Tinnitus Models — Learn How Tinnitus Originates

Just a thought. I must excuse myself if it's been thought up before.

But it struck me that this web forum is the perfect place for conducting surveys or for constructing a database. It might help the researchers and technologists when they are thinking up their theories.

The big problem with figuring tinnitus out is that we can't observe it. Both the cochlea and brain are very difficult to access.

But maybe some simple surveys might bring us forward.

One obvious categorization on a database is whether one is early onset (acute) or chronic. And then the nature of the tinnitus itself. Mine is continuous, high-pitched ca. 6 kHz. It never stops. Every few years it might change gear but otherwise is continuous.

In my case, hyperacusis and a severe throat infection preceded my onset of tinnitus.

My worsening of tinnitus that came 25 years later was preceded by worsening of hyperacusis.

Of course it's not rigorously scientific as it relies on patient's memories, but the idea might bring some results...

At the moment we are all optimistic that by restoring hair cells and synapses will help solve the problem.

I hope so too.

 

No, hearing loss is not always the cause of tinnitus. Tinnitus can exist without hearing loss.

 

My compliments on such a polished and thorough resource.

@Hazel, my feedback is that the author's treatment of the Central Gain Model contains a few errors and misunderstandings. What does not come through in their description is that excess central gain is a consequence of reduced inhibition in auditory centers of the brain. It is not - by definition - a homeostatic plasticity process. Also, "gain", whether in the context of your stereo or your brain describes how the output of a system scales with the input. In this context, Central Gain specifically refers to how the growth in neural response grows with sounds of increasing intensity. Excess Central Gain refers to a fundamental observation in laboratory studies of animals with partial hearing loss, synaptopathy, salicylate administration etc. that sounds of increasing level elicit a disproportionately steep growth in neural responses. What the authors may not have fully understood is that Central Gain, per se, was not intended to be the mechanism of tinnitus but rather something that is relatively easy to measure in animals and humans and is closely linked to the underlying causes of tinnitus.

If you elect to revise this text, it might be an interesting idea to ask a research group familiar with the neurobiology of tinnitus and hyperacusis to propose some revisions to the Central Gain model and/or contribute to this resource by explaining - in their own words - a model for the causes of tinnitus that is grounded in the current thinking on biological mechanisms (e.g., genes, proteins, synapses... the stuff the brain is actually made of). The ball and stick diagrams found throughout the document have their uses for illustration but - in my opinion - they do a disservice to the community if the goal is to communicate how the brain actually works.

More broadly, I don't see the state of the field the way it is presented here. I don't think there is that much debate about the causes of the phantom sound. The clearly dominant explanation for tinnitus can account for all of the complexities regarding the contributions of hearing loss, contributions of cochlear neuronal degeneration, and why all the various forms of auditory-somatosensory bimodal stimulation offer an essentially equivalent moderate benefit. It's true that there are still some important unanswered questions on the precise event that generates the phantom sound and important work left to do on why tinnitus is a mild annoyance for some but is accompanied by intense sound sensitivity, anxiety, sound aversion etc. in others. But from my perspective, the causes of tinnitus are mostly solved and the next steps needed to amplify the benefits reported with bi-modal auditory/somatosensory stimulation are quite clear.

It's the first of the year, so a good time to look ahead. As a leading researcher in this field, I'm quite optimistic that accurate, objective biomarkers are coming into focus and that highly efficacious non-invasive treatments are within our grasp.

 

@HomeoHebbian, thanks for the thoughts on the current model and your optimism.

Having listened to various researchers and having had a Zoom discussion with Dr. Dirk De Ridder, the research field seems scattered and sometimes with great conflicts of interest. We've all asked for collaboration, which still seems elusive. Yes, there are money, patents and grants in the way. A shame.

Recent research points to the signal being triggered and started by damage to the auditory nerve. Professor Peter McNaughton has tested this hypothesis of a peripheral pain phenomenon using HCN2 blockers. It worked in animal models but the compounds are not selective enough. The RNID, Merck and Kings College London are all in partnership with new molecules ready to test. There was also a paper recently showing auditory nerve damage accounting for tinnitus prevalence. What about the work by the Hough Ear Institute on NHPN-1010? It's stuck. Yet that drug is said to repair auditory nerves. Rinri Therapeutics have a product that proliferated into auditory nerve cells, but are a year away from a pilot trial.

