All right. Good morning, everybody. And I think there are virtual attendees as well, so good morning to all of them, to the session, Point, Counterpoint, Debating Controversial Topics in Neurorehabilitation. This will be, hopefully, a very lively discussion about two different topics that are very salient to neurorehabilitation. We chose this point-counterpoint format because there are really somewhat polarizing elements to these topics, and we thought it would be more lively to get some very dynamic people to go back and forth a little bit about what some of these issues are. So just as a way of introduction, I believe if you saw us clinically, we would give a slightly different message, and what we're going to give now, our message here will be very one-sided, anticipating that our counterpart will provide the balance to that. Having said that, let me just introduce our speakers, and I probably should have allotted like 10 minutes just for that, because it's quite a distinguished group of panelists. I'll start with Dr. Zephant, who's the president of Spalding Hospital, chief of physical medicine rehabilitation at Mass General Hospital and Brigham and Women's Hospital, the Earl P. and Ida Charlton Professor and Chair, Department of PM&R Harvard Medical School. He's the principal investigator of the Football Players Health Study. He has received, as you know, multiple awards, honors for his work in really an astounding range in rehabilitation, not just neuro-rehabilitation even. Dr. Gerard Francisco is the Wolf Family Chair in Physical Medicine Rehabilitation, Professor and Chair of Physical Medicine Rehabilitation at McGovern Medical School, UT Health. He's the CMO of Tier Memorial Hermann Hospital. He is a leading expert in brain injury medicine, stroke rehabilitation, spasticity management, and assistive technology. He was inducted into the National Academy of Medicine, which was formerly the Institute of Medicine, has multiple leadership roles and honors from AAPM&R, as well as ISPRM, AAP, and a host of other societies. Dr. Eskenazis, the John Otto Haas Chair of PM&R at Albert Einstein Medical Center, Chief Medical Officer of Jefferson Moss McGee Rehabilitation, Director of the GATE and Motion Analysis Lab, and Professor of Rehabilitation Medicine at Thomas Jefferson Hospital. He's published over 140 articles and book chapters and is also on multiple editorial boards nationally and internationally, past president of AAPM&R, multiple awards and honors as well, many of which you're aware of. I guess I don't have to read my bio. I'm the Clinical Director of the Drucker Brain Injury Center, Director of the Stroke Program at Moss Rehab, part of Jefferson Moss McGee Rehabilitation, Co-PI of the TBI Model Systems, grant through NIDILRR, Assistant Professor of Rehabilitation Medicine at Thomas Jefferson Hospital. Okay. With that as introduction, we're going to move on to our first topic, and I'm going to read a little bit of introduction, and then we'll get started. So the first session is looking at the role of robotics in stroke rehabilitation, and what I pose to the discussants is the following. You're the director of a stroke program of a large rehabilitation center. A grateful patient has recently donated $500,000 to aid in the stroke rehabilitation program. Two different proposals have been brought forward regarding the use of this money. One proposal is that the money should be spent on a new robotic device for inpatient rehabilitation unit that will aid patients in the recovery of gait. The second proposal is to support an ongoing program to assist physical therapists with obtaining continuing education. Which proposal do you choose? And Dr. Francisco will start. Tom, thank you so much. When he invited me to do this initiative, I said, oh, debate. Do I want to do it? But when I saw that it will be with Alberto and with Tom and with Ross, can't say no to that opportunity to work with them, because we've been collaborating for the last three decades or so. So I was given this topic, and I was asked to take the no side, just to understand that I'm not really anti-robots. I love robots. I love technology. But given the premise of this debate, how to use that $500,000 right now, I gladly accepted the challenge to talk about giving it to the physical therapist for continuing education and professional development. It's hard for me to not like robots. Our hospital at TIER was among the first in the country to have this back in the 1970s. There was an exosuit from Yugoslavia, now Serbia, that was tested in the U.S., and it was tested in our facility before it was called TIER. We were one of the early adopters of robots. I think my collaboration with Alberto became tighter because of our shared interest in exploring the possibility of using robots. So at one point, we had all four of the commercially available robots that we were testing. The one in the middle was actually a prototype. It's now available commercially, but we were also testing prototypes of different robots from different parts of the world that they bring over to Houston. In fact, our lab was designed with exoskeletons and robots in mind. It's an open space. The whole idea is for the users of this exoskeleton to be able to walk around the lab. We put in a platform with force plates. We have cameras to be able to look at kinematic data. You see this thing on top? We even put in a vector so that we can try and explore the possibility of people with complete cervical spinal cord injuries with very poor trunk control, if they can use robots as well. I think it's because of the advice that we got from one of the early users in Houston, who's a surgeon. When we were establishing the lab, he sat down. We were sitting together and told me, sit down and let me give you an advice, even if you don't want it. It will be foolish for you to study robots for mobility. I can share with you that when I use the exoskeletons regularly, I feel better. I don't have a lot of bladder trouble, et cetera, et cetera. He said, if you will study it, look at other parameters rather than just gait. We looked at our early experience. We published a very early report. There is some promise that certain parameters will improve. It wasn't global. For some users, those with spinal cord injuries, there seems to be some changes in gait. We also published something in multiple sclerosis, looking at different parameters, gait speed. We even looked at muscle synergy patterns. There was a trend toward normalization. These are all short-term data, just perhaps after about 30 to 60 days of training with robots. This is our experience so far. While we are still using robots and still exploring the utility of robots, we're not really clear which of the patients that we treat currently will benefit from what robot, from a specific type of exoskeleton. In fact, when I proposed this at the hospital, I think it will be wise for us to have more than one robot because the conversation that we should have with our patients