OHBM 2021 Keynote Interview Series: Q&A with Anna Wang Roe - Mapping Mesoscale Connectomes

By Nabin Koirala

In light of her upcoming Keynote lecture at OHBM2021, we wanted to get up close with Anna Wang Roe. Dr. Roe is currently the director of the Interdisciplinary Institute of Neuroscience and Technology at Zhejiang University, China. In the interview, we talked about her academic journey and were lucky to hear some backstage stories to get to know Dr. Roe even better.

Nabin Koirala (NK): I would start by saying thank you for making time and agreeing to the interview. I am very excited to find out more about the keynote lecture that you are planning for the annual OHBM meeting 2021 but also in general about you and your personal experience in research. To start with, maybe you could introduce your research to our readers who are not only scientists.

Anna Wang Roe (AWR): I've been trying to understand, for a long time now, what it is about our brain that makes it capable of doing abstract things like sensation, cognition and emotion. I've been mystified by the fact that the brain as a structure is physical, but still able to generate these abstract behaviors. So how does abstraction arise from a physical entity like the brain? And after all these years now, I believe that I may have an approach that will lead us to an answer.

NK: That’s fascinating. Could you maybe also tell us a bit more about all those years you mentioned, or in other words your journey in science so far?

AWR: Sure, let me go through a little bit of my travels through these ideas. So, I started off in college as a math major at Harvard, where I took a course on logical systems with elements, theorems and rules. This led to a lightbulb moment in which I suddenly needed to know whether the brain qualifies as a logical system. So, kind of overnight, I turned myself into a biologist and filled my senior year with neuroanatomy, neurophysiology and laboratory work, which I immediately fell in love with. So much so that I ended up as a graduate student at the Brain and Cognitive Sciences department at MIT. My mentor at that time, Mriganka Sur, gave me a really great project on brain development. The question we were asking was whether the visual cortex was visual because of the cortical tissue itself or whether it was visual by virtue of the inputs that it gets? In some sense it was a very philosophical question. In the experiment, I rerouted the visual inputs from the eye into what normally is the auditory pathway to observe whether the auditory cortex would behave like a visual cortex, or whether it would still behave like an auditory cortex. Using electrophysiological methods, I found, lo and behold, that this cortex was definitely more visual in the sense that it contained a visual map and contained cells that were orientation selective. This was a very big finding with huge impact (even yielding a couple of Science papers!) because it showed that the target structure had an internal inherent circuitry that processes whatever it receives as an input, suggesting there are standard canonical cortical circuits. Importantly, this result had a huge impact on me personally because I was very attracted to the idea of cortical columns, made famous by Nobel laureates David Hubel and Torsten Wiesel, as fundamental elements of very systematic architecture to the brain. I was really attracted to the computational, genetic and developmental efficiency of this architecture. So I wanted to know whether columns are ubiquitous in the brain, and if so, what are the rules that govern their organization and their connectivity? Are the observed functions in the brain a result of a system of such elements and rules? These questions then drove my research and my career in science because if they were to be true, then this would suggest that the brain really has some machine-like qualities, bringing me back to my original question of whether the brain is a logical system. I hope to find the answers to these in the coming years.

NK: That’s very interesting. So, at what stage are we in this path of getting the answer? As you mention in your webpage, do you think we are close to developing a mind-machine interface and how far are we from being able to modify it to enhance brain function or human behaviors for therapeutic purposes? It would be great if you could give us more insight with your current research focus in achieving these goals.

