#3 Brain Fog not ‘just in your mind’: new insights into physical markers of Cognitive Impairment with Dr William Hu

[Music] Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host, Emily Kate Stevens, and I've been living with an energy limiting condition since 2020. Here I will speak to the world's leading experts to bring you the latest science, research and insights into invisible illnesses, including MCFS, EDS, fibromyalgia, pots, long COVID, and more. [Music] Welcome to the latest episode of Make Visible, where this week we are going to be discussing brain fog. Thank you so much to those of you that have left reviews, comments, or messaged us with what you are enjoying and what you would like to hear more about. That is so useful to us. So this week we are bringing you a conversation with Dr William Hu, a cognitive neurologist at Rucker's Institute for Health. Dr William Hu has taken his understanding of dealing with cognitive impairment and applied it to looking at the physiological changes that have taken place in long COVID. His findings suggest that brain fog is not something that is simply in your mind. There is actually a physiological route to it. I hope you find this conversation useful in understanding your condition and can see the ways in which research into certain areas such as long COVID are hopefully enabling broader research into other related conditions. [Music] I've spoken to quite a lot of neurologists, but this description of cognitive neurology was something that was new to me. Can you define that cognitive neurology? Sure, this is a relatively small field and the cognitive neurology sits on the interface between dimension neurology and cognitive neuroscience. So on the one hand we are trained to detect people with Alzheimer's disease and other related dementia. On the other hand we also study cognitive aging in people who are healthy as well as how the brain is perhaps altered in non Alzheimer's disease conditions, such as long COVID, such as multiple sclerosis as well as HIV. See some of these things. We already have an understanding of the pathogenesis of them, but there are multiple of these conditions that we still don't really understand. That background coming to it from Alzheimer's. Can you tell me how that led you into long COVID? Yeah, because we take many comers with memory issues, beyond just Alzheimer's disease, we often take a more agnostic approach in terms of what the cause for underlying memory issue is. When COVID began, the first time that I got involved was when people developed acute COVID and cephalitis, then their cognitive issue is really quite severe. It's often coma if not very severe brain injury. And that's in the acute phase. That's in the acute phase. But after a while we started getting requests and calls to see people who only had mild COVID, but with lingering and persistent thinking issues. Back then, the term brain fog was not as popular as it is now, and we didn't quite know what it was. So we started seeing patients such as I described, only having had mild COVID often not hospitalized and sometimes may not even have any cognitive symptoms during the acute infection. But then a week, three weeks after the infection resolved, they would have really sluggish thinking. Really, that was the best way they put it. We started testing many of them, and in terms of using pencil and paper tests and using some of the other speed-based tests. Then we found that a number of them actually had deficits in what we were considered as in the range of mild cognitive impairment. And that's what you term it normally is cognitive impairment. In terms of this term brain fog, I know that we have historically had things like chemo fog, but there are some patients who find this term brain fog to be actually mildly offensive. You just described it as cognitive impairment. How do you term it or what defines it in other conditions that you've been studying? Well, generally, we were administrators to a certain set of standardized tests and to see how someone is able to learn a list of words, how to remember that list of words after a brief delay, how you able to count some numbers forward and backwards, how you able to generate a certain set of words under certain instructions. So there were a number of some people may call brain games, but these are what we call tests or tasks we were asked people to do. And then compare them to people of their age, gender, and educational level without any cognitive impairment, brought in prior to COVID. And if they do perform below expectation, then that's a suggestion that there is cognitive impairment. Did you find that there was an issue with some of this because we didn't essentially have the controls of these people of measuring them before? How did you deal with the fact that you were having to understand people saying, but this isn't how I was before. This is not how my cognitive function was previously. Right. And we tested that. And then that's not uncommon in the general memory clinic as well. I often tell my patients and participant research participants that I use an example from education. If somebody's grade is dropping from an A to a C, our approach would not be able to pick that up. Our approach only picks up the people who drop them an A to an F. So that's why we actually separated people into those in whom we know there's a cognitive impairment for sure. But then also the people will recall subjective cognitive complaints in that they notice a difference. But we could not pick it up because we didn't have this prior baseline. I