent to each other throughout the brain and were likely being blurred together by lower resolution approaches to brain mapping or those that average data across individuals because that induces blurring. And so that's how we started down this line. And it turned out that the distinction, the functional distinction was that one network seemed to care about thinking about scenes and events. So for instance, if you're thinking, you know, about something you're going to do later on today or how you got to work, etc. that involves thinking about scenes spatial. It's more of a spatial type of thinking. One network cared about that, but the other network seemed to care about this other type of thinking, which is when you're thinking about what someone else what is in someone else's mind. And so that's what we call theory of mind. And that's the interesting distinction. In this study, you were able to take some highresolution seven Tesla MRI data.

[00:07:35]This is pretty powerful imagery. Can you talk to me a little bit about the role that these images play in your research and in this study? Yeah, sure. So, three Tesla scanner is very commonly used.

[00:07:48]They're found in most hospitals and most universities. And then you have the seven Tesla which is a much stronger magnet. It's it's not as widely there aren't as many of them in the US for instance. So, that was one leap where you can go to 7T and you can get you can actually make an image of the brain which has smaller pixels. You can think of it as taking a high resolution photo where you can zoom in and see very detailed, very crisp image. So that's the one innovation is going from 3T to 70. But the main innovation that my whole lab is based around is this idea that it's a it's a it's a quirk of the field in a way because it goes back to the days of PET scanning. So pets posetron emission tomography is a it involves a radioactive tracer and so you can only do so much PET scanning, right?

[00:08:38]You can do like one session and then you really should not do that much because it's it's hazardous. is ionizing. And so a lot of the tools in my field were borrowed from that pet field where because you can only scan everybody once, let's scan lots of people and then that will give us a more stable map because we're looking for things that are consistent across people. Basically, a map from a single session is not really stable enough.

[00:09:06]And so we borrowed those tools and in fMRI we were basically many many of us in fMRI especially the network mapping field we were doing the same thing we'd scan everybody once and then we'd average across people to get a more stable map but what came around about 2015 I was just starting my posttock a paper came out where a scientist called Russ Paul Pdra who's at Stanford he scanned himself over about a year and a half and so he had lots and lots of data from his own brain which meant he didn't have to average across any subjects. He could just average across all the different sessions from his own brain. And that meant he could make a map of just his individual brain network. And when we look at those maps, they look much more detailed. The it's like looking at a much more crisp image.

[00:09:53]And so that really has sparked a a revolution in the field. And and we've been a lot of studies have now coming out that are using that approach to dive into the individual because you can see so much more. Okay. So tell me about the results of the study. What did you find and how does it contribute to the literature? What do we know now that we didn't know before? So what the study contributes is that we show that those cortical regions that I mentioned are in the really expanded parts of the human brain. They are in constant communication with a really important structure called the amydala. And the amydala is a really important structure for lots of mental health reasons. It's implicated in depression, anxiety, PTSD, schizophrenia, lot many things. It's also known to play a role in things like fear learning. But there's also a really broad literature showing that it helps control social behaviors. So for instance, people that are born without amydala, they have different abilities to detect emotion in other people. So whereas when you see when you and I look at a face, we may instantly focus on the eyes and thereby quickly learn the emotion that that person might be experiencing, someone without an amydala might not their eyes may not be drawn to the eyes of the other person. So they're not sampling the world in the same way that we are. That's one example. You know, there's lots of studies showing how the amigula controls parenting and aggression. And if you leion amigdula, your social status will will change.

[00:11:23]So we know that the amigula is involved in this controlling social behaviors. But then we also have this broad cortical network that's involved in thinking about what's in someone else's minds. And so it seems like there must be a link between those two. And and indeed there is evidence from lots of different tasks that people are performing in the scanner where you show that both the amydala and the cortical network are active for some kinds of social thinking. But what we did is we just had people lie in the scanner and do what's called a resting state scan. They're not doing anything. They're just staring at a plus sign to keep them in a calm state where they're not moving their head. And then you can do this approach called a functional connectivity approach to brain mapping where you're looking at regions of the brain that are correlated with each other which means they're fluctuating.

[00:12:10]They're going up and down at the same time. And using that approach you can map brain networks. And so we mapped the social cognitive network just using this functional connectivity approach. And when you do that, you can see that it's connected to the amydala. The other thing that was really cool is because this was a seven Tesla high resolution image, we could actually dive deeper into the amigdala and say, well, the amydala has many, many different structures. So which one is specifically connected to the social cognitive network? And that's where things became really cool because what we saw is that the network is connected to a specific part called the medial nucleus which is very underststudied in humans very small very hard to study but it's implicated in social behaviors that specific nucleus and that's the part that we saw is in communication with the social cognitive network. In the paper, you talk about the fact that there could be new targets now for stimulation therapy, either non-invasive or invasive therapy to help people perhaps with anxiety or depression because of what you found in this study. Can you tell me about that?

[00:13:13]Knowledge of these circuits is really important because often you can apply stimulation to a connected part of the brain and it will have downstream effects in other parts of the brain. And so our our paper is showing well there's a connection to the amydala which is a really important structure for a lot of mental health conditions. And so now we're showing these parts of the brain especially the parts on the outside on the cerebral cortex specifically this part that's in the social cognitive network has this connection to the amydala. And so you could take from that that perhaps stimulating those cortical regions will affect the amydala. Now we don't know what effect that would have.

