Study about brain fog and the other neurological symptoms experienced by some COVID patients.

Dr. Michael Lawrence, PhD, Corewell Health, and Bengt B. Arnetz, MD, PhD, Michigan State University

Sarina Gleason [email protected]

Media Register to Attend

Hello and welcome to today's Newswise Live virtual press briefing. We have embargoed research from Corewell Health in collaboration with some researchers at Michigan State University. I have here the lead researcher on that project, Dr. Lawrence. Dr. Lawrence, please introduce yourself and your position there at Corewell and tell us a little bit about the findings of this study to get us started. 

Sure and I could tell you that Dr. Arnetz is on, under iPad.

Got it. Thank you. Perfect. 

No worries. We could have him join as well. So my name is Dr Michael Lawrence. I am one of the division chiefs in our Neuroscience Department at Corewell. I run our Neuropsychology department here, and this study was completed in conjunction with researchers from Michigan State University and Dr. Arnetz. There, he is.

Awesome. Dr Arnetz, welcome. Please introduce yourself and your position there at Michigan State.

Yes, hi, here at the time I was doing this work. I was a professor at the Michigan State University Department of Family Medicine, and I'm an occupational environmental medicine specialist.

So Dr. Lawrence, tell us a little bit about how you research this group of patients experiencing long COVID and especially a subgroup that experienced some cognitive and psychological symptoms, and how you went about comparing them with the fully recovered control group, and what you found?

Sure, so when we ventured into this study as a neuropsychologist, I was very much interested in patient’s cognitive and emotional complaints as it related to COVID infection, and what we knew, and what research was telling us early on is that individuals with COVID, some recovered well, and others did not. And interestingly, with COVID, it's not really the severity of initial infection that tends to predict that. So we see individuals that are extremely sick, that are hospitalized for weeks, that recover really well, and we see individuals that never have to go to the hospital, that are plagued by long COVID related symptoms. And symptoms tend to be non- specific, and what I mean by that is individuals that experience long COVID report a constellation of symptoms, and these symptoms can be cognitive, they can be physical, and they can be emotional. And so working with Bengt, what we looked at is a number of different objective markers of recovery, cognitive, emotional, quality of life, and then various biomarkers that Bengt has looked at in other conditions as well.

From your study and from the other literature, what kind of population of patients are we talking about? How many COVID patients typically fall into that long COVID category, and how many of those experience those brain fog and psychological symptoms?

Yeah, they you know, of course, given the number of dying of COVID in the States was around 100 million, and of those, around 10 to 30% of long COVID, and among those around it's not a good estimate, but around 10 to 30% developed brain fog and so on. And CDC just did an estimate, and they estimate that 6% of American adults are suffering from long COVID. Among those two can estimate around three to 4% of all Americans will be suffering from brain fog and the symptoms. So it's quite a substantial number of people.

Dr. Lawrence, this is coming out in PLOS ONE on Thursday the 15th at 2:00 PM, just a reminder to reporters that everything is embargoed until then Thursday at 2:00 PM. So Dr. Lawrence, what were some of the other specific self-reported factors, of their symptoms, their quality of life and other factors that you found that were worth highlighting here?

I think one of the challenges that we had with this study is one of the things that we really thought was important is to have PCR-confirmed COVID patients. And I think one of the things that makes our study very unique is that we had PCR-confirmed COVID patients. And so we looked at a sample of 17 individuals, 10 that had long COVID, and we defined long COVID much more conservatively than other literature. Other literature says that you have to have persisting symptoms for greater than three months. In our study, we actually made it greater than six months. And so we evaluated 10 individuals that continue to have symptoms six months post confirmed infection, compared to seven individuals who fully recovered. And what we found is that from a neurocognitive standpoint, most individuals reporting long COVID and reporting cognitive symptoms look generally normal on neurocognitive testing. Out of the multitude of tests that we gave, only one test seemed to show group differences, and that test is a test of what we call letter fluency. It measures executive functioning, but executive functioning under time constraints. And what we often see from a cognitive standpoint that patients with COVID describe is that cognitively they describe challenges, but a lot of those challenges relate to fatigue and just being effective and efficient. It's this processing speed related issue that we think is somewhat related to COVID fog, but also somewhat different, outside of the cognitive domain, what we found is individuals with long COVID reported significantly lower quality of life, significantly lower physical health, worse emotional functioning, and physical well being. And so these individuals with long COVID on self-report questionnaires did report more mood-related symptoms and did report lower quality of life.

