- [Jeff] Welcome to "Healthy Minds," I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence.

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(bright music) Today on "Healthy Minds."

- If we stay conservatively with the idea that it is about, let's say, 10%, we might be having 65 million people affected by long COVID out of the 650 million that had COVID-19.

- Extraordinary numbers.

- Yes, people who have been vaccinated tend to be less affected, less at risk for long COVID.

- That's today on "Healthy Minds."

This program is brought to you, in part, by the American Psychiatric Association Foundation and the John & Polly Sparks Foundation.

Welcome to "Healthy Minds," I'm Dr. Jeff Borenstein.

COVID, what are the effects of COVID on our brains?

Today, I have a followup conversation with Dr. Maura Boldrini.

We had spoken at the height of COVID, and now we have the opportunity to hear more about our understanding of the effects of COVID on the brain.

Maura, thank you for joining us again on "Healthy Minds."

- Thank you for having me.

- We last spoke about two years ago, and I'd like to jump in by asking you, what have we learned over these last two years about the effects of COVID on the brain and on psychiatric symptoms?

- Yeah, so when we spoke, we had many hypothesis about how COVID could damage the brain, how the virus could penetrate or affect brain vasculature and brain biology, the immune system.

And at this point, we have very new studies that are basically confirming many of those hypothesis.

There has been a very recent study, for instance, talking about the blood-brain barrier, which is something we talked about last time.

And this blood-brain barrier is a protection that the brain has from the blood.

And the disruption of this protection, we thought it would be involved in leaking of inflammatory molecules inside the brain.

And in fact, that's what this study is finding.

And if you wanna go more in the details, I can tell you that basically they have identified with brain imaging regions of the brain where the blood-brain barrier would be more leaking.

And that has been correlated with certain factors that can be traced in people's blood.

And also with reduction in brain volume in specific areas, which we means that the brain is really damaged.

- So a part of what occurs is going through this blood-brain barrier that protects the brain, the inflammatory response in the body is getting into the brain and negatively affecting the brain?

- With inflammation, this blood-brain barrier is made by cells that have tight junctions between each other.

And this way, they really make a barrier that doesn't allow things to leak into the brain.

And when there is high inflammation, these tight junctions get more loose, and inflammatory cells and molecules can leak into the brain and basically start an inflammatory cascade right in the brain tissue.

And with that, there are several changes at the level of coagulation and inflammation that disrupts the neurotransmitters in the brain and also creates toxic molecules that make neurons die in certain places.

- So when this occurs, what are the types of symptoms that a person may experience as a result of this mechanism?

- There are cognitive symptoms that are known as brain fog, largely.

There have been also symptoms that are more anxiety, depression and fatigue.

People have experienced also organic hallucinations, depending on the location of this damage.

Now, some of these symptoms appear to be more reversible than others, in the sense that maybe study have shown that about 12 months after the start of these symptoms is more likely that symptoms like anxiety and depression can recede and go back to normal, and while the cognitive and more organic symptoms tend to persist.

And we are talking about pretty severe cognitive impairment that has been compared to basically being drunk at a level that it would impair driving or about 10 years of brain aging.

- How common are these symptoms in people who have had COVID?

- Yeah, so if we are thinking that it's about 10% to 30%, and that depends on the level of severity of the initial infection.

Even though this data are not really always showing that more severe COVID is associated with more long COVID brain symptoms because they are seen even in people that have not been very severely affected on a pulmonary level, let's say.

If we stay conservatively with the idea that it is about, let's say, 10%, we might be having 65 million people affected by long COVID out of the 650 million that had COVID-19.

- Extraordinary numbers.

- Yes, and people who have been vaccinated tend to be less affected, less at risk for long COVID.

People that have not been intubated have less risk of having long COVID.

And there are other factors, like having an autoimmune disease, that's a big risk factor because some of the mechanisms also involve the development of autoimmunity, which is when our immune system basically attacks ourselves.

Other aspects are that there are changes in long COVID that involve the rest of the body.

Now we learn that there are changes at the level of the microbiome, which is something that we hear a lot in psychiatry these days, as we have discovered that our gut microbiome, which is the group of bacteria that basically live in our gut and allow for gut health, are disrupted by this infection, like it happens with most infections, and this has also an effect on brain function.

So this is one of the things that I guess we didn't realize immediately.

- And you mentioned the potential benefits of the vaccine in terms of reducing the risk of long COVID and some of these symptoms.

