#72. Touching a Nerve - Adarsh Makdani

In this fascinating episode we dive into the world of somatosensation with Adarsh Makdani, a researcher at Liverpool John Moores University. Discover the intricacies of mechanosensory receptors, the science behind pain and itch, and the groundbreaking techniques used to study these sensations. Adarsh shares insights into his research journey, the importance of collaboration, and the ethical considerations in experimental pain research. Whether you're a science enthusiast or just curious about how our bodies perceive the world, this episode offers a deep dive into the sensory experiences that shape our lives. Don't miss out on this enlightening conversation!

https://profiles.ljmu.ac.uk/8382-adarsh-makdani

Chapters

• 0:00 Understanding Mechanosensation and Its Role
• 13:31 Techniques in Somatosensory Research
• 25:58 The future aims of nerve research
• 45:22 The Experience of Participants in Research
• 1:05:20 Surprising Findings in Neurography Research
• 1:08:27 Collaboration in Scientific Research
• 1:11:48 The Journey into Neuroscience

Transcript

0:03

Hello, hello, hello, and welcome to the Smooth Brain Society. I'm Bethany Facer and we have Sahir Hussain here. And today we're gonna be, we've brought Adash Makhdani onto the podcast. He's a researcher at Liverpool John Moores University and he focuses on on somatosensation. Now to start us off, Adash, can you tell us a little bit about your work and maybe... What is somatosensation and what's your work in the simplest terms? short somata sensation is, I guess, very simply our skin senses. Very often it's just kind of uh limited to touch or considered the touch senses, but in reality it also encompasses pain as we tend to feel it, temperature sensation, itch and various other senses including proprioception which is, where our body is in space. Ooh, very cool. With touch though, I feel when you say skin, I'm trying to think like, you can also like touch things with your tongue or touch with like other parts that you would not consider skin or like the feeling which you get internally. Does that come under touch as well or is that slightly different? Yeah, that's an interesting question, I guess. anything that has mechanosensitive receptors, so we do tend to count the lips and the oral mucosa as within that same boundary. em Anything, I guess, on the tongue where it's mechanoreceptors maybe would come under somatosensation, but if it's on temperature sensation, but the taste receptors. would come under taste. um That's an interesting uh way of thinking about it. um It probably doesn't strictly include things like the visceral sensations that you get within your body, such as, you know, if you feel your stomach a gurgling or um if you've got, you sort of feel internal sensations from within your organs. uh I guess strictly speaking that doesn't count as a skin sense, although it probably relies on very many of the same mechanisms as well, and may well project to similar parts of the brain. What's mechanosensory? So mechanosensory is a very uh posh way of saying um any sensation that is causing movement or anything that affects a mechanoreceptor, a skin receptor that uh responds to touch, pressure, stretch, vibration or any any of those motions or movements that we tend to feel. So like when I touch my skin, there's receptors in there which are mechanical almost and they sense that and then that's going up to the brain. Is that in a simplest form? Is that explained? And within the skin, there are multiple different types of mechanoreceptors um that are specialized for different types of touch. Some of them are very, very simple free nerve endings. um And some of them are linked to quite complex structures within the skin that allow them to receive, perceive and transduce. um some quite specific types of touch like vibration at a specific m frequency or pressure or skin stretch and those are essentially um complex structures that um move in a certain way that then cause that nerve to react in a certain way as well. Cool. And is temperature one of those as well? Is that included? Vibrations? Temperature? Is that slightly different? So temperature does it does come under I would consider a somatosensory sense um but it is um based on the activation of ion channels uh and in fact um a Nobel Prize was recently awarded to the groups that discovered these receptors that activated ion channels depending on different temperatures and also in response to different chemicals. So you may have heard of the TRP ion channels and so capsaicin is a very good example. The reason that chilies feel hot is because they contain capsaicin which activates a ion channel that is linked to temperature sensation or heat sensation. And when you say an ion channel, do you mean that's how the neurons, so the signals to the brains are activated via these opening of these ion channels? And that's how the signals from the neurons get up to the brain from the skin, which is. Yes, precisely. guess it's a whenever you start talking about this and you start saying things like ion channels and I'm sure that suddenly people will switch off or if they know all about it they go no that's wrong and you can never really win but in either case um a a neuron is the most basic cell structure within the nervous system it is a single cell and signals are uh sent along a neuron uh in what's called an action potential. And it's basically just a bioelectrical signal that starts at one end of the neuron and goes to the other. And then it's transmitted from there to potentially another neuron and then another neuron all the way up to the brain um or potentially to some other part. So like a muscle, for example, if you're talking about... um muscle activation from a neuron. uh And so at the start of that neuron you will have different types of things that can trigger an action potential um and one of those is an ion channel. Basically it causes an influx of ions which are positively charged or negatively charged depending on the type of um ion channel you're working with and an ion channel that um causes an action potential can be activated through either a mechanical force or a chemical that allows these ions into the cell, causes this action potential and then that signal cascade starts in that nerve cell and then starts that first process of sensation, And then lots of complicated things happen all the way up to the brain. temperature thing's really interesting. Is that sort of why, like, you know how at colder temperatures you start feeling numb in your hands and things like that? Is it because, like, certain, I guess, certain nerves or, like, get shut down or action potentials don't get generated under certain temperatures? think. Yes. So one of the most interesting things is that there are some nerve channels, nerve cell. ion channels that are much more temperature sensitive than others and some of the ones that are linked to pain which i think are nav 1.8 or nav 1.7 now and nav basically means it's a sodium and ion channel and it's voltage gated um but they are different types of ion channels and i think these are the ones that are the ones to shut down the slowest or the ones that come back on the quickest during when the skin gets too cold. And that's the reason when a lot of other sensations start to go away, one of the slowest to go away is pain and why cold can feel painful and numb at the same time. So you may not get pressure, you may not get stretch, you may not get hot sensation. What you just get is cold and And I could be wrong here, Adosh, but I think your particular area of interest, is it pain and itch? Is that correct? That's correct. Well, it's one of my areas of interest, I guess. Yeah. I guess it's always fun to have an excuse to torture your participants in the lab and to do it with a, you know, a good purpose in mind. So chronic pain, chronic