Frequency Therapeutics — Hearing Loss Regeneration

[serendipity1996]

Aren't Hough Ear Institute working with synapses?

Yes - Hough Ear Institute, Otonomy, and Pipeline Therapeutics.

 

[WillBeNimble]

Ugh, someone else broke the NDA? FGG's points are right about how this will affect the study. I wish these people would stop just throwing that they "received FX-322" when in the next sentence they go on to say, "Oh, I might have got the placebo." Let the science happen, guys.

 

[serendipity1996]

How hard is it for people to just... not break the NDA?!

 

[Watasha]

1. 10 dB at 8 kHz is small potatoes... Sure it's a miracle that they were able to do anything at all and a breakthrough by itself. Most people though are down 20 dB, 30 dB, 40 dB, 50 dB, ... at lower frequencies, not just at 8 kHz where FX-322 might not have reached. The word scores improving mattered though. If the 10 dB at 8 kHz helped get better word scores then great but we are still speculating on that one. Extended audiograms could also provide more insight on that one. If people were gaining 40 dB at 10 kHz because FX-322 got there easier... that could be something to celebrate.

2. I was one that reported having hearing aids and I didn't get tinnitus until I was much older. I've worn them for approx 25 years. Hearing aids get you back to baseline if the hearing test is correct and the hearing aids are programmed correctly. That kept me from getting tinnitus. Once my hearing dropped to the point where the hearing aids were no longer able to get me to baseline, I got tinnitus. There were other factors as well. I'm older now, and have had some bad anxiety...
Without the hearing aids I have a rock concert going on in my head. They do help keep tinnitus down when I wear them, but they don't make it go away. Just like everyone, I have good days and bad days.

Don't get me wrong. You are correct that every little bit helps. If you are down 20 dB at 8 kHz and you get back 10 dB this is great news. That might be the difference between hearing well and saying "what" some of the time. Even in this case though I don't think it's enough to make tinnitus go away or something someone would notice. It might provide a little relief though. Again it's just my theory from a guy that likes to experiment on himself and dealt with hearing loss all his life...

I'm sorry that you've had to deal with hearing loss all of your life.

 

[patorjk]

I agree with @FGG, this person was irresponsible and put their own frustrations over the importance of this study.

The best way to think about the patients in the study is as puzzle pieces. Some will not improve, some will improve a bit, and some will improve tremendously. These pieces will all come together to create a clearer picture of how FX-322 will move forward, what its impact is, and who the most suitable patients are. But separately they are just pieces of a puzzle, and you can't tell what the end picture will be from one tiny fragment.

I agree, though after researching this a bit some, the comment from Tim occurred in a private Facebook tinnitus support group. My guess is he did not think it'd get re-posted elsewhere. It's still inappropriate, but not as bad as openly posting about the study. The comment appears as a reply to a post that was asking what people's thoughts on FX-322 were. Searching back through the group, Tim appears to have been incredibly well versed in FX-322 and Frequency Therapeutics, writing many long comments about the drug, so he clearly knew his stuff. My guess is he got excited and joined the study when he saw an opportunity.

Also, as an interesting aside, while researching this, I came across a foreign language hearing loss forum and saw posts referring to this thread. There are people who use google translate to read this thread and keep up with FX-322. It was a little surreal, it's like we're in a fishbowl. It made me wonder how many lurkers this thread has.

 

[RB2014]

I'm going to dissect your post bit by bit and give my view on what you said.

We know people have tinnitus and no hearing loss and people have hearing loss and no tinnitus. What this tends to indicate is that tinnitus and hearing loss are actually not inherently linked.

Multiple participants in the phase 1 trial noted improvements in tinnitus. However, what we don't know definitively is whether their tinnitus improvement came from improvements in hearing thresholds or from another source such as synaptic recovery. This is due to insufficient testing. Therefore, we still do not have any clarity as to the reason participants had a reduction in tinnitus. Hence it is impossible to determine both what type of hearing improvement is needed and also what level of improvement is needed to improve or eliminate tinnitus.

CI and hearing aid users have had improvement in their tinnitus (and quite significantly too). The generally well established reason is the extra stimulation delivered, particularly to the high frequency range where the overwhelming majority of daily sounds sit.

However, what we do not know is how much extra stimulation is given to people when utilising a hearing aid. Apparently the amount of stimulation delivered at a particular frequency can often be insufficient to theoretically return someone to baseline level. Yet while using a hearing aid, the user has no symptoms of tinnitus. This suggests that it isn't actually necessary to return hearing thresholds to baseline to eliminate tinnitus.

