Avi Nath and his group at the National Institute for Neurological Disorders and Stroke (NINDS) at the US National Institutes of Health (NIH) work on many projects. One of them is: what might underpin the symptom of brain fog in long-COVID.

In my reporting I speak with researchers around the world and also produce podcasts to share more of what I find out. This podcast episode is one of several I am producing on long-COVID, which is such a challenging diversity of symptoms that people experience after recovering from COVID-19.

Here's a conversation with Avi Nath, who is intramural clinical director at NINDS. It's part of my reporting for a story on long-COVID in Nature Methods.

Note: These podcasts are produced to be heard. If you can, please tune in. Transcripts are generated using speech recognition software and there’s a human editor. But a transcript may contain errors. Please check the corresponding audio before quoting.

Vivien: Hi welcome to conversations with scientists, I’m Vivien Marx.

Avi Nath
Let me tell you, myself included, and a lot of my colleagues are very motivated to do something about this disease. So in a way, you're currently interviewing me. I'm sitting at home now and a lot of us and we all think about how are we going to get out of this place? Is the vaccine going to be enough or not been doing this for over a year. So you can imagine that no matter who it is, they are all thinking about what can they do for it We've been doing this for over a year. So you can imagine that no matter who it is, they are all thinking about what can they do for COVID?

If you are a biochemist, you're thinking about what expertise do I have that I can apply to it? If I'm a musician, what can I do to apply it to it? If I'm a reporter, what can I do? Everybody is doing that. You can imagine you have kids. They're going to ask you. You're a researcher, Dad, why don't you do something to figure this out? So our motivation level collectively, it's extremely high.

Vivien: That’s Dr. Avi Nath talking about COVID-19. He’s intramural clinical director of the National Institute for Neurological Disorders and Stroke at the US National Institutes of Health (NIH). You will hear more from him and about him in this podcast.

In my reporting I speak with scientists around the world and this podcast is a way to share more of what I find out. This podcast takes you into the science and it’s about the people doing the science. You can find some of my work for example in Nature journals that are part of the Nature Portfolio. A lot of papers are published there. Those papers are written by working scientists and are about the latest aspects of their research. And a number of these journals offer science journalism. These pieces are done by science journalists, like me.

This podcast episode is one of several I am producing on long-COVID, which is this difficult diversity of symptoms that people experience after recovering from COVID-19. Scientists are working on what might be causing long-COVID. I am doing a story on long-COVID for Nature Methods.

After recovering from COVID-19, people are, of course, grateful and relieved. They’ve survived a scary ordeal. But many people find that even months after their infection they struggle with symptoms. And those symptoms can include difficulty breathing, muscle or joint pain, fatigue, heart palpitations, they might have sustained damage to their lungs, heart, kidneys. And they might experience what is called brain fog. When the symptoms are severe, the lives of many, many people get completely derailed. Here’s Avi Nath:

Avi Nath 2:40
Now talking specifically about the long haul covid there is a huge interest. Not that I mean, you can see the socioeconomic consequences of that are phenomenal. You have millions and millions of people who are probably going to be affected. Well, even if you got rid of the virus today.

The average age is 40 for the long haul patients. And so they are in the most productive phases of their lives. It's not my data. It's and it may not be very accurate. Data is coming out, but that's what it what it suggests, that's the age group around what most of these patients are developing.

Vivien: The average age of people with long-COVID is 40. Wow. Petter Brodin at Karolinska Institute age told me that the majority of cases of acute COVID-19, that means people with life threatening illness are men. And the majority of people with long-COVID are women.

Around the world clinics are now focusing on treating people with long-COVID, sometimes called long-haul-COVID. They are beginning to study what underlies this array of symptoms. Post Acute SARS-CoV-2 syndrome they’re called collectively. NIH has launched a big research project focused just on this and it’s quite broad in its scope. Avi Nath explains:

Avi Nath 3.54
They want to make sure you're not missing some other organ involvement. When we are focused on the brain, that's our area of expertise. But, you know, the virus affects the lungs. The heart, the kidneys can affect a number of other things in the acute phase. So a multidisciplinary approach makes a lot of sense.