think it was important for me and for my team to remain agnostic. As to which bucket of people had what we were studying in an eternal cell that both of them did. I knew actually separated out those cohorts within the study. So you had the post-covid cognitive impairment and the post-covid subjective cognitive complaints. That's correct. So you were looking at them separately. Is that in terms of the neuropsychological testing? Is that what you've just described? It's based on the assured neuropsychological screening. And one thing again we were learning from our patients was that they got tired very quickly. neuropsychological testing generally would take anywhere from one hour to four hours. Sometimes in the rare instances eight hours. And if you were to apply that to this group, what we would really be detecting would be the fatigue ability rather than the cognitive aspect. So we used very brief batteries that we've using other instances to screen people. But then we also follow up in a subgroup of them with more extended neuropsychological testing. That's really an interesting tailoring that you've had to do there. That kind of adapting to the patients shows actually quite a lot of forethought at the time that you started to look at these patients. We were kind of tinkering if you well with what to do. What type of tests can be done at the pace that the new COVID cases were coming on. And then also something that could be not too taxing on the patients. And so there was a lot of tinkering back and forth and using tools that are available already. We didn't invent any new tools. You was more about tool selection. And then thankfully we got a number of tools available to us that we could just deploy quickly. And do you think that there's tools that you deployed in themselves that were sufficient actually for diagnosis before even the MRIs or three risk final fluid testing? Those cognitive tests could actually prove long-haired. I don't think so. I think there were so many other factors at play. People were anxious. People were losing sleep because they couldn't go to work. Their loved ones were so. sick, so there were many, many factors that could potentially play into why somebody may not be remembering things or thinking things as fast as they used to. So very often we say that cognitive impairment is a syndrome. It's a description of a set of symptoms. It doesn't tell you what the underlying cause is. And very often somebody in there that say late fifties, early sixties were coming and they were asked me the question, do I have the earliest stage of Alzheimer's disease or do I have long COVID? And that was where the clinical assessment could not tell them apart. Yeah. So you went on to look at these patients with MRIs. Was that the first step that you took in terms of actually trying to look at something physiologically different or trying to find something that you could see that might be able to define the condition that they have? Yeah. Whenever there's a new disease, a new brain disease, one of our favorite tools is brain imaging. We can take a picture of the brain to see whether there being signs of injury or signs of active infection and anything like that. So we had a group of people, about 60 of them, undergo MRI and we were able to see some changes in about just a little under half of them. Okay. What sort of changes? There were various types. And one particularly striking type was as if somebody had what we would call encephalitis. The middle parts of their temporal lobes just behind your temple and each side looked at as if they were in the hospital intubated with severe seizures. But they didn't have that. They did have radiographical appearance of that. So that was striking to us. There were other people with some brain stem changes. There was a lot of talk about how the brain stem area could control autonomic function and may underline some of the pots symptoms. And so we made a particular note of that. And then finally, they were these other areas we've seen other more acute COVID cases. And some of these look like the classic mini strokes, but in people who are much too young to have them. But then also there were these avoid lesions. This was describing a literature in that it's almost too perfect as shape to have come from a mini stroke. We still don't know what they are, but we saw a fair number of those as well in our long COVID patients. Wow, and that's something that you don't typically see in a control room. No, we don't. Sometimes we see these lesions in people's suspected of having autoimmune brain diseases and such as multiple sclerosis, but they don't quite look alike. They look similar, but not identical. Those things that you've described, they're in different points of the brain, aren't they? Yes. The first two types were in specific areas, the the medial temporal region for the encephalitis and also the brain stem that's in the back. But then for the avoid lesions, we saw them in the temporal lobes, we saw them in the frontal lobes, we saw them in the parietal lobes. They can appear anywhere. So this is jumping ahead quite a few steps in terms of our conversation. But does that suggest that there has been some viral infiltration at a different point of the brain or? It's hard to say if we focus on the avoid lesions, it could be that there was a local inflammation. It could be that there was a virus infection in the blood vessels and then the blood vessel itself caused a reduction in blood flow to the surrounding brain. There are a number of potential explanations. Okay. We'll