Pain Hyperacusis in Relation to Acoustic Shock & Synapse Disconnection

I wouldn’t necessarily say you are clutching at straws. If it’s possible for these synapses to recede as someone said above, I feel like a more normalized auditory system could only help that process.

 

Yes it would be good to know if they went hand in hand. I wonder how it would apply in cases of hidden hearing loss where people did have presumed synapse disconnection (good audiograph) but not noxacusis.

 

Back to XEN and RL-81...

 

Yeah that's a good point - there are many people who acquire tinnitus / hidden hearing loss from noise damage who don't go on to develop noxacusis even if they continue to expose themselves to dangerous noise in some cases.

I wonder if it could possibly come down to differences in genetic susceptibility for some of us - the type 2 fibers may not have the same pattern of gene expression in every person, according to Fuchs.

It is baffling how noxacusis sufferers are seemingly a tiny minority whereas tinnitus is relatively common, as is hidden hearing loss I would wager.

 

So will we need to be on Retigabine for life since there is no medicine in the pipeline to disconnect synapses? This research is a grim finding in terms of regenerative medicine. Why spend $20k if you're still going to be left with pain hyperacusis?

 

I'm not sure - there's still a lot of questions left unanswered. Something I was wondering (and this is just pure speculation on my part) is whether the upregulation and increase in type 2 ribbon synapses is in response to loss of the type 1 afferent fibres (which are more vulnerable to damage than hair cells). It's interesting that in the study they noted an increase in type 2s, whilst there was a decrease in type 1s in response to noise trauma - essentially, they have opposite responses to acoustic trauma.

I was wondering if therefore a synapse drug would be helpful, e.g. by restoring input to the type 1s would that downregulate activity and decrease the number of the type 2s.
They pointed out that the extra ribbon synapses of the type 2s bear a resemblance to 'silent synapses' in the nervous system and they exhibit plasticity, so presumably their presence in the cochlea may not be permanent -perhaps restoring input to the type 1s would then downregulate the type 2s.

It's just a theory though so I don't know.

 

People here are literally discussing nerve pain and in comes in the sound therapy.

This is like telling someone with trigeminal neuralgia to massage their face to get used to the sensations. I don’t disregard TRT completely but doesn’t belong on a thread such as this one.

 

This is what I'm thinking too.

Isn't there a video about hair cell regrowth somewhere on YouTube where they state that synapses "automatically" regrew when new hair cells were created? Wasn't that FX-322?

 

Frequency Therapeutics has stated that if there is hair cell loss, then the hair cell will be regenerated along with its synaptic connections.

 

Ah, right. Is there any clinically defined difference between "lost" and "damaged"?

 

This is something I'm not quite sure about - I think damaged hair cells eventually undergo apoptosis and get ejected by the body but don't quote me on that!

 

I asked this question a while ago and no one knew the answer. I would think if the synapses were damaged they would be repaired as long as the hair cells that are connected to those synapses were damaged - then FX-322 should work.

I have no clue if damaged synapses is the same thing as lost synapses.

 

This would be really useful to get a definitive answer to (do hair cells get damaged or just die). This quote below suggests there are levels of damage before OHCs get to apoptosis:

'Loud sound progressively damages type I afferent neurons and OHCs. Once damaged beyond repair, these do not regenerate as they do in non-mammalian vertebrates.'

I'm sure I remember reading recently that synapses are in effect connections so they do not get damaged as such, once the synapse is gone the connection is lost, but I don't think they can be in a 'damaged' state.

But when I read this from the latest research it makes it sound like it could be possible to have noxacusis while our OHCs are in fact generally OK. As someone who honestly does not seem to suffer from hearing loss I do wonder about this possibility. If however I've got loads of IHC synapse damage then a synapse drug would be very interesting to see if it balances things up like @serendipity1996 suggests.

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.'

 

It makes sense that we could have noxacusis with no perceptible OHC damage. I do wonder about synapse loss though because A) they are the most vulnerable to acoustic trauma, moreso than hair cells as Liberman's research shows and B) the vast majority of us with noxacusis also have tinnitus, it seems which indicates that we must have some degree of NIHL.

