Palm Springs Hearing Seminar December 2022: Coverage

[Markku]

I and @Hazel are currently attending the Palm Springs Hearing Seminar, which takes place on December 2-3, 2022.

The seminar is split into 5 sections:

1. What is Tinnitus?
2. Clinical Management of Tinnitus I
3. Clinical Management of Tinnitus II
4. Biotechnological Treatments for Hearing Loss
5. Sound Therapy and Beyond

We will use this thread for updates; there will be some live commentary after each slot, and in the near future you can expect an overall summary presenting our key insights. If you are interested, please check back here over the next few days, as we will be continually adding to our notes and finetuning them.

 

[Hazel]

Section I - What Is Tinnitus?

We're attending remotely via MS Teams. So far so good.

First up was Fan-Gang Zeng talking about tinnitus models. Essentially, he set out to dispel three (according to him at least) myths about tinnitus mechanisms:

• Myth #1 - tinnitus increases sound discrimination thresholds. Zeng mentions as an example this paper that shows people with tinnitus and normal hearing are better able to discriminate between sound intensity (dB SPL) than people without tinnitus. But Zeng and one of his students published a study that shows, when matching an external sound to one's tinnitus in terms of intensity and frequency, tinnitus does not in fact "fill the gap" when the sound is played intermittently; subjects are still able to detect the gaps, regardless of whether they have tinnitus or not.
• Myth #2 - tinnitus affects speech in noise comprehension. Zeng mentions as an example this paper that seems to prove individuals with tinnitus and hearing loss have more trouble hearing speech in a noisy environment than people with only hearing loss. However, Zeng and one of his students published a study that shows no impairment; in fact, it shows a very slight advantage for individuals with tinnitus. I guess the devil is in the details here, and I must admit I do not fully understand how these effects are measured. He furthermore hypothesizes that this effect is to be expected because tinnitus is generally soft and high pitched, thus it should not logically affect hearing. He believes that some tinnitus patients erroneously blame their tinnitus for their speech recognition issues, when in fact they have (hidden) hearing loss.
• Myth #3 - tinnitus impairs cognitive efficiency. Zeng mentions as an example this paper that seems to show (with a rather small sample) that people with tinnitus on average perform more poorly on certain cognitive tasks. Yet, Zeng & Co have used data from the large-scale population study NHANES to prove the opposite. His results show that while hearing loss by itself does cause (quite significant) cognitive decline, this decline in fact is mitigated to some extent by having tinnitus (!).

It feels a bit like Zeng strives to prove that tinnitus is not all that bad, and in fact that is quite literally his conclusion. We should all be lucky to have tinnitus, apparently. All kidding aside, I do find these results interesting. But I also have to wonder whether it is possible that these positive effects noted by Zeng are in fact caused by some other factor that is related to tinnitus, and not by the tinnitus itself. After all, correlation is not causation.

Next was the presentation by James Henry on auditory gain and sound therapy. My first thoughts are:

• Interesting to learn more about James Henry - I'd mostly just heard his name around here and there; I knew he was closely involved in veteran's care, and to be honest kind of assumed his ideas must be somewhat antiquated, but he seems quite on top of current developments. Also, he has a deaf daughter and has suffered from both tinnitus and hyperacusis for decades.
• His presentation centered around the concept of auditory gain, which forms the basis for many theories about tinnitus. The core concept is that when sound from outside, carried through the auditory nerve, gets reduced (due to hearing loss for instance) your brain 'dials up the volume' and by doing so creates tinnitus and/or hyperacusis (the two co-exist together so often that they are theorised to share a similar mechanism).
• Theoretically at least, sound therapy should be able to eliminate the tinnitus signal, i.e. not just mask it but actually remove it, wholly or partially. But this is not fully proven.
• It is theorised that tinnitus is a symptom of 'maladaptive plasticity', whereby spontaneous/random neural impulses that would otherwise be ignored by higher brain functions are picked up as sound. Our central auditory system has a mechanism to balance neural activity by tuning down some signals and turning up others.
• This study showed that two weeks of sound enrichment will reduce auditory gain, whereas two weeks of sound reduction (ear plugs) will increase auditory gain. This means that depriving yourself of sound input will make you more sensitive, perhaps intolerant, of sound.
• This study shows that Loudness Discomfort Level (LDL) testing does not agree with a person's own judgement of sound discomfort and also can cause harm to the patient. Henry recommends against it.
  
