Tinnitus and the Power of Prediction - Dr. Will Sedley

But the thing I do occasionally take a bit of issue with is the argument that the treatments are there already and the reason they're not working is because of some types. That actually if we just took up a match to our existing treatments correctly to the right people that everyone or lots of people could be cured, I think the response I give to that is we'll show me the one person who cured and then we'll deal with why we're not curing everybody. Hey everyone, welcome to the Tinidistok podcast. I'm very happy to be here today with Will Siddley. Will is a researcher at Newcastle University in the UK and also a clinician in the field of neurology. Am I saying that correctly Will? You are, yes. Thanks Hazel. It's great to be here. Great to have you on. So can you maybe just start by telling our audience a bit about your background and what it is you do? Yeah, so I'm a medical graduate and I spend at least half my working life working in the neurology department that's running clinics and dealing with emergencies and referrals on the wards and then I've been fortunate enough to be able to be conducting research in areas of my interest in parallel with my clinical training ever since I got out of medical school. So I've been very interested really in just how the brain works and what goes on in the brain to shape our experience of ourselves in the world which is what's brought me to Tinidist which I've been working on for over 10 years now and has remained an enduring interest in mine. Yeah and can you tell us how that interest first got sparked because I imagine something must have happened that made you think okay, Tinidist might be an interesting or worthwhile subject to study. It's a good question and I'll be totally honest because I think this is relevant that that point where I realized yes Tinidist is a really interesting thing to study came considerably after I first made the decision to start working on Tinidist which really was pure accident. It's something my research supervisor suggested. I'd been working on very basic science processes by which I mean trying to understand normal functioning of the brain but without there being a direct applicability to people or patient groups struggling with any particular symptoms and it's suggested working on Tinidist and within a little while after of beginning that I think I began to realize that actually I mean I've always known this was an important problem. Experience by many and not not adequately solved you know not by a long shot and what it took me longer to realize although not that long was to really understand Tinidist you've got to understand every level of the sensory and perceptual pathways you know right down from the hair cells in the ear that turn sound energy into electrical energy right up to the brain's higher perceptual network and generic but very complex mechanisms for how we really make sense of the world around us and react to things. All right so if I understand correctly you kind of just happened on the topic and as you were studying it got more and more intrigued by it. Yeah so we started out by testing some really simple hypotheses that had been around at the time saying all will Tinidist is just directly correlated to this or that one particular process in the brain and that's that then all all you have to worry about is how that process is generated and I started out trying to replicate or support some of these theories and found that actually the results I was getting were really surprising and a much more complex pattern that could not be so easily explained and so I'd really started grappling with just however I think would be put together for a number of years really keeping on returning to it in light of the things we were still still learning about the condition and about neuroscience in general just in terms of how to explain things because it's funny you enter a field of research and you just assume that so much is known and what's what's been written is all correct and then the more you get into it you realize the less is actually known confidently and the more questions have raised and the more questions that answers are often raised so it was an illuminating experience entering this field. Yeah that's that's interesting and I guess it applies probably to a lot of fields but maybe particularly Tinidist because it's still very young right it's not that long ago that people started seriously looking into it. I think you're right that I think it is a young field and we may return to you know arguments as to whether it's generated the interest it deserves given its scale and an impact. So it's a young field and you know it's maybe not much over two decades that sort of serious attempt to pin down the neuroscience of Tinidist has been made and it's either towards the latter half of that there's been that real exponential expansion in the number of studies done but I don't think it's just that I think it is inherently an extremely difficult thing to study because it is a very subjective personal experience and I think a huge part of it is actually being just checking that we're measuring we're measuring the right thing that what we're measuring really is correlated to that experience of Tinidist and not so many of the other factors that surround it whether that's the hearing loss that predisposes you to it the alterations in attention that follow and the hyperaccusis that very often but not always goes with it. So this has been increasingly recognized recently that it's extremely hard to know even in human studies where people can tell you very eloquently what they're experiencing let alone animal studies where they can't tell you anything. Yeah exactly. For instance I've only recently understood that when you compare brain imaging pictures of people with Tinidist and without that a lot of what you're seeing is in in terms of the big structural differences is due to hearing loss and not Tinidist per se and so a lot of the early imaging studies on Tinidist that were done I think they didn't correct for hearing loss and therefore you can wonder in retrospect how valuable those results were. That's an incredibly important point you hit upon and you do just have to keep that in mind with every study you read about Tinidist and where it hasn't been controlled for hearing loss it's just as big question mark is it hearing loss Tinidist or hyperaccusis? I mean to the point that there was a review paper by Joseg Amont is a huge figure in the field with almost exactly that title of focusing on animal research of Tinidist and what we were really measuring but it's surprisingly difficult to control for hearing loss. One approach that's been taken for instances is study entirely people with with or without Tinidist who have normal hearing quote on quotes. The trouble is we know that the pure tone audiogram which is the standard clinical measure of hearing is not that sensitive to the various forms of hearing loss that exist it really just looks at one type of hair cell function and you can have really quite significant impairments and noise damage that's accumulated over time that isn't measured by this or you can't have measurable deficits then they're just very narrow this slip between the frequencies of the audiogram or their higher frequency than the normal audiogram goes to and again you can just end up measuring correlates of these subtle subtle changes in hearing unless you're very very careful. Yeah yeah exactly can you tell us a bit more about some of those early theories when you came into the field that that later turned out to be false or most or just much more complex than was initially thought. I'm not sure I've come across a single theory I would claim to be false as such but yeah as you say I think still an open question or perhaps not not the whole answer. I mean one interesting thing was that there's been this big ear or brain question and way back people assumed that because you heard the sound in the ear tinnitus was coming from the ear and there were a number of attempts made to try and cure tinnitus by severing the auditory nerve surgically that connects the ear to the brain and the fact that that very often made tinnitus worse was one of the very strong initial pieces of evidence for why tinnitus is generally now understood as a brain condition if it was just as simple as cutting off this firing that was being passed through to the brain from the ear that should get rid of it but it often made it worse and that's what led to this idea that actually the ear's role was to it until it was to have reduced input coming in and that the brain somehow did something a bit like phantom limb pain to overcompensate for that but actually it's still not that simple because what then got glossed over was the fact that some people's tinnitus did improve after cutting the auditory nerve. Yeah I recall that being the case. So not so straightforward and maybe some inter individual differences there and those interesting work that came out after I started in the field guinea pigs showing that you can give medication that only acts on the cochlear in the ear not has no action on the brain and that if you give that very early after causing tinnitus in animals, it looks like you may be able to get rid of the tinnitus just in those initial weeks. But there may be