Preeti Raghavan, M.D. presents at the Johns Hopkins Department of PM&R’s Grand Rounds on December 17, 2019.
Hi, everyone. Thank you for having me. Um So before I begin, I just want to disclose that I am co-founder and scientific advisor of two companies, Mirrored motion works and movies. Um And I do intend to discuss the off label use of highly run A which is an enzyme for the treatment of muscle stiffness. But um I have not received any financial remuneration of any kind from uh this work. Um So the objectives of today's talk are to discuss the philosophy of stroke recovery. Um And I want to distinguish between recovery and rehabilitation and share some information about some current and upcoming studies in the motor recovery research lab, uh which is my lab and there are some flyers um that are um in the back on the right hand side. Um Matt from the lab is here. He just raised his hand. Um So please do stop by and uh take a look at them. And I also wanted to articulate the stroke Institute's vision for recovery and rehabilitation. So for a long time, we never thought recovery was really possible after a stroke. So all of our efforts were quite naturally focused on helping the patients compensate. But I think over the last decade, it's become clearer that recovery is possible. And now it's about finding how to make it possible for each one of our patients. So really behavioral recovery, which is what we are concerned about is about restoring the ability to perform a movement in the same manner as it was performed before the injury. Right. And clearly, the central nervous system is involved, the peripheral nervous system involved is involved. And you know, it involves not only the outputs of the central nervous system and peripheral nervous system to control the muscles, but I think it's very, the inputs are equally important. And I think a lot of the research that I'm going to talk to you about today is about inputs from the skin, from the muscle, from normal movement that can actually shape the pathways towards recovery. So um the philosophy, my personal philosophy of recovery is that behavioral recovery actually requires three things. You need neural restoration, which simply put is about being able to activate the muscles, right? Because stroke really paralyzes the muscles. And so we need to activate them, we need peripheral restoration so that the correct sensory inputs are available to modulate the muscle activity patterns. And then you need cardiovascular restoration, which is about having adequate blood supply both peripherally and centrally to meet the demands, right? And that's not just restoration of blood supply through TP A or through extraction of the clot. But I think a huge component that we don't always provide is cardiac rehabilitation. And there's more and more evidence now that that should be a component of stroke recovery and rehabilitation. Um A lot of the research I'm gonna talk to you about is really about, you know, uh the relationship between neural restoration and peripheral restoration and how they work together. So it's been said that research is research. Um So I really got into this because I was actually quite clumsy as a child. And so I've spent a large part of my life trying to understand dexterous movements, right? And so it's through my own experiences in music and dexterity in that way as that, as well as that of my Children. What I've come to realize is there's a very important relationship between dexterity and biomechanics. You can't really, they, they go together. And um and that's actually informed a lot of the questions and experiments in my research lab. So the mission of the lab was has been to develop innovative therapeutic strategies for recovery of movement and function after stroke. And when I started the lab in 2006, we, I was really after hand function, you know, because, you know, the thought was that if a patient is paralyzed and has no movement, well, where do you start? But for a lot of patients, you know, they may have movement proximately but they may not have distal function. So what we did was we created a model uh device and that is a group instrument which is, which has got uh force sensors. So you can measure fingertip forces and you can look at how these fingertip forces adapt when you change the weight of the object and change the texture of the object. Right now. This is actually very functional because it's something you're doing all the time, you're constantly adapting the forces, depending on the weight of the bottle you're lifting or how slippery it is, you know, and all our functional tasks. But when it comes to hand rehabilitation, we don't necessarily have the tools to figure out are patients able to do that? Are they not able to do that? And if not, how can we actually rehabilitate that ability? Right. So with this object, we could actually, you look at the grip forces which start when you touch the object, you look at the load forces, when you start to exert forces in the vertical direction, which is about here. And you can look at the temporal um you know what's happening temporarily even before you actually lift the object. So there's a lot of rich information um which told us a lot of which has provided a lot of rich information. So for example, if you have a healthy person, lift a light object and a heavy object, you see that even before lift off, if you look at the load force rates and the grip force rates, you see that the force rates are lower for the lighter object than for the heavier object. Right. This is happening as soon as you've learned the relationship, even before you actually lift the object. Now, it does take a few trials of practice. Usually you just have to lift the object once just one trial practice will allow you to do all subsequent trials in this manner. right? And in fact, even if you practice with one hand and lift the object with the other hand, for the very first time, you see that the nervous system has transferred the information from one hand to the other. OK. So you on the very first trial, with the other hand, you see evidence of having learned this relationship. Now, when we looked at patients with stroke, what we actually found was despite repetitive practice, they did not learn this relationship between the force that they needed to use and the weight of the object. But surprisingly, when they did it with the unaffected hand and then with the affected hand, they were now able to learn this