come back to your thoughts on that. But in terms of the cell study that you published, can you tell me going one step further than the MRI, the way in which you then decided to test your non-covid patients and what you found from that? Well first with again, we reached out into our toolbox then to use what was available. We tested for the Alzheimer's disease biomarkers. There were some early studies suggesting that some people with low-covid may be developing acute Alzheimer's disease, which is a scary thought. From a neuroscientific perspective, it is not impossible, but it's not likely. At the same time, this was a new disease. So we had to empirically prove that that was or was not the case. And when we measured Alzheimer's biomarkers in a spinal fluid among the patients who are consented to it, we really didn't find a whole lot of difference in Alzheimer's disease markers between low-covid and people who are healthy. And then the next step again was the exploratory stage and we had to find out what was going on. If we say what it was not Alzheimer's disease, what is it? We took advantage of very, very new technique that we were just developing by collecting all the little cells in the spinal fluid and characterizing their gene expression at a single cell level to get an idea of what the entire population immune cells are saying, but also what individual cells may be saying. And it was quite gratifying to see this new technique applied and actually give us some insight as to what was happening in low-covid. That just is on such a microscopic level, isn't it? Can you describe that technique of how you look at things? You'd identified certain things that you, certain cells that you were looking for or looking at? What we'd look at all cells we could collect in the spinal fluid, it's actually still quite amazing to me for me to describe what is happening. The technique was developed in the mid-20 teens where scientists could encapsulate individual cells in little oil droplets and do the PCR reaction within that oil droplet with a little zip code saying that this came from the same cell. So that when we decode all the genes, each gene has a source code as to which cell this came from. It's just an incredible. It is incredible and sometimes I don't even believe it when I'm doing it. It's just hard to believe that this is doable in 2023, 2024. But the findings are just so informative compared to what we were able to do before. So we're able to see up to 15 different immune cell types in the spinal fluid, some of which were only described in animals before because we're just not being able to do this in humans until now. And then we were able to compare the subgroups of cells in people with long COVID with the same subgroups in people who are healthy as well as people with Alzheimer's disease. So we can ask the question, what is different from health and what is different from another type of brain disease? What were those cells of the proteins that you noticed were different in the long COVID patients? So what we found was that a particular family of cells, in this case, the myeloise cells, the myeloise cells that are primarily responsible as the body's first line defense against viruses were quite different between people with long COVID and healthy people. But then the T cells, which gained a lot of attention during the development of vaccine process, really wasn't that different. They were subtle differences, but relatively speaking, it was the myeloise cells that were primarily different. And what are the myeloise cells? So they are the macrophages and they are the monocytes. They are the dendritic cells. They are the ones that capture that say an antigen invading virus bacteria and it presents a different pieces to the T cells. So the T cells can develop further defenses against these invading pathogens. So they are part of the innate immune system. And that's why it's actually the primary, the first line defense. But the first line defense is something that should be active during the first onset of disease. That's correct. And what you're saying is that you were seeing these cells in action months after the acute onset. And average of nine months after the initial COVID symptoms resolved. And then I think the more we dug, the more we saw these cells in action. We developed several different analytical pipelines to look at individual genes that were just highly regulated, individual cells that were highly active, and then also that they're protein counterparts that were secretive. it. In everything pointed to the fact that in long COVID, there is something going on that is causing the brain's immune system to recruit more milder cells from the blood to turn into macrophages to mount a response. In any other setting, we will see this as an active or new attack. And this is the body's response to an active new attack. And when we compare the gene profiles against a large database of experimental findings and other models and disease and so forth, the one that bears the most striking resemblance is acute COVID infection in the cells as well as in people who died from acute COVID. So that is the comparable time that these cells were at a similar level. It seems that they are in a persistently activated state, peering to still respond to something. We were never able to directly recover SARS-CoV-2 virus in the spinal fluid. And that is not surprising because we tried this at the beginning of the pandemic as well. In people who died from flurid SARS-CoV-2 infection in the brain, and we could not get it in the spinal