itch are conditions that affect many of us throughout our lifetimes. um A chronic condition is anything that basically lasts. months or more. So some of us may experience or develop a chronic pain condition that lasts the whole of our lifetime and can become debilitating. Others may develop chronic pain or chronic itch following for a short period of time. But in either case it can be incredibly distressing, incredibly painful, incredibly uh difficult to live with and so having the opportunity to research that and m understand the mechanisms of those sensations and m those processes can hopefully lead to um understanding how we can help those conditions as well. I am under no illusions that the very very basic neuroscience and some of the very very basic psychological questions that we're asking in our research are not going to lead immediately to a target drug target and are not going to immediately become you know the the cure for pain but I think that it's always really really important to understand those um those mechanisms as well as we can um and I guess an example of that is that for a long time if you were to look in any textbook um you would find that pain was defined as a particular type of sensation that was transmitted by a particular type of nerve cell um and these are what we call unmyelinated nerve fibers so they don't have a conductive sheath they don't have an insulating sheath around that cell which means they transmit those action potentials we spoke about earlier much more slowly and they were either c fibers or a delta fibers and so typically you would be looking at a sensation like pain or heat would take would be traveling at say half a meter per second or two meters per second by contrast some of the touch that we perceive can travel at 30 or 40 meters per second which is why if you stop your toe initially you get that sort of crick, painful, not painful, sorry, you get that initial sensation of, I've done something, there's pressure. And then maybe a couple of seconds later comes the ow and the hurt and the swearing and all of all the things that comes with it. And that has been the textbook explanation of how pain is transmitted and pain is perceived for a very, very long time. And some of the work that we did in our lab at John Moores in collaboration with others in Sweden and then ultimately all over the world in this project was following the discovery and description of a nerve fiber that previously had probably just been hypothesized but never been seen in humans at least and this is an ultra-fast nociceptor and this is a pain fiber that kind of defies what we know of in the textbooks um and is present in humans and transmits at 40 meters per second as well. And understanding why that no fiber is there, what it's responding to, is it a potential target for pain therapies? um All of these things come from that very basic understanding of actually, yes, it's there, ah even though we've never seen it before, and it's not been in the textbooks. And so this was only in... 2019, this paper that was published describing this no-fibre. That's very cool. And what kind of tools and techniques do you use to get this information? For example, I'm a neuroimager, so I use an MRI scan. So here, as we all know, it's like looking at rats. So it's all behavioral testing. uh What about these pain markers almost? What torture do you have to put your participants through? Torture with commas, it's not actual torture. Sorry if you... If you're listening on the radio, I'm doing the little bunny ears torture. As far as our ethics applications are concerned, it is very much quote Marx torture. um And we'll leave it at that. um So I think the techniques that we use are some of the coolest, actually. I. m When I did my undergraduate degree, I really wanted to do neuroimaging because it was very cool. can image the brain and then I realized that involves maths and physics. and I didn't understand maths or physics that well. And so now when I look at neuroimaging, kind of go, that's really cool for whoever understands that. I do not. And then even more so because the brain starts to become very, very complicated. The more you learn about anything, I do not want to deal with that. em And then I'm also too much of a vegetarian to start um working on rats. uh Although from what Sahir said, his rats are very, very well treated and have a lot of fun as well. So there is that. However, I was very lucky to come across this technique when applying for a PhD, which was called micro neurography. And it gets to doing really, really cool, what I would call sort of hard neuroscience, but in humans. So they get to consent. So it's informed consent. They know what they're signing up for. You can talk to them. You can understand them. You can get them comfortable. and then you can poke them with needles and listen directly to their nerves. So that is a technique that I've been really, really lucky to be able to learn about and develop and use within my research and even go away and train other people on how to use this technique as well, which I think is really, cool. So micro neurography involves a, it's an electrophysiological technique. Basically what you're doing is putting some electrodes into a nerve fiber. So a very good example is if I wanted to listen to the nerves in the arm, I might put some needles up here and we guide one of those needles directly into the nerve bundle, which is a bundle made up of hundreds or thousands of nerves and single neurons. And then you can record from that whole nerve bundle. and you get sort of mass electrical activity from that nerve, from that whole nerve bundle. And a lot of, um, lot of the time, similar techniques are used in clinic because if you're doing a nerve conduction study following an injury, you might do something quite similar. Although the clinician doesn't have to typically go all the way into that nerve fiber, but they'll record from that nerve and record it's a sort of mass activity from it. The cool thing about microneurography is that allows you to dive even deeper and record from single cells. So it's a bit like having a Petri dish with a single cell in it, except this single cell happens to be attached to a human and happens to be attached to their brain. So you can understand what they're feeling and how they're responding at the same time as how that single nerve cell is responding. and we're able to record from a cell a neuron at the very first point of sensation. what we're recording is essentially we're doing the wiretap from that cell to see what signals it is sending the moment a sensation enters the body through those mechanoreceptors or thermoreceptors or chemoreceptors that we spoke about earlier. And that's a technique that we've got to use in our lab and we've had to been able to develop. And so we've had recent advancements, I think, with using ultrasound guidance to try and get into different nerve fibers and nerve bundles uh more easily. And we get to pair that with psychophysics techniques. so psychophysics is a term for basically really well controlled physical stimuli uh such as uh temperature or pressure and then you can ask somebody how they perceive it. So an example of that is we have a set of von Frey filaments. So von Frey filaments going back many many years were developed by someone von Frey and they were hair fibers from a goat or a horse or a human and because they were all different thicknesses he would be able to say well this you know this goat hair is stiffer than this cat hair for example and if you can feel the cat hair then you're more sensitive here whereas if you can only feel the goat the horse hair then you're less sensitive here. These have obviously been developed over many years now and now we have them so we can go all the way we can have very very precise forces so an example is say one gram two gram all the way up to 