Vivien:
The virus wreaks havoc throughout the body. In the hospital, physicians and staff do their best to keep people alive. With long-COVID what is important is to distinguish the scope and breadth of what ails people.

Avi Nath 4.25
So I've talked to at least two hundred patients and myself with all of these things. And we've brought in a number of these patients to study them we're going to bring in more. And so, roughly speaking, at least the way I look at it, you can divide them into three broad categories. And these are individuals who have once you've excluded all the end organ damage and you've excluded all the patients who had some underlying diabetes or other hypertension, whatever it is, you get rid of all that stuff. Now you're left with a more smaller subpopulation of these long haul patients.

You can divide them into three categories. One is the brain fog. The second is patients who complain of dysautonomia. That means they have autonomic symptoms. And I'll describe them in just a bit. And the third patient is the exercise intolerance.

So let's start with the exercise in tolerance first. People call it fatigue, but it's not pretty. It's not like when you run a marathon and you get tired and you relax and you'll get better again. That's not the kind of fatigue they complain of there it is exercise. An example, I'll give you of a cardiologist. I was in New York. She got infected and she then recovered from it. And then she says that she developed this exercise intolerance. She couldn't even do telemedicine any longer. She says that her office was the first floor on the second floor of her our apartment. And so she has to take a flight of stairs.

When she gets up there, she's so exhausted, she has to lie down for the rest of the day. And because he is a cardiologist, she got all kinds of cardiac work up, they can't find anything wrong with her. So it's a very strange, but that's an extreme phase of exercise and tolerance, but various degrees of what these patients are complaining of.

And then the brain fog is an interesting one. So here patients complain of difficulty finding names they can't remember names and trying to think about what is it called? I mean, that happens to me once in a while. (laughs)

But they notice that it's an acute change. And they also complain of an interesting type of memory lapse. What it is, is that they can remember objects they cannot remember time, a time table when the event occurred.

So you ask them, what did you have for breakfast? They'll tell you this, that or the other. But I can't remember whether it's today or I did yesterday or was it a week ago. Yeah, so it's a very bizarre type of a memory loss that they have and then there are emotional at things so mood disorders that occur.

And so I'll give you an example of another person who works in construction here at NIH. He recovered from COVID. This was an older individual who had no history of any sort, hare and hearty otherwise. And he says all of a sudden he started getting suicidal ideations. He says, there's no reason for me to want to kill myself, but I can’t control it. So he got scared of himself, goes and admits himself in the hospital. He was there for a month. He's doing fine after that.

Vivien
These syndromes that just affect the brain and central nervous system all seem to be quite different. But Avi Nath sees a pattern.

Avi Nath 7.40
If you look at these syndromes, they are defining very particular areas within the brain. And so there are certain areas in the brain that are being affected in these individuals, and that's what is causing these kind of symptoms.

And then lastly is this category, what I call dysautonomia, and then some people call it POTS syndrome

And what it is that people complain of the heart racing. You know, they can't control it. Oftentimes they stand up, they get dizzy. And so their blood pressure falls. And they can also develop difficulty with either constipation or they can get diarrhea and they can get a tingling in their hands and fingers because the blood vessels constrict, so they can get a wide variety of autonomic symptoms.

And there was one neurologist I talked to. She says that her this disorder was so bad that she has to lie down all the time. And even while she's talking to me, she cannot sit up and talk because when she sits up, she can’t think any longer. Her blood pressure falls. I mean, these guys are living, but they're not really living now. They're just barely alive.

Vivien: Long-COVID arrives and stays. And sometimes things gets better on their own.

Avi Nath 9.05
And I've talked to a lot of people now after the first phase, a month later, they were developing all these symptoms, I followed up with them. And some are getting better. Not everybody has gotten better. But, you know, more and more time lapses, more and more people do spontaneously keep getting better to some degree. So that is really there. Now, do they get better to the degree where they can resume their normal activities, that varies from individual to individual But yes, there is a little bit of hope in that regard.

