Preeti Raghavan, M.D. presents at the Johns Hopkins Department of PM&R’s Grand Rounds on April 24, 2018.
So I'm gonna talk to you also on the use of upper limbs and barriers uh and potential solutions to fix some of these barriers. Um I need to disclose that I'm co-founder um and scientific consultant of a company called Mirrored Motion Works. Um And another company called Movies. Um and that I will be talking about the off label use of highly for muscle stiffness for which NYU has filed a patent. But I haven't received any funds from uh all of this uh uh commercial work. And um also no, none of the work I am going to present has been funded by a commercial entity. Um So, really my objectives are to discuss the barriers to stroke recovery and to define some strategies to overcome these barriers. Um So I'm sure all of you who treat stroke or do research uh will agree with me that, you know, the upper limb is a particular barrier to recovery of quality of life. Because if you have hemiparesis and you're using a cane or a walker, you know, both your limbs are used up. Uh essentially one limb is uh is not usable and the other is used up, you can't really do very much. Um And this was a problem that struck me during my training in residency, uh which I thought is really strange. You know, so much of our brain is devoted to arm and hand function and yet 86% of survivors have persistent dysfunction. Um So the question was, can we actually fix this? Can we get to a point where someone has very little movement and use of their arm and actually restore functional use? And if so how, um so this has been the focus of my uh work in research as well as clinical work. Um And I established the motor recovery research lab uh when I was at Mount Sinai, where we measure a movement, kinematics and muscle activity and fingertip forces like the, you know, like you do in the gate lab here. Uh But this is primarily for the upper extremity. Um So, you know, we know that the brain changes behavior and we know that there's a huge role for stroke neurobiology, you know, all the changes that occur immediately after the stroke um to lead to central reorganization that there's a role for spontaneous recovery. There's clearly a role for rehabilitation. But exactly what or how do changes in muscles, in sensory input, in the pattern of movement and in social and emotional aspects of behavior. How do they change the brain? Right. So that's uh sort of what I've really been trying to get at and um patients clearly care about getting back to normal behavior. So, really, what I'm telling you is that I'm working on behavior. Uh I'm not really going to present anything on exactly what's happening in the brain. If the behavior improves, we assume that all the changes in the brain are positive, right? But I can't tell you exactly what is changing. Uh And a lot of my research has been driven by the questions from clinical practice. And my goal is to help address some of the questions that we have as clinicians through the research. Um So what I've really found is that there are three main barriers that we face over and over again. One is that often, you know, at some point during the course of recovery, a patient may say, gosh, I'm too stiff to move. Um And you know, is it spasticity, what is this thing that they are talking about muscle stiffness? And you know, how do we treat them so that their function improves, you know, not just their spasticity or muscle stiffness. And second, many of our patients are too weak to move in the beginning. And then over time, the stiffness plus the weakness can uh give rise to particular challenges. And so what therapy can they engage in then to change their pattern of movement, they often seem to be pushed in certain patterns. Um And finally, even when patients can move, even when they have uh the ability to say grasp a bottle of water. They don't often use that hand to do functional activities, that dexterity is limited. So, uh you know, what, what is it that's really missing? After all, they've recovered enough to be able to do this task somewhat, right. So these are some of the questions I'm gonna address um in the next hour or so. Uh So this idea of stiffness and spasticity, you know, we have neurologists in the audience. It's been so hotly debated. You know, some people say, gosh, spasticity is not really an entity that, that affects motor control. And yet, for many of us, it's a huge, you know, it's a real entity and we are constantly looking for ways to treat it. I have patients um where I refer them to therapy and then the therapist says you're so spastic, I can't even work with. You. Go back to your psychiatrist right now, what we know is that stroke disrupts the control to the spinal neuronal networks that ultimately lead to muscle activity and function, right? So, the pathways that are often implicated in um abnormal control are um are the brain stem pathways, some of which are excitatory and some of which are inhibitory and these pathways ultimately control the stretch reflex, right. So the stretch reflex has been thought to be, you know, one of the main factors in the um in the presentation of a spastic patient. And so the idea is that as a result of reduced descending uh inhibitory input, you have an imbalance because uh essentially there's lack of suppression of the stretch reflex. Ok. Uh So when the muscle is stretched, there's afferent information that goes into the spinal cord, there's a monosynaptic uh uh connection here and then it activates both the alpha motor neuron that makes the entire muscle contract and the gamma motor neuron that uh controls the activity of the muscle spindle, which is your uh sensory organ inside the muscle. Now, all of our treatments are really designed to suppress this quote unquote muscle overactivity that seems to arise, right? So you can give botulinum toxin directly into the muscle and uh make it weaker. You could do a dorsal rhizotomy, cutting off these Affin fibers that take information to the spinal cord. You can increase the suppression in the spinal cord internal networks by giving intra baclofen or central nervous suppressants. You can give nerve blocks. And the end result is that all of these can give some