Everything about neuroimplants and brain chips

Hello everyone! Welcome to the BrainCAN channel. This episode will be about neurotechnologies and brain implants and I'm happy to introduce you the expert in all these spheres, Professor Dr. Uli Hoffman. Professor Hoffman, Uli, I'm so happy that you could find time for my project and I know that you have started your career in biophysics. So, please, could you tell us a bit how you come from physics to neuroscience and why you have done so? Well, actually, I didn't start my career in physics or in biophysics. I started my career at school. I'm of that age where I saw the original Star Wars episodes at the time when they were still denumerated by 1, 2, and 3. That's how old I am and that's actually 1984. Number two was 1984 roughly and I was impressed at this time, deeply impressed, about the scene where Luke Skywalker, the hero, who, for those of you who don't know Star Wars, it's a pity for you, but for me, Luke Skywalker, who lost his hand in a battle with his dad and he needed a replacement hand, right? Because, of course, he needed to play another episode at And this replacement hand was so cool for me to see. There was a medical robot and this medical robot was kind of playing around with the tendons inside the hand and the fingers were twitching and then he was poking into the hand and the fingers were twitching and that was so cool and I thought, that might be useful for somebody who lost his hand and how to do that. And that was at school and I decided I want to be a part of that thing and so either I'm going to study medicine or I do something really cool, which is I decided to start studying physics, applied physics, after that, after my school time. But in order to get a little experience in medical stuff and medical terminology, I went to the army and actually I became a paramedic. So, my medical expertise starts before I did study anything and then with physics, I tried to come with physics as close as possible to this goal, to this grand idea of having a mind-controlled, intuitive robotic device and that's actually when I started physics. I got my PhD in a more or less related field and then I went to Caltech for two years and I came a lot closer when it came to implants and silicon probes at that time and I brought that knowledge from Caltech back home to Germany, to Europe, got the first European grant on silicon implants, kind of the rigid implant-side recording systems and from then on, everything else developed. Next one was steel electrodes, multi-side steel electrodes, next one was multi-side polyimide electrodes, flexible ones, soft ones and that's where all that kind of came to happen. That was a very quick run through, so feel free to ask whatever you want. Am I correct that this field is quite old already? So, I mean brain implants, you say that this story with silicon materials has started about 30 years ago? A little older actually. The first idea about a silicon multi-electrode implant was published in 1972 by Ken Weiss. So, that's a paper where he kind of was projecting the methods developed very recently in the semiconductor industry and he transferred those ideas then to this implant technology, literally. So, 1972 I think was the original publication of that paper and from then things took on very slowly actually. In 1972, this first paper and in the 80s, the people of the so-called Michigan group, they used the lithography methods and had those finger type, we call them like prong, like a time-type electrode which you plug into and which has the electrodes on the side of its single fingers here. They developed this on a flat lithographic basis whereas the people in Utah, Dick Norman and his group, they used the silicon devices and then silicon and a die saw, literally a saw, in order to cut from a solid piece of silicon several electrodes and we call it bed of nails implants which is then just the structure bed of nails. You plug that into the brain and you get then recordings from the very tip of those nails. So, these two opposing methods were developed roughly in the 80s and then the 90s is picked up a little more because people found it useful to get recordings from neurons, from many neurons. Well, then one neuron was sufficient to have a career. By then, it turns out that you want to have more recordings, more and more by roughly 1999 or so, Miguel Nicolales and see, my memory is failing me but anyway, Miguel Nicolales came up with an idea that let's put silicon arrays into rats and see what we can make out of all those recordings and they learned to use, it's called the so-called neuronal population code. So, the more neurons you can record from, the easier it is to deduce something from it. If you only use one neuron, you have to record a long time but you cannot use that to run anything in real time but if you record from, Miguel showed that when you record from at least 30 neurons at the same time, you can run a simple switch, a simple system which can be driven by the thoughts, by the neuron activity. So, that's roughly the time and unfortunately, in 1999, 2000, so the silicon arrays were kind of relatively popular and they were put by 2004, the first time into humans. I mean, you can imagine it's kind of a tough one because silicon is fragile, right? So, put that in a human is a trade-off what might happen. So, there were people who were willing to risk that which were terminally ill or which did not have any other chance anyways. So, by roughly 2003, 2004, you had the first monkey and you had the first humans implanted with the silicon bed of nails arrays and since then, they were using this type of array. It's called the Blackrock array nowadays. It used to be the Utah array and this Blackrock array now is in a relatively long period of time used for, unfortunately, not so many patients but a lot stronger in neuroscience and non-human primates monkey research. So, it's kind of an upstream process but it's very slow. Altogether, there was something right now, I think the state of, I'm not sure about the current state but something in the range of 30 patients have been implanted with a silicon bed of nail array ever. I have a question. If we talk about humans, how many electrodes do we need to have these sufficient, more or less accurate recordings? That is a difficult question because you have to look, you have to see that over time. So, you can get nice recordings, you can get nice output for controlling something, at least in animals, already with 100 electrodes and 100 neurons. Not every electrode you plug in reaches one neuron. So, if you plug in a 10 by 10 array, you might theoretically get something like 200, 300 neurons. Practically, you will not get more than, say, 60. It really depends. Unfortunately, it will change over time, which is even worse because the brain will react on the implant and this reaction will cause neurons to lose contact to the recording site. So, you do not get the original action potential of the neurons anymore. So, the question, how many do we need to implant, is really difficult to say. My feeling is that you want to start with something like 600, perhaps 1,000 electrodes, which give you something like 500 neurons, which will stay then for a longer period of time, something like a couple of hundred. They may even change over time. That is wild guesses, but that is the order of magnitude I am thinking when it comes to how many do we need. Okay, I see. But if, for example, we have a patient with different pathologies, will it determine the number of electrodes? Because I guess, since patients may possess different pathologies and different brain regions that are impaired, probably it will define how big our chips should be and how often should we replace chips. Okay, so this is a really, really, it is an excellent question. The question is very difficult to answer, but I think it is actually a crucial question because whatever you do when it comes to patient and clinical use, you want to know for what purpose you do that. So, there is clearly in this context no one size fits all. So, what do you want to treat? This is the first question you have to ask if you come up with anything for patients. What do you want to treat? By the way, this is, to me, completely unclear when it comes to the neural link system. What the hell do you want to treat? One has to keep in mind that with the current systems, when it comes to single electrodes, to single neural recordings, to small stuff, you are only reaching the first top layers of the cortex. So, none of those things goes deeper than a couple of millimeters, make it three. Two, three millimeters. So, it stays in the top layers of the cortex. None of them goes deeper. Not the silicon probes of Utah, not the flexible probes of Neuralink, not the probes of Paradromics, MedEngi, they all have wires. They all are content with the surface of the brain. Now, what pathology can you treat there? That is the question. Yes, because in neurodegenerative diseases and in many pathologies with paralysis or with trauma, generally, the impaired regions are located much deeper. So, this is my question. Yes, what you can treat if you can place a chip only on the top of the cortex? What you can imagine is that you can implant into the motor cortex area and use that signal to control something, whether it's a robotic hand, like in Star Wars in the end, or whether it's a direct hookup to your computer system just to run the screen and to type, essentially. It's a different story. Motor cortex, you record from. When you want to replace lost senses, like touch, you can go in the somatosensory area, implant there, and stimulate them there, which needs a different type of electrode than what you use for recording. If you want to treat blindness, you need a different type of electrode because the stimulation you want to apply, the current you want to apply, needs bigger areas. You cannot use the small areas, which are usually used for recording from single neurons. You need a bigger area in order to reduce something, which is called the charge density, how much current goes through the area of your electrode. If that is exceeding a certain limit, you're frying the neurons, which are away from this electrode. So, it really depends on what you want to achieve in order to decide what is the best strategy to achieve that, what is the best material, what is the best implant. It's really difficult. The answer to your original question is really, what do you want to achieve and where is it? Current neurodegenerative diseases like Parkinson's or tremor, essential tremor, or there's others like major depression disorder, or there is obsessive-compulsive disorder, they do get brain implants deep in the brain with, from my point of view, big electrodes, relatively big electrodes. We talked a lot of magnitude. I talk about micrometer, they talk about millimeter electrode. So, that is the difference. But they need that because, again, charge density needs to be low in order not to destroy tissue down there, and they need to go very deep. So, there needs to be a certain mechanical stability to it. Again, it's a different approach, it's a different story. Yes, thank you for this wrap-up about general principles. I have a question about materials. So, you said that the initial material was a silicone, but it's quite rigid. Talking about modern technologies, which materials are usually applied, especially if we want to go deeper in the brain? Yes, so, if you go deeper in the brain, it's usually thin wires which are coiled up into helicals. So, they, per se, are very flexible, and they are wrapped up, they are covered by a silicone, by a silicone rubber sheet. If you have them in your hands, I mean, they feel like a cable. They feel very, very soft. I need to find a cable. They feel very soft, even more like this, actually. They are okay, and you can still put them in. However, when you look at the softness of the brain, you find out that even those silicone cables are a