What would you consider good further research to do, to expand on and deepen the understanding of these findings?

Bengt, do you want to..

I think, you know, Mike mentioned a lot of very important findings. In addition, I think we also found biological changes. I think it's very strong, a big strength of this study. So in parallel with effect executive function, we also saw that one hormone that reflects the brain's ability to adapt to grow new neurons and connection was suppressed in long COVID, which is aligned with the findings in the neurocognitive test, and that's a very novel finding, and no one has really looked at that before, with proven cases that have recovered, not recovered from the infection. And the other finding we found was that there has been discussion of whether or not long COVID is partly related to residual inflammation, and we have some indication here that, and one of the inflammatory marker was actually more likely to be higher in the long COVID group. And that could be a sign that there's an ongoing inflammation which a lot of patients perceive they have. And that's also a rather novel finding. So I just want to put that in there. And so I think it's important to note, this is not just self report findings. Those are actually biological measures. Some of them are cutting edge but they are possible to measure now in the clinic.

That's very helpful, bringing us to those biomarkers. And that's a further question that we have for you about what were the key biomarkers? There were measurable substances in the body that correlate to these changes and showed statistical significance.

We target a very, very specific mechanism, one mechanism we had. One thing was that, how can we measure some marker that reflects by executive function, where we looked at no nerve growth factors, a factor in the brain that stimulates neurons to grow and interconnect in a way, and it seems to be very important to develop strategies to deal with stress and in the long COVID patient that the level those were lower than in the control group. And the other thing we looked at was Interleukin-10, which is a very, very interesting marker of inflammation, but it can also kick in where you want to try to drive energy in the body. So this could symbolize that there was an ongoing inflammation in the long COVID, but it could also be a sign that the body is trying to do something with the fatigue. Michael was talking about how the long COVID group is really suffering from fatigue, and the body seems to be trying to find a mechanism to deal with that from a biological perspective, not effectively, but there's a biological mechanism. We looked at stress hormones, we looked at other markers, and we didn't see anything there. We didn't see anything in anti-stress hormones. So it seems to be very specific to some marker that relates to brain function and inflammation.

Tell us, if you can, what these biomarkers essentially mean, the nerve growth factor being lower. What's the result of that? What does that mean for the patient?

We think it's the mark that the brain. And Mike can tell you much more about this, but these patients suffer. They perceive that the brain is not working at the capacity used to your memories decrease. You feed brain fog. You're not as sharp as you felt you were before. And we think this hormone might be partly explaining those symptoms. It's an indication that the brain is not as active in regenerating and connecting neurons with one another as it used to be. So that's why we think this nerve growth factor is something you really want to look at in the clinic. Now, when you look up, when you start following up on patients on COVID,

Dr. Lawrence, anything you'd add about the nerve growth factor?

I think you know, when we think about brain plasticity, what we know is, every time we learn new things, our brain changes, and our brain is extremely flexible when we're always creating new pathways and road work, and what we hear from COVID patients is, “I can still do things, but everything takes more energy. Everything's harder. Nothing's as automatic as it used to be. I'm just exhausted every day and I feel foggy. I can still do it, but I'm kind of moving through this fog to be effective. I'm just much less efficient.” And those symptoms really, I think are very well explained by what Bengt knows about these biomarkers. And I think what's interesting about this and further study, I think tracking these patients over time is going to be essential, because what we know is that the more neurons you form, the more protection we have later in life, because as we age, we lose cells, and we lose neurons and we lose connection. And so the question is not only focusing on these patients and how they're plagued by symptoms now. But what's life going to look like for these individuals 10 years down the road, 20 years down the road, 30 years down the road, are these individuals going to be more at risk for other neurologic conditions, vascular compromise, or things such as Alzheimer's disease?

What can you tell us about the other biomarker that was brought up, the Interleukin-10, and what that one means an elevated level of that Interleukin-10 means what?

Interleukin-10 is. It's part of the inflammatory system. So when you're trying to activate inflammation in the body to defend itself, this is one of the key response variable. You need a response to this Interleukin-10, really, to get an efficient anti-inflammatory response. So it's part of the way the body is trying to find inflammation, and it also seems to be trying to drive energy to generate energy in the body. So we interpret this like there is ongoing inflammation in patient with long COVID, and that it is important to take that in consideration, even in long COVID. And typically, the workup with long COVID patient doesn't really contain many of these biomarkers. You know, we assume that everything is going to be you're not going to find anything. But this is a very small study, because we had to follow up. We had to expand the study. But it indicates that these days, worthwhile looking at some biomarkers. In addition to what Dr. Lawrence is mentioning about neuro cognitive testing.

Dr. Lawrence, how does inflammation affect the brain? Are mental health symptoms and other psychological and cognitive symptoms affected by higher inflammation?

No, I mean, I think inflammatory process can lead to pruning of nerve cells, and so you can have less nerve growth. And I think there is a correlation there between nerve growth factor that we're seeing in this Interleukin-10. I think the other piece is how Bengt talks about the fatigue, what we know. And I think what is very frustrating for COVID patients that we work with is we really haven't been able to objectively identify anything up to this point that differentiates those that recover and those that don't. Many of these patients describe fog, but fog isn't necessarily reduced processing speed. And a lot of neuro cognitive tests that we give that measure processing speed, patients do just fine. It's this idea of, I just feel mentally slower. I feel a bit out of it, I feel more fatigued, and there's no way to really identify or capture fatigue, right? It's the self-report variable. But I think that Interleukin, given that it's an energy production and Bengt, can talk better about this than I can I think there is a relationship there, and I think it's helpful, because now we have some objective findings that really confirm what patients are describing and feeling,

And tell me a little bit about why you feel. It's important to identify these objective measures to really support and validate the reality of what these patients are experiencing. Symptom wise, that can be very subjective sounding. Why is that important to you?

Yeah, Bengt. Do you want to go first?

Sure, yeah. I think first of all, it's very, very important for the patient. You know that the symptoms I have are real. You know this is not just something I experience. It might be hard for the medical establishment to identify the markers, but it's real. And now we have indicated there are some changes that might be worthwhile to pursue. The second one is extremely important, that in focusing treatment and also follow up on treatment to see early changes before you might see changes in brain fog. You might see normalization of these biological variables. For example, we decrease inflammation, or we might actually stimulate nerve growth factor. So I think, and then third of what is also drives theory, right? What creates long COVID? You know, we don't know very much about that, and knowing some possible biological mechanism is going to help us zoom in when we look for this in the future.

I think, as a clinician, what I hear when patients come in is they often feel invalidated by the medical community. They come in with various symptoms, and there's really not an explanation for it, and oftentimes we do a thorough medical workup, and everything looks normal, and physicians kind of throw up their hands and say, This must be psychological. And I think you're struggling with anxiety, stress, depression. Go see a therapist, they see a therapist, and they work on the mental health piece, but they're still left with these physical symptoms. And so I agree with Bengt. I think one of the great things about these biomarkers is it validates changes that they subjectively are experiencing in an objective way. And I think validating a patient is the first step in terms of treatment. And the other piece that Bengt is mentioning is what we know, given this multitude of symptoms, is the treatment is going to need to be multimodal. We're going to need to focus on physical symptoms. We're going to need to focus on cognitive complaints, and we're going to need to focus on a patient's emotional health. And so if we can identify these individuals based upon these biomarkers that may be vulnerable to experiencing long COVID, then we can wrap care around them early and hopefully affect change soon, because many of these individuals six months out, are still left feeling as if they're not understood and they're not receiving any treatment.