symptomatic relief, but they also give rise to um weakness. Right now. In my lab, I was seeing the same kinds of patients and one of the most common problems we face is we have a patient who has a stiff wrist, right, their, their wrist, flexor are stiff or um spastic. And so the tendency is to think, ok, the flexes are overactive. We've got to reduce the activity in the flexes. But when we actually measured the flexor activity during wrist extension, in three groups of patients with stroke, those who were predominantly weak, those who you would call, you would call them, uh having a lot of plastic co contraction or minimal pres note that the wrist flexor activity was not really different, right? What was really different in these patients was that the patients who seemed to be more spastic where they were, you know, contracting their flexes and extensors at the same time, potentially during wrist extension, had more weakness, right? So this whole idea of, you know, so would I want to inject Botox in the muscles of in the wrist flexes here, maybe to make this a little bit more active, but, you know, perhaps not. And this has been a major clinical dilemma um that it's been found by other people as well that the stretch reflexes, first of all may not be overactive. Um And or at least hyperlexia is not associated with muscle stiffness. And initially after a stroke, uh a patient may be hyperactive, their reflexes may be overactive, but they may not be stiff at all. The stiffness actually progresses over time. Um And all of our current treatment options also invariably exacerbate the muscle weakness that they have. Now, other people have recognized that and they've proposed that, you know, there are three kinds of muscle stiffness, there's the reflex induced muscle stiffness that I've talked about that causes this overactivity. Um But then there's also something called active muscle stiffness or shortening where somehow the muscle gets stuck in a shortened position. Ok? We don't quite really understand that. And then we do understand fibrosis or contracture when you know, you passively, you cannot get the muscle back into its original position. So as psychiatrists and as clinicians, you'd appreciate that, you know, it's a balancing act, um we overtreat and we get issues, we undertreat and we still have lack of function, right? So how do we go about this? Um So one of the key things that happened in uh my clinical practice was, you know, I was doing randomized clinical trials on Botox trying to adjust the dosage. I wanted to see, you know, how can we give it? So we don't cause the weakness but still improve control. And um I could convince myself I could convince my patients. Um and once uh this mother of a child that I had injected came and told me, you know, I had clearly documented, you know, at six weeks, she was, the child was much better. And at 12 weeks, the mom said, you know, he's worse and I said, no, he's better, you know, and it became this little um uh game that we were playing and I decided that as part of standard of care, I've got to measure, you know, I've got to document and so now as standard practice, I actually videotape every patient during range of motion, it only takes five minutes. But I have this, you know, this um data that is actually very valuable to even find out and to be on the same page with the patient. So, um now there's a lot of literature on the effects of Botox on muscles. Ok. And um what's been shown is that after a single dose of Botox, we think it wears off in about three months. But the day data, uh the histological data and this is from a rabbit muscle suggested that that the changes actually persist further and the changes are not only in the injected muscle but on the same muscle on the other side as well. Ok. So this has been kind of interesting um that first of all, it persists. So even at six months, the uh muscle didn't look like the uh preinjection muscle. Um And then, you know, there are, if you give Botox every three months, um you have all these fatty changes, which you know, after repeated injections, you still have these changes. They're not more than they were at the uh after the first set of injections, but you have persistent changes. Now, what happens if a person has been getting Botox every three months for the last 5678, 10 years, right? Um Well, what's been shown is that clearly muscle strength is decreased compared to controls and remains decreased. Um And when you stimulate the muscle directly versus when you stimulate the nerve, you clearly see uh more weakness when you stimulate the nerve, which is understandable because Botox affects the discharge from the nerve ending. But what was really interesting is that there's no change in muscle mass, right? We seem to see the pseudo hypertrophy in some of our, in our, in our stroke patients. And we wonder, hey, that's an overactive muscle, right? But what is it really, the muscle is weak, it's replaced by noncontractile tissue. Um But where, what is this extra mass coming from? So really, we started to think about how does stroke alter muscle architecture? Ok. And um you know, the muscle fiber is surrounded by a collagenous network made up of Endomysium. So, Endomysium is uh this collagenous um layer that surrounds each muscle fiber, then the muscle facile, which is the bundle of my muscle fibers is surrounded by perimysium and then the entire muscle by ey. And so this is this this collagenous network along with everything that's between the muscle fibers, the extracellular matrix. Um you know, it it all forms together, it's the extracellular matrix, right? It's outside of the muscle fiber. And now what's been found is that this collagenous network made up of Endomysium and perimysium is really important for force transmission. So, forced transmission doesn't occur just from the uh the sliding of the active filaments inside each muscle fiber inside each Saara that force that is generated has to be transmitted uh across the muscle fibers to, to, to pull, to, to change the length of the muscle. And uh these collage, this collages network plays a really important role in force transmission. Um And what's been found it is is that in chronic plasticity, it is these