300 grams and all the way down to 0.08 grams and then you can sort of press that von Frey filament against someone's skin, ask them if they can feel it and at the same time record from that nerve fiber the receptive field of where that nerve fiber is connected to on the skin and see how that nerve fiber is responding to it. Is it able to respond to really really really low forces or does it only respond to high forces? m does it feel painful when that nerve fiber responds? And alongside that we have a number of very cool tools, a stroking robot which unfortunately does not look like the image that you have in your head currently, but I won't tell you what it looks like because it feels wrong to spoil that, m and also thermal stimulators, a uh A new newly developed hair pulling device is one of the ones that we and some of our collaborators use. We've also tried using sort of ultrasound stimulation. So like for haptics devices to see how that responds, how no fibers respond to that as well. So many different tools and toys that we get to play with in the lab alongside the really cool technique of micro neurography. I have so many questions. um First of all, actually, the first question was something which you said early on when you said, when you're talking about microneurography and sort of getting it, putting an electrode into a nerve fiber, a nerve fiber bundle. um Sorry, I do not know this. Could you tell me, in a particular nerve fiber bundle, are the nerves the same type or are they different types? For example, in one bundle, do you get a thermoreceptor, a pain receptor, blah, blah, blah? Or is each nerve bundle its own thing and you have to make sure you're picking the right nerve bundle when you're... It's a bit of both. When you say, oh, so and so is getting on my nerves or, oh, I hit my funny bone and that twinged my such and such a nerve, or if you get carpel tunnel syndrome and it compresses a nerve, that nerve that you're talking about is a bundle of bundles of neurons. That nerve will contain um many, many fascicles. So a very good example is the radial nerve that projects to the back of the hand here. It also projects to the muscles and tendons along here. So if you were to put a needle into the radial nerve, or rather if you were to get a cross section of that radial nerve, you would see uh lots of different bundles within that whole nerve. And those nerve bundles will be somewhat anatomically and functionally divided. So you might have a bundle that projects to certain muscle group, another bundle that projects to the back of the thumb, another bundle that projects up to the fingers here. And then within that, you may also have functional division as well. So you'll have obviously not just the skin and muscle divisions, but things like um Pain versus... m pressure versus vibration. There are... Those boundaries are a little harder to define. I think it's very, clear whether you're in a muscle bond, a bundle that supplies muscle fibers. They're all nerves, but we call it a muscle bundle because it's supplying muscle fibers or a skin bundle because it's supplying the skin. ah But then the functional definitions can be a lot harder to determine. And sometimes they feel like they're all mixed in together. Other times you feel that. ah you if you find one type you'll find lots of that type. What tends to be clearer is that they are quite anatomically well defined so if you're in a bundle that's supplying the thumb you tend to find more nerve fibers that are supplying similar regions in the skin there. That's one of the challenges of a technique like micro neurography is that you can't target very well beyond ah Well, very, very good micro neurographers or very, very lucky micro neurographers can target specific bundles because they understand the anatomy. They might understand the arrangement and what fascicles and what angle to go out in order to get to say the fascicle that supplies this finger. But it's very, very difficult to go any to be targeting any more specifically than that and say, I really want to get a uh pain fiber today. So that's what I'm going to aim for. because that just does not happen. And it has been the downfall of many, many experiments and many, projects that you just do not find what you're looking for. You have to be very, very lucky and or very, very patient and or very, very well funded. I guess there's also variability between people, I feel, right? In terms of where the bundle would be if you're trying to pick out a specific bundle, like, because all these nerves are going up the arm, but they could be in slightly different locations. So you can't even pinpoint per person. individual variation. It's actually... We are surprisingly consistent beings, despite that. Obviously, we can't pinpoint and kind of just kind of have a setup that's right and ready and you get someone to slot their arm into a little jig and you kind of go, broad, that doesn't work. But generally speaking, over the years, myconeurographies in Sweden have developed... em very good anatomical cues and they kind of go right well if you go two centimeters above this crease and two centimeters to the left of that tendon and then prod around a bit you will find this nerve fiber so yes there's a lot of individual variation but we're also quite thankfully quite consistent as well That's really interesting. So it sounds like the future is a future of this. The fact that you want to try and find these individual bundles. A bigger future question or the biggest is that what is the biggest unanswered question in your field or area that you know, a new technique could really help out with. The one thing that we're currently lacking that I know that a lot of animal neurophysiology or electrophysiology does or a lot of cell kind of electrophysiology does is uh electrodes with multiple um contact points or multi-electrode uh needle. So at the moment um our technique has been a single electrode which has got one contact point and so you get one channel and you have to be able to then move and manipulate the tip of that needle which is sometimes bigger than the nerve fibre that you're trying to record from. So typically the needles we are using have a electrode tip of 20 microns. Some of the nerve fibers we're recording from are in the region of five microns, I think. So the tip of the needle is bigger than the actual nerve that you're aiming at. So the idea that this technique works at all is magic to me, but it does work. But it does mean that if you're not directly on top of that nerve fiber, you won't get a very good signal. And also, you kind of have to go from one of one neuron to another neuron to another neuron what we don't currently have is kind of sticking the needle in and just see what's there and out of say 32 channels you might get three or four that are really really good and you can test those individually that you would be able to do with a kind of a multi electrode array or a multi-channel electrode that you can get in different techniques and I think that probably is likely the next step although I guess it takes away some of the romanticism of myconeurography as a technique potentially and it's it is likely to be a long time because um one of the reasons we know that myconeurography is safe is because the technique hasn't changed significantly for over 60 years now. uh since its development and when you're doing it in humans you kind of want to make sure you're not causing damage and so far it seems that with the safety protocols that we have in place it's actually minimally invasive and so people do walk away quite happy having been prodded for multiple hours and having received their vouchers. Okay, so basically what you're saying is, although this is the safest option, something that would push it forward is maybe smaller contact points and multiple. So that brings me on to my next question, which