• Henry mentions several studies about 'sound desensitization' that seem to indicate sound exposure is useful in reducing tinnitus; however, these were mostly uncontrolled studies. This study shows that sound stimulation particularly in the region of the hearing loss reduces sound sensitivity.
• Henry concludes that sound therapy can be particularly useful for hyperacusis. Tinnitus might also be supressed by sound therapy, but there are likely other mechanisms involved than just auditory gain when it comes to tinnitus, and the evidence that tinnitus can be supressed long term through sound therapy is far from definitive.
  
• He recommends that patients perform self-experimentation with techniques like tone matching and notched music (which you can for instance try through our TinnitusPlay app if you have an iPhone). But be careful to use only low level, comfortable sounds.

I will add here that we will soon publish a podcast about sound therapy that outlines all the different approaches you can try (and most are free).

Next up was Susan Shore talking about brain stem plasticity, but they were having some serious technical issues and we were not able to hear most of the presentation, only see the slides. That wouldn't happen during one of our live events, LOL! I must say this makes it very challenging to provide notes, because her presentation was highly technical and tough to follow by visual aids only. Luckily, this presentation was basically a summary of her published work so far, nothing new. Anyway, here are my (very amateur and heavily dumbed down) notes:

• Dr. Shore's central theory is that tinnitus related neural activity begins in the cochlear nucleus, a part of the brainstem and thus the lowest level of the brain where the processing of acoustic information begins.
• Animal studies have shown that the 'fusiform cells' of the dorsal cochlear nucleus (DCN) encode tinnitus in their spontaneous firing rates and synchrony (firing together).
• Furthermore, the DCN also receives signals from somatosensory nerve fibers, such as the trigeminal nerve, which sends information about sensations and movement in the face. A glutamate transporter called Vglut2 seems to play a role in this. These somatosensory 'projections' seem to increase after hearing loss.
• In vitro (test tube) experiments have demonstrated that fusiform cells after high frequency stimulation (100 Hz, 1 sec) show an increase in synaptic strength (called 'potentiation'), while after low frequency stimulation (1 Hz, 5 min) they show a decrease in strength (called 'depression').
  
• Animal tests (Dehmel et al., 2012) have shown that this kind of plasticity can be long term in nature, and this effect can be achieved through a certain pattern of 'bimodal' stimulation, meaning a combination of auditory and somatosensory neural input.
• Animal studies (Kaltenbach, 2004) have further shown that in animals with tinnitus a significantly higher spontaneous firing rate is achieved post exposure versus animals without tinnitus. In addition, the fusiform cells in tinnitus animals show increased synchrony, i.e. they fire together (Wu, Martel & Shore, 2016) and they fire in a completely different pattern than without tinnitus (Koehler & Shore, 2013).
• This study shows that "stimulus-timing-dependent plasticity (STDP) can be induced in DCN fusiform cells using paired auditory and transcutaneous electrical stimulation of the face and neck to activate trigeminal and dorsal column pathways." This leads to the suggestion that some form of bimodal stimulation could be used to treat tinnitus. And indeed, this has been shown to be true, at least in guinea pigs.

Finally, you will probably be excited to hear that Dr. Shore announced that during her presentation tomorrow she will be presenting "some of the results" from her human trial for the very first time. So stay tuned!!!

 

[Hazel]

Section II - Clinical Management of Tinnitus I

This section started off with Colleen LePrell (PhD) talking about the pharmacology of tinnitus. Her talk started off with a long summary of the ototoxic effects of certain drugs, then covered pharmacological treatments, and ended with dietary supplements. Needless to say, the second part was the most interesting

• Ototoxic medications: As most of you are no doubt aware, there are literally hundreds of medications that have been flagged to have tinnitus as a side effect. It's important to note, however, that there are only a few that are considered to be very high risk and/or for which the effects are more likely to be permanent. These include: the painkiller Vicodin and the chemotherapy drug Cisplatin.
• Pharmacological treatments: LePrell provided a very diligent overview of what the drug approval process looks like. She noted that the process typically takes 10-15 years but has been longer for tinnitus drugs (!). She then provided a very useful overview of all the current studies (commercial and academic) into potential pharmacological treatments for tinnitus:
  • In 2o19, there were two companies with a Phase 1 tinnitus program (Otonomy and Otologic), one with a Phase 2 progam (Autifony), and two with a Phase 3 progam (Auris Medical and Kyorin/Merz). However, in 2022, none of the Phase 2 and 3 products were still in development, due to disappointing results. This is obviously very disappointing.
  • According to ClinicalTrials.gov there are currently over 300 studies on tinnitus (a lot more than mentioned above, because it includes academic studies, studies that have not yet started or are discontinued). It's interesting to note the distribution of types of interventions that are studied: 106 device studies, 41 behavioral interventions, and 61 drug studies. It's somewhat encouraging to see that behavioral studies are the minority.
  • Drugs being studied for their effects on tinnitus include:
    • Local therapies: NDMA receptor antagonists, prostaglandin receptor antagonists
    • Systemic therapies: calcium/potassium channel activators, mGlu7, antioxidant support, Kv3 potassium channel modulator, ...
  • Currently, many drugs are prescribed off-label for tinnitus, but these have not been well enough studied, including many anesthetics, antihistamines, antidepressants, and others.
  • Challenges with drug development for tinnitus are mainly related to the heterogeneity of the condition and the fact that some individuals seem to benefit a lot while others do not benefit at all.
• Dietary supplements: These are vitamins and herbal supplements that are available over the counter (OTC). Crucially, these are NOT subject to the same stringent regulations as prescription drugs or regulated OCT drugs. Most of them have not even been studied in human (or animals) to any extent. Manufacturers do not even have to prove that their supplements are safe to use! Yet, people may spend up to hundreds of dollars per month on these sham products. Some of the ones mentioned frequently on this forum include lipoflavinoids and ginkgo biloba.

In the Q&A, some interesting questions came up. One person brought up that a lot of hearing aids are not FDA approved, which I was shocked to learn. LePrell also responded to a question on the various potassium channel activator drugs, where she noted that the data on tinnitus relief is limited as most of the clinical data is on hearing loss instead.

Due to the last-minute scheduling change mentioned by Markku above, we missed some of the session by Fan-Gang Zeng on electrical stimulation. Luckily, not anything new was presented here, and this is the same topic on which we already published a podcast this year; this was the episode about Brian Fargo and his 1-million-dollar donation, which you can find here.

This section ended with (again) James Henry, this time presenting on his own method for tinnitus management - developed over decades - called Progressive Tinnitus Management (PTM). It was extremely long, and I must say I generally find these kinds of presentations less interesting that the ones that really bring something new and point in the direction of a cure. But I tried to give it a chance, and overall, I will say that at least PTM inspires (some) more confidence than for instance TRT in terms of diligence.

So, what is PTM? It's a program for treating tinnitus patients through five steps:

1. Referral: This includes both mental health referral as well as referring people to specialists for physical trauma and vestibular symptoms.
2. Audiologic evaluation: This includes (obviously) hearing tests, but also an in-depth analysis of the tinnitus itself, e.g. is it occasional, intermittent, constant? Besides assessing the bothersomeness, he also suggests assessing laterality, loudness, reactivity, and many other tinnitus characteristics, as well as reduced sound tolerance. PTM provides in-depth tools for all these assessments.
3. Skills education: This part was a bit vague to me, but essentially consists of providing the patient with tinnitus management tools like sound therapy and behavioral tools like stress management and CBT.
4. Interdisciplinary evaluation: This includes audiological combined with psychological evaluations.
5. Individualized support: For those who still need support, this should be one-on-one by an audiologist and/or behavioral health provider.

Does it work? Well, according to Henry's own studies, which to his credit are randomized controlled trials (RCTs), it seems quite effective at reducing tinnitus related distress. I didn't have time though to dig into the trial results and I'm sure these would trigger a lot of questions (e.g. about selection of participants, dropouts, control methods, etc.). Not to mention, it is of course not a cure. But I will note (quite objectively) that some of the clinical trial results for PTM are more impressive than those for Lenire. I guess that says more about Lenire than anything else though

 

[Hazel]

Section III - Clinical Management of Tinnitus II

This section started with a talk by Mark A. Parker (PhD). I had never heard of him, but he's an audiologist with a PhD in neuroscience.

He spoke on managing bothersome tinnitus using CBT and noise maskers. I'm struggling what to tell you about this one. He talked about some very common-sense stuff for tinnitus management, such as "seek distraction from your tinnitus" or "do activities that you enjoy". Maybe it is useful for some people who have never had any advice about tinnitus management? I'm trying to see the positives here

He did have some interesting case studies from his practice. For instance, one person who blamed all her problems on her tinnitus and was sure she had perfect hearing, and indeed standard tests seemed to corroborate this. But more enhanced testing found that she suffered from hidden hearing loss. I do like the message about the need for enhanced hearing tests. But for the rest, he mostly spoke about CBT and hearing aids, the usual.

Finally, the day closed with a breakout session on tinnitus therapies utilized by Widex, Treble health, Resound, and Signia. Interesting to hear what these companies are working on and if there is anything new in the land of hearing aids.

A representative from Widex, Jodi Sasaki-Miraglia (AuD), talked about some new Widex offerings:

• SoundRelax – This seems to be just the usual nature sounds and the like.
• MySound 2.0 – This is a bit more interesting. It is an artificial intelligence that provides equalization and compression control over your hearing aid, giving recommendations based on the specific activity you are performing and your own preferences.
• Sound Assist – This is a piece of hardware that partners with a hearing aid to function as microphone, remote control or phone.

The most interesting part for me was where she spoke about sound quality. I really am not knowledgeable enough in this regard to judge whether Widex provides better sound quality than any other hearing aid company (although of course, according to their own presentation, they do). But nevertheless, I was enticed to learn how processed sound comes across as more natural when the sampling rate is accurate and when the sound is processed as quickly as possible.

Next up was Treble Health, represented by Tracy Peck Holcomb. We were particularly curious about this one, because Treble Health has such a strong online presence, with hundreds of YouTube videos and constant social media messaging. In fact, the company started as just a YouTube channel in 2020 and turned into a full-blown clinic today.

It seems they jumped into the obvious market gap that exists for people who are struggling to find any kind of tinnitus care, a problem we are all familiar with. They market themselves as a "telehealth specialty clinic for tinnitus and sound sensitivity". To me, however, this seems a bit misleading, since they do not provide comprehensive tinnitus care, only audiology and counseling services -- although they can of course refer to specialists like ENTs. Their ultimate aim is to guide each patient towards habituation.

I don't want to be too negative here. I am sure they provide care that is a lot more knowledgeable and compassionate than 90% of providers. But on the other hand, that's not a very high bar. And I do have questions about their business model (including pricing and commercial ties with other companies) that were not addressed during the presentation. Maybe I am too skeptical (?).

Interesting point: Treble Health claims to achieve on average a 21.5 TFI reduction in three months, which is a better result than most RCTs that test tinnitus treatments. It just makes me wonder, once again, about the value of the TFI and similar surveys as a measure of success. But that's a whole different discussion.

ReSound is another hearing aid provider. My main question in watching this presentation was whether they would have something different to offer than the other hearing aid providers. They started off with some tinnitus sound generator, playing white noise and nature sounds, so nothing new there. At least it also applies an amplitude modulation technique, which is known to temporarily reduce tinnitus in some people. And there are some other enhanced features like frequency filters. Their app ReSound Relief also offers meditation and breathing exercises and a personalized 'tinnitus plan'.

Then came Signia, touting the benefits of their hearing aids with the statement that "amplification is the #1 treatment for tinnitus." One interesting thing I learned here was that the most effective hearing aid settings for communication are not necessarily the best for reducing tinnitus. I guess that makes sense, particularly when you think about using environmental noise for masking, whereas you might want to screen out environmental noise when you're trying to have a conversation. To me, this just seems to make the use of hearing aids for tinnitus management more challenging, requiring constant tinkering with settings. Finally, Signia also claims to be the only hearing aid provider that offers notch therapy through their devices.

 

[Hazel]

Just a personal note, at the end of day 1 of the seminar. It's nearly 4 AM over here in Europe and we've been at this for 10 hours, doing our best to listen intently, take notes, and share our thoughts with you live. Quite the challenge.

I'm not sure what we will think of our reports when we re-read them tomorrow. We will probably refine them, and perhaps add some screenshots from the various presentations (if we're allowed to do that).

We hope you're enjoying our efforts at live reporting. Tomorrow is the second and final day of this event, including Susan Shore's big (?) reveal. See you back here tomorrow, folks!

 

[Markku]

Aaaand we're ready to start the second, and final day.

You can expect notes from both sections, IV (Biotechnological Treatments for Hearing Loss) and V (Sound Therapy and Beyond). The seminar day culminates into Dr. Susan Shore's presentation at 2-3 PM (PST).

 

[Hazel]

Section IV. Biotechnological Treatments for Hearing Loss

This section was all about hearing loss and what the clinical pipeline looks like. I have to admit, this area is really not my strong suit, so I apologize in advance if I misrepresent anything; feel free to correct me (once we open up this thread for comments). I did my best anyway to follow everything and type up quick notes.

One general insight from this session is that there are no less than three companies working on a treatment to protect the ear from cisplatin (cancer) treatments. I think they're all taking a different approach, but nevertheless apparently this is a competitive field, but also of course a very narrow use case.

