#7. Discovering new treatments for Brain Fog

Emily Kate Stephens (0:07): Welcome to the latest episode. We are trying to weave between hard peer-reviewed science, anecdotal evidence, and theories that have some weight, and present as balanced a view as possible of the ideas that are out there in this invisible illness space. So, following the previous episode with Professor Amy Arnsten, who has looked in great detail at the prefrontal cortex, and she referenced working with a doctor by the name of Arman Fesharaki-Zadeh, who has been using the protocol of guanfacine and NAC to work with his Long Covid patients in his clinic. Arman Fesharaki-Zadeh is a behavioural neurologist and neuropsychiatrist at Yale Medicine. His primary focus prior to the pandemic was traumatic brain injury and other neuropsychiatric conditions concerning cognitive deficits such as Alzheimer's, dementias, and he's taken his expertise of these conditions and their impact on the brain to formulate a regimen for Long Covid patients, from which he seems to be getting positive results. I have been interviewing doctors and medical experts specifically about Long Covid, and now what I am trying to do is actually broaden out some of that work that we have done and really focused on in Long Covid, and see how we can also apply that to other complex conditions.

Arman Fesharaki-Zadeh (2:26): Great.

Emily Kate Stephens (2:26): Some of those being the post-infectious conditions, but we're also interested in whether we can apply some of these theories to things like EDS. Or I know that you do a lot of work in TBI, so that's sort of where my positioning is. We feel that I know that people are frustrated in terms of the Long Covid community, but there's been such a wealth of research compared to the things that other illnesses have received that we're trying to open it out.

Arman Fesharaki-Zadeh (2:56): I have been here since 2016 here at the Yale School of Medicine, and my specialty has been focused on traumatic brain injury and dementia, so that's been my focus for the past eight years of being here. I've been treating Long Covid patients shortly after the pandemic started, and again, as far as the span of time I've been seeing these folks, I should say. So since June 2020, that was my very first patient who had Covid, and to this day, continue to see them.

Emily Kate Stephens (3:24): You've had a big focus on TBI, but in terms of your clinics historically, who was coming through your doors? Were you only treating traumatic brain injury patients, or were you at that time also treating people prior to Covid, with some of these other conditions, which could be perceived as sort of neuroinflammatory or neuroimmune conditions.

Arman Fesharaki-Zadeh (3:49): Right, that's a great question. So, I'm a memory cognitive specialist. So, in the context of Covid, folks who had memory cognitive issues came to see me. They continue to come see me. Folks with brain injury, same story. What we call persistent post-concussive syndrome. In more rare cases, even chronic traumatic encephalopathy or Alzheimer's, perhaps due to multiple concussive injury. There's a link between the two, by the way. So, in that context, I've been seeing folks from a variety of different medical conditions ranging from Covid to TBI to dementias, and our clinic, the core bases of that are dementia patients, so folks with Alzheimer's and more rare subtypes of dementia clinic, frontotemporal dementia, which I also do research on, by the way, and other subtypes as well. So the starting point to answer your question, is memory and cognitive deficits in those contexts the

Emily Kate Stephens (4:45): Memory and cognitive deficits? Obviously, when you started seeing Long Covid patients, was one of the prevalent symptoms for people that were coming to see you. Can you tell me what this term? You've written papers on it. Everyone talks about it, but how do you define this term, brain fog?

Arman Fesharaki-Zadeh (5:12): That can be a tricky topic in a sense that it could be somewhat vague and non-specific. But what I learned in terms of the way the patients were referring to it was difficult in focusing, difficulty multitasking, difficulty in organisation, difficulty in recall of immediate information, what we call working memory deficits. And what struck me was how similar, and I think this has been mentioned in the papers also, how similar the Long Covid patients' presentations were to post-concussive patients, so folks who had prior concussions and have this kind of what we call persistent post-concussive syndrome. How similar the overlap of the symptoms were, and I will also add to this that I've seen patients who have MS and cognitive deficits. I've seen patients who've been on chemotherapy and have cognitive deficit. There is quite a bit of kind of this neuroimmune presentation, as you mentioned also earlier. There is quite a bit of overlap between these presentations also. So I was struck by the similarity of the phenotype of these folks, and what I learned from the world of TBI is what kind of inspired the regimen that I use for Long Covid patients also.