I think you'll enjoy. So I want you to pretend you've got infinite funding. There's no such thing as an ethics board anymore. What experiment would you run? Or what maybe, yeah, something kind of that you think would be outside the box, something to kind of like would push it forward. Um. What experiment would I run? The uncreative uh person in me right now says I'd probably rerun the experiment that I last tried to do that failed because we just didn't get enough data. And so as I said, the challenge of this technique is that you can't target what you're going to find. You find what you find. It's very much like fishing. You throw in your line and you look for what comes up. You kind of know what you're aiming for. You know what's there in the sea, but you don't necessarily know what you're going to find. Um, one of the most interesting nerve fibers that we have in our skin that has been relatively recently been, um, discovered and described is a, um, C tactile or C low threshold mechanic receptor. It works. quite unlike many of the other nerve fibers that we have. So it seems to be tuned to a very specific velocity. um So most nerve fibers, the faster you move across their receptive field, the faster their fire, the faster the fire, the more intense that sensation. um The C-tactile or the CLTM seems to have a preference for slow movement across the receptive field. So not too slow. So anything below say one centimeters per second, it has a relatively slow firing frequency, but anything that's sort of above 10 centimeters per second, it has a relatively slow firing frequency. And it's that in between that one to 10 centimeters per second, it has this kind of much more intense reaction. And from that has stemmed um a lot of, that data comes from myconeurography experiments that were done over three years and painstakingly done, um but, and it stemmed this kind of this field of um affective touch research where we're looking at the dynamic movement of this. uh across that nerve fiber and what does that mean? Why does it, why does it respond in that way? Why has that nerve fiber been preserved? Is it because it feels like it could be linked to the slow gentle caressing touch that you get from a caregiver or a partner, know, evolutionary evolutionarily speaking, it may be very, very important. And also what happens when that goes wrong? things that we don't know about the snowfibers, sort of what pathways does it take all the way up to the brain? What happens in the spinal cord? We haven't been able to characterize fully where it's located in the skin. Can you get it in your hands or not? um Is it linked to hair fibers or is it not? One of the recent papers that ah my colleagues put out is that it seems to be linked to hair follicles. but not always. And it's one of these really, really fascinating nerve fibers that we want to study more of, but finding them is a real pain because not for the participant, just for us, ah just because of how rare they are and how difficult they are to get to. So I think if we had infinite amounts of funding and infinite amounts of time, and if we had a really, really sort of advanced development in technology, what we'd be doing is being able to target these specific populations of nerve fibers. the ultrafast nociceptors to try and find out more about their characteristics, the CLTMs to try and find out more about those characteristics, and then also discovering you know more about the itch and pain nerve fibers because if you're able to do, I think if myconeurography was easier and being you were better able to target these nerve fibers you could do a lot more when you did find them potentially test drugs. the receptive field of a specific nerve fiber and if you could guarantee that I would definitely find this nerve fiber you'd have a much easier way of testing those medications out on humans and human participants on human nerves. So an ointment that took away pain on the skin would be amazing and you wouldn't have to test it on a rat or a cell because you could test it on a human participant. So basically saying it's it's good to do because then we don't have to test on animals as much. It's mainly more human-based. But I guess, so I you kind of spoke about kind of earlier on, you said that you're not to do with like the drug sections of it. You're kind of like, you know, further up the line before it, you know, reaches kind of clinical trials. How does it get from your research to kind of like, kind of targeting real world problems? um I guess there are two pathways. So there is the long and slow pathway, is understanding the mechanisms, understanding the neuroscience that underpins a particular um sensation or biological process and then finding um all of the steps that go from there upwards all the way to behavior on individual levels, social interactions between people um and even interactions at a sort of population level. So the C.tactile afferent apologies for the pinging. uh The C. tactile afferent is a very good example of that where the neurobiology of that is leading to an understanding of touch and social interactions and the importance of touch and social interactions and how that contributes to development at a very young age and preterm infants and young children all the way through to how it may have an impact on loneliness in adults which seems and and and elderly people in particular where it seems to be um really a lack of touch seems to be closely linked to mortality and depression and uh loneliness and all of these things so by understanding those mechanisms you're able to better study the psychology and the epidemiology and and all of those things and i guess that's the long and slow process where you've got to understand those basic steps and then you can build on top of that the rest of the science. a more direct route is simply by being able to understand those mechanisms you may be able to find a specific target. So if you can isolate specific nerve fibers for example that cause itch in chronic itch patients. And not only specific nerve fibers, but you can then isolate those nerve fibers and find what ion channels are present on those nerve fibers, what are the biological markers for those nerve fibers, and maybe find biologic pharmaceutical targets that can turn those nerve fibers off. Potentially you can develop a treatment or an ointment that rub onto the skin or a tablet that you take that then targets specifically the channels on that nerve fiber and that causes the relief of itch. And is it turning off almost? it desensitizing it? uh I think, yes, potentially, I think with the skin, I don't understand enough of the sort of digestive processes and things like that to talk about sort of like a tablet that you can take or something that, know, anything that has to go up to the brain has got the brain, blood brain barrier to deal with. But I think it's not unreasonable to think about an ointment that you can use to target specific nerve fibers because you know what you put on the skin. with the right formulation goes through the skin. If you know where those neurofibers are, you can then target those receptors at the very point of perception. And you can basically stop that before, know, stop that itch or stop that pain before it even starts. And that is, I mean, we already have that because we have lidocaine is a very good example of that. You can get lidocaine patches or lidocaine cream, which turns off uh large number of nerve fibers um and is transmitted through the skin. I guess lidocaine is a good example where it also turns off um all types of touch so you get that full numbing sensation. uh Potentially you may just want that one that turns off the pain sensations uh and Another really interesting route to go down might be how we can turn off pain, but not temperature. So one of the things that I've always like, we, you sometimes have