AWR: I chose non-human primate brains as an animal model because of the similarity to humans. They have a similar visual system, they use their hands for manual behaviors as we do, and their brain architecture, including columns, is very similar to that of humans. We train monkeys to do behaviors, and then image their brains while they're performing different visual tasks to understand the functional role of columnar units in vision. Because these functional units are very small, in a sub-millimeter range, we developed imaging techniques which provide high spatial resolution and help us accurately map the brain. In the last three decades, I've mapped these columns throughout the brain, particularly in visual and somatosensory areas, but also in motor and prefrontal areas. And based on the findings from these studies, I believe that these columns exist at least in 80% area throughout the cortex.
The next step was to study how these units are connected to each other in networks, something that really no one has done systematically and at this columnar scale. I believe the word connectome is probably a familiar term referring to all the connections in the brain. There are a lot of connectome projects throughout the world and many millions of connectome dollars have been spent. But ours is the first in primates at mesoscale (or columnar scale).

To give you an example of why imaging spatial resolution is important, let's say you and I are standing next to each other and I am talking to Person A, and you are talking to Person B. Now, if a method could not resolve you versus me, then it would appear that both you and I as a unit are speaking to both A and to B, which would be incorrect. So the importance of high spatial resolution and developing methods to achieve such resolution cannot be overstated. The method I will talk about at OHBM is called INS-fMRI (or infrared neural stimulation with fMRI). This is an optical stimulation method that activates neurons but, unlike optogenetics, does not depend on viral transfection. This new method directly stimulates neurons with infrared light in a way that doesn't harm them, and at the same time, activates them effectively. With this method, we’ve shown in our 2019 Science Advances and our 2021 Neuroimage papers that brain networks are indeed based on activations at columnar scale. I'm now planning to apply this technique across the brain, systematically and hope to learn about the overall architecture of connections in the brain. I predict this focus on the fundamental units of processing will strongly impact the world of brain machine interface, medicine, and AI. That is, to effectively interface with the brain, you must understand its basic architecture.

NK: I hope that happens soon so that we could actually have the mesoscale level connectome. I believe this is also part of your upcoming keynote lecture, so let me try to understand this a bit more. While explaining the advantages of this method, we talked a lot about  the spatial resolution which could be in the sub-millimeter scale, but what about the temporal resolution? Isn’t this also an important aspect to understand these functional units’ behavior? Is the temporal resolution in your method somehow better than established imaging techniques like fMRI?

AWR: That’s an important issue and I am glad that you brought it up. There is definitely a limit to the temporal resolution. So, with ultra-high field imaging, you could gain a lot in terms of signal to noise ratio, but the temporal resolution is still limited to that of the BOLD signal which is on the order of seconds. So to study the rapid dynamics of these units, you need to add other methodologies such as electrophysiological recordings. As my papers will attest to, I’m a true believer in multimodal solutions to challenging questions.

NK: So, are you already exploring the possibility of combining all three techniques – infrared neural stimulation, fMRI and EEG (for example)?

AWR: Yes, absolutely and this is exactly what we're planning to do. Right now, we have the INS and fMRI in anesthetized and behaving monkeys, and have already developed electrodes that can record during the MRI. We are investing resources into EEG recordings covering the whole brain to provide a more complete picture of the temporal aspects, so bit by bit we hope to crack this nut!

NK: Do you think it might have a translational possibility to humans at some time point?

AWR: I wasn't going to raise this but yes, we are already starting to explore this possibility with some neurosurgeons. You know, having interfaces with the brain is an idea that is becoming more widely accepted. People are walking around today with stimulators in their brain, for example, deep brain stimulation for Parkinson's patients, psychiatric conditions, cochlear implants etc. The whole field is still developing. So, we are working on that direction and I think it will happen sooner than we expect.

NK: That's fascinating to hear, and I believe with the newer technologies for deep brain stimulation forthcoming like high intensity focal ultrasound which provides the possibility of non-invasive stimulation will further escalate the possibilities. Turning to your experience in academia so far -  You have worked in many different universities and eventually moved to China from the US. Could you maybe walk us through what drove this decision? Is it actually like the media portrays that the weight is shifting to China in terms of research resources available etc.? 