relationship, right? So this whole idea, this was actually published in 2006. And a lot of subsequent research has been about, well, what are the inputs that inform this type of learning? Are they sensory inputs? Are they muscle activation inputs? And how can we actually use that to rehabilitate hand function? Now? What we have also found is that if you, if, if, if, if an individual is grasping a smooth object versus a rough object, then also you see that the grip force rate is scaled to the roughness. But we did another experiment where we had a range of textures, but we blocked the fingertips with, you know, is like tape. It's a sticky thing that we sometimes use um as a dressing. So once there was stagger on the fingertips, they did not scale, right? Suggesting that the inputs from the fingertips, sens sens uh sensors are really important. So what is it on the fingertips where we all know that uh fingertip sensitivity is critical. But the in your fingerprint, the raised parts are your papillary ridges and a lot of your tactile receptors are associated with these papillary ridges. So, pushing against the ridge, you actually have the sna coral which uh senses touch and in the troughs between the pap ridges, you have um the Merkels discs which also sends touch, right? And so what's been found is that as soon as you touch, start touching the object, these receptors are activated and they are responsible for the four scaling that we see. OK. So uh this now what we've been able to do is using 3D printing, we can create textures which with varying degrees of roughness, but the roughness is very clearly defined. You can define the roughness by the size of the bumps and the distance between bumps. So our papillary ridges are about one millimeter apart, right. So, in this way, you can actually figure out which receptors are potentially responsible for giving us the various types of sensations that we experience. And what happens if you know, a person is able to sense certain textures but not able to sense certain other textures, you know, what could be the underlying cause and potentially how can you treat it. So that's um you know, so the basis of this first study, which is an NIH funded um R 21 with collaborators at NYU, where we're really going to look at changes in grasping forces to various 3d printed textures when we age. So in healthy people, in people with peripheral sensory disorders like carpal tunnel syndrome, where the problem is entirely peri peripheral nerve related and then in central sensory disorders such as a stroke where you have, let's say hemi anesthesia or reduced sensation uh on that side of the body. Um And the other thing that we're going to do is just as I showed you previously, we want to look at how inputs from the unaffected side can actually substitute or help relearn this relationship between texture and dexterity. Um So all of this work has been done pretty much in the lab. So we've been tethered to the lab, but we also created a portable grip device that works just like the device I showed you, you can change the weight, you can change it textures, but the difference is you can give this to the patient at home. You can use it in the clinic. And this is a study where, which is being done at NYU. It's a study in multiple sclerosis. It's funded by the dod. And we are really using the um the grip device, this portable grip device to evaluate changes in hand function, using remotely supervised during remotely supervised therapy, which is provided at home with brain stimulation. Um And so we've actually, we're halfway through the study. Uh Hopkins is involved in data analysis and it's sort of the gateway for the next study where we can actually even train with this device. So the device provides inputs to a video game so that patients can learn how to scale their fingertip forces according to the various parameters of the object. And you know, they're not even, they don't even realize they're rehabilitating because they are focused on playing the game. So this is something that we also plan to test in patients with stroke. Um So the the next study that we have is a multi center study um out of Metro Health in Cleveland, which is contra laterally controlled functional electrical stimulation. So we all use electrical stimulation uh in therapy. You know, we prescribe it to our patients. The idea here, but we are often not able to grade it. So how do you give less or more stimulation based on what the patient is doing at that moment functionally, right. So the idea of contra laterally controlled functional stimulation is that there are actually sensors in a glove that is worn by the unaffected hand. And that triggers the stimulation of muscles of the weak hand or the affected hand. So the idea is if you want to open your hand, you just open your unaffected hand and it provides the right amount of stimulation to the muscles of the affected hand so that you can open the hand, right? And if you open the unaffected hand just a little bit, then your affected hand will open just a little bit too. So the stimulation will be graded again. The idea here is that the inputs from the unaffected side are being used to modulate the stimulation of the muscles of the affected side. And um and in this way, it's sort of reshaping the circuits in the brain. Um So this is a multi center three group study uh where one group gets the contralateral functional electrical stimulation. Another group just gets neuromuscular electrical stimulation. So it's not, the input is not coming from the unaffected side. And the third group gets conventional therapy. So this is IRB approved, we are currently recruiting and it will also provide in home therapy and 12 weeks of one on one therapy, right. So it's for patients who still have hand function deficits, but they, you know, have finished all their therapy visits and they're looking for more options. So, um again, there are flyers in the back. So if you come across any patients that you'd like to refer, uh please do, let us know. Bye. Um, the next graduate study. Yeah. So what's, what's the goal when you say there efficacy of this? Is this the outcome? Yeah. So basically the, the expectation is to examine for a long lasting effect. So the study itself is 12 weeks long, but the follow up is after six months. So the idea is to see uh if there is a long lasting effect of this on hand function of ccfes compared to the other two groups. Um Another stuff. So, you