Further on the first stop of the brain, the cochlear nucleus, is showing importance in the primary generator of tinnitus in the brain. The Auricle device targets this and there have been findings of reduction in Kv7.2/3 channels and loss of neuronal 5-HT1A receptors (Nicholas Barnes, Birmingham University, UK) in this area of the brain.

Dr. Dirk De Ridder is losing the faith of many in the community. He is focusing on neuropathic pain and the peripheral areas of the brain, and generally avoiding the nerves and brainstem to a large degree.

Of course the biggest issue is increasing and broadening the research field. Awareness is low and therefore we are not attracting significant funding.

 

It definitely seems like we're on the cusp of something great, but there's so many walls in the way.

 

Thanks, I would enjoy the chance to be a part of that. I take a lot of inspiration from the Tinnitus Talk community.

Hi @Nick47, yes, there is a lot of noise out there. Recognizing which peer-reviewed results are breakthroughs versus short-lived sparks in the dark is not obvious and seems to be a source of great frustration for people in the Research News section of Tinnitus Talk that sift through press releases, interviews, and the primary literature in search of concrete answers. Amidst the noise, a solid framework is forming but the progress is slower than it should be because it is a relatively small field that is furiously mining away at everything from cochlear hair cells to the prefrontal cortex with toolkits assembled from molecular biology to cognitive psychology. The resultant parameter space is too vast for the number of workers in the mine, so there is a low probability of hitting a rich vein of gold and drawing other researchers to focus their efforts in this area to see what can be replicated, amplified, and enriched.

Like I said in the post that you quoted, the explanatory models of tinnitus have advanced to the point where one can design principled experiments to test possible treatments. As a field, tinnitus research has many challenges but the biggest setback has come from not having a widely accepted behavioral demonstration of tinnitus in laboratory animals or widely accepted objective biomarkers in humans for tinnitus triggers (e.g., cochlear neural degeneration), generators (e.g., disinhibition) and incapacitators (e.g., sound aversion, anxiety, pain, loudness hyperacusis etc.). But the biomarkers in humans are beginning to improve, so I sincerely hope that interventional studies searching for treatment effects will take the place of descriptive studies.

Personally, I think it is remarkable that five studies from three different research teams have basically found the same thing, even though the methods are quite different and none exactly support the model from animal research that inspired the work (10.1126/scitranslmed.abb2830; https://doi.org/10.1038/s41598-022-13875-x; 10.1001/jamanetworkopen.2023.15914; 10.1126/scitranslmed.aal3175; 10.1101/2022.11.28.518290). It is so rare to find a confluence of positive results like this in tinnitus research. This isn't the best thread to discuss the research but I mention it only to acknowledge that this is rare and special and I think it should help people feel encouraged that a few footholds have been identified in the smooth rock wall. Still a long way to climb but it feels pretty good to be off the ground.

 

This is indeed interesting. There are also anecdotal reports from folks who tried DIY bimodal stimulation using TENS devices or some other contraptions, reporting positive results. Maybe bimodal stimulation does not need to be perfect, just good enough to disrupt the bad pattern that gets etched into the brain after loss of input (for acoustic trauma induced tinnitus at least). Like the brain can only do so much at the same time. It can do tinnitus and one other thing at the time (outside autonomous functions). Give it two things, and the capacity for processing tinnitus get reduced.

Anyway, layman speaking here.

 

Hi @HomeoHebbian, and thanks for your input. I just wanted to address the comments above.

As you'll notice from my profile I've experienced tinnitus for over 30 years so I'm somewhat of a seasoned patient. Also, although I don't tend to talk too much on this forum about the arc of my own career, I started off my working life in a civilian/military electronics and electrical engineering setting. I think it's important to state because that kind of environment sets up a person's approach to problem-solving for life. When it comes to working through technical challenges I can be a bit pedantic.

I'm not sure I agree with your statement that there isn't much debate about the causes of the phantom sound. If anything, from my perspective at least, the lack of an agreed model about why these sounds set up is the main barrier to a cure right now. I agree that noise-induced hearing loss is a primary indicator for tinnitus - in fact many if not all of the research papers I have read about tinnitus state that. Nevertheless, I don't believe I've encountered a single publication that can square the circle as to why not all noise-induced hearing loss leads to tinnitus. It seems to me that is a critical part of the puzzle.