fluid. It appears that the virus does not get into the spinal fluid easily. But that does not mean that there's not residual virus elsewhere in the system. I know that a lot of studies have found persistent virus in the gut. But other people have said that they must only be in autopsy, but have they not found persistent virus in the brain? They have. In autopsy cases, they have found persistent virus in the brain. The spinal fluid is an overall sum of materials for many places. So what's in the middle of the brain may not be released to the spinal fluid. Not finding the virus in the spinal fluid by no means says that there's no virus in the brain. In fact, if we consider the immune reaction as a reflection, and I tell many of my colleagues, it's like a mirror image. If we consider the immune profile to be a mirror image of what's happening in the brain, we know the virus in the brain. So normally what happens is you have the acute infection, say the Cated infection comes in. The immune cells mount a response, and then everything calms down. If the initial response is sufficient, a clear infection. And which cells are involved in doing that? Everything gets pulled into that, do they? Everything is. And the innate immunity translates into the adaptive immunity, involving the B cells and the T cells so that if the person is exposed to the same infection again, they will mount a more successful and faster response. Okay. What it looks like from the cerebral spinal fluid that you have tested is that that immune response is continually being activated. So it wasn't necessarily fluctuating in terms of, well, this person was not having such a bad day when we took the fluid. It was across the board change. It was across the board. Generally, if people didn't feel well enough, we didn't have them coming to participate in the studies. Because that's quite invasive, is it to take the. It's what we consider minimally invasive. Okay. Very often people say that I had a really bad experience in the emergency room. That's when somebody is acutely ill and a doctor is thinking of meningitis. And when we do a research spinal fluid visit, it's very well controlled and everything, there's calming environments and we anesthetize the area well. And about half or more of the people often don't even realize the needle has gone in and come out. Wow. Okay. So it's quite different. It's quite different from the usual lumbar puncture or spinal tap that people talk about. Yeah. Can you go into a little bit more detail about the specifics of what you found in terms of what cells were activated? So in people with lung COVID, one particular cell line was in a way the coordinator or the quarterback. It was the myelorid-dengerid cell. It is a type of what we call "energy presenting cell." It seems to have captured something and its job is to tell the other cells to activate. Right. And then it releases signals called cholesterol 25 hydroxylase CH25H. In CH25H is involved in recruiting more monocytes, often times from the periphery, into the brain to become macrophages. And each partner in the sequence will be able to detect gene changes in a spinal fluid. And so we were able to see the quarterback, we were able to see the white receiver and we just about could see the touchdown based on the sequence of events. That's absolutely remarkable. I agree. I don't want to took my own horn, but I think this technique has just really opened a lot of windows into a novel disease. So what does this mean in your opinion? What does that show us? Well, I think there is a bit of a convergence of data between our study and others that being published in suggesting this virus persistence. For a long time, there was this dichotomy of is this virus persistence or is this a post-infectious autoimmune process? And in neurology, we see a lot of post-infectious autoimmune disorders. And the most common of which is Guillain-Barr syndrome that people talk about as a potential complication for vaccination. And when we look at the cell activation profiles, when we look at some of the proteins and compare to existing models related to SARS-CoV-2, either acute infection or posting infectious autoimmune process, what we found favored persistent infection over autoimmune. So what that tells me is that number one, we can't expect people just to get better. We can't expect them to wield themselves better because we don't do that to other people with viral infections. And number two, in people that who don't recover after prolonged period of time, an entire viral therapy is likely necessary to help them clear it. For whatever reason that some of people cannot clear the infection, we really need to offer them something. Now you did see some people part of your cohort recover. Yes. And what was remarkable about that is that you saw differences in the levels again once recovered. Is that so? That is true. They're myeletic dendritic cells were doing the same thing. They were recruiting the monocytes to become macrophages. But then when we tracked the downstream events, there was a difference between people who recovered and people who didn't. And I should say that people recovered, it was a very prolonged recovery process. It took about two years for 50% of the people to recover. So this is not even like mono. I think mono takes a while. This takes even longer. And what we found was that people who were recovering were able to mount a successful interferon process. And remember, this is two years before they recovered. And so we don't know for sure that between a time the spine of flu