While a 10 dB improvement as indicated in phase 1 results isn't significant, it is meaningful. Also the increase was only shown at a single frequency due to the testing criteria in the inaugural trial. It is very much possible that there was an improvement above 10 dB in the very high frequencies in the initial trial and this is plausible due to the word recognition score test results.

Therefore I very strongly believe that it is near impossible to determine how much hearing improvement is required and also where that improvement specifically needs to be had in order to eliminate tinnitus. Since we have evidence which suggests you can eliminate tinnitus without returning hearing thresholds to baseline, I would hypothesise that the required improvements you mentioned such as returning hearing levels to baseline levels are not actually required to eliminate tinnitus entirely.

You make some really great points.

 

[WillBeNimble]

How hard is it for people to just... not break the NDA?!

I mean, it's human to talk about our frustrations, but if you don't know what you've gotten, it's best not to even mention your results.

I also suspect that for those who got the placebo, it's more likely they'll break the NDA, as they have more frustration and reason to complain. It's similar to Yelp reviews at this point, but it's two separate restaurants that keep getting mixed up.

 

[Lucifer]

I mean, it's human to talk about our frustrations, but if you don't know what you've gotten, it's best not to even mention your results.

I also suspect that for those who got the placebo, it's more likely they'll break the NDA, as they have more frustration and reason to complain. It's similar to Yelp reviews at this point, but it's two separate restaurants that keep getting mixed up.

That's true. If I were to have got FX-322 and it worked I would not have posted it publicly like Tim did and would only tell you guys through private DM.

I still believe the drug works and that Tim got placebo. What would be most interesting to know about the Phase 2a clinical trials is whether those who got 4 shots of FX-322 not only experience tremendous improvements in their hearing but also in their tinnitus and hyperacusis as well.

 

[GregCA]

I mean, it's human to talk about our frustrations, but if you don't know what you've gotten, it's best not to even mention your results.

Even if you know what you've gotten, breaking the NDA, in addition to landing you in potential legal trouble, has a strong possibility of delaying the trial due to data leakage, which is absolutely counter productive to your own interest, not to mention the interest of everyone else who would benefit from the drug being tested ASAP.

 

[Diesel]

In other news... looks like a great time to buy FREQ shares.

 

[FGG]

In other news... looks like a great time to buy FREQ shares.

The entire biotech sector is down, it could drop even more but it is difficult to "time the bottom."

 

[GlennS]

people who it works for are more likely to stay quiet

Being one of the first in history to have hearing actually restored?

 

[GlennS]

How hard is it for people to just... not break the NDA?!

Funny how back in the Lenire thread people were bashing Lenire for having one in the first place (which I don't think they even did).

 

[djdavid]

It made me wonder how many lurkers this thread has.

Interesting point, I am a lurker. It's a useful thread but I only wish people would post when they really have something useful to add. 343 pages but some of it is unhelpful chit chat.

Let's keep it focused please.

 

[Jimjoe]

It made me wonder how many lurkers this thread has.

I am a "lurker", so to speak... well I WAS at least. Nice to meet you all. I tried to join the FX-322 study in Omaha and Louisville and was denied due to my "good" word recognition, although my 5 kHz+ hearing is basically non-existent. Might try again if they can't fill the spots by fall.

 

[Paulmanlike]

The entire biotech sector is down, it could drop even more but it is difficult to "time the bottom."

My TCON shares were up about 35% today. But if you want to buy FREQ shares, the time is now. Hasn't been this low in a while.

Give it a month, FREQ should be back in the low to mid 20s again.

 

[Diesel]

Re: Hyperacusis and OHC Damage, and how FX-322/regeneration may help.

Some have expressed concern that hyperacusis must be the case of "really really" bad hearing loss; and perhaps regeneration may not help. Which may be why it is left out of studies like the FX-322 Phase 2A. I offer you the perspective that its probably so much harder to quantify than tinnitus, that there aren't good mechanisms in place to measure improvement against placebo.

I have now met two people that have suffered from hyperacusis for months without tinnitus... which led me on a little investigative research...

We have discussed before that a few theories of hyperacusis revolve around the depletion of OHC, and likely the role of the Type II OHC Nerve.