a critical period where that's the case after which the brain may take over, although some of the work to fill in and do those further studies hasn't been done, but that's the suggestion left by hand. Yeah, and in terms of other other popular theories, there's a very popular theory called phalamacortical dysrhythmia, which is popular when I started and remains popular, will all be it with some refinements. And what that had said is if you take away some of the normal input to the thalamus, which is the main sort of deep down relay station for sensory and other pathways, so that gets a lot of input coming up from the ear. And if you take some of that input away, it goes from what they call an alpha rhythm, which is eight to 12 cycles of activity per second, or bursts to a slower rhythm of more like four to six cycles per second. And that then projects up to the auditory cortex, the sort of higher hearing centres, and entrains it in part of it that's lost its input into this abnormal rhythm. And the idea was that the interface between the normal bit and the abnormal bit gave you these very fast, what they called gamma-rosolations, which are kind of 40 plus cycles per second. And that it was the gamma-rosolations themselves that triggered this perception. And that's what I says out, trying to test. I mean, as you say with many studies, there weren't always the best controls for hearing loss or age or other factors, attention and things, which can all influence these things. And the approach I took was one that wasn't new, but it was new in this context, with these measurements, which was to use residual inhibition, where you play a loud masking sound, and once you stop it, the tenetist takes a while to recover. And the theory was, well, look, if this is true, if these gamma-rosolations are the basis of tenetists, then when you suppress tenetists with residual inhibition, the gamma-rosolation should go down, and then they should return to normal, as the tenetist does. And we did see this in some individuals, so far, no surprises. The real surprise, and by far the stronger finding was we had a smaller group of people in whom the tenetist got temporarily louder after the mask has sat, which is something I called residual excitation, but there's otherwise no proper term for it than I know. And again, if these gamma-rosolations were the basis for tenetists, when the tenetists got louder after the acoustic stimulus, the gamma-rosolation should go up. But the weird thing was they went down. They showed absolutely the opposite trend, and this was consistent across every individual who showed this phenomenon, at both the individual and the group level. And that, thus, I found extremely difficult to reconcile with the contemporary theory, and it took me a long time to come up with what I thought was an adequate explanation for the findings. But I may refrain from going on too much about that at this point. Well, we can briefly get into that. What was your explanation? I did spend a number of years going over it, and eventually at the end of my PhD, I just wanted to put all the facts, everything I thought I knew or didn't know or may know about tenetists in one place, just put it all there, draw it in together, and just think, well, how do all these different bits at different levels of the auditory pathway and everything, everything all fit together? What's this really telling us? And part of what came out of that was the idea that there was a fairly newly emerged view. I mean, it's very well established now that not just looking at tenetists, but in general, these gamma oscillations. What they are, what they're indicating is prediction errors. Now, to explain what that means, we have to first accept, which is fairly widely accepted now, that the way perception works is we make a model of the world, whether that's what the different bits we hear or we see, or what's going on in the environment around us. And we update and maintain that model all the time, and that model, those models make predictions about what we're expecting our senses to tell us, and that's much more efficient than just waiting for our senses to keep on telling us every frame, so to speak. And then when our senses do pass the information on, those are compared against what the senses are telling us, are compared against the predictions we already generated, and that's used to update the predictions and to influence what we actually perceive. And one part of that, the prediction error, is the mismatch between what we expect it based on our models, and what our senses actually told us. And the view was that gamma oscillations are indicating prediction error. And at once, once we accept that, it frees things up a lot, because it means they don't have to simply correlate positively or correlate negatively with tenetists or be the cause. They're simply a signature that what the signal being passed on from the ear is to some extent not matching with the signal or with the expectation of the hearing part of the brain of what it thinks the meaningful real sounds in the environment are. And that led to this idea that actually perhaps the biggest difference between what really fundamentally separated people with tenetists from people equally predisposed with the same hearing loss who didn't have it, is whether they changed, whether their brain changed the predictions of what they were hearing to expect a constant sound. And the reason they change that is you've got this noisy signal coming up from the ear, which everybody has, but when you've got hearing loss, that's amplified. But then it's down to higher levels in the brain as to whether they accept this as a real sound. And that helps and get rid of those prediction errors by accepting it as real, but in doing so accepting something that on another level isn't real and all the consequences of that, or whether to keep on having these prediction errors and keep fighting it so to speak. And that depending on certain factors, the brain can go one way or another. That's what it led to this idea anyway. I think this is a nice segue, I guess, into you explaining your view theory model of how tenetists is generated. I think you were already sort of on the way to explaining how you see this. Absolutely. Yeah. So to take a step back, because I realized I was launched straight into the thick of it, what's been thought of as a basis for sentinitists for a long time, which I can take no credit for, is that firstly, every pathway in the brain has spontaneous firing of brain cells, spontaneous activity. That's just a thing they do. And the auditory system is no different. Now if you want an analogy here, for the visual system that's a bit more familiar to everybody, whether or not they get tenetists, if you go and stand somewhere completely pitched dark, there is not a single photon of light in the environment. And you concentrate on what you can see. You'll see phosphines as in little flashing, dancing, random blobs, colors and things like that. And what that is, it's not a hallucination. That is spontaneous cell firing from the retina being passed on upwards. And in fact, there's some good evidence showing that even if you take people who have no awareness of having tenetists or ever having had it for more seconds at a time now and then as everybody does, you put them in a soundproof room with no sound around and get them to concentrate on what they can hear, more than half will report hearing some high pitched sound, either a pure tone or a narrow band noise like any of us who get tenetists are familiar with, but quieter and only there and very quiet conditions. So in a sense, that spontaneous cell firing in the cochlear or the auditory nerve pathway is, for everybody, like it is in the visual system. It's normal. So to an extent, we have to see tenetists as the norm. What's abnormal is when it gets particularly prominent and starts to declare itself and just detract from other things, even in the presence of everyday sounds and background noise. So it's the extent not the presence per say. Could we say that for people who don't have tenetists that that's spontaneous firing from nerves in the auditory pathway is somehow filtered out of the conscious experience? I think that is exactly it. So at some point, the brain has to decide what to do with this information, with this cell firing and there's two ways it can go. It can accept it as a real perceptual entity, as a real thing in the environment, a real sound in this case. Or it can ignore it as noise and noise is in random activity that doesn't carry a meaning in the sort of information theory sense. And if it ignores it as noise, all it goes on and perceives is either silence, if there's nothing else going on or whatever other sounds are going on in the environment. So what would argue is actually that the signal is this, what I would call the tenetists precursor, this random firing is there in everybody. And normally it is ignored as noise because it's random, it doesn't correlate with anything else, there's no prior experience of it. There's a large number of cues inherent in it that tell the brain it's not important. Right. To clarify, when you say ignore, you don't mean like consciously ignore, but this happens at a subconscious, involuntary level. Absolutely. Absolutely. All of this taking place before anything reaches conscious attention. So