This conundrum has vexed me to such a degree that a couple of years ago I took it upon myself to try and produce a speculative tinnitus model that will leave us in no doubt as to why not all noise-induced hearing loss leads to tinnitus. I'm hopefully going to be in the position to publish that essay, which currently runs at circa 3000 words, on this website within the next couple of weeks or so.

During my research of this problem I've found the timeline of pivoting perspective both intriguing and a bit depressing. For example, in 1990 Jastreboff firmly stated that changes in the limbic system came about as a reaction to tinnitus. Although there may have been various publications after that which contradicted his point of view, I tend to consider Josef P Rauschecker's 2010 paper, Tuning Out the Noise: Limbic-Auditory Interactions in Tinnitus to be the landmark publication. It eventually turned Jastreboff's theory on its head: the limbic system plays a key role in the generation of tinnitus.

This turnaround in thinking took 20 years. Of course, it's now been 14 years since Rauschecker's paper was first published. As brilliant and observant as that paper is (in fact I have used its premise as the foundation to my own homegrown theory) it still falls short (as far as I can see) of answering the question, what causes tinnitus and why?

This brings me to my final point where I feel I should address @Nick47's comment about Dr. Dirk De Ridder. I don't believe this community necessarily harbours any animosity towards Dr. De Ridder; it is just that he is renowned for prescribing various cocktails of powerful drugs to patients suffering tinnitus. In principle I have no issue with that, however, when those drugs are prescribed to treat a condition the causes of which the scientific community cannot agree on, the patient essentially becomes a guinea pig. I only speak for myself regarding that, however, that is the point where I have reservations about the kind of approach Dr. De Ridder takes.

This brings me full circle back to my original point. I think it is essential that tinnitus research focusses roundly on building testable models that leave no question as to the cause of tinnitus. As I have already stated, I personally don't believe I've received the full answer to that question. Suffice to say I'm quite willing to accept that I may have missed something along the way and am happy to be corrected.

 

My issue with Dr. De Ridder is he seems to be going off his own hardwired theories. His latest proposal 'War on Tinnitus' seemed to be a pitch to raise €700,000 EUR to test out a bunch of experimental treatments based on different types of non invasive brain stimulations. This after all the previous, yet similar methods have failed. To make matters worse these are not experimental treatments based on findings with lots of good evidence. Is he now just pitching for funding to see himself into retirement?

To add to this, there is ample evidence now of tinnitus generation first starting in the cochlear nucleus, an area of the brain he rarely focuses on. As @HomeoHebbian has sighted, there are treatments that target this through somatosensory nerves that have shown positive results in animal and human trials.

More recent research has found evidence of auditory nerve damage in patients with tinnitus and normal audiograms versus those without tinnitus and normal audiograms. Recent research and testing of HCN2 blockers in animals has shown efficacy and they do not cross the BBB. If this translates to humans, it shows the signal starts from a chronic pain type response from damaged nerves which in turn alters the firing rate in the cochlear nucleus. There is then a rewiring that occurs in various parts of the brain until it's perceived in the auditory cortex. The NHPN-1010 product that repairs nerve fibres from the Hough Ear Institute (and citing their positive case study and claims) makes their product a plausible treatment. Added to this is the success rate of cochlear implants, which bypass a lot of the damaged nerves. Many patients experience tinnitus reduction in sound proofed booths with the processor switched on. So it's not increased access to external sound masking the tinnitus, just bypassing the original damaged structure seems ample.

It seems in the whole those that have sudden hearing loss experience tinnitus more frequently than say those with age-related hearing loss. Is the damage to IHC and OHC not sufficient to cause tinnitus but nerve damage is necessary?

 

I read that study you're referring to and yes, I believe the upstream effects of auditory nerve damage could play an important role. My problem with these observations in this line of research is that they don't appear to offer a method of action.

This is exactly the reason why I've gone out on a limb to try and build a layman's tinnitus model (based upon aspects of the research you're citing, including that of cochlear implant patients). I wanted for my own peace of mind to unequivocally demonstrate a hypothetical method of action.

@Utdmad89, I'm at pains to understand which part of my previous post you find funny?

 

No, I can't get my head around it, only to think that damage to nerve cells changes the action potentials. We know that the HCN channