1. I reckon if the trial results really are good from FX-322, SPI-1005 and OTO-413 it will firstly alleviate a lot of people's concerns and secondly also actually mean that treatment will be coming sometime soon after hopefully. Having a look at the desires of these companies, I cannot see them delaying access to treatment if they are ultimately demonstrated to be successful.My thoughts on the timeline for the next few years.
2021: Good news and trial results. FX-322, OTO-413, and SPI-1005 (might even be released by then).
2022: More results/good news. Possibly some news from Hough Ear Institute regarding their pill and maybe Dr. Shore's device will be released (have my doubts though).
2023: OTO-413 should be released, SPI-1005 will definitely be released if not already released, all Trobalt variants should be out or really close. FX-322 should be either done or close to done with phase 3 (provided they don't have a phase 2b) and possibly available for compassionate use.
2024: Everything released or very close to being released.
2025: Freedom for almost all of us.
Some exciting new research has just been published - as of last week looking at the function of the outer hair cells and the Type 2 afferents post-trauma. This is from Paul Fuchs and his team at Johns Hopkins. I also posted this on a thread in the hyperacusis sub-section but figured I'd post it here as well.
It's entitled Acoustic Trauma Increases Ribbon Number and Size in Outer Hair Cells of the Mouse Cochlea
https://link.springer.com/article/10.1007/s10162-020-00777-w
So how do we reconcile this with our current knowledge of the ear? Clearly, this seems to stand in contradiction to the prevailing theories of tinnitus, or at the very least, make it seem that currently proposed therapies do not address what's happening here.
Type 2 afferent of the OHCs are the "pain receptor neurons." The synapses in "cochlear synaptopathy" are between the IHCs and the SGNs. There is no contradiction. Type 2 afferents are involved in noxacusis, not tinnitus.So how do we reconcile this with our current knowledge of the ear? Clearly, this seems to stand in contradiction to the prevailing theories of tinnitus.
Hey, @100Hz, would love to read your assessment of this one!Some exciting new research has just been published - as of last week looking at the function of the outer hair cells and the Type 2 afferents post-trauma. This is from Paul Fuchs and his team at Johns Hopkins. I also posted this on a thread in the hyperacusis sub-section but figured I'd post it here as well.
It's entitled Acoustic Trauma Increases Ribbon Number and Size in Outer Hair Cells of the Mouse Cochlea
https://link.springer.com/article/10.1007/s10162-020-00777-w
I misread it as acoustic trauma increases size of the outer hair cells... my bad.Type 2 afferent of the OHCs are the "pain receptor neurons." The synapses in "cochlear synaptopathy" are between the IHCs and the SGNs. There is no contradiction. Type 2 afferents are involved in noxacusis, not tinnitus.
So here's a quote from the study:Some exciting new research has just been published - as of last week looking at the function of the outer hair cells and the Type 2 afferents post-trauma. This is from Paul Fuchs and his team at Johns Hopkins. I also posted this on a thread in the hyperacusis sub-section but figured I'd post it here as well.
It's entitled Acoustic Trauma Increases Ribbon Number and Size in Outer Hair Cells of the Mouse Cochlea
https://link.springer.com/article/10.1007/s10162-020-00777-w
Wow, so the hyperacusis-nut might basically be cracked?Some exciting new research has just been published - as of last week looking at the function of the outer hair cells and the Type 2 afferents post-trauma. This is from Paul Fuchs and his team at Johns Hopkins. I also posted this on a thread in the hyperacusis sub-section but figured I'd post it here as well.
It's entitled Acoustic Trauma Increases Ribbon Number and Size in Outer Hair Cells of the Mouse Cochlea
https://link.springer.com/article/10.1007/s10162-020-00777-w
This might give us some solace though: "It is not yet known how long the change in number of OHC ribbon synapses may persist...".
I wouldn't say cracked but it's given us more ideas and insights. They caution at the end of the paper that many questions still remain unanswered.Wow, so the hyperacusis-nut might basically be cracked?
We have a potential mechanism for initial and maybe ongoing sensitization. We don't know how to turn it off. How do you reduce synapses? Based on a lack of progress in solving phantom limb pain/neuropathy in general, I don't think science understands how to reverse maladaptive synaptic plasticity yet.Wow, so the hyperacusis-nut might basically be cracked?
Yeah sorry, I didn't mean "nut cracked" in terms of treatment, more in explanation of the condition.We have a potential mechanism for initial and maybe ongoing sensitization. We don't know how to turn it off. How do you reduce synapses? Based on a lack of progress in solving phantom limb pain/neuropathy in general, I don't think science understands how to reverse maladaptive synaptic plasticity yet.
Something I was speculating about - it seems like the type 1 afferents decrease as a result of acoustic trauma whilst there's an increase in the type 2s.We have a potential mechanism for initial and maybe ongoing sensitization. We don't know how to turn it off. How do you reduce synapses? Based on a lack of progress in solving phantom limb pain/neuropathy in general, I don't think science understands how to reverse maladaptive synaptic plasticity yet.