um people who have a congenital insensitivity to pain, or you have diabetic uh neuropathy or any kind of other neuropathy. um Or sometimes there are treatments that we do. say we being the scientific community or the clinical community, not me personally, that say use radioablation to turn off pain nerve fibers altogether. When you do that um you also lose temperature sensation and can you imagine how dangerous it is to make a cup of tea if you can't tell how hot the water is? And so it would be really really cool if you can by better understanding all of these no fibers if you can get more specific targeting as well. Oh, that's really, that's a really good point actually. Of course, even if you're, let's say you've got chronic pain, like just off all kind of sensation. Yeah, you could scold yourself. What's the, there's a, what's the disease, I don't know what called, condition called where you can't feel any pain at all. I don't think you can feel temperature or anything. It's quite rare. You see the classic house episodes where they're on. But there's a lot of things with that. Yeah, they burn themselves. They hurt themselves without realizing it. So yeah, that temperature thing would be incredibly important and probably why it's so important in 2019 when they discovered the exact kind of changes on the skin and the ion channels that was causing the temperature. Yeah, how fascinating. Just really quickly, uh just because I've had this in mind for the past two statements you made, oh is there a chance that there's certain nerves and neurons which we have not even discovered yet? If you're saying that we're still finding out so much information about certain ones. imagine so, yeah, I wouldn't be surprised at all. Certainly there are, I would say without any hesitation, there are populations of nerve fibers that we already know about, but there are subpopulations that we don't, of those specific ones that we don't know enough of, because we've found, we've maybe found lots of different subpopulations and grouped them all together because they look roughly the same, but there are very, very key differentiations that we haven't yet been able to make. So that I would say is a 100 % guarantee. A very good example of that is the C-tactile nerve fibers. For a very long time, it was thought that they are just free nerve endings that float freely in the skin, but we're finding that there is a subpopulation that seems to be very, very closely linked to hair follicles and they behave ever so slightly differently. But I would suspect that yes, there are also no fibers that we just have no idea about because we're so rare that we haven't found them yet. I mean, it's hard to imagine because in theory, you know, we think, well, we found all of the sensations that we know about. um But. at the same time, you know, we don't, certainly don't know all of the signals that our skin will send into our brain at any one time. That's one of the things I find most fascinating about this kind of, this, uh, as a thought experiment is that when we're doing micro neurography, we're focusing really, really carefully on a single cell on a single nerve fiber response. But in reality, every time you touch the skin or every time your skin touches something else, clothes you're wearing right now that is causing thousands and thousands and thousands of signals to go from your skin to your spinal cord and up to your brain. Your brain then has to do the very complicated process of working out which ones it listens to and which ones it doesn't listen to. So for example, I don't really feel the fact that I'm wearing this t-shirt on because it's not causing me any discomfort and it's a soft material. It's not causing me any pain. It's not feeling scratchy. But in reality, all of the cells underneath that skin are going, there's a t-shirt on me, there's a t-shirt on me, there's a t-shirt on me the whole time I'm wearing it. It also, when the temperature changes, if I get a cool breeze, there'll be temperature sensations that are going, it's a bit warm now. Oh, it's a bit cold now. It's a bit warm now. But all of this time that's happening. And I guess that's why it also becomes quite fascinating when you think about what happens when that process goes wrong and you get overstimulation or hypersensitization when something that is innocuous starts to become irritating or painful. You get that in, say, hypersensitivity in some people who are autistic. as an example, you know, this is why the sort of scratchy label at the back of your neck, when if you're a neurotypical, it may not bother you in the slightest, but if you're an autistic child, it may cause you to have meltdown, just because it's just overstimulating and hyperstimulating. And at the same time in chronic pain condition as well, where uh a very good example, I guess, is CRPS, where your skin becomes so sensitive that anything within your peripersonal space, including a breeze from or a draft across your skin can feel intensely painful. um and so yes, understanding what goes wrong when those sensations are happening all the time is really, really fascinating as well. think. I wanted to ask about the experimental setup a little bit. So when you're studying sort of itch or pain, you've got someone there. Suppose I'm there, you've jabbed me. I have an electrode there to connect to a nerve. How are you inducing pain, itch, those kind of things into someone to measure? I think em one of the things that we try and do is we try to have a protocol for every type of nerve fiber that we can find. And we have a whole host of things. So my can you over three experiment can be a little bit boring and is not really a spectator sport whilst you're searching for a nerve fiber. And then when you find something and you want to record from it, suddenly you need about six pairs of hands. uh need the participant to stay really really still and then you need someone to make notes on a computer and someone to go and grab you all the different brushes that you've got so we've got like a soft goat hair brush and then a rough brush from a hair dye thing um and then for the pain or the itch stimuli so um itch an example we haven't done it with microneurography in our lab um but um there are some previous experiments looking at uh ion to phoresis of histamine. So you're basically using a very mild electrical current to force histamine ions through the skin and into the receptive field of a nerve fiber and causing an itch by the sort of whole cascade of responses to histamine. There is also an itch, sort of itchy powder that you get called cowage that comes from a bean plant. If you rub that against the skin, you can cause an itch like that. So uh Anything that causes an itch, can also use sort of mechanical itch or electrical itch, know, like something that's irritating or vibrating against the skin in a particular frequency. uh Pain, we will look at mechanical pain, pin pricks, ah pressure over a blunt, blunt using, you know, blunt force. uh Heat pain. So we've got uh thermodes that will go up to sort of 50 degrees. And also will go down to zero degrees so you get hot and cold pain potentially And electrical stimulation as well so we can stimulate using an electrical stimulator uh Relatively From relatively mild shocks all the way up to sort of hundred milliamps and nothing that's dangerous are going to cause anyone to sort of jump out of the chair But as far as that nerve fiber is concerned it would potentially be very unpleasant and sometimes as far as the participant is concerned it can be very unpleasant. Other techniques um including the use of um hypertonic saline into the muscle which causes a of a cramp like sensation as well. So we did that for one of our experiments. I cannot imagine trying to stay still if someone's put itch powder on me. Like scratching feels so nice. That is one of the experiments we were