Vivien: Some people with long-COVID say that they feel better when they receive the vaccination against SARS-CoV-2 the virus that causes COVID-19.

Avi Nath 9:45
It's an interesting phenomenon. The thing is, this is known to occur in other diseases. Patients with ME/CFS or Chronic fatigue syndrome, they will also tell you they got the flu vaccine or something, they actually got better. But what they will also tell you, it doesn't last that long. Yeah. So about a month or something or whatever. And then it comes back. If they have undergo surgery or something, they'll feel better for a little while.

There are very rare individuals who say they got completely different actually. I think these patients are still early. But the question to ask these individuals is they're saying they got better after the vaccination. The question to ask them is: how long?

Vivien: For now there is no clear treatment strategy for long-COVID, certainly not a quick fix, says Avi Nath.

Avi Nath 10:35
No, it's not a quick fix, but what it does tell you is about the underlying pathophysiology. Why is it that if you produce this acute inflammation--f people think that all these long-haul COVIDs are inflammatory syndromes, then why is it, you produce even more inflammation, they actually get better? That's the question you want to ask. And so I don't know the answer to that, but I have some hypotheses that I'm willing to share.

Vivien: COVID-19 is a new disease caused by a virus not seen before. Long-COVID is new, too. And in labs, like Avi Nath and his group, researchers are exploring what might be the underlying cause of long-haul COVID. It seems clear the virus is what is starting people’s troubles.

Avi Nath 11:15
We know here, the virus comes first. I mean, you never had the virus. You never have the long haul The virus did something to initiate the process. Now, the virus may be gone, but the music lingers on. But what is lingering: is it the immune system that is lingering or is it parts of the virus that are lingering?

Vivien: Avi Nath has long studied viral diseases and persistent symptoms. In a number of instances he has encountered conditions that were thought to be post viral syndromes of an immune system still in overdrive from an infection.

Avi Nath 11.50
My career has been spent studying viruses, studying restricted viral replication, persistent viruses. And we've shown in many different diseases where people think that these are all immune mediated. And you look hard enough, you actually find the virus was missed in these patients. One was a patient with dengue and this patient was thought to have some immune mediated phenomenon treated for years, probably had multiple sclerosis we gave all kinds of immunosuppressant drugs, more and more powerful. Ultimately, the patient died.

Then we looked at the brain at time of autopsy and we actually found there was dengue virus all over the place. And this patient had been, people had looked at a spinal fluid, PCR, for all kinds of arboviruses. They never found anything. That phenomenon is also known and measles is a classical one.

Vivien: And here is something funky and kind of spooky and kind of clever that these viruses can do. It’s called restricted replication. Restricted viral replication is yet another way viruses evolve and survive. And it could be a way for viruses to be able to combine with others and form new viruses. Avi Nath explains how restricted viral replication works.

Avi Nath 13.00
The virus in the brain is mutated. Mutated whereby it doesn't form a complete viral particle. It is restricted viral replication, it can form some RNA or form some proteins and even has the ability to go from cell to cell but won't come outside the cell.

There's a disease called SSPE Subacute sclerosing panencephalitis that occurs in children after measles infection. You can get measles, you recover from it, and a few months or years later, sometimes even years later, the child now develops a progressive neurological syndrome and eventually the child will die.

You can look for measles everywhere. You're not going to find it. You look at the brain, it's loaded with the virus. But if you sequence it, it has two important mutations there. One is in the matrix protein and the other is in the in the fusion protein the mutation in the matrix protein prevents the virus from forming a complete viral particle. The mutation in the fusion protein causes the virus to become more fusogenic.

So now it's present in the neuron. When it sees the next neuron, it fuses the cell membrane there. And now the RNA with the protein gets from one cell to the next.

