The Science of Stress: Exploring Brain Function, Inflammation, and Cognitive Health

Emily Kate Stephens (0:07): Hello, lovely people. You are here listening to episode six of Make Visible. Thank you for showing up and giving us your support as we try to support you in navigating complex illness. We endeavour to take the highly scientific and distil it into a form that is accessible. And this week, I had the pleasure of talking to Amy Arnsten, who is a professor of neuroscience and psychology at Yale University, where she studies the brain on a molecular level. She has found that in conditions such as Long Covid, there is dysregulation in the prefrontal cortex. Or, in plain English, she and her lab have found that inflammation and stress, and that's both physical and mental stress. And here she says that we can't differentiate between them. Inflammation and stress have a physiological effect that has a considerable impact on the way that we think and feel. In this conversation, Professor Arnsten explains how they're able to look at the brain in this way, talks us through those findings, and discusses the potential treatments that they have found that might help. So I approached you because I had seen your most recent paper that was published about the role of stress and inflammation on the prefrontal cortex, and that then caused me to go back and look at some of your previous work. Could you, to start with, give me an overview of your role, what you do, because you are both a neuroscientist, professor of neuroscience, and a professor of psychology, which is interesting because I've interviewed a lot of neuroscientists, but I don't necessarily think there are a lot of people who have the overlap of the two.

Amy Arnsten (3:00): I think the reason I'm relevant to psychology is I study the parts of the brain that generate our highest order cognitive functions, and these are often studied by psychologists in humans. So our work is immediately relevant to a lot of psychology, and even more relevant to psychiatry and neurology, where it's disorders of these higher cortical circuits.

Emily Kate Stephens (3:29): And you're based at Yale, where you run your own lab. And can you explain some of those things that your lab focuses on in terms of your expertise and research. You just mentioned the higher cortical circuits, but it's the molecular regulation. Can you just explain that for me, please?

Amy Arnsten (3:50): Yes, we study the molecular regulation of higher cortical circuits. So, how at the level of molecules, in particular, how the arousal systems have these huge effects on our ability to think, decide, focus our attention, remember things, have insights, be creative-all these wonderful operations are also, as all of us know, incredibly vulnerable. For me, they fall apart by about noon every day. And certainly, if we feel under threat with an uncontrollable stressor, mind goes blank. We can lose our higher abilities and revert to a much more reactive, primitive state, and our brains are set up to do that as a survival mechanism. But of course, it doesn't help with survival if the threat is something that's very complex and needs a really thoughtful solution.

Emily Kate Stephens (4:57): Is that to do with the brain sort of conserving energy? To put into survival, so it's almost shutting off molecules to certain other functions.

Amy Arnsten (5:06): So I think it's both that, and we'll get back to that in terms of inflammation. I hope because I think that conserving energy when you're sick and giving that energy to the immune system is really critical, or if it's a long-term stress and you're needing energy just for survival, but under an acute threat, I'm guessing it was something that evolved suddenly. There's a tiger, and instead of being thoughtful contemplation of the stars in the universe, you need to have these fight, flight, freeze reactions, and so we get to see how these very primitive reflexive circuits that lower animals have as well get strengthened under stress, whereas these recently evolved thoughtful circuits instantly get taken offline, and that I've often told the story of I was walking through the woods one summer on a soft dirt road. That's important because I wasn't making any sound, and suddenly a bear dropped out of a tree like 30 feet in front of me. Luckily, looking the other way at first, and I froze. And it wasn't like I was saying to myself thoughtfully, "Now bears, like most other animals cannot discern object from ground unless the object is moving. So if I stand perfectly still, the bear will not see me. No, I had no thoughts in my head other than the word bear, and I was totally frozen, including eyes not moving. So when the bear turned around two seconds later and looked right at me, he didn't see me. It was just amazing, and then he lumbered off, and so freezing, which people are often, why on earth would freezing be helpful? But it's not helpful if your predator is a primate who can easily discern that you're there. But for many animals, their brains don't allow them to do that unless you're moving against the background. And so freezing can actually be a really helpful survival skill. And so you can see that under stress, our brain has these mechanisms where we suddenly have very high levels of norepinephrine that shuts off our prefrontal cortex, which is a very recently evolved region, strengthens our amygdala, which is an ancient area that then has connections to brainstem that then can induce this rapid freezing response. So that's wonderful under conditions like that. But if the stress instead is public speaking, and there I am in front of 1000 people, and my mind goes blank, and the word bear is not there, but it's just like ah, that is not helpful. And I think many of us get to experience that even in non public speaking, where you get bad news, for example, and you're unable to think how to proceed and just have this stress reaction. Okay,