Emily Kate Stephens (6:22): Okay, and before we really talk about that regimen, does that mean that those conditions you talked about the similarities, presumably in presentation in terms of the symptoms that the patients were coming in with? Can you say that you can actually see physically in the brain similarities between those conditions in terms of neuroimaging or in terms of neuroinflammation? Is there actually a physical insult that you are able to see?

Arman Fesharaki-Zadeh (6:59): That's a great question. There is a great degree of heterogeneity in the presentations also, so oftentimes we may not be able to see on MRI actual distinct focal lesions or morphological changes. But on select cases, I have seen what we call white matter changes, so diffuse white matter lesions that I also see in concussive patients. I've seen it also in lupus patients, and I've seen it prevalent, quite prevalent in MS patients. So this kind of diffuse white matter changes due to inflammation, and inflammation is a big umbrella. So we're talking about this phenotypic similarity. There is kind of this pro-inflammatory process that you know we speak to TBI researchers and experts. Inflammation is one of those pathophysiological changes that occurs in post-concussive patients, and what might be shared amongst all these disease processes, be it synaptic loss or network alteration. So the outcome may be very similar, and inflammation might have that kind of common pathological sequelae in all these conditions.

Emily Kate Stephens (8:06): So actually, inflammation in the brain.

Arman Fesharaki-Zadeh (8:10): That is correct. And the idea that it can be pervasive and it can be extremely heterogeneous in population. Pathophysiologically, it also makes sense because we have what we call the ACE2 receptors, where the Covid virus attaches itself to, and the expression of ACE2 receptors is variant amongst population. The response to Covid infections have been very divergent. There are folks who recover in the span of two days, and there are folks who have these persistent Long Covid symptoms. Again, speaking to the fact that the inflammatory response might potentially explain part of this scenario, and obviously the research is still ongoing on this topic. So

Emily Kate Stephens (8:48): Now, obviously, we've had a huge number of people with this symptomatology as a result of a Covid infection, but that's actually also to do with the sheer number of people that got infected with Covid globally. Do you, in your work, view that post-Covid syndrome as similar to ME/CFS or other possibly specific, possibly non-specific post-viral infections, in terms of the way it affects the brain?

Arman Fesharaki-Zadeh (9:20): I think they share a great degree of similarity in terms of the mechanism. So, one of the areas of the brain that is extremely vulnerable to both neuroimmunological changes or injury, for that matter, is prefrontal cortical area, and those are the areas. If I describe the functionality of these areas, it will make a lot of sense. So, these are the areas in charge of executive functioning, and what that means is ability to multitask, to task switch, ability to recall immediate information, emotional regulation. Also, a lot of folks with post-concussive or Long Covid symptoms, they have a lot of emotional dysregulation symptoms. Also, and in addition to the cognitive deficits, we were focusing on the cognitive issues, but the affective emotional problems are also described in this population as well,

Emily Kate Stephens (10:06): And that's because it's all controlled by the prefrontal cortex.

Arman Fesharaki-Zadeh (10:10): The prefrontal cortex has a regulation role. Think of it like that: there are a lot of fibres attaching what we call the limbic network, what is colloquially called as limbic brain, also the amygdala, you know, the insula, and there are a lot of connection, kind of going back and forth between the prefrontal cortical area and the subcortical limbic brain, and those connections are also vulnerable to the inflammatory process as well as the prefrontal cortical area. So the idea that even though the conditions could be quite distinct in kind of descriptive sense, but the outcomes are often again the same vulnerable areas are affected.

Emily Kate Stephens (10:46): And is that why many of these conditions progress into people having conditions such as depression, anxiety? Are those all regulated by this same part of the brain?

Arman Fesharaki-Zadeh (10:59): Well, the areas of the brain that I mentioned play a major role. So when it comes to emotional regulation, I see that in our TBI patients also very frequently. So the rates of depression, anxiety, and impulsivity and emotion dysregulation is extremely high in traumatic brain injury patients. The rate of substance use is also extremely high. Again, the idea of substance use also you can look at it from different perspective is as a coping strategy for emotional regulation. So folks drink because they feel anxious, they feel depressed, they have difficulty controlling their emotions. So that's why the rates of substance use are also high in folks with Long Covid. I haven't looked at those studies recently, but I do believe that folks have depression, anxiety, extremely comorbid with Long Covid cases as well. Yeah, and it's been reported. The Lancet journal that came out in 2021, looking at I believe 236,000 plus patients, reported a third of these folks had neuropsychiatric symptoms, and kind of lumped in that category, the combination of cognitive deficits as well as emotional and affective problems as well.