collagenous networks that are really thickened. Ok. And so at this point, you know, a person is the muscle has fibrosis, right? So you're heading towards a contractor. But interestingly, right around these collagenous networks, there is uh a layer of some of of Ronan a molecule called Hyon which forms part of the extracellular matrix. Um And you can see in muscle, you know, it's right around here, we are staining the brownest hyaluronic acid binding protein. It's right around the end of my OK. And um this fairly old study shows that when the rat ankle was immobilized for a period of time, the Hyaluronic acid actually increased in concentration. OK. And they knew it was Hyaluronic acid because it was washed out with highly Roid. OK. So this was four weeks after immobilization. You see that there's a higher concentration of highly acid. Oh the synonymous. But what happened is that at 12 weeks, the Endomysium itself got thickened. OK. So before the Endomysium became thickened, at four weeks, you saw increased deposition of hyaluronic acid. So, you know there are so many molecules out there in the extracellular matrix. Why? Highly? OK. Um Well, highly first of all, is present in all tissues. We know it best from the joint fluid, right? We know that it contributes to viscosity. And when you lose highly, it predisposes one to arthritis, right. So, in muscle tissue, it's really important for sliding and I'll tell you how. But the idea is that uh it's present in muscle tissue and it's a very large molecule and when it accumulates, it actually changes the viscosity of the muscle tissue. Ok. So it's typically, it's also hydrophilic, it absorbs water. Ok. But when its concentration increases a lot, then the viscosity of the tissue increases so much that both lubrication and tissue sliding decrease. Ok. So, uh this biophysical property of hyaluronic acid seem really interesting. Um And so we know that when the viscosity increases the, um there's the the sheer wave velocity decreases. That means, you know, normally you can when the muscle fibers slide against one another and there's a thin layer of high ionic acid around the Endomysium, you know, your shear wave velocity could be pretty high. But then just imagine that this layer becomes thickened, you know, then your shear wave velocity decreases considerably. So we thought that maybe lack of mobility, um a weakness um after a stroke could lead to accumulation of this highly which we know can happen and can increase the viscosity of this extracellular matrix eventually leading to muscle stiffness and reduced movement. Right. And what's even more interesting is that um in other tissues, like in the lung and the liver and the kidney, they've actually measured hyaluronic acid uh before fibrosis occurs. And they found that when the concentration increases a lot, it's a signal of impending fibrotic changes. Ok. Um So the idea was that when you have hyaluronic acid accumulation, then it's potentially reversible muscle stiffness. But if you don't do anything about it, then the muscle could become fibrotic and at that point, it's irreversible. Um And so the idea was that there could be many factors that could potentially lead to muscle stiffness. Um for example, immobilization, but perhaps there's a role for inflammation, you know, it's not clear. Um And that could either lead to red reduction in the degradation of H A or increased production. And um you know, and then this cascade cascade. Now it so happens that there is an enzyme called Haida that's been on the market for more than 10 years. Um It's been found to be fairly safe, it's FDA approved. Um And um uh it was available. So we got permission to use this in some of our patients who did no longer responded to Botox. We had no way to really treat them and they were uh they were suffering and the idea was could injection of high Leonida to reduce extracellular matrix viscosity potentially disrupt this vicious cycle of stiffness. Um lack of function pain eventually leading to fibrosis and contracture. Uh So we gave it in uh a number of muscles along the kinetic chain. And we measured range of motion like I always did in the clinic and we looked at proximal joints. Um We looked at passive range of motion and active range of motion. Um And you looked at it across four time points before the injection within two weeks. Post injection, most people seemed to respond within about three days and um all the patients came back within about two weeks. We also looked at them within 6 to 8 weeks and then 3 to 5 months. And, you know, noticed that past the range of motion increased, which was great to see. But what was really exciting is that active range of motion started to increase, particularly in some people where we would not expect, you know, they were in the chronic stage, post stroke, we may not expect them to change dramatically at all. And we saw that even in the distal joints, right? And if you looked at the modified AWI scale, we saw 100% reduction in muscle stiffness. Uh for those who had pretty uh severe increase in stiffness, they were not contracted. But, you know, about 50 al, almost 40 to 50% of the joints had a modified ash of three and that came down to almost zero, right? So this was really interesting. Um, and we published these in 2016. Um And I just want to show you an example here. So this is a young woman I had been treating with Botox for a few years prior. Um and she, she could extend her wrist but she could not flex. OK. Um And this was one week post injection for the first time. She has some reflection and then this is her two month post injection where, you know, she had pretty good control of the wrist, but also of all the other proximal joints, you know, this was the one that changed quite a bit. Now, she actually has full hand function. Um So up until this point, it was still a hypothesis, we couldn't really measure it and it's very difficult to do um pathologic studies, you know, where you get tissue biopsies. So we were fortunate to uh collaborate with someone who uses something called a T one row MRI of the muscle. Um And you can see that it's, it's measuring glycosaminoglycan content. The largest component of the glyco amino glycan content is uh from