was collected, two to time that had recovered interferon was the only thing that was making a difference. But we could definitely see a difference in interferon pathways. Comparatively when we look at the people who did not recover, their interferon was activated in different ways. And we could see that because we're able to tell the cells apart. And this is incredible. You can see the different interferon cells. Exactly. We could see that the some of the protein, some of the chemokines and their receptors had an inverse relationship compared to the relationship that they had in people who recovered. So it wasn't that the players were not there. The players were there. But the play was off. Something was not right. And that so the people who had persistent lung COVID could not mount right in a interferon response. If that's the hypothesis, the virus remain in the system because the interferon responses, what is normally responsible for ridding it of the virus. Yes, that would be the theory. There are many viruses that have evolved over time to either suppress or evade interferon response. SARS-CoV-2 obviously is a new virus, but it's mutated on the number at times over. So until we're able to capture the viral sequence in the people with non-recovering long COVID, he would still be a guest as to why in this particular group of people, they can't seem to clear the virus despite the same signal from the quarterback. And despite this seemingly ongoing signal activating through our bodies, does that suggest that it's specific to the virus or that it was something in our immune systems that might have reacted in this way to any major virus? It's just that we are seeing so many non-c COVID patients because of the number of people that are COVID. Those are great questions that I don't have answers for. And like you said, the COVID had happened at a time, it just happened to coincide with great technical advances in the past when they were viral infections involving the central nervous system. We didn't have these technologies available at that time. So if we start studying other people with brain viral infections, we may find similar things. That would be a really important study to do. One thing that we know to have a similar clinical picture is in HIV, in people with HIV, even when they are virally suppressed in the blood and in the rest of the body, many people can still have what is called HIV associated neuro-cognitive dysfunction. There is a very similar discussion as to whether this is viral persistence, whether it is posting infectious or immune etiology. If we apply this set of tools to study that disease, I think we can start to get some answers. That's so interesting, isn't it? Because HIV has been so well studied, but we are nearly 40 years on. Yes, 40 years. In terms of our technology, the focus has just so heavily been on COVID because of the sheer numbers. What about other conditions that are typically fairly underfunded and understudied the post viral conditions such as ME/CFS? Is this sort of technology something that we could actually take and start to really get more of a definitive handle on those conditions? And you mentioned mono as well. I think so. I think these technologies should really open up new doors as to how scientists and clinicians can understand these diseases that come up with treatments. One of the limitations, if you will, is that the spinal fluid has to be processed immediately. So we have a whole team on hand whenever we are doing this test so that they can process the cells, put the cells into the little oil droplets, express the genes. So we have this rich body of data. This technology is not available in most centers. Once we start to expand its use, we also need to start thinking about expanding the availability of the technology. Can you tell me the advantages or the differences of what you're able to see with this spinal fluid versus the blood draw? Yeah. So one of the long-standing truth is that if you want to study the brain, you have to get close to it. We can't buy up to the brain like we can in liver, skin or even heart. So all we can do is study the spinal fluid. The spinal fluid is in direct contact with the brain. Some people consider that as the circulatory system for the brain. So when we do draw spinal fluid, it's like drawing blood from the brain. And the reason that things in the blood are different from things in the spinal fluid is because of the blood-brain barrier. It is designed to keep things out and keep the majority of things in. There are instances where the disease can be significant and therefore when you compare the extreme abnormal versus the extreme normal, there's a correlation between test running the blood with this test run and spinal fluid. But the majority of the time, they are not related. That said, we do have cells, like I mentioned earlier, that traverse the blood-brain barrier in certain conditions. So the myelotin-dritic cell would be recruiting the peripheral monocytes into the brain compartment. So if we're able to capture these particular cells, we can study some aspects of what's happening through a peripheral blood draw. But the cerebral spinal fluid is a more accurate representation of actually what is going on in the brain. Now obviously you're a cognitive neurologist. You study the brain. And therefore that's the cohort of people that you've looked at with specifically with this brain fog. Were there patients who had other symptoms alongside the brain fog and do your results also correlate with other symptomatology in non-covid? We