That was a very interesting study.Something I was speculating about - it seems like the type 1 afferents decrease as a result of acoustic trauma whilst there's an increase in the type 2s.
This is just something I wondered in light of something Paul Fuchs has said -that in the normal nervous system, there is a balance between input coming on pain fibers and input coming on the cognitive, touch, motion or other fibres - that these cognitive nerve fibers inhibit the pain pathway.
He also said that when it comes to tinnitus, as we begin to lose inputs that are delivered by the cognitive nerve fibers that tell us about sound, then it's possible that the type 2 neurons begin to gain more or stronger access to parts of the nervous system which mediate pain.
I'm just widely speculating here but could that possibly suggest that synaptopathy drugs could play a role? If you can restore the input that's been lost by the type 1 fibers, then could that possibly downregulate the type 2 fibers and reverse the maladaptive plasticity that has taken place leading to a more 'normalised' auditory system once more?
I could be completely off-base here but it made me think. But then again, I feel like from the way Liberman has referred to noxacusis, it seems like a totally different entity? So I'm not sure.
Great question @serendipity1996 and I've been having exactly the same thoughts since you shared that study. I have since read this recent study by Wong et al., which looks at synaptic ribbon regulation in zebrafish. It has some interesting parallels with the Paul Fuchs study and raises some interesting questions. Here are just a few quotes below from that study and my thoughts on them:Something I was speculating about - it seems like the type 1 afferents decrease as a result of acoustic trauma whilst there's an increase in the type 2s.
This is just something I wondered in light of something Paul Fuchs has said -that in the normal nervous system, there is a balance between input coming on pain fibers and input coming on the cognitive, touch, motion or other fibres - that these cognitive nerve fibers inhibit the pain pathway.
He also said that when it comes to tinnitus, as we begin to lose inputs that are delivered by the cognitive nerve fibers that tell us about sound, then it's possible that the type 2 neurons begin to gain more or stronger access to parts of the nervous system which mediate pain.
I'm just widely speculating here but could that possibly suggest that synaptopathy drugs could play a role? If you can restore the input that's been lost by the type 1 fibers, then could that possibly downregulate the type 2 fibers and reverse the maladaptive plasticity that has taken place leading to a more 'normalised' auditory system once more?
Great points to bear in mind as we parse over these studies.That was a very interesting study.
I just wonder if part of the sensitization that noxacusis sufferers experience is related to this increase in synapses.
I would caution people into inferring too much yet because:
1) This was done on 6-week-old mice (they did this to avoid any possibility of age related hearing loss) and 8-week-old mice are adults. Mice auditory systems have a lot of plasticity in the neonatal period (unlike humans) and that disappears sometime before adulthood so this could be a much smaller effect in an adult.
2) The greater noise exposure the greater the possibility than more synapses between type 2 afferents and OHCs would occur which means it's not universal and what ever that factor is that affected some mice more than others may or may not be a factor in humans.
Some things are well conserved in the auditory system between rodents and humans and some are not. For instant, neonatal mice can actually regenerate some hair cells on their own but their auditory neurons degrade over a short period of time after injury and based on autopsy studies humans take decades to never (the degree of myelination is the big difference).
3) They aren't testing the mice with gradually repetitive sound exposure but rather for ease and uniformity use a very substantial and extremely damaging acoustic trauma. It's possible that this effect wouldn't be seen as much with the more common scenario of repeat exposure as the body's adaptation to help avoid further sound and more extreme hearing damage.
I would also guess that if the synapses between OHCs and Type 2 afferents can be increased in noxacusis, it could also be decreased through chemical signaling and that does hold a lot of promise if this is a mechanism of sensitization.
It's also possible, like you suggest, that increasing input (hearing) would help the body not want to continue to report warning for hearing damage and homeostasis (whatever signals used to decrease synaptic connection) would help it to revert back to normal.
You made perfect sense and that was my thought too.Great points to bear in mind as we parse over these studies.
Something that stood out to me when they discussed the OHC to type 2 afferent contacts is that they mentioned that are akin to the 'silent synapses' in the CNS that "act as a reservoir of plasticity for activity induced upregulation."
So, would this suggest that the synapses could also be decreased through chemical signalling, as you said? Since their upregulation seems like a form of maladaptive plasticity in response to trauma, then restoring homeostatis/input could result in them being downregulated and decreased? Ie they're not necessarily a permanent feature and would be amenable to change?
Don't know if I'm making sense.
This is where you lose me a little. I think grouping kids who are potentially "born" with hyperacusis and adults who acquire hyperacusis through NIHL/SNHL should be considered separately. One seems like a genetic condition, one is acquired.This for me says a lot. The first quote says that OHCs decline soon after birth and the last one says that sensitivity to ATP is reduced after the onset of hearing (i.e. birth), implying that there is a direct correlation between upregulation of pain receptors due to excess ATP and the number of ribbons. I would therefore guess that kids who are born with hyperacusis don't 'shed' their excess OHC ribbons, leaving the type II afferents prone to sensitivity. The question then is: how we can shed our excess OHC ribbons, which we seem to have to gained following noise exposure?