Emily Kate Stephens (8:48): What I was very curious about reading your paper and listening to your introduction is how do you measure in molecular terms, what that reaction is, what is taking place? I know that you use both animal models and human. How do you study it?

Amy Arnsten (9:13): In a whole bunch of ways that are complementary, and you know, it's tricky to study stress because you need to have it be very mild to have it be ethical, and so you want then your baseline to be really happy, so there's room to move. In humans, this kind of research is particularly challenging because the person has to sign something saying, "I can stop this at any time, and yet, what really makes something stressful is when you feel out of control. And so, some groups have been very clever in interviewing people and using stories of their own stressors in their own lives, and then playing those back to them as a way of trying to create a stress response that's truly relevant. Others use things like putting hands in very cold water, which on a hot summer's day would not be stressful at all. But this points out that stress is very context dependent, very personal, so needing to do that thoughtfully, we look at brains across species and see where molecules are. We also collaborate with groups who do what's called transcriptome studies, so see what kinds of molecules different cells are capable of making, and then we do a clever thing of recording from neurons in animals that are doing a higher cognitive task, and we change the molecular environment just around that cell, so we can make it stress-like around the cell, but the animal is still happy. And you get to see how that neuron shuts off, for example, or how it can be rescued. And then, using those clues, we develop treatments for humans and see if our hypotheses are correct.

Emily Kate Stephens (11:20): And how are you changing it, and how are you viewing it? Is this through magnetic resonance imaging, or is this using molecule chemicals that you're putting into the brain? Because the brain is incredibly difficult to study.

Amy Arnsten (11:35): Yes. So the human work, which, by the way, I don't do personally, but I collaborate with people who do that, is very often using functional MRI as an assay. We have a whole multitude of methods. One thing we're able to do is electrically sprinkle drugs into the brain; these tiny amounts that only affect a few neurons, and we can infuse then drugs that block the actions of molecules that are already inside the brain to see what they're normally doing, or we can give drugs that mimic those molecules to see is our hypothesis correct? Indeed, this is what they do. So, for example, we can give drugs that mimic norepinephrine's actions as part of the stress response and work that out.

Emily Kate Stephens (12:43): That's absolutely incredible, isn't it? I mean, working on that level and being able to assess things in that detail is just remarkable.

Amy Arnsten (12:53): What's really remarkable is being able to see it using something called immunoelectron microscopy. We're able to see where molecules are with nanometer resolution, so we can see things that are nanometers apart and see molecules interacting within nanometers and how they relate to the synapse, which is where one neuron talks to another. So that work is just beautiful, conceptually and physically, and it's kind of our map, our guide. It's being able to see where molecules are from that, develop hypotheses that we can then test with the physiology and the behaviour, especially trying to develop treatments for cognitive disorders based on what we see. Because what we've been learning is these recently evolved circuits have very different molecular needs than our more primitive circuits. Sometimes even the opposite, and so we need to know what shuts them off, why they're so vulnerable, so we can protect them and restore cognition.

Emily Kate Stephens (14:13): So, when you were putting together this recent paper, you talk about the dysfunction in mental disorders, and within that, you mentioned schizophrenia, Alzheimer's, Long Covid, depression.