couple of orders of magnitude bigger, more rigid than the brain itself. Because when you talk with people like neurosurgeons, or we with our animals, you ask a neurosurgeon, how do you describe the brain, how does it feel to have a brain in your hand, which they usually don't do, right? With your fingers, for example. So, how does it feel? The answer you usually get is, it feels like a very soft tapioca pudding, okay? Literally like cream caramel, pudding, whatever. It's more or less the same consistency as a cello. In the United States, it would be cello. Very, very shaky, very soft stuff. That's how they describe brain tissue. Now, if you go into such a structure with something which is more rigid, even a silicone cable, or even this cable, you put that into jello, the jello will still float around it, and it will be cut off. There will be destruction, just because whatever you put in there is less flexible as the brain itself. And this is a good point to ask you about allographic reactions. So, this is the reactions that the body provides to reject some materials, some immune materials. And this is very common for any kinds of implants, but the strongest reactions are described actually for brain implants, because the brain has a very strong immune system that possesses all these rejecting mechanisms. So, could you please comment, do modern implants wrestle this problem, or this is just a question of time, and people have to replace old implants with new, or people, for example, patients have to take some drugs that cease their immune reactions. How people behave in this situation? That is a literally and clearly ongoing research, which we are actually doing ourselves here. So, the brain is, if you look, if you know from school still, right, then people, if they think about the brain and they tell you about the brain, they tell you neurons. Cool. They do the calculation, nice, wonderful, but they are racehorses. They need people to help them, to pamper them. And those racehorses neurons are encapsulated, are surrounded by astrocytes, which are trying to maintain the environment as much as they can. And then there is a police team, which is called the microglia cells, which are running around. They are very peaceful if they're not disturbed. I adore them. Yes, they're cool. They're nice pictures. And then you have other ones, oligodendrocytes and a couple of others. The interesting thing is you have at least as many neurons as you have astrocytes. And as you have new microglia, they are completely undervalued at this time, but they are the ones which are responsible for the answer to an implant. Now let's implant something very soft into the brain. Let's take the soft thing you can imagine, which would be something like a rubber film. You put that thing in, whatever that means, but you put it in. And then it swims with the brain, and you hope that by swimming with the brain, it won't cause the foreign body reaction. But that's completely wrong. Whatever you put in there, as soon as you cause a trauma, meaning that you pluck something, the microglia get activated, activate the astrocytes, and they all together try to get rid of that intruder. Plus, you're opening blood vessels, because there are plenty of blood vessels in the brain as well. You open blood vessels, and then all of a sudden, in addition to what is already there, you get leukocytes and different other cells. Macrophages, T-cells, yes. They all come in through the open blood brain barrier, and they try to respond on the intruder too. But by doing that, they are even more activating the other cells in the brain, except the neurons. So what you have here, as soon as you open up the skull, literally, as soon as you open up the skull, we had that with rats, you open up the skull, you implant something or you don't implant something, you get a response which is highly inflammatory. It's a neuroinflammatory response. And what we found out with our implants, and we try to have the softest possible, so it's a polyamide, it's plastic, it's a very thin plastic film, essentially. It swims through the brain, at least supposedly. Even with these polyamide films, we never go back to a healthy, stable state in the brain. We always are away from what is called homeostatic situation. We have always something like a little inflammation going on. It does not go away even after half a year of implantation in a rat. And the lifetime of a rat is something like two years, so it does not even go away after a quarter of a lifetime. And that is something which is, at this time, completely underrated from the complete community. And that is something which we're going to go on a conference next week and present that stuff. We will get a lot of punishment for it, clearly. But that's why we do that. And we're using a lot of new methods, which are not so popular in the field. But what we learned is that literally, as soon as you plug something in the brain and you're opening just the brain to the environment briefly, it's a trauma. And whether this trauma goes away or not is an open question. And for me, my fear is, and that's when it comes to popular methods of implanting, this might literally cause on the long term really big problems by, for example, causing brain tumors. So there are cases out there, and if you look carefully, you'll find more and more of them. There's one paper which I really like because they describe one case study. It's only one case, but they come up with a lot more statistics to that. One case where somebody used a staple gun and shot himself a nail in his scalp. So the guy went into the hospital. He got CT and everything to find out where does it sit? Do we have to do surgery? And as it turns out, they didn't have to do surgery on him because the nail fell out at one time and it didn't do any further damage except that he had a scar on his skin and everything was cool. Except 20 years later, and I'm talking 20 years lifetime. It's really, he was at the time when he got the nail. 20 years