Sometimes when people have COVID, at least in the initial part of the illness, they may take a medicine, Paxlovid.

Does have an effect on the things that we're talking about in terms of these long COVID types of symptoms?

- Yes, absolutely, because one of the factors in having the long-term consequences is related to the two main things.

One is the viral load and one is the immune activation in the beginning of the infection.

And so with people that are treated, we have less of both, lower viral load and also less immune activation.

And so we have less chance of having a long-term immune activation, which is what really drives this long-term inflammation that is responsible for long COVID brain symptoms.

- Now, you mentioned that sometimes this can happen even in mild cases of COVID.

So what should a person do, if anything, to minimize that risk of these long-term sequelae that are so troublesome?

- The very first and obvious things is try not to get COVID and protect yourself, get vaccinated.

Then when people are positive, even vaccination after having the infection has been shown to reduce this immune activation, getting the medication, the antiviral medication right away.

And then reducing inflammation that can be done in the first days even with over-the-counter, anti-inflammatory drugs.

And then long-term, in some cases, there is the need of cortisol supplementation replacement because the long-term consequences of COVID have been shown to be more pronounced in people that have lower cortisol levels.

And these, for instance, are older people or people with some medical conditions.

- So these are all important points.

Obviously people wanna avoid getting it, but so many people have and still do, even if they're vaccinated.

So if somebody gets it, they wanna keep this in mind so as to not only get better from the case of COVID that they're experiencing physically, but decrease the risk of these longer-term effects?

- Yes, then there are also medications that we use for specific symptoms.

So in the sense, if there are psychosis presentations like hallucinations, or sometime delusions, or depressive symptoms, studies have shown that we can use the normally available antidepressants and anti-psychotic drugs that also have an anti-inflammatory effect on the brain and can replace those neurotransmitters that are disrupted by the inflammation so that certain symptoms can just be blocked that way.

- So symptoms of depression, symptoms of psychosis, such as hallucinations, we would treat the way we treat them in somebody who didn't have COVID, but who were having those symptoms?

- Yes.

Yes.

- And those treatments are effective for people who have it as a result of COVID?

- Yes, absolutely.

- And how about for the brain fog, for the cognitive issues?

What are the treatments for that?

- For the cognitive symptoms, we rely more on the anti-inflammatory agents.

And there are some aspects of the cognitive symptoms that have been treated also with antidepressants or with medications that we use for ADHD that can improve focusing and concentration and performance.

- If a younger person gets COVID, we see it happening in children and teenagers, what's the risk for them to experience some of these long COVID symptoms?

- Well, we tend to think that children are more resilient than adults because their brain is more plastic, they likely have less inflammation as a baseline, which is already more active in people that are older.

This reminds me of a study that I was looking at about the exposure of moms that were pregnant and had COVID during pregnancy.

And now we have new studies showing that children that are born from moms who had COVID during pregnancy can have some attention deficit that they show when they are very young.

- Again, if somebody's pregnant, try to avoid getting COVID.

And then if they do have it, reach out to your primary care doctor, to your OB-GYN doctor to see what they recommend for you at that point in time?

- Yes.

- What do you see moving forward?

So maybe we'll get together again in two years from now, and what do you foresee us learning, better understanding the effects of COVID, and potentially new treatments to minimize these long-term effects?

- So we are studying now more the brain of people who died of COVID.

And we are using new technologies to do multiome sequencing, which means that we are studying the transcript of DNA in single cells in brain tissue.

Doing this, we are going to be able to identify disruption at the gene expression level, including immune activation in specific cell types.

And this way we can understand which molecules are altered in different kinds of cells in the brain of people who get COVID.

And this would allow to specifically design medications that target certain aspects of immune activation and autoimmune activation in patients that develop this long COVID so we can design more specific treatments.

- Two years out from our last conversation, what are we seeing the effects of the pandemic on our youth?

- Yes, I feel that there has been many changes in society.

And now we know that some things are probably never gonna be the same.

Starting from the way we study and go to school, the way we do work, and how people gather is also becoming very different.

And it feels that for people that are basically growing up in this new reality, there has been an adjustment in the way they do social networking, in the way they see their friends.

And we have now a whole new environment, which is virtual.

(laughing) And I guess-- - You and I are in that environment right now.

- Exactly, (laughing) and some things are very convenient with these new technologies.

