Pain Hyperacusis in Relation to Acoustic Shock & Synapse Disconnection

I do remember reading somewhere that cochlear inflammation in mice lasts up to 6 months post-noise exposure. This study shows that auditory nerve fibre degeneration in the cochlea nucleus (brainstem) continues 6-9 months post-noise exposure - almost in parallel. I wonder then if there's a relationship between the two or whether this is just a coincidence. Are the same mechanisms responsible for inflammation in both areas, or does brainstem inflammation occur because of the inflammatory processes happening in the cochlea? As @100Hz was alluding to (I believe), it is also very interesting that those who experience their biggest improvements seem to do so after this timeline of 6-9 months has elapsed.

It's a minefield, isn't it? In any case, I think it's worth giving some kind of neuro-protective protocol that addresses neuroinflammation, oxidative stress and apoptosis a shot - for example, by supplementing with Lion's Mane, Curcumin, Resveratrol, Nicotinamide Riboside and Astaxanthin (or Krill Oil with Astaxanthin in it) - while getting in some healthy amounts of sleep and exercise too. I've read that to see the benefits of such an approach you may have be on these supplements for at least a few months. I'm about to start my full protocol next week (already on Lion's Mane and a bunch of other stuff), will add Resveratrol to the mix once my microscale arrives. I feel when one is in such a desperate situation where modern medicine is still unable to help, once can leave no stone unturned. I know that many on here have tried these supplements, but I wonder how many have taken all of the ones I listed above for an extended period of time and whether they saw any results in treating their hyperacusis.

 

This is a good question. I wonder if the (sensitized) trigeminal nerve stimulation could be getting triggered actually from within the cochlea by cochlea inflammation as well.

I'll be following your diet, good luck with it. I'm on NAC at the moment, whether its doing anything or not though I'm not sure. I'm nearly 15 months into recovery so might just be the timeline. By the way I saw someone mention taking NAC with something called selenium on the NAC page, apparently it made a big difference.

I'd love it if SPI-1005 could just fix this in a flash.

 

Since the severing of my tensor tympani muscle did not help at all, I'm now on Prednisolone cure at the moment. Just 6 years too late . I'm on it because they have found something in my brain lining on an MRI. Just hoping it could help me if I have an inflamed cochlea or brainstem. But I'm convinced now really that it is the type II nerve fibers causing my noxacusis. Just find it a bit odd that neither Gabapentin, Pregabalin nor Amitriptyline seem to help with such nerve pain. I can't find anybody who has benefitted by Prednisolone on the net.

 

Sorry to hear that surgery hasn't helped you yet. I'm hoping that SPI-1005 works in a radically different way to those other drugs you mentioned by reducing cochlear inflammation (quickly). The only thing that's ever sort of worked for me out of that lot was Pregabalin (Lyrica). But never when I'm severe am only when I'm doing slightly better and more manageable. The side effects of it are not worth it to me at this level though.

None of these either help to prevent a setback or help to negate the effects of setback for me though which is the most important thing.

 

What do you mean by sort of worked and what side effects did you experience?

 

I took it a year into recovery for a few months (had tried it earlier on but it didn't work while I was in real pain) and it had quite a good effect in that if I knew I was going to be exposed to noise it would make the effects of it not so bad, or not as bad as I anticipated and manageable afterwards.

I don't like the side effects though, I found it a real creeping drug that works quite well at first without too many side effects but then changes once you've had it for a while. Suicidal thoughts were one serious effect for me. Also I found that I was having weeks of after effects from just small courses of Lyrica in the end. Negative feelings, depression.

Again though, it didn't work when I was really in the depths of pain. I didn't find it useful for setbacks etc. and it didn't stop me from getting them either. It's not really what I'd call any kind of fix.

 

What are your thoughts on taking an SSRI or SNRI when having tinnitus/hyperacusis?

 

I see. Thanks for telling me. I reckon it was a bitch to get off as well?

It's a downer none of these drugs that usually treats neuropathic pain work with these type II nerve fibers we struggle with. The only thing that helps me is a benzo (20 mg Vival) or Oxycontin (15 mg), but it's hardly viable.