Amy Arnsten (14:30): Not suggesting that they are all the same condition, but suggesting that they have elements, they have similarities in terms of what is going on in the dorsolateral prefrontal cortex.

Emily Kate Stephens (14:45): In those, what were what you defined as stress initially? What were the stresses that impact the prefrontal cortex?

Amy Arnsten (14:55): Well, if I can go back to the disorders, as I think there's a lot to say there to make that more understandable. Great, they might seem very different: depression, schizophrenia, Alzheimer's disease, and Long Covid, but they actually share many features. And interestingly, schizophrenia used to be called dementia praecox, premature dementia, and so profound cognitive deficits in schizophrenia. And there's also often hallucinations and delusions in people with Alzheimer's disease, especially related to pathology and prefrontal cortex. So, things that sound very different actually can have many essential features in common, and Long Covid also preferentially or consistently impairs the cognitive functions of prefrontal cortex. And part of what prefrontal does is top-down control of our thoughts, our actions, and our emotions, and there are connections from dorsolateral prefrontal cortex through the medial prefrontal down to the structures that are overactive in depression that are positioned to be able to regulate those and shut them off, and be our emotional cheerleader. And work has shown that there's synapse loss in that very circuit that correlates with the severity of depression and PTSD. So studying this part of the brain is particularly relevant to human mental disorders, including the spectrum we just talked about, and why we're hoping we can understand what this cortex needs to have treatments. I should say it's also the circuit that's most affected in ADHD, and yeah, especially on the right side, where when I'm talking about top-down control of attention and action, if you have less of that, you can see where you would have symptoms of ADHD.

Emily Kate Stephens (17:14): I was reading about some of your work into ADHD, and one thing that I was curious about was in all of the reporting, in all of the articles that I found that reported on this work of yours relating to Long Covid, it talked specifically about brain fog, but I think what your work is more than about brain fog. It's about the regulation of emotion, action. It's not. It's not the brain fog that you sort of typically think of being just that confusion or that word loss.

Amy Arnsten (17:48): With the great prevalence of brain fog from Long Covid, there's now been a lot of research on it, and what that research shows is major components of brain fog are prefrontal dysfunction, often coupled with fatigue, depression, loss of motivation, and much of that also is relevant to dysfunction of other parts of prefrontal.

Emily Kate Stephens (18:20): Okay, so they are actually tied to other symptom sets within, or the suggestion is that they could all be from a similar root.

Amy Arnsten (18:30): Yes, I think brain fog is the nickname for this spectrum of things that, when people have experienced it's a shorthand for being able to say this entire thing that happens to you, where you have a hard time concentrating, and your working memory is shot. Part of how they can tell that it's more prefrontal than hippocampus is usually people's recognition memory remains intact. So, if I showed you something, and then 10 minutes later say, "Have you which one of these is the new thing? You would recognise that you had seen the thing before. But if I gave you a list of names and said 10 minutes later, "Okay, give me those names back again, where you had to recall them. Then you need prefrontal as well, and then you're impaired. So preserved recognition memory, which is one of the, so recognition memory is very much afflicted in Alzheimer's disease, because hippocampus and especially the nearby entorhinal cortices are affected very early, and then you have a hard time creating new long-term memories, and you actually don't recognise that you had seen something two hours before. With prefrontal deficits, that's usually intact, but you have this whole spectrum of other cognitive changes that are very much a part of brain fog.

Emily Kate Stephens (20:14): But am I right in thinking that there are also prefrontal deficits in Alzheimer's on top of those that you just mentioned?

Amy Arnsten (20:20): Yes, indeed. So the earliest in people with a typical course of Alzheimer's, because there are atypical ones, the medial temporal lobe is affected first, and so recent memory is often the first symptom. But then, as the disease spreads, it involves prefrontal and a whole spectrum of cognitive alterations, including in language, executive functions that top-down control. Abstract reasoning is a key part of prefrontal, so people can become very concrete and insight about yourself as well as others. So that is often a time when a person sometimes blessedly loses insight that they're ill.