I welcome comments on this thought; of course I realize I'm going to get them either way:

I have not spent much time looking at this site, but found an excerpt interesting: https://hyperacusisfocus.org/innerear/

"A single type II fiber generally connects to an estimated 7 OHCs."

"Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

Researchers from Johns Hopkins have been examining these nerves [Type II OHC Nerve] over the last several years. Below are several critical observations made in these studies.

• It requires almost complete excitation of OHCs for the afferent type II neurons to be activated.
• These neurons can be activated by extracellular ATP, a chemical that can produce pain when released by damaged cells including OHCs.
• Mechanical rupture or removal of OHCs causes a robust activation of these neurons. Note that OHCs are much more likely than IHCs to be similarly damaged from sound.

First, let's assume hyperacusis is a symptom of hearing damage; most commonly noise induced. Where, IHC/OHC cells are damaged, destroyed.

It seems common that hyperacusis sufferers (loudness, pain, etc) note similar high-frequency noise (silverware, etc) responses. So, it stands to reason the site of damage likely starts at high frequency, where FX-322 may treat. Perhaps it is simply the depletion of large enough clusters of OHC that cause the symptom. 7 dead/damaged OHC connected to a single nerve is enough to start the effect taking place.

If we accept this conclusion, perhaps treating hyperacusis with FX-322 may be more realistic than we think. With what is described above; FX-322 may stand to effectively treat all 3 bullet points. It may not take even restoring an entire "bank" of OHC connected to a Type II nerve to begin providing ample communication to the nerve. Assuming of course, there is some type of "plasticity" present in regeneration. Restoration of new OHCs should certainly treat any issues where damaged/removed OHCs are causing excitation of the nerve.

Over the past year, we have been fortunate to witness a lot of dogma in the hearing space turned on it's head. For example, most recently, learning that age-related hearing loss is basically just SHNL/NIHL that happens over a long period of time.

I continue to look at hyperacusis as the next hearing loss issue where current dogma is about to be turned on its head.

In my opinion:
- Hyperacusis might actually be more treatable than tinnitus in terms of regeneration. Only some of the OHC "bank" may need restored given a single nerve connection to cut the primary symptoms.
- Hyperacusis isn't as dependent on hearing "clarity/sensitivity" as tinnitus, just quantity of functioning OHC as it seems.
- IF we see tinnitus improvements from FX-322 in the Phase 2A, it might as well be interchangeable with hyperacusis.

What say you?

 

[Rubenslash]

Interesting point, I am a lurker. It's a useful thread but I only wish people would post when they really have something useful to add. 343 pages but some of it is unhelpful chit chat.

Let's keep it focused please.

Agree, especially things like daily stock fluctuations are literally adding zero value to the discussion here. I mean, the stock will go up and down on no news all the time, no need to mention this imo.

 

[FGG]

Re: Hyperacusis and OHC Damage, and how FX-322/regeneration may help.

Some have expressed concern that hyperacusis must be the case of "really really" bad hearing loss; and perhaps regeneration may not help. Which may be why it is left out of studies like the FX-322 Phase 2A. I offer you the perspective that its probably so much harder to quantify than tinnitus, that there aren't good mechanisms in place to measure improvement against placebo.

I have now met two people that have suffered from hyperacusis for months without tinnitus... which led me on a little investigative research...

We have discussed before that a few theories of hyperacusis revolve around the depletion of OHC, and likely the role of the Type II OHC Nerve.

I welcome comments on this thought; of course I realize I'm going to get them either way:

I have not spent much time looking at this site, but found an excerpt interesting: https://hyperacusisfocus.org/innerear/

"A single type II fiber generally connects to an estimated 7 OHCs."

"Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

Researchers from Johns Hopkins have been examining these nerves [Type II OHC Nerve] over the last several years. Below are several critical observations made in these studies.

• It requires almost complete excitation of OHCs for the afferent type II neurons to be activated.
• These neurons can be activated by extracellular ATP, a chemical that can produce pain when released by damaged cells including OHCs.
• Mechanical rupture or removal of OHCs causes a robust activation of these neurons. Note that OHCs are much more likely than IHCs to be similarly damaged from sound.

First, let's assume hyperacusis is a symptom of hearing damage; most commonly noise induced. Where, IHC/OHC cells are damaged, destroyed.

It seems common that hyperacusis sufferers (loudness, pain, etc) note similar high-frequency noise (silverware, etc) responses. So, it stands to reason the site of damage likely starts at high frequency, where FX-322 may treat. Perhaps it is simply the depletion of large enough clusters of OHC that cause the symptom. 7 dead/damaged OHC connected to a single nerve is enough to start the effect taking place.