Hyaluronic acid. And so there's quite a bit of Hyaluronic acid in a normal muscle, but in the stroke affected arm. And here we're looking at the upper arm notice that there's quite a bit of excessive hyaluronic acid, all this red and look at the shape of the muscle. It's triangular, you know, as if the fibers are all stuck together. And then one week after injection, notice the change in shape of the muscle, right. So this is, um, still indirect evidence. But the first evidence that, you know, maybe the right track are the pros and cons are, it's a fairly simple injection uh directly into the muscle, but it's very different from injecting Botox because you don't necessarily inject it into the belly. Um And, um, and, you know, the selection of these points is a little tricky something we've been figuring out. Ok. Um, so at least it doesn't cause any weakness, right? So we can in, and what we've seen is this consistent increase in muscle um in active range of motion. And now we're beginning to tease apart, we just have a um uh r 21 grant that's been funded where we can look at how it changes the reflexes, right? Is this, does it have anything to do with the stretch reflexes or is this completely independent and uh a peripheral thing? Because it, it could be that it changes the afferent input into the reflexes, right? Or it could be that it is a completely peripheral phenomenon independent of the central changes that are happening. And yet, you know, the changes in active range of motion and the type of recovery that we're seeing suggests that, you know, it could excessive accumulation of hyaluronic acid could be some sort of an inhibitor of plasticity. You can't move, you can't change the brain. Now you can move, you can begin to effect changes. Uh you know, perhaps in, in the nervous system too. And we don't, you know, that we haven't begun to really measure that yet. So, um, so I'm gonna move on to another topic now, right? Uh, and that is, you know, so maybe we can take away stiffness. But what if they're still weak? Right. And I always tell my patients, you know, we're, we're actually removing the resistance to movement. The high the injections are not restoring strength, right? Because uh patients, if they were, if they had some movement before, and actually, it's the patients who did really well initially and then became stiff, that really show a great response to these injections because now they get their old movement back, which somehow they last, right? But if they have no movement at all, if they cannot activate the muscle at all, then you still need to activate the muscle. Um So what, what can you engage in if uh someone has a really limited repertoire of movements? So, you know, we've been um one of our, the constructs that we base our rehabilitation on is that the two sides of the brain compete with each other, right? That you need to suppress the activity on the contralateral side because if you or, or you have to take the unaffected arm out of the equation when you do therapy, because they've got to practice with the affected arm. And that's the constraint induced therapy model, right? And um you know, it's been shown though that after a stroke, the activity on the unaffected side of the brain increases, right? Is that good or is that bad? Uh People think that it's bad because if you have persistent increase in activity on the unaffected side of the brain, that tends to correlate with uh very severe patients who may not recover movement on the affected side in the affected arm. But what's been shown is that if you need to have increased activity on the e unaffected side of the brain to even down the road, restore con restore activity in the affected side of the brain. Ok. So the point is that perhaps the increased activity in the unaffected side of the brain is part of the repair mechanism to ultimately uh change the connectivity of the brain to restore function to restore activity on the effect in the affected arm. And uh some of these ideas came from some of our work, you know, it's been taught that movement of the fingers particularly is entirely controlled by the opposite side of the brain. OK. The IPs leal side has no role to play in the fine distill movements. But here this is data from a patient where um this patient was able to move the fingers a little bit. Um And on this side of the screen, I show he's, he's asked to move the thumb, just the thumb alone back and forth and then the index finger and the middle finger and the ring finger. And you can see that, you know, the movements wane off fairly rapidly. Now, it's the same patient performing the same movement with the same hand. The only difference is they are moving both sides simultaneously. OK. But we are measuring from the affected side and notice that the characteristics of the movements are quite different, right? So is the other side helping what, what's really going on here? Um And so we came up with this whole idea, you know, there's been a lot of literature, part of the back track work has been done over here. Um And you know, the review um of bimanual versus uni manual suggests that, you know, there's really not much difference if you force somebody to use uh the affected side, uh they may use it more, but the quality of movement may not necessarily get better. And of course, the vast majority of patients with stroke don't have enough movement to enable them to just use the affected arm alone, right? So you might do bimanual. Um But here, the idea was, well, can we do bimanual? And then can we assess its effect on uni manual movements? Can there be some transfer of learning or control that changes the nature of the uni manual movement that follows this bimanual movement? Right? And potentially there, you know, there's the uncrossed pathway, the ipsilateral pathway or there there's crossing over um through the corpus callosum, you know, they're potentially pathways which I'm not measuring. So, I don't know. Uh that's a question for dr sick and esteem. Um But the idea is that um perhaps if we can change the behavior, then maybe we can start to investigate the neural mechanisms. So what we did was we developed a set of devices where you can with one arm, you can move the