Colleen LePrell (PhD) started off the session with an overview of hearing loss drugs in development. Very useful for those of us not in the know! It is hard choosing what part of her presentation to tell you about, because it was very dense with all kinds of useful tables and summaries. I was impressed, as each of these must have cost her many days of data collection, digging through clinical trial databases. Anyway, let me try to pick out some highlights:

• Good news is that in September 2022 the FDA approved the first ever medication to protect from drug-induced hearing loss. Sodium thiosulfate reduces the risk of ototoxicity from cisplatin cancer treatments in children. Children treated with cisplatin plus the protective STS suffered from hearing loss in 44% of cases, versus 58% for those who received only cisplatin.
• When it comes to development of medicines for protecting the inner ear, this is an active space, with over 40 companies developing potential drugs to prevent different types of hearing loss. However, the big challenge is that often animal models do not translate well to humans, because of differences between laboratory and real-world conditions or differences in treatment paradigms.
• Then of course there are the general challenges of drug development, and it doesn't hurt to remind ourselves from time to time how few drugs make it to market. This slide summarized the challenges very well:

• Another challenge is that there is no consensus on what the appropriate outcome measures and endpoints (measures of success) are. LePrell compared all current 61 hearing loss trials posted on ClinicalTrials.gov and found vast differences, read more about this here. Audiogram was by far the most used outcome measure, whereas hearing-in-noise was not commonly used, despite the fact that this is generally a more meaningful measurement for patients. Even among the trials that used audiogram, definitions for the so-called 'threshold shift' varied widely.
• Reviewing the scientific literature more widely for noise-induced hearing loss (NIHL) studies, it seems again that audiograms are most widely used as the primary endpoint (70% of studies), while changes in objective measures like otoacoustic emissions (OAEs) are used much more rarely. Tinnitus is never used as the primary endpoint and in only 13% of studies as the secondary endpoint.
• She then covered the importance of hearing-in-noise as a key outcomes measure. As we all know, it is very possible to struggle with hearing speech in noisy environments even with a perfect audiogram. This can indicate damage to synapses (connections between ear and auditory nerve) but emerging literature shows it can also mean damage to outer hair cells. LePrell gives the following useful overview of speech-in-noise tests:

• Investigational medicines for hearing loss prevention/restoration have diverse mechanisms of action, from protecting the ear from medication to regeneration of hair cells to targeting specific causes of hearing loss. This chart (from this paper) gives a nice overview of the current pipeline:

Next up was Mr. Dyhrfjeld-Johnsen from Acousia, a hearing loss focused biotech company:

• He spoke about their drug candidate that protects against hearing loss from chemotherapy (Cisplatin). Cisplatin is damaging to especially the outer hair cells. The function of outer hair cells is to mechanically amplify soft noises. Outer hair cell damage is correlated strongly with hearing-in-noise problems.
• Acousia's drug candidates focus on activating the Kv7.4 channels, which 'flush' potassium through cells. Much can be learned from studying a particular form of genetic hearing loss called DFNA2. These patients develop profound hearing loss over the course of their lives, due to disruption of potassium recycling, which leads to loss of outer hair cell function and cell death. This suggests that therapies to activate Kv7.4 channels could have therapeutic benefit to preserve hearing.
• Acousia has one drug candidate in Phase 1b for protection against Cisplatin induced hearing loss, delivered through intratympanic injection. It seems to work well in guinea pigs so far; the Phase 1b results have not yet been released.
• They also have a drug candidate in the late pre-clinical phase that protects against age related hearing loss, meant to be taken orally. This drug supposedly fosters a ten-fold reduction of hearing loss in mice (though we must keep in mind the above-mentioned issues with translating animal to human models).

More results will be presented at the 46th Annual Mid-Winter Meeting of the Association for Research in Otolaryngology in Orlando (FL) on February 11–15, 2023.

During the Q&A someone asked whether he believed that tinnitus is caused by hyper excitability of neurons due to problems with Kv7 potassium channel. His answer was no. He believes in the central gain theory ("homeostatic plasticity gone wrong"). These Kv7 channels have indeed been targeted in the cochlear nucleus to treat tinnitus (for instance through the drug retigabine), but the idea there was to limit the excitability of the brain by opening up the channels, not the other way around. I'm not quite sure I understand this answer, but hey, I'm just the messenger

The final talk in this session was from Tera Quigley from Decibel Therapeutics talking about a locally delivered small molecule being developed for the prevention of cisplatin-induced ototoxicity. Sound familiar? Indeed, yet another drug to protect hearing from Cisplatin effects. Of course, it works by a different mechanism. I will summarize it only briefly here, in order to be able to focus on the next section:

• 60-70% of cancer patients treated with Cisplatin experience ototoxic effects, including tinnitus. Hearing loss can be severe, up to 60 dB loss in certain frequency ranges, even for young children.
• Cisplatin accumulates in the cochlea and literally kills hair cells.
• There are different ways of preventing this (reference to other companies working on same goal), but Decibel has chosen to try to 'chelate' the cisplatin in the ear, meaning it is bonded with other atoms to turn it into a different and harmless compound.
• DB-020 is injected into the ear so it can work locally. A Phase 1b trial in humans have proven the substance to be safe. It also does not seem to interfere with the cancer treatment. Furthermore, the initial results indicate that over 50% of patients experienced complete hearing protection, as measured through speech audibility.

 

[Hazel]

Section V. Sound Therapy and Beyond

This section was all about new approaches to sound therapy, including bimodal stimulation.

I can be brief about the first talk, from Jodi Sasaki-Miraglia (AuD) about stress and sound therapy. She talked a lot about the effects of stress on the body. She also seemed to be mostly addressing audiologists and coaching them on how to convince patients that hearing aids are worth the money and effort. I don't think there was much of interest here for this audience, although I must admit I was only half listening as I was trying to catch up with my notes!

Then came David Eagleman with his Neosensory device. This was a lot more interesting, especially as I had only heard of this device in passing but never really looked into it. Also, Eagleman gets browny points from us for having the slickest presentation. He had excellent audio and video and was using software that made it look like he was in his presentation.

Eagleman, who is a neuroscientist, starts with the central presumption – which to my understanding is indeed conventional neuroscience wisdom – that our brain does not actually 'see' or 'hear' anything directly, but rather it takes data input from electrochemical signals and then figures out how to translate that data into its own version of reality. This is why something like a cochlear implant – a non-organic replica of the inner ear – works. The Neosensory device works on the same principles, converting information of all kinds from the outside world into sensory patterns on the skin, which over time the brain learns to interpret. One study conducted by his team seems to demonstrate that deaf people can learn to identify different types of sounds through the device.

So how does this help with tinnitus? According to Eagleman, he was inspired by bimodal stimulation efforts like Lenire and University of Michigan. By listening to tones with synchronous vibrations on the wrist only ten minutes per day, 85% of people experience a clinically significant improvement in TFI score.

Although I did not study his results in detail (you can view the full results yourself here), and Eagleman's claims definitely require a bit more scrutiny, I will say that there are two things I like about the device: 1) There are many different potential applications – the company is running dozens of trials for different conditions – so even if it ends up having only one or two valuable use cases, this seems like a worthwhile investment. 2) The device, although not cheap by any means, is a whole lot cheaper than hearing aids or Lenire, Desyncra, and similar sound stimulation devices. It costs $999 and you can apparently also rent it. If they have a good return policy, it might be worth a spin (not a recommendation, since I have not tried it).

Then came the moment we had all been waiting for. Dr. Susan Shore spoke on precisely timed bisensory stimulation to treat tinnitus. She presented, for the first time, some of the results of the Phase 2 human clinical trial for her bimodal stimulation device.

• The Michigan Tinnitus Device aims to alleviate tinnitus through a sequence of auditory and somatosensory stimuli to the face or neck. The treatment utilizes a stimulus protocol consisting of precisely timed sounds alternated with weak electrical pulses that activate touch-sensitive nerves.
• Her trial selected for people with somatic tinnitus (60-80% of tinnitus patients, depending on the definition). Dr. Shore's definition of somatic tinnitus is being able to modulate your tinnitus through certain jaw or neck movements. Her theory is that these tinnitus patients would be more receptive to somatosensory stimuli.
• Before presenting Phase 2, she summarized the results of Phase 1 (published in 2018):
  • 20 adults with chronic (6+ months) somatic tinnitus, and hearing loss up to 40 dB
  • There were some exclusion criteria, including Meniére's Disease
  • They matched tinnitus likeness and loudness using Tinn Tester
  • They adjusted peak intensity to 40 dB SL and max intensity capped to 90 dB SPL
  • Very diligently designed study: double blind, randomized, sham controlled, and crossover
  • Control: Participants were not able to distinguish between the sham (control) treatment and the real one, because the electrical stimulation is so soft you cannot feel it.
  • Crossover: This means that all participants get both the active and the sham treatment, first one and then the other or vice-versa. This adds an additional element to the control and makes the results even more robust.
  • Results Phase 1: Sound alone did not lead to (much) improvement in TFI scores, but the active treatment did. However, TFI score improvement was statistically significant but not clinically significant. Hence, they decided for the next trial to increase treatment length to 6 weeks instead of 4 weeks to get better results.
• Phase 2 design:
  • This was a larger study, with 99 adults. The same participant selection criteria were used, only hearing loss up to 50 dB was now included.
  • Treatment period was extended to 6 weeks.
  • Outcome measures: TFI and tinnitus loudness (not clear to me how loudness was measured)

• Phase 2 results:
  • Clinically and statistically significant TFI decrease for active treatment, in the 15–20 point range, which maintained during washout period and up to 30 weeks post treatment. The sham treatment showed no clinically significant results.
  • Cumulative decrease in loudness:
    • -6 dB by week 6 = 50% reduction
    • -12 dB by week 12 = 75% reduction
  • Both the TFI and loudness continued to further reduce after the 6-week treatment period had ended, which according to Dr. Shore suggests long lasting plastic changes.

• The loudness reduction to me is most interesting. The TFI score reduction to be honest is far from impressive and we've seen similar results with many other treatments. However, the loudness reduction seems promising. (And if anything, this demonstrates to me just how inadequate TFI is as an outcome measure.) Dr. Shore also noted that while normally TFI and loudness do not correlate, in her study TFI and loudness were correlated with the active treatment, but not with the sham treatment.

• Commercial launch:
  • Dr. Shore co-founded a company called Auricle Inc. to commercialize her device and patents. Tinnitus Hub has been in touch with the company's CEO earlier this year, and we will reach out again to see if we can glean more information.
  • Auricle is working with the FDA to get market approval. Dr. Shore did not say much more about this since it's not her area of expertise. She also would not give any kind of timeline.
    
  • It is not clear if there will be a Phase III study, but there will be other 'real world' studies once the device is in the market to assess efficacy.
    
  • The device would probably be distributed through audiologists/health professionals, at least initially. Tinn Tester is important step because you need to target the same frequencies as a person's tinnitus.

• Q&A:
  • How do you match tinnitus frequency if you have a lot of frequencies? This was not really answered.
  • Will the device later on be developed for non-somatic tinnitus? Probably, yes.
  • What about people with extremely bothersome tinnitus? Her view is that if we can reduce tinnitus loudness by 75% it should help the people who are most bothered. [To me, this still leaves the question of whether the device is more/less effective for people with severe tinnitus, which remained unanswered.]
    
  • Might the device also work for hyperacusis? This has not been investigated, but from a theoretical perspective, it is a similar mechanism; depressing the output of the DCN circuit might also reduce hyperacusis.
    
  • Could it be used for other phantom perceptions like phantom pain? Not necessarily. You could use the same principles, but the type of stimulation would look different.

 

[Hazel]

Hey folks!!! It was a pleasure being your 'roving reporter', though also somewhat exhausting

I hope we captured the highlights for you well enough. We prioritized speed in this instance, which means accuracy sometimes has to suffer, especially since we're not experts on all the topics (or even any of them really!). Please feel free to correct us where needed — we will now be opening up the thread for comments — and we will improve our reports based on your feedback. We might also add some more screenshots and visuals.

As follow up, we will of course be approaching Auricle and inviting Dr. Shore to the Tinnitus Talk Podcast. Let us know if you can think of any other interesting follow-ups.

Hopefully, the topics presented will yield a lively and interesting discussion! It is always so cool so see how actively involved this community is in research and development. This is what inspired us to do this kind of crazy marathon reporting session — because you guys care. And not to sing our own praises or anything (well, maybe a little bit) but I cannot see ATA, BTA, or any of those organizations doing the same, even though they have way more funding than we do.

This might also be a good moment to remind you that we depend mostly on individual donations. We do not take a salary and have very limited overhead (no office). Your donations could help us attend events like this in person in 2023.

In my experience, being there live adds so much more to the experience, because you can talk to people behind the scenes and form relationships for future collaboration. Whenever I have attended such events in the past, like the TRI conference, I was often the only tinnitus patient present — it is so important that we show our faces when it is our health on the line! Perhaps some of you could even join us there in future

​

 

[Gb3]

Thanks @Hazel and @Markku! Dr. Shore's results are exciting! I think an important question that needs to be asked, and I don't know if it was, does extended use past 12 weeks lead to greater improvement? I know their trial only focused on 12 weeks but I wonder what their expectations are.

Thanks again for all your hard work!

 

[UKBloke]

Thank you so much @Hazel and @Markku for a brilliant job!

Now over to the UMich thread

 

[Samwise_The_Loud]

Amazing work and some very exciting developments! I think I can speak for all of us when I say what you both have built here is such an important lifeline for so many! I remain thankful and grateful for everything you do, come what may. This has definitely sold me on donating to keep this vital work going, God knows you have done more for me than the ATA/BTA combined.

Perhaps it may be pre-emptive, but Dr. Shore's work really feels like the breakthrough we have all been banking on for so many years. Even just seeing these preliminary results brings an insane amount of hope around the world for those who have tinnitus. There will likely be problems and setbacks as with anything, but for today at least, life feels good.

 

[be6z]

Amazing, thanks so much for your work on your reports. Dr. Shore's Phase 2 results sounds really promising!

Appreciate I haven't been suffering for long and hopefully my tinnitus will go or get better, but in case it doesn't, the idea that something with proven results is making its way is really comforting to know. Hopefully this will encourage more funding if companies think there is money to be made with a clinically proven study.

 

[BadNeighbors]

Great job with all the updates and honest feedback. Thanks

 

[KotaDomowa]

Is it stated what percentage of participants responded to the treatment? I don't see this information.

 

[Rb86]

Thank you very much.

 

[Anomalous]

Thank you so much @Hazel and @Markku! I promised myself that I would donate to Tinnitus Talk if Dr. Shore's Phase 2 results were good. I'm now keeping that promise.

 

[Hazel]

I think an important question that needs to be asked, and I don't know if it was, does extended use past 12 weeks lead to greater improvement? I know their trial only focused on 12 weeks but I wonder what their expectations are.

Actually, the active treatment period was only 6 weeks. I've now added an image in my post above about trial design that clarifies this. Dr. Shore did not comment on whether longer would be better (she's not one to speculate if it has not been investigated). What we do know is that the 6 week treatment in the Phase 2 trial worked better than the 4 week treatment in the Phase 1 trial. She also noted that improvements continued even after the 6 week period ended. But again, no comment on whether a longer treatment period would yield better results, that remains to be seen.

 

[Hazel]

Is it stated what percentage of participants responded to the treatment? I don't see this information.

That would indeed be very useful information. It would also be useful to know which groups were more responsive than others. Unfortunately, she only presented aggregate data and did not drill down into more granular results. Perhaps she wants to leave something for the publication, or await peer review.

See also the image I added just now above to my notes on her presentation, which shows how the results were presented with regard to loudness reduction. There was no more detail than that.

 

[Nick47]

Was there anything else that stood out for people in this conference? For me there wasn't, although I kind of expected that.

 

[Nick47]

In vitro (test tube) experiments have demonstrated that fusiform cells after high frequency stimulation (100 Hz, 1 sec) show an increase in synaptic strength (called 'potentiation'), while after low frequency stimulation (1 Hz, 5 min) they show a decrease in strength (called 'depression').

Would this make the rationale to use low-frequency sound therapy? Thinking out loud...

 

[Alberte]

Thank you so much @Hazel and @Markku. I was pleased to make a donation.

Let us know the news once you speak with Auricle.

 

[lusiol]

Thank you a lot for all the effort you put into Tinnitus Talk and this cause in general, you are truly amazing and inspiring human beings!

I wish I could give more but my modest monthly donation is the best I can do!

 

[katri]

Well I respect Dr. Shore's judgement. I don't think she'd be as open if the news was bad. She's been working for years on this project and has always treated everyone respectfully. I'd like to celebrate her integrity and patience working on tinnitus. I have my own reserves but I believe that she wouldn't continue to pursue something for selfish reasons.

I'm happy that there are some indications that her work can pay off. It's also a good sign that she's talking about the commercial usage of her device. There's a lot that she probably knows and will share in the future.

 

[NancyL]

Thank you so much @Hazel for this most excellent reporting! I will be watching with great eagerness.

 

[ZFire]

Very meaty write-up! Appreciate the dedicated effort from the staff.

Thanks.

 

[slc]

Thank you so much for reporting on this. What is particularly exciting is Dr. Shore's device, however, there are a few other hopeful nuggets in there as well!

In terms of Treble Health, they have an intake survey that I filled out (I am working with them as I decided to try hearing aids with Bluetooth and pink noise; being able to play the water mix sound from TinnitusPlay through Bluetooth is helpful).

The big question is the scientific validity of the survey that is used for the intake. I'm assuming here they're using the online form that I filled out. Perhaps I'm wrong. What is the outtake measurement? Who is filling it out and when? Are they counting for people who wash out without filling in some kind of outtake form? And so forth. That being said, it's been helpful working with Tracy Holcomb as it gives me another point of reference from a trained audiologist who is familiar with tinnitus. As to whether the hearing aids make a difference, that remains to be seen.