is that not whether or not you are a candidate for exoskeleton use, but rather based on your impairments and the characteristics that we have assessed, robot A won't work for you, but exoskeleton B will. That's why we at one point, we had more than one robot in our facility, both in research and in the clinical space as well. Although our early studies and experience do not really demonstrate superiority over other therapies, we still do not know, is this better than treadmill-based training? Is this better than just conventional training if we increase the intensity or change some of the techniques? I'm sorry for the misspelling of gait. I thought I had corrected it. It appears that the main benefit of the lower limb exoskeletons is not really in gait, as what that physician told me, that surgeon told me. To him, it's important to have that robot because he's able to take a few steps, no matter how slow it is, but he can continue operating. One of our other patients with spinal injury, when I asked her, what is the best thing about using the exoskeleton? She said, the fact that I can stand up and I am talking to you at the eye-to-eye level. That was the most important thing to her. It's not mobility. It's not other things. It seems like the impact of using the exoskeletons is different for each end-user. There are a lot of reviews regarding exoskeleton. Dr. Eskenazi has more than one. I just put one here. It can be very confusing. Part of the problem is that many of the systematic reviews themselves are problematic. I will save you time. Just read this paper that was published in the archives a couple of years ago, pretty much summarizing the quality of the existing systematic reviews. I'm bringing this out because I'm concerned that some people may read one review and not the other and make a false conclusion that was presented by one review that was not totally a perfect review. It's good to read more than one in case you want some guidance in your decision-making whether or not you should incorporate robots in your clinical practice. There's some benefits. I said some. Actually, there's a lot, but this is not complete. It can improve mobility and walking ability. In our early experience, there were some improvements in the gait pattern, stepping, weight shifting, et cetera, et cetera, promote standing and position changes. Obviously, that's very important to combat some of the effects of prolonged immobilization, reducing the risk of pressure sores. It can improve cardiopulmonary function, not infection, improve metabolic function. It can decrease the incidence of urinary tract infection. It's a novel locomotor training. It's more portable than treadmill-based systems. Some of our therapists love it because it's less physically demanding for them. As I mentioned earlier, the psychological boost that it offers our users. But a lot more needs to be done. It doesn't fit everyone, especially the early generation exoskeletons. When we were doing some studies in people with spinal injuries, the two most common reasons why we could not enroll potential subjects to the study are one, the hip girth was too big that they could not be accommodated by the more rigid early generation exoskeletons. The other one is the presence of ankle-pant reflection contracture, which disallowed many of the end users using exoskeletons where there was no ability to manipulate the angle of the ankle. It cannot be used by some with upper limb weakness, especially if control will be needed. Those with poor trunk and neck control, but there are ways around it. We published a case report or a case series of how we were able to rig up the system so that those with cervical injuries can use the exoskeletons. Now, somewhere in New York, they're doing some studies. It's like a neck brace that can be used in addition to the other contraptions to allow people with less or difficulty with keeping the upright posture use exoskeletons. Some of them are really slow. Some are poetically slow when they're moving and you hear this. It's not true anymore because the design has improved, but it's still not at the speed that we would want it to be. Implication, it will limit the use in the community. Just imagine how difficult it might be for one to cross a large avenue or a large boulevard because of the slowness of the exoskeleton. Also, some of them still have rigid parts, but there have been innovations. This is an example. This is from Harvard. It's now with Rewalk. It's one of the soft exoskeletons, which is great because it's not rigid, but because it's not rigid, it's not going to be useful for those who need more support. Again, there are limitations to this. Some people can use it. Others may not. Just recently, there are still publications about newer soft exoskeletons that are being developed. The nice thing is that we have learned from the early experience of the newer designs in robots are getting better and better. Also, we're still not clear. Is this a mobility device or a training device or both? What is the optimal exoskeleton training dose? Just like any other kind of therapy, we still have not ... It's important to deliver the appropriate dosage in terms of frequency and the duration of the training. It's still not clear as to which ones are the optimum candidates for a particular exoskeleton. In those who are hemiparetic, should we use both sides of the robot for bilateral training or should we use unilateral training because some exoskeletons are modular and you can break it down so that you will only have to control one side. We also do not know if one exoskeleton is better than the other. Of course, when these are marketed, they will tout the feature of each and every robot. If you are in the market wanting to buy a robot, it can be very confusing. Just keep in mind, if you're going to purchase a robot because of a particular feature, make sure it is a feature that will be important for the patient population that you are intending to use these robots for. We still do not have data regarding the comparative efficacy, safety, and cost effectiveness compared to other techniques and other assistive devices or just conventional physical therapy. We still do not have information on the long-term effect on overall well-being, so hopefully there will be publications, follow-up for those who have been using it for many years, and again, community translation. I may be wrong, but I think it's only Germany right now where the Paris system, the insurance, is covering home use for certain exoskeletons. This is not stopping people from trying to figure out how this can be delivered in a more inexpensive manner. I will use this as an example because I'm most familiar with it. Pepe Contreras-Vidal is our collaborator from the University of Houston. He and his team designed this robot that's 3D printed. It's not the whole robot, but the certain parts can be 3D printed, so the actual motor will remain the same, whereas features such as the cuff and the shank can be 3D