later with age 40, he went into the hospital and because he developed an epileptic seizure or he developed seizures, they found out that at the spot, at the very spot where the nail went into the brain, he developed a glioblastoma, a brain tumor based on the implant. Now, the fun part is that if we look at the genes, which not many people do, something like five groups do it right now in the world, you look at the gene, which are turned on with an implant, you see that you are activating from the very first day you're activating so-called onco genes, which is precursor genes, which may or may not lead to tumor. And this is the stuff which we right now are a little concerned about thinking of widespread implants for people with young age for whatever purpose may lead to those people to brain tumors down the road of their age. If you get a brain implant for Parkinson's disease at age 70, it doesn't matter because hey, age 90, it's very hard for you to reach having that disease. But if you get this implant age 20, because you have a major depression disorder, you have a good chance that, or not a good chance, but you have a chance at least, there is a chance where you might expect in age 40 that you have a brain tumor or not, or you might get one. That's something which we need to be kept in mind if people are discussing, yeah, a brain implant is cool, let's have one, we need that for this or we need that for that. Let's boost our abilities, yes, but still, if you have a foreign body, this body works as a permanent trigger for your immune system. Exactly. So that is the stuff which concerns me right now. And we are playing a little Cassandra of the ancient history. And we are yelling into the void and saying that, hey, be careful, watch out, it might be dangerous. Yes, but I think we are the only ones in the world who are doing that. But this is science. This is why we all do this. Yes. Yeah, this is science. And this is, we get attention once in a while, we'll see what happens. As I said, we have next week a conference in the US, Baltimore. It's about neuroengineering. And we do have a seminar on this or a workshop on this particular topic. And we'll see how many people are interested in that. And we'll then attend and we'll keep that in mind. It is not, it's like everything, there is no free lunch, right? So you implant something in the body, in the brain, we have to expect consequences. The question is, are those consequences bearable or not? Yes, that is just the answer. And depending on the disease, I mean, if I would get Parkinson's my age right now, I would get an implant because I'm not making it to 80 anyways, with all the other diseases I have. So I wouldn't mind, right? But if somebody asked me, your son needs an implant, he is age 25, he needs an implant in order to treat that disease, I would really think of, is that a very severe disease? Is that something which is critical right now? Or is that something which would be just nice to have? And nice to have, I would just not go. I agree with you, but there is one moment if we speak about immune reactivity, reactivity of immune cells in the brain, there is one point I would like to mention that with aging, this reactivity grows actually. And even if we talk about implanting something necessary into the brain of people at the age over 60, for example, 70, still, there is a high risk of these abnormalities in brain immune system. And thank you a lot that you pay attention on this, because this is crucial. And this is what people only are getting to understand. More often, people are actually afraid of ethical moments about chips. I remember a presentation of Elon Musk several years ago, when he suggested that by using neuro-linking plants, people can just call Tesla without any physical contacts. But my question was, can Tesla call you in return? And also other devices or other people who can control your chips, can they manipulate you in order to get money, for example? Is it possible? No. You see, that's what I started to explain. Whether you're recording that information out of the brain, or whether you would want to put information into the brain, it does not, even other people claim that, but it does not work well over the same channel. So you have to keep channels separate. So stimulation areas, simulation electrodes need to be bigger than recording electrodes. Because of the electrical activity you are causing, you are injecting energy. So have them both together, it's really, really tough. And I don't see that happening. And that's why I'm completely not concerned about getting something in my brain in detail, is that there is nobody in the world right now, and not even the brightest minds right now, have any idea of how to do a proper physiological ride back into the brain. There is some riding back, sure, that's what we do in the brain stimulation. That's what you do with other stuff. But it's a very crude method. It's like you would hit somebody with a hammer. Yes, it's a way of communication, right? But it's not a good one. So it's not a really sophisticated one. And that's why I'm not concerned about this kind of controlling or that putting ideas, I mean, like transcendent also, right? In this movie, in the movies, you get dreams implanted and stuff like that. In high resolution, Dolby stuff, what the hell? Nobody knows really how that should work. You need to get access to all your neurons right away. At the same time, and you need to know exactly what to which neuron in order for this neuron to interpret it in something which is useful and interpretable and relatable to you. That's so far away. That's nothing I would be afraid of right now. What is an issue is that you can put by a relatively crude stimulation, put people in a certain emotional state. So that is something which happens with deep brain stimulation. If the people having a deep brain stimulation, and they get rid or at least they get ameliorated their Parkinson's symptoms, they might, because of the place you need