CCTS KL2 scholar, Dr. Perry Tsai, is exploring better ways of testing for cognitive dysfunction- or "brain fog"- in people suffering from Long COVID through the use of digital technologies.
Perry Tsai, MD, PhD
Assistant Professor
Department of Psychiatry
UIC College of Medicine
Dr. Alex Leow's BiAffect: The first study on mood and cognition using mobile typing kinematics
Check out our episode on BiAffect!
0:00 Dr. Perry Tsai
As we understand the mechanisms by which Long COVID is happening and how some of these symptoms occur from Long COVID, it's a model for how inflammation can affect mental illness.
0:16 Voice Over (VO), Lauren Rieger:
Welcome to Collaborative Endeavors, a podcast about how experts from different areas of research come together to tackle big health challenges, leading to better therapies and healthier communities.
In this episode, we meet Dr. Perry Tsai, an MD, PhD and assistant professor in UIC’s department of psychiatry and one of CCTS’s newest KL2 grant scholars. One of the benefits of this mentored career development award is that it offers junior faculty 75% protected time to pursue their research interests. Dr. Tsai shared his ambitions for his project titled “Investigating Digital Biomarkers for Post-COVID Cognitive Dysfunction,” starting with his professional background and how he arrived at the intersection of infectious disease and psychiatry.
1:03 Tsai
It's a great question, and my answer to it is, it’s not totally linear. I started as an undergraduate at Harvard, and I studied biochemical sciences, really interested in biology and biological sciences, and was interested in either going into medicine or research. I really wanted to be able to apply my knowledge in biochemistry and biology towards something that was going to be helpful for others and in healthcare or researching disease. I took a little bit of a break after college working in a lab and then ultimately decided to pursue a dual degree program- so MD/PhD programs. I had the fortune to be able to attend at the University of North Carolina Chapel Hill, where I did my medical training medical school training and my graduate school training. At that time, I thought I was going to be an HIV doc. Thought I was going to study and see patients with HIV or AIDS, and that's where I was headed for several years. I did my PhD in a research laboratory studying HIV in a translational mouse model, and I absolutely loved it. It was really cool science. We were doing really cool stuff with an in vivo model of HIV, which was quite useful for translational and preclinical studies on HIV. My thesis was trying to look at various strategies for curing HIV, and spoiler alert: I did not cure HIV. But I was able to use our mouse model to try to set it up as a potential experimental model for studying potential cure strategies for HIV.
When I went back to medical school- usually with MD/PhD programs, you do a couple of years medical school, you do your PhD work, and then you go back for a couple more years of medical school for your clinical rotations- and during that time, I did a couple of rotations in infectious disease, and it didn't click with me in the way that I expected, but I really enjoyed my time in psychiatry and within that world as a clinician and on a day-to-day basis. That's what really grabbed me. That's what really made me feel at home. And so, I ended up applying into psychiatry for residencies as my specialty, and also applied specifically to research track residencies which would offer me protected time to do research and develop my own research profile and portfolio. I was lucky enough to match here at University of Illinois. Over the four years of 2019 and 2023, I did my training in general psychiatry. I was able to work under one of my mentors here, Olusola Ajilore, who's also an MD/PhD and has been really prolific in neuroscience and technology, in doing studies looking at the brain and the networks within the brain. As well as working with Dr. Alex Leow, who is using mobile technology and mobile device technology in order to monitor things like mood and cognition. So, it's been really fortunate for me to be able to find mentors here who are doing research in psychiatry. UIC has a really robust department within psychiatry that's doing research on a lot of different levels, and has a lot of support and funding for that research.