other. So basically, the two arms are linked in such a way that you could, uh let's say the good arm does wrist extension. The affected arm also does wrist extension at the same time. Ok. So in this way, there are no compensatory movements, right? Your training exactly the movement that you want. Um And also we wanted to train out of synergy movements, right? The idea was that if patients are internally rotated and flex at the elbow and the wrist and the fingers, you want to train the opposite. And um so uh uh and the idea is here, the patient is able to engage in the movement by themselves. Ok. Um And so we did a little study using all these devices. Um And uh there was a change in the Fugel Mayer score and these were patients with chronic stroke. Uh they said that, you know, they had better sensation um in the affected arm. What was really interesting is they said their fingers were not as tight anymore and um that they had a sense of control because they were now in charge of their movements, right, while they were on this device. But the problem was that it wasn't really very fun, it wasn't engaging. So since then, uh we've come a long way, we have a, you know, much better looking device. We started off with the arm training because what we found was the vast majority of patients, you know, it's been shown also in the literature that a lot of the problems begin at the shoulder, right? Even though uh patients have problems throughout the arm, um they get tight in the pectoralis. OK. And they cannot externally rotate. And as you know, as many therapists know if your arm, if your shoulder is internally rotated, there's not much you can do functionally, right? Because your forearm is in the wrong position, your hand is the wrong position, your work space is limited. So the first idea was if we can get the the arm to be oriented in a functional position, then perhaps there's a chance, right. So the idea was we picked external rotation as the first movement. But we um in this device, we can also measure how external rotation changes, forearm rotation and grasp and release. OK. So there are sensors embedded in this device and then it's interfaced with the video game that is um you know, uh straightforward rowing game, which I'll just show you and you can, the patient gets feedback on how far they can move and you can also move just one arm or both arms and begin to look at while they're moving, while they're training, you can collect all of the data on movement in the background. And um so this is kind of what it looks like. Um So they're rowing a boat here and we also have some other stimuli that can be used to examine the extent to which the affected arm learns more or less from using both arms together, right? Uh So for example, uh OK, so I'm gonna get to that. But in our initial pilot study where patients use the device for only 12 sessions over a period of six weeks, what we were surprised to find that an extremely low level patients with fugel Myer scores of between four and 20 right? They were, they, they still showed some degree of improvement in the fugel Mayer score particularly in the change in the flexor synergy component, which means that now they can isolate the elbow from the shoulder, making it easier to stretch their arm out to put on a coat, for instance. But more interesting in these really low level chronic patients were the changes in active range of motion, both in the trained joint as well as the untrained joint movements that we saw, right? Uh So this was quite interesting to see in only 12 sessions. And now with the new device, what we can do is we can measure um joint range of motion as it's happening, we can look at the change in trajectory, look at, we can look at the slope of the range of motion and we can do it with different kinds of feedback, visual and auditory, right. So we can uh or a combination or none. And so we can begin to understand how other systems we know that motor control is just not motor control, it's sensory, motor control, right? And we change the way we move based on what we hear and what we see. So here we can sort of probe exactly how patients learn and particularly how learning can improve with input from the unaffected side. And so this is some of our more recent data where the same patients. So again, this was their fugel my score uh relatively low here. And we we we had um uh a phase where they just participated in conventional therapy and we looked at the change in the f my score and then we looked at the change with uh the bimanual arm trainer. So you can see that overall there was quite a significant difference. These are the same patients who went through a control phase and then a training phase. And then these are the changes in range of motion in these uh in, in the same patients across these two phases in the trained movements as well as the untrained movements. So, so what was most interesting? And I forgot to put that slide in was that frequency of training really has an important role to play, right? So if you gave just 12 sessions over six weeks, the improvement was far less than if you gave the same 12 sessions over four weeks, right? Which uh which again is very interesting and we are beginning to try to probe that a little bit more, you know, when is more better and what, what exactly changes, right. So the this is some new data that we're collecting. Um So the exciting thing is um am I doing OK for time? OK. So the exciting thing is if we can reduce stiffness and if we can restore some degree of active range of motion, now we have a little bit of hope, you know, once we restore mo movement perhaps, then now we can ask the question, well, how can you improve control? OK. Um And actually this is how I started my research career uh with John um back there. Who you know? Well, so we started really looking at um you know, what are the components of hand function? Because hand function is complex. It requires an inherent flexibility or adaptability, right? So if I'm uh grasping this bottle of water, I have to make sure I don't squeeze it too tight, right? I have to squeeze it just enough. Uh And it's quite different if I'm lifting apla uh a steel bottle, for instance, a metal bottle, right? Then perhaps