If we accept this conclusion, perhaps treating hyperacusis with FX-322 may be more realistic than we think. With what is described above; FX-322 may stand to effectively treat all 3 bullet points. It may not take even restoring an entire "bank" of OHC connected to a Type II nerve to begin providing ample communication to the nerve. Assuming of course, there is some type of "plasticity" present in regeneration. Restoration of new OHCs should certainly treat any issues where damaged/removed OHCs are causing excitation of the nerve.

Over the past year, we have been fortunate to witness a lot of dogma in the hearing space turned on it's head. For example, most recently, learning that age-related hearing loss is basically just SHNL/NIHL that happens over a long period of time.

I continue to look at hyperacusis as the next hearing loss issue where current dogma is about to be turned on its head.

In my opinion:
- Hyperacusis might actually be more treatable than tinnitus in terms of regeneration. Only some of the OHC "bank" may need restored given a single nerve connection to cut the primary symptoms.
- Hyperacusis isn't as dependent on hearing "clarity/sensitivity" as tinnitus, just quantity of functioning OHC as it seems.
- IF we see tinnitus improvements from FX-322 in the Phase 2A, it might as well be interchangeable with hyperacusis.

What say you?

I see loudness hyperacusis addressed by the same regenerative treatments that address tinnitus because I don't expect that central gain will not respond to normalized input.

Noxacusis... I really don't know. It makes sense that, over time, the type 2 afferents could become less sensitive again after damage is resolved but there are other nerve pathologies/allodynia type conditions that don't resolve even after the noxious stimuli is removed. I am not sure anyone knows which category the cochlear type 2 afferents are (or if they do, I just haven't seen the study). I can't help but think there would be at least some response (but again might take time for the excitation to normalize) to healing the hair cell damage but I do think it may come down to Nav channel inhibiting drugs, too. I really hope it helps those with noxacusis.

 

[Diesel]

I see loudness hyperacusis addressed by the same regenerative treatments that address tinnitus because I don't expect that central gain will not respond to normalized input.

Noxacusis... I really don't know. It makes sense that, over time, the type 2 afferents could become less sensitive again after damage is resolved but there are other nerve pathologies/allodynia type conditions that don't resolve even after the noxious stimuli is removed. I am not sure anyone knows which category the cochlear type 2 afferents are (or if they do, I just haven't seen the study). I can't help but think there would be at least some response (but again might take time for the excitation to normalize) to healing the hair cell damage but I do think it may come down to Nav channel inhibiting drugs, too. I really hope it helps those with noxacusis.

I see your point on noxacusis. One would think that restoring the connection with the biologically correct cell would resolve the excitement.

 

[Lucifer]

Re: Hyperacusis and OHC Damage, and how FX-322/regeneration may help.

Some have expressed concern that hyperacusis must be the case of "really really" bad hearing loss; and perhaps regeneration may not help. Which may be why it is left out of studies like the FX-322 Phase 2A. I offer you the perspective that its probably so much harder to quantify than tinnitus, that there aren't good mechanisms in place to measure improvement against placebo.

I have now met two people that have suffered from hyperacusis for months without tinnitus... which led me on a little investigative research...

We have discussed before that a few theories of hyperacusis revolve around the depletion of OHC, and likely the role of the Type II OHC Nerve.

I welcome comments on this thought; of course I realize I'm going to get them either way:

I have not spent much time looking at this site, but found an excerpt interesting: https://hyperacusisfocus.org/innerear/

"A single type II fiber generally connects to an estimated 7 OHCs."

"Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

Researchers from Johns Hopkins have been examining these nerves [Type II OHC Nerve] over the last several years. Below are several critical observations made in these studies.

• It requires almost complete excitation of OHCs for the afferent type II neurons to be activated.
• These neurons can be activated by extracellular ATP, a chemical that can produce pain when released by damaged cells including OHCs.
• Mechanical rupture or removal of OHCs causes a robust activation of these neurons. Note that OHCs are much more likely than IHCs to be similarly damaged from sound.

First, let's assume hyperacusis is a symptom of hearing damage; most commonly noise induced. Where, IHC/OHC cells are damaged, destroyed.