conscious ignoring is more like it's bituation, which is a whole other matter, although we might draw parallels, but it is largely separate. So then in terms of things that predispose people to dynatists, again, this is nothing I can take credit for, but if you if you damage the input to certain nerve pathways from the ear by damaging the ear or the auditory nerve, then through homeostasis, the cells that are fed by those, they like to maintain the same overall firing rate. That's how much they fire in response to sounds they hear and spontaneous firing rate. And because they've been deprived of a lot of their input, that sort of response gain or volume is turned up to preserve the same firing rate. And what happens is most of that becomes spontaneous firing now. And that's well documented if you damage someone's hearing, a human or an animal, spontaneous firing rates go up significantly. And not only that, but how synchronous the firing is across different nerve cells again goes up. And that's important that if you have a lot of nerve cells all saying the same thing at the same time, they're much more impactful and are much more likely to affect ongoing brain processes than if they all say fire and say things at different times. So again, that's how someone's predisposed, but that you can have two people with the same hearing loss. One of whom gets tenet and one of whom doesn't. And what I've argued is the key step is this, it's this, it's whether it gets accepted as a sound source and therefore a model and a prediction and everything corresponding to it is set up, which suddenly correspond with the activity and then the whole system makes sense and you perceive it or whether whether that part of the system continues to ignore it as noise. So it's not, it's not just the hearing loss in that activity itself, but it's these other factors. And I'd come up with a list of a number of things that might influence this. And the term we use is precision, which is the brain's estimate of how important or reliable source of information like this tinnitus precursor, spontaneous firing signal is. And that's influenced by things like chemical factors, sleep deprivation, stress levels, attention plays a big part. So focusing attention in many views of brain function, focusing attention on a particular sensation is exactly the same as increasing the precision on it. So there could be a whole host of single or interacting factors that are changing all the time and depend on your individual state where you're focusing your attention, other things that are going on. And that what needs to happen for tinnitus to occur, I think, is that the together, these give that tinnitus precursor signal enough precision that it gets brought over that threshold where it gets accepted as a real sound source, a real sound entity and you hear it. And after that, it's only a matter of time before those, that sort of learning of it, that acceptance, that forming a prediction in a model to go with it becomes persistent. Once you've recognised it once, it's very hard. It's very hard to unlearn something, to forget it, or to no longer recognise it. The example I use, I know this is a podcast, so we can't quite illustrate it, but there's a very famous picture which is a load of black dots on a white background. And they just look like random dots at first, but if you look at it for long enough, at some point you realise it's a Dalmatian dog sniffing at the base of a tree. And once you've seen it, that pattern in it, you can't get rid of that. It doesn't matter how many years go by and you see that picture again, you'll see it straight away. And I think there's something similar with tinnitus that once you've seen the pattern in the meaning, again, totally subconsciously before anything, you have any choice over kicks in. Once you've seen that meaning in the pattern in the random firing, then you can't really shake it unless you get, unless you get rid of the random firing or suppress it enough that it goes back below the threshold, or you have enough competing noises or sound sources, or unless you were able to find a way to see how that learning process were actually maintained in the brain, which would be a very subtle thing that's to do with particular connections between multiple centres and disrupt that. So actually getting rid of tinnitus once is established, it's not to say it's impossible, but it's a huge challenge. Yeah, I think we want to get back to that later, for sure, but to maybe make an attempt to very crudely summarise your model. So can we say that someone with chronic tinnitus, their brain has learned to predict the tinnitus signal and because there's this prediction or expectation to hear the tinnitus, that is why you continue to hear it. Yes, I think absolutely. The prediction and the expectation is there, and there's still the spontaneous firing in the de-ordinary pathway that corresponds with it. So it's enough, the prediction is enough to keep hearing it, and that activity is enough to keep on reinforcing or not challenging the prediction. So you've talked a little bit already about that there's many factors that could go into sort of triggering this kind of prediction. Can you talk a bit more about that? And can you also explain whether you are saying that the brains of someone with tinnitus are innately predisposed to having this prediction or is it more like environmental factors, changes that cause the brain to start to predict the tinnitus signal? True, no, it's a good point, and I think there's two things here because what I'm arguing is the initiating event is actually getting the precision of this spontaneous firing in the pathway in the order true pathway, the tinnitus precursor. It's getting the precision high enough to get it noticed, and then there's sort of accepting it as a default state or default prediction so that there may be different factors that influence the two things. And I wasn't initially making any claims about genetic traits, although it would always kind of surprise me if there were no genetic and individual traits here because individual genetics affects so much. But I would say on an aside that more recently there has been some very nice work in the genetics of tinnitus coming out and there does seem to be a sin, it's not that it's a sort of hereditary condition, but there does seem to be a significant genetic element in that if you've got family members with tinnitus, you are more likely to develop it. It's always a little hard to tell and see through how much of that is explained through genetic susceptibility, susceptibility to hearing loss versus other factors, but there does seem to be a significant genetic component. Given that a lot of the factors that I think will determine whether you, you know, when and whether you get tinnitus related to your, you know, to the state, to your particular state of mind and physiology and everything at the time, I think there's likely to be, you know, genetic and personal elements to this and then a large part being particular circumstances just at the time on the day that these may fluctuate a lot from time to time and you've only got to be unlucky and get over that threshold once for long enough for the city and for the tinnitus to be learned. But anecdotally people, you know, I mean, you may get tinnitus at the same time as the hearing loss was caused, but the usual scenario is it's a gradual onset hearing loss and then people will say either the tinnitus came out of the blue or it appeared during a time of great stress or difficulty or when physical illness was happening. Sometimes it's other things, it's a very innocuous thing. So I saw somebody who had a hearing test, just a routine screening hearing test and then involves having to listen out very hard for quiet sounds in a quiet environment and the tinnitus just emerged during that and never went away again. I don't know whether you've got people who report similar things. But that seems quite a rare case, but on the other hand, it doesn't entirely surprise me and it does seem to fit with your model for sure. On the subject of whether people with tinnitus have fundamental differences in the way in which they form auditory predictions, there is some interesting work starting to come out about this. So I've got some colleagues based in Zeltzburg who've looked out the formation of auditory predictions in people with tinnitus and people without and these are very low frequency sounds in the range of normal hearing well away from the tinnitus. And it's a complex pattern of different pure tones and there's different structures and rules about how they're related to each other, so that it lends itself very well to people needing to form predictions in order to best predict and anticipate what's coming up. So naturally people will do that. And then by looking at the exact brain responses, you can see which frequency of sound is being represented or even predicted at any one moment in time. And the people with tinnitus, if anything, seemed to actually show a stronger or more accurate pattern of brain responses in terms of predicting what were genuinely likely to be the next upcoming sound. So they're almost more likely to have started representing the correct upcoming sound before it even started playing or at the time it started playing, but too soon for the response. to that sound