Our next speech here will be our Secretary-Treasurer of the NERF section, Dr. Mark Mahan, and he is Assistant Professor at University of Utah, talking about neural interfaces and rehabilitation applications for amputees. Once again, this is part of the rearrangements of our talk, and I'm filling in for a little bit for what you see on your schedule as being Dr. Mark Pruhl. I have no disclosures. The topic of AANS, of course, was the question of service to country, and so one of the important things that we wanted to discuss is what our role is as peripheral nerve surgeons into the service of the country. For most of the audience here, we know that war has promoted leaps in surgical treatment of peripheral nerve injuries. If you take, for example, the 19th century bayonet wars, those led to some of the novel innovative therapies we think of, like coaptation under tension, graft repairs, and some even the depression development of the nerve transfers occurred at that time period. But the bayonet wars are no more. What we see now from improvised explosive devices, we're seeing loss of soft tissue, right? So that means that amputations have become much more common, and what we can do with that is regard to replacement of the limb. And so we'll talk a little bit about the peripheral nerve interfaces and the techniques that are used to power or integrate sensation into electrical prostheses and in a little bit discuss the difference between peripheral nerve interfaces and those on the cortical side, because as being brain surgeons, we love to talk about both. Now we'll also talk about some of the limitation that peripheral nerve interfaces have. They have to live in the environment of the extremity, which is subject to unique forces and has caused failures in many of the earlier designs. But we can also use the innate capacity of peripheral nerves to regenerate, and that means that we have a bright future ahead of us with this problem. And what we need for a hand, obviously, is something useful. Right now, one of the most useful things harkens back to 1912 with the Hosmer hook. And it's a relatively inexpensive and very effective device in that it is very stable, it's lightweight, and it's very effective. This is one of our patients that can show just how effective this can be in durability sense that he is able to climb rock walls, do other things with this hook device, simply because it's powerful, it's stable, and it's intuitive for his use. Now on the other hand, you take that same individual, ask him to tie a tie, and you'll see the challenges that the Hosmer hook has for this, right? It's frustrating, it's lengthy. These are self-care type of activities that he has to use his mouth for as a third hand to try to complete this. And I will let you know that the video runs for 11 minutes. We're not going to see the end of him trying to tie a tie. So with that as a setup, what are the requirements for improving on something that is relatively effective? We have to have a hand that's effective, it's durable for long term, it has to be lightweight because plenty of people have received myoelectric prostheses, have them on, don't use them. You know, $120,000 arm goes away every time because it's just too heavy. It has to be dexterous, it has to have in the long term some sort of tactile response because you want to be the patient to embody the prosthetic. It becomes their hand, they understand it, it becomes intuitive, and ultimately cosmetic as well. Myoelectric hands, there are several on the market. They range from those that are provided by large manufacturers like Ottobock, and those are more innovative, you know, recently like the Deka hand. If we look at it, this is a video from Oskar Osman's group. Many of the audience will recognize Oskar Osman. He's an Austrian plastic surgeon and he had a patient with a brachial plexus injury. He decided he was not going to have a successful hand after the brachial plexus reconstruction, so he decided to do a transradial amputation and give him an electric hand back. And you can see that in this video, this young gentleman has been able to use that hand relatively effectively and with great dexterity. The thing is, if you knew the rest of it, is that he has eight independent EMG signals to control his hand, which is relatively uncommon in a lot of our brachial plexus injuries to have a forearm with eight independent muscles for control. And so for those myoelectric prostheses, obviously you need something that is already suited to having dexterous control. That kid nearly had a hand, right? He just didn't have maybe the perfect hand. As I said, they can be relatively heavy. Sensory feedback is limited. It takes a lot of visual interrogation, meaning that they're just going to see what's going on and try to react to it. And obviously durability. These are relatively precise, delicate machines. So how do we take the step forward from a myoelectric prosthesis? As I said, it has to be precise motor control that's intuitive, that's based on prior patterns of thought and technique for the individual. You have to have the ability to decode numerous movements, even for those that are above the elbow amputations. We like to provide tactile feedback and ultimately proprioceptive integration. So it's not something someone has to look at to use, but could act spontaneously and understand where their limb is in space. And so the question becomes, for us, where do you stimulate in the nervous system? So talk real briefly about cortical interfaces. Cortical interfaces are really threefold, right? Scalp electrodes, E-cog type arrays, as you see in the lower right corner, and then penetrating microelectrodes as hallmarked by the Utah array developed by Greg Norman at the University of Utah. And what the idea was simply to have closed-loop systems where you could read out of the primary motor strip, activate the robotic hand, and then stimulate back into the sensory motor strip, and then iteratively develop better and better and more refined algorithms for limb control. And we have seen that, obviously, in a high spinal cord injury. Many of you know this from 2014. It was featured in 60 Minutes, I think it was at Pittsburgh. Using two Utah arrays, this patient was able to develop relatively dexterous control of a hand just through thought, right? This is that fascinating exhibit of someone who's able to use multidimensional control of an arm from two simple lead arrays, and in a second, you'll see those head stages hooked up right there. Just simply that that's all the connectivity she has with that robotic arm and being able to do relatively complex tasks with a reasonable degree of training. Now, the challenge, of course, is that penetrating electrodes have all the challenges you would expect from penetrating electrodes. You get hematomas in the subcortical matter, which obviously limits, both in the acute phase and in the chronic phase, recordability and stimulation. You get the electrodes tend to dissolve over time. So the best we have is about two, two and a half years of recording from those tend to be degrading over time to local field potentials, not necessarily single neuron recordings that you had early on. And so more than likely, these will become less and less effective. And so when you think about all the problems in totality, access, not every brain surgeon is going to be able to do this. They're not going to have the techniques available. They're not going to have the staff that's going to be there. Cosmetic appearance, obviously. These require complex head stages that penetrate through the skin. The commercialization and cost are right now prohibitive, and there's probably not a great pathway to commercialization and the fear of obsolescence, for those of us who know about freehand. Same thing, as I said, it's a relatively complex system. As we talked about, the tissue interface, the heterogeneity of the brain itself, complexity of the programming, how do you create modular programs, invasiveness, how real does it feel to the person? The big questions of is this reliable for the patient, will it become a long-term solution, and is it even valid in the state? So probably a limited market potential that won't really apply. Switching gears, let's talk about peripheral nerve interfaces. We've been stimulating peripheral nerves for 50 years, at least. We have basic techniques, as you know, the cuff, which is a wonderful success for vagal nerve stimulation, and then interfacicular arrays, such as the LIFA array, that was Ken Horch at the University of Utah, as well as sieve electrodes, where the nerve is required to regenerate through an electrode panel. Cuff electrodes are fantastic. We know they have great chronic stability, but they also have a limited use. Selective activation, those large fibers that tend to be not fatigue-resistant, and there's indiscriminate sensory stimulation, but we do know they work well. This is the group out of Case Western, and they were able to show that for patients that were given cuff electrodes for femoral nerve stim for standing, that even at, you know, four years, the majority of them were able to sustain enough contraction of the muscle so that they work, and they work long-term for effective nerve stimulation. Going on again to the interfacicular electrodes, we're going from those 8-lead contacts to something like a 100-lead contact, as you see in this Utah slant array. You see different depth of electrode penetration, so you can reach throughout the nerve. Here's one being attached to the cat sciatic nerve, and this is what it looks like in its acute entry. You can actually record right at the tips of different large axons, and when you do that, you are able to get graded, progressive, fatigue-resistant stimulation. This is a cat sample, and you're also able to develop relatively good and discreet sensory perceptions, as well as even proprioceptive perception when using interfacicular arrays. This is stolen from our bioengineering group when they had a median and an ulnar, and you could see the degree of different percepts in a human. And they account for the majority of sensory patterns that we typically exhibit, right? We have different ranges of sensation. Vibration, pressure obviously predominate, but all the range of sensation was present. But they tend to fail, and they can fail very early. Just putting the implant in, a number of these have failed just from at the time of no successful recording after the implant is, and almost universally having late failures. The electrodes go perpendicular to a nerve that slides up and down, and they fracture. They get torn apart over time. Even the signal fidelity, only a fraction of them are meaningful. You have 100 electrodes. Only a fraction of those, anywhere from, you know, at most 30% are going to be meaningful. And the signal degrades over time, and the electrodes start to dissolve. People have talked about sieves more recently, instead of hard sieves. This is where the idea that the nerve grows through an electrode array, having softer sieves. But you'll notice when you look at the data, in the upper panels, in immunohistochemistry, and you see that in the far right corner, the number of nerve fibers relatively scant and well encased in scar. They do promote that over time, you see a reliable signal, but you can also see in the lower right panel that that varies quite different between different animals. So it's really hard to actually figure out. You have to base that on each individual animal. So the problems with all silicon electrodes, biomechanical compatibility in a dynamic environment, it's an aqueous environment that tends to dissolve both metals as well as silicon. There's an acute foreign body reaction and the ability to have long-term stimulation. But most importantly, all of these technologies currently require wires. Wires fracture. Every one of us who knows to use peripheral nerve stimulators with the old spinal cord stimulators, they fracture. So the idea of wireless came up. There's IMES. It's an implantable, essentially injectable, EMG signal. And you can see it's about 15 millimeters. And if you implant enough of them in the forearm in a transradial amputee, you can create enough signals to control the prosthetic. It's a great idea, a great solution. Even further, this came out of Japan, this idea of a neural dust. They have these microprobes where you have piezoelectric elements that use ultrasound to power them. They react to the ultrasound wave. They get enough energy to communicate back to the system. And they can record both EMG and nerve signal. And they've shown that in reference to an outside electrode array, that these micro-micro elements are able to do faithful record both muscle and nerve. But the challenge with all the wireless elements, power consumption, you have a tiny little item. How does it derive power? Is it going to fail over time? What kind of information? Radio frequency is actually relatively poor for transmitting a lot of information. And then tissue homogeneity, interference, et cetera. So then we come to regenerative