It seems common that hyperacusis sufferers (loudness, pain, etc) note similar high-frequency noise (silverware, etc) responses. So, it stands to reason the site of damage likely starts at high frequency, where FX-322 may treat. Perhaps it is simply the depletion of large enough clusters of OHC that cause the symptom. 7 dead/damaged OHC connected to a single nerve is enough to start the effect taking place.

If we accept this conclusion, perhaps treating hyperacusis with FX-322 may be more realistic than we think. With what is described above; FX-322 may stand to effectively treat all 3 bullet points. It may not take even restoring an entire "bank" of OHC connected to a Type II nerve to begin providing ample communication to the nerve. Assuming of course, there is some type of "plasticity" present in regeneration. Restoration of new OHCs should certainly treat any issues where damaged/removed OHCs are causing excitation of the nerve.

Over the past year, we have been fortunate to witness a lot of dogma in the hearing space turned on it's head. For example, most recently, learning that age-related hearing loss is basically just SHNL/NIHL that happens over a long period of time.

I continue to look at hyperacusis as the next hearing loss issue where current dogma is about to be turned on its head.

In my opinion:
- Hyperacusis might actually be more treatable than tinnitus in terms of regeneration. Only some of the OHC "bank" may need restored given a single nerve connection to cut the primary symptoms.
- Hyperacusis isn't as dependent on hearing "clarity/sensitivity" as tinnitus, just quantity of functioning OHC as it seems.
- IF we see tinnitus improvements from FX-322 in the Phase 2A, it might as well be interchangeable with hyperacusis.

What say you?

I still believe in this theory that the OHCs are causing pain hyperacusis and that if we can restore OHCs which FX-322 does then this could reduce hyperacusis or completely get rid of it with additional doses. I think FX-322 has a better chance at completely getting rid of hyperacusis than tinnitus.

 

[serendipity1996]

I see loudness hyperacusis addressed by the same regenerative treatments that address tinnitus because I don't expect that central gain will not respond to normalized input.

Noxacusis... I really don't know. It makes sense that, over time, the type 2 afferents could become less sensitive again after damage is resolved but there are other nerve pathologies/allodynia type conditions that don't resolve even after the noxious stimuli is removed. I am not sure anyone knows which category the cochlear type 2 afferents are (or if they do, I just haven't seen the study). I can't help but think there would be at least some response (but again might take time for the excitation to normalize) to healing the hair cell damage but I do think it may come down to Nav channel inhibiting drugs, too. I really hope it helps those with noxacusis.

I know I posted an article on neuroplasticity and pain a few pages back in relation to tinnitus but do you reckon it could potentially have implications for pain hyperacusis too? I think it's frustrating because at this point in time there is limited knowledge about noxacusis so it's all speculation - it makes sense to me though that there would be *some* response to OHC restoration. I feel like inducing a positive change in the environment like that could help restore things to 'normal' even if it takes a period of time (e.g 3 months or so) to start observing these changes.

The nerve pathology/allodynia thing does worry me, though - what other conditions can give rise to this sort of intractable pain? From what's been written about noxacusis, it seems that the type 2 fibers most resemble C fibers elsewhere in the body. It does seem for many people with noxacusis that it does tend to resolve somewhat (although not to the level of a healthy cochlea) - there does seem to be an 'acute' phase where the sensitisation is at its worst and then with time and rest this decreases.

My gut feeling is that noxacusis will not be a one-size-fits-all treatment - this disorder is extremely heterogeneous and there is a massive spectrum of severity between those who can live a pretty normal life with certain precautions and those who are in excruciating pain 24/7. Perhaps more severe intractable cases will require hair cell regeneration in addition to a Nav 1.7 drug.

 

[weab00]

I still believe in this theory that the OHCs are causing pain hyperacusis and that if we can restore OHCs which FX-322 does then this could reduce hyperacusis or completely get rid of it with additional doses. I think FX-322 has a better chance at completely getting rid of hyperacusis than tinnitus.

And do you think the same for noxacusis?

 

[Lucifer]

And do you think the same for noxacusis?

Yes I think so.

 

[100Hz]

"Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

This bit is really interesting, hadn't read this in this way before. I'd always read it as though if any singular instances of OHC damage occur then it causes type II activation.

I always thought the idea of hair cell damage causing pain hyperacusis was not a very solid theory because there is apparently so little pain hyperacusis going around compare to what must be a huge amount dead hair cells. But if it's something catastrophic like the above where an irreversible threshold gets crossed to activate the pain, then it's much more believable, especially as pain hyperacusis seems to be highly frequency specific, i.e. when I'm recovering and feeling brave enough to handle some sound, something as specific as a particular part of a particular song will start to feel dangerous to my ears.