Emily Kate Stephens (12:02): Yeah, and I think a lot of the time those people are told, "Well, obviously you're going to have these various issues. You're going to have anger issues because you are frustrated about your condition. And I think sometimes it's actually quite important for some of those people to be validated and told, actually, it's not just that you got really moody because you have to spend all your time in your bedroom. There are actually physiological things that are going on in your brain that have created these things, and that's not to exonerate people's behaviour completely, but that's to give some context to why there's this shift in personalities.

Arman Fesharaki-Zadeh (12:44): Absolutely, there is a paper that was published. If I may just open a small plug here, out of Yale back in 2019, and this was published in Nature Communications, and the old adage, the old paradigm, has been that psychological conditions are completely separate from neurological conditions. So there's a chasm between what we call depression, anxiety, even more severe conditions such as PTSD and bipolar and schizophrenia versus neurological deficits. There was a study that came out that was published in 2019. First author Sophie Holmes, who's actually British, and collaborated with our group in psychiatry here, and they looked at synaptic density in the brains of patients with major depressive disorder, and what they found was really remarkable, as was PTSD. So they looked at two groups of patients: MDD, major depressive disorder, and post-traumatic stress disorder. And what they found was there was loss of synaptic connections in the same area that I just mentioned earlier, the prefrontal cortical area. So there was loss of synaptic connection in those areas in folks who had symptomatic major depressive disorder, as well as PTSD. So there are physiological biomarkers that if you have sensitive enough of a scan, so in this case was SV2A, which looks at synaptic density. This SV2A PET scan that I'm doing research on right now. Also, the idea that we could actually capture that in patients who have this long standing psychiatric conditions. Now, yeah, looking at from the Long Covid perspective, it does lead to this chronic inflammatory process, then the parts of the brain that are more vulnerable, also that are prefrontal cortical area, the PFC area, and those are the same areas that have been affected in depression. Those same areas that have been affected in traumatic brain injury, the same areas that have been affected in neuroimmunological conditions such as Long Covid or post viral symptoms. We can talk about the regimen also, but I will mention the same regimen that I've tried for Long Covid patients. I have tried also for MS patients, and I've seen success in a clinical setting. We have not published these studies, but anecdotal I can mention that the same triple modality that has been effective for Long Covid patients has been tried also. For other kind of post infectious and post viral scenarios,

Emily Kate Stephens (15:04): Picking up on something that you just actually said almost at the beginning of that section is that this differentiation that there has always been previously of neurology and psychiatry, and that's why I feel like you are perfectly placed because you are a neuropsychiatrist, so you are presumably trying to bring both sides of that, so you are looking at the way that the psychiatrist looks at the brain almost as a separate entity, and reinserting it into the body and looking at it holistically. Is that what you try to do in your work?

Arman Fesharaki-Zadeh (15:39): There are a lot of bridges going back and forth, and the reason there has been a separation. One of the reasons there has been separation between neurology and psychiatry is because our imaging modalities, our biomarkers, have not been sensitive enough up to a decade ago to capture those changes in the brain. Now we do have those modalities available. The synaptic density PET imaging was just an example. There is functional MRI studies that have also captured this in the research setting, which is not clinically available yet, but it's an exciting forefront and will be coming up soon. And also, we tend to forget that Sigmund Freud, you know, the father of psychoanalysis, was a neurologist, and the reason he became fascinated with psychoanalysis because he didn't have the necessary tools at that point. This is more than a century ago to explain the behavioural symptoms. Now we're getting closer to a point that we can actually have again sensitive image markers that can potentially open up that window to look at these patients differently.

Emily Kate Stephens (16:40): It's amazing. So let's at that juncture talk about the protocol that you actually have developed for treating Long Covid patients. Where did this initially come from? Because it is FDA approved drugs. It is not something that is completely plucked out of the air. Can you tell me what you previously used it for and how you thought it might help with Long Covid?