to implant that thing, they might lose control. They might kind of start getting a gambling habit or something else. There are stories about this that people really get out of control. They have for different reasons. But this is very unspecific. This is not that somebody could tell you now you need to kill these people by stimulating your brain at the right point. You could make somebody probably in the next 20 years, you could make somebody hate somebody else. But again, it would not mean that because you hate somebody, you would right away go kill him. Or you could make somebody, well, not sure love is very complicated. Hate is a lot easier. You could love somebody, but that doesn't mean that you would just hug him on the street right away if you don't even know that guy, right? There's a lot of different levels at play. And this is one of the issues, which is the most important in the whole of neuroscience. We are talking, we have a literal problem across scales. So we have the whole brain scale, which you can test by MRI scanning, fMRI, for example, you see a lot, you use EEG, but then we need to go down to the single neurons. And perhaps you need to get all single neurons at the same time in order to understand a thought. And that's something which I'm not concerned about at all. And I guess that there is no mathematical methods that could reveal at the level of recordings, like the feel of love, the feel of hate, or actually they exist. I don't see, well, I would not see any reason why a recording of somebody, and if I'm recording from my rats, whether or not they love another one, I would not see the difference. I would not see the difference. The main reason is that for all that, for very high complicated emotions, which I don't know whether a rat has this emotion actually, but for high complicated emotions, you would need access to so many different places in the brain because they are acting together in order to feel some very complex and behavior. I would strongly doubt that I would see that in any of those animals, or even in humans, if I would record single cells, I wouldn't see the difference. Thank you. Also, I read in some publications where researchers worked with mice, they also applied deep brain stimulations, and they claimed that they can control mice at the decision-making level. Is it possible? Yeah, that is easy. It is easy, okay. If you have a left or right, I mean, that is known for a couple of years, people did that kind of remote control of animals over a maze or so. I mean, think about it. The animal has, it's in so far very easy because the animals, for example, they feel with their whiskers, right? So they have whiskers, and now these whiskers are projecting to the sensory areas in the brain. Now, if you are on purpose, very, very softly actually stimulating one side at a time when there is a decision to be made, and the animal feels that as unpleasant, it will turn the other direction, right? So you are influencing the decision-making by influencing selectively left or right. There are other places you can do that, but that is nothing I would say that you are influencing its decision-making. You are just influencing the senses and you are influencing the pathways it is using anyways. You can modulate them perhaps slightly. Thank you very much. So we talked about brain implants, but do people use some implants for peripheral nervous system, for example? Yes, in research. There is nothing in the clinic. This is one of the issues, by the way. Most of the stuff we are talking about here, except the brain stimulation, everything of that is still in research. Nothing is really solid in the clinic. And there is peripheral nerves, peripheral nerve stimulation and recording. A couple of years ago, somebody, well, one of the people here, actually Stieglitz and his group, and actually a group from ETH, they implanted an electrode array across the onion nerve of an amputee, and they were recording signals which were sent down, used that for controlling an artificial hand, almost like Luke Skywalker, and they did the same part on the way up. To my knowledge, there are not more than five people in the world who ever had any useful implant on the peripheral nerve that way. I may be wrong. I may not hear that. But the point is that it's a complicated implant. It's a complicated surgery. And it is risky because in this case, we are in the experimental phase of new materials and of materials which are useful for the future. But right now, there is not a lot accepted for human use for a longer period of time. And if you think about human use, you always have to think about how old are we becoming, right? So people are becoming 80 easily. So if you are implanting something to a 30-year-old patient, you have to expect that the thing is going to last for the next 50 years. And I'm not aware of any technology that could promise that right now easily. Not at all, actually. Very interesting. Thank you. I also read in a recent publication in Nature that there is one group, they have actually big collaboration. They constructed implants to control bladder. So how is it realistic? Because this is a very common problem in aging and after That is actually something which is in the clinical use in a way. Because it depends on how you define bladder control. The most important problem for many paraplegics is actually mutation. When to start relieving yourself on command. That can be done by stimulating one of the peripheral nerves in the lower body. However, this is a little touchy because these nerves are highly intermingled and they have more effects than just start mutation right now. And that is something which is not easy to achieve by electrical impulses, which are very precisely timed, which are blocked at another time. And so things like that are happening. There are not so many people who have such an implant as well. I don't know the exact numbers, but I think it's not bigger than in the range of a couple of thousand. What is currently the