I want to make sure to remind our audience that the floor is open for questions from reporters. Please chat those to me, and I'll ask them. I think we have a couple people submitting questions, and I'll come to that in just one second, but first, before we turn to those questions, you've identified these biomarkers, and you know, compared the long COVID group to the control group of people who fully recovered, is it also safe to assume that during the actual disease period of COVID similar patterns are probably present for the people experiencing brain fog and other symptoms like that, even if they do fully recover in that more short time period, as most patients do, without it becoming long COVID. Are patients experiencing that during the regular course of the sickness, in your opinion?

So I would say, and maybe Bengt can speak to this. I have no idea. I have no idea if these individuals that recover well would test positive for these biomarkers during their acute phase of injury. And so I think that's one area or avenue of further research is doing biomarker work in the acute phase to see change over time. Yeah,

You've identified now what to look for. And so maybe that can be one of the next studies to look into. We have some questions from the audience. I want to go first to Laura from IFLscience. She says I'd be interested to know if the doctors believe it's possible that their research might translate to similar patient populations with other post viral conditions, or whether something more specific about COVID is at play here. Does this seem like something that's very unique to COVID, or do there seem to be connections to other viral disease that you might look into?

Mike, you want to start with that?

Yeah. I mean, I, I really do not know. I know that what we often see in the medical community, and probably the biggest parallel from a medical diagnosis, is fibromyalgia, and individuals with fibromyalgia describe a lot of what they call fibro fog, which is very similar to the fogginess that post COVID patients experience as well. And so I think looking at a Fibromyalgia population and comparing these biomarkers would be very interesting as well. Individuals with fibromyalgia often report a number of different symptoms that involve physical complaints, cognitive and emotional as well, and so I do think there's some parallels to that population. 

Yeah. I think it's a very intriguing question, because a different source infections are this is not the first source, and fatigue is a common symptom among people after virus infection and post viral infections. So it certainly is worth considering moving forward.

Another question from Crystal, who is a freelancer, given how COVID-19 deaths were mediated by racial health care disparities, are you able to comment regarding the racial makeup of the study?

We had 14% you know, we had one African-American study, and we had like 15 white and that was just the challenge of actually recruiting people. And if I but one into the health disparity that is very, very observant is we know that those economic stress and health disparity or is affecting immune system. We know it's much, much more stress if you live in a much, you know, more socio-economically challenged environment. So this could be contributed to the findings, even though we don't have enough in this study to talk about different racial groups, the study is too small.

Another question from Francesca, it has been reported that some people who had asymptomatic COVID have also gotten long COVID. How do you identify these individuals having COVID originally, and for example, she says immune mediated, small fiber neuropathy has been reported in these individuals. So even people who are asymptomatic from a respiratory point of view, might still have some of these other complications.

Yeah, there's 100 million I mentioned to start with, is only confirmed cases in United States, so that there might be much more than 100 million who got COVID. And that's why we were so meticulous about, you know, identifying, making sure that everybody that was part of the study, through a test, PCR test, actually had COVID. So we don't really know about, yes, we're aware of that. You know that neuropathy, pathology and the relationship with immune system. The immune system is delicate, both in learning, you know, stress mediation, but neurologic  function. But this study doesn't you know, we specifically just looked at people that had confirmed COVID, had had the infection. I think it's a very interesting comment about young people, they were never aware of it.

And I think that's, that's one of the things when, when you look at the psychological aspect of this, is, you know, we interviewed all of these patients. I interviewed all these patients significantly. And we look for common themes and interviews. And I think one of the themes that patients often describe is, “My family, my physicians, everyone else doesn't understand why I'm still struggling so much, because I really didn't have it that bad.” And what we see is, with a lot of other neurologic and medical conditions, the more acute illness or injury the individual has, the longer it takes them to recover. And with COVID, it's different. What we see is individuals that have medical symptoms can transfer to long COVID And those that have very significant symptoms that require hospitalization, can recover very quickly, and that's why it's even more important to try to find biomarkers or something that we can differentiate who's vulnerable, so that we can wrap around treatment early.

It seems remarkable, with five years now into dealing with this new virus that we're still discovering areas that we still know little about. It's really fascinating. Another question, Don from United Press International asks, is there any earlier research on long COVID that your work is confirming and building on or perhaps even refuting anything?

I think some of the biomarkers that you looked at, we have seen, kind of confirmed in rodents, but not in humans. Is that correct?