did not look at other symptomatology, but our participants certainly had other symptoms. They had shortness or breath, some had pod symptoms, some also had peripheral neuropathy, like pain, even that we couldn't quite pick up the findings of peripheral neuropathy. So we didn't pre-select a very healthy cohort. In fact, and I would say it's very hard to find someone with long COVID with only one set of symptoms. Yeah. And one thing that I'm always fascinated in asking is, do you think that all of the long COVID symptoms could be neurological? Because if you've mentioned pod several times, so there were a lot of people with cardiac symptoms. Are we actually looking at a majority of cardiac patients who have pots, which is driven by the autonomic nervous system? Are there various of the symptom sets that we could actually put back to the neurology? I think there are certain symptoms that are clearly not related to neurological dysfunction, such as the finding and pulmonary fibrosis on the chest CT. In those people, I don't think there's a correlation. It may have originated from the original infection. It may be viral persistence. I don't know. I think it would be really interesting for the pulmonologist to go in that direction, given that we've now looking the brain and others have looking the gut. But certainly some of the other symptoms, and then one thing I forgot amensions headaches. Headaches are extraordinarily common. And I don't think it's just because people are thinking too hard. I've heard that quite a bit. I don't think that's what's happening. In some people that the headaches have proceeded to something more serious and almost stroke-like. So I think we need to again think about the shared potential etiology. What causes headaches sometimes is vascular constriction in the brain. And again, we're talking about this blood brain barrier, where something in the brain is pulling cells into the blood brain barrier to mount a counterattack. Could that be the cause of the headache? Could it be that the blood vessel wall cells are infected and they are getting sick and causing headaches? It's hard to know. But I think there are a lot of useful investigations that can be conducted to answer these questions. Headaches have probably been my primary symptom in long-caved you said that the headaches might be from thinking too hard. And I think this is something that you actually not just have an opinion on. You were able to prove in your testing. So many long-caved patients are told, of course, you've got brain fog. You haven't slept properly. You've got brain fog because you're depressed or you're worried about being ill. It's a hangover from the pandemic. You've got PTSD or deconditioning. What did you see in terms of that? Well, first of all, even though I was a brain doctor and a neuroscientist, we left this possibility open. We tested whether the cognitive findings were independent or dependent on the psychiatric findings. And what we found was that depression anxiety were common, but they were independent. And this was something that we've known in Alzheimer's disease for some time that if you talk to people with persistent mild memory loss, nobody's happy about it. This may seem silly, but this doesn't really enter the mindset of a lot of physicians. So we acknowledged that depression and anxiety were real. We even showed that depression and anxiety were dependent on each other, but they were separate from cognition. And as were sleep and fatigue. So each had their own thing and they were commonly co-present in the people, but we don't think they're causal in any way. And again, if somebody was purely depressed, maybe I will find one population of cells that would do something, maybe I'll find a signal down the stream, but if we're able to part out each step of the way that everything looks like infection, we can't say that depressions are underlying cause. Yeah, one thing that I was curious about and this in Long COVID is a very divisive subject is that obviously movement exercise has a huge impact on the endocrine system and doesn't it also produce growth factor which then promotes a healthy and effective brain. There is a lot of pushback from Long COVID patients who are told oh you've got this because you're deconditioned, you've got a heart problem because you're deconditioned. Is there any element in the cognitive impairment that comes from us moving less? I think there are two aspects. One is that before we had these biochemical findings, the closest thing clinically to Long COVID was MECFS. So I routinely recommended when I was hearing my clinician had for people to pace because that was the one thing demonstrated to work. While there were others promoting physical therapy and other type of rehabilitation based approaches, I only saw negative consequences in people going down that path and in a way I was a zealot in promoting pacing because it worked. The other aspect however is is something having to do with deconditioning and it's not in a sense a long COVID. It is in a sense that because of pacing because of Long COVID, once people have recovered some, there is some deconditioning and then there needs to be part of the overall recovery process but it should not be the first thing to offer to people. Yeah. In terms of actually at your clinic there, what sort of process or pacing model do you try and put in place for people? What's your primary advice? For Long COVID and for MECFS. I think do less listen to your body and I think the listen to your body is somewhat an obvious one. Do less is not