The Association for Research in Otolaryngology (ARO) 2024 MidWinter Conference

Thanks @Hazel.

Of interest;

Efficacy of AC102 in a Noise-Induced Tinnitus Model in Mongolian Gerbils

 

Thank god for the studies in the Mongolian Gerbils. What would we do without them!?

 

This one has piqued my interest from the University of Pittsburgh:

M154 Biomarker Profiles of Cochlear Injury in Tinnitus

I like studies that try to investigate the complex link between hearing loss and tinnitus. We know it’s not straightforward. I’m really curious about their methods of using non-invasive biomarkers — OAEs, EFRs, and WB-MEMR — to detect “audiometrically hidden components of sensorineural hearing loss” in people both with and without tinnitus.

 

Interesting. I wonder if I was a part of their data. They were pretty interested in my case and talked with me quite a bit when I was getting treated at UPMC. None of it helped, though. They just offered TRT and benzos.

 

Hello @Hazel.

I can suggest five subjects that might be of interest.

The first is by Stéphane Maison, Charles Liberman, Neural Signatures of Tinnitus in Subjects with Normal Hearing. It would be interesting to find out a bit more and ask them what solutions could reduce the cerebral hyperactivity that produces tinnitus. Bimodal stimulation? Molecules that open potassium channels? Other solutions? Finally, to get their point of view on the localisation of tinnitus. Is tinnitus located in the cochlear nuclei?

Four other subjects:

• Reduced Sizes of Efferent Nerve Termini in the Cochleae of Rats with Noise-Induced Tinnitus and Evidence of Therapeutic Mitigation with NHPN-1010
• Up-Regulation of Gaba Type a Receptor α1 in the Dorsal Cochlear Nucleus of Rats with Noise-Induced Tinnitus and Evidence of Therapeutic Mitigation with NHPN-1010
• Efficacy of AC102 in a Noise-Induced Tinnitus Model in Mongolian Gerbils
• Cross-Modal Stimulation in Changing Hearing Sensitivity and Tinnitus in Humans

Thank you.

 

Sensorion Announces its Participation in the Association for Research in Otolaryngology ARO 47th Annual Midwinter Meeting

I am particularly interested in whether Sensorion SA has any plans of testing SENS-111 (an histamine receptor 4 antagonist) for the treatment of tinnitus.

Sensorion filed a patent for H4 inhibitors to treat tinnitus in 2013.

Unfortunately SENS-111 was not effective in treating acute unilateral vestibulopathy in a Phase II clinical trial. SENS-111 doesn't seem to be included in Sensorion's pipeline at the moment. But maybe conducting a trial for SENS-111 in treating tinnitus is still a possibility in the near future? Maybe some expanded access options are on the table as well?

Would this be something to discuss with representatives of Sensorion, @Hazel?

 

Maybe a little late now, but could you share something about what Megan Beers Wood has presented?

 

It's curious how the questions around tinnitus have changed -- which by the way is maybe a sign of progress of sorts.

Instead of "does this new pharma/method cure or alleviate tinnitus", the question seems to have moved more in the direction of "what sort of tinnitus do you have... and maybe you should try A, B or C which might help alleviate it".

 

@Hazel, when do we get an update?

 

Hi @ZFire, I'm starting to answer some of the questions related to the ARO 2024 meeting. So here goes:

This poster explored the use of MEMR as a biomarker of cochlear injury in tinnitus (although the abstract mentioned the use of OAEs and EFRs, only MEMR data was presented). The study asks if individuals with normal hearing and tinnitus have a higher rate of cochlear syaptopathy.

MEMR stands for Middle Ear Muscle Reflex and is a sound-evoked involuntary contraction of the middle ear stapedius muscle. This muscle stablizes the stapes which is attached to the oval window of the cochlea. MEMR has been shown to be an indicator of cochlear synaptopathy in animal models. In the chinchilla, reduced middle ear reflexes have been measured following lab-induced synaptopathy.

These investigators used an NHANES dataset composed of people with and without tinnitus when MEMR data was included, and also those with hearing loss over a specific range and matched thresholds between tinnitus and no-tinnitus groups.

NHANES asks about tinnitus being present and, if so, whether it is occasional or constant. Therefore, the investigators first looked at the data from people with normal hearing and found that those who did not experience tinnitus had the strongest MEMRs and those that reported constant tinnitus had the weakest. People experiencing occasional tinnitus had MEMRs that were between these two groups (supports a relationship between cochlear synaptopathy and tinnitus.)

NHANES also asks about tinnitus severity. So, next they looked at MEMRs from people with normal hearing and tinnitus and found that MEMRs become weaker as the reported severity of tinnitus increases (cochlear synaptopathy increases with the severity of tinnitus.)