If it's something like this then it renews my hope for FX-322 for pain hyperacusis. Otherwise I'm back to the theory of nerve damage and some kind of blocker.

 

[FGG]

I know I posted an article on neuroplasticity and pain a few pages back in relation to tinnitus but do you reckon it could potentially have implications for pain hyperacusis too? I think it's frustrating because at this point in time there is limited knowledge about noxacusis so it's all speculation - it makes sense to me though that there would be *some* response to OHC restoration. I feel like inducing a positive change in the environment like that could help restore things to 'normal' even if it takes a period of time (e.g 3 months or so) to start observing these changes.

The nerve pathology/allodynia thing does worry me, though - what other conditions can give rise to this sort of intractable pain? From what's been written about noxacusis, it seems that the type 2 fibers most resemble C fibers elsewhere in the body. It does seem for many people with noxacusis that it does tend to resolve somewhat (although not to the level of a healthy cochlea) - there does seem to be an 'acute' phase where the sensitisation is at its worst and then with time and rest this decreases.

My gut feeling is that noxacusis will not be a one-size-fits-all treatment - this disorder is extremely heterogeneous and there is a massive spectrum of severity between those who can live a pretty normal life with certain precautions and those who are in excruciating pain 24/7. Perhaps more severe intractable cases will require hair cell regeneration in addition to a Nav 1.7 drug.

I agree with your assessment and even if the fibers are sensitized and remain sensitized, I still think they can eventually at least improve to some degree (and hopefully more) given enough time because as you pointed out it does improve on its own in people which means there is at least some potential to.

And in cases of allodynia in the peripheral nervous system, I also suspect some of the cases where they *think* the noxious stimuli is gone (e.g. post viral or Lyme), it may be still ongoing without the same level of detection but since the nerve is sensitized, it doesn't need much noxious stimuli to perpetuate it. So many unknowns.

 

[100Hz]

"Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

Makes me wonder if this could be the actual event that triggers the acoustic shock symptoms cluster that then subsequently kicks of pain hyperacusis for so many people.

 

[Billy_Shears]

My TCON shares were up about 35% today. But if you want to buy FREQ shares, the time is now. Hasn't been this low in a while.

Give it a month, FREQ should be back in the low to mid 20s again.

FREQ currently has a Quantitative Rating of 4 - BUY! Interestingly, they announced $42m in private placements by a group of investors in late July, approximately 9 months after the start of Phase 2a. The additional revenue is expected to finance their next clinical trial phase for FX-322. It leads me to believe that some good news is being delivered from the ongoing Phase 2a.

 

[serendipity1996]

Makes me wonder if this could be the actual event that triggers the acoustic shock symptoms cluster that then subsequently kicks of pain hyperacusis for so many people.

What about people who experience pain hyperacusis without also experiencing an acoustic shock? My first experience with noxacusis was more gradual as opposed to being kickstarted by a sudden event. According to the team at Johns Hopkins (Fuchs et al) even progressive damage over time can increase ATP levels in the cochlea.

 

[serendipity1996]

This bit is really interesting, hadn't read this in this way before. I'd always read it as though if any singular instances of OHC damage occur then it causes type II activation.

I always thought the idea of hair cell damage causing pain hyperacusis was not a very solid theory because there is apparently so little pain hyperacusis going around compare to what must be a huge amount dead hair cells. But if it's something catastrophic like the above where an irreversible threshold gets crossed to activate the pain, then it's much more believable, especially as pain hyperacusis seems to be highly frequency specific, i.e. when I'm recovering and feeling brave enough to handle some sound, something as specific as a particular part of a particular song will start to feel dangerous to my ears.

If it's something like this then it renews my hope for FX-322 for pain hyperacusis. Otherwise I'm back to the theory of nerve damage and some kind of blocker.

It is intriguing how pain hyperacusis is very rare when you think about how common hearing damage is. Paul Fuchs was asked about this and he pointed out that there could be genetic factors that play a role. Or he said we could think of it similarly to allergic reactions except for an unlucky minority our systems seem to have react catastrophically to hearing damage - e.g there could potentially be a genetic difference in immune systems that confers different sensitivities. For instance, he mentioned that the type 2 fibers may not have the same patterns of gene expression in every person hence why one person may be more likely to develop pain. Additionally, inflammatory responses may be different in different people according to him.