Emily Kate Stephens (21:08): Okay. So, tell me what you define as stress in these conditions, because you look at things on a molecular level, on a physiological level. Some people would say that stress is psychological and therefore different. Explain to me how these are two sides or all sides at the same time.

Amy Arnsten (21:45): You know what's remarkable: the more we learn, the more we see that there's no difference between psychological and physiological stressors. That, for example, this is other people's work, but we look at what happens with traumatic brain injury or hypoxia, and it induces the same changes at the molecular level in prefrontal cortex as a psychological stressor. In terms of psychological stress, what's a stress? This is work of other people, but the key issue is control. If you have a sense of control over the stress, you're confident. Then it doesn't evoke these mechanisms. If you feel out of control and threatened, then it does, and so you can imagine that can be really different for different people, and that even a mild stress, if someone feels out of control, can induce at least some of these actions,

Emily Kate Stephens (22:58): And that's therefore why you have this. If your body is stressed by a virus, or you're unwell like that, then you're actually mentally less able to handle cognitive stresses, and vice versa. I think that is there not the idea that sometimes when you're psychologically stressed, you can then be more susceptible to having a less robust immune system. Is that a two-way street? So

Amy Arnsten (23:30): This is an area where I'm not expert.

Emily Kate Stephens (23:32): Okay,

Amy Arnsten (23:33): But there are multiple interactions with the immune system, and whether you're stressed in there in a way that has suppressed the immune system, so it can't mount a proper response. I would guess that's what's going on when we're sick. We're just starting to study how inflammation affects these higher cortical circuits-it's one of the most complex arenas because the immune system is incredibly complex, the nervous system is incredibly complex, and you put those together, and it's even more so. But we're already getting some clues about how powerful these interactions are, and we get to see that when we're under conditions of inflammation, so that occurs when we're sick, there are molecules made that actively shut off our prefrontal cortex. So something called kynurenic acid that's made in our brains, and it stops the neurotransmission that's needed in dorsolateral prefrontal cortex, and it's emerging data suggesting this is one of the key factors in Long Covid, and so we're trying to develop treatments to stop that to protect these circuits, because this particular molecular mechanism is self-perpetuating, so kynurenic acid leads to more kynurenic acid production, and we think that might be why in Long Covid it keeps itself going. So already, I work with a physician at Yale, Dr Fesharaki-Zadeh, who prescribes N-acetylcysteine, which you can actually get over the counter here in the U.S. Which inhibits the production of kynurenic acid, but it's also an antioxidant that's been used for decades. So he prescribes that plus guanfacine for people with Long Covid. The guanfacine helps restore connectivity of prefrontal cortex.

Emily Kate Stephens (25:50): Now, tell me a little bit about guanfacine.

Amy Arnsten (25:53): Well, I didn't create the molecule that was created like 50 years ago, I think, in Switzerland. So it was originally used to treat high blood pressure, and it was lousy at it, so it was no longer used for that very much. But it was proven safe, so we were able then to really quickly employ it for other uses in humans. So what we discovered when I talk about how prefrontal goes offline during stress. The way this happens is fascinating. There's something called potassium channels right next to where neurons connect in prefrontal, and when they open up, it shunts the connection. So one cell can no longer excite another. They can't talk to each other anymore, and that can happen very quickly. That's what happens with stress: is those potassium channels open, and now these neurons can't excite each other, and this part of the brain goes offline. What guanfacine does is close those potassium channels, so it strengthens the connections, protects from stress, and it seems to protect under other conditions as well. So we got to see that our animals were very focused, calm, and from that, then I worked with a physician who tried it in adults with ADHD and they found it very helpful. So then he tried it in some older kids, and then we reached out to this little company that then developed it as Intuniv. Intuniv being the long-lasting form, and the reason it needs to be long lasting is because in children and teenagers, guanfacine is metabolised very quickly. Someone older, like my age, it's metabolised slowly, so it's once a day. But this longer acting version of it is helpful for younger individuals.