Arman Fesharaki-Zadeh (17:08): Yeah, that's a great question. So the combination regimens includes guanfacine, which is an alpha-2 agonist, and NAC, N-acetylcysteine. Now guanfacine was initially FDA approved back in 2009 for ADD, ADHD. So in a lot of mechanistic, you know, makes a lot of sense. The pioneer, by the way, behind this drug is a neuroscientist here at Yale. Her name is Amy Arnsten,

Emily Kate Stephens (17:34): Who I have interviewed. Absolutely wonderful lady.

Arman Fesharaki-Zadeh (17:37): She is. She is wonderful, and who happens to be the senior author, who's been a mentor on this project, also.

Emily Kate Stephens (17:42): Yeah, and you've done a huge amount of collaboration with her on these things.

Arman Fesharaki-Zadeh (17:45): I have, and again, she's been wonderfully supportive. She was a pioneer behind guanfacine’s approval back in 2009, and she's worked on it for decades, using primate studies and eventually clinical trials with patients. So this was back in 2009, and the work of guanfacine, the idea of using guanfacine for post-concussive patients, was initially utilised by a TBI researcher who is a few years older than I am, but he's been doing this for longer than I have, Thomas McAllister, who I believe has been the chair of psychiatry in Indiana University. Last time I checked, so he used guanfacine for post-concussive patients and using fMRI studies and showed that it led to working memory improvement. And this was published in 2012. We were talking about more than a decade ago, 12 years ago. So the idea that post-concussion again, this was a small study, small-scale study, and that became the inspiration of using guanfacine in a clinical setting. So for more than a decade, nobody used this in the clinics, even though guanfacine has been FDA approved for ADD and ADHD. The N-acetylcysteine is a very useful, robust supplement. Has anti-inflammatory or antioxidant benefits, and the lab that I did my PhD in had published on NAC also

Emily Kate Stephens (19:07): For use in what

Arman Fesharaki-Zadeh (19:09): For use in injury models or brain injury. It has also been published by the way for clinical TBI patients as well. So it's a safe supplement. It's a very robust antioxidant, and it has some anti-inflammatory benefits. To give you an idea in terms of how robust it can be, folks who either intentionally or unintentionally overdose on Tylenol, which is really unfortunate, and the liver can become necrotic, NAC has been used to rescue the liver due to this toxicity. So, in the emergency room setting, God forbid if somebody overdoses on Tylenol, NAC is usually the first agent that is used to rescue the liver from that injury.

Emily Kate Stephens (19:50): That's so interesting because it's actually something that I have been recommended previously by neurologists that I hadn't necessarily understood of its healing benefit. In other circumstances, so is that its anti-inflammatory properties, or what is its oxidative properties? Okay,

Arman Fesharaki-Zadeh (20:07): So it has very robust antioxidant properties.

Emily Kate Stephens (20:09): So it's the detoxification.

Arman Fesharaki-Zadeh (20:11): Yeah, you could think of it like that. So it's a precursor of glutathione. So glutathione is a compound that is in the liver, and it's a major detoxification antioxidant system in the body, so and it essentially replenishes that system. And also, there are studies that are showing that it can modulate glutamate and dopamine levels, which is fascinating. So, in the world of psychiatry, there are studies that are published even is used in OCD patients. It's such a safe regimen that if you speak to psychiatrists who've been doing this for decades, they use NAC often as an augmenting regimen to add it to other regimen to increase its efficacy. So it can play kind of quote unquote multiple roles, complementary roles, I should say.

Emily Kate Stephens (21:00): Some of these things are so interesting because there is such a sense that these conditions are treated separately. But I have spoken to multiple people now who have married these conditions that one perceives to be completely psychiatric or completely, but that are now with this research that we're doing being married on a physical level with other conditions. I mean, the fact that you can use something to treat ADHD and Long Covid, and there are correlations between people getting post Covid syndrome and ADHD. It's interesting. It's also a very contentious topic, but I do find it fascinating the way that we're joining these dots together in this space.

Arman Fesharaki-Zadeh (21:52): Why we're having this discussion because when you speak to a post-concussive or Long Covid patients, they can look like an ADD patients also. Really, just the way they're manifesting their symptoms, so difficulty with focusing and attention and multitasking. Those are the same type of symptoms that ADD patients often complain about. Also, we're talking about this kind of dorsolateral based executive function and deficits. Those are the same phenotypes that we see in these conditions. So they do share a lot of kind of phenotypic similarities. I can't imagine, again looking at this inflammatory hypothesis, that it's not affecting the outcome in terms of brain development or the outcomes of that and I haven't looked at the studies look at specific Covid and ADD and ADHD diagnoses, but I mechanistically it wouldn't be shocking to see that whether there is some sort of convergence of these disease processes.

Emily Kate Stephens (22:44): That's fascinating. So tell me about the protocol, how you started developing it for Long Covid patients. The results. Now you said in 2023 that obviously we need to have placebo controlled trials in it. When I have searched, I have not yet come up with any of those placebo-controlled trials. Although it is labelled as a drug of interest in this space, and I don't think we've done any clinical controlled trials into guanfacine since 2012. In Europe, obviously, we have not caught up on this side. But tell me the process that you went through and the stage that we've reached.

Arman Fesharaki-Zadeh (23:24): Well, I like many other physicians in my space. I was frustrated about not having effective regimen for Long Covid patients when I started seeing these folks. But fortunately, three plus years ago, I started our concussion clinic here, concussion TBI clinic. Me amongst other interested parties. We didn't have a TBI unit in the outpatient setting. So when I did my fellowship here back in 2016, 2017, my primary interest has always been traumatic injury, and from the very beginning, my PhD work was also in TBI as well. Where the inspiration of Long Covid treatment came from, as I mentioned earlier, were the phenotypic symptom similarities between these two groups of patients? So the guanfacine–NAC combo I had been using for TBI patients for a number of years prior to trying that also for Long Covid patients because these drugs were safe to use also guanfacine had already been FDA approved for ADD/ADHD, so its safety profile has been established, and the NAC had also been used in a clinical setting for decades. So I knew that I wouldn't be worried about quote unquote side effects, and following these patients longitudinally for that purpose. There are side effects for guanfacine or NAC, of course, and we have to be mindful of they're not major side effects. They're also mentioned in the paper as well, but just the idea that their side effects are mild enough that the benefits can outweigh the risk of this use. So, and essentially cross-purposing a regimen that's already been out there for more than a decade. So, when I started using guanfacine the first time, I believe it was back in 2021. This was the medication was. There a lot of neurologists didn't know about guanfacine because it's predominantly in ADD ADHD space, and either child psychiatrists or adult psychiatrists kind of use it more often. TBI specialists, in spite of Thomas McAllister publication in 2012, nobody picked up on that, which to me was a significant surprise because whenever I spoke to my neurology colleagues here at Yale, when it came to treatment of post-concussive patients, they treated them with therapy and maybe cholinesterase inhibitors like donepezil, but nothing was established. So the idea came from the TBI world, but I used the same application process, and I started to see benefits in Long Covid patients.

Emily Kate Stephens (25:42): So there was a Long Covid patient in your clinic, and you said to them, "Would you like to try this on this basis? Or how did you even approach that first trying out of the regimen with your patients?

Arman Fesharaki-Zadeh (25:56): So the thought process behind it was that I have been struck by how similar your symptoms are to the TBI patients that I see in the clinic, and there is a treatment protocol that is safe because again these regimen have been around for a while, and since no you're having these persistent symptoms and it's been months or even years of these deficits, and I've seen patients who are extremely high functioning, by the way, and these Long Covid symptoms have been debilitating. It have been really almost traumatising for these folks. So, trying out a regimen that is safe and has been established for other conditions, they were very much open to the idea out of also frustration and not having anything else available. When I started to see benefits. I almost felt a sense of obligation to get this out on a larger scale, be it through publications, but also doing clinical trials, which I'm still interested in pursuing and have been pursuing it. And that's when I reached out to Amy about the guanfacine idea, and we decided to formalise this regimen on a kind of case series basis. Yeah, and I will also add again nothing self complimentary about this. But the two of us, between the two of us, Amy and I, we received a slew of emails from, especially in 2023 and part of 2024, slew of emails from across the planet, all the way from Australia to Europe, to Middle East, to North America, South America, folks that have tried the regimen and some of them benefited from this. And again, no drug combination is perfect, but the idea that it did provide benefits for a good portion of those folks. So, and that this was very encouraging.