I'm more worried also about not dropping it, right. So the forces have to be just, right, not too much and not too little. So how do we know when to use the, just the right amount of force? And how do we know exactly what type of hand posture to use? Um uh how to modulate our forces according to different textures that we manipulate and to move our fingers individually. Right? So these are some of the questions I uh started out asking and one way to really examine this was using this little test device that was equipped with four sensors. So there are little sensors that you grasp and you can change the weight of the object. And you can also change the texture at the fingertip interface. And what happens is that when a person touches this object, their grip force starts to increase. And after a sharp delay, they then start to increase their load forces, which means they are beginning to initiate activity in the muscles that are eventually going to help them lift the object, right. So this delay actually represents the time taken to coordinate the grasping action with the lifting action. And then all of this is happening even before you actually lift the object off the table. OK. All of this coordination and this device, uh these four sensors allow us to really uh get a window into that. And then we can look at the rate of change of the grip force, how fast it changes and how fast the load force changes. So, what's been found is that in, in completely healthy individuals, it takes us only one lift to really get a good sense of the weight of the object. And you might have experienced this if you open your refrigerator door and, you know, reach to grasp that carton of milk. Right. Once in a while, you might, you know, get a little bit of a jolt when you realize, oh wow, there's no milk left, right? Because the, because you anticipate there is milk, you reach with a certain uh you anticipate that you're gonna use a certain amount of force. And then you realize, oh no, you know, there's no milk left. So it's the same thing. But the second time you go to grasp that cotton, you're going to use just the right amount of force because you've learned, right. The same thing happens in healthy people. After the first trial, you see that the rate of change, the rate of change, the rage is much more sensitive. It's basically the slope of the forces. The rate of change of forces tells you even before the object is lifted, whether a person is anticipating uh to use less forces or more forces. OK? And um what is even more interesting is, let's say you've practiced with one hand, you've lifted that carton of milk with one hand and now you open the next refrigerator door and you decide to use your other hand, right? You actually everything that you've learned with one hand you can use with the other hand on the very first time, you don't even need that practice lift. Ok. So essentially the other hand, access ha the other hand has access to all the learning that one hand seems to have experienced. And that's what this graph shows you. Ok. So the unpracticed hand and um now this is not just true for a light or heavy weight, it's very finely graded for a range of weights. And so this metric is uh very linearly related to uh the weight of the object. And similarly the rate of change of grip force uh changes according to the friction or the texture of the group surface. Um So overall, if you look at uh a patient, a a healthy patient, you see this behavior in a patient with stroke, even if they grasp and lift the object several times, you may not see this behavior, right. So we started to probe, you know why and can the other hand help you? Right. So actually this is where we first got the clue that, you know, first of all, we saw that the patients, despite uh a modest number of trials, in this case, it was only five trials, we found that they really could not uh change their fingertip forces according to the weight of the object. But if they lifted the object five times with the unaffected hand. And then with the affected hand on that very first trial, with the affected hand, they could change the way they manipulated this object, which was quite interesting, right? Because it means there's some information that they don't get when they repeatedly practice with that affected hand. But that information, if you provide that information as a result of practice with the unaffected hand, you can change performance. Um And so we started to probe a little deeper and uh we asked, you know, how does it change muscle control? Because that's what we, that's what we want to change, right? The forces are the behavior and it's the muscle activity that's leading to this behavior. So we wanted to understand that and what we saw was that in a healthy subject, the difference between lifting a light object and a heavy object was really seen in the lifting muscle. So in this case, we had asked them to lift the weight by flexing the shoulder, right. So the anterior deltoid showed higher activity for the heavier weight compared to the lighter weight. And that was very well correlated with the change in the load force rate. But in patients with stroke, even though they were also lifting the light and the heavy activity, the signal from the anterior deltoid was missing. Instead, there was a much higher signal in other muscles, right, suggesting that, hey, wait a minute, they're supposed to lift, they're lifting the object with elbow, uh with shoulder reflection. But you're not seeing the same relationship between, uh in the, the signal in the muscle is not from the lifting muscle. Ok. All these other muscles seem to want to help, right. Uh So can we even restore the pattern um to the control pattern? And so what we found was that if a patient used the unaffected hand to practice and then the affected hand, then at least for, you know, one trial. And that's, that's the, that's the caveat, right? We could see this relatively normal pattern, right? Suggesting that it's possible. But now, you know, what kind of training strategy do we use to actually make this more permanent? Um So, uh so I'm, I'm gonna skip a few things, but really what we did this was a um a study where we measured the uh fingertip force