to have occurred. They were anticipating it better in advance than people without tinnitus. So, you know, you could turn things on their heads and go, well, actually, given that we've all got this sound source there, that, you know, is the anomaly, is the worst performing brain actually the one that doesn't find the tinnitus and doesn't find the, doesn't find the pattern there. That's an interesting way of looking at it, yeah. So, the brains of people without tinnitus are worse at predicting sounds. I guess it's not necessarily an advantage that you want to have as a person with tinnitus, but it's an interesting way of looking at it. No, I think there's few people who would want to want that tinnitus, they've given the choice. Yeah, exactly. I think the best case scenario is something approaching and indifference. But, yeah, so these are new preliminary findings from a single study. So, I mentioned this as something, you know, people beginning to look at this rather than us being able to draw any firm conclusions. But, you know, I think things like this when we're dealing with conditions that are so common, we do need to try and ask ourselves, actually, is the condition itself of an evolutionary advantage or does the condition arise from other traits that present an evolutionary advantage? So, you know, that may turn out to be something to this. That's a very interesting question, and I hadn't considered that before, but I could imagine, you know, when we were all living in caves in the stone age, and if you're very attuned to environmental sounds and pick them up quicker or also more attuned to changes, if it sound is there and it goes away or the other way around, that could be an evolutionary advantage in terms of waking up in time when a predator comes close or things like that. It's a good point, and it makes a lot of sense and has a lot of a lot of face validity. I'd need to check and couldn't tell you whether, whether any such factors have been explored for intensities. I think it's always difficult once the intensities form to know what's a sort of predisposing traits versus a reaction or in some way a downstream consequence of the tenetus, but I like that thought. I like that thought and that would concord with the way in which I've been maybe starting to see things. So it seems like whatever it is that sets off the tenetus, it's got to be quite a complex interrelation of different factors, including spontaneous firing in nerve cells and then potentially some kind of genetic predisposition and then whatever environmental factors come in in terms of injury or disease or stress, those kinds of things. If that's the case, then I think a lot of people when they get tenetus, they start googling causes for tenetus and you find these lists online of causes. It's a long list, including things like certain medications, head and neck injuries, mayors disease, acoustic trauma, emotional stress, temporal and tubular joint disorder. But really we've got to say it's much more complicated than that and those things might be triggers but not per se causes. Would you agree with that assessment? Yeah, I think we should maybe draw a distinction between causes and mechanisms because causes are what would think about in a kind of medical or clinical setting, which are the things that put you at risk for the tangible things that put you at risk and then mechanisms is what's actually happening in the brain. I think the mechanisms are inevitably complex. But I think we can take a big step back and zoom out and actually reduce tenetus down to a pretty small number of simple elements. I think what we'd say is tenetus is your brain picking up on random cell firing in the auditory pathway as if it were a source of sound. Why this happens is either that is some combination of that random firing, getting amplified and becoming very loud or the brain tuning into it more or both risk factors wise. I tell people all you need to develop tenetus is generally some amount of hearing loss, which can be anywhere from mild or undetectable upwards. And all these other causes in my mind are just things that cause hearing loss. And yes, they're all worth considering but it's almost never the case that any of them are there. So you know, it is tenetus is a tendency to hear random cell firing in the auditory pathway as if it were real. The risk factors are hearing loss in anything that causes it and how it happens is some combination of amplification of that activity and changes in the brain's vigilance or the way it picks up on it. It's a condition or a state, not a disease as such, which doesn't detract from its impact in any way. And the only thing I add on top of that that I think it's relevant to pick up on aside from considering reversible causes of hearing loss is whether there are pointers towards somatic tenetus, which are TMJ or more commonly the cervical extensor muscles at the base of your neck just because there is some evidence that those can respond to successfully targeting those sources of muscle tension, which maybe around 20% of cases. But other than that, it's deal with hearing and then manage tenetus in the standard or one of the standard repertoire of ways for managing tenetus, which we may come onto when I realize are not not satisfactory for most. Right. Okay. I think that's a very nice summary of your model. Could you maybe talk a little bit about other models out there and you know, are they very different to your model and are these different models mutually exclusive or could they somehow all be true? So can you talk a bit about the other models? Yeah, no, absolutely. And I don't think they're mutually exclusive. And I think they're complementary. So I think it could be that multiple ones of these are true in each part of the story or some apply more than others in other cases. What I was trying to do is come up with a framework as such by which they can all work together and not be contradictory towards each other. But no, it's fairly, I mean, I, I've, it's fairly straightforward. I tend to see things in quite simplistic terms. So you either have something causing excess activity in the ear or the auditory periphery sending signals through that'll be peripheral tenetus. The next model is the ear's role is to be underactive, send to a little input and therefore the gain is turned up in the central pathway and it's just overactive for the central gain models. This is a popular model about fronto-strayatal gating whereby there's a or noise canceling, where there's a system that involves parts of the prefrontal cortex and basal ganglia. This feeds back into deep pathways in the ascending hearing pathway and can that has a gating role in determining what gets tuned down or filtered out and what gets tuned up. Yes, so you know, it where that fits in if that's the case, that's another gating, that's another gain model because ultimately all that's doing is turning up or down what finally gets through to auditory cortex. And then you decide, you know, do we think that's enough if it if a certain amount of input gets to auditory cortex will you hear tenetus, which I've argued, I don't think it's enough to explain things in which case you need another mechanism such as this sort of prediction based models whereby how do you actually, you know, how is that actually incorporated process interpreted and incorporated into perception and this involves some wider brain networks. And the only other real remaining model I'm aware of is then a sort of a, it's the sort of filling in model or the phantom limb type model where you say, well, actually a part of the auditory cortex has lost its input that it's just not getting from the ear and that what it's doing is therefore has to get it from somewhere else, which is either pull it in from neighboring parts of the auditory cortex from frequencies that haven't been damaged or damaged so much or pull it in from memory if the hearing so bad it's pulled in from memory. Those models, I think are difficult, I think that's the only one that doesn't fit really neatly with with the account of, I've put forward, it is a bit of an alternative. And then, you know, then you have to say, well, which, which is it, is there too much activity, too much gain, therefore too much comes from the auditory periphery, from the ascending pathway and reaches auditory cortex or is there not enough reaching auditory cortex and it has to pull it in in a top down manner from somewhere else. And I'm not, you can come up with nuanced ways in which they can be worked together. The other popular thing I mentioned, a popular model I mentioned was Thalamacortical Disrithmia, which again says that the Thalamus, the auditory hearing thalamus below the level of cortex isn't getting enough input. And therefore it goes into this mode where it changes its frequency and paradoxically it gets to a little input and that makes it give too much output. So that's another variation on central gain? It's another variation on central gain exactly and I think most of tenet, you know, most of tenet which comes down to central gain. If your angle is brain chemistry, too many excitatory chemicals, not enough inhibitory chemicals, again, that's gain. If you're interested in synchrony, so how into the firing of all your different cells in the auditory pathway across different frequencies are, again, that can be understood