printed. So we are going to start the study pretty soon in children. Our premise is that in the long run, this is going to be less expensive. There will be an upfront investment because you have to buy the robot, but as the child grows into adolescence and into adulthood, they will use pretty much the same robot, but certain parts are going to be 3D printed, which is less expensive than the current manufacturing techniques. So in the long run, in the lifetime of this device, most likely it's going to be cheaper than having to buy one exoskeleton when the kid was five feet tall and then another one when the kid grows into six feet. So we'll see if that assumption is going to be correct. So are lower limb exoskeletons worth the price? And with budget constraints nowadays, will it be wiser to invest in robots or in the professional development of our colleagues, our therapists? Let's look at the workforce challenge in physical therapy. During the COVID pandemic, there were two estimates that I found. Anywhere between 15 to 22,000 left the profession of physical therapy. There are actually more nurses and more physicians who left the profession, but by percent of the total number of professionals, physical therapists had the most. About 11% of their workforce left during that pandemic. And different reasons, burnout was one of the things that was cited. Turnover rate currently is around 11% for hospital-based PTs, and almost 14% for home health therapists. And no one here will argue that we need our physical therapists to work with us to improve the outcomes for our patients. So here are some ways to mitigate the physical therapy shortage and burnout. Using technology, especially for documentation to increase efficiency, find alternative staffing models and more incentives. And one of those incentives is continuing education. And if I were to use this $500,000 for a multi-year plan for the professional development of our therapist, I would like them to learn cutting edge techniques. Of course, they can learn how to use this newer robots. Some of them perhaps can do dry needling, blood flow restriction therapy, high intensity treadmill training, gamified physical therapy, or using other monitoring devices such as this one called SWORD or Stroke Wearable Operative Rehabilitation Device. So I will use the $500,000 to support physical therapists continuing education and professional development. I always think that people are more important than robots. People first before equipment, because without people who will manage the robots and train patients to use the robots. And even if robots are not available, the therapist will still be able to treat patients with conventional therapies and cutting edge techniques that they will learn from a more robust continuing education program. Thank you. Thank you very much. Thank you for your great presentation and certainly for making my life easier. You help us figure out many of the strategies that are needed for the future and you're very correct. There has been a great loss of therapy staff, which is a significant problem, but it's a great advantage from the point of view of robotic devices. And we'll talk about that. I don't have any relevant disclosures. So I wanted to start by just telling you what the literature says. I think that that would be the easiest way. And by the way, for those of you who are sitting all the way in the back, you can't see our T-shirts, but our T-shirts said Robotics and Rehabilitation, AAPMNR, and it says I'm interested if you're at the bottom, I love them if you're at the top, and at the very bottom it says not interested. And you can see my big check mark, it says I love them. If you look at Gerard, Gerard has a big X over I'm not interested. So we'll see if it's true. And then we'll want to hear from all of you about it. So we know clearly stroke is a major cause of impaired trunk control and gait disability. We can't argue with that. Everybody is aware of it. We know that weakness plays a role, spasticity plays a role. And particularly in acute rehab, you know, this donor has told us he's going to give us half a million dollars to set up robotics for early stroke rehabilitation. So I'm really very, very gung ho on that. Airwalking ability reduces independence, definitely affects quality of life, and we know that patients who walk who are post-stroke have a higher risk of falls than the normal population. Falls lead to injuries, injuries lead to further deterioration of their function and life. Also we know that repetitive motor skill learning is critical to improvement in recovering the walking function. Also you need to be sure that those movements are repetitive, that they are precise, and that we are doing that in a constant manner. Of course, there is not only an issue of how many repetitions or how often we do them, but also how much engagement from the point of view of the patient on rehab. And I think that it is well established that if you're going to do rehabilitation in stroke patients, you ought to do that in the first three months, because that's when you're going to get the most bang for your dollars. And I've put a whole list of references. The slides are on your deck when you look at them later. So I thought I'd show you this, and sorry the video may look a little distorted. It's not me, it's just because we switched. This is a patient acutely after stroke in rehab, and there is one, two, three, four therapists trying to get this patient, and a resident who went by, trying to get this patient to take a few steps. And I'll just let it play. Again, sorry that it looks a bit distorted. My computer looked pretty good. But it gets you the point. It takes a lot of effort, effort that can injure therapists, effort that is frustrating to both patients and the therapy staff, and effort that is very likely to burn out our therapy staff. So this is what you see. Lots of people trying to move this one patient. Also, how many steps can you get from this? 10? If you're lucky, maybe 15. So here's the same patient using an exoskeleton. This is the same day, or the day after. This is not like we waited for six months to do this. Single therapist walking the patient, the therapist is safe, the patient is safe, and the patient is definitely accomplishing many, many more steps out of this intervention. Risk for injury, greatly reduced for the therapist, greatly reduced for the patient. Higher expectations, higher patient satisfaction. There is great information. You can tell from the literature that exoskeleton training has advantages over body weight-supported training. And it doesn't require a lot of intervention, a modest amount. You could see the difference between manual and robotic therapy. So robots are definitely better. It's the way to go. We've done this with tether exoskeletons. So here you see a locomot. It's a type of a tether exoskeleton. And we actually have a publication on it. We looked at acute stroke patients. We look at comparing these patients who