Yeah, that is correct. And there was, there has been a circular focus. The Fauci has focused on inflammatory system, right? We knew that was high, likely culprit of these symptoms looked, also some studies that looked at brain markers, but we don't. We really, I think, more confirmed theories. You know, there have been speculation about these things. I don't think we refute other studies. I think, I think, I think this neuropsych is probably very important, right? They were so focused. I think people thought it was more, broader impact before we could show us rather focus impact of the long COVID.

Yeah, there's been a wealth of research on mental health aspects of long COVID, and I think this confirms that and previous evaluations of cognitive functioning often show that individuals with long COVID look generally normal on objective neurocognitive tests. And for the most part, our study confirmed that as well.

Yeah, and I think you mentioned before, Mike, but just confirm that, or stress that, fatigue has been confirmed in almost all studies, is that we were able to link it to possible biological mechanism. But fatigue is enormous, and it's a substantial challenge, and that is what other studies have found the same.

It really strikes me as something with these sort of subjective self-reporting measures of that sluggishness, the effort it takes to do certain tasks or thinking, and while those are not necessarily raising red flags on the typical screenings and testing that we have in place that our own perception of something is there and yet we don't necessarily have the tools to measure that very clearly. Is that great, in your opinion?

Yeah, absolutely. And I think it further compounds the psychological impact of this, because patients need to feel validated and understood, yeah, and when they're not, it's, it's extremely challenging and difficult.

Moving ahead then to potential treatment and what insights this might provide for ways of helping these patients. Are there specific medications or any other sorts of advice and recommendations that you might make out of this study?

From the biological perspective, it's worthwhile, and it's already tried, and it's also off-label use in the clinic. You look at anti inflammatory, Naloxone, or, you know, low dose people are trying different kind of PAXLOVID, for example, Metformin is being tried now to see if you can affect long COVID and interesting, also, antidepressant, not because of the depression. We didn't find that these people more depressed than the control group. However, it stimulates the brain neuroplasticity that Dr. Lawrence was mentioning, and that might there's some off-label use of that. That's a very interesting aspect. Can you actually stimulate the brain to generate more neuro connection, neuroplasticity? So that's being tried. Maybe, Mike, you want to talk about the psychosocial support?

Yeah,I mean, I think from a clinical application standpoint, what we know is, at least the patients that we've seen and what we've read about for other patients with long COVID is they don't typically report unimodal symptoms. And so it's rare for an individual with long COVID to say, I just have mental health related issues, or I just have physical complaints or I just have cognitive complaints, but some constellation of all of these things. And I think if we can identify these individuals early with biomarkers, then we can develop multidisciplinary treatment to focus on all aspects of the individual. And I think patients and I think our medical community, at least years ago, tended to separate the mental health from the physical. And what we know is they're all very interconnected. And the more we can improve mental health related symptoms, what we see is decreased reports of pain and fatigue. And so we really need to treat the whole person, but we need to treat it early. And I think what's cool about this study, and I think future research can look at these biomarkers over time to see what treatments tend to affect or change these serum levels.

Thom Canalichio:

That's a good note to end on. I think we've come to a good conclusion here with our discussion. Thank you so much, Dr. Arnetz and Dr. Lawrence. Members of the media, please remember this is under embargo until Thursday at 2:00 PM, Thursday, May 15th at 2 p.m. Eastern, the journal PLOS One is publishing the study. And at that point, you are permitted to publish any articles about the subject. If you'd like to follow up with either Dr. Arnetz or Dr. Lawrence here with any further questions, I've chatted Sarina's contact info at Corewell Health.So feel free to shoot her an email and she'll get you in touch with Dr. Arnetz and Dr. Lawrence if you have any further follow-up questions. We will provide this recording and transcript to you later by email. And please feel free to get in touch with us here at Newswise if you have any questions or need any assistance. So with that, I'll say thank you, Dr. Lawrence. Thank you, Dr. Arnetz. And to everyone, thank you very much for attending. Congratulations on this study. It seems very important and a step in the right direction for helping these people get the treatment they need. Thank you very much. Namaste and good luck.