Frequency Therapeutics — Hearing Loss Regeneration

[Jack V]

I will reiterate this point. "Performance boosts" and placebo cannot do things that have historically not been possible. I.e. concentrating doesn't help someone get out of a wheelchair.

If the "super responders'" response was more moderate, your point would be more valid.

There are two possibilities here: fraud or the drug regrows IHCs (the part measured by word scores and not audiogram).

I would expect the percentage of responders to go up when they design a trial to select who got genuinely low word scores and they have indicated that's how they are proceeding.

Performance boosts and placebos can do things that have historically not been possible.

Concentrating can help someone get out of a wheelchair (maybe not for long, but possible? For some people? Sure).

And I don't agree that there are only two possibilities, fraud or success. "Fraud" is a loaded word. There could be other things at work, not necessarily fraud, not necessarily drug response. But not to get caught up in the weeds, we agree that it either worked or it didn't, and if it didn't work, the response was due to some combination of conscious and/or unconscious manipulation.

Finally, I HOPE - hope hope hope! - that a well-constructed trial can show efficacy.

 

[DaveFromChicago]

I must unconditionally agree with FGG; if, for example, if nerve damage or severance is involved, it is absolutely not possible to get up from a wheelchair no matter how determined the individual is. It would be equivalent to being determined to turn on a lamp when it's cord was severed. It would be stupid and cruel to insist that such people with varieties of extensive paralysis-causing tissue damage could have learned to walk if only they convinced themselves that it was doable with the correct frame of mind.

Look as such famous examples as Christopher Reeve or Charles Krauthammer (who himself was a widely regarded psychiatrist who acknowledged that from hitting his head on the floor of a pool he was permanently paralyzed for life).

 

[Diesel]

One explanation is that the drug worked.

Another explanation is that other factors were responsible.

There is data that supports the 3 super responders in the Phase 1/2 had established histories of hearing loss. So it seems to be certain that these 3 subjects were well known to have a deficit prior to joining the trial. In particular, the 21 and 5 year participants.

Subject 1 (916) : 21 years
Subject 3 (936) : 5 years
Subject 4 (937) : 1.7 years

What other factors would we point to in the trial other than FX-322 that caused them to deviate from their previously established, multi-year baseline to the improved score? Then, to retain that improvement at a minimum, 13 months later? Can anyone specifically come up with any evidence that points to a non-FX-322 event that would cause this effect AND explain the duration of improvement? Is there none?

Only @FGG seems to have provided additional evidence to support in detail that ONLY IHC regrowth may have caused this increase + duration of improvement?

 

[FGG]

I must unconditionally agree with FGG; if, for example, if nerve damage or severance is involved, it is absolutely not possible to get up from a wheelchair no matter how determined the individual is. It would be equivalent to being determined to turn on a lamp when it's cord was severed. It would be stupid and cruel to insist that such people with varieties of extensive paralysis-causing tissue damage could have learned to walk if only they convinced themselves that it was doable with the correct frame of mind.

Look as such famous examples as Christopher Reeve or Charles Krauthammer (who himself was a widely regarded psychiatrist who acknowledged that from hitting his head on the floor of a pool he was permanently paralyzed for life).

Yeah the placebo effect is powerful but not "miraculous".

 

[Zugzug]

There is data that supports the 3 super responders in the Phase 1/2 had established histories of hearing loss. So it seems to be certain that these 3 subjects were well known to have a deficit prior to joining the trial. In particular, the 21 and 5 year participants.

Subject 1 (916) : 21 years
Subject 3 (936) : 5 years
Subject 4 (937) : 1.7 years

What other factors would we point to in the trial other than FX-322 that caused them to deviate from their previously established, multi-year baseline to the improved score? Then, to retain that improvement at a minimum, 13 months later? Can anyone specifically come up with any evidence that points to a non-FX-322 event that would cause this effect AND explain the duration of improvement? Is there none?

Only @FGG seems to have provided additional evidence to support in detail that ONLY IHC regrowth may have caused this increase + duration of improvement?