were on a robotic device versus patients that were receiving additional therapy provided by manual means. And we show that patients who receive less sessions, about one-third less number of sessions, because of the intensity of walking, they did much better. Their FIM score was higher. Their GG walk score was higher, for those of you that understand FIM or GG. There was definitely an improvement in walking velocity and tolerance to walking. So we actually did then a comparison across three different systems, and we were able to prove that patients that use end-effector devices, another kind of robotic device, were able to do better than those that receive manual therapy. And the locomot moved the patients a little bit further along in a little shorter period of time. There are guided suspension systems as well. So think about these gadgets as additional robotic devices that can be used, particularly under the face of rehabilitation. You could see, you could trial steps. All you need is one therapist. You can walk the patient around. So it really makes a huge difference in our ability to provide care. Dr. Francisco talked about the idea of soft exoskeletons. So this is a non-tether soft exoskeleton for stroke. It's called a Restore. And this was not used in acute stroke patients. It was used in the later phases of recovery. But even in this case, Dr. Francisco and the crew that worked with us in this project, I have to rub it in, showed that there was improvement in walking velocity for this patient. It is a soft device, so it doesn't require all this big hardware around. It is a gadget that you have to apply to the patient, but definitely it shows improvement. Now, some patients are in need of restoring force at the ankle. Some patients would do better if we restore force at the hip. And so this is a power-generating device for the hip. It is pretty unique in the sense that it has the ability to look at how a patient is walking, measured through the device, and from that, create an algorithm that optimizes the power generation for the hip, both inflection and extension. It is in a test right now. All I have is preliminary results. Let me conclude by saying that robots improve care. And I hope I've shown that to you. So that's three publications from our facility that shows that. And definitely there are many more. Staff feels that they are not getting injured or burned out because of the amount of effort that it takes to walk. Robots attract and retain staff. provide higher experience care for your patients and so that's what you want. Robots do not get sick and do not take vacation so but you know you can fix it. This walking velocity with this much hip or knee flexion so you could really be very precise in the way you are. Robots are very smart in that sense they know how to do the same thing over and over and robots save money. Why? Because I can have less staff dealing with each patient so and so I have to say that you know we love robots for rehabilitation at motions in robotics is really the future of what we are doing today. Thank you. Okay to finish up that session of the presentation Alberto gave me a t-shirt that I'm supposed to put on as well so I'm supposed to vote I guess for robots or for physical therapists that's and I don't know some of you may know me but my wife is a physical therapist so I don't know if she's watching or not but I'm definitely gonna have to take that into account when I make my vote and I'm gonna be like Switzerland and go down the middle all right. Thank you so much. All right for the second part of our talk we're going to shift gears and let me give you this introduction. Much attention has been paid to the symptom of COVID fog as it relates to persistent cognitive complaints in some people after COVID-19 infection. A number of etiologies have been suggested and considerable research has been initiated in trying to elucidate the cause or causes for this problem. It is also not clear how unique the symptom is. There are these are important issues because there are important implications regarding diagnosis, management, use of resources and for research and for clinical care. So with these questions in mind this debate will focus on the basis for post COVID fog and I will introduce reintroduce Dr. Zapata. So thank you Tom and I think we certainly owe Alberto and Gerard a remarkable round of applause for what was a very cool presentation. I don't have a t-shirt. It's okay but what I do have is a few minutes to explore with you this idea of COVID brain fog and is this biologically plausible? Is this a myth or a mystery? And so these are my disclosures none of which are related to this presentation. So I'm going to try to examine some links and mechanisms related to COVID brain fog and I'm going to take the position that we have very complicated people who have a maladaptive phenotype. Some of which some of which could be biologically driven or driven off the edge. And I'll review what I think is a multimodal pathology. So I show you a slide here that doesn't appear adequately well but in the corner what you see is an article pulled from the old New England Journal before it was the old Boston Medical and Surgical Journal right after the 1918 pandemic. And what did we see? We saw burnout, health disparities, but we also saw a cohort of people with long-lasting problems some of which were cognitive. Suggesting that this is not mass hysteria. So what is COVID fog? COVID fog is poor concentration, feeling confused, fuzzy thoughts, forgetfulness, lost words, mental fatigue. My faculty might say it's me. So what do we know about other parallels right? So if this is all psychosocial it should either be linked to this or there should have been some nocebic introduction. So this is a paper we did with Haley Prescott in critical care medicine a few years ago. And basically what Haley and the group showed is that in people who had ICU sepsis they have long-standing problems for years afterwards that are multi-domain that affect their cognition but they also affect their mobility and a number of different issues. This is a polymodal problem. Next. This is a New England Journal paper published by some friends. Again people in the ICU long term cognitive impairment after critical illness. 