Have Charles Liberman or Paul Fuchs come up with any suggestions at all at this point?

I'm so sick of my claustrophobic and isolated existence constantly terrified of any unexpected noise. Even though I wear ear protection all the time.

 

I don't know because I haven't really seen any trends that suggest anything really works. Some things / combinations do a bit for certain people etc. but I've never seen the magic formula to either stop a setback or prevent one in the first place. I think the best thing I've used, again purely for pain only and not setback susceptibility, is valium but I'm very wary of benzos as well, I know @grate_biff is too. What about Mirtazapine @serendipity1996?

 

I'm actually back on 10mg Valium every day to counteract the effect of Prednisolone. I've been 11 months without it but the withdrawals never got any better. I'm going to be on it until I get into psych ward. I'm also on 30 mg Mirtazapine. It helps a little with the noxacusis when I take it. In the long run it might be part of the problem I suspect.

 

I'm also on 30 mg Mirtazapine - been on it for 4 years and had no issues with it regarding my tinnitus or hyperacusis. I think ADs are in general fairly safe for ototoxicity but it may be a case of your mileage may vary.

 

Hyperacusis Research posted a link to this on their Twitter page - the Hearing Health Foundation is accepting grants for research on hyperacusis. Interestingly, one of the topics they've listed is the 'Interaction between auditory nerve and trigeminal nerve information.'

https://hearinghealthfoundation.org/grants/hyperacusis

 

Well, it looks like we have some fresh research papers to pore over @100Hz and @Aaron91! Also tagging @FGG in case it's of interest.

In a happy accident, I stumbled across this paper just now - it was only published last week and it's from the Johns Hopkins team - Fuchs and researchers in his lab studying the function of the OHCs and the Type 2s.

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

https://link.springer.com/article/10.1007/s10162-020-00777-w

 

So... nothing is wrong with our hair cells and we have too many synapses? In other words nothing except Retigabine successors might help?

Edit: this sentence seems important: “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.”

Maybe this is implying that it’s possible for the new synapses to recede. Maybe that’s why we get better with silence. It would also explain setbacks if new exposure causes these ribbons to grow back.

 

I need time to properly digest it but what it seems to be suggesting is that acoustic trauma results in a loss of IHC type 1 fibers whilst the synaptic ribbons on the OHCs increase in number, in response to this trauma. Paul Fuchs hinted that this sort of process could be at play a few years ago in an interview he gave:

"So when we come to tinnitus, as we begin to lose inputs that are delivered by the cognitive nerve fibers that tell us about sound, then conceivably the Type II neurons which we have been studying, which we think may be analogous to pain fibers, begin to gain more or stronger access to parts of the nervous system which are going to mediate sensations of pain and the kinds of behaviors that mean withdrawal or aversion."

So it seems like some form of maladaptive plasticity perhaps? I don't think it's suggesting per se that we have nothing wrong with our hair cells - hyperacusis follows on from some form of peripheral damage and I think there must be some real damage that triggers it. But there's a lot to digest in that paper.

 

I just hope FX-322 helps us. It can restore both OHCs, IHCs and synapses where there is lost hair cells and the likelihood that we had no hair cell loss is quite low so it should do something.

I honestly believe one or multiple of OHCs, IHCs or synapses are causing pain hyperacusis. I don’t think it will be anything else other than these 3.

 

“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.”

 

I sure hope so man. It’s scary that the implications of this study are that no upcoming therapies will cure hyperacusis.

 

I think that this is the real winner.

I entirely agree and actually think that this is likely to be the cause. Consequently regrowing either of these three (or all of them when necessary) is probably going to overcome the issue as it is incredibly likely that one or all of these are actually what is causing the problems of various kind.

I certainly hope that FX-322 does help, however I still hold the same view that the issue is going to be most likely with medicine delivery and/or dosing and not with the medicine itself. It has been shown that FX-322 can regrow a whole ear in the lab work. What just needs to be solved now is getting the medicine to work widely within the ear, which is possible, but it is also just a matter of getting this done.

 

Yeah that was an interesting bit and will surely generate some discussion - personally speaking I'm sure I must have sustained hair cell and synapse damage since I acquired noise induced tinnitus 5 years prior to hyperacusis. The majority of people with hyperacusis also have tinnitus so I suspect there will be actual hair cell/synapse loss to address as well.

 

Yeah - the thing is, most of us don't have noxacusis on its own. It seems that the majority of us also suffer from tinnitus, reactive tinnitus, and distortions etc. The fact that we experience this cluster of symptoms makes me think that there's some sort of hearing damage underlying it whether it be hair cell loss or synaptopathy.

 

This is really interesting. The highlight for me is that it's further evidence to back up why noxacusis pain is frequency specific. The next research I'd love to see is noise induced ATP release (location & quantity) measured pre and post acoustic trauma to see how ATP released in a simulated setback may be interacting with these newly hyper-connected type II's. You're in contact with Paul Fuchs aren't you @serendipity1996 wink nudge

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

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

 

I could be wrong but I reckon most hearing issues are caused by one or multiple of the three things that tend to cause hearing issues which are busted synapses, busted hair cells and inflammation. It is likely I think that if you treat these then you will probably treat a lot of ear issues like hearing loss and tinnitus etc. Essentially I think fixing these is really going to be a big part of treating these issues.

 

If I'm interpreting it correctly would this suggest that we struggle with certain frequencies because they would have more OHC ribbon synapses?

The one thing I was confused about is even if we don't get OHC loss, would we also have loss of the type 1 synapses? Does an increase in OHC afferents go hand in hand with a decrease in IHC ones?

Apologies if these are inane questions I need to read the paper again lol.

Also, Hyperacusis Research will be hosting their end of year benefit soon, although no word on the date yet - maybe this research will be presented there?

 

I think even if FX-322 doesn't directly benefit noxacusis, it should hopefully alleviate other symptoms that go along with hearing damage and hopefully loudness hyperacusis at least.

 

There appears to be dormant non-connected OHC type II contacts that become synapsed due to noise trauma, this increase could lead to significant increased type II activity.

'The “ribbonless” OHC to type II afferent contacts are reminiscent of “silent synapses” in the central nervous system that act as a reservoir of plasticity for activity-induced upregulation.'

'Despite the modest increase in the number of OHC ribbons, the model predicted a doubling in action potentials generated by type II afferents.'

'A potential role for increased type II afferent neuron activity relates to the condition of hyperacusis whereby louder sounds can provoke pain.'


Yes, the study shows that IHC's lose ribbon synapse due to noise trauma but that OHC's type II ribbon synapses increased due to noise trauma. Whether they are explicitly linked or not though it doesn't say.

'Noise exposure producing a 40-dB threshold shift resulted in a significant increase in the number of synaptic ribbons in OHCs. In these same cochleas, IHC ribbons decreased in number as described previously.'

'Thus, not only do the synaptic arrangements of inner and outer hair cells differ, but they have an opposite response to acoustic trauma. This has not been reported previously for OHCs or other mammalian hair cells.'

 

Yes agree synapse drugs for IHC synapses, but this is not talking about busted synapses though (in the OHC). It's talking about an increase in synapse connections to a pain receptor. It would suggest we need a synapse disconnecting drug rather than a drug that connected more.

It's baffling and probably the biggest curve ball I've seen in trying to work out noxacusis mechanisms, but when you think about it it actually makes sense.

I wonder if this is actually how sensitization physically happens?

 

It would be good if we could find some more literature on 'silent synapses' and what their function is. Definitely lots to pore over.

 

It would be interesting to know if the decrease in type 1 afferents is intrinsically linked to an increase in type 2 afferents and whether they are contingent on each other.

I'm actually wondering if a synaptopathy drug would be helpful -if you could restore the lost input of the Type 1 afferents, would that then downregulate the activity of the Type 2s and help 'normalise' the auditory system? Just a wild speculation and probably clutching at straws.

 

That does make sense. It seems you need to lose those synapses first, then take the synapse medicine to restore them. This tends to mean that while regenerative treatments will probably work with those issues, they won’t overcome the issues for this.