Emily Kate Stephens (27:38): And how long did it take you and your patients, to see a difference, how long does this combination take to take effect?

Arman Fesharaki-Zadeh (27:50): So typically, the dosing regimen I start with one milligramme for the first month. That's kind of the ramping up period, and we reach the two milligramme after the first four weeks or so. By the time patients get on the two milligramme, if they tolerate the regimen okay, that's when they start to see the benefits. And the side effects I was just mentioning that's been mentioned in the paper also can include blood pressure changes. So making sure that we kind of watch the blood pressure a little bit closely, dryness of the mouth, which is shared amongst many other medications also. So those are the potential side effects that give a little bit of warning.

Arman Fesharaki-Zadeh (28:27): I've had a couple of patients who had constipation issues, but again, nothing really major. Right, and the dizziness and the hypotension can be a problem for some folks, and in those cases either we have to stop the regimen, or we can lower the dose. I saw a nurse patient of mine whose story was published in the case series as well, and she continues to be on this now, years after. So this is three plus years after the Covid infection, and all the rest have resolved, and she's still working. She's productive, so I think that's very encouraging. I had a patient who I saw two weeks ago with significant Long Covid symptoms. Also, she was very high functioning prior. And interesting enough, by the way, I do want to add that vast majority of my Long Covid patients have been coincidentally females, and I don't have a viable mechanistic explanation for that. But I can tell you anecdotally that in the clinic, a good portion of my Long Covid patients have been women, and I'm not entirely sure why.

Emily Kate Stephens (29:38): A lot of people have different theories on that.

Arman Fesharaki-Zadeh (29:41): Yeah,

Emily Kate Stephens (29:41): An interview that I did was the suggestion that also the demographic of the women. It's a lot of 35 to 50-year-olds. I think it's interesting when you look at those demographics. Do we have more of a susceptibility in our systems, or is it a lifestyle thing that actually causes the demise,

Arman Fesharaki-Zadeh (30:04): Right? And also the hormonal changes in that age category-not to mention premenopausal, menopausal periods that women go through. Whether there is a correlation between those, that's quite interesting.

Emily Kate Stephens (30:14): Isn't it? Because in terms of oestrogen, the suppression of inflammation by oestrogen, and then if you are beginning to lose oestrogen or be depleted in oestrogen, perhaps the homeostasis there is somehow there's somehow an imbalance,

Arman Fesharaki-Zadeh (30:30): Right? And I think mechanistically, I think there's a lot to be found out in that space. But I can tell you, anecdotal, as I mentioned earlier, is an interesting correlation that I keep continue to see in our patient population. The two patients that I mentioned, they're both women, of course. The most severe ones, and I've had these physician colleagues of mine with Long Covid whose jobs were severely affected because of this condition, which is really unfortunate. Yeah.

Emily Kate Stephens (30:57): Do you find that in some of your patients, you're treating the brain fog, the neuro inflammation, but by treating that it actually cascades to deal with others of their symptoms that are often seen as being physiological, but actually essentially could be classified as neurological. So things like the POTS. I know that you said with the guanfacine you can have blood pressure changes, and perhaps it's not that suitable for POTS. But if there are certain things like that's autonomic, that's actually a neurological dysfunction. Have you seen improvements in symptoms that you wouldn't necessarily classify as brain fog with your regimen?

Arman Fesharaki-Zadeh (31:40): Right. That's a great question. Not so much for POTS patients, and I think that's the population that I also am very careful with when it comes to prescribing guanfacine for the exact same reason I just described. Because it does lower blood pressure, and that's the population that is vulnerable to blood pressure changes and autonomic changes. So I tend to stay or be very cautious with guanfacine. I did not prescribe that at all, or just be very very cautious with that. In regards to other symptoms that have been surprisingly responsive to guanfacine, and I think that's a great question. Sleep, surprisingly enough, which I did not expect, and there have been a few cases in the clinic where patients mentioned to me, "Look, I've been surprised how well I sleep at night," and as added to that component, and or mood, there have been couple cases that they mentioned that the mood was improved. And again, going back to the idea of your prefrontal cortical area having a very really predominant role when it comes to emotional regulation, we tend to like separate out, so it's kind of the our human cognitive biases that we like to put things in boxes. So certain parts of the brain are in charge of certain functions, and certain other parts of other functions. We don't look at this as a network, and we should look at it that way also because the brain is even though it's modular, there's also a very dynamic, interactive network, and by forgetting that component of it, I think we're missing out the bigger picture. So when it comes to emotional dysregulation in Long Covid patients, and I'll give you another example, I had a TBI patient of mine who perseverated quite a great deal. She one of the most debilitating symptoms in her case was she tend to perseverate on a topic, and she would go on loops essentially.