prediction and grasp execution and grasp execution. As I had mentioned a few slides earlier is a time taken from touching the object to actually exerting forces in the vertical direction, right? So it's the coordination between the gripping muscle and the lifting muscle. And that coordination occurs so quickly, it's only 100 milliseconds in a normal person. And even in the unaffected hand, it's really short. But look in a patient with stroke, it can take up to two seconds, right? So that can really lay the time taken to manipulate objects. And that's what's been shown this preload phase duration that we can measure is correlated with the time taken to do your um Jeb and tailor or the wolf motor or any functional task. Right. So if you can reduce that, you can potentially uh something is changing in terms of the control. So in this study, we just had um a a therapist worked with us to train patients to use the unaffected side before they use the affected side. So it was alternate hand, right? Um Every before you use the unaffected, the affected hand first grasp the object with the unaffected. And after four weeks of training, you know, one hour of training each day, um we saw that there was this change in their ability to anticipate the light and heavy weights. There was a change in the time taken uh for coordination of the preload phase duration. And uh we also saw a number of changes in their sensitivity, right? The pressure sensitivity threshold, the stereoagnosis, static two point discrimination, pinch strength increase, lots of things changed suggesting that maybe this is a viable training strategy. But and I'm gonna skip over a little bit but not all patients are the same, right? And here, what we're showing is that um we also, we did a study where we looked at the corticospinal tracts on the affected side and on the unaffected side. And what we found was that this change in the preload phase duration, which is functionally very relevant was related to was correlated with the uh the axonal density in the contralateral corticospinal tract in the intact corticospinal tract. Right? Suggesting that, you know, if your other the corticospinal tract of your intact side is also affected. So if you have much more extensive stroke, uh then potentially this would not be a good strategy, training strategy for these patients. So what we've been able to do now is you know, how is a therapist to know which strategy to use? Are they learning or are they not learning? Right. It's difficult. It's a black box unless you can measure it. So what we've done now is we've uh created the um uh tool. So we've created a group instrument that can be used in a therapeutic setting and it is interfaced with um uh with a display which can actually tell you uh whether the fingertip forces are abnormal with the affected hand and the extent to which they become more normal with alternate hand training, right. So for example, in this cohort of patients, it was abnormal with the affected hand, but it became more normal with the affected hand after the unaffected hand. Now, in some patients, it remained abnormal, right? And so in these patients, you know, it was abnormal, but it remained abnormal. Perhaps no strategy will work, perhaps they just don't have the neural substrate, right? And then there could be other patients who get worse if they use the other hand, in which case, the constraint induced uh way might be the way to go for them, right? So, in other words, there isn't a one size fits all strategy. But if only we could know, then we could select the right strategy for the right patient. Um And so, so this is where we are uh to summarize, you know, this whole idea of stiffness is a real problem for clinicians. Uh But it seems that it, it's a separate entity from the city and that, you know, changes in the chemical composition of the muscle could play a role in this and we can actually begin to change that now. Um And, you know, we could perhaps increase muscle activation by borrowing strength from the unaffected side. We kind of know that and yet we also don't know it because we don't know exactly how to actually make it happen in reality, right? Because if a patient in a patient with stroke, we already know that they are over using the, the uh unaffected side, they depend on the unaffected side. But how do you transfer that activity to the affected side? Is the key question. And then finally, it seems that sensory feedback and substitution of some information from the unaffected side can lead to changes in control in the affected side to improve dexterity. So, um so I'm gonna leave you with these thoughts and I'd like to acknowledge all the people who've helped us uh do all of this work um including my collaborators and the funding sources. So, thank you very much. Yes. Yes. And my exemption. It was only, yeah, sorry, I'm gonna repeat the question. So the video I showed uh I showed the video at uh one week after the injections and then two months, she only got one set of injections and that was between the baseline that I showed you and the one week. So it was the it was only one set of injections and then she was doing what she was normally doing. Um So in her case, we injected a whole range of muscles. Um So definitely it involved the wrist flexor as well as the extensor. So that's the key thing because you know, we're not, we we're, we're injecting agonists, antagonists and synergist. Yes, station how many patients involved um in for the injected or in general in my studies. So, in my studies, we make sure that um all patients can comprehend. So none of them have severe aphasia, right? Um Some of them have expressive aphasia, right? But all of them comprehend. Um I can't really tell you the. So in some of the early studies, they were mostly right handed uh right hemi periodic patients with left brain damage. So uh at some point, they perhaps had language dysfunction. Um but all of the latest studies I'm showing you have both left and right hemi heretics. So some of them clearly have language impairment. Thank you. Yeah, I, I haven't measured. It is an intriguing part but I actually don't know. How long does the hour on a, yeah. So in the initial studies, you know, we were, they