View attachment 44564

View attachment 44563

So here's a question. How do we explain Patient 5 being worse 1-2 years out than at baseline? Moreover, every single person got worse from Day 90 to 1-2 years out.

Don't OHC wear out easier than IHC? A hair cell grows or it doesn't. And the patients are screened so it's not like they have primarily diseases that kill hair cells. Under the IHC theory, shouldn't we see word score growth and then from there, mostly margin of error deviations.

In other words, why are they all worse? Why not a mix of slight improvements and worsenings? Does it at least make us wonder if the Day 90 and the 1-2 year tests were different? Were the baseline and Day 90 tests the same?

 

[FGG]

So here's a question. How do we explain Patient 5 being worse 1-2 years out than at baseline? Moreover, every single person got worse from Day 90 to 1-2 years out.

Don't OHC wear out easier than IHC? A hair cell grows or it doesn't. And the patients are screened so it's not like they have primarily diseases that kill hair cells. Under the IHC theory, shouldn't we see word score growth and then from there, mostly margin of error deviations.

In other words, why are they all worse? Why not a mix of slight improvements and worsenings? Does it at least make us wonder if the Day 90 and the 1-2 year tests were different? Were the baseline and Day 90 tests the same?

OHCs do not uniformly wear out quicker than IHCs.

For some individuals, their IHCs "wear out" much quicker, though it's less common and people with genuinely low word score would likely fit this profile better obviously.

I saw the uniform decreases as most likely from continued wear over time, especially in areas the drug couldn't penetrate.

I hope they continue to test them further out.

Patient #5 is a mystery, though. Agree. I would love to ask their thoughts on that one individual, if they were allowed to disclose their medical history.

 

[Diesel]

So here's a question. How do we explain Patient 5 being worse 1-2 years out than at baseline? Moreover, every single person got worse from Day 90 to 1-2 years out.

Don't OHC wear out easier than IHC? A hair cell grows or it doesn't. And the patients are screened so it's not like they have primarily diseases that kill hair cells. Under the IHC theory, shouldn't we see word score growth and then from there, mostly margin of error deviations.

In other words, why are they all worse? Why not a mix of slight improvements and worsenings? Does it at least make us wonder if the Day 90 and the 1-2 year tests were different? Were the baseline and Day 90 tests the same?

Great questions @Zugzug! As always, I appreciate your engagement in discussing the details...

Why everyone got a little worse, and some fell out of significance:

Frequency Therapeutics has shown that a single dose of FX-322 only penetrates to a certain depth in the cochlea, and therefore can only activate progenitors to a certain depth where the drug is concentrated enough. They actually measured the perilymph to provide additional evidence. It is shown here:

But more simply, here:

This is generally reinforced by subjects 1, 3, and 4 showing improvements of 10 dB+ on the audiogram at 8 kHz. So, we can conclude that the subjects, all 5 of them, had improvements detecting sounds in the highest frequency ranges. In the English language, the language used for the word score tests, this is where the fricative sounds are distinguished. IE: Consonant sounds created by, "f", "th", "h", "z", "v", "s", "sh"... As English speakers, looking at those consonant, many, many words are made up of fricatives that we use every day, that could easily be mistaken for one another on a 50-word C-N-C word list. As has been researched and shared here, as the IHC/OHC cells degrade over time, it becomes more difficult to distinguish the subtle differences between these sounds. So, the evidence points to the fact that restoring the hair cells with FX-322 made these consonants distinguishable to the listener.

So how did the word scores decline in 1-2 years?

As we are all aware, and as all research has shown for SNHL, damage is cumulative and damage is permanent to these fine hair cells. So, all of these participants have accumulated significant life-long damage. And, more recently, damage can be an accelerant to earlier hearing loss in life.

As we are aware, the entire cochlea wasn't regenerated. The 8 kHz+ area was restored with "new" cells, but below that, the cells continued to contain the damage absorbed from birth, and continued to wear at the normal expected rate for someone with considerable hearing loss damage. So, while they may have been able to distinguish fricatives at the follow-up, the set of hair cells below 8 kHz continued to decline in sensitivity from the original baseline, and therefore reduced sensitivity to distinguish affricates, for example sounds like: "ts", "ch", "j", and soft-"g", respectively.


Notes on Subject 2 and 5:

Their follow-up tests were the furthest out, so they absorbed more wear to the "original equipment cells" than subject 1, 3, and 4. It also stands to reason that their losses were more concentrated more deeply in the cochlea where no FX-322 could reach. So, while FX-322 did help provide some gains, the continued wear of already highly damaged cells outweighed the benefits of the high frequency cells that were regenerated.


On OHC + IHC wear:

It is believed that in a healthy cochlea, research shows that OHC tend to wear out first, and then the IHC follow. The mechanisms for wear actually point to OHC actually creating a turbulence buffer in the cochlea, that "protects" the IHC. Also, research shows that OHC are more sensitive to the turbulence in the cochlea due to their mechanical nature, and can be damaged more easily. IHC though, are also protected from a certain amount of turbulence in the perilymph because OHC are in place. So, if OHC were never regenerated to begin with, the IHC would wear at a faster rate because they are subject to more turbulence in the perilymph.

Why are they all worse?

I actually think this shows promise. It's accepted that hair cells continue to wear from life to death. So, we're observing regular wear and tear over time from a single dose. It would actually be more suspicious, in my opinion, if a patient continued to improve significantly, while others continued to decline. What's interesting though, is 4/5 actually fell by a somewhat similar amount.

 

[Zugzug]

OHCs do not uniformly wear out quicker than IHCs.

For some individuals, their IHCs "wear out" much quicker, though it's less common and people with genuinely low word score would likely fit this profile better obviously.

I saw the uniform decreases as most likely from continued wear over time, especially in areas the drug couldn't penetrate.

I hope they continue to test them further out.

Patient #5 is a mystery, though. Agree. I would love to ask their thoughts on that one individual, if they were allowed to disclose their medical history.

I think my issue is more like, is 1-2 years really that long? I would think it would be short enough to see more of a mix between small worsening and small improvement. If it was like 10-20 years, okay, that makes sense, especially since these are people with noise damage, not diseases.

 

[FGG]

I think my issue is more like, is 1-2 years really that long? I would think it would be short enough to see more of a mix between small worsening and small improvement. If it was like 10-20 years, okay, that makes sense, especially since these are people with noise damage, not diseases.

Phase 1 was not all noise induced. The requirement was any sudden hearing loss (SSNHL). Viral etiologies that can cause severe sudden loss, can persists and cause further degeneration (e.g. CMV). Some retained toxins do the same thing.

In fact, noise is less likely to cause severe IHC death.

 

[livewire77]

Patient #5 is a mystery, though. Agree. I would love to ask their thoughts on that one individual, if they were allowed to disclose their medical history.

What about continuous loss of IHCs' synapses from SGNs? As far as I know, FX-322 doesn't influence this. Charles Liberman says that synapses and axons degenerate most rapidly. If IHCs are left without synapses, it's almost the same like being dead. That would result in distortion and reduced WR score.

or

What if the regenerated hair cells are of "lower quality" than natural hair cells? Maybe some piece of puzzle is still missing.

Who knows.

 

[Zugzug]

Great questions @Zugzug! As always, I appreciate your engagement in discussing the details...

Why everyone got a little worse, and some fell out of significance:

Frequency Therapeutics has shown that a single dose of FX-322 only penetrates to a certain depth in the cochlea, and therefore can only activate progenitors to a certain depth where the drug is concentrated enough. They actually measured the perilymph to provide additional evidence. It is shown here:

View attachment 44565

But more simply, here:

View attachment 44566

This is generally reinforced by subjects 1, 3, and 4 showing improvements of 10 dB+ on the audiogram at 8 kHz. So, we can conclude that the subjects, all 5 of them, had improvements detecting sounds in the highest frequency ranges. In the English language, the language used for the word score tests, this is where the fricative sounds are distinguished. IE: Consonant sounds created by, "f", "th", "h", "z", "v", "s", "sh"... As English speakers, looking at those consonant, many, many words are made up of fricatives that we use every day, that could easily be mistaken for one another on a 50-word C-N-C word list. As has been researched and shared here, as the IHC/OHC cells degrade over time, it becomes more difficult to distinguish the subtle differences between these sounds. So, the evidence points to the fact that restoring the hair cells with FX-322 made these consonants distinguishable to the listener.

So how did the word scores decline in 1-2 years?

As we are all aware, and as all research has shown for SNHL, damage is cumulative and damage is permanent to these fine hair cells. So, all of these participants have accumulated significant life-long damage. And, more recently, damage can be an accelerant to earlier hearing loss in life.

As we are aware, the entire cochlea wasn't regenerated. The 8 kHz+ area was restored with "new" cells, but below that, the cells continued to contain the damage absorbed from birth, and continued to wear at the normal expected rate for someone with considerable hearing loss damage. So, while they may have been able to distinguish fricatives at the follow-up, the set of hair cells below 8 kHz continued to decline in sensitivity from the original baseline, and therefore reduced sensitivity to distinguish affricates, for example sounds like: "ts", "ch", "j", and soft-"g", respectively.


Notes on Subject 2 and 5:

Their follow-up tests were the furthest out, so they absorbed more wear to the "original equipment cells" than subject 1, 3, and 4. It also stands to reason that their losses were more concentrated more deeply in the cochlea where no FX-322 could reach. So, while FX-322 did help provide some gains, the continued wear of already highly damaged cells outweighed the benefits of the high frequency cells that were regenerated.


On OHC + IHC wear:

It is believed that in a healthy cochlea, research shows that OHC tend to wear out first, and then the IHC follow. The mechanisms for wear actually point to OHC actually creating a turbulence buffer in the cochlea, that "protects" the IHC. Also, research shows that OHC are more sensitive to the turbulence in the cochlea due to their mechanical nature, and can be damaged more easily. IHC though, are also protected from a certain amount of turbulence in the perilymph because OHC are in place. So, if OHC were never regenerated to begin with, the IHC would wear at a faster rate because they are subject to more turbulence in the perilymph.

Why are they all worse?

I actually think this shows promise. It's accepted that hair cells continue to wear from life to death. So, we're observing regular wear and tear over time from a single dose. It would actually be more suspicious, in my opinion, if a patient continued to improve significantly, while others continued to decline. What's interesting though, is 4/5 actually fell by a somewhat similar amount.

I read everything you wrote, but it just sort of cherry picks some of the explanations. For example, in one regard, we are supposed to believe the drug was incredible to some of those people in the >=8 kHz IHC range. So presumably, these people got a bunch of nice, fresh hair cells. But then their prior hair cells degrade so much over 1-2 years to offset the new durability of these tons of fresh ones?

I just have a problem with all of them worsening. It doesn't paint a picture of a bunch of healthy new IHC are coming to save the day.

I agree with you, and don't have a problem with the nuances of the consonant noises. However, it would be hard to go after those measurements, as it would add further variability to the word score tests, along with further difficulties in showing off the drug.

I don't agree that it's audiograms or bust, but it is a little weak to play this game of "some cells were damaged, but the good results were regrown ones." I would be interested in seeing if there is a strong way to break down the tests into clean, statistically sound consonant based tests, where performance over a placebo is clear-cut -- would be kind of beautiful, actually.

 

[FGG]

What about continuous loss of IHCs' synapses from SGNs? As far as I know, FX-322 doesn't influence this. Charles Liberman says that synapses and axons degenerate most rapidly. If IHCs are left without synapses, it's almost the same like being dead. That would result in distortion and reduced WR score.

or

What if the regenerated hair cells are of "lower quality" than natural hair cells? Maybe some piece of puzzle is still missing.

Who knows.

FX-322 is not a synaptopathy drug.

If you look at later Liberman studies, he lists the axonal degradation as "decades". At the time of the original studies, it was not known that human spiral ganglion neurons have a different composition and do not degrade readily like the rodent neurons.

Unless you are saying the new inner hair cells would be more prone to synaptopathy later? I guess anything is possible.

 

[Diesel]

I don't agree that it's audiograms or bust, but it is a little weak to play this game of "some cells were damaged, but the good results were regrown ones." I would be interested in seeing if there is a strong way to break down the tests into clean, statistically sound consonant based tests, where performance over a placebo is clear-cut -- would be kind of beautiful, actually.

Yeah it would be great if there wasn't so much deduction used to associate test performance, which in isolation are all not great at illustrating much of anything (WR, WIN, Audiogram), to point to specific regeneration / loss. Perhaps the OAE route(s) will be more revealing.

 

[livewire77]

FX-322 is not a synaptopathy drug.

If you look at later Liberman studies, he lists the axonal degradation as "decades". At the time of the original studies, it was not known that human spiral ganglion neurons have a different composition and do not degrade readily like the rodent neurons.

Unless you are saying the new inner hair cells would be more prone to synaptopathy later? I guess anything is possible.

Yes I know it is not a synaptopathy drug. I wrote "As far as I know, FX-322 DOESN'T influence this".

Charles Liberman says that SGNs last for decades, not their axons. Axons and synapses degenerate quickly. SGNs survive decades without these axons.

Link to video, time 4:50-6:00:

 

[FGG]

Yes I know it is not a synaptopathy drug. I wrote "As far as I know, FX-322 DOESN'T influence this".

Charles Liberman says that SGNs last for decades, not their axons. Axons and synapses degenerate quickly. SGNs survive decades without these axons.

Link to video, time 4:50-6:00:

Thanks for the link. I listened to this talk before at some point and it is a good one.

I pulled up your time stamp and he says the axons survive "months, years, even decades".

I posted a recent autopsy study awhile back (I will see if I can find it again. I believe it's somewhere on this thread but from quite a few months ago) that showed no degradation in humans after decades. They looked at humans with very long term hearing loss.

Rodents, in contrast, degrade quickly. Cochlear implants would not work nearly as well in them if not given relatively quickly.

 

[livewire77]

Thanks for the link. I listened to this talk before at some point and it is a good one.

I pulled up your time stamp and he says the axons survive "months, years, even decades".

I posted a recent autopsy study awhile back (I will see if I can find it again. I believe it's somewhere on this thread but from quite a few months ago) that showed no degradation in humans after decades. They looked at humans with very long term hearing loss.

Rodents, in contrast, degrade quickly. Cochlear implants would not work nearly as well in them if not given relatively quickly.

He says central axons, not peripheral axons (between IHC and SGN). It is a big difference.

One more thing:
Without central axons, cochlear implants would not work.

 

[FGG]

@livewire77, I couldn't find the autopsy study (yet, still looking...) but this publication describes the morphologic difference in human vs rodent neurons (Liberman's studies are in rodents):

Auditory nerve preservation and regeneration in man: relevance for cochlear implantation

In a nut shell, the neurites extending from the axon are receded but can outgrow and re-synapse after a long period.

The author of the above paper describes cases of people getting CIs after 40 years of single sided deafness and having a good response as a result.

 

[Jack V]

I must unconditionally agree with FGG; if, for example, if nerve damage or severance is involved, it is absolutely not possible to get up from a wheelchair no matter how determined the individual is. It would be equivalent to being determined to turn on a lamp when it's cord was severed. It would be stupid and cruel to insist that such people with varieties of extensive paralysis-causing tissue damage could have learned to walk if only they convinced themselves that it was doable with the correct frame of mind.

Look as such famous examples as Christopher Reeve or Charles Krauthammer (who himself was a widely regarded psychiatrist who acknowledged that from hitting his head on the floor of a pool he was permanently paralyzed for life).

Of course you're right that in those circumstances it is not possible to get up from a wheelchair regardless of determination, and I wasn't suggesting otherwise.

But what FGG said was "concentrating doesn't help someone get out of a wheelchair." But there are, in fact, circumstances where someone in a wheelchair does have the ability to stand for a moment.

And there are circumstances in which you can elevate performance on a hearing evaluation without necessarily reflecting genuine change. FGG suggests one explanation for that - fraud. I think there are other, less nefarious possibilities as well, particularly during the rarified circumstances of an early stage trial for a potentially revolutionary drug.

IF FX-322 caused the improvements in those Phase I responders, THEN Frequency Therapeutics will be able to replicate them in a larger study, and let's hope that happens ASAP.

 

[Lucifer]

@FGG, do OHCs have synapses as well, or just IHCs only?

 

[FGG]

He says central axons, not peripheral axons (between IHC and SGN). It is a big difference.

One more thing:
Without central axons, cochlear implants would not work.

All the synaptopathy treatments involve correcting the neurite/peripheral axon recession. Hough Ear Institute even has histology showing the outgrowth with their pill. Though I admit it was acutely.

Otonomy, however, selected for more long term patients or at least didn't exclude them. Acute loss was not a requirement and would be hard to determine in many cases anyway.

And, in fact, for hair cell regeneration to produce IHC hearing signals, peripheral axons would have to reconnect or there would be no signal (since it starts with a new, unconnected cell).

 

[FGG]

@FGG, do OHCs have synapses as well, or just IHCs only?

Yes, all nerve cells do. "Cochlear Synaptopathy" refers to IHC synapses, though. OHCs don't tend to lose synapses and in fact may gain synapses after acoustic shock according to one (acute) rodent study, which might be part of why noxacusis happens and why it can take a long time to heal:

Acoustic Trauma Increases Ribbon Number and Size in Outer Hair Cells of the Mouse Cochlea

 

[livewire77]

@FGG, do OHCs have synapses as well, or just IHCs only?

Yes they have.

 

[livewire77]

And, in fact, for hair cell regeneration to produce IHC hearing signals, peripheral axons would have to reconnect or there would be no signal (since it starts with a new, unconnected cell).

Of course. That is true. What if patient #5 had lost some IHCs but still had peripheral axons. They could reconnect. I know that it is unlikely, but that can be a reason why it happened only in one patient. But as I said: who knows.

 

[Jack V]

There is data that supports the 3 super responders in the Phase 1/2 had established histories of hearing loss. So it seems to be certain that these 3 subjects were well known to have a deficit prior to joining the trial. In particular, the 21 and 5 year participants.

Subject 1 (916) : 21 years
Subject 3 (936) : 5 years
Subject 4 (937) : 1.7 years

What other factors would we point to in the trial other than FX-322 that caused them to deviate from their previously established, multi-year baseline to the improved score? Then, to retain that improvement at a minimum, 13 months later? Can anyone specifically come up with any evidence that points to a non-FX-322 event that would cause this effect AND explain the duration of improvement? Is there none?

Answer: I don't know. Do I have evidence? No, none of us do.

Can I speculate? Sure. An enthusiastic audiologist artificially guided results in a way that would please his charismatic boss waxing poetic about building a one billion dollar company. Then, the company, flush with cash, purchased an exceptionally comfy sofa and an imported cappuccino machine for their chic new waiting room where the three "super responders" were super consuming super cappuccinos during their super year of follow-up, with continued assistance from the super audiologist.

Alternatively, the drug worked.



I have no idea.

All that matters is data, in larger, replicable quantities.

Only @FGG seems to have provided additional evidence to support in detail that ONLY IHC regrowth may have caused this increase + duration of improvement?

FGG has extraordinary knowledge and insight. But I don't believe anyone here has provided any "evidence."

 

[FGG]

Of course. That is true. What if patient #5 had lost some IHCs but still had peripheral axons. They could reconnect. I know that it is unlikely, but that can be a reason why it happened only in one patient. But as I said: who knows.

If Frequency Therapeutics did a follow up Tinnitus Talk Podcast, I would love them to be asked about Patient #5 specifically, especially if they could relay medical history.

One of the potential possibilities that occurred to me was that, since VPA can lead to herpes viral re-activation (in fact, it's being studied for use with anti-virals to knock them out of latency so the anti-virals might be more effective) and viral causes are a common cause of severe SSNHL, the drug may have made that individual worse with viral reactivation and a more delayed but secondary immune trigger. Having had viral vestibular illness, I would definitely take anti-virals with this drug "just in case."

But yeah, agree. Who knows?

 

[paul mclean]

How do you know what type of hearing loss do you have and where the damage has happened? Is there a way to know?

I've had multiple audiograms done and the specialist said they were fine with no damage at all.

The thing is I struggle in almost every social situation with background noise. I can't understand people and everyone is mumbling, but when I'm at home lying in bed for example with no noise in the house, I can hear birds outside clearly and even people talking a little down the road just fine. Put me in any situation with background noise, music or even multiple people talking, and I struggle.

So all that plus obviously annoying tinnitus.

Cochlear synaptopathy = speech-in-noise impairment.

 

[Lucifer]

Yes, all nerve cells do. "Cochlear Synaptopathy" refers to IHC synapses, though. OHCs don't tend to lose synapses and in fact may gain synapses after acoustic shock according to one (acute) rodent study, which might be part of why noxacusis happens and why it can take a long time to heal:

Acoustic Trauma Increases Ribbon Number and Size in Outer Hair Cells of the Mouse Cochlea

If it's true that OHC synapses increase after acoustic shock, do you reckon by restoring IHCs, OHCs or IHC synapses that it would decrease the OHC synapses and reduce noxacusis?

 

[OptimusPrimed]

I've had multiple audiograms done and the specialist said they were fine with no damage at all.

The thing is I struggle in almost every social situation with background noise. I can't understand people and everyone is mumbling, but when I'm at home lying in bed for example with no noise in the house, I can hear birds outside clearly and even people talking a little down the road just fine. Put me in any situation with background noise, music or even multiple people talking, and I struggle.

So all that plus obviously annoying tinnitus.

Cochlear synaptopathy = speech-in-noise impairment.

I have the same problem except people sound distorted. Like a tinny distortion. I have electrical chirps in that ear along with a ringing "metallic sea shell sound". And lastly a nice solid 4500 Hz tone to finish it up. Chronic pain of the worst kind.

I wonder if any of my issues are cochlear synaptopathy.

From what I understand drugs are being formulated to both regrow OHC and IHC but ALSO regrow and repair neural ganglion fells and cochlear synaptopathic ribbon cells. Maybe the new synaptopathic ribbon cells that grow in response to acoustic trauma are responsible for the tinnitus and hearing issues? Solution might be to calm the auditory system?

Is there any hard truth that tinnitus is caused by losing OHC or IHC? I know the deeper pathology is questionable but what about the early pathology?

Are any of these treatments worth waiting around for? Could hearing regeneration drugs restore hair cells to ganglion neurons and end tinnitus once the external sound is sent back to the brain?

 

[FGG]

I have the same problem except people sound distorted. Like a tinny distortion. I have electrical chirps in that ear along with a ringing "metallic sea shell sound". And lastly a nice solid 4500 Hz tone to finish it up. Chronic pain of the worst kind.

I wonder if any of my issues are cochlear synaptopathy.

From what I understand drugs are being formulated to both regrow OHC and IHC but ALSO regrow and repair neural ganglion fells and cochlear synaptopathic ribbon cells. Maybe the new synaptopathic ribbon cells that grow in response to acoustic trauma are responsible for the tinnitus and hearing issues? Solution might be to calm the auditory system?

Is there any hard truth that tinnitus is caused by losing OHC or IHC? I know the deeper pathology is questionable but what about the early pathology?

Are any of these treatments worth waiting around for? Could hearing regeneration drugs restore hair cells to ganglion neurons and end tinnitus once the external sound is sent back to the brain?

What was the cause of your tinnitus? Any hearing loss?

I don't think "metallic sea shell sound" is very typical and I have read that as a description for tinnitus being caused by less common things like patent cochlear aqueduct, Perilymph Fistula, hydrops, etc. Did they rule those kinds of things out?

 

[FGG]

If it's true that OHC synapses increase after acoustic shock, do you reckon by restoring IHCs, OHCs or IHC synapses that it would decrease the OHC synapses and reduce noxacusis?

As far as I know, no one yet knows if this is true in people or what the implications are or even if the extra synapses are maintained long term. But people can recover from noxacusis at least symptomatically so there is probably some regression of the extra synapses with (extended) time if further injury is prevented. That's just a guess though. There is no data on this.