Emily Kate Stephens (33:29): Right.

Arman Fesharaki-Zadeh (33:30): And what I saw and I thought was really fascinating was Guanfacine kind of broke that loop essentially. So the idea that this perseveration, this rumination on a certain topic-it almost like reintroducing brakes in the brain, like we can move on from this topic to the next. And I thought that was really interesting. And mechanistic also again makes sense because your prefrontal cortical area also provides emotional brakes. So when we get angry or frustrated, what keeps us grounded and continue to have social decorum in situations that are really anxiety or anger provoking is your prefrontal cortical area. So it creates that space. Like, look, I know this is frustrating. Let's think about this for a moment. That's your prefrontal cortex area kicking in, essentially your PFC kicking in, and guanfacine is strengthening that network. It would explain a lot of these again outcomes that we're seeing.

Emily Kate Stephens (34:26): That's absolutely fascinating, and I think that we also need to apply that network basis not only to the brain but to the whole body because it's that flow of information backwards, the afferent and efferent that is so misunderstood or ignored, certainly right

Arman Fesharaki-Zadeh (34:45): And overlooked and often. And that's I think that's and as science and medicine is moving forward, even in the world of I have folks and my colleagues in Parkinson, and there's a whole new movement looking at gut and microbiome, and its relationship to Parkinson. The fact that a lot of the I do see a number of Parkinson patients just because a lot of them have memory issues also, and the GI symptoms in Parkinson's is very prevalent, and that's been known for decades. So this idea that we tend to again put things in boxes.

Emily Kate Stephens (35:19): Yeah, and that's fascinating, isn't it? Because of the way all of these things actually, so many of them seem to be coming back to the gut. Even if you talk about potential viral persistence, there is talk that is quite specifically. Well, there's a suggestion it might be in the brain as well, but the viral persistence has been found in the gut. And then when you sort of dig deeper into all of your different immunological systems of the body, the mast cells, and there's so many connections. There are so many connections between the conditions and between also what we're putting into our bodies.

Arman Fesharaki-Zadeh (36:01): Very true.

Emily Kate Stephens (36:02): And that network of the cascade effect. So you mentioned there that the guanfacine had assisted with sleep, and I think that is one of those things that is such a big area in so many of these chronic conditions is the lack of ability to sleep, whatever an infection has done to your body and makes it difficult to sleep, the healing that can come once you are able to sleep creates a positive cascade effect. And I don't think necessarily everyone's keen to take actual sleeping tablets. So, I mean, there have been things like amitriptyline used. I was put on amitriptyline to help with my sleep, and I didn't find it effective.

Arman Fesharaki-Zadeh (36:48): I mean, the whole area of sleep is fascinating because it's been overlooked for decades. Now there's more attention to it, and there's this other network barrier that was newly discovered called the glymphatic network, and essentially, I'm sure you're familiar with this kind of brain clearance network. So you have the lymphatic system of the body, you also have the glymphatic system of the brain, and that network is usually active during our sleep. So your brain kind of detoxifies itself in your deep sleep and your REM sleep. So folks who have ongoing neurological psychiatric conditions, oftentimes you can tell by their sleep patterns, so they tend to have less time spent in deep sleep or REM sleep. So it becomes this kind of this negative vicious cycle that can feed onto each other. Essentially, so we see it in our TBI patients, we see it in our patients with psychiatric conditions. Also, sleep is one of those domains that is often affected.

Emily Kate Stephens (37:40): Yeah,

Arman Fesharaki-Zadeh (37:40): And of course there's psychosocial issues, and that as well that you mentioned earlier in our conversation that we can't overlook either. So that the societal kind of logistic psychosocial toll of the disease as well, and I think that certainly plays a factor.