know, another theme is that we want to actually promote or provide more rehabilitation than we can in our current peer environment. Uh So we've been testing various kinds of tele rehabilitation setups. And one of them is a connect based tele rehab, tele rehabilitation environment using citizen science. So citizen science is the idea that if you actually are doing something useful, let's say you're doing research, um it might be more motivating than just doing exercise. So the idea is doing something useful, useful work can be used as a motivator to get more exercise in the the the the useful work is really about tagging objects on a screen. So all it requires is a computer and a mouse. But a lot of patients can't use a regular mouse or you can't give rehabilitation using a regular mouse. So um engineering students have created sort of a glorified mouse which is really uh uh something that looks like a baton which is interfaced with Kinect and Imu or inertial motion sensors on this button. So in this way, what happens is that you can perform very specific movements. So for example, if you do elbow flexion and extension, then you can select an item on your screen, right. If you do shoulder flexion and extension, you can move the cursor up or down. If you do shoulder abduction and abduction, you can move the cursor left or right. So essentially, you're controlling the cursor on a screen with gross movements of your arms through this uh button. And um the idea of that is that you can actually rehabilitate specific movements and you can look at and remember they're using both hands. So the inputs are coming from the muscles of both the unaffected and the affected side. But you can also look at the movements of each side alone. You can look at, you know, whether they are tilted, are they compensating? And then uh the idea is to also look at what happens when you do this for an hour. Do you get tired? Do your movements deteriorate things like that, which are actually really important questions, but we often don't have the tools to measure it in a clinical setting. So for example, here you can look at shoulder abduction, abduction, flexion, extension, forearm, rotation, wrist flexion and extension and elbow flexion and extension. Now, one of the problems with something like the Kinect is that actually it doesn't measure some very critical movements of the upper limb after stroke and that is rotation. OK. So we've also worked with um engineering folks to create sensors that could be used for tele rehabilitation and can actually provide simultaneous information from many sensors to really look at. How are you moving? Are you compensating? Are you moving well at one joint? But compensating at another joint. So, and you can also, so the idea here is it's also a tele rehabilitation platform where a therapist can wear the sensors and easily program any task or any exercise that they want the patient to do. And then when the patient is ready, they wear the sensors and they do exactly as instructed on the screen by the avatar of the therapist or the instructor, right? Um And it's um easy to calibrate and to put on and what it does is and the patient doesn't need to see this. The patient is getting feedback from the avatar on the screen. But what you can see here is that when in order, so these movements represent flexion extension at the shoulder, abduction, abduction, elbow movements, et cetera. But one of the key things that I want to point out is that when a person is abducting at the shoulder. Notice that they are almost fully externally rotated at the shoulder. So in other words, if you cannot externally rotate fully, you actually cannot abduct your arm all the way. And that's a, it's a key problem in our patients with stroke. And the second thing is that when you externally and internally rotate your shoulder, you're also pronating and stating a little bit right. So training the rotational movements of your shoulder can also help with recovery of rotational movements of your forearm, right, which is these are, these are two things that are extremely challenging for patients with stroke. So we know that because we see it every day, right? We see that when a patient, when you ask a patient with stroke to flex their arm or to flex at the shoulder to reach forward, they invariably abduct just slightly. So it's not a true abduction, it's like a partial abduction and it's an elbow flexion, right? And this has been studied extensively and it's been found that the culprits are specific muscles in the front of the body that don't allow the patients to externally rotate fully. So they can't, you know, abduct fully and they can't do you know all the movements at the shoulder correctly because of that. So in order to change this pattern, we thought it's really important to enable the people, the individuals to externally rotate. And you actually do that by activating the external rotators which are in the back, the lower trapezia, the Intrasinus, the triceps, the la do these are your stabilizing antigravity muscles that also allow you to get your, your upper body in the right position for all kinds of functional movements. So what we did was we created a device where again the inputs are coming from the unaffected hand. So the unaffected hand moves into external rotation and it automatically moves the affected hand into external rotation, right. So this is an FDA cleared device and initially it's passive, but then you can look at how much the affected arm is learning from moving both arms simultaneously. So for example, this is what it looks like. No oops, sorry, it's a little choppy but it's usually not choppy. So that's just the video uh and it's interfaced with a video game. So again, it's engaging and with very easy set up, you're able to see what's happening in the background and how the patient is learning to move. And what we found is compared to a control group that did not receive training with the bimanual arm trainer for 12 sessions. You see that training with the device for 12 sessions did increase activation in these muscles that I described earlier. So these are the back muscles and as a result, they had increased active motion in external rotation um as well as inter rotation shower reflection abduction as well as elbow movements. So the idea and these were actually really low level patients, patients that you would think that in the chronic stage, if they don't have much movement, that they're probably not going to recover it. But we found that you can actually change the movement pattern and get active movements despite that. So um making me believe that really recover, there isn't necessarily a very brief window for recovery. That window can be extended by the right kinds of inputs, whether they are sensory inputs or movement inputs from the other hand, muscle activation from the unaffected side can actually activate the same muscles on the affected side. And with this device, what you can see is you can provide different kinds of stimuli. Using the video game, you can record the movement in the background and you can plot the learning curve of the affected arm and see how it's uh it's improving. So, so far, I've talked to you a little bit about inputs uh that will shape perhaps the neural circuits. So we've talked about neural restoration and clearly some of all of the exercises that we do have a peripheral component because you're providing sensory inputs, you're providing uh proprioceptive inputs into the nervous system. But still we struggle a lot with abnormal muscle activation patterns, right? So sometimes we want the patients to externally rotate, but they just can't, they are tight in internal rotation. And we don't quite know, you know, there's a lot of confusion about the terms muscle synergy and spasticity and stiffness and very often we use them all quite interchangeably. So, um and we, we have taught and this is what we are taught in our textbooks that this kind of uh these abnormal muscle patterns are due to the brain stem pathways that substitute for the damage to the corticospinal tract pathways, which are, which are often damaged as a result of a stroke. And we think that really the the ultimate uh area of the nervous system that is affected is our stretch reflexes, right? Because the stretch reflexes has been taught to control the activation of the muscles. So, in fact, almost all of our treatments for past the city are related to changes in the stretch reflexes. So the idea is that spasticity occurs because the stretch reflexes are no longer normally suppressed. So you have hyperactive stretch reflexes and somehow that causes the muscle to become overactive. And so you have a very interesting problem where you have muscle weakness. And we say the person also has muscle overactivity, right? It's been very difficult to reconcile, you know, as to how an individual can have muscle weakness and muscle overactivity in exactly the same muscle groups, right. Um And almost all of our treatments, whether it's botulinum toxin or whether it's a dorsal rhizotomy or intrathecal baclofen or cns suppressants or nerve blocks, they all attempt to target the stretch reflex and basically reduce the muscle overactivity that is thought to be caused by these overactive stretch reflexes. So um when we started to look at the EMG data from my lab, we really thought things are not adding up. We perhaps need to look more closely at the changes in the muscle itself, right? What's happening to muscle architecture? You know, we've, we've talked a lot about neural restoration, but clearly when there aren't nervous inputs, when the, when the inputs to the muscle are not coming through as well, then they are bound to be changes in the muscles as well, right? And what are these changes? So we know a lot about muscle activation through the sliding mechanism, right? But we know much less about forced transmission through the noncontractile elements in the muscle. So this is basically an electron micrograph of what a muscle looks like when you dissolve all the muscle fibers, this is the collagenous lattice like network that is really critical for force transmission. And you know, so the endomysium is what surrounds each muscle fiber and then around bundles of muscle fibers, you have the perimysium and then around the entire muscle, you have the epimysium. Right. Now, what's been found is that in Children with chronic spasticity, the perimysium is extremely thickened. So all this red that you see is really thickened perimysium. Um Now, what's been found is that not only so the perimysium is made up of collagen, but right around the collagenous structures. That is the Endomysium, the perimysium and the epimysium there is a non collagenous structure which is hyaluronic acid, right? You've heard of Hyaluronic acid, perhaps in joints, it's a lubricant. You've perhaps heard of it in cosmetics because the skin is very rich in Hyaluronic acid and a lot of um and hyaluronic acid absorbs water, right. So it helps maintain skin t but in the muscle, it's also a lubricant. So this brown stuff that you see where you should see collagen, right? This is basically a layer of hyaluronic acid right around the collagen, the Endomysium and in the now, in a very interesting study that was done in rats, what they showed was just four weeks of immobilization led to accumulation of hyaluronic acid, right? And they knew that it was so all of this brown stuff that you see here in b this is accumulated Hyaluronic acid just after four weeks of immobilization and it is washed off with the enzyme hyaluronidase. But what was even more interesting was that after 12 weeks of immobilization, the collagen actually got deposited around the Endomysium and the Endomysium itself became thick, right? So in other words, what happens is first, you had accumulation of hyaluronic acid and then you had thickening of collagen. So what does the hyaluronic acid do in uh right around the muscle. It's a lubricant which facilitates sliding. So when you are moving the muscle fibers have to slide against one another. And as a result of that, the force is transmitted to the other end of the muscle. But hyaluronic acid is actually a very interesting molecule. It's a non Newtonian molecule. In other words, if you shake it up or you let it sit, it changes its consistency. So when the consistency changes, it becomes highly viscous, right, it becomes thick and especially when the concentration increases. After a short period of immobility, you can see that this uh hyaluronic acid accumulates becomes really thick and then lubrication and tissue sliding actually decrease, right. So now you may have this thick layer between the muscles and the person is trying to move, but the muscle fibers are not moving and the force is not being transmitted. So, what we hypothesized was that this accumulation of highly Ronan can lead to an increase in extracellular matrix viscosity. So just