[00:13:50]We don't know whether that would be therapeutic or not, but it's still it's opens up for future research which could potentially have uh implications for those diseases. Can you tell me a few more specifics about these different types of stimulation? The two that are particularly exciting right now, TMS, transcranial magnetic stimulation, where they stimulate actually it's through the the skull and so you have to do it at parts of the head that you can access.

[00:14:16]one of the main ways to target that because you could target it anywhere around the head. But what they do is they target a specific part of the brain which is thought to be connected to a part of the brain called the subgenial singulates. Now basically do the classic approach is to take a network approach and say well the subgenial singulate is connected to this part of the prefrontal cortex which is more accessible.

[00:14:39]Therefore, let's apply TMS to the part that's accessible, thinking that we're going to be activating that part downstream. And literally, one approach to do it is to do an fMRI scan and look at what's connected to to that part of the brain and then stimulate those connected regions. The other approach is to do an intraranial a deep brain stimulator which is also another we had Helen Mayber come and give us a talk a couple of weeks ago about this where you apply you target an electrode to the subgenial region and then you stimulate that and some people really respond quite well to that and so those are two good examples where one you're directly stimulating it but you need surgery to get to that part of the brain and the other one you're using the network mapping to say well this part is way more accessible and I can stimulate this through the skull Well, let's see if that has an effect. And it seems, again, it's not my area of expertise, but it seems like it does have an effect in many patients. So, this study is a great example of how using the latest technology can really help advance the field. What are you excited about for future studies? So the findings from this paper they show us the power of individualized brain mapping where if you take an individualized approach and map that individual's brain networks you can gain insights not only into the nature of organization of certain cognitive functions but also more you know practically where is the network in this person you know is it in this gyrus or this part of the brain a couple of centimeters across you can imagine how that's really important important for things like neurodeenerative disease where you have gradual thinning of the cortex that if the if the thinning misses the key network then that function might be spared in that patient right and so we're trying to combine this individualized mapping with some of the patients we have there and it's the same for stroke you know stroke you have a certain area that's damaged we want to be able to say well the damage affected 50% of this network's region and what does that mean for long-term prognosis, your likelihood of improving language function for instance. We think those are some really cool applications. Tell me about the your students in your lab and uh how they contributed to this particular paper.

[00:16:57]Yeah, we have a a very collaborative lab where we because we focus on broadly similar techniques. Um the knowledge gained by one is shared between everybody. The student that really led this work that was published in science advances was Denisa Edmonds. She's a graduate student uh in my lab and she was the recipient of an NSF GRFP scholarship. Um and she really you know from inception she was working on defining the network maps and really a lot of the work we do is just how do you demonstrate what you're seeing clearly and so she really did an excellent job of making figures that will really highlight uh the observations for the reader. Tell me about the next steps in your lab and where where you would like to see some of these findings end up someday. Some of these recent findings.

[00:17:47]We have some projects that we are ramping up. So we are currently collecting data on the primary progressive aphasia to study degeneration of the language network which we can map with individuals. And a counterpoint to that is a study we're just starting in stroke patients where we're looking at individuals that have had stroke that affects language. So they have a fasia but then we're going to track them over a year where their language function is probably going to improve in some of them and we can do the brain mapping at multiple time points and see how exactly the language network is changing whether there is evidence of plasticity. What does that look like for someone to improve function? Does it mean the network is shifting, growing, going to the other hemisphere? Or is it just a case that it's the same network region, same location, same everything, but some something about its properties are adapting to the injury or or healing from the injury. So those are some really cool areas that we're that we're investigating. Our work with epilepsy patients, I think, is also very cool. We have some cool experiments looking at the presence of sharp wave ripples which is a a signal in the hypocampus that seems to be related to recollection or the forming of a mental image about something. And so we have some studies where we're looking at those ripples in the context of imagining different things. So whether that's imagining a person, imagining a certain location or even using inner speech which is another form of thought which most of us are familiar with. you know, we often make lists or we'll have a song in our head or whatever it is we're using. Yeah.

[00:19:19]Mental workspace in different ways.

[00:19:21]We're trying to understand the nature, the relationship between those sharp wave ripples and these different forms of thoughts. As we wrap up today, is there anything you would like to leave our listeners with as they think about their own brain and the research that's taking place at Northwestern and what we might expect in the future, what what we're learning that they might find interesting. just a little tidbit as we leave today that you would like to leave people with. Yeah, we we all have fascinating brains and their complexity is being unraveled not just by us but by lots of scientists around the world and here in the US and that you know we're at the beginning of a really exciting era that we should support science and support scientists because who knows where this research will lead one day.

[00:20:06]Fantastic. Well, thank you so much for coming on the show and talking about your latest research, Dr. Rodrigo Brega, and we look forward to seeing new papers coming out of your lab and those from your students, and we will follow up with you to find out more in the future.

[00:20:22]Thank you so much, Aaron. Good to speak with you.

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