looking at was simply trying to understand the um why it is or what mechanisms underlie the um the pleasure that you get from scratching an itch. um And this is unpublished data. So we did do an experiment um looking at patients with a neuropathy versus healthy controls. And the patients with a neuropathy had um a specific um lack of function. in so they didn't have certain types of nerve fibers in the skin but they did have others that were preserved obviously the healthy controls had the full gamut of nerve fibers and we were trying to see does that patient still have that that case study patient still have that sensation of pleasure when they scratch that itch and if they did then um it uh suggests that it's one of the nerve fibers that they've got still present that conveys that sensation or at least contributes to that. And scratching and itch is particularly interesting because what you're essentially doing, although some itches are conveyed by pain nerves, by introducing a pain stimulus, you are removing the itch. So you're stimulating that same nerve fiber potentially in a slightly different way, and that somehow relieves the itch. So... it tells you a little bit about how the brain works when it's receiving the signal. It's looking at the kind of not just the fact there's activation there but the quality of that activation in those nerve fibers. um And um I've lost track of what I was going to say there. But that's very interesting that you, because in my head up till this point, I thought that there's very different nerve fibers and they all do very specific things. therefore very specific sensations. But you're saying that potentially even the quality of something, the quality of how a sensation is felt can also be picked up by a nerve fiber and change the perception. So I think. um One of the things that you learn about action potentials em very early on, you were doing a neuroscience degree of any kind, is an action potential is an all or nothing response. You either get an action potential or you don't. um And so when we're recording, although the amplitude of our signal can change, what we're always seeing is either a response or no response. You don't get kind of half a response. And that... is a truth that seems to exist all as far as I'm aware all the way throughout the nervous system. So even the neurons firing in your brain in the same way there's the neurons firing in your skin you either get a signal or no signal not half a signal. So the amplitude is not where that signal is is not where the information is conveyed. Where the information seems to be encoded is in the frequency of the firing and so a rapid burst of activity versus a slow pulse will convey a different sensation. And then that is mediated by all of the steps in between. So we might get rapid firing at the very, very start of the system, but somewhere in your spinal cord, your brain is sending down a signal that says, calm down, I know about this, I don't need to hear about it. And so that signal is then mediated and reduced. But it's that frequency of firing that is really important. It's why the C-tactile afferent is so interesting because of that weird response curve where it fires more in the middle versus at either end when you're looking at speed of sensation. um And it's why... um it's interesting to look at the firing frequency of different nerve fibers in response to different sensations and where the uh in where the information may be contained when you're looking at say a itch nerve fiber that is also a pain nerve fiber but different firing frequencies may mean different things and may be interpreted in different ways by the spinal cord and the brain. Really interesting. Thanks for sharing that, Ash. I guess a question I had like a little while ago is how do you persuade people to get involved in these experiments if you're causing pain and itch so much? borderline torture even. So. Where did I torture? any potential participants out there, experimental pain tends to not be the same as real pain. It's very rare that we can or should deliver the kinds of pains that you may feel in real life in a lab setting. It's incredibly well controlled. It all has to go through ethical approval. It tends to be incredibly short lasting. m And all and in fact the control is one of the reasons we do it in the lab and one of the reasons we do it because it has to be controllable and reproducible. So although we talk about torturing our participants and poking and prodding them and giving them pain and itch, it is you know a short lasting sensation that is not going to harm them. For the itch experiments, the itch usually goes away within five minutes. The redness of the skin that may last for like half an hour. For the pain experiments, literally the moment that pain sensation goes away, sorry, the moment the pain stimulus is withdrawn, the pain sensation tends to go away. We don't tend to do anything that will cause lasting damage, partly because we'd like you to come back. especially if we had a successful recording. So one of the best things about myconeurography is that unlike a lot of psychology experiments or possibly even the imaging experiments, it doesn't matter if it's the same body in the chair again, the next time round. What we're interested in is individual nerve fibers. So we could potentially use the same person and get multiple data sets from them. as long as we, you know, we do it safely each time. So we want our participants to be comfortable and happy. And a lot of the time they tend to be people who are well known to us and they are relaxed and they're comfortable and they're happy to be in the chair. Sometimes you have to stop them from falling asleep. um And so in that sense, the pain experiments, they tend not to be hugely unpleasant. One of the ones that I guess we've got a couple of pain stimulators, the hypertonic saline does feel like a real cramp sensation. um And we have a laser pain stimulator. We don't tend to use that with microneurography yet. I'm hoping to at one point set that up if we can, but... that does cause a uh very short-lived pain sensation that feels like real pain. It's like a splash of oil that you get from when you're cooking. And if you drop like a drop of water into and you get that splash back on your hand, that's what it feels like. It's a really, really, really, really sharp, sharp, sharp, short pain sensation. um But I guess the other way that we ensure that people come back or people sign up in the first place is that we always test everything out on ourselves as well. There is nobody in a pain research lab that doesn't know what their experiment feels like. I think that's pretty much a guarantee that everyone who is doing pain research has had the pain done to themselves multiple times or the itch. I remember so with One of the itch materials that we were using is called, I mentioned cowage. is uh spicules that come from a bean plant. And if you look at the papers, when I first did this, was working with cowage, one of the papers I was looking at as a reference talked about how they glued these individual spikes onto a stick. and then they would use that stick to gently prod against the skin in order to introduce that cowage itch onto their participants. So I sat there with a stick and some glue and these little tiny little microscopes and tweezers painstakingly trying to glue 20 of these spikes onto a stick and failing miserably and ending up just like with a mess of these itchy spikes. all over some like this paper towel that I had underneath and just glue all over my fingers and everything else so I thought what does this actually feel like so I took a little bit of one of those spikes and I rubbed it against my skin I thought well that's not too bad and then I find I've got this sort of bit of paper with lots of spikes all over I go well that wasn't so bad I can't feel