lasted, it lasted for at least 3 to 5 months. Right. That was the window that we waited. Um, what I find now is that I've injected more than 100 patients. Um, that, that the injections are cumulative right now, I do tell. And this is part of my standard of care. I give everybody range of motion exercises to do. Right. I pretty much I give them a hand out, right. These are the exercises you can do by yourself. Here's a stick. You know, this is how I want you to move your shoulder, your forearm, your wrist, uh, stretch your fingers this way. So, um, the, it doesn't wear off the way Botox wears off if I give an injection once and I give it again at three months. It's the results that I see are additive, right? Um, if I give it at a shorter interval, uh, also it's edited. Yeah. So your control group for the therapy, um, or what is happening with the time that the, of the opportunity? Which therapy? Oh, the one with the bimanual. Yeah. So it was time matched. So during the, so conventional therapy was basically, so people were at different. We did not actually provide conventional therapy, we, the con, the control period was whatever they were doing. Right. So, some of them, uh, and so we, they, they filled out logs so they were going for therapy, they continued to go for therapy. If they were doing a home exercise program, they continue to do that. Right. So, I can't tell you exactly what I know what each person was doing. Uh, but it was highly variable. So, so it's only kind of a single intervention, the bilateral, no versus whatever. Exactly. Yeah. Standard versus life is more like it. Yeah, that, that will be important. Correct. Absolutely. Yes, we, we want to know that. Yeah. But you know, it's very hard to control. As, you know, in rehab studies, there's a control, the control intervention also has an effect but the control intervention may not be practical, right? So uh it's actually tricky to design. So we've got to work out things like, do you know what? Actually you wanna know exactly what you drink, what you drink? Exactly. Yes, you are trying to address and you control that. Correct. And that's actually what we're trying to do. Understand the ingredients, including the dosage of the ingredient, right? Because if you don't know the dosage, then yeah. Yes. Great tool. I love that everyone who does chronic patients and throws the kitchen and study or study the ones coming down the pipe that raffle to get to four times and lo and behold said if you absolutely. It's ironic, isn't it? You want this check kind of the scale? And as I said, she, but Delta, we have no idea. Exactly. Nice to see some, believe it or not. I'm saying this in functional scale. Right. Yes, I didn't. I have it though. This is back as small change probably a little bit and to involve all these tragical moments. I mean, all that inter iser stuff and, you know, the very art thing was all rubbish. Yes. Um Basically far too much neural explanation for what's probably still jitter around the system that peripheral and central. If you're going to start invoking these very impressive neural mechanisms, let's get some big effect sizes, two or three points on the view liner and anyone doesn't need at two, they change their y axis. So it's not a zero, right? I think it's just we should just admit that the small females should be interpreted with other measures and stop over interpreting them morally. You're absolutely right. Um And you know, and the, and the thing is, I think that and, and as you said, you know, you can instantly change the fugel score by putting them in an, you know, in a different by supporting the weight of the arm, right. So uh the what do the so clearly, you know what we do know? So the Fugel Mayer score, the Fugel scale came from Twitch's observation that stroke patients tend to move in characteristic patterns and that led to the brainstorm stages of recovery. What we see that over and over again, patients move in stereotypical patterns, right? But when you want to make a change in that pattern, what should you look at? Right? Should you look at the change in this typical pattern? But then you don't know exactly what is leading to that change. I will admit we have no idea. And it's true. I'm not measuring anything in the brain. I am, you know, just speculating about what could be happening. I'm really, you know, so it's possible that all the changes are entirely peripheral, right? I mean, the periphery is very important. Um So I cannot comment on, on on the central changes. Only one can only assume that central changes are happening if peripheral changes are going in the right direction. And I think that's what we care about that the peripheral cha whatever changes there are they go in the right direction. And then you know, so I'll tell you why I'm excited about this whole bimanual is first of all, you know, movement is key, right? We know that experience is really important, right? You if you what happens to vision, if you blindfold during a critical period, you lose vision, right? If you stop moving and and this is your work, John, if you don't move during that critical window in the acute phase, then maybe you'll never move, right? Because you are not uh you're not providing the experience to stimulate the changes in the brain. But so that's the problem that we face. There is no way to get the patient to move in the right way. And the whole idea of the technology is only to help facilitate that, right? And then we can begin to measure changes in the brain and we need to do that, we need to measure it. Uh And I think that's where I'd love to collaborate with uh doctor Sicks lab and, you know, figure out what's really happening, what's changing, how are the, how is the connectivity changing? Um We do need to get at that. Yeah. No. Yeah. Well, because, because that was done, uh that was done in the clinic. It was not a research study to begin with. Yeah, I would have and I definitely will, I expect to get it right. It has nothing to do with the brain. Exactly. We don't really know what's happening in the brain, I will admit. Right. And I, and I said that in the beginning as a disclaimer, but thank you for bringing the point home. Yes, Stacey. I'm sorry. Ok, thank you all. Yeah.