Vivien: Wow. That is insidious and clever and evolutionary speaking, although there might not be
Avi Nath: Viruses are smarter than we think.
Vivien Wow, what a way to get around.

Avi Nath 14.50
Yeah, I think that's how these viruses are getting transmitted. You don't need the complete replication. You need defective viral sequences. HIV is another example. You can control HIV really well. But if you look at the brain, defective viral sequences sitting there.

Vivien: Viruses can linger in the body after infection. This is also true with SARS-CoV-2. Rockefeller University researcher Michel Nussenzweig and his team as well as colleagues from other institutions found that after COVID-19, people had viral RNA and protein in their intestines. These biomedical souvenirs, these viral remnants are known to occur in other viral infections.

Avi Nath 15.25
There are lots of examples of that. Ebola is a good example. So I was involved in the Ebola epidemic. In fact, I went down to Liberia, saw all these patients with neurological complications there. We still have a cohort of two hundred patients we follow. So we did that in collaboration with NIAID, They were the primary guys, they were kind enough to involve me. But what they found was that they were looking at these patients seminal plasma after they recovered and they found that up to nine months you could find virus by PCR in the seminal fluid.

Vivien: Oh, wow. Now it's somewhere in their testicular tissue or it's just feeding from somewhere.

Avi Nath 16.05
Yeah, the thing is that but it wasn't being sexually transmitted at the time. So it's that's why the restricted viral replication so important must have acquired some mutations. It’s still coming up.

Vivien: I see, but it doesn't mean that that is infectious and it doesn't and they were no longer sick or were they also know they have never recovered. I see a little spooky. This idea that you have c you had COVID.

Avi Nath
A lot of viruses come out that way. The thing is there must be an advantage to the virus to come out in a restricted form. I think the opportunity for the virus to recombine with others to form new viruses must be there must have evolved that way.

Vivien: As part of the NIH’s large-scale program devoted to long-COVID, there will be an autopsy cohort made up of people who had long-COVID and agree to donate their bodies to science after they have died. Their bodies will be studied in great depth to better understand what kind of damage SARS-COV-2 has done to their body.

Scientists will be studying a dedicated group of people now suffering from Long-COVID. The way they will be studied is far beyond the occasional conversation.

Avi Nath 17.15
I'm a virologist, so I look at viruses. I'm going to look at, very deeply, any evidence of restricted viral replication, remnants of the virus or any signature of it. And with the virus comes the immune system. So we're going to look at the immunology in great depth.

But you cannot do that without imaging the brain. And the advantage of the intermural NIH program is they have the best toys that anybody does.

So we're going to put the individual into a seven Tesla scanner and try to see if we can find these remnants of vascular pathology that we demonstrated an autopsy.

So we're going to put the individual into a seven Tesla scanner and try to see if we can find these remnants of vascular pathology that we demonstrated at autopsy. Can we actually find it by imaging? So that's our goal. Then, as I mentioned, we will do neurotransmitter, we have a really good program in studying the autonomic nervous system here. David Goldstein does a fabulous job. So we partnered with him and he's very passionate to study these patients. So he will do all the neurotransmitter analysis.

Vivien: Nath and his group will assess people and analyze biopsies in many ways, for example. Perhaps there are viral signatures in these peoples’ bodies that have been missed. It will take high-resolution sleuthing.

Avi Nath 18.00
We have we've got to admit them to the hospital for a few days and we're going to do a High-Resolution MRI scan, the spinal fluid. We will do the single cell sequencing of the cells from the spinal fluid. Look at the blood. You know, we've got to do sleep studies on a functional MRI cognitive batteries, very detailed autonomic testing on each one of them. We'll study them, in great depth.

Vivien: That was Conversations with Scientists. Today’s episode was with Dr. Avi Nath, the intramural clinical director of the NIH National Institute for Neurological Disorders and Stroke.

And I just wanted to say, because there’s confusion about these things sometimes, the NIH did not pay to be in this podcast. This is independent journalism, produced by me in my living-room. I’m Vivien Marx. Thanks for listening.