as gain, because ultimately they all pass their messages on to the same targets. And if they all fire at the same time, that triggers a much stronger response than if they all fire at different times. So again, a great deal can come down to gain, and I think it's useful to kind of think of a common currency here. The way I see it, it's gain, but it's something more, and it's how that signal is processed, not which is influenced by how much gain there is or how strong it is, but also by our predictive mechanisms, by precision, and how tuned into it, how receptive to it we are, how vigilant we are for sort of newer unfamiliar or potentially threatening sensations. Is this related to a comment or claim that you made in your 2016 publication entitled an Integrative Tinnitus model based on sensory precision, where you say something like all the other models face a paradox? Can you explain what you meant by that? It is sort of yeah. It is very much related to that, and I think what I was trying to solve were two issues with that paper, one of which was that the some of the models seemed contradictory to each other. And I was trying to explore whether we could put them into a framework by which they were no longer complement, no longer contradictory, but complementary or at least non mutually exclusive alternatives. And then the other things were what I highlighted is these paradoxes, for instance, if you were to take central gain as a model that actually hearing loss seems to be the main thing that changes central gain more so than Tinnitus. It's actually not that clear whether Tinnitus explains it any more central gain, once you've fully taken into account hearing loss and hyperacusis. And given that that would have occurred at the time the hearing loss occurred, and then you get these massive changes due to hearing loss and comparatively smaller changes if they do occur at all due to Tinnitus. Well how does that really present the whole explanation if the level of hearing loss isn't the predictor of Tinnitus, if the timing of the hearing loss isn't the predictor of Tinnitus, if actually you can go on and develop the Tinnitus as much later. Then again there's something unsolved and unexplained here. I think the other paradox is one I mentioned before with these high frequency fast gamma oscillations that they seem to have different relationships with Tinnitus in different settings or depending on exactly how Tinnitus changed. And again it starts telling you that they're really not the whole story, they're part of the story. So I think it was highlighting things like that that just showed the incompleteness of existing models. So one of our Tinnitus talk members submitted a question which has also occurred to me, whether any of these models can be really proven to be true with the current brain investigation tools that we have at our disposal such as MRI and ABR, etc. It's a really good question because each of these gives you some sort of indirect measure of brain activity and then the measurable brain activity gives you part of the story of what is actually going on underneath. I mean I sometimes liken this to it, we're trying to judge or prove the or measure the content or meaning of a conversation by listening from a few miles away by simply measuring the volume of the conversation and it's an extremely indirect measure. So what you end up having to do is construct theories or models of what you think may be going on underneath and then use that to sort of model what you would anticipate your things like the volume of conversational things you can measure, the brain responses we can see under different conditions and see if it all matches up. And obviously you know that the arguments are relative or models are relatively weaker when we just take all the existing data we have and say well what's the best explanation or the least worst explanation for it and a bit stronger if we can go well yes I'll do that based on that model if we run this or that new experiment then this is what we expect to find. That's a bit stronger if you then confirm that hypothesis. If you can truly sort of understand a system in mathematical terms or computational terms you can build a computational model, computerized model and see if you can use that to sort of fully explain tinnitus, perception or tinnitus behavior in animals under different conditions and that's been done for certain levels of the auditory pathway which are quite well understood. They're just not quite there for the more complex systems evolving higher brain centres as well. So I've been trying to do a sort of middle ground thing for now which is the second scenario saying well if this is our theory what else would we expect to find if we run these new experiments and have been running some of those new experiments and so far coming up with more or less what we would expect to see given given the model I'd come up with albeit there are always going to be other potential explanations so that something we have to continue working out. The short answer is it can be done but it is very difficult to really prove how something is working when it is a subjective perceptual entity that's an emergent property of these very wide, very detailed brain networks. It's not impossible, it's just a massive, massive challenge. Maybe this is a good transition for you to talk a bit more about your current research or your plans and what is it you most would like to find out going forward. I imagine you want to prove your theory to greater degree of certainty. Well if it's correct, I want to know what to discover what's going on, whatever that is, whether it concords with existing theory, my own or others or something totally different. The preferable answer is the correct one. But yeah, I'd like to understand Tinnitus better and get at what's going on. That's a good point in science, I guess, disproving a theory of as much value as proving it. Yes, there is. There's a time to knock things down when they're a bit too established in yet not adequate and there's a time to build when you're left saying, "Where do we go from here?" And to some extent it's an ongoing cycle of breaking and rebuilding. So I'd love to make headway with what's going on. I'd love to help work towards better treatments for Tinnitus. So barring any practical or financial constraints, what would you most like to research in the coming years? I'm really interested in Tinnitus and related conditions where there are ongoing unpleasant perceptual unwanted experiences, which include Tinnitus and also chronic pain and some other conditions like fibromyalgia and disturbances of sensory processing, of which pain can be a part even in the absence of tissue damage. And I think there's a lot of parallels. So I think with all of these and Tinnitus as much as ever in an ongoing fashion, try and really add like to nail down what it is that's controlling the extent to which sensations are tuned up, tuned down, allowed to reach conscious level or not in a way that opens the door to being able to modify that and tune things down that are too intense or too allowed like hyperaccusis or turn the switch back on things that are there when they shouldn't be like Tinnitus or ongoing pain. And I think there's a lot of parallels across the different fields because fundamentally the brain isn't going to have totally different tools redesigned from the ground up from one modality like bodily touch sensation to another like hearing to another like vision. The commonalities are going to be very large here. So I'm really kind of looking to try and understand the fundamentals of these systems but in a very clinically relevant way and never losing the focus on Tinnitus here. So you will be studying actually these different conditions that are perhaps analogous to Tinnitus such as chronic pain you mentioned? Yeah. I mean the plan is to continue to spearhead things with Tinnitus. I think the research is much more, you know, particularly mine is much more established in the methods. So I think that for the foreseeable future will remain my primary focus but I'm keen to sort of start to bring what we're learning from this to other conditions subsequently. And I think eat the study of it's one of these things where actually you can often make less progress focusing too narrowly on one thing as opposed to considering the bigger picture when when you're. dealing with things that are so similar? So a few months ago, you shared with the Tenet Stoke community and there's a thread you can find on the forum for our listeners. You shared with us a research idea which entails different elements, but amongst those elements is finding or defining an objective marker of Tenetists. So can you talk a bit more about that? What is currently the closest thing we have to an objective measure and why is it so important to have a reliable objective measure of Tenetists? Yeah, it's a good question and the first thing I'd say is nothing is intended to become a diagnostic test because we're fortunate that you're anyone working with people with Tenetists has a very reliable measure which is more reliable than any medical test will be and that is simply asking the person, what are you hearing or even just do you have Tenetists? There is, I think for research points of view, it's useful to have objective measures, particularly objective measures that