Brain Fog

In this episode, neuroscientist and pediatric oncologist Michelle Monje helps us understand the mystery of the persistent "brain fog" that often plagues Long COVID patients.
From Our Neurons to Yours Wu Tsai Neuro Podcast

One of the strangest and most disconcerting things about the COVID-19 pandemic has been the story of long COVID.

Many COVID long-haulers  have continued experiencing cognitive symptoms long after their initial COVID infection — loss of attention, concentration, memory, and mental sharpness — what scientists are calling "brain fog".  For some patients, the condition is so serious that it can be impossible to go back to their pre-COVID lives.

Today’s guest, actually had an early intuition that COVID-19 could trigger a neurological health crisis.

Michelle Monje is a pediatric neuro-oncologist here at Stanford who treats kids with serious brain cancers. She also runs a neuroscience research lab that studies how the brain develops during early life. For the past decade, she has been focused on how chemotherapy triggers a cascade of inflammation in the brain that leads to so called “chemo-fog” — a very similar set of symptoms that we now see in many people with long covid.

In this episode, Monje helps us understand what brain fog is, what seems to be causing it, and how her team and others are trying to develop treatments that could help with other conditions linked to inflammation in the brain, such as chronic fatigue syndrome.

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References

Read more about Monje's work

Episode Credits

This episode was produced by Webby Award-winning producer Michael Osborne, with production assistance by Morgan Honaker, and hosted by Nicholas Weiler. Art by Aimee Garza.

Episode Transcript

Nicholas Weiler:

This is From our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we crisscross scientific disciplines to bring you to the frontiers of brain science. I'm your host, Nicholas Weiler.

Here's the sound we created to introduce today's episode.

Perhaps that is the sound of brain fog. One of the strangest and most disconcerting things about the COVID 19 pandemic has been the story of Long COVID. These are people who, long after their initial COVID infection, have continued experiencing cognitive symptoms, loss of attention, concentration, memory, and mental sharpness, what scientists are calling brain fog.

For some patients, the condition is so serious, it's been impossible for them to go back to their pre COVID lives. Today's guest actually had an early intuition that COVID 19 could trigger a neurological health crisis because she has spent many years studying a very similar set of symptoms in chemotherapy patients. Michelle Monje is a pediatric neuro oncologist here at Stanford who treats kids with serious brain cancers. She also runs a neuroscience research lab that studies how the brain develops during early life. And for the past decade, she has been focused on how chemotherapy triggers a cascade of inflammation in the brain that leads to so-called chemo-fog, a very similar set of symptoms to what we now see in many people with Long COVID. Now, the term brain fog gets tossed around a lot these days so I started the conversation by asking Michelle to help us understand exactly what scientists mean by this term in the context of Long COVID.

Michelle Monje:

Long COVID represents persistence of symptoms, usually multiple symptoms, after the resolution of an acute COVID infection. And one of the most distressing and common components of Long COVID is what we are calling brain fog. It is a cognitive impairment syndrome characterized by impaired attention, memory, speed of information processing and multitasking.

Nicholas Weiler:

Is it something that people experience in their regular lives, but then this is just, you can't get out of it? Or is this something that's completely different from what might be in people's regular experience?

Michelle Monje:

Yeah, I think it is on the spectrum of what is in people's regular experience, but perhaps more severe and perhaps much more persistent. It is, I think, not uncommon to feel not quite yourself, not quite able to focus at work, not quite able to really function at the level that one previously did after a variety of illnesses, actually, fairly commonly after inflammatory illnesses, but the persistence and the severity of this is ability limiting. It is something that means that people can't return to their previous level of function, they're not able to go back to work either full-time or to go back to work and perform at the level that they previously did. It is a really life-changing syndrome, and it seems to be, unfortunately, persisting quite some time in a lot of people.

I have to tell you that when the pandemic began in March of 2020, seeing how just profoundly immunogenic, seeing how very inflammatory the response to this virus seemed to be compared to other more common respiratory viruses, I was actually very worried that we were going to begin to see a syndrome of cognitive impairment because over the last 20 years, I'd been studying the cognitive impairment syndrome that happens after cancer therapies. And surprisingly, in that context, at the center of that pathophysiological process seems to be immune dysregulation in the nervous system. And so I worry that even relatively mild acute respiratory COVID might induce a similar set of symptoms that, like after cancer therapy, might persist for a long time. And very quickly, it was clear that people were coming to the neurologist's office in droves complaining of exactly the syndrome that I worried they might experience.

It mirrors what we see in patients after cancer therapies, this impairment in attention, concentration, memory, cognitive and mental energy, if you will, throughout the day. This is something that many patients, after cancer therapies, experience and like Long COVID, and like the cognitive impairment that happened after Long COVID, after cancer therapy, this is also persistent. We had found over, actually, a couple of decades of work that one central component of the pathophysiology contributing to that, that it underpins the neurobiology of cancer therapy related cognitive impairment was a persistent dysregulation of the nervous system's immune cells, microglia, and so I worry that we might see something similar.

Nicholas Weiler:

Inflammation seems to be so central to many neurological diseases. It seems like we've been learning over the last few decades because information comes up a lot even when we talk about dementia or forms of neuro-degeneration. And I'd love to dive into that in just a moment, but you've called this a neurological health crisis. You've described how serious it is, but how prevalent is it?

Michelle Monje:

If you simply ask how many people have persistent cognitive complaints, persistent cognitive symptoms, one meta-analysis looking at about 10,000 people after resolution of COVID, and chiefly in a relatively mild respiratory COVID, they found that as many as one in four people have some persistent cognitive complaint. So I think that while there's a wide range of severity, this is affecting as much as 25% of the population of the world. It's a major problem. On one spectrum of the estimate, I've seen other reports claim that it's as many as one in 10 as opposed to one in four. But however you look at it, this is tens and tens of millions of people who were previously fully functional, who now have cognitive symptoms that impair their ability to perform in their lives. And for some people, this is really debilitating. It means they can't go back to work, and for others, it looks like an accelerated onset of dementia. We have really clear epidemiological evidence that the risk of diagnosis of dementia in the year following COVID diagnosis is markedly increased.

Nicholas Weiler:

Well, you and your colleagues have made some significant breakthroughs in understanding what is going on in Long COVID. Can you give us a high level overview? You already mentioned that inflammation is an important player here. Can you walk us through what you think is happening when someone gets a COVID infection? And, are we talking about COVID infecting the brain or what is going on?

Michelle Monje:

Yeah, great question. So there are multiple different things that can happen after COVID, including the effects of inflammation in the lungs, or in the respiratory tract in general, inducing inflammation in the nervous system. I'm going to come back to that because we've studied it in depth. Other things that can happen and do happen in some people include COVID inducing autoimmune responses. COVID can infect the brain. That seems to be much more rare than might be assumed, but it can happen. It probably doesn't happen in the majority of people. There can be reactivation of latent other kinds of viruses, especially viruses in the herpes family. There can be small vessel disease. COVID is very good at inducing small clots that can impair delivery of appropriate nutrients to the brain, and that, alone, can induce an inflammatory response around the blood vessels, and that can be a really important source of inflammation.

And then of course, in more severe COVID where people have had decrease in blood oxygen levels, multi-organ damage and failure metabolic disturbances, all of those things can have profound and lasting effects. But I want to go back to the first possibility. What we hypothesized might be a major contributor for a lot of people, this peripheral or non-central nervous system inflammation inducing inflammation in the nervous system. And that inflammation dysregulating the coordination between neural cells that have to work together in order to support healthy neural circuit function, healthy cognition.

Nicholas Weiler:

So you're saying inflammation that starts elsewhere in the body, in the lungs, for example, that inflammation is getting into the brain?

Michelle Monje:

That's right. And that signal can be relayed to the nervous system even without any direct viral infection. And we wanted to test that hypothesis and understand how inflammation just restricted to the respiratory tract might influence the homeostasis of brain cells. And to do that, I reached out and collaborated with a really brilliant fault leader in COVID biology, Aki Kawasaki at Yale. She had developed, very early in the pandemic, a mouse model in which we can engineer the mouse to only be infectible within the respiratory tract alone. In this mouse, it's a very mild disease, the mice don't get very sick, they don't look sick, they don't lose weight, they clear the virus within a week. It's a very mild COVID case in these mice. But what we've found is that when we studied these mice in which we knew the infection was restricted to the respiratory system, we found prominent and persistent brain inflammation.

We saw reactivity of microglia, the resident immune cells in the brain, in a pattern that mirrored exactly what we see after cancer therapies, for example, which we've been studying for a couple of decades. We saw elevation in the cytokine and chemokine profiles in the cerebral spinal fluid. Those are the inflammatory communication molecules that immune cells use to talk to each other and to which many different kinds of nervous system cells are responsive. And together with that neuro-inflammation, we saw what we expected to see in terms of cellular dysregulation of multiple different brain cell types. We saw a dropout of the oligodendrocytes for myelinating glial cells that ensheathe axons to facilitate fast and coordinated communication between brain regions. We saw a decrease in neurogenesis and one of the memory centers in the nervous system, the hippocampus.

Nicholas Weiler:

Oh, interesting.

Michelle Monje:

And interestingly, this pattern of inflammation was restricted to the axon tracts, to the subcortical white matter and to the hippocampal white matter. That's the same pattern of microglial reactivity that we see after certain forms of chemotherapy, after certain other immune challenges. It seems that the microglia in white matter in axon tracts are more sensitive to these signals.

Nicholas Weiler:

So these are the nerve bundles, those like information superhighways of the brain, right? That this is where you're seeing the biggest problem.

Michelle Monje:

That's right. And the information superhighways of the brain, these axon tracks, these white matter regions are indeed information super highways. And what we're finding is that after mild respiratory restricted COVID, the highways are left swell paved, quite literally, and we know that microglial reactivity can induce that kind of dysfunction in the oligodendrocytic lineage. Something that's really helpful is that in other disease contexts that we've been studying for many, many years, we can reverse that. We can encourage appropriate pavement on the superhighway, if you will, by addressing that microglial inflammation. And that's part of why we know that this is potentially reversible, that everything we're seeing so far is a potentially reversible dysfunction caused by the brain's immune response.

Nicholas Weiler:

Right. So let me make sure I have this straight. So we can get infection in the respiratory tract, in the lungs, that triggers an immune response. The immune system is sending messages with its chemokines and cytokines. Those are getting into the brain activating microglia, particularly in these sort of information superhighway nerve bundles that are crisscrossing the brain and impacting the myelin insulation that basically it's slowing down and disrupting the brain signaling. Is that the big picture? That you're...

Michelle Monje:

That is the big picture. And this is sort of a principle of brain fog syndromes that is emerging in multiple different disease contexts. So we've seen this after cancer therapies, we've seen this after other systemic immune challenges like models of bacterial sepsis, we've seen this, now, after mild respiratory restricted COVID models.

Nicholas Weiler:

It reminds me of chronic fatigue syndrome as well. Is that something similar?

Michelle Monje:

I think that chronic fatigue syndrome is clearly on the clinical spectrum with severe long COVID, and I am hopeful that what we learn in Long COVID and using, now, laboratory models where we know how to induce this syndrome, that we'll learn potential therapeutic avenues that will inform therapy for chronic fatigue syndrome.

Nicholas Weiler:

So let's dive into therapy a little bit. I mean, are these changes that we're seeing in the brains of people or of mice and we you think are also happening in people with Long COVID, is this reversible? Are we on the path towards finding treatments for this neurological disorder?

Michelle Monje:

Yeah. A couple points I want to make is that we see these changes in mouse models and the one question is, is this actually how what's happening in people? And we had the opportunity, by collaborating with some investigators at NIH and at NYU, to look at the brains of some individuals who died suddenly after COVID, that did not have severe lung disease, but died soon after having COVID. However, in their brains, we saw the same pattern of selective white matter enriched microglial reactivity.

Nicholas Weiler:

It seems like the same thing is probably happening.