most used, and you can call it a peripheral nerve stimulation in a way, the most used and most implanted new prosthesis is actually the cochlear implant. So you have people who are deaf, but still have a cochlear and still have an auditory nerve. And then you are stimulating the auditory nerve cells, extending into the cochlea electrically and present them some hearing information and which they can, or perception, which they can learn to interpret as speech, as sound, not quite the full range of symphonic music, but at least in a wide range for speech is sufficient. And you are stimulating the auditory nerve. Unfortunately, auditory nerve is not counted as a peripheral nerve because it's a facial nerve, but that's a different story. Thank you very much. I also saw some patients and some companies that work with retina stimulation. So patients have implants and they wear something like big glasses. And in the most successful cases, patients could distinguish different geometrical patterns. I think this is a great achievement because people couldn't see anything and then suddenly they can at least see a path, see a table, black and white, but still. There's one thing to notice actually, there used to be two companies out there. I mean, the point is you only bring something to a patient if you go through a company, whatever we do in research in our labs here, it's no value for any patient out there if it does not go through the whole approval and the whole safety issues and everything. So there is really, there needs to be something behind the whole thing in order to push that into a patient. Now that needs money. And of course they get reimbursed if they are surviving long enough. And that's exactly what happened to the most successful technologically, most successful retina implant companies out there. They went belly up. They did not get the money back they needed and they went belly up. And now you have in one case, something like 300 people with a retina implant, which giving them a rudimentary, say brightness information, not really details, but brightness information. And the other one was a lot fewer, something like 50 or so. And these implants now are inpatient and they don't have technical support anymore because the companies are gone. So what to do with these patients? That's something which I think is a really big concern. I mean, because the way the economy works and the way the risk taking in economy works is that you have something like a startup company who is taking the risk. You have somebody who is putting the money into the startup because he thinks he might get money out of it, kind of earn a lot of money. And then there are milestones and things to happen. And if those things don't happen, then the investor says that, okay, I pulled the plug. I don't give you any more money. And then the company who is already halfway down the pathway to a commercialization has a couple of volunteers who have the implants, who have the device, who use the device. But there is no funding for them anymore to get the implant removed. And on the other side, there is nobody taking care of the implant anymore, at least not officially. And how often should implants be removed? They should not be removed at all if there is nothing wrong with them. Nice. But still, people have allographic reactions. Yeah, right. If they have this reaction, then you need to remove them right away. If that's too strong, you cannot leave them inside. But what happens with the retina implant, different companies, there are healthcare providers who pay for the removal of this non-functional implant now. But that's not feasible for everybody. You know how the system in the US is. It's a little different in funding for healthcare. In Europe, it's easier. So, just remove them on purpose. If it's working, you don't do that. You remove it if it's not working anymore, if something is broken, or if there is some other inflammation, or anything you need to remove for medical reasons. Otherwise, you leave it there. But unfortunately, with the eye, and the retina implants are usually behind the retina with a little, I mean, you do a cut from the side of the eye and push the flexible electrodes behind the retina or on the retina. It's a bad place to have an implant because your eye, even for blind people, the eye is moving all the time. Interesting. That is something which needs to be considered for each patient out there. And I really feel for them. But it's not new. That's something which happened in the end of the 1990s, actually. There was a company which called Freehand, not many people know it anymore. See, I'm so alone in the field now. There's a company named Freehand, and they were implanting electrodes for paraplegics, high paraplegics. They had electrodes under the skin. So, there was an inflammation issue to the muscle on the arm, on both arms. And then the stimulation would give those, an electrical stimulation would give those patients a certain type of freedom. They could lift their arms, they could even grab something. There is even people who use that Freehand system to control into the BCI with the brain computer interface. So, a lot of things were, and then Freehand went belly up because they didn't get the money back. And the investors just jumped. And now you had a couple of dozens, I'm not sure how many, but Freehand was very popular at this time. You had a couple of dozen, at least, patients out there with an implant under their skin, which had no further use. And they had nobody to support that, at least not in general. What to do with this patient? So, this is not a new situation. We had it several times. Nothing happened until now. I'm a little concerned about that. I personally would require the authorities like the FDA. So, you have the money for producing implants, then you need to put the money into an insurance, which is paying if you go belly up and it's removing it again. But that's not part of the game yet. Thank you for sharing this because, yes, many people discuss mechanism principles of implants or multi-arrays, but not so many people think about how to maintain these implants in patients. Yes. Practicalities are an issue. And that's what I said in the very beginning. If you recall what I said about the bed of nails implants in patients, the BlackRock or the multi-arrays, the first implants in humans were something like 2004, maybe three, I'm not sure about it, roughly four. It was published in 2006. Since then, we have now 2023. Since then, we have something like 30 implants and it's still considered extremely experimental and it's still collecting information in order to get it into a state that it can be used on a wider range, on a clinical range. 