Inner Ear Hair Cell Regeneration — Maybe We Can Know More

Here's a NFP in Australia:

https://www.bionicsinstitute.org/restoring-hearing

 

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.

2. I reckon that there tends to be a possibility that we will see information about Dr. Shore's device released next year, as this is when the trial is scheduled to end if she can get it finished. From how I look at things, I think that the possible release of Shore's device will depend on whether the phase 2 trial is successful.

3. Hough Ear Institute's pill probably is going to be very quickly sped up if their hints are accurate according to their website. We have suddenly seen that the time for the proof of concept study has gone from being given an indefinite start date due to Hough Ear Institute claiming that they wouldn't start it until they obtained full funding to now stating that the proof of concept study would be complete in 6 to 12 months. My feeling is that Hough Ear Institute will ultimately end up pushing the phase 2 trial through very quickly following the successful completion of this study and also actually now might consider releasing the pill early under compassionate access. At this point, I believe that they have seen what other firms are doing in this space and have realised the benefit and the need to get this released ASAP if their treatment is successful to avoid being pushed by competitors.

4. I think that there is a likelihood that most medicines (or at least something from each of the relevant types of medicine) could be released by 2023 or 2024. However I reckon right now that if companies like Otonomy or Frequency Therapeutics have a treatment that turns out to be successful then they will be doing all they are able as soon as they know their medicine is successful to release it.

5. I certainly agree that by 2025 there totally could be a situation where we are all able to have treatment and/or actually have had the treatment too.

 

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.

 

Hey, @100Hz, would love to read your assessment of this one!

 

I misread it as acoustic trauma increases size of the outer hair cells... my bad.

 

So here's a quote from the study:

"It is not yet known how long the change in number of OHC ribbon synapses may persist or whether additional noise exposure would prolong this effect. In this context, it may be of interest that ribbon numbers did not increase in OHCs of the 32-kHz region and above (data not shown). This may be a ceiling effect due to trauma from ambient noise exposure in the more vulnerable basal portions of the cochlea even at 6 weeks of age."

I have no idea what the similarities are between mice and humans in terms of cochlea structure/anatomy, but I remember my audiologist once telling me that somewhere around the 6 kHz to 8 kHz region is the most vulnerable part of the human cochlea - the basal area. I think what she meant was that the higher frequencies in general are the most vulnerable part, given that audiologists and ENTs see anything over 8 kHz as academic. My own recent reading has informed me that the basal area of the cochlea is closer to the stapes, which pushes into the cochlea when exposed to noise, than the apex is to the stapes. As a layman, these two things made sense to me: the closer to the stapes, the more risk of damage, hence why most people suffer hearing loss first in the higher range than the lower range.

But what this study is saying is that, in mice, ribbon numbers in OHCs increase after noise exposure, but NOT in the basal area. Where is the basal area in mice? Is it closer to the stapes than the apex, as is the case with humans? Assuming the anatomy is similar between humans and mice, this would suggest that if indeed there is a relationship between increased OHCs ribbons and hyperacusis (and the paper isn't saying that, although it suggests there could indeed be a relationship), we are seeing the exact opposite thing happen in humans. Namely, that given hyperacusis patients suffer disproportionately with higher frequencies, this would suggest that there are more (as opposed to less, which the study is suggesting) OHC synaptic connections in those basal areas of the cochlea post noise-exposure.

TL;DR: this study has added to the confusion lol.

 

Wow, so the hyperacusis-nut might basically be cracked?

 

This might give us some solace though: "It is not yet known how long the change in number of OHC ribbon synapses may persist...".

As a lot of people are reporting hyperacusis getting better over time (including myself, several times over), the case is probably that some of these newly formed ribbon synapses subside with time. And hopefully if something like FX-322 repairs the IHCs, this might signal to the OHC synapses that they're in excess, and have them dissipate further. Just me thinking out loud here, though...

Question: With "OHC ribbon synapses" increasing, do they mean the actual number of "outer hair cells" are increasing as well? Or is that the same thing? I'm confused...

 

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.

 

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.

 

Yeah sorry, I didn't mean "nut cracked" in terms of treatment, more in explanation of the condition.

 

How similar are mice and human cochleas? I’m assuming fairly similar since they chose to use these for studies.

What I’m also wondering is with studies such as these, especially when speaking of noxacusis are they mostly addressing the issue of stabbing pain directly from sound?

Both hyperacusis and noxacusis are words used to cover such a huge range of symptoms. Even when we get down to ear pain, some have stabbing pain directly from sound. Some have burning pain that comes directly from sound. Some have random stabs or random burning that appear even in silence (could be delayed or could also just be coming with no trigger).

I’ve gotten stabby ear pain from pressure changes while being congested. So I wonder how much pressure issues or even something like TTTS/issues with the middle ear add to ear pain. There’s also geniculate neuralgia where people experience attacks and ice pick pain in the ear that is sometimes solved by decompression surgery.