anything that so I'll try a bit more and so I've got like 20 30 on this of paper that I'm rubbing against my skin for about 10 seconds or so. I don't feel anything at all and then I wait two minutes and then it's really itchy. Um, You learned the hard way. And then you go, this is why you don't do this. But again, it lasted for 10 minutes, 20 minutes or so and then we're fine. We also do tend to compensate our participants for their time. But also, I guess, if we're doing any kind of pain or anything with a patient population as well, what we tend to find is often... the patients really want to contribute and I think Beth you may find this with some of yours if you're looking at any clinical populations they're often the most motivated and the ones that most want to be there and sometimes you have to go look don't worry about it this is fine this was more than enough and they go no no I really want to help how can I come back Yeah, so many times, I've been told by at the end of if you want me to come back, not a problem. So I've contacted people who have just been diagnosed with Parkinson's disease and absolutely very keen to get involved. But I guess like even when we get control participants in, I think a big thing is like, oh, actually, I just want to help. When I say about, you know, there's a bit of compensation, like, no, don't want that, totally fine. I mean, I give it to them anyway. But I do find something similar even with the control. because mean, mine sitting on an MRI scanner for an hour isn't the nicest thing in the world, but I guess, yeah, people just want to help. I we try and make, I try and make my participant information sheets relatively scary. John Moore's helps with that because they're already like 40 pages long with all of the various like data things and all of the information that we have to include. within that, I also tend to make them relatively scary. It's like, you must be able to sit still for four hours at a time at least. You must be okay with having needles prodded in you. These are all the things that we'll be doing to you. These are all the things that may happen if it goes wrong. They've never gone wrong before, but this is what could happen. As a result, the people who do tend to volunteer, which are not always that many admittedly, um tend to be the most motivated and most interested. And I think one of the coolest things about myoconeurography is you get to sit there and listen to your own nerves and hear your own nerve fibers responding. So I can move a hair fibre on my skin or a single hair on my skin and see that nerve fibre responding which I think is one of the most amazing things that you can... if you're as geeky as I am I think it is one of the coolest things. You get to see it and hear it at the same time and the noises they make are incredible. So if you're as geeky as Adarsh is and wants to see and want to see your own nerves talk to you, hit him up. Absolutely, I also, what I'm getting from this is you're not going around breaking people's hands in your thing for pain, and you also torture yourself. So you make sure that... exactly. Have you ever seen those videos of the, I think it's in America, they have taser guns and they have to be tasered before they're allowed the taser gun. It's giving that. You have to do the full on experiments beforehand on yourself so you fully appreciate what you're administering. Definitely and I think one of the one of the things we say to anyone who's interested in myconeurography Obviously not a hard and fast rule But if you're interested in doing it, you should experience it as a participant because you've got to understand what that feels like as well um Generally speaking it's it's not uncomfortable the hardest thing is sitting still and Not drinking multiple cups of tea beforehand um But it's generally a relatively pleasant experience. can, unlike a lot of experiments where you're committing a large amount of time, like an fMRI experiment, you're committing a relatively large period of time and you can't go in wearing any metal and you've got to take out all your piercings and you've got to leave your phone behind in a metal cage somewhere outside in a different building and all of these things. With the micro neurography, we have had people trying to reply to emails and do some work while we've got needles in their arms. Not often, not always, but you you can be really, comfortable despite the fact that you're, taking up all of your time. And then comes the interesting parts when we actually find a no fiber that we're interested in poking and prodding. By that point, most people are really invested. Although we did have an experiment when we were in Sweden, I think it was... probably one of my best sessions where normally a micro neurography experiment can take anywhere from say 30 minutes to three hours before you find a recording that you're happy with and you can do things with. I was within the nerve and found a recording within 15 minutes and then we could not lose this nerve fiber. It was so clear and so clean and so such a good signal that we just could not get rid of it. So we had at one point, you know, two professors and three researchers distance and two medics and all, and all sorts of people coming in and out of the lab prodding this poor participants toes, trying to make this nerve fiber do things whilst we, whilst we recorded from it. So that's probably the, when, when, when, when you get a recording, that's probably the, most fun part but also it does mean that you get random people from all over the department coming along to poke you. uh I guess in interest of time, because you've been recording for about an hour, there's a few questions I wanted to ask or finish up on. One of them was sort of, you've done a lot of research in this area. Are there any findings which you were surprised by in your work? Or was there something which you found or you're part of which kind of jumped out to you being like, okay, this is different. This is not what we were expecting. um I think I've spoken about it before already. um Obviously, I find the whole research area fascinating and I have to make it clear that a lot of the work or pretty much all of the work that I do is alongside multiple other collaborators in different labs across the country. We're very lucky that Liverpool has got two microneurography labs in two different institutions, but we all work very, very closely together. um but we have multiple people working all over the world on and collaborating on these projects. And one of those kind of multi-people collaborations was this finding of the ultrafast neuroceptor. That started off as a much more simple project where basically we'd seen a paper that described a particular type of nerve fiber as a mammalian sort of feel uh it was a low threshold mechanoreceptor which basically means it's a touch receptor that responds to low forces much like many of the other nerve fibers that we'd found it hadn't really been particularly well described in humans and the paper described it as a mammalian nerve fiber so we thought okay well that's cool let's look for that we know we found them in the past let's describe them and we can describe them in humans as well as the mouse models that they that used. Really, really simple. And it was in the process of doing that experiment and it was a cross cross lab collaboration between our colleagues in between Liverpool and our colleagues and Linkshipping in Sweden. um And while we're doing these experiments, we keep finding this neurofibre that behaves not dissimilar to the one that we're looking for. but has this high threshold or high force profile that we've never seen before. That hasn't really been described ever before. And that was quite surprising that, and the shift that that project took as we find more and more of these and start to describe them. And then I