20 years of data collection on that issue, I think I'm not expecting to have anything close to approval for any of these devices for human use cortical implants within the next 10 to 15 years. You may see experimental issues, but I don't expect to see any really true clinical use which is useful for the patient in the next decade or so. So, what we can say about brain implants? They are risky, they are difficult to maintain, but still, this is a very promising device. And especially, I agree with it if we talk about some chronical diseases. But could you please tell when people use deep brain stimulation if they have depression? Yeah, that is a relatively new development. I'm aware of two different schools. It depends on where do you implant. So, the stimulation is always the same, essentially. It's the electrode, which I just explained, the silicone virus, silicone rubber insulated virus, four electrodes, 32 electrodes, different ones of them. And now the question is where do you put them in order to have the maximum effect for treating a major depression? And there is a group in, or it's a school actually, in the US, which decided that this is, we put that in the area, don't nail me, area 20 something of the cortex or of the brain, and we stimulate there. And then the initial results were very promising. And then Medtronic took over that project and they were recruiting, they were looking to recruit 200 volunteers who got the implant, but they had to stop after 100 volunteers, the project, because the implantation at that particular location was not sufficiently effective. So, it did show effects in some patients, but not in general. Kind of hard to say because it's a commercial decision to make, but that's the impression you gain from the outside if you talk to people and read papers. There is another group, which interestingly is actually neighbors of us here in Freiburg, and they decided, we think that we need to implant it to a completely different place. And this is the so-called medium forebrain bundle. There are other people out there who do that too. The people here with the implant to the medium forebrain bundle, I think they are now in a number of 150 or so. They have this mid-sized clinical study as well now, and it looks actually very promising. Most of the patients who have this implant at the proper place do show a beneficial effect. So, that might be really something down the road which is useful for the patients, particularly for patients with untreatable major depression disorder, because that's a bummer. If you have that, it's really nothing I would like to share to anybody. And it really depends. So, everything, all of those strategies, whatever you want to treat, all of those strategies depend on where do you find the access point to attack it. Yes. And if we are talking about the same pathologies, still the targets could be different. Yes. And of course, just very practical, the targets are different for different patients, right? I mean, it's anatomically the same region, but it's not at the same spot from patient to patient. So, you need somebody, you need a neurosurgeon who is really able to kind of cope with that situation too. It's not an easy medication. It's not an easy pharmaceutical solution for something. Like you throw a pill and in 99% of the patients, it works somehow, somehow, somewhere at some time. Not necessarily with depression, but with most of the other stuff. But when it comes to electroceuticals, to implants into the brain, to electrical stimulation, modern world is by electronic medicine. If it comes to that, it is still more hard than industry. Speaking about patients with depression, is it possible to, for example, in the situation when researchers found the place for perfect stimulation in a patient, is it possible that this patient with depression has the stimulation for some time and then he or she have this explanting of this device and became healthy again? Is it possible that this is not permanent stimulation? I can't comment on that. It's imaginable, but it's easy to be tested because you just turn on your stimulator, you have it sitting in the right spot, you turn it off, you see how you feel, how it works, whether you still need it or not. And if you find out that yes, I still feel depressed, then you turn it on again. So it's easy to test technically. But I guess nobody yet discovered, is it possible to use deep brain stimulation to totally treat the major depression? No. I mean, this is what all those deep brain stimulation, electroceutical things are doing. Actually, we are only treating symptoms. We do not treat the disease. Never. Not in Parkinson's, not in OCD, not in depression, not in whatever. We are only treating symptoms. Very important to notice. Okay, thank you very much. Yes, many people speculate about Neuralink. Could you please, as a professional neurotechnologist, give us some comments, what is new, what is not new? So Neuralink is actually very heroically producing something on an industrial scale, which anybody else in the field only did as proof of principle. So the implant of flexible probes was done in 2001 by a complete other group on a laboratory scale. Neuralink now scales everything up into an industrial scale in order to have a lot more of that, in order to have it