Pain Hyperacusis in Relation to Acoustic Shock & Synapse Disconnection

Yes Megan Wood explained her cochlea research really well, I understand what's going on in the images better now as well on that latest piece of research. It was good to see Arnaud emphasize on the trigeminal nerve as well. It's good to get the 2 areas of research into the same forum for the first time though and hopefully they can start considering how the 2 pathologies may inter-relate.

The takeaway point for me was that Megan said the activation of neurons by ATP is a separate route of activation from extra ribbons. So more questions to be answered. I.e. Does one activation type have different consequences / symptoms / lasting effect etc. to the other?

Yeh its time that hyperacusis sub-types had well defined pathologies (even if theoretical), and differences defined. I also think that susceptibility to setbacks should be defined as the central point of what noxacusis actually is.

 

Yes Megan Wood explained her cochlea research really well, I understand what's going on in the images better now as well on that latest piece of research. It was good to see Arnaud emphasize on the trigeminal nerve as well. Its good to get the 2 areas of research into the same forum for the first time though and hopefully they can start considering how the 2 pathologies may inter-relate.

The takeaway point for me was that Megan said the activation of neurons by ATP is a separate route of activation from extra ribbons. So more questions to be answered. I.e. Does one activation type have different consequences / symptoms / lasting effect etc. to the other?

Yeh its time that hyperacusis sub-types had well defined pathologies (even if theoretical), and differences defined. I also think that susceptibility to setbacks should be defined as the central point of what noxacusis actually is.

 

It makes me wonder what the minimum threshold is for initiating type 2 ribbon synapse proliferation. From the studies they did there was a clear level of hearing loss. I just wonder how much damage/hearing loss is needed at minimum to trigger the ribbon synapse increase and size increase.

I also thought it was interesting how, when asked whether this proliferation, could be called neuropathy, Megan Wood said she would term it 'plasticity.' It would be good to get further studied of whether this proliferation is long-term or not.

 

Is that to say the trigeminal nerve is involved, with sensitized type II fibers?

 

Plasticity implies reversibility. Of course if it were that simple then CBT would easily solve phantom limb pain. However, the physical cause of phantom limb pain (amputation) can’t be fixed, whereas there is some hope that most forms of cochlear damage can be addressed. Perhaps after hair cells/inflammation/IHC synapses are treated, there will be some validity to using CBT to reverse sensitization.

 

There will definitely be value in CBT and TRT counseling once we can address the underlying damage, since we'll still be dealing with the psychological phonophobia after deeply ingraining in our lizard brains that sounds are painful.

 

No, the type 2 nerves and the TN irritation were being looked at by two separate researchers.

 

Something that I wonder about the ATP involvement. So it appears that you can get ribbon synapse increase from acoustic trauma - in these same ears there was synaptopathy of the IHC afferents but in the paper they noted that there wasn't significant OHC damage.

Does ATP only become involved when there is cell death i.e. OHC damage/loss? Or could you get increased ATP that causes sensitisation from acoustic trauma that just damages synapses and not hair cells?

Not sure if this quite makes sense lmao, hopefully you get what I'm saying.

 

I agree with this. TRT will be no use to us as we need to fix the underlying issues in the ear for the pain to stop. Once the drug starts kicking in and reducing our pain we will most likely need sound therapy as well as FX-322 to improve our hyperacusis due to phonophobia/misophonia.

 

I have been following this thread for a while now. When I think about it, wouldn’t it be reasonable that if you lose synapses to the IHC then the ribbons between IHC and OHC increases to get more input from the OHC? Like an amplifier. Maybe certain frequencies are louder to us because synapses are missing in those frequencies. That would not explain the pain but maybe the loudness.

I unfortunately missed the webinar but what happens in the middle ear when a acoustic shock occur and why is the trigeminal nerve reacting?

 

Yes, it does imply that, and I wonder whether that also explains why some people do recover (to various degrees) from hyperacusis.

I doubt, however, that Megan Wood would have made the inference of plasticity just because some people get better from hyperacusis - so this term must obviously be grounded in the molecular processes she is studying. In fact, I do remember reading a study (I don't remember by whom but perhaps one Megan Wood was part of) that described the upregulation of type 2s as a type of 'maladaptive plasticity', which according to this paper is defined as changes that happen

"along the sensory pathways, from the peripheral to central nervous system, which may contribute to the generation, development, and maintenance of neuropathic pain."

 

Probably not directly involved. trigeminal nerve would be down to acoustic shock, while sensitized type II afferents would be down to noise induced cochlea damage. After the damages are done however it's how they may inter-relate with each other down to factors like heightened neural response, inflammation etc.

Hope you're doing good.

 

Yes I'm asking the same questions right now because I've read about 2 types of 'sensitization' now and there seems to be quite a few variables and conditions in the loop. I wonder if one of these scenarios may be more of a temporary / less life changing version of noxacusis.


1) Max stimulation of hair cell bundles that do die causing ATP release that causes sensitization of type II's

2) Max stimulation of hair cell bundles that apparently don't die causing extra synapse connections causes sensitization of type II's

3) Possible to have both in the same OHC bundle region (extra ribbons plus excess ATP plus dead OHC's)?

4) Possible to have both in the same OHC bundle region (extra ribbons plus excess ATP plus intact OHC's)?

5) A combination of the 2 scenarios at different regions of he cochlea. Say 8K had extra ribbons but intact OHC's and 9K has no extra ribbons, dead OHC's, and excess ATP being released? Could the excess ATP from 9K interfere with the extra ribbon type II's at 8K?


I'm gonna read them again today, here they are for your reference.

This one is about ATP release upon OHC death - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664349/

And here's the latest one about extra ribbons - https://link.springer.com/article/10.1007/s10162-020-00777-w

 

Do you think palliative ways to encourage neurogenisis like yoga, meditation, sleep, diet/fasting, supplements, HBOT, etc could help hyperacusis by forming new neural connections? Basically everything I'm not doing right now.

 

For those who missed the webinar or simply wish to rewatch it again, both talks have been posted on YouTube by Hyperacusis Research. Arnaud Norena's talk doesn't have closed captioning, however, Megan Wood's does:

2020 Hyperacusis Webinar: Middle Ear...

2020 Hyperacusis Webinar: Inner Ear Mechanisms...

 

Regarding ATP, it says that it's released upon 'tissue damage' - I take it that refers to actual hair cell damage/death? I'm starting to wonder if you could get noxacusis from both hair cell and/or synapse damage - I feel like a lot of the prior speculation has gone back and forth between 'is it OHCs?' or 'is it synapses?'. Perhaps, if you suffer an acoustic trauma that only results in synapse loss but not cell death, then you get the extra ribbons leading to noxacusis. But then perhaps once you suffer acoustic trauma sufficient to trigger OHC death then the ATP comes into play too.

One thing I'm still a bit confused about - the term 'maximal acoustic stimulation' gets thrown around a lot in the papers. What does this actually mean, in real terms? Like, does that refer to noise that is sufficient to actually damage the cochlea? Probably a very basic question but I feel like I'm still not exactly clear on that!

 

Yes it's that relationship between OHC death / ICH synaptopathy / Type II sensitization (and type of sensitization) / ATP that need to be homed in on somehow. I agree with you that it could suggest that depending on the combination that you have of these factors could dictate what type of hyperacusis you have, and if you do have noxacusis then how severe it is, how likely you were to recover from it etc.

What I get from 'maximally stimulated' as far as I can tell is that if the noise is enough to 'maximally stimulate' the entire bundle of hair cells that a type II afferent is connected to then it will sensitize that afferent, and I think this is the extra ribbon synapses route of sensitization (it's actually mentioned in both papers and is the main focus of the most recent paper). The other type of sensitization appears to be via hair cell destruction and the release of ATP (the focus of the older paper). I think I understand this a bit better now, Megan actually said in the webinar that they are 2 separate 'routes' of sensitization.

 

Here's the quote from the older paper that suggests the 2 routes of sensitization. And I've only just noticed it but it suggests ATP release into coclear fluid can occur without OHC ablation.

'This work provides direct evidence that type II afferents, in addition to sensing glutamate release from OHCs, are activated by cochlear damage in the young rat’s cochlea. This observation may help to resolve the decades-long conundrum that type II afferents in vivo are very insensitive to sound and yet presumably carry some information to the auditory brainstem. Likewise, measured ex vivo, synaptic excitation is weak and could activate type II afferents only if all of the presynaptic OHCs were maximally stimulated. Alternatively, ATP potently activates type II afferents and serves as a major contributor to the damage-induced response. ATP can be released into cochlear fluid after tissue stress (even without OHC ablation) in vitro or noise exposure in vivo'

 

According to Arnaud Norena the inflammation in the TTM is due to low frequency hearing loss, meaning FX-322 won't be able to fix this issue?

 

We recently got an anecdote in the Frequency Therapeutics thread from someone who broke their NDA that suggests it may treat lower frequencies than we thought.

 

I meant to reply to this earlier @Loui. It doesn't work that way I don't think (@serendipity1996 knows a bit more about the IHC synaptopathy I think). IHC synaptopathy loses synapses that are connected to the auditory nerve (type I afferents). It's suggested that this could be responsible for hidden hearing loss and a big part of tinnitus. The OHC synapses that are newly generated upon noise exposure are connected to type II afferents that apparently act as nociceptors sending pain signals and not auditory. So basically you're losing hearing and gaining pain upon noise exposure.

The part about middle ear Acoustic Shock Symptoms Cluster is what damages the middle ear tensor tympani, causes inflammation, and sensitizes the trigeminal nerve leading to the facial pain side of noxacusis. Just have a read through this thread and see the few bits of research it's based on (also linked in this thread), it will give you a good idea of the theory of this thread. It helps to think of it as 2 separate injuries (one cochlea, one middle ear) that end up inter-relating.