34% of whom had findings in line with a moderate TBI. 24% in line with Alzheimer's 12 months later. So there's something about an ICU stay and fomin and sepsis that is badness. Likely inflammatory. So what about these non-hospitalized people because you could make the case that they're all sort of like my mild TBI cases. There's nothing there. Well maybe there is something there at least in a group. So this is some data that suggests that this cognitive fog this COVID fog is quite persistent and we have people with impaired attention and memory loss that can occur as much as 31 to 60 percent of the cases. That seems over-the-top for me but certainly a systemic illness that hits multiple different domains, one's respiratory system, one's hearts, one's other areas can produce a situation where you're producing a maladaptive phenotype. Now let me take a step back and say is there another parallel and the other parallel might be chemo brain or chemo fog. A chronic inflammatory state that results after chemotherapy. So could this be a multi-system stress and indeed that's what some colleagues who recently published this in Cell found, a pretty good journal. They found that even if there wasn't ever a direct nerve effect from COVID-19. Seven weeks afterwards in mice, you're still seeing profound central inflammation and microglial activation, very similar to chemo fog. So there are multiple mechanisms and Tom will argue that we have a social scenario and I'm gonna say we have an at-risk group of people that is pushed the wrong way. That could be persistent gut infection, inflammation in the astrocytes, autonomic dysfunction, vascular problems, neurotransmitter related issues that put a at-risk group of people over the top. What is some suggestive evidence? I go back all the way to 2020 in the journal Brain. Look at these rates early in the pandemic of encephalopathy, inflammatory syndromes, stroke, Guillain-Barre, suggesting there is a nervous system component. Even more compellingly was this early paper that talked about stroke and microhemorrhage and indeed you put a number of these people into a 7T scanner and you can see microbleeds all over the place like scattershot. Why are we seeing that? Well, we're probably seeing it because we're producing two things. We're producing an element of brain atrophy from the systemic inflammation. This is a paper about two years ago from the United Kingdom's Brain Bank in which they follow neuroimaging and follow post-mortem brains over time. And what did we see? We saw pretty profound atrophy in the left hippocampus in these people in the insula, apparently affecting both their memory and emotion. And we find signs of microvascular clots all over the place. Protease activities, change in their blood-brain barrier. We have people who are inflamed and are micro-infarcting. Now, do we have other evidence of a central neurologic or neurologic system dysfunction producing these problems? And indeed we do. We have findings consistent with an autonomic dysfunction. I spelled it the English way. These people have altered medullary system signaling likely because of ACE2 receptors in their midbrain. And therefore I would argue knowing about the biologic part will help repair pieces of the maladaptive phenotype. So if this is biologically possible, we should see some markers of it in the living. And indeed in the living, you can find elevated ferritin, inflammatory links, longstanding hyposomia, suggestive of neuroinflammation, deficits in prefrontal function, EEG linkage to a phenotype that isn't working. We've also been recently able to demonstrate plasma proteomics. Plasma proteomics that say there's oxidative stress, there's neutrophil infiltration, there's phosphorylation of protein COX7A. So we're seeing inflammatory biomarkers linked to a maladaptive longstanding phenotype. Is it everything? Likely not. Is it a cofactor pushing over the edge? Likely unquestioned. And then among the things that have been really interesting is the findings recently that there's a gut brain interaction in COVID. And then maybe it never goes away in some people, that there's long-term colonization, neurotoxicity, and inflammatory substances driven by that long-term colonization that results in further neurocognitive impairment. There's also this very interesting paper recently from our colleagues at Penn that discovered a subset of patients who had traces of COVID again in their gut for a long period of time, months after their infection, and that COVID impacted their serotonin system, impacting their cognition and their affect. That there was a disvirtuous or toxic cycle here with longstanding COVID. Now, I would argue some of these are primarily neurologic, and then some of these COVID-based events that could be biologically inflammatory are also neuropsychiatric or psychiatric. So here's some early data from 2020. This data is mostly held up that suggests the PTSD rate after an ICU stay in COVID is over 30%. 30% of the people wound up with PTSD. And for those who do traumatic injury, they know PTSD can have devastating sequelae on our cognitive and behavioral function for a long period of time. They also note that frankly, there was a very high secondary effect in healthcare workers. So I show you here a paper that we did that is in press from our recover study. And you look at the most symptomatic versus the least symptomatic. So the most synthetic are in the red bars, the least symptomatic are in the green bars. And when you take a look at the long-term sequelae of these cognitive scenarios, the Z-scores on cognitive testing on these people, they actually are doing worse. They're actually doing worse. There's a real dare there. Now, the why could be certainly biologically inflammatory, could also be behavioral and other dysfunction. So I make the argument, I hope, that there are significant biopsychosocial impacts to this event. That in my eyes, this is unlikely, purely a nocebic event, which requires social infection, or frankly, mass hysteria, because people had this symptomatology before they ever knew about the long-term sequelae of the event. That there are multiple mechanisms, probably persistent infection, inflammation, and dysvascularity that plays into the maladaption of COVID-FoC. And that what's really important is understanding the targets. Who's at highest risk? What is the duration? How does that correspond to a phenotype? And how do we try to think about the whole person in an attempt to deal with their post-COVID care? So I leave Tom with a few extra minutes. Thank you. Okay, always tough to follow Rastafant. I think his strategy in work is read everything, understand everything, remember everything and utilize everything. So that makes it tough when we're trying to debate him. Now he took it to another level, you know, we did these things independently, but he actually used some of my articles. So we'll see how it goes anyway. But I am going to spend a little bit of time talking about some of the reasons why we may not want to focus so much on some of these biological issues. Let me start with this. Cognitive deficits are seen in up to two thirds of patients after COVID-19 infection, rates generally more about one third. And a recent meta-analysis that I have here reports at 12 weeks, about a third of patients report fatigue, 22% with cognitive complaints. And these are persistent. So following this cohort out six months or longer, the rates remain about the same. So it's certainly an important issue, not a short-term issue. My points here are not to say that it's not an important thing. It's a brain fog, not a specific diagnosis, symptoms that Ross reviewed, and has a major impact on social activities, on psychological