Emily Kate Stephens (28:06): Is that a sort of slow release?

Amy Arnsten (28:08): Exactly, slow release over the whole day, and so you only have to do once a day dosing. And the smoothness seems to be something the brain really likes that helps keep us chill, and so it was approved by the FDA in 2009 for treating ADHD. I'm surprised it isn't used more because it's a non-stimulant, and so many people don't want to take stimulants. But I think there wasn't that much advertising, and so a lot of people don't even know about it. But it's also used off-label to treat a lot of stress-related disorders, as makes sense from our conversation. For example, children who've been traumatised. It helps them have top-down control of their emotion, so like adolescent boys who've been traumatised and become very aggressive, it helps them have self-control again. So that can be a really useful use of it. And as I said, now being used in Long Covid off-label, and there are currently several very large phase three studies to see if it's helpful in treating delirium. So delirium is often a state where somebody can be awake but unaware. They're totally cognitively impaired and often very agitated, which can be a danger to themselves coming out of surgery, or if they're being treated in the ICU and have oxygen, and they're trying to pull it out. And so they're testing to see if guanfacine helps, basically prefrontal reconnect, so that a person can understand. Yes, you know you're going to be okay. We're doing this for this reason, etc. So there are trials right now in people who have serious illness or post-surgical anaesthesia who are delirious to see if guanfacine helps.

Emily Kate Stephens (30:18): I would definitely, as you suggested at some stage, like to talk to Dr Fesharaki-Zadeh about his use of the combination of the guanfacine and the NAC in Long Covid, because it sounds very sensible. I take the NAC because it's available to buy in the UK as it is in the US, but I have not yet been able to access guanfacine. But I have been advised previously to take it again because of anecdotal evidence from various clinicians here, but I have not yet managed to get hold of it.

Amy Arnsten (31:00): I take both myself. So the way we initially discovered guanfacine was giving it to aged animals because with ageing you naturally develop prefrontal deficits. It helped them. These prefrontal deficits actually begin in middle age in humans and animals, late middle age. So there I was, forgetting where I parked my car, and I was like, "Well, do I believe my own data? So I have been taking guanfacine, and then I got Covid last fall. It at long last caught up with me, and so I started taking the NAC as well, and so I take both now every day. Yes, because I have to stay sharp enough to try to be half a step ahead of my lab, and that's tough because they're brilliant.

Emily Kate Stephens (32:02): Picking up on a couple of points that you made, one thing: this suggestion that the guanfacine can smooth things a little in that aggression, I think that's something that's not often discussed in Long Covid, and I appreciate that you're not a clinician. But in addition to the brain fog and the reduced functioning in certain parts of the brain, I do think that a lot of people with Long Covid have experienced anger or a loss of patience, and they're told, well, you're like that because you're sick, so you're obviously annoyed, you're irritable, you fly off the handle much more easily because you're frustrated at being sick. But is there a suggestion, therefore, that that's also controlled by the prefrontal cortex?

Amy Arnsten (33:00): Totally. That irritability, lack of patience, reactive anger-that's the loss of top-down control and of specifically top-down control of emotion. And there have been studies in people and animals. Perhaps do you know about the marshmallow test? This was done years ago, where it was studies with children. So whatever the child's favourite thing was, be it a candy or toy, they got to choose it. It was put in front of them, and if they could wait, was it five minutes? I think they would get two of them, so they could either take it right away, or if they could wait five minutes, they'd get two. And the first little girl to be tested wanted a marshmallow, so that's why it's called the marshmallow test. So this ability to wait for a larger reward, which is what we often call patience, and being able to tolerate frustration, being able to sustain yourself through that, very much a prefrontal function, and that's one of the things guanfacine very much helps with.

Emily Kate Stephens (34:21): Oh, that's absolutely amazing that connection. Because I think it's the case with a lot of different elements of the brain function in these conditions. People are told you're depressed because you've been sick, and there is an element of that. Obviously, the inflammation in your body, causing some kind of depression, but the fact is not something that you have psychologically manufactured as a reaction is quite fascinating.