interfaces. We know the nerves have the innate capacity to regenerate. Paul Soderner's group out of Michigan have created what they call regenerative peripheral nerve interfaces, wrapping an end of a nerve in a muscle and then recording it electrically. And you can see, although that little bit of muscle gets reinnervated by the nerve, it's also surrounded by other muscles. So it still requires wires. But they've been shown that they've been able to get monkeys to move under control. Something potentially more powerful is what Greg Dumanian at Northwestern has done with the idea of targeted muscle reinnervation. As you see, this is one of his patients that had lost both limbs from an electrocution injury. He took the nerves of the brachial plexus and then wired them into the pectoralis muscle and used the pectoralis muscles essentially as an inherent signal amplifier. So the radial nerve might be up, the ulnar nerve might be below. And then you can then, with a series of surface skin electrodes, be able to record implied activity in hand grasp, others, that does not require any sort of programming. And then surgeons in Canada took the same idea and then targeted sensory reinnervation, as you see here, dissecting out the stump of a median nerve that was, you can see the distal neuroma in the lower panel. Using that with SSCPs, looking at the recordings of the fascicles, coming back, identifying which are the sensory fascicles, and then co-opting them to skin in the residual limbs, such as the medial brachial cutaneous nerve. And so what you see with those, when you have both involved, this is a patient with both targeted muscle reinnervation and sensory reinnervation, is that she is able to feel the stimulus on the electrodes on the tips of the fingers of the prosthesis, as well as control it from targeted muscle reinnervation. And you can see some of the excitement in her face with being able to move the prosthetic without training, as well as feel the sensation from tactile manipulation. Longer-term outcomes, of course, from targeted sensory reinnervation still have to be worked out. It's a relatively new technique, and it tends to migrate over time. One last item, optical electrodes become all the rage in rodent models. You're taking a channeled rhodopsin, transfecting into neurons, and then making a neuron electrically excitable to pulses of light. You take an optrode and then stimulate, and you can get the neuron to fire. I don't know where this is really going to affect within humans, but they can, obviously, with different viral targets, you can selectively choose different neuronal pools. So in conclusion, what it looks like, some things that have been shaking out over, like, we're now looking at three decades of attempts of integrating prosthesis into neural integration. Motor control probably will be best achieved with residual muscle as a natural amplifier. Sensory interface is still yet to be worked out, but it either is going to be something with direct nerve electrodes or something like targeted sensory reinnervation. Because the appropriate stimulation enhances the embodiment of the prosthesis, avoiding that inappropriate stimulation allows for better control. And obviously, the participation of small fibers has been relatively challenging and will be important for future understanding. So in summary, soft tissue loss is what dominates this period of war-related injuries. Developing dexterous prosthetics is now. We have them. The challenge, of course, is making them meaningful, making them easy to use, and ultimately, figuring out what is the right peripheral nerve interfaces. And I'd like to say it exists in this room, right? Everyone here, all of these techniques are able to be accomplished by the surgeons in this room. There's nothing beyond our capacities for doing this. And with that, I thank you. Any questions? Yes, Dr. Kline? Could you opine on the situation where there's a flail arm and all five nerve roots are embossed on one side, how are you going to, people have suggested amputation and some sort of prosthesis, but how are you going to control that from the brain without cortical electrodes or is there some way you can hook into the opposite brachial plexus and people can learn to work that prosthesis through, I'm just asking because that remains a huge problem for us, the flail arm with root abulsion and where are you going to pick up and where are you going to lead to other than the spikes in the brain, which I think most of us feel is not going to ever go anywhere and there's nothing wrong with that, I mean we just worry the obsolescence of that, I don't have good answers, I wonder if you do. I certainly don't and I do think it's one of those orphan populations we're always going to struggle with. What? Orphan populations we're always going to struggle with, it's such a small group of individuals that we'll probably never come up with the best solution we could provide because it's so challenging. Yeah, because it seems like most of the things even from the Michigan group, which I admire greatly, I have some background there of course, but it's dependent on some nerve, you know somewhere that you're then putting on the pectoralis muscle or picking up from electrodes on the pectoralis or somewhere, you know, and the flail arms, they don't have that, I guess accessory or, well... Accessory nerve, also cervical plexus, there's a thought we have that we have to get the nerves of the plexus to work, but really, some people are able to certainly move their neck around and do funny things that we don't think about, a lot of that can be retrained to have an output that's something to learn. That'd be terrific. So that helps. People are limited to using a bunch of major standard outputs. Just a quick thought, you know, we always talk about trying to flip across pieces of steel, of course, and these people will play along, that's awful, but is anybody ever just basing it on the hip? Not like the arm has to be out here. You just base it, you see these other people where they don't have any hands at all and they're able to move it, why does it all have to be here? If you base it on your hip and you have it come off, it can still be very functional and you could use, you know, like wall muscles and all sorts of things. Oh, absolutely, that's another great idea. Right? Absolutely. I think it's a great idea. It's great, it's a great discussion and great session.

neural interfaces

rehabilitation applications

amputees

peripheral nerve interfaces

prosthetics

regenerative interfaces