well-being, on return to work, return to school, and other important community-based activities. It also has direct impact or indirect impact on mood, sleep, self-confidence, fatigue, and other conditions. And I'll spend some time talking about that. And there are similar presentations of this in other conditions, concussion, chronic fatigue, chemotherapy, as Ross, again, stole from me, but that's okay. But given limited and sometimes competing resources that we have for patient care and research, part of what I'm going to talk about here is where should we be focusing our efforts and why. And to some degree, it's a deviation from what Ross suggests. Okay, proposed etiologies, he covered this as well. There's CNS dysfunction. Typically there is ongoing infectious processes, post-infectious processes, systemic complications that might impact the brain, relation to medical illness in general, and then biopsychosocial factors and really more of what I'm mentioning here as psychosocial factors. So I'm not at all suggesting that there is not CNS dysfunction, but just, you know, what's the relative contribution of that versus other reasons for the problem? Okay, so let me start with this, relation to infection. So this is an interesting article that I just came across last month. It evaluated patients who had cognitive deficits related to COVID at least nine months after infection. And they were looking for markers of infection, markers such as COVID antigen, evidence of ongoing immunoactivation, and measures of CNS injury. So they obtained serum samples and CSF samples, again, at least three months after infection has resolved. The focus was on assessing whether there's ongoing viral infection that might be driving some of these complications that patients are still having, maybe some altered immune activation or evidence of ongoing actual CNS injury. So they assessed patients with neurocognitive deficits, compared this with a group of post-COVID control, so those who had COVID but had no symptoms, and a group that didn't have any history of COVID infection. So what did they find? They found that subjects who were complaining of neurocognitive deficits four months after infection did not demonstrate markers of neurologic damage. Looking at things like neurofilament, light chain, gliofibrillary acid protein, and tau. They were looking for evidence of cytokines associated with inflammation, did not see an increase in those compared with control population, or evidence of ongoing COVID infection itself, so the COVID antigen. So this is one of their findings in graphic form. Looking at in green, this is COVID-19 controls, those who have no complaints. Red is those who have post-COVID complications, and looking to see if there's an increase in any of these markers of infection or inflammation, and demonstrating that there is not, despite the fact that these patients are complaining of problems. Do we see similar problems and illnesses in non-COVID subjects? So Ross did touch on this a little bit, but I'm going to use this to give maybe a different spin on how to take a look at what's going on here. So I found two intentionally pre-COVID era studies looking at symptoms related to medical illness and ARDS and the like to make the argument that maybe what we're seeing in COVID is not necessarily much anything new that needs a lot further investigation as to mechanisms. So the first study shows that with patients who are ventilated for greater than 48 hours and assessed at 3, 6, and 12 months post-discharge, they had a host of complications that we're seeing now in this population as well. Problems with sleep, problems with attention, memory, cognitive function, and the like. Both at 3 months and 12 months, so very persistent, and in some cases, even worsening at 12 months compared with 3 months. Wilcox also did a narrative review looking at survivors of ARDS, again, a pre-COVID cohort, demonstrated cognitive impairments in over half of patients at one year and up to half in two years. And these deficits are noted in attention, concentration, memory, executive function, similar to what we're seeing often in the post-COVID population as well. And then the third study that I mentioned here, this is actually a study of inpatients who were post-COVID, assessed after, and this was a mean of about 5 days from discharge from the ICU, I'm sorry, 5 days from the ICU, mean 28 days from infection. Demonstrating a pattern of cognitive deficits very similar to ARDS, again, suggesting that what we're seeing here with COVID-19 sequelae is not different from what we've seen previously. This is another study looking at problems in the general. Again, this is a pre-COVID population and what the experience of an ICU stay has. So these are data from 2016 to 2019, again, pre-COVID, demonstrating very high rates of psychological distress. And they're looking, it's a study from Holland, over 2,000 patients were enrolled. The control group here, which is in orange, was an elective surgery group. So this is a group who were in for elective surgery, still had an ICU stay, but it was more for monitoring. So they felt that this would be appropriate control. And again, seeing high levels of fatigue, anxiety, depression, PTSD, and cognitive impairments one year after their ICU experience. Ross touched on this as well, but I'm going to take a slightly different spin on this too. So we do have experience from SARS, from MERS, and there's even, there are reports, of course not studies, going back to not only the Spanish flu, but epidemics in Europe from the 16th and 17th century. This is a condition known as encephalitis lethargica, which has some features common to what we're seeing with post-COVID fog as well. So there were epidemics in the 16th, 17th hundreds in Europe and descriptions of people who had similar complaints. In the literature with SARS, we're seeing high rates of PTSD, greater than 50 percent, depression about 40 percent. Again, suggesting that what we're seeing here is not new, not unique to COVID-19. And what is the prevalence of psychological problems in the general population? This is, so now I'm interested in the population during the COVID pandemic, but also population just outside of the pandemic as well. So this is a study that did look at prevalence of psychological distress related to the COVID-19 pandemic in those who did not have an infection. So depression rated at 16 percent, anxiety, 15 percent, insomnia, 24 percent, PTSD, 22 percent. And in a second, I'm going to try to link that to some of the cognitive problems and other problems that patients are having related to COVID-19. This is a 2021 study and it attributes most of these findings to fear associated with the pandemic. And we all recall how stressful the situation was, reaction to the containment measures of sheltering and things like that. The high numbers of people who were being infected, the high mortality rate, especially initially, as a way to explain why there was such a high prevalence of these problems. This is a study that looks at depression, again, in a non-COVID population, pre- and post-illness depression in post-ICU patients. Looks at cognitive issues measured by the MoCA blind, which of course is a relatively – it's not the most sensitive measure, but it is a measure of cognitive difficulties. The hospital anxiety and depression scale, as well as the impact of event scale. The impact of event scale is a way to measure subjective stress caused by traumatic events, a measure that can be used, for instance, to assess for PTSD. And what you see here is that at baseline, which is leaving the ICU, and at three-month follow-ups, very high percentages of cognitive problems, high rates of anxiety and depression as well. So now I'm going to try to link some of these psychosocial stressors to cognitive deficits in general outside of COVID. So the relationship between mood disorders and cognition has been well-studied, and there are a number of articles that suggest that. Multiple etiologies for cognitive deficits in major depressive disorder conducted a systematic review related to COVID. Forty percent of patients with COVID had anxiety. So this is something to really consider that if anxiety and depression on their own play a role in cognitive deficits and fatigue and the like, that should be taken into account. Some of the findings here are reminiscent of neural deficits we see with other acquired brain injuries. This is a fMRI study, and you see similar images for other neurologic conditions. Where in healthy subjects doing a test, in this case the NBAC for cognitive function, you see certain elements of the brain lighting up. For patients who are depressed, you see more areas of the brain lighting up in easy descriptive terms. I would call that more inefficiency of the brain if it's not acting optimally. So we see this with a number of neurologic conditions that more areas of the brain are lighting up for a specific test than in a control population. And this is just one example that for depressed patients, there is this impact on brain function. And if the issues are so related to the infection itself, I was also curious to see, well, why do we have so many deficits in those who are less critically ill from COVID-19 as well? And I will say this, the literature on that is mixed. So there are certainly a number of articles that suggest that a greater disease burden with COVID-19 is related to these cognitive deficits, but there are a number of articles suggesting that patients who had lesser illness also have a high rate of these problems. So this is one study that looked at comparing those who were hospitalized to those who were non-hospitalized. So maybe not a direct measure of severity of injury, but I think to some degree it's a fair measure of that, and noting no difference in proportions in fatigue or cognitive complaints in those who are hospitalized versus those that weren't. This study also shows that at six months, if you divide the studies into those who looked at patients prior to six months or after six months, that the rates stay the same. And you would think that with resolution of illness, if that was an important part of the presentation, that the rates should be decreasing. As I mentioned before, there are other studies that report high levels of cognitive complaints, not only in hospitalized, but even in asymptomatic COVID patients. So there are studies looking at some who didn't even know that they had COVID infection, yet were having complaints, and those complaints were then, because of that, they were screened and found to have COVID-19. So this is a position statement that was published in Archives of PM&R this year, and I think it kind of summarizes maybe what both Ross and I talked about. But I really want to highlight, and this article also highlighted, this position paper highlighted the recommendation to really focus on the social factors, the neuropsychiatric factors. It didn't say ignore the biological factors, and I'm not saying that as well either. But I would say that a disproportionate amount of the problems and perhaps the solutions are more driven by social and neuropsychiatric factors, and therefore, that should be the primary focus of attention for further evaluation of the problem and management. So in summary, the etiology of persistent cognitive problems after COVID-19 infection is indeed multifactorial, but there's good evidence to support the argument that direct biological factors that Ross very nicely explained play a lesser role in the development of brain fog after COVID-19. It's also unclear how novel the biological factors are regarding post-COVID cognitive symptoms compared with other processes that we know about. So the focus on causes of management, in my opinion, should be on the psychological and social factors leading to this widespread and functionally significant long-term problem. Again, I'm not trying to minimize the problem at all, just suggest a different way to approach it. Okay. Okay. So I believe we have about 10 minutes left, so I will see if there are questions from the virtual audience, but there may be questions from the audience, so if I can invite everybody back up, please. Yes. Thanks, everybody, for a wonderful presentation. I do have one comment, and that's that for many of us who work in for-profit rehabilitation institutes, the only question on the robotics versus non-robotics is going to be the return on investment, of course. Could I ask the experts on the panel to discuss what they think the advantages and disadvantages to return on investment would be with robotics or non-robotic investments? I didn't hear. Can you repeat the question? Return on investment for the robotics versus non-robotics. What are some of the pros and cons for each side? Yeah, he's asking what's the return on investment for robotics. For robotics. I mean, I honestly do not know yet. I think we're at that stage that we're still exploring to begin with what are we going to track. The return on investment in terms of what great outcomes you have achieved by using robots. Money. Oh, money. I don't have that data. Yeah. So I think the return on investment can be laid out in different ways. One is how much staff you're using, so staff utilization would be one. The other one is effectiveness of care. So currently you're paying per day or per treatment, but in the end, maybe in the not so far future, you're going to see payment on outcomes. And so what you want is to have higher outcomes. So I think that's where the return on investment may be. Hi. Thank you. That was always provocative. So I've been working on electric stimulation for 20 years, 30, and there is new stuff. They're full body electric stimulators in like a Lycra bodysuit that you can then program for walking, sit to stand, upper extremity movements. And you can use them in conjunction with body support tracking systems like the zero gravity programs. So you can use them in conjunction. They don't cost anywhere