I didn't want to leave behind my immunological background my virological background. Having gotten a PhD in the department of microbiology immunology, having done HIV research, I was really looking for a space where I wanted to be able to continue to have that lens and use that lens in looking at disease and looking at medicine and healthcare. And what happened was, COVID happened. And COVID happened in the middle of my residency, and it affected me in a ways that it affected a lot of people. Long COVID then happened after that. And this is about the time that I was finishing residency. I had the fortune that as I was graduating, we needed a psychiatrist to start seeing Long COVID patients because it was a problem that was popping up time and time again with patients. We have a couple of neurologists and pulmonologists and critical care docs and family medicine docs here at UIC who had been seeing patients with long COVID problems, but we hadn't yet had a psychiatrist who had sort of been able to fill that niche. When I graduated, that's exactly what I wanted to do. It was a space that I could think about an infectious process, a chronic illness due to an infectious process as well as neuropsychiatric problems from that. And so, I have been really lucky to be able to bring those aspects of my training together into starting a psychiatric clinic for Long COVID patients, which I've been seeing these patients for a little over a year now. And then also now, with support from the CCTS, to conduct some research to study these problems in long COVID patients.
6:54 VO:
A huge investment has been made into research examining the cause of Long COVID, what is technically referred to as post-acute sequelae of SARS-CoV-2 infection or PASC. When most people hear “Long COVID,” they immediately think about the impact to the physical body: ongoing respiratory issues, headaches, fatigue, digestive issues, and more. However, a commonly reported, though perhaps less talked about symptom, includes “brain fog” – a blanket term for symptoms that include difficulty concentrating, confusion, forgetfulness, mental exhaustion and slow process time. Dr. Tsai described his patients’ experiences.
7:37 Tsai:
Long COVID spans a huge variety of symptoms. A lot of people might have persistent respiratory symptoms, but it also spans to potentially musculoskeletal symptoms, like pain in the muscles around the joints. It can be fatigue or sleep disturbance. It can also be psychiatric symptoms. So probably the most common one that that we hear within this realm of Post COVID is cognitive dysfunction, and a lot of people describe it colloquially as a brain fog. This is difficult to define, but is often described as a sort of fogginess within their thinking, sometimes slowness. Sometimes people have memory problems where they aren't able to remember things that just happened or were just told to them. Some people have difficulty with finding words that they have used a lot. There's a vast number of ways that cognitive function can present, and probably about half of patients who have Long COVID also report these problems.
In terms of other psychiatric problems. I've often seen patients who have depression or anxiety, and sometimes this is a new onset in the context of Long COVID, or sometimes it's a worsening of their depression or anxiety symptoms they might have had before COVID, and this could be sort of on its own something new. But you can imagine that with all of the other things that are happening within Long COVID, it could be secondary to the brain fog or secondary to problems with sleep or fatigue, or often it can have a psychosocial aspect where a person who has had brain fog is suddenly no longer able to work or no longer able to function in the same way that they did prior to COVID, and that can result in some depression or anxiety about their loss of function or the loss of ability to work. Some people have post traumatic symptoms, particularly if they were in the ICU, or were hospitalized for their COVID experience or their acute COVID infection. Or sometimes people might have lost loved ones and family members to COVID and can have some post traumatic symptoms from that experience, too. So a lot of these different stories. I will say, while a lot of the stories sort of have a similar ring to it out of my patients, every story is a little bit different, too. So, depending on your own history before COVID, your experience during COVID, and your current symptoms, everyone has been a little bit different. So I can't say that that the same story applies to all the patients that I've seen.
10:33 VO:
Our conversation pivoted to what Dr. Tsai is hoping to accomplish through his protected time under the CCTS KL2 award, including how this digital intervention can address some critical gaps in care for patients struggling with cognitive dysfunction.
10:50 Tsai:
The impetus for this project was this observation or realization that the cognitive testing we have come to rely on to measure cognitive function is usually done by neuropsychologists and neuropsychological testing. What I had been seeing or hearing, and from talking to our neuropsychologists, is that we've been doing pretty diligent neuropsychological testing and cognitive function testing with these patients who had these complaints of brain fog and cognitive dysfunction. But a good chunk of the time, they weren't scoring below average or with specific deficits in the neuropsychological testing. And there's various reasons that could be. One of them is that neuropsychological testing typically happens in a pretty controlled clinic setting- so in a clinical office. You don't really have distractions or other things going on in that setting so people might be performing better in that type of setting. Another aspect of neuropsychological testing requires several hours within the clinical setting, and you typically can't do that multiple times during a week. Maybe you could do it once a month or something like that, but who has the time to be able to go to a clinic office for several hours to do a full battery of neuropsychological testing.