Amy Arnsten (34:51): Yes, I would reword the statement to say you're depressed because you're sick. The sickness is making you depressed. The sickness is making you irritable. The sickness is making you cognitively impaired.

Emily Kate Stephens (35:07): Do you know Edward Bullmore at Cambridge? He wrote a book called The Inflamed Mind and that was one of the first things I read when I had Long Covid because I had this sort of depression. It's a fascinating book, and it talks about that how your body is actually one of the first examples is he talks about after he's had root canal surgery and how your body actually to protect you essentially puts you into this depressed state because it doesn't want you to be going out and socialising and mixing when you're prone to infection.

Amy Arnsten (35:43): Exactly, wonderful book.

Emily Kate Stephens (35:45): I'm sure you know all of it, but I think there's so little understanding of that, or of the. It's the same back and forth, isn't it, between the psychological and the physiological?

Amy Arnsten (35:55): Yes, and that either a psychological stress or adverse conditions in the environment are putting your brain in a state where it's a hide away in the cave. It's dangerous out there. I don't care if you're miserable. I want you miserable, so you'll stay put in the back of the cave and stay alive. Yes, Mother Nature doesn't care if we're happy, just that we continue.

Emily Kate Stephens (36:24): Yeah, that was such an eye-opening thing. I did a neuro yoga course last year because I've become very much interested in the neuroscience of our physicality, and that was the thing that we got drummed into us the whole way through. Your brain is not interested in you thriving; it is simply interested in you surviving. Once you sort of understand that and stop trying to fight against it all the time, it's quite eye-opening.

Amy Arnsten (36:54): Yeah, it's very important to stop blaming ourselves. And there's a whole history of the medical profession, especially for women patients, blaming the patient for anything that's not understood. Schizophrenia was blamed on bad mothering, and that's why science is so important. Because when you understand the mechanism, you're no longer having to blame the patient, blame the victim, as it were. You can now understand and treat, and the doctor themselves can feel effective and non-stressed, and use their prefrontal cortex instead of a primitive reaction of it's the patient's fault

Emily Kate Stephens (37:44): And the patient themselves as well, not blaming themselves because I think there is so much onus in these conditions. If you look at the way that ME/CFS patients have been treated for the past 30 years, or I mean even longer, because it actually is a condition, I think, that has been around a long time. Look at all of the people who used to just get sent to the mountains in the 1920s, and people have been always made to think that it was something that they did, even with the derogatory names that it's been given. It's their fault.

Amy Arnsten (38:18): That's right. It's a lack of will-that if they only had stronger will, they could overcome it. And what we get to see very clearly is the very circuits that allow you to overcome under healthy conditions are the ones that are taken offline with chronic stress and inflammation, and so the very muscle you need to lift yourself out is gone.

Emily Kate Stephens (38:50): You mentioned a moment ago, and you referenced it earlier on as well. In the study, it says early life stress may sensitise the system for dysfunction. There is the suggestion in Long Covid and other conditions, and this again often is sort of attributed to a blame thing, that there is some residual trauma in patients that has exacerbated the condition. Is that one of those things that you discuss in the study as creating a vulnerability, that kind of stress in early life?

Amy Arnsten (39:38): Yes, our own research does not address that, but from my reading of the field, that's certainly what it looks like. And again, we see how the physiological and the psychological are the same, because you also have this from, for example, in utero hypoxia, perinatal hypoxic events, and so far it looks like all of these events may prime the immune system, prime inflammation, so you then have a larger or qualitatively different inflammatory response as an adult, and so I think that kind of rational explanation for that holds out some hope, other than the fact that the immune system is immensely complex. But this idea of if we can understand what changes occur to sensitise the system, and then have treatments for that, we get to see how effective this approach can be when we're lucky enough to be able to really understand these relationships. For example, new treatments for psoriasis, antibody treatments that target very specific cytokines, and just can wipe out psoriasis like that, and so the hope is we'd be lucky enough because, of course, it has to be that cytokine isn't doing something else that's really helpful, and that's when you get horrible side effects. But that degree of understanding with luck can really have huge effects.