Emily Kate Stephens (37:57): Yeah, I found it absolutely fascinating when I learned about that glymphatic system and the need to actually have sleep and what our body, the fact that our body is actually clean, almost cleansing itself, detoxifying whilst we sleep. As someone who had never previously really needed that much sleep or had that much sleep, I was always fine on five hours. Suddenly, I became someone who really needed to sleep, and I couldn't sleep for about a year and a half. I didn't sleep. I sleep pretty well now, and I have to say that has made such a world of difference. It's just improving that sleep and finding any tools that you can use, and I particularly love the tools that are multi-purpose or have dual purpose, so that byproduct of guanfacine in improving sleep is a definite plus. So tell me, you said that you are focused on pushing forwards for clinical trials with this. Tell me what stage you have reached, or that we have got to collectively. If there are other researchers also looking at this, where are we with actually some more empirical evidence for this regimen?

Arman Fesharaki-Zadeh (39:14): So I'm still in the funding application phase. I have applied for one cycle previously, and this was my first R01 application. It was scored and it was scored well. And again, this these days everything is super competitive, so it hasn't been funded yet. Right, but I'm hoping to get it funded for next cycle. And apparently, there was an announcement that there is increased funding for Covid research here in U.S. So I'm hopeful that in the near future this will get funded, and also in the world of TBI space, the same idea that I use this regimen for post-concussive patients. So there's kind of two parallel tracks, but they're nevertheless they share kind of same regimen. So I'm that work is still ongoing, and we're collecting data still to this point. And so that's I'm excited about that and we'll keep make sure if I have further results to keep everybody updated and hopefully further publications as well.

Emily Kate Stephens (40:10): Amazing. And in terms of anecdotal efficacy, how many patients have you treated with this regimen or how many people have you seen benefiting from it anecdotally?

Arman Fesharaki-Zadeh (40:22): Make sure that I check the numbers here, and I have right now about 1400 patients in my clinic, so a very very packed clinic. And about a fifth of these patients are combination of Long Covid and post concussive patients. So in the orders of hundreds by now, a combination of two, either Long Covid or post-concussive, and certainly in the order of, I would say, between 50 to 100 patients have been treated with this combination regimen. And so, I'm again the fact that it's safe, the fact that it's been FDA approved, kind of lowers the barriers, but at the same time, I think what's really important to have more empirical, kind of double-blind control studies that can really establish efficacy, and that's what I'm aiming for still. And this time is of the essence, so I do know that this needs to get out as soon as possible. It gets you know gets really established and prioritised.

Emily Kate Stephens (41:22): Yeah, we really, really appreciate all of the people who push on the timing of things like that because there's this, there is this view that we have moved so fast in terms of actual Covid, the way that the vaccines were developed, the treatment of it, and then subsequently in Long Covid, compared to any other illness, we have moved incredibly fast. But obviously, there are such a huge number of people suffering from these conditions that there is definitely an urgency. But we very, very much appreciate the efforts that people like you have put into expediting these things.

Arman Fesharaki-Zadeh (42:00): No, thank you very much. I appreciate that, and our research is both inspired and moved by the need that is there, and that's what continues to inspire me right now as well. The folks that it continues in the clinic, and the fact that when I see results, and my work is also inspired by that. So, what inspired the publication was also the fact that I saw real clinical results and outcomes in the clinic, and kind of getting out of quote unquote the quotation of kind of ivory towers of the Ivy League and academic settings and getting this message out to the public, folks who don't have access to research, and they want to get to know and they're nevertheless suffering with the same type of symptoms. How do we expand on this? So that continues to inspire me, and I appreciate the opportunity to share a few thoughts here.

Emily Kate Stephens (42:50): Thank you so much.

Arman Fesharaki-Zadeh (42:51): No, thank you very much.

Emily Kate Stephens (42:58): We would love to hear if you have tried guanfacine and NAC, and if you have found it to be effective in your condition, one of the things that we are trying to do at Visible, alongside helping people to pace, is to drive research in a direction that is helpful to the patient community. So the information that you feed into us, we are then trying to work with the medical community and with researchers to develop strands that will help move forward our comprehension of these illnesses. Please keep feeding back to us. Tell us what is of interest to you. We are working through an ever increasing list of things that you want to hear about and people from whom you want to hear. Stick with us. There are so many exciting interviews coming up. I do hope that you're surviving this period, being gentle and kind to those around you and to yourself. 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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