Finally, they looked at the group with hearing loss with and without tinnitus. They found that the difference in MEMR responses between the two groups becomes smaller as the degree of hearing loss increases (suggests that cochlear synaptopathy is less of a contributing factor in individuals with tinnitus and elevated audiometric thresholds indicating hearing loss.)

I hope that helps with understanding MEMR and what the data suggests. The poster also mentioned that additional work at U Pittsburgh Medical Center is ongoing and aimed at clarifying the relationship between hearing loss and tinnitus, translating work in animal models to humans and assessing top-down attentional control in tinnitus patients and its link to severity.

TC

 

Wow, thanks for sharing the insights, @TuxedoCat! Very useful information.

Much appreciated.

 

Hey @Nick47, your interest in AC102 is next...

The authors of this podium presentation state that the underlying pathology of tinnitus is associated with cochlear neural degeneration and the brain's reaction to it. Although tinnitus is associated with hearing loss, often individuals presenting with tinnitus have normal audiometry.

AC102 is being studied for the treatment for Sudden Sensorineural Hearing Loss. In animal studies for this indication, improved ribbon synapse counts were found in animals treated with AC102, which is perhaps important for tinnitus perception. Therefore, it was hypothesized that AC102 can ameliorate the behavioral signs of tinnitus in a synaptopathy-associated animal model.

Mongolian Gerbils were used in this study. At Baseline (Day -7), behavioral (tinnitus perception) and electrophysiologic (ABRs for function hearing) recordings were made. These measurements were also recorded at Day 0, 7 and 35. At Day 0, the animals were exposed to loud noise which was not strong enough to cause apoptosis, but strong enough to cause synaptic damage. The presenter likened this to a night at a club. On Day 35 samples for histology were also collected.

Results showed a mild transient threshold shift in ABRs which completely recovered to baseline in the AC102 group. AC102 administration also significantly reduced behavioral signs of tinnitus, measured by the gap startle response, for up to 5 weeks. Behavioral signs of tinnitus were unaffected in most animals in the vehicle control group.

The effect of AC102 administration on ribbon synapses was also considered. Loss of synapses was present around the frequency of the noise exposure used in the study. Administration of AC102 reduced synaptopathy compared to the vehicle control. This is thought to be suggestive of better alleviation of tinnitus.

This experiment was repeated with only one injection at Day 0 and similar results were obtained for both behavioral and neurophysiologic measurements.

The effect of AC102 on neurites has also been studied. Neurites are projections from the neuronal cell body that develop into axons and dendrites to form complex neuronal circuits. Hippocampal cells in cell culture were injured using ethanol. The cells somewhat recover from injury when fetal calf serum is applied. However, faster recovery that included regeneration of neurites and neuronal connections was observed when AC102 was applied rather than fetal calf serum (the photography of this occurring was pretty impressive; now if it just worked in the brain!)

The effects of AC102 in these models of tinnitus and neuronal recovery are consistent with its performance in other studies for SSNHL.

 

Thanks @TuxedoCat. This lines up quite well with my current understanding of the literature, in that tinnitus is a peripheral phenomenon that causes changes in the brainstem, which in turn affect other areas of the brain. The treatment seems to work as prevention, or in acute settings to prevent neuronal damage.

 

AC102 is no good for "chronic" tinnitus?

 

Not to be impatient but is the staff still planning to share some news about this?

 

Hey @StoneInFocus, I'm sorry that I haven't gotten back to you here. I had to prioritize a fundraiser that came up from the conference, my own work in the last few weeks, and trying to finish up the write-up on the ARO 2024 as soon as possible. I didn't get Megan Beers Wood's poster talk at the conference. I was primarily on desk duty as I couldn't dictate or understand a lot of the content of the talks, and I soon realized my skills were best used to network.

I did, however, find the transcript and poster for you. See attached.

She did a presentation we were invited to at a Hyperacusis Research dinner. There's a little more info on it here.

By this stage, it was late in the evening after a very long conference day, and I didn't have my notebook with me, so forgive my memory and lack of detail. If I recall correctly, the conclusion was that different types of mice could be used to advance the study (@TuxedoCat might be in a better position to elaborate).

I saw your other thread about your discussion with her, so maybe she'll be happy now to give you a more detailed update. She's a super friendly person and very committed to her research.

 

I wish I could understand properly what she is saying lol, I'm definitely not a scientist, ha.

 

It looks like Megan Beers Wood's research is about trying to better understand the immune response in the part of the cochlea (spiral ganglion, responsible for innervating - connecting to the nervous system - the inner hair cells) after noise trauma in mice. In particular, lymphoid cells responsible for macrophage activity (read as: what white blood cells do when they work properly.) It has been identified that a particular type of lymphoid cell, ILC2 cell, activated by IL-33 within the cochlea itself, is expressed after tissue damage in mice.