increased viscosity in the muscle, but outside the muscle fibers, which may lead to this entire cascade that we are so familiar with muscle stiffness, exacerbation of the stretchy flexes, eventually contractor formation pain disability. So we're all very familiar with it. So the idea was, well, can we do anything to block this cascade? And we learned that highly raid is an enzyme that's been FDA approved and on the market since 2005 and that it's an extremely safe drug to inject. Um So we actually got permission to use it off label and uh wanted to reduce the extracellular matrix viscosity. And what we found was that muscle stiffness dramatically decreased after just one injection and within one week, so T zero is before the injections. And what I'm showing you is the modified Ashwood scale, which is a measure of muscle stiffness. It's a clinical measure that we uh use frequently. Um And two and three represents marked increase in muscle tone. So you can see that approximately two weeks, between one and two weeks after the injection, you had a dramatic reduction in muscle stiffness, which actually persisted for 3 to 5 months. And this is something that has been very exciting to see. And we also found there were changes not just in passive range of motion, but interestingly in active range of motion in patients that we would never expect to see any change in active range of motion. Um We saw this at many different joints and just to show you an example, this was a person who had received Botox for many years, but she still could not actively flex her wrist, right. There were lots of movements that still seemed very stuck. Um After one injection, she for the first time was able to flex her wrist right, ever so slightly. But after two months, see how fluid her movements are, right? And after two injections, she actually regained full arm function and never needed an injection again, which was really quite dramatic. So this is something that, you know, I'm seeing uh often in my clinic uh that, you know, even patients 10, 15 years after a stroke, if they are not contracted already, they could respond to this. We have just published a study in a nature scientific report that shows images of the accumulation of hyaluronic acid in the muscle. So this is a special kind of MRI it's called T one row. Um And the top panel here shows you a normal muscle where uh there is quite a bit of hyaluronic acid. The green represents hyaluron deposits in a patient with post stroke, muscle stiffness. All the red represents excessive hyaluronic acid deposition and notice the shape of the muscle, it's triangular rather than circular, suggesting that the muscles are literally stuck together, right? And within two weeks after the injection, the same patients um looks dramatically different. So, um so the idea now is that perhaps we can break the cycle, you know, the progression to contractor, um even as early as possible, right? So, if we notice muscle stiffness, we could potentially treat it and prevent the progression to contracture. So this is another study that's coming up. Um We've got an uh IND from the FDA to conduct the study. It's a randomized control trial which um it's a single center randomized control trial. It's gonna be a crossover trial where everybody will get the drug and placebo. Um And we're going to ask exactly, you know, now in a blinded manner. So, everything that's been done so far has really been retrospective clinical studies. So this is going to be the first prospective study um that will look at 50 patients, post stroke between six months and five years, post stroke, right. So again, if you come across a patients who you think might be interested, uh do let us know. Um so sort of these are some of the studies and the directions that uh we've been working on. Uh and it's very exciting to be here and to uh define the direction of the Sheikh Khalifa Stroke Institute. The mission of the Stroke Institute is really to do cutting edge stroke diagnosis and treatment informed by the latest scientific research and discovery. So that's the overarching goal of the institute and the vision for recovery and rehabilitation is multifold, right? We really, it's our opportunity to change the standard of care for stroke, which is highly prevalent, but our patients are in silos, they go to acute stroke units and then they may we may never be able to follow them all the way to complete recovery, right? So it may be a Utopic view. But assuming that there are ways to make recovery possible, we need to make sure that we have exhausted all our options before we say recovery is no longer possible, right? And so that's the idea and so we intend to integrate care across all levels. So we're trying to create programming by which, you know, the the general idea is no patient should be left behind, no patient should fall through the cracks, right? So we want to make sure that if we see the patient in inpatient, we are able to follow them through to outpatient and beyond. Right. And so we are the only institution that actually provides three hours of therapy in the acute stroke unit. So even before they come to inpatient rehabilitation, they are now getting three hours of therapy. So, Kudos to Annette and her group and you know, all the people who've made that possible. So that's going to be, that's already showing safety and feasibility of pro provide, providing very early rehabilitation. Um There's a lot of literature on using T MS to understand whether there is the possibility, whether the tracks that allow the muscle muscles to be activated are intact or not, right. So there's already a protocol that has been proven. So part of what we're trying to do is incorporate all the evidence that exists to make sure that we give you the latest that there is to our patients. So we intend to assess the potential for recovery through the tools that are currently available, that is imaging through TMS and through measurement of kinematics to see, to measure more accurately what kind of movements they have. And the idea is not just to segregate patients into recover versus non recovers, but to really see how can we push the boundary and make you know who we might label non recovers into potential recovers if we do the right things, right, and to understand what are those right things. Um So the prep algorithm is the T MS algorithm that predicts recovery potential. Uh So we want to uh start to institute that. And we're also trying to build an outcomes database that will enable us to keep the patients to really follow these patients over time. So we're starting to implement a number of clinical outcomes right in the stroke unit itself within seven days and then at 30 days, days, 60 days, 90 days, 180 days, all the way out to one year and then every six months thereafter, right? So the idea is we want to follow the patient and ensure that we're doing everything possible to make them to help them recover movement that is as normal as possible. Um And we are also going to assess not just movement but also emotion, cognition, language and swallowing, you know, which are all, which can all be affected as a result of a stroke and which will all be um important in the recovery process. So, um this is actually also part of the Precision Medicine Center that is spearheaded by Pablo. Now, um we've just uh received notice that we're gonna have a Precision Medicine Center for Rehabilitation. And so where it interfaces with the Stroke Institute is where we're going to stratify patients based on their recovery potential in the beginning using kinematics and behavioral metrics into those who might have inadequate shoulder movements. So they actually need to strengthen their muscles, activate the upper back muscles, regain active shoulder movements. And then we can try to give them more therapy through other technology that's been created at Johns Hopkins like the mind parts and see how intensity can further push their potential recovery beyond just active movement to function. Um So this precision rehabilitation stroke project will be inpatient as well as outpatient um across time. And then we'll compare those who actually stay at Hopkins and complete are eligible for these projects versus don't ver versus those who don't. Right. So we're going to match the groups. Um We're still figuring out the study design, but maybe we'll borrow from Dr Wegener and do a smart study design. And um so the idea is really to demonstrate efficacy of the interventions, especially of new interventions that are coming out and to test the hypothesis of intensity and dosage and you know, of normalizing muscle patterns. The other objective of the stroke institute is really to disseminate the knowledge that is gained through a learning network. So we, we are already starting educational sessions that steers just presented last month. Um We want to teach one another to develop clear standards for practice and we want to develop minimum standards for stroke rehabilitation. You know, here we are trying to push the boundaries but our funding source, so the Sheikh Khalifa Stroke Institute is funded from the UAE and part of our mandate is to teach them what the minimum standards for stroke rehabilitation are, right? So that, you know, we don't just better ourselves, we actually better the community across the world. Um And then this way we raise the standard of care for stroke overall, right? So, so that's the very lofty goal of the Sheikh Khalifa Stroke Institute. But it's very exciting and I think this work is only possible because of all of you. And I think everyone here is part of it. Um And with that, I want to acknowledge people in my lab. So Matt is here and Maria and the therapists who are going to work on the new Multi Center Clinical trial, Joe and Caitlin, they're going to provide the, the treatments for this multi center uh clinical trial on functional electrical stimulation. My graduate students who are working on all the new technology, uh the funding sources and collaborators both at NYU and now at Hopkins, with whom we're going to do a lot of this work. And I think uh a big thank you to all of our therapy leaders and the therapy teams um that are going to make, you know, this whole clinical program come alive for our patients. So um thank you very much for your attention. Like just um repeat the microphone and uh does anyone have any question? Yes, there are a number of interesting things about this. But one of the really interesting things is that you are implementing something that people have known for a long time and not paid any attention to, which is that uh the important stuff about brain is is network function. And so like uh you know, stroke purists will talk about when you lesion, the right motor cortex, you get left Greis, they talk about the more effective hand and the less effect because the right hand is not fine without its partner. And, and you can see detriments in right hand function, even though it's a collateral. So the more effective it and the less effective. And so this network stuff with the bimanual training is just is something people have known for a long time but never really implemented. And and it's really exciting to see that kind of network we have as opposed to focusing on a particular muscle and, and that's when you get into things like dance dexterity and like using instruments and you know, these kind of time sequential whole body functions that are, that are so important. So I just think that's really exciting. Thank you. Um That's a bit hard to paraphrase. What's the question? Sorry. Yes. So, really great talk. Thank you. That's very, very nice uh for you. Thank you. And I was here. Why I, I wonder what, what are your thoughts about this bilateral training? So when you do this and you're talking about improving muscle activation. And the few studies that you are proposing to do here with bilateral control, the, and the training, is this something that you are just uh what, what do you think? The, the I'm I'm, you know, ask you perhaps some, your thoughts and mechanisms, what do you think is happening? Is this a peripheral thing that uh you are activating the muscles and now the muscles are inactivated or are you, do you think it's more of a central recruitment or combination of both? Yeah, great question. So um Doctor Sel is asking, you know, what are the mechanisms of bilateral control? So, you know, we really got interested in this when, so we saw the changes in in force scaling, right? Which I showed you subsequently, one of my graduate students did a study where she looked at the emg activity. So one hand was moving, the unaffected hand was moving and we wanted to know is there a signal that's still going through to the unaffected hand to the affected hand or to the other hand, even if it's not moving and it turns out that there is right? And in fact, you know, it makes perfect sense given all of your work, right? With brain stimulation. And what we know about uh interhemispheric inhibition, what we know is that information from one side is automatically going to the other side. That's how the neural circuits just exist. The neural circuitry is redundant information, sensory information from one side goes to both sides of the brain. And also motor activity is mirrored on the other side, even when we are not thinking about it, right? So you're actively suppressing that mirrored movement when you want to do unilateral movements, right? And you can measure that inter inhibit interhemispheric inhibition. So at baseline, there's already information exchange going on, right? So that's, and in fact, there've been a couple of very interesting articles over the last couple of years where they've used this interhemispheric exchange of information to drive brain computer interfaces. So let me context but the question is if you are learning to control both arms at the same time in a coordinator synchrony, what does? Yeah, correct. So the idea is if you just, if the issue is lack of muscle activation, then at that point, you want the mirrored motion to generalize, right? And then on top of that, you need functional training to help you generalize. Now you have movement. Once you have movement, you can do other things with it. But the issue is if you don't have movement in the first place, right? Or you cannot activate those muscles, then you're at ground zero, right? You cannot even think about function yet. So it's so the idea is that this could be very helpful for the lower level patients, right? And the question of, you know, so there's been a lot of information in the literature about whether hand function or hand muscles are controlled bilaterally or they are controlled only unilaterally. Right? And what I've seen in my data, you know, and now that initial data was a small cohort. Now we have more than 100 patients in our database and we see that in a large fraction of patients, there is information exchange across the hemispheres that improves movement and function on the affected side, right? So, so it's quite interesting um to see that against the backdrop of the literature that exists. Yeah, I sort of followed a question about that. So I don't think you've explicitly stated this, but you've sort of implied that one of the key ingredients to this like transfer of movement or function is the intent or the the attempt to activate the side. Um because otherwise, like people more non use wouldn't be an issue, right? If we constantly use our less impaired hand, correct, you would expect an automatic improvement in the more impaired side. So that's so it's implied that there's the necessary attempts or to activate the credit side as well. And if that's the case, then how in these tools that you're proposing to use? Do you ensure that it's not just going along for the ride? That it's? Yeah, that's a great point. So the idea of bimanual training or, you know, it is not just to be a passive driver, right? But so the idea is even the idea of active passive training, right? Active passive is when the unaffected hand drives the movement, right? But the affected hand is going along for the ride, right? The idea is to follow that with active movement. So in all of my paradigms, there's an element of just moving the affected arm alone after the bilateral, right, which so I think uh an important question. So at least in our hand function trials where patients did have the ability to move the affected hand somewhat, right? We and we were looking at, you know, dexterity. So we were looking at scaling of forces, you know, that was fine motor control. What we found, what the way we design the paradigm was, they do it with the unaffected and then with the affected in an alternating manner, right? For the very low level patients who are not able to activate appropriate. So, so let me just go back. So in these high level patients, what we find is that patients are able to use the affected hand, but the movements are not clean, right? They're using many different movements when they just need to use just one muscle and do it in a very fine way, right? And what we find is after alternate hand train, alternating hand training, now they're able to fine tune sensory motor control, right? Um In the lower level patients, it's about just muscle activation, right? So I do, I think there's, there's, that's why I think there's motor inputs and sensory inputs from the unaffected side that potentially drive these changes on the affected side. And, you know, there's still some work to be done. I think along with T MS to even, you know, to further flesh out the mechanisms. Um clearly walking is a bilateral activity, right? And you know, you would think that with that reciprocal activity, everything should be normalized, right? But clearly there's a way to deliver it too. So the homologous muscles, what we have found is that, you know, I was telling you that even when you're not moving you on one side, but you're moving on the other side, you see mirrored activity, even though it is subtle, you find that mirrored activity in the homologous muscle groups, that means the exact same muscle groups that were moving on the other side. So if you train in a way where you're doing one movement on one side, but doing the opposite movement on the other side, you may not see these transfer effects, right? So it has implications for how you structure your training paradigms to capitalize on this, these inputs from the other side. Yes. Um How are you deciding what dose to give people like is everybody getting the same dose or is it based on the MA S scale or? Yeah. So great question. This is about um dosing of high. So um for the study, we have a standard dose overall, right? So for example, 1200 units. But how much you give in each individual muscle is, would be graded based on the degree of muscle stiffness. So we just published a paper a couple of months ago where we proposed a matrix, a stiffness ecogenicity matrix where you're looking at ultrasound to see if there are changes of fibrosis. And you're looking at muscle stiffness, you're trying to assess the degree of muscle stiffness by palpation and then you're trying to make an informed judgment as to how much to inject in any given muscle, right? So we've proposed this stiffness, ecogenicity matrix. But through this study, we are actually going to test its value in informing the dose. So right now, uh I will say that, you know, it's uh I've used, it's a lot of subjectivity but over the last five years that I've been giving this, you know, my uh I've become sort of implicitly, there's a method, you know, now it's about making it more explicit and to use metrics to make it explicit. Does that make sense? Yeah. Other than the dosage, is there an issue of how you, how you actually inject the technique of that distributed throughout the muscle to actually look at certain part of the? Yeah. So this is a question about technique of injecting Hyaluron. So the technique is the actual injection is an injection. But in terms of choosing where to inject and which muscles to inject the technique is very different from that for Botox. So the key thing is you're looking for muscles that are stuck, right? And you can assess and they're usually throughout the limb, right? So for example, if you want to improve, so, so really part of the assessment includes assessment of range of motion. So you want to see which are the motions that are not possible. OK. Where is the movement restricted? And then you look at which are the muscles that are restricting the movement both in the front of the body, the agonist and the antagonist and the synergist, right? And you want to examine these muscle groups and examine the degree of stiffness and then choose where to inject. So I think down the road, we'll uh probably uh create a course where we can, you know, like I said, so much of this has been implicit, you learn by doing and then, you know, I think as we finish this clinical trial, we'll have information to actually teach someone how to do it, you know, in a, in a sort of more controlled way within that one muscle you choose or are you the substance through the, in terms of the distribution or are you just going to one part of the distributing itself? Yeah. So in the images that I showed you, you know, basically we injected at one spot in, you know, the biceps and the triceps, right? So to get these results, we really, we tend to inject the biceps more just because of, you know, the background from having injected Botox. So here, for instance, I probably uh I gave, if I remember correctly for this particular individual, I probably gave one injection of one ML in the biceps, right? And you see these results. Now, if patients are very stiff and you know, I might give more injection, I may give two injections, right? And they may be distributed. Second thing is the stiffness is often not in the belly, which we're used to injecting. It's often at the muscular tendinous junction. So that's another big difference, right? You don't wanna, yeah, you it's really you want to inject in the muscle, not in the tendon, but it's usually closer to the muscular tendinous junction. I had a question about the acid and what is the understanding of what causes the excess in the muscle? Um Kind of like what signals that excess is a lack of destruction? Is it over production? And are there uh without understanding, are there other things that can be done to prevent that? Yeah, great question. You know, why does Hyaluronic acid accumulate in the first place? So what we know about Hyaluronic acid is that it, it has very high turnover, right? So when we exercise, we are releasing Hyaluronic acid from the muscle uh into the bloodstream, right? So immediately after the exercise, if you did do a blood test, you would see high levels of Hyaluronic acid and when we are not moving. So, so basically the body is programmed, you know, in a normally moving individual, there's a certain amount of production going on to compensate for, you know, the destruction that's also happening, right? So, tool we are producing and destroying pretty much at the same rate depending on activity levels. Now, if you actually stop moving suddenly, like it happens after a stroke or after a fracture even, and you're immobilized, there's going to be more accumulation, right? Until there's a feedback loop that regulates it. So we don't know for instance, why some people with flad plegia, you know, they, they also get stiff, but it's a totally different kind of stiffness, right? Uh So there are so many nuances that we don't understand yet, right? But definitely there is a lot of turnover of this molecule, right? The second thing which is also very interesting and it's, you know, applies to beyond stroke is that there are a lot of people who come with a history of, oh, I had a trauma, I fell down, right? And clearly there was sudden movement, right? Sudden acceleration and deceleration, for example, after a concussion, let's say they had a whiplash injury and they get really stiff. Right. Again, the idea is that at that moment of acceleration, there was sudden production of hyaluronic acid because it's protecting the joints, right. So in order to prevent injury to the joint, the natural uh reaction is to utilize whatever you have. And so they are. So a lot of people report that they were fine immediately after the injury, but over time, they became really stiff. And sometimes years later they have this, you know, severe stiffness that never went away and you ask them and they go all the way back 10 years to that one accident or one traumatic event. So that's another thing which is, which is actually also relevant to musicians. You know, musicians, we call musicians with Dystonia, get really stiff and their muscles literally are stuck together. So they have to move certain movements automatically happen together, right? So the idea is that this may all be part of one large continuum that affects how we move one time. Sorry. Um So I'm sure um Dr Van will happily take some questions offline, but we are done on time. Um I just want to remind everyone from ac me perspective if you try to text the number to the phone number here and you got an error message that means that you have not signed up to receive CME through the CME office of Hopkins. The way you do that is through your jet, the education tab, you click on the CME link and you have to sign in with your jet ID and sign up to be able to do that from that point on these texts should work for you. So if you have not done that already. Please do so. The number will continue to work for the next eight hours. So if you have time, you can do that. Beyond that, the CME office does not accept um credit for the event. Sorry about that. They're very strict. Again, the number is 21449. If you haven't texted it. Thanks everybody for joining us. Thank you. I Yeah.