near what a full scale exoskeleton robot does, but you get benefits where you actually get muscle contraction and you get sensory feedback. Now, if you don't have good sensory feedback, the system tries to adapt. The system would be your brain. And the only way it adapts is by putting out more norepinephrine and increasing tone. Also, now, in other words, we don't have 20 different ways that we respond to things that we don't feel are correct. In other words, what we expect to feel. We only have like a couple. So the couple, the primary one, is to increase norepinephrine, which increases tone. Now, if you increase norepinephrine and you've had... So that's it with the robots and the alternative sort of like hybrid treatment using robots or non-robots or therapists. Now, I'm going to switch to COVID. Now, I just came back from D.C. where they had a really nice presentation on sepsis-induced secondary problems, whether it's COVID or whether it's just ICU. And the presentation had to do with exactly what you guys presented. In fact, two of the slides were exactly the same that they presented. But one of the things that I didn't learn in med school is the cilia that's inside the small blood vessels called endocalyx. And in their presentation, they talked about how the small blood vessels have this lubricating cilia and the endothelium. And when the viruses and other complement antibodies come through, they just shear the stuff off, which promotes micro clots. And so what Ross was talking about is like, what the hell? So I want to try to... There's a question here. Yeah. So I'm waiting for the question because there's people behind you. Yeah. You guys ever heard of this stuff? You know, glycocalyx? I'm sorry. What was the end question? The end question is, have you heard that you can get micro bleeds or, excuse me, micro clots from having the... 100%. In COVID. Yeah. I can demonstrate 100% that there are these case series of people with both micro hemorrhage and micro clots that I showed. Absolutely. The exact mechanism is likely multifactorial. Hypercoagulability, say, some of the markers that you talked about, also micro bleeding, blood brain barrier disruption, et cetera, et cetera. So is it been reported? Yes. Is it a real entity? Likely, yes. Thank you. And just to answer your question about electrical stimulation and robotics, that's already in place. There are several of the devices that can have electrical stimulation. The nice thing about robotic devices, just to make the point, is you can actually grade the amount of effort you want the patient to make. So I'll stop to that. Thank you. I have a question for Dr. Zafant. Hi. Of course, what we know about TBI and about post-ICU syndrome is going to inform the way that we approach the post-COVID population. I was just wondering, in your practice, is there anything you've found that's unique about this population in terms of how you're managing them? Yeah. So I think that that's the critical issue. Are there unique elements of a maladaptive phenotype with this? And then Tom brought up something that I think is really important, which is, what is the actual comparison group, right? And the reality is that during the middle of the COVID pandemic, my good colleague Maurizio Fava at MGH Psychiatry reported that between people 18 and 28, the depression rate was 63%. That's stunning. It's devastating, right? It's also very inflammatory. PTSD is very inflammatory. That's the biologic side. The practical clinical slide is what we're seeing is this Gordian knot, in many ways, of people with everything from mobility issues to the interaction term of behavioral and this cognitive fogging things that require us to at least do what we know now, and when we know better, do better. Thank you. Thank you very much. You gave great opinions on how to move forward with each of these particular struggles. My question, or really, the first thing I want to do is let you know that as far as broad coverage for exoskeletons, recent changes, we have 250 million, roughly 250 million adults in the United States. Currently now, 73 million do enjoy coverage through the VA and through Medicare. So we are not quite at the 50% mark there, but we're getting closer. My question is, we've all been experienced with utilizing GME and braces and looking at prosthetics, and sadly, you look at 5 to 10 years out, how many of those very same devices just end up being in a closet collecting dust? When you start looking at that 500 that you were looking at, whether or not you're going to invest that into exoskeletons or into PT, I ask you, here's the question, 10 years out, where do you see that value? Because if you've invested in your PT, as we all know, education is something we build upon, we continue to receive benefits for it long term. If the exoskeleton ends up becoming just merely a device in a closet, where is that long-term value? So any opinions as far as where we're headed on that? So I think it's, you know, the whole process today was to bring a counterpoint or point counterpoint and have really a discussion about a made-up scenario. And so that was the intent of the presentation today. There is a lot more depth into the benefits long term, and certainly you can't select one over the other. This is a, you know, you don't need a half a million dollars for a single robotic device. You certainly could buy, you know, a couple of robotic devices and still implement education. So if you have a donor with a half a million dollars, just have them call me. I'll make sure that we do it right. Thank you. And if Alberta doesn't answer, I will. Good morning. My question is in regards to the post-COVID and cognitive defects. What, if any, correlation have been identified in patients who have certain gene mutations such as MTHFR or their various, perhaps, methylation pathway pathologies? Yeah, so that work is underway in the Restore and other projects that are these large data sets that have not only accumulated a large number of biosamples in these groups of people, the data houses with Sean over at Mass General, and looking at how those biomarkers link to phenotype, right? Biomarkers are lovely. No one loves them more than I do in everything from head injury to other things, except when they don't correspond to anything meaningful. So the critical issue is what's meaningful for what. There are early syncs to various inflammatory and other markers. To really support what Tom was saying, though, I'm very interested, our group is very interested in looking at some of the genetic markers that are linked to a nocebic response. We've been doing this work for some period of time. In other words, if I tell you you might do bad, you might do bad, and you might be genetically predisposed to do so. I think our time is up, but thank you so much. Thank you.

neurorehabilitation

robotics

stroke rehabilitation

physical therapists

cost-effectiveness

effectiveness

mobility

walking ability

COVID fog

cognitive deficits

holistic approach