Another potential thing is that we often don't have pre-COVID cognitive testing for most of these patients. It's possible that they were functioning maybe higher than average prior to getting COVID, and now have dipped their function into a normal range. It's hard to necessarily see that change, and particularly for people who might have higher demanding jobs or who have a higher level of education or function, a small drop in their cognitive deficit or in their cognitive function might result in them not being able to work that kind of job anymore. This was a discrepancy between the subjective report of what these patients were experiencing. We’re not saying that it's invalid, or we're not saying that anyone is misrepresenting themselves, but it's discrepant with what we're finding on the objective testing that we have available. We had this idea to find a different way to measure and to monitor cognitive function. If we could find something that was potentially more in line with their subjective experience and the subjective reporting of their cognitive dysfunction, this could potentially give us a way to measure improvement. If we were to, you know, test a treatment or to at least monitor over time how these things change.
The idea was to find different ways of a marker for cognitive function. There's been a lot of literature looking at blood biomarkers. There's literature looking at neuroimaging markers. We were trying to develop an approach that we might call digital biomarkers. So, I'm using digital technology as a way to develop a marker for post-COVID cognitive dysfunction, and specifically, this would be through mobile devices. Now, the project is going to look at two different ways to use mobile devices to measure cognitive function. One of them is to translate some of those tests that we do with neuropsychological testing into mobile cognitive testing. We're going to be working with a company called NeuroUX that has developed a lot of this translation and has worked with other research groups and taken some of the neuro-physical psychological testing cognitive tests that that are used and translated them into sort of these games that you can play on your mobile phone. For example, a reaction time game where, when a picture of a dog shows up, you have to tap the screen, and one of the measurements is how quickly you react and how quickly you tap the screen.
The benefits potentially of this approach is that we can get measurements of these cognitive tests multiple times in a day and over the span of maybe a week or two, and so it gives us slightly richer data on more data points, but also feasibly takes these measurements more in a real world environment, a patient or participant who is using their phone out in their daily lives. So, there's multiple advantages to this approach. The other approach that we're going to take is with BiAffect, which was the app developed by Alex Leow and her group where they have been able to reproduce a mobile device keyboard. That doesn't record any of the content of what you might be typing, but records metadata about how you're typing. So again, not what you're typing, but how you're typing it. For example, how many times you're using backspace, how many times you're using auto correct or how quickly you're typing or how many pauses you're taking between keystrokes. A lot of this data can tell us a really rich picture about how you're typing, and they've already been able to look at this as a potential marker for mood. They've been looking at this in the context of mood disorders like depression or bipolar disorder, and what they're starting to do- and what I'm also hoping to do- is using this as a marker for cognitive function. You can sort of intuitively guess that someone who is complaining of brain fog, or who's complaining of being a little bit slow in their concentration or their word finding, that they would have more difficulty with typing on a keyboard. And so, we are hypothesizing that this could be a useful marker for cognitive dysfunction more broadly, but specifically going to be in post-COVID or Long COVID patients in our study.
16:47 VO:
Dr. Tsai went on to describe his mentor team and how they are helping to strengthen his skills as a translational investigator.
17:00 Tsai
I have been really fortunate to find some amazing mentors here at UIC. So in addition to Olu and Alex, a couple of other people that I'm going to be drawing on their expertise are Neil Pliskin, who's a neuropsychologist here at UIC, as well as Jerry Krishnan who, I would say, is sort of the father of our Long COVID clinic and Long COVID care who's a pulmonologist, critical care doctor himself and has been seeing a lot of these patients as well. And each of these people brings a really great level of expertise and approach to what they do. As I mentioned, Olu and Alex are very much on the neuroscience side. Alex is doing the BiAffect and a lot of the data analysis, which is something that I don't have a ton of experience and education in. This approach is going to give us a much richer data set but is also going to require a much more sophisticated methods of data analysis. So, I'm going to be learning a lot from Alex Leow as well as her collaborator, Alexander Demos, who is one of the statisticians that they've been working with. As I mentioned, some of the meat of this is going to be in understanding neuropsychological testing and what it means or what it doesn't mean or what we can conclude or not conclude, as well as trying to compare these in terms of their validity, because our gold standard right now is in person neuropsychological testing. We're trying to demonstrate some validity with NeuroUX and mobile cognitive testing in order to compare it with the in-person neuropsychological testing. And then, I think, Dr. Krishnan has been really supportive of me joining the efforts in treating and researching Long COVID here at UIC. He has been able to connect me with community partners, he's been able to help me think about how we're going to be recruiting participants. Those are aspects of the study that, again, I was not doing this kind of work before, but I'm going to be learning a lot of those aspects of clinical and translational studies from him and from the rest of my team.