are tied to or linked to particular parts of the mechanisms of a condition so that if you're testing treatments, for instance, you can tell not only that someone says their symptoms are better but also that you can see some additional line of evidence that you're modifying the related brain processes assuming the treatment works on those processes. So that's a desirable thing, it's not essential and you can absolutely get by just asking people if their symptoms are better and if you conduct your studies properly and have a good placebo group, then you'll still see your effects. But nonetheless, it has still been a bit of a barrier for the drug companies and enticing them to invest in Tenetists research. I think the bigger issue is for animal studies where there's so much more we can learn about brain mechanisms, there's things we can do in animal studies, not that I do them myself, but I recognise their importance in animal studies that we can't in humans, not ethically or not feasibly. And for that, it is really important to know is your animal hearing Tenetists or not because otherwise you may be misled into studying the wrong condition and studying hearing loss or hyperaccuses or impaired other aspects of impaired sound processing that follow what you do to the animals. And there are measures of Tenetist in animals and these are ingenious, some brilliant creative minds have gone into producing these and by and large, they fall into two categories. You either train an animal to do something or not do something, a particular behaviour in the presence of noise and then you do whatever you think may cause the Tenetists to see how it behaves, whether it's behaving like there's a noise there or it isn't. Or you can look at the startle response, sort of involuntary responses that don't need that prior for a laborious training. That's the main one is this gap pre-pulse inhibition. So there's something called the acoustic startle response. If there's a very loud sound, it's startling and for rodents they actually should visibly twitch and move their ears and things like that and that can be measured quantitatively. And if you give a warning, an implicit warning that startling stimulus is about to occur, then there's less of a startle because they were expecting it. And one form that that warning can take is that you can play an acquired ongoing narrow band sound of some kind and there can be a short gap in that sound very shortly before the startling stimulus will sound and that diminishes the startle response because they were expecting it. However, the line of reasoning goes if you've got Tenetists and it will feel in the gap in that sound so you won't hear the gap and therefore you won't be any less startled than you would have done without the gap. And there's a way you can compare with gap without gap, different frequencies and things and to come up with this index of whether the animal has Tenetists. And there's a number of controversies here and there's also the fact that this is not clearly replicable in humans so that there's no validation against any gold standard for any of these measures. You can kind of you can show that some animals will behave in the manner that you think they should behave if they have Tenetists and that that is more likely to occur after you damage their hearing or not overexpose them to noise. But there's no gold standard at which you can go, well actually this is the accuracy, this is not. So at the moment we have this big unknown over how accurate the animal models are, they may be brilliant, they may be very much misleading us and it's very hard to be sure. So what I was, what I'm very interested in is can we come up with an objective market in humans that then the animal research community could use equally in animals and if it can be validated to be very accurate in humans they could either use that as a test for Tenetists in animals or even just use it to validate the existing models which ever proves to be more more convenient. And once you have that and you absolutely know which animals are experiencing Tenetists, then actually the results of one can put a lot more stock in the accuracy of the results of any of the studies derived from those methods really. So it is again a bit of a limiting factor on these lines of research and again if your measure doesn't accurately reflect Tenetists but something else and then you come up with a medication that you give to animals and it normalises it, you may be treating something other than Tenetists and that would be one of the several possible reasons that treatments that work in animals often don't seem to work in humans. So it is really important to know particularly in animals and what it is we're actually studying. So what objective measure are you proposing? Because I think it is related to your prediction model correct? It is absolutely yes. So the idea is we can't measure predictions themselves in the brain. These are just at a level of subtlety. They're down to connections between large numbers of cells, not any activity we can observe. But what we can make use of is that there are well characterized brain responses, even ones you can measure with EEG for instance, that indicate the violation of predictions and the more strongly a prediction has been violated, the bigger this brain response. So with the right different conditions that you're measuring these prediction violation responses across you can start to work backwards and say well actually it's telling us this or that about about the predictions. So what I'm focusing on is again my theory that people with Tenetists have an ongoing prediction of a Tenetist like sound, a sort of quiet ongoing sound at a particular frequency. And the idea was that that prediction may not necessarily only act on the firing, the spontaneous firing that causes the Tenetist itself, but may act on other sounds of similar frequencies played. And it's quite a simple design what we've been using. You just play a series of beeps at the Tenetist frequency or close to it at a particular intensity that's generally louder than the Tenetists. And then every so often they switch and they switch and they go louder in intensity and they place the louder ones for a while. And then every so often there's a switch back to the quieter ones and it just all today it's at random intervals between loud and quiet. And every time there's a switch this so-called deviant response because there's a deviation of the the intensity or the loudness of the sound. That triggers a large brain response where there's been this perceptual change. What I hypothesized is that actually because in one case when the sounds getting louder it's getting less like the Tenetists and in the other kind of deviant it's getting quieter and getting more like the Tenetists. We should see an asymmetry here that the ones getting less like the Tenetists should give you a much bigger mismatch or deviant response because they're more unexpected and the ones that get more like the Tenetists should actually have been much more expected. And so what we expect is very much that asymmetry that sounds getting a bit louder should give you a much larger response than the ones getting quieter. And this is after correcting for straightforward things just like the responses to the different sound loudnesses themselves. And that's what we've seen in the initial studies, in the first few studies. So it's encouraging. It seems to support the hypothesis and potentially have potentially, which should be a strong enough effect to actually help tell you whether not only a group of people but whether an individual has Tenetists or not. So there's further work ongoing that Kate, my PhD student, is doing to replicate this, to refine the methods, try and make me affect as strong as they can and run some additional controlled experiments to be sure that we are really the reason for these effects really is the reason we think because obviously as I've mentioned there can be other explanations we haven't thought of. So what level of accuracy have you been able to achieve in terms of this test being able to determine does someone have Tenetists or not? Yeah, so we look at something called the ROC or receiver operator characteristic curve, which is something you make for any diagnostic test in it. It looks at all the different positions you can put your cutoff point, your threshold, what you say is a positive or a negative test. So at one end you could say you could set a very low threshold and so you would detect everybody with Tenetists because they'd all be over that threshold. But you'd also probably detect everybody without Tenetists. So that's what you'd call a test that's it's sensitive because it picks up everyone but it's not very specific. So even if you test positive it doesn't mean you have that condition and at the other end you could set the threshold very high. you detected almost nobody with Tinnitus, but you were fairly confident that if they tested positive they would have it. And you can draw a graph of every different place you can put your cutoff. You can look at the area under the curve of that graph, and a perfect test has an area under the curve of 1, meaning it perfectly discriminates everybody. And a useless test, it's 50%, so it's no better than chance. So it's about an 0.5 area, we were up to about 0.74 if I recall correctly. So about halfway in between, which is what gets classed as fair diagnostic accuracy, not quite good and not excellent, but still showing some significant value. We'll have to see what that comes out as for the replication study, and then with further refinements of the methods. We'll have to wait a little bit longer due to the global pandemic for when we get those next results. Of course, yeah, that's been affecting many, many researchers. And does a refinement of this objective measure also help you to refine your model of the mechanisms underlying mechanisms of Tinnitus? I think there's two ways in which we're sort of trying to move things forward. So there's refining it just to make it, just to give you as clear a result as possible, which should make it a more useful test. But not shed any more light on the basis, you know, the actual mechanisms behind it or proving models. And then the other thing we're looking at doing is slightly changing the methods and exploring slightly different conditions again to just try and approach, testing that hypothesis from slightly different angles and see if it holds up to an unit to additional conditions and relaxing some of the assumptions we've made. So it's a little bit of both probably with separate experiments. And I understand you're also working or planning to work on some type of sound therapy. Can you tell us a bit more about that? Yeah, so that's something something we'll hope to hope to start testing fairly soon. It's a little bit more work for the infrastructure to be done. Now there's obviously been a lot of sound therapies tested in Tinnitus before most of which haven't worked and the remainder may work a bit. It's not that clear. There are some that seem to work slightly, but yeah, one has to bear in mind that when you approach these just from history of how they've gone before, there's a high chance that it doesn't work. But it is taking a new approach. It's not something that's been tested before. And it is again focusing on this concept of precision, which is the the cue to how relevant or how important that activity in the auditory pathway that gives rise to Tinnitus is. And we've said that there's too much, too much synchrity associated with Tinnitus and probably hearing loss that cells are firing in the same rhythms at the same time and that makes their message much more powerful and harder to ignore. And you can look at this two ways either as breaking up synchrity or aiming to break up or reduce precision. But it's all it's all down to sounds. We've got these sounds and how the different the relationship between the firing rates will cause in different frequency channels at different times and how these are varied. Again, to try and to try and break up any systematic relationships between them and kind of teach the the cells in each in each frequency channel to be firing at different times and not correlate with each other. So that's the idea. It's anything else I want to say. We're on the subject would probably just be excessive jargon at the moment. All right. What are you hoping for? Ideally, what would be the ideal outcome of that therapy? The ideal outcome would be that people's Tinnitus gets quieter. So just to be clear, this is not intended. It is not sound therapy aiming to promote coping and habituation. This is aiming to suppress the loudness of Tinnitus. I think if it has any effect there, then that's great. And you know that really gives us something to run with. It may it may be that it doesn't. I mean, I should say I've got three different slight variations on the theme to test. So there's always a chance that at least one of them does. But I really don't want to promise too much and risk creating false hopes because as I say, there have been a lot of sound therapies tried. This is just one more to test. But if it works, the idea is to make this widely available. So once this is up and running, I don't want anyone to be too bothered about whether they get into initial studies or not because if it works, there's going to be more and it's going to be widely available. So don't no one's going to miss the boat as such. Okay. Good to know. Where do you stand on the issue of sub-typing? Because I've it's in recent years, more and more researchers have started saying that if and when we find a cure, it will actually be different cures for different patient groups because tinnitus is such a heterogeneous condition and you can't compare one type of tinnitus with the other. Would you agree with that? Yeah. I mean, this is a long-standing raging debate. There is clearly a diminimum heterogeneity. So tinnitus does vary. Well, to some extent, it is causes certainly in the perceptual features and its characteristics. So does that mean that there's just a smooth spectrum across all these different factors? There's one condition that can just occupy different points or are there distinct sub-types that are just fundamentally different through all their mechanisms. I couldn't tell you anything authoritative on the subject. My feeling is that I'm quite content with heterogeneity rather than sub-types unless compelling evidence comes along that there really are distinct sub-types that are just fundamentally separable throughout all levels of the pathway. I can believe a sort of single middle common pathway. There's something, perhaps again, to the model I'd put forward in 2016 that is common to all tinnitus and then when you move a bit upstream from there in the causes, different balances of causes, different combinations and then again moving downstream slightly different characteristics and reactions. I suppose whether you need different treatments for different ones, whether that's the case, it depends on are you intervening with that core bit of the mechanism that's common to all? Or are you intervening with something a bit further out that is just addressing one of many potential causes? Right. Something more peripheral, perhaps, like a somatic tinnitus where you can resolve it by correcting a jaw issue or something. Quite, yeah, I think that would be a very good example which might not work in someone where there isn't any somatic influence there. So I think that's a very open question whether we need one or many treatments, it really depends what those treatments are going to be and yeah, sub-typing versus heterogeneity. What's this space really? It's a very difficult thing to prove because actually most studies will only show sort of group level differences and it can become quite artificial how you put your groups together. So it's a tricky thing to tricky thing to deal with. Yeah, I haven't heard one sort of authoritative concept of what the subtype categories then should be. No, no, and every time I meet it, every time I would any venue where this is being discussed, I sort of stick my head off of the parapet and go, well, I'm not persuaded that some types exist. I'd like to see some evidence and I have yet for this to be met with anyone claiming that there is solid evidence. So I think we just don't know, I'm just sharing a personal viewpoint. But the thing I do occasionally take a bit of issue with is the argument that the treatments are there already and the reason they're not working is because of subtypes. That actually if we just took up a match to our existing treatments correctly to the right people that everyone or lots of people could be cured, I mean, I think the response I give to that is we'll show me the one person you've cured and then we'll then we'll deal with why we're not curing everybody. That's a good one. Yeah, because those cases are few and far between and we see it on the Tinnitus talk forum. Obviously, I don't have hard statistics, but you know, I feel like we would see a lot more people there saying, okay, my Tinnitus completely went away after trying this or that and it just doesn't happen that often. Maybe last question in terms of cures and treatments, would you view acute Tinnitus and chronic Tinnitus as two separate conditions that would require different treatments and do you believe it should be possible theoretically to treat or cure Tinnitus regardless of how long someone has had it? I see them as the same condition, but there may be some differences in the acute and chronic states. And the reason I see them as the same condition is there's quite compelling evidence now that by the time Tinnitus has been there for four weeks, unfortunately, unless there's a reversible cause of hearing loss that it was that happened at the onset like loud noise exposure or an ear infection. You've only got about a 10% chance of it disappearing by six months and if it's there by six months, it's likely to continue long term. It's not to say anyone newly developing Tinnitus to be put off, obviously there's huge, there are naturally huge improvements for most people in awareness and suffering and distress and the impact of Tinnitus, but I see I'm seeing them as the same condition. Now I do think that it's probable that there's a shift in terms of, I mean, I think probably there's what I'd call precipitating mechanisms that actually cause the Tinnitus to occur to begin with and these are things that impact on sensory precision and get it over that threshold. And then maybe perpetuating mechanisms that are to do with learning the tinnitus prediction and pattern that may be coming over time. I think it might be hard to draw an absolute hard distinction what you've probably got as more of one at the beginning and more of the other later on. And then there is evidence showing that there are probably some brain network changes that continue to happen even after years with tinnitus, how critical they are to maintaining it. I don't know. It's hard to say. I think we're all working, you know, everyone's working towards trying to come up with eventually ways of getting rid of tinnitus regardless of its stage. And I don't see anything that should make it fundamentally impossible to get rid of. That said, I think it's highly likely that if there are things that help suppress tinnitus, that there'd be more effective in the early stages, and it would be a bit weird if it wasn't. Certainly if you look at the pain literature, there's overwhelming evidence for the benefit of pain killers and neuropathic pain agents for acute pain. For chronic pain, the evidence is really not so compelling. They're still used. But actually, I've got a number of colleagues in neurology who spend a lot of time just trying to get people off long-term side effect, laid-in pain killers for ongoing pain that isn't responding to them. And when they manage it, the person is no worse with their pain, but they're better with all the other side effects. So I think it's a bit of both. I think if any of our existing drugs do work on tinnitus, they're probably more likely to be effective earlier on. But then I've also said at the same time, I don't think any of the existing drugs we have are going to be the ultimate tinnitus cure, which we're still working towards. So will I'm mindful of having already taken quite a bit of your time on a Sunday morning. Maybe we can wrap up the discussion by talking a little bit still about collaboration within the research field with patients and funding issues and such. How do you see your work in relation to the overall tinnitus research community? Do you think there's enough collaboration there? Are there more synergies that could be leveraged? Yeah, I mean, there's great things like the tri tinnitus research initiative, you know, really established structures to get networks of researchers working together with collaborations, common methods and all of that. So I mean, I think I'm sure that as with everything, there's always more that can be done. But I think there's been really positive things put in place to facilitate this. And I speak with other people in other centres across the tinnitus field, to share ideas or share methods and things. So I think it's all there. I don't think there's much of people being too cagey with their ideas and methods and not sharing them. So as to hold things back particularly. I mean, I can see that if people are sort of in the middle of a clinical trial or something, they'll keep their cards close to their chest, just while that's running in that. But aside from those things, I mean, more collaborations always better. And I think we don't so much need it to be able to run big studies because actually because tinnitus is so common, there are so many people with it. It's not like some of these rare medical conditions where you need huge international trials just to get sufficient numbers. And actually people with tinnitus are just, you know, it's quite inspiring how incredibly enthusiastic about taking part in research. That, you know, Verona, Matt seems to be with tinnitus really. So, you know, I think collaboration and talking, sharing of all of these things is all very important. You know, will that ultimately be what gives us the breakthroughs? Who knows? I think there's got to be enough collaborative thoughts so that people are sort of end up on the same page about things and not coming into conflict too much. And then there has to be enough independent thoughts so people don't get sucked into the trap of accepting things as definitely true that aren't actually true. Or, you know, just following accepted wisdom too much. I probably collaborate less than I shared and work a bit too independently. Well, whether that's a good thing or a bad thing, which side of the optimal amount of money I'm not sure. But I probably tend to try and accept nothing is given and pursue my own ideas. Let's talk a bit also about collaboration with patients or people who have tinnitus. So, you actually came to us a few months ago seeking input from the tinnitus talk community for your new research idea. Why was that important to you? I think it's always important because, you know, as I think as researchers, we can have an idea about what we think is important. But actually, at the end of the day, we are fueled by public money, donated money, the generosity of time and effort of everybody who chooses to volunteer in research and for the benefit of people living with a particular condition. And I think a big part of it was wanting to, it's really wanting to check that actually people living with tinnitus thought that this was a worthwhile thing to be doing was a worthwhile approach to take. I was aware that in my mind to really understand the bits I'm interested in if tinnitus and think will make the difference. One needs to take a step back into basic science to an extent because there's parts of just normal functioning that are not sufficiently understood, as well as a little bit of side step as I was saying into related conditions. So again, it's part of it sort of checking that people wouldn't feel, would still think this was worthwhile, wouldn't feel short-changed at widening the focus there. And then there's more sort of a technical, pragmatic manner is about what it's like to be involved in the research, the methodologies, the methodologies use, actually just understanding the rationale for it, you know, it's not all about just the distant delivering of a cure, but the knowledge gained and what we can be reporting back to people that, hey, you know, we're not there yet, but we've found this or we've found that. So yeah, I think it was a number of approaches and then, in fact, these are people who think a lot about tinnitus and care a lot about tinnitus. And I think it's important to value everybody's thoughts because everybody can have good ideas and it's often only when you sort of present things in a more open forum, you start opening yourself to just other ideas and things you wouldn't have considered otherwise. Yeah, it's um, we did a poll a year or so ago, which a few hundred people answered asking them, which stage of the research would you most like to see more patient involvement, you know, so there's the initial, the research ideas or the research agenda, there's then research designed, then the clinical trials, then data analysis and communication of outcomes, etc. So you've got the whole, all the phases of the research there and overwhelmingly people wanted to be involved earlier on. So actually at the very conception of, you know, new research ideas. And I thought that was a really interesting and telling outcome. And I think therefore all the more we appreciate it, you know, you coming to us with a new idea and asking for, for input because what we see all to often is that we, that patients do get involved or consulted, but at a time moment when basically the whole plan is already set in stone. And there's not really any room for further influence there. That's what happens when we get invited to research consortiums like Tynact and E-Sit, not that we don't value being a part of that. There is definitely value in that, but we didn't get to influence the research agendas there. So that's, I think we'd like to see more of that. So I think you're setting a good trend, hopefully, in that regard. Good, hopefully. Yeah. No, I think that's, I think that's how it should be. You just, there's much more room to influence things if you're involved earlier. Is there anything else that we as a patient community could do to influence the research agenda, you think? I think it's really difficult. I think the, I think the biggest two things are joining the campaign for increased funding and, you know, dedicated funding for research or clinical care for Tynatus, which is going on. And the other side to things is, it's the harder one, which is getting more people interested in it, which is, it's a sort of public, public awareness, you know, gradually fueling an increased public awareness of the existence of Tynatus, the impact, and the huge challenge, the huge challenge in tackling it. Yeah, yeah. It's definitely a challenge. We'll keep pushing for sure for, for that funding and increased awareness and attention. Will I want to thank you so much for this very insightful discussion. Again, sacrificing half your free Sunday. Thank you so much. That's quite a, my pleasure, my pleasure. It's Monday, by the way. Oh, it's Monday. It's funny, funny, the things locked out, Mr. One. I said that I said Sunday before then. Yeah, so I took the day off from my day job. So in my mind, it's Sunday. Yeah, I do this all the time. Yeah, yeah, and you have a regular day off, I think, for your family on Monday, correct? More or less, yeah. It usually ends up for the things I have to be done. Work anyway, yeah, exactly. Yeah, yeah. All right. Well, then thanks for it. Never the less for sacrificing your time. Yeah. My absolute pleasure. Thanks for having me and thanks for a very enjoyable discussion.