easier. So it's not new in a way, but it's a step in the right direction when it comes to patient use, right? So I'm very impressed of that. They thankfully do not claim to be new. They always, not always, but they most of the time say that, yes, somebody else did that already and somebody else did that. But hey, we do it better. Fine with me. I'm completely fine with that. It's the same with the spaceship, with the Starlink satellites. Other people did satellites. With the rockets, other people did rockets. We do it now a little, we do it cheaper, we do it better. Fine with me. That's completely okay. I'm absolutely fine with that. What I'm not fine with, what I'm really not fine with is the statement I hear from Neuralink, particularly Elon Musk. Very often, or not very often, he says that and he thinks that this is really the way to go. It will be as easy as implanting a Lasik eye surgery. Yes, and it will be used for us to hook up, to connect our minds to the artificial intelligence, which will be our overlord. There is so much wrong in this statement, which he's coming up with, and so many dangerous things in these statements that I'm really a little disappointed that he still collects money for his company. In a way, he's a salesperson just trying to get money from venture capitals. Yes, it's like the rising capital of your company. AI is a very popular topic. Implants, I don't know why he does that. The point is, from a clinical, say, commercial point of view, I have no clue what he wants to treat, which disease he wants to tackle. That's why I asked you in the beginning, you asked me, well, different pathologies need one implant. I say, what pathology do you want to tackle? In his case, it's the same thing. The stuff he's doing right now is technologically super cool, but what pathology can you treat by implanting something in the cortex? That's his goal. He can only implant into the cortex, right? So, what is the pathology he wants to tackle? What is the market behind it? How many does he need to implant every year in order to get his money back for the investment he's doing? I'm not an investment person, so it's not my point. I don't earn money in that game, but if I would invest into a company, I would ask, so where is the money coming from after you have your wonderful solutions and your first FDA-approved implant? By the way, thankfully, FDA at this time did not approve his first in-man trials because they did not completely fulfill their requirements. I don't know whether you heard about that. He was claiming that by the end of the year, he has the first implant in a human, and FDA said, not so fast, we are missing information. Good point. Thank you. Also, I have some concerns about this manipulation of the highest levels of the neurocortex because their dream, their goal is to make this brain-computer device to create... Give me a second. I need to put you on hold for a minute here because somebody seems to break into my room here right now. Okay. Always busy, Ugrich. Yes. Nice. My concern is that these people want to create these brain-computer interfaces to boost up learning capabilities of humans to enhance probably some memory capacities and help them communicate with the world without our typical ways of communication, for example, without speech, without some movements. I'm a bit afraid of this because these actions that we normally use, speech and movements, these are things that are naturally maintain our brain activity and brain functions. And if we will use implants as toys, I guess humanity will lose it. Not will boost it, but will lose it. I'm not too much afraid of that. I think the example of Google Maps on the cell phone is a bad one because if you have nobody tries to orient himself around anymore because, hey, I have Google Maps, I don't need to know where I am. But that does not work with the brain activity and stuff behind the brain activity. If you have a medical reason, a serious medical reason, not for a toy, but a serious medical reason in order to get some information channel out there. There is really cool work recently from San Francisco group. They have an implant. They even have an EEG system. They record from the brain and they transfer that into written signs, so literally handwriting, or they transfer that into speech, into language. That is something which might be extremely useful for the patient who is not able to talk and to communicate properly. And he will use that channel in a way which is not foreseeable for us right now. He will start with somebody who has an implant then or who has the proper VCI system then for the speech recognition stuff. This will be used. And I strongly doubt that he will lose speech capabilities because otherwise he would have lost the speech capabilities the time he was muted by whatever disease. Get my point? So what they do is right now there are patients out there who have lost the capability to control their vocal cords and their vocal structure, but they still think of speaking, right? They did not use it and they still think and the signal is still there. Why should it go if you are using now the signal to do something different with it or to use it on an electronic device to put it out there? I don't see that as a serious concern. Okay, thank you. So if we use implants in the correct place and for the correct purpose for patients, yes, we have a hope for a better life. I do. I really have. I mean, I still hope that we will, with our research here, we will find a way of avoiding all these oncology problems which might appear over time. So I really have hope in doing that. Otherwise, the implants will be used for people on a very careful way for really patients who need that. If there is a need for it, it's a good idea in order to continue research on that direction. Thank you, Uli. It was a pleasure for me to have a talk with you. Time is flying. So to conclude, could you please describe your work in three words? Do not implant. Surprising, bold, brief and genius.