The hair cell damage question is interesting-it mentioned in the paper that there can be damage to the stereocilia. Do the stereocilia repair?

 

Yes it is interesting. Do you remember when I started this thread that I plucked synapses out of the air (over OHC death), only because I didn't consider that OHC death could cause noxacuis otherwise so many people should in theory have it due to the amount of OHC death (deafness) floating around? But if noxacusis can exist without OHC death then it could turn the spotlight back onto synapses, (or a completely independent problem, i.e. solely sensitized type II's / extra type II synapse connections). It still baffles me how the relationship between ATP and the type II's works (now with their extra synapses)!

I mean what if hearing loss, hidden hearing loss, and noxacuis were 3 totally separate things down to their individual pathologies? Tinnitus could more than likely be easily be a combination, but you could almost put hearing loss down to OHC death, hidden hearing loss down to IHC synaptopathy, and noxacusis down to either type II sensitization, extra synapses, and / or the relationship with excess ATP release.

One thing that bothers me though with all this type II research, is even though it can establish that activity is happening in type II's upon exposure to noise, and even though it can be established that extra synapses can be formed to type II's, and that type II's respond to ATP, how can it be established that it is actually causing pain?

As for the stereocilia damage I'm only aware of the tip link damage that I think does repair itself every couple of days.

 

I'm also wondering where things like reactive tinnitus and distortions fit into this. It's interesting that for many of us the sounds that trigger noxacusis symptoms also trigger reactive tinnitus so it makes me question whether there are common pathogenic mechanisms at play.

Regarding pain, I also wonder why for some people there is an immediate pain response on exposure to noise whereas for some of us we get a delayed reaction? Not to mention the fact that hyperacusis pain can be stabbing or burning or tingling. Trigeminal and jaw pain too.

 

Speaking for myself, fluctuating tinnitus and distortions seem to get triggered with setbacks and I think its due to the rise and fall in inflammation that does it, those symptoms always seem to go hand in hand with pain levels as well. Reactive tinnitus I guess is a bit different, my tinnitus goes up anyway when I've had noise exposure even if not enough to cause a setback. It goes though the roof with a setback though and then fluctuates up and down but on a downward trend as recovery goes on.

I think the facial pain side of it is down to whether you've got a sensitized trigeminal nerve or not. It could be down an acoustic shock that causes it but, I also think that it could be possible to have a sensitized trigeminal nerve from something else, maybe even years beforehand. I don't know but say a bad sinus or ear infection could cause it and then years later noxacusis caused by inner ear damage causes not just the inner ear pain and setbacks to sharp sounds but then flares up our sensitized trigeminal nerve again thanks to inflammation. There seems to be a definite difference between the immediate sharp stabbing pain upon certain noise exposure compared to the delayed aching pain around the face and neck.

 

Maybe SPI-1005 can relieve some of those symptoms by reducing inflammation. I didn't get trigeminal pain until after hyperacusis with no prior history, so I think hyperacusis alone can induce TN.

 

I didn't get trigeminal pain until hyperacusis from noise damage either and no history of sinus issues/ear infections - I think I recall reading that there are projections from the trigeminal nerve into the cochlea so perhaps that's also why hearing damage can cause facial pain? It also sounds plausible though that if you have a history of ear infections etc then perhaps your trigeminal nerve has a lower threshold for being sensitised?

It's also interesting that the type 2 afferents bear a resemblance to C fibers elsewhere in the body apparently these are responsible for slow, aching sensations of pain so perhaps that's also why we get delayed pain.

 

Also no history of ear infections or sinus infections here and got trigeminal irritation post acoustic trauma. The trigeminal nerve innervates the tensor tympani but what’s interesting to me is how noise can affect it and cause it to malfunction.

“An ear specialist is often called upon to manage facial nerve problems because of the close association of this nerve with the ear structures. After leaving the brain the facial nerve enters the temporal bone (ear bone) through a small bony tube (the internal auditory canal) in very close association with the hearing and balance nerves. Along its inch and a half course through a small bony canal in the temporal bone the facial nerve winds around the three middle ear bones, in back of the eardrum, and then through the mastoid to exit below the ear. Here it divides into many branches to supply the facial muscles. During its course through the temporal bone the facial nerve gives off several branches: to the tear gland, to the stapes muscle, to the tongue and saliva glands and to the ear canal”

My question is, does this nerve get sensitized as a secondary effect to cochlear damage of some sort, or does it also just get sensitized by noise for whatever reason. Within the trigeminal neuralgia communities, ear pain, tinnitus and sound sensitivity are also very prevalent so there’s definitely an overlay of some sort.

Nerves tend to cross talk too. For example following trigeminal nerve pain, I started having occipital pain too. Neither my trigeminal or occipital pains are “shock like” such as with classic TN/ON but are more lingering in nature which leads me to believe it’s a sensitization/irritation issue and not a compression.

 

I really do hope it is either OHCs or IHCs causing pain hyperacusis. If it ends up being synapses then it will depend on how much hair cell loss we have.

 

The problem I have with this is how it fits into the overall hyperacusis prognosis/recovery process. If indeed hyperacusis is the result of an increase in type 2 synaptic ribbons (in response to a decrease in type 1 synaptic ribbons), how would that explain some people's hyperacusis improving in the absence of a regenerative treatment to restore those type 1 synaptic ribbons? In other words, if hyperacusis is the result of upregulation of type 2s (due to loss of type 1s) - maladaptive plasticity, as it's been put - what would explain the improvements that some have, given that there is no increase in input?

I think there must be something else going on here. I posted this study the other day on the regenerative hearing thread but it didn't seem to get much of a response. It came out just over a year ago and was cited in that recently released Fuchs study @serendipity1996 shared. It effectively looks at how synaptic ribbon sizes (not just number) change after noise-exposure in zebrafish. I think the potential implications for hyperacusis must be considered, so I encourage anyone who likes to dive into these medical papers to take a look at if they haven't already.

 

Yeah, that's a really good question. Rereading the paper just now - I think a key point that it mentions is that: "This proposed increase of hair cell to afferent signalling is just one of many changes that may result from acoustic trauma."

Then it goes on to point out that there is also ATP release and a "prolonged inflammatory response." So, perhaps when our symptoms improve, it is a result of cochlear inflammation subsiding and less ATP in the cochlea? The thing is, many of us do improve but only to a certain extent - even if our symptoms and pain subside, it's not unusual for us to get setbacks from sound levels that do not bother healthy ears. E.g. I experienced setback after 4 years of pretty much feeling 'normal' from sound levels that were quite loud but did not cause any problems for any of the other people I was with, with healthy ears. Perhaps that lower threshold for re-initiation and limited recovery has something to do with the imbalance between the Type 1 and Type 2 afferents?

I'm just thinking out loud here, though.

The change in ribbon size is really interesting as well, especially in zebrafish - from the OHC ribbon article it says that: "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." I wonder if the change in ribbon size, however, is something that would persist or not?

 

It helps to think of it as 2 separate injuries that then get linked together, I think it works like this,

First Injury - Noise causes cochlea damage. What ever this is is the physical reaction of what noise does, so it could be dead OHCs, disconnected synapses, type II sensitization etc.

If the noise is loud enough and importantly persistent, which presumably it is, it also causes the second injury,

Second Injury - Noxious noise is now loud enough to heighten the middle ear response to noise via the central nervous system. So basically the central nervous system puts pressure on the middle ear to protect the cochlea. The tensor tympani then hyper contracts, and causes itself loads of damage (acoustic shock symptoms cluster), I cant remember specifics but it goes into a loop where it basically deprives itself of oxygen I think, releases ATP, causes massive inflammation, and sensitizes the trigeminal nerve as a result.

Now you have the 2 pathologies and the corresponding permanently damaged components primed and ready for repeat setbacks. I think it's possible to suffer either or both of these and it could explain why some people don't get for instance facial pain but they do get inner ear pain and sensitivity.

From here its just a matter of time before noise triggers the reaction in the cochlea, whatever it is. Say for example noise causes ATP release from support cells that trigger the sensitized type IIs. I think this could do one of 2 things, either cause inflammation in the cochlea that triggers the facial pain via the cochlea innervation, or, as the type IIs send pain signals to the brain, the response to noise heightens and causes the middle ear to over react once again ignite middle ear inflammation that then sets off the trigeminal nerve. Its why I dont think you nessecarily need to suffer an acoustic shock to get the trigeminal nerve symptoms. If the trigeminal nerve was senstized earlier on in life by something completely unrelated the result is the same in that you'd now have a dormant, primed trigeminal nerve.

 

A steady reduction of inflammation while taking real care not to cause more. I think I remember reading that cochlea inflammation can take months to dissipate. But as we know if you get a sudden stab due to a sharp noise it sets it off again. In the early days after an acoustic shock, it's inflammation on top of inflammation, we just cant escape it until we really learn to rest in silence.

 

Yeah, I'm always wondering whether the pain I'm experiencing is temporary inflammation or physical damage. If it were just inflammation then why do people get setbacks they never recover from? Is it because enough inflammation causes OHC/synapse loss or this synapse proliferation we're just finding out about?

 

Inflammation is what causes the pain, but it goes away. Even though you are not in pain anymore your susceptibility to repeat inflammation remains in place because of the physical damage and nerve sensitization. It just doesn't help that sound of all things is the trigger. It's why we keep focusing on fixing the physical damage because it will also in theory fix the susceptibility.

This is the rub though. If it's OHCs, or IHC synapses, then we may stand a good chance of getting it repaired. If ATP is the main ingredient of a setback it depends on whether the excess release gets fixed by FX-322, but if it continues to leak elsewhere upon noise exposure then I'm not sure if FX-322 would do much for us noxacusis wise. If type II sensitization is an integral part of a setback whether or not everything else gets fixed leaves us with the option of XEN or RL-81. As far as the inflammation goes that could really be helped as needed by SPI-1005 but would be ongoing if the underlying damage couldn't be fixed.

 

So if it’s inflammation causing the pain, could we just be on SPI-1005 daily indefinitely?

 

I think if it comes down to hair cells and/or synapses then we have a good chance of regenerative treatments helping us. This was discussed at the 2017 ARO conference on hyperacusis, where they proposed a thought experiment, that if hair cells and synapses were the only permanently damaged elements, then regenerative treatments should help:

"Then (in this thought experiment) we should be able to cure hyperacusis, because any central component would be functional (not permanent)—that is, it would have developed solely as an accommodation to (or consequence of) what had been permanently damaged—the cochlea."

https://hyperacusisresearch.org/wp-content/uploads/2017/03/ARO-2017-Technical-Summary.pdf
(It talks about this on page 6)

 

Ok, but how does the inflammation pathology fit into this recently discovered model describing an inverse relationship in numbers of type 1 and type 2 afferents synapses post noise-exposure? Are you saying you think inflammation causes an increase in type 2 afferent synapses and then they downregulate after the inflammation settles? In which case, I would imagine what happens with the type 1s (up or down) is redundant. Or do you think the increase in synapses is a red herring altogether?

Personally I think this recent revelation about the synapses is huge and makes a lot of sense to me. My audiogram is pretty decent (up to 8khz, it's probably pretty tragic in the UHF), but I know I can't hear for shit half the time in a semi-noisy environment and that had been the case in the year leading up to me developing hyperacusis, so I'm sure most of my issues are either synapse related and/or UHF OHC related.

Let's say for a moment it is inflammation. Why do some hyperacusis sufferers suffer disproportionately with artificial/distorted sounds even on good days? Why does this very specific type of sound cause inflammation and not other types of sound? I feel this is a point of inquiry really worth investigating if we are to understand the pathology behind this condition a bit better.