 

So if most of your symptoms come from facial pain, that’d lead you to believe that most of your damage is in the middle ear, not the inner ear?

I’m only asking because most of my problem is the facial pain. Like I have some ear pain but if it was just that, I’d be a lot more functional. My bad days are the days where sound makes my face burn and if take a gabaergic, it makes me feel a lot better if not take it away entirely.

 

Yeh, it's quite weird the way it works and it's quite subjective in how a sufferer decides which is the worst of the 2 injuries. I think the cochlea damage is the by far the worst of the two injuries for a couple of reasons, even though the middle ear damage causes the most severe physical symptoms. The first reason is simply because I can hardly tolerate any kind of sound anymore, the second reason is because I believe the damaged cochlea is the trigger upon noise exposure that sets off the middle ear cascade of symptoms. Again, this is just speculative discussion but I really believe that if the cochlea didn't respond negatively to noise anymore (was fixed by FX-322, Xenon etc), then there would be no more triggering of the damaged middle ear components. They would still be potentially dangerous but would be isolated and dormant until I suppose either something else triggered them, or if the cochlea became damaged again. It would be like removing the detonator from a block of C-4.

The trigeminal nerve sensitization we kind of always assume takes place during an acoustic shock but it can apparently be sensitized by a whole range of other things maybe even years before your cochlea damage which might explain why people can suffer the full range of noxacusis symptoms without necessarily suffering an acoustic shock. If this is what can happen then it makes me feel quite confident that a sensitized trigeminal nerve can sit dormant although not really bothering us. This tends to be the case anyway after a long recovery and the presumed inflammation has settled down. Until it's triggered again by noise via the cochlea. I really hope the cochlea can be fixed with the options that are hopefully upcoming.

 

The one thing that I still wonder about is how do the acoustic shock findings fit in with Jaime-Garcia Anoveros' findings that the trigeminal nerve and middle ear don't react to intense noise? Or do you think for acoustic shock sufferers there may have perhaps been a trigger completely unrelated to noise exposure, possibly years before that means their trigeminal nerve/middle ear is more liable to be sensitised/inflamed when the cochlea is damaged? That would make sense.

 

So guys, I’m just curious, what are you guys feeling when you talk about having pain hyperacusis?

The more I think about what I’m reading here, the more I’m convinced that most of it trigeminal nerve sensitization.

But I don’t think everyone with pain hyperacusis has that. If they don’t, what do they feel when they hear sounds that they can’t tolerate?

 

The way I understand it is that at the time of acoustic shock, the trigeminal nerve although not responding to noise itself, gets sensitized by the inflammation as a result of the tensor tympani responding to genuinely noxious noise. It's supposed to be a defense mechanism but it cripples itself with an acoustic shock symptoms cluster leaving the very thing its defending (the cochlea) open to attack, and which will get damaged if the noxious noise continues for long enough, this is why I think it ends up being 2 separate pathologies. One of the unknowns I think is whether or not the tensor tympani is permanently damaged as a result of hypoxia during the acoustic shock that makes it susceptible to inflammation / ATP release, at least more easily.

So when a noxious frequency does whatever it does in the cochlea to give you a setback (ATP hitting type II's for example), I'm guessing either the startle response to the nociceptor type II stimulation (I think its called sympathetic nervous system) causes the tensor tympani to hyper contract that in turn causes the middle ear ATP release, or the cochlea trigeminal nerve innervation gets stimulated from within the cochlea by cochlea ATP.

 

I get intermittent ear pain, like random stabs or random periods of achiness but it doesn't follow noise. My face feels "flared" and numb 80-90% of my day and very often my inner canals too. Sound has never felt "painful" to me even at it's worst, it just felt "too loud". Perhaps this will change at some point but my biggest issues with sound itself are some things feeling uncomfortably loud and the fear that it's going to set off more burning, louder T and TTTS.

 

I don’t have any facial symptoms. What I do have is stabbing pain in response to sudden noises and an earache that progresses over the day from cumulative sound exposure. I wouldn’t describe it as burning. Sometimes it resets after sleeping, sometimes not. Along with eardrum spasming and autophony from my right eustachian tube getting stuck open.

I think the middle ear symptoms are communicated through the trigeminal nerve, maybe that counts as TN sensitization? Perhaps not.

 

Stabbing instant pain upon the noise assault itself. Then the facial pain sets in after a delay and lasts for ages.

I guess it depends on whether your trigeminal nerve is sensitized whether you get the facial pain or not. Otherwise it would just be the stabbing sensation, ear fatigue, and sensitivity. I'm sure I went through this stage before acoustic shock. But you are right, after the acoustic shock things got so much worse once the trigeminal nerve came into play.

 

So you have stabbing pain that stays in the ear? That’s interesting to me because in my 13 months now of having hyperacusis I’ve never felt any stabbing at all.

It’s a good thing researchers are investigating different pathways here.