The purpose is more on identification, but the potential application is to identify how the inner ear responds to damage and how our bodies naturally fight it to inform either how to supplement this repair process someday and/or complement/assist it.

 

I'd like to know if there's a possible link between contractions of the tensor tympani muscle, which also causes pain in and around the ear and in the head, and Megan Beers Wood's research. Is this different? Can we have an answer to pain in the inner ear (Megan Beers Wood theory) and contractions of the tensor tympani muscle (Arnaud Norena theory)?

@Hazel, could you please ask Megan Beers Wood these questions during your future exchanges? Thank you.

Thank you @gillme for your feedback on Megan Beers Wood's work.

 

Hi @Josh59,

I went back and looked at the Neural Signatures poster; the title of it is 'Evidence of Cochlear Neural Degeneration in Normal-Hearing Subjects with Tinnitus.' Unfortunately, it won't download from the conference website, so I'll have to find out if it's OK for me to share it.

In the meantime, these investigators recruited and enrolled 294 native speakers, 18-72 years old, with normal audiometric thresholds and middle ear function. Tinnitus, if present, had to be related to sensorineural loss from noise exposure or aging. The subjects were divided into 3 groups: control (no tinnitus), those who experienced at least one episode of temporary/intermittent tinnitus less than 6 months duration, and those who reported a continuous percept of tinnitus for more than 6 months. The 3 tests used it the study were ABR, Middle Ear Muscle Reflex, and Medial Olivocochlear Reflex. The results of all three tests support the hypothesis that damage to the cochlear nerve can exist even when hearing thresholds over the range tested are normal.

It's really interesting that they observed a mid-range of cochlear damage that was associated with intermittent tinnitus, suggesting that reaching a threshold of damage moves someone from intermittent to chronic tinnitus or skips the intermittent part altogether. Last year at the ARO, Christopher Cederroth presented work on genetic links in tinnitus using data from large population studies. He proposed a model in which intermittent tinnitus moves into chronic tinnitus. Could we be seeing some external validity here?

I can't comment on the tests themselves and I am again reminded that I need to learn to understand a little more about exactly what is being tested. For example, MEMR & MOCR were included and, since they are both reflexes, I am curious about the afferent and efferent nerve fibers that are involved, specifically how they relate to inner or outer hair cells.

Stephane Maison stopped by the Tinnitus Hub booth at ARO and talked to @gillme and me for a good while. He made the point that loud noise may damage cochlear nerve fibers without damaging the hair cells and, if I remember correctly, the synapse is left intact as well. Measuring threshold by pure tone testing will not pick this up so additional tests, like speech in noise, are needed for a thorough examination of patients.

I know you had other questions for him. Since he has opened a dialog with Tinnitus Hub, I can reach out to him for answers.

Also, you mentioned other topics. I've already touched on AC102 for sudden hearing loss, but I think there were other AC102 presentations as well. I will also look into the other topics you suggested but it will take a little time. Although I consider myself pretty much habituated, I do need mental health breaks from talking about tinnitus!

TC

 

Megan Beers Wood briefly discussed that in her hyperacusis central interview:

What are your thoughts on the middle ear theory of pain hyperacusis presented by Noreña et al. (2018)?

I think this is one area where we need to have better diagnostics of ear pain. It is possible that painful hyperacusis comes from the middle ear and that the facial pain that some people experience is related to this. I think it is also possible that some people have pain hyperacusis that comes from the cochlea itself. I think all possibilities need to be studied simultaneously with the hope that people with hyperacusis get answers faster.

...

 

Thanks to the both of you again! I had to look up what attentional control means :/

It’s interesting research. They indicate a correlation between the strength of the Middle Ear Muscle Reflex (MEMR) and tinnitus severity and hearing loss.

I guess I’m still uncertain about how reliable the NHANES dataset is for analyzing people with and without tinnitus on a large scale, but it’s intriguing nonetheless.

 

I know n=1 anecdotes aren't super helpful, but my MEMR has become so strong and pronounced in the last year that I can physically feel it reacting to almost any abrupt sound (particularly high-frequency ones) after acoustic trauma-caused tinnitus and hyperacusis one year ago. The hyperacusis is unilateral, the tinnitus feels central at this point (not even really in my ears, more so in my head), and the MEMR was right-sided but has since become very pronounced in both ears.

Kind of interesting to see research on the subject potentially validate some of my experience. I yearn for the day when an ENT will say to patients, "oh yeah, that progression of symptoms is pretty typical for a middle/inner ear injury; you should pursue X, Y, Z treatment," or "stay in earmuffs for XYZ time period to ensure this issue doesn't become permanent/chronic," or "take this pill before anticipated noise exposure to prevent further damage." I've just been winging it here in 2023-2024 as best I can.