Michelle Monje:

It seems like the same thing is happening. And one of the signaling molecules that we identified in the mice as being elevated in the central nervous system, persistently after viral respiratory infection, some of the microglial reactivity, and specifically the microglial reactivity in the hippocampus in the white matter of the hippocampus. When we examined the serum levels of this chemokine in people who are suffering from brain fog and have Long COVID compared to people who have Long COVID without cognitive symptoms, we found the same chemokine was strongly up-regulated in people who had the brain fog symptom.

Nicholas Weiler:

So this could be one of the culprits.

Michelle Monje:

One of the culprits, and also one of the therapeutic targets, potentially.

Nicholas Weiler:

Right.

Michelle Monje:

And so, as to therapy, we are working hard on identifying potential therapeutic targets and potential therapeutic strategies. I think the hopeful thing is that we're not starting at zero. We've been studying a very similar syndrome caused by very similar brain pathophysiology after cancer therapies, and several of the strategies we've been studying for many years, and are close to translating to the clinic in that disease context, may be helpful in this disease context as well. And we're trying to target the microglial reactivity to reset those microglia, which are very important brain cells. We need them, but we need them to behave the way they're supposed to behave. We need to return them to a homeostatic state. And when we have targeted, in our past work, in the context of cancer therapy related cognitive impairment, so-called chemo-fog, we've been able to rescue cognition in mice and so we're hopeful that we'll find the same thing after mild respiratory COVID, and that's something we're working on right now.

We also may be able to promote the appropriate pavement of those superhighways, restoring myelin homeostasis as a specific target. And then finally, some of these very specific signaling molecules from the immune system that we think is underpinning the communication between the respiratory system inflammation and the brain inflammation, those also may represent therapeutic targets, all of which we're working to study right now in the laboratory.

Nicholas Weiler:

Well, that's really gratifying to hear that there's at least good reason to think that some of these symptoms may be reversible, that if you can get rid of the inflammation, if you can help reinsulate those nerve bundles, then people may be able to regain some of their cognitive function.

I just want to close by asking sort of a broader question about what does this teach us about the impact of inflammation in the brain, in general? I mean, we've talked about a couple of other conditions where this happens, of course, following chemo treatment that you've been studying for many years, in other forms of bacterial infection, possibly in chronic fatigue syndrome. It strikes me that multiple sclerosis is also a disorder of the myelination of nerves. I don't know if that's actually similar underlying mechanisms, but what does this tell us about the importance of managing and protecting against and finding treatments, in general, for inflammation in the brain?

Michelle Monje:

Yeah. I think that it's becoming increasingly clear that a range of immune challenges outside of the nervous system can induce immune responses in the nervous system that then dysregulates the important coordination between brain cells that allows for healthy cognition. That dysregulation in the central nervous system can be really persistent. Once microglia shift from being helpful and homeostatic to being reactive, they both are not doing their homeostatic jobs in the nervous system, but they're also inducing dysregulation of multiple other brain cell types through mechanisms like cytokine secretion. That is a reversible process. And so, the extent to which this contributes across a range of diseases, I think, is really important to understand. There are different immune challenges, different toxic challenges may induce microglial reactivity in a different way. There may be different initial mechanisms. But what is clear is that once these cell types are reactive and dysregulate the interactions between neurons and various glial cell types, that can induce cognitive impairment in a way that is potentially reversible.

So that's our challenge, is to figure out how best to restore the appropriate balance, the appropriate regulation of these really critically important neuron-glial and glial-glial interactions so that we can help support healthy cognitive function.

Nicholas Weiler:

Well, thank you so much for this work that you're doing and for coming on the show to talk to us about it. It's important to remember that this is not over, that there are a lot of people who are still dealing with these symptoms and that there are a lot of people who are working hard to find solutions, so thank you.

Michelle Monje:

Thanks for having me.

Nicholas Weiler:

Thanks so much, again, to our guest, Michelle Monje. For more info about her work, check out the links in the show notes. This episode was produced by Webby Award-winning producer, Michael Osborne, with production assistance by the fabulous Morgan Honekar. I'm Nicholas Weiler, see you next time.

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