ARW: Well, one of the main reasons I moved around was because of the technology that was available at the places that I went to. For me, science and technology go hand in hand, so to answer the questions I have, I need new technologies. For example, as we talked earlier, we need higher spatial and temporal resolution to be able to answer the connectivity problem and the technical possibilities to be able to stimulate the brain in specific ways. So, that is my main attractor and was the reason as well why I moved then from Yale to Vanderbilt because Vanderbilt was establishing a new MRI center and a whole new group for that. I benefited a lot by working with them at Vanderbilt.

Now regarding my move to China, I believe it was a combination of things. In 2012, I took a sabbatical in China and visited many universities and institutions, where I discovered Zhejiang University here in Hangzhou. I was really wowed by how collaborative people were here, and on top of that the city is truly one of the most beautiful in the world! The collaborative atmosphere made me believe that it would be a great place for an interdisciplinary institute. So I made the proposal to the university to set up a neuroscience and technology Institute and they went for it, so that's how that started. It's been a gradual transition moving from US to here and in the meantime, I also joined Oregon National Primate Research Center in a half time position. ONPRC is a huge primate resource with over 5000 monkeys. It's absolutely amazing. The resources they have, like a dedicated MRI for monkeys and lots of NHP expertise in the campus, attracted me to get involved there. But eventually, my projects in China - especially the connectome project - required my full time. Here in China, I’ve got students of different backgrounds in my lab, including medical science, optical engineering, computer science, biomedical engineering. It’s a real collaborative team effort! And as the institute is growing with about 15 PIs, an MRI center with 3T and 7T, nonhuman primate facility, two photon and three photon imaging facilities, and multiple teams of researchers working here, it is difficult to get out. (laughs)

NK: That's great. It's very rare that you can gather all these technologies in one institute and focus on your research question. Also, it’s good to know that this kind of research is still possible. Because with the recent incidents in Tübingen, Germany and a couple of labs in the US, scientists were thinking twice before starting the primate research. Anyways, as you now have research experience in both China and the USA, could you tell us something about similarities and differences in terms of research culture?

AWR: Well, there's definitely differences but I would say that, as far as the quality of research goes, the best research here is as good as the best research in the US. I have found not only are the scientists excellent here, but the students are fantastic as well. They're very motivated, hardworking and inquisitive and that's important. The students here though have different backgrounds than those in the US because for the students here it’s been a competition at every level: they have to be the best students to get into good middle schools and the best high schools and then on to college. So, by the time they get to join the university, they are really the cream of the crop. It’s been really a privilege to be working with them. They might not be thinking outside of the box enough and opening themselves up as much as the students in the US because of their culture, but I challenge them on this front. They also benefit from our international profile, as we have researchers from different cultures, including non-Chinese speaking scientists from different parts of the world.

NK: I think this is an interesting point that you brought up regarding the non-Chinese scientist coming to China. So, how is the trend now compared to, say, 10 or 20 years back? Do you think it is increasing given China’s investment in science? Or how do you think it will go on in the future?

AWR: I would say that it was really good for a while. There were a lot of foreign scientists coming here and Chinese scientists going abroad. But in the last few years, particularly since the Trump administration, it's really kind of shut down. I would say in the last three years it's changed drastically. And now the feeling is that, well, you might get in trouble if you collaborate, which is not a good feeling to have. I became very sensitive because I am working on both sides of the ocean. So, it has become difficult these days to collaborate or develop technologies collaboratively. Even NIH has become sensitive towards these interactions. This is not good for either side. According to my colleagues and friends in the US, they are having such a hard time finding postdocs to fill their labs. On this side, the students are not able to gain the exposure and experience because these days they cannot get visas to go to the US. I am sure this is a passing thing and science will prevail.

NK: Hopefully this political tension will improve soon, and they will leave the scientist to do science again. So, we have talked a lot about science and as we are almost nearing the end, I would like to talk about some of your personal interests. So, let’s start with your hobbies: what kind of hobbies do you have outside of science?