19:16 VO:
Dr. Tsai had already explained how this study is repurposing a pre-existing technology, BiAffect, to identify digital biomarkers of cognitive functioning in Long COVID. But I asked him what could be generalized within these new findings to address future research questions. He was excited to share his thoughts on the translational science potential of this work.
19:41 Tsai:
My long-term goal for myself is to be a physician scientist who's looking at mental illness and inflammation. That's something that, as I've transitioned from being an HIV researcher towards being a psychiatric researcher, this is ultimately the goal: I want to bridge these two aspects of inflammation and mental illness. We sort of know broadly that these two things are connected, but we still don't know how on a more granular or specific level. And one of the ways that I'm hopeful this research can contribute to that field is that this is a very specific situation where we have a known infection, and then we have known sequelae from that infection. It’s very likely that inflammation plays some part in this and these are the leading hypotheses of how this works. As we understand Long COVID, and as we understand the mechanisms by which Long COVID is happening, and how some of these symptoms occur from Long COVID, it's a model for how inflammation can affect mental illness. And so, I'm really, really looking forward to, as we learn more about long COVID, we might be able to extrapolate some of these findings into other diseases or other inflammatory processes, and potentially other cognitive problems as well. One of the things that Dr. Ajilore works in is late life depression, and one of the hypotheses around late life depression, development of late life depression, or relapse of late depression is that there may be a cognitive decline that precedes this. And we don't always know exactly how that happens. But within neurocognitive disorders or neurodegenerative disorders, there's a pretty strong likelihood that inflammation happens to sort of drive this process. And we've often known about the connections between aging and inflammation, how inflammation starts to either increase or become a little bit dysregulated as we age, and this could contribute to cognitive decline and or depression later on. And so, the use of mobile cognitive testing, or BiAffect, could be helpful in trying to measure cognitive decline as well in older populations. There's a lot of interesting directions that this could go, and we're not only hopeful about treating Long COVID patients, but utilizing some of these models scientifically in terms of implementation in other patient populations.
22:34 VO:
Dr. Tsai concluded our conversation with a personal sentiment on COVID post-pandemic.
22:48 Tsai:
I think the message or the story that I have gotten from my patients I would like to spread is that COVID isn't gone yet. Some of the stories that I've gotten have really been heartbreaking, and I can recall very vividly one of my patients telling me how people will look at her, and tell her like, “Aren't you better yet?” And it's really challenging for people who have Long COVID to describe and to validate or justify their symptoms or their experiences to their friends, or coworkers, or family, or also to healthcare providers, too, because a lot of people will be very dismissive of these symptoms. And while our society has seemed to move on from COVID, COVID is stuck with a lot of patients who are struggling with Long COVID. And so, I encourage everyone to have a little bit of grace and a little bit of kindness for anyone who says that they're struggling with Long COVID. Unfortunately, we don't have treatments yet, but I also would like these patients, and anyone who knows them, to continue to have hope for treatments that are going to going to be coming soon in the future.
24:22 Voice Over Outro:
Collaborative Endeavors is written and produced by me, Lauren Rieger, on behalf of the Center for Clinical and Translational Science (AKA the CCTS) at the University of Illinois Chicago.
To learn more about Dr. Perry Tsai and the CCTS’s KL2 CATS and CATS affiliate program, visit the links in our show notes.
The CCTS is supported by the National Institutes of Health’s National Center for Advancing Translational Science through their Clinical and Translational Science Award. Opinions expressed by guests of the show are their own and do not necessarily represent the views of myself, the CCTS or our funding agencies.
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