as obvious and I'll explain why. Very often they people with Long COVID cherish that one day they feel great and then it takes a lot of bargaining to convince them to not increase their activity level on that day because energy level will fluctuate just like we don't consider gloom and doom when you're having really bad day. We don't also expand all the energy on a good day. The goal is long-term recovery and the only thing that's helped with long-term recovery as of today is consistent pacing and so that you don't go into that deficit. This is where I'm really speaking as a clinician rather than as a scientist because I can't explain how it works or why it works or I can tell is that it seems to work and so I want people to get the most benefit out of what I'm able to recommend. And do you see also the opposite? So the people who do go all out on that day when they're feeling good? Do you see actually a demise? Almost the opposite of pacing. Yeah there's a little bit of the one step forward, two steps back, phenomenon. Very often people have come to me realizing that already. They'll feel great one day. They would do a lot but then they are down for the next three days even worse than before. So I'm also learning from our patients who tell me these things. I think a lot of us have been learning that I've been learning it over at nirvana half years but because especially if it's the cognitive thing if you're suddenly able to process, get worked on, there's a real tendency to try and use that. Get on with it whilst you're actually functioning. And I tell my patients that I acknowledge that. I recognize that it is exciting. It feels great and you want to make them most out of it. But again we have to be conservative. And what we're hoping for is more of a consistent feeling good rather than that one day. And the only way I know for sure of how and get there is consistent pacing. It's a marathon. It's not a sprint. Such good advice. In terms of where we go next with the research that you have done. I believe that you think that trials in interferon supplementation might be effective. Is that what you would suggest as an antiviral or is there a different route to antivirals? Well there are multiple interferons that are FDA-approved and there are a couple that are pending. I still have more than experimental phase. And I think a trial had to have trial comparing the multiple interferons would be key to understand which one perhaps is able to do the job and is best tolerated. Interferrum is a harsh drug. So we don't recommend don'tling it out. Have hazardly people in the initial phase may feel like worsening of the long-covid symptoms. The goal hopefully is that you would take that one shot or multiple shots to to get rid of the viral reserve or reservoir so that you don't have to continue taking it. At the same time to perhaps help make that happen. We're also trying to develop a marker for long-covid because like I mentioned before, what we did for research, it cannot be readily applied everywhere. And for a trial to be successful, it has to happen away from rockers as well. So we want to come up with a simpler test, a simpler biomarker to identify people who can participate in the trial. And I also mentioned a caveat that just like when we talk about assessing cognition, just because you don't have the marker doesn't mean you don't have long-covid. The marker can only be so good. We've only had a little bit of time to work on it. But at least we can identify a group of people for the purpose of the clinical trial. And then such that if a drug is proven to work can be applied to more people beyond just those who've had a spinal fluid test or a fancy blood test. Interfer on supplementation that actually behaves differently to something like the Pax Love is or the in its antiviral mechanism. What you're trying to do is boost our innate immune system for us to clear the virus ourselves. That's correct. The goal is to mount a sufficiently robust and accurate interferon response so that we can shift the people who are on a non-recovery phase towards the improving profile. Well, I find your work absolutely remarkable. And obviously I don't want to have long-covid. I'm sure there are a lot of people out there who would rather not have it. But I have to say that the medical advances that we have made by having this huge global cohort is just incredible. The leaps that we've made in some of the medical research. And I've read a lot of papers and I've spoken to a lot of people up to this point. It's really quite remarkable. And as I say, I don't want to have the illness. But it's exciting that there is that interest and hunger from scientists, researchers, doctors. It's very exciting for us. And I want to acknowledge the people who volunteered for my study. I know that people don't feel well with this condition. Yet many of them travel great distances to participate in the study. And some even surmount would seem like insurmountable obstacles to get to me without the people who participate as volunteers. None of this will be possible. So I'm a human doctor and human scientist. I believe in studying diseases and humans, not mice. So really that for a new disease, we need more volunteers. Both those with long COVID as well as those without low COVID. Yeah, thank you so much. Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping a hundred thousand people measure and manage their complex chronic illness. To find out more about what we're working on and how visible could help you visit our website at makevisible.com (upbeat music)