Emily Kate Stephens (41:25): Wow, just incredible. Just related to the kynurenic acid, could the levels of kynurenic acid be used as a biomarker of some of these conditions, is it something that can be tested

Amy Arnsten (41:46): Indirectly? So, kynurenic acid is made from something called kynurenine. Let me actually go back and describe the whole pathway because it. I think people would be interested. The amino acid tryptophan can get made into serotonin or kynurenine, and under conditions of inflammation, it gets turned into kynurenine. In particular, that happens in both brain, but also in the body. And in the body, then the kynurenine enters the blood, and it can be actively taken up from the blood into the brain, and that's where it gets turned into kynurenic acid. Kynurenic acid itself is electrically charged, and so it doesn't get across the blood-brain barrier, so you may have it in your blood, but it's not going to be able to get into your brain. But nonetheless, you can use levels of kynurenine in the blood as an indirect measure of whether somebody might have a lot of kynurenic acid in brain, and indeed in Long Covid, they see high levels of kynurenine in blood,

Emily Kate Stephens (43:09): And that's something that we can test in a normal blood draw, or is that something that is only available if that blood is then sent to a lab such as yours for assessment?

Amy Arnsten (43:22): Yes, I think it would only be special labs. Yeah, we work with other labs that are expert in measuring it. I don't think it's a typical thing that's measured in your usual blood test.

Emily Kate Stephens (43:37): Okay, what's next for you in terms of where are your studies taking you next, or where is your lab heading? Because I know one of your focuses is the development of treatment. Are there treatments that you're working on? Are there further studies that you're doing?

Amy Arnsten (43:58): Yeah, one of the things that we're learning is that inflammation dysregulates the stress response. So normally, when we have an acute threat stress, we have our stress response, but then we have all these molecules that, thank heavens, chew it up. And what happens with many inflammatory mechanisms is they destroy the things that chew up the stress response. So therefore, we have a prolonged stress response. So we're working with Johns Hopkins Drug Discovery testing some treatments that help to eliminate those inflammatory pathways, and hopefully allow the brain to regulate itself more quickly. We're also testing more agents that might inhibit the production of kynurenic acid, but a whole other arena is looking at how the dysregulated stress response leads to tau pathology and Alzheimer's disease, and it's known that psychological stress, just like a traumatic brain injury, is a risk factor for future Alzheimer's disease. So people who had, for example, the death of a spouse or a child at age 50 have a higher risk of Alzheimer's disease at age 70, and we've been seeing how increased stress signalling specifically increases calcium levels inside the cell to the point where they can be toxic and activate something called calpain-2, which then drives Alzheimer's pathology, and we're hoping to test the first inhibitor of calpain-2 to see if it will stop all that at this early stage and could be an actual preventive treatment if taken early enough. So the idea would be it would be like a statin you'd start taking when you're 50 years old. To do that, though, it has to have no side effects, and so we'll have to be lucky with that.

Emily Kate Stephens (46:26): Fascinating and validating findings, I thought, and we have indeed subsequently had a conversation with Arman Fesharaki-Zadeh, who talks to me in more detail about the combined treatment of guanfacine and NAC amongst his patients, and I look forward to putting that out for you to listen to next time. I find that every single one of these conversations almost throws up as many questions as it answers, and one of the big things to come out of this interview for me was the comment that your brain either decides to produce kynurenic acid, which, as we see here, is elevated in Long Covid, or serotonin, which we know is depleted in many of these conditions. So, serotonin is something that I would be interested to explore further with our experts in coming weeks, please tell me what questions were brought up for you in this episode, and let's continue to build a useful, informative resource. I look forward to joining you next time. 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 100,000 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.

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