On the other hand, I'm not sure that we are yet fully aware of what we are missing and gaining from this new reality and how people will develop and grow.

- One of the things that I find striking is, and we discussed this last time, if you think about young people, a significant percentage of their life has been during COVID.

And a friend of mine who's a nursery school teacher was showing me pictures that the children drew of faces that had a face mask on them, that was their view of a face.

So it sort of is very different from how people might've grown up before.

I'd like you to comment on that and on how that affects a young brain that's developing.

- Yeah, there is definitely a difference in the way we perceive closeness and facial expressions.

It changes things at so many different levels.

On one hand, not seeing people 3D actually has a totally different impact in the way we perceive them.

It has happened to me with my patients, that I've seen several patients throughout the pandemic only in 2D (laughing) through a screen, and I never met them.

And then when I met them for the first time in the office, I felt I had immediately a whole new set of information about this person that I didn't catch when I, it's like the difference between watching a movie and being in a theater, (laughing) a live show.

And in terms of obviously the mask, we really don't have half of the face of somebody.

So even reading emotions and what people communicate for these children, it must be very different.

And maybe they're learning more cues from the eyes that we were learning when we were young, and they are gonna have to decode that.

But yeah, it's really puzzling what we can do.

Another study I was looking at was looking at this anxiety in being close to people.

And they were measuring, in fact, how people were physically close to how much they were physically close to each other, what was the actual distance between people?

And they found that there was actually no correlation between their perception of the distance and the actual distance.

The only thing that the perception of the distance was correlating with was their anxiety, was the anxiety of being close to somebody and with the fear of getting contaminated.

And I've noticed even in my lab with my students and a research assistant that I work with, people now tend to wear the mask for several reasons that we didn't do before.

We tend to be more careful, maybe even if we have the cold, or a flu, and any little thing.

So it has become part of our lives in a way that it wasn't before, and not just for COVID at this point.

- I wanna ask you, again, something we've discussed before, which is the ability of brains to grow new brain cells, and what that means in the context of everything that we're speaking about.

- Yes, so that's something we are studying in my lab.

We've been focusing on the ability of the brain to regenerate for a long time.

And part of this multiome sequencing studies are done now to verify that.

We are discovering stem cells in the hippocampus of the human brain, which is a region that is important for memory and for stress responses.

And making new neurons in this region we know is necessary for learning new patterns, for responding to the environment for memory.

And in fact, this is the brain region that disappears first in Alzheimer's disease, when, at later stages, is completely destroyed, disappears.

So in COVID, we did publish that with the increase of blood-brain barrier leakage and increased inflammation in the tissue, we also noticed that the cells that were proliferating and making new neurons in the brain of COVID people were 10 times fewer than in the healthy brains.

And this could be one of the explanations of why brain fog and memory, the cognitive symptoms of COVID are showing up because these new neurons are, like I said, in mice, people have done studies ablating these new neurons and they have seen that the mouse is not able to learn new things.

This has been shown in birds, that now we're in the spring when the bird needs to learn new songs.

If we ablate these new neurons, they are not able to learn the new songs.

So in COVID brain with the inflammation, if these cells are not growing, this could be one of the factors.

And for instance, we think that this probably is also the reason of what we call chemo brain, when people do chemotherapy and they have also similar symptoms.

There is a syndrome of people in chemotherapy that is associated with cognitive dysfunction and some sort of brain fog.

And we think that one of the possibilities is that this brain plasticity making of new neurons is not happening because people are under these medications that are supposed to, any cell of the body basically to stop growing because we're trying to attack cancer, right?

So yes, it's one of the very important components of these cognitive symptoms, we believe.

- The good news is that, through neurogenesis, which is the growth of new brain cells, our brain can continue to replenish itself even at an older age.

The bad news is, sometimes inflammation in other activities can negatively affect that, as you described.

I wanna, as we finish up, thank you for joining us again and for sharing important information that's been developed by you and other researchers over the last couple of years.

And I'm gonna make a reservation to have you back in a couple of more years so that you could give us a further update on this important topic.

Thank you so much.

- Always a pleasure.

(bright music) - If you or a loved one are experiencing some of the brain-related symptoms of long COVID, such as depression, anxiety, hallucinations, brain fog, don't suffer in silence.

Remember, with help, there is hope.

Do not suffer in silence.

With help, there is hope.

This program is brought to you, in part, by the American Psychiatric Association Foundation and the John & Polly Sparks Foundation.