guess how the cool development of science is how my colleagues then build up the story and then find collaborators in. in America who looking at patient populations where they have a particular type of um genetic mutation that has a particular ion channel that's different. And so this project grew from very simple of let's just find this in humans and describe it to let's describe something that we've never really seen before and have, I think, you know, in the region of 20 or 30 people on this paper, ultimately, it was a very, different project from where it started, so much more interesting potentially as well. Awesome. That's so cool how science grows as well. I think so. And I think that's that's that's one of the things I like a lot about this field is that is it's very it does tend to it feels very open and collaborative, I guess the the. em The number of micro neurography, micro neurography in the world and certainly single cell micro neurography is very, very small. ah If you got 20 of us in a building, that would be about half of the world's micro neurography if not more. um And there have been times when that has been the case and we've gone, okay, this is quite cool when all of these people ah do the same thing. and no one, it's a very, very small exclusive club, but it's also a very collaborative club, which is very, very nice to see. And I'm very, very lucky to be a part of that, I think. And it does mean that you get some very interesting science that comes out of it as well. And I think the same is probably in your fields as well, where I think it's always better when people are working together. Definitely more data, guess more power of a study, isn't it? just more ideas as well different different ways to do things or whatever come up And there's different thoughts, don't they? And when they're of combined together, it could be innovative Very much so, and I think different expertise, different perspectives. I think I'm very lucky that the lab I'm in at John Moores University is incredibly multidisciplinary by design. So we have me who tends to be very, very focused on the peripheral nervous system, very much focused on single cells. And then you have people who are um self-confessed health psychologists. and they look at, you know, population level and epidemiology and behavior change. And, um, it's always nice to see one influence the other and back and forth and you get to work with those people as well. and also, I guess if you're, if you have that same kind of collaborative attitude, um, I've been very lucky to be involved in projects in, um, computational neuroscience. So my micro neurography data. an experiment that I did in the researcher himself, stuck a needle in his nerve, got a recording from his nerve fibers and that data he then used in a computational model for a robotic hand. I have very little understanding of the computational stuff and the kind of modeling and all of those, the mathematics involved in all of that. My contribution was purely the the needling and the data but I get to be involved in a project looking at creating a computer model of what a real hand would respond like um in software. That's so cool. Next step of AI. Yes. Awesome, Beth, any final questions from you? guess the last kind of question I thought was, what made you get into this area? um A lot of luck, think. oh I think I've always, I've been very lucky to fall into some of my, some of the roles that I've been in. I didn't get the grades I wanted at A level. I tried and failed resets and didn't quite do as well as I was hoping to. So I went through to clearing and I was like, what do I want to do? Well, to be honest, I actually really want to do neuroscience. So I found a neuroscience degree on the clearing and it was like Aberdeen University. And they were like, yeah, we're fine. We'll take you. We'll give you a go. It's like, great. Where's Aberdeen? Oh. that is quite something if you didn't know what that was. I mean, you didn't do well in your A level, so kinda... that's just a question. Aberdeen on a map and then going, right, okay, it's a long way away. And then absolutely loving it. And then they came away from there with like a real interest in sort of in proper neuroscience and in brain computer interfaces and the kind of merging of technology and human neuroscience. And like I said, I didn't really want to do anything with animals. I... I was interested in psychology, um but I found it very, very difficult because I found that, you know, whereas I was very good at understanding sort of concepts, I was never very good at remembering that so and so in 1998 did X, Y, Z experiment and has this model of behavior. I didn't really quite get that, but I was always interested in sort of psychology as well as the neuroscience. And then I was like looking for a PhD and I was very lucky that the supervisory team was just about to advertise this project using micro neurography, a technique I'd never heard of. And I started frantically searching and trying to understand it. thought, wow, this is amazing. And then you get to do it and you get to experience it. think actually part of the interview, informal interview process was was having Needle stuck in me and trying to do a micro-neurography recording. uh we potentially they felt sorry for me after doing that a couple of times. then, yeah, actually we probably will give you the PhD project. And then I've been very lucky to just be continually involved and working with all of the right people um to build on that. And... um not just within microneurography but all kinds of pain and somatosensory projects as well. That's really nice, I think a lot of people always feel quite fearful to be like, actually I didn't do as well in some point in my life, but actually it's turned out for the better. I know being A levels were so stressful and I had quite a similar experience as well, I swear. Didn't do quite as well as I wanted to, went to my second choice and actually worked out so much better than my first choice would have done. So I think a good message to leave on is even if you don't do as well in the A levels you expect, it is not the end of the world. you take it and you run with it and it'll work out. you definitely say yes to those opportunities. One of the reasons I think, Beth, we spoke before the recording started about getting involved in um public engagement. so we've both been heavily involved in the Liverpool Neuroscience Group, which is bringing together neuroscientists from all across Liverpool. And one of the reasons I've always wanted to stay involved in that is just because the opportunity came up and I... wanted and I think just say yes to those opportunities where you can. um If you can say yes, if you can go to those meetings, if you can get involved, if you can, you will find that serendipity will lead you to places that you didn't think you would before. Saying yes to that potential PhD opportunity meant that I got to go to Moscow before all of the war and horrible things. but I got to go to Moscow to try and do a micro neurography experiment there, which was just incredible. um yes, and I guess the luckiest people are those who work the hardest by saying yes and working through those. But yeah Sure, no, that one didn't hit quite as well as we thought it would. I won't pretend to work overly hard now. Others may disagree and I would happily let them. I think you work pretty hard, Ardash. I think it's fair to say LNG would be lost, lost without your help. think working on things you enjoy is probably a better way to put it than working the hardest. and potentially finding people who also work very, who finding all the people that work hard for you is quite nice. That's ideal. I guess on that note, thank you very much. Thanks Adarsh for joining. Really appreciated it. And thank you everybody for listening and until next time, take care. Bye.