Also wondering why hyperacusis and noxacusis sometimes resolves for people with time?

I’ve seen reports of sound sensitivity going away (this one makes the most sense as it can largely be an anxiety thing) but when people say they had stabby pain, burning pain and so on and it absolves after time, what exactly is happening in the ear?

 

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.

 

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.

 

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:

"in the mammalian auditory system, ribbon size is correlated with differences in afferent activity".

"Compared to smaller ribbons, larger ribbons within inner hair cells are innervated by afferent fibers with higher thresholds of activation and lower rates of spontaneous activity"

"Functionally, compared to controls, hair cells with enlarged ribbons were associated with afferent neurons with lower spontaneous activity"

So my first obvious takeaway here is that there is relationship between ribbon size and afferent activity. My second takeaway is that the larger the ribbon size, the more likely there is to be an innervation between the inner hair cell and the afferent type I fibres, although I can't be sure on this and would like to have this confirmed. My third takeaway, assuming my second takeaway is correct, is that once you have that innervation because of the enlarged ribbons, there is less spontaneous activity. Now, I really emphasise the word spontaneous, because as we have all read before, the argument goes that it is spontaneous "activation" of neurons in the type II afferents that causes hyperacusis. This would confirm my thoughts, and I believe what @serendipity1996 was also trying to get at: that there is an inverse relationship in the number and activity between the type I and type II afferent fibres respectively.

So this is all really enlightening and I'm sure some of you are now wondering what can we do to affect ribbon sizes. This is where the news isn't so great:

"After a 1 hr treatment with 100 µM NAD+, we found that the ribbons in developing hair cells were significantly larger compared to controls. In contrast, after a 1 hr treatment with 5 mM NADH, ribbons were significantly smaller compared to controls. Neither exogenous NAD+ nor NADH were able to alter ribbon size in mature hair cells. These concentrations of NAD+ and NADH altered neither the number of synapses per hair cell nor postsynapse size in developing or mature hair cells. These results suggest that in developing hair cells, NAD+ promotes while NADH inhibits Ribeye-Ribeye interactions or Ribeye localization to the ribbon. Overall these results support the idea that during development, the levels of NAD+ and NADH can directly regulate ribbon size in vivo"

The long and short of it here is that NAD+/NADH do seem to affect ribbon sizes, but not when they come from exogenous sources. It goes without saying this absolutely sucks, because it means not even an NAD+ or NADH supplement could help us, although it is very unclear to me which of the two we would need because they seem to have the opposite effect. A larger ribbon size induced from NAD+ would help with IHC innervation to the type I afferents, but does this mean it would also help with innervating OHCs to the type II afferents, which presumably is something we don't want? Conversely, a smaller ribbon size would reduce the chance of OHC innervation to the type II afferents, but then also do the same for IHCs and type I afferents. This sucks because the relationship here, as I said above, is an inverse one. If one goes up, the other must come down.

Finally, I feel that these two studies have perhaps answered a question I've had for a long time: why are there some children with seemingly perfectly healthy cochleas that have not been exposed to noise damage but have hyperacusis?

Well, here's a quote from the Paul Fuchs study:

"The number of ribbons in OHCs declines soon after birth, with that change essentially complete in the first postnatal week"

And here's a quote from the 2019 Wong study:

"Interestingly, in mice differences in ribbon size can be distinguished just after the onset of hearing. This timing suggests that similar to our data, activity during development may help determine ribbon size"

And here's one more quote from a study quoted by @100Hz.

"Of interest in this context is the previous report that sensitivity to ATP is reduced in type II afferents after the onset of hearing"

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?

 

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.

 

You made perfect sense and that was my thought too.

 

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.

 

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 ties in with my experience whereby certain frequencies trigger not only noxacusis but also reactive tinnitus, trigeminal symptoms 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:

a) The number of ribbons in OHCs, which these studies allude to playing a role in hyperacusis.
b) A decrease in sensitivity to ATP, or more specifically, the downregulation of pain receptors in the type II afferents.

I just think it's worth digging a little deeper here, as it could give us some more insight into the condition, that's all.

 

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.

I believe that it is lost input that causes hyperacusis and tinnitus.

 

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 pretty 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.

 

Exactly. Similar to how tinnitus is very prevalent amongst those who are on the spectrum without having had any acoustic traumas vs those of us who get it from noise or ear trauma of some sort

 

I don't get it though. The synapses increase in number/size, but not their hair cells?

 

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.

This bit below was interesting to me because I've wondered before if OHC death is a certainty or not. Given how good some peoples hearing remains I think it's very possible that the below has happened.

However, it should be noted that the acoustic trauma used here did not result in significant OHC loss, particularly in the most apical cochlea where the increase in ribbon number was most pronounced. Therefore, increased OHC ribbon synapse number may be a response to maximal acoustic stimulation, rather than an effect of cell damage.'

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?