AWR: Well, I have to be honest, I don't have a lot of free time (laughs). But what I truly enjoy is cooking. That's something my husband and I do a lot together. We enjoy that and having friends over, trying different recipes and enjoying the time. The other thing I enjoy is art and nature. So, whenever I get the chance, I go to galleries and museums, or outdoors in nature. The city is truly beautiful and with emphasis on nature, so I enjoy that a lot here.

NK: Sounds great. So, as this blog is read by lots of young scientists, what would be some suggestions you would like to give them, not only to be successful but also to do good research.

AWR: Okay, I generally don't prefer to say this is the way you should do things. But if I had to answer that question, I would say to do good science, follow your heart and your intuition. Often, people think of scientists as these logical beings, but sometimes some of your critical decisions are really from the heart. If it works for you, you should go for it. Another useful quality is being able to fight and be persistent. If somebody says you’re wrong, you should not give up, if an editor rejects your idea, you have to tell the editor to reconsider - I know that's not always easy though (laughs), but you should really stand up for yourself. It doesn't have to be obnoxious, but persistence has to be there. A third suggestion is probably a more practical aspect of science, which is money. I would say, always plan for a rainy day and use your funding wisely. The last thing I would like to add to that is you should always know that science is full of different personalities and people with different backgrounds. So, as a supervisor it's good to try to figure out what somebody is seeking and what they are good at and try to use that to their advantage and as well as your own advantage. It's not always easy to do but everyone's got skills and talents that can be useful in science.

NK: These are great suggestions, thank you. Maybe a bit of fun now, as you've been working in neuroscience for so long, what would be your favorite brain region and a toolbox?

AWR: I guess for the favorite brain region, I'm biased by the brain region I'm studying now. I've been studying sensory systems for a long time and trying to understand the hierarchy of the processing within a sensory system. Now I'm in an area called the amygdala, which is a part of the limbic system and primarily processes emotions. And this is a region I am really in love with now because this is an area that's tied to all different parts of the brain, including your sensory, motor, cognitive regions up to the autonomic and visceral systems. And it amazes me every time thinking how this tiny region could handle all this complex integration of different information. This area not only filters your incoming information through cognitive and emotional filters to make a final output or so to say generate feeling, but at the same time it also controls your physiology, including your heart rate, your breathing and all sorts of things. I should mention that this will be a part of my keynote talk in OHBM this year as we are studying these connections using the INS-fMRI technique. For the toolbox, I am not using any actively at the moment but my students and postdocs love AFNI. Personally though, I still love mathematics and most of the time I am still wondering how to develop a math theory of the brain. Recently I am trying to think more about recursion and how that might bring succinctness to our brain architecture. So from that sense I am more interested in basic equations rather than toolboxes (laughs).

NK: That’s great. I think it would be incomplete to conclude this interview without mentioning the pandemic. As there are lots of discussions about productivity, how it has been impacted, how it should be handled and so on. So, maybe you could say how it had impacted your research and research in general.

AWR: Well, last year in 2020, I spent 9 months in the US as I got stuck there when the pandemic hit. I could not do lab work and mostly stayed home, but I became very productive writing papers that were backlogged. So, it still was a good use of time. When I returned to China, I immediately felt that I landed in a different world. Society was functioning pretty much like normal. Just because they were able to control the pandemic here, the return to normal was fast. In the US, even though things have slowed down a bit, with the COVID vaccinations going well, things are picking up and returning to normal, too. People have found ways to adapt, and sometimes challenging times can also be good for science. For example, I was recently invited to a meeting organized by PRIME-DE (international primate data exchange group), and there were no presentations or talks but instead just primate researchers getting together for discussions. I really loved that, and the response to the pandemic showed that we can be resourceful and find alternative solutions.

NK: I would like to say thank you again for talking with me and sharing your experience with us. Looking forward to your talk.

AWR: Thank you so much for this opportunity. It was a pleasure talking with you and I wish you great success in your research.