This ties in with my experience whereby certain frequencies trigger not only noxacusis but also reactive tinnitus, trigeminal symptoms etc.Other than synapse restoration, what other sorts of chemical signaling might be appropriate? My understanding is that Trobalt only had a temporary effect so I'm not sure if the potassium channel drugs can permanently reverse the maladaptive synapses.
Edit: I think this research might have some implications for tinnitus as well. My hyperacusis influences my tinnitus in all sorts of ways and I don't think I'm alone. This brings us back to the question of why sensitized type II fibers can influence tinnitus, TTTS, trigeminal symptoms, ETD, etc.
Right, but I don't think the two things are necessarily mutually exclusive in terms of what happens on a cellular/molecular/biological level, although then again I'm not a doctor/researcher. That is why I've always been interested in what exactly it is these kids are going through. I brought this point up because I've now seen this point made several times in three or four different studies, including the one @serendipity1996 posted and the one I shared above: that the onset of hearing itself, after birth, triggers physiological changes in the cochlea at a cellular/molecular level and quite specifically two things:This is where you lose me a little. I think grouping kids who are potentially "born" with hyperacusis and adults who acquire hyperacusis through NIHL/SNHL should be considered separately. One seems like a genetic condition, one is acquired.
That's also with me as well. Certain frequencies sound worse than others. This is why I believe in FX-322. If we can restore OHCs, IHCs and synapses this should help issues such as hyperacusis and tinnitus to decrease or get rid of completely with more doses.This ties in with my experience whereby certain frequencies trigger not only noxacusis but also reactive tinnitus, trigeminal symptoms etc.
This is where you lose me a little. I think grouping kids who are potentially "born" with hyperacusis and adults who acquire hyperacusis through NIHL/SNHL should be considered separately. One seems like a genetic condition, one is acquired.
I'd imagine hyperacusis in autism, for instance, to stem largely from differences in how the brain processes sensory input, whereas our kind of hyperacusis stems fundamentally from a damaged cochlea.Agreed
Hyperacusis in kids is more consistently seen in combination with something else, such as autism, or children who also suffer with seizures, and so on.
They typically have the "Loud sound is painful" aspect of hyperacusis, but not so much the burning, pain even in silence, trigeminal irritation sort of hyperacusis that accompanies an acoustic trauma. For many, they're diagnosed with hyperacusis but the hyperacusis manifests more like sensory overload (so children struggle being in crowded noisy places because it's overwhelmingly loud) and audiologists give them the hyperacusis diagnosis as well.
I'm sure there's a bit of overlap but overall it seems to be a bit different
I'd imagine hyperacusis in autism, for instance, to stem largely from differences in how the brain processes sensory input, whereas our kind of hyperacusis stems fundamentally from a damaged cochlea.
I don't get it though. The synapses increase in number/size, but not their hair cells?Type 2 afferent of the OHCs are the "pain receptor neurons." The synapses in "cochlear synaptopathy" are between the IHCs and the SGNs. There is no contradiction. Type 2 afferents are involved in noxacusis, not tinnitus.
Hey @Diesel, the highlight for me is that it appears to be further evidence to back up why noxacusis pain is frequency specific. The next research I'd love to see is noise induced ATP release (location & quantity) measured pre and post acoustic trauma to see how ATP released in a simulated setback may be interacting with these newly hyper-connected type IIs. If it could be shown to be a certain location along the frequency range that was releasing excess ATP and also showed the type IIs with the extra ribbon synapses at the same location it could indicate the mechanism of a setback. What would be of further interest would be to see if the relative OHCs were still OK or not because it would give some indication if FX-322 was likely to do anything for certain cases of noxacusis or not.Hey, @100Hz, would love to read your assessment of this one!
Yes I can see where you're going with this @serendipity1996. If it is the case though that they are linked, whether or not the additional connections would be reduced once the input was restored would presumably depend on whether or not sensitization (which I'm assuming this is), is a permanent on switch or not. There's still everything to suggest that fixing the cochlea could work though I think, because what if our 'noxacusis recoveries' are the effect of slowly dissipating extra type II connections, and our setbacks are IHCs / OHCs responding adversely and negatively to certain frequencies that then repopulate the extra type II ribbon synapses again each time. Wild speculation now though plus where does excess ATP fit into this theory?Something that stood out to me when they discussed the OHC to type 2 afferent contacts is that they mentioned that are akin to the 'silent synapses' in the CNS that "act as a reservoir of plasticity for activity induced upregulation."
So, would this suggest that the synapses could also be decreased through chemical signalling, as you said? Since their upregulation seems like a form of maladaptive plasticity in response to trauma, then restoring homeostatis/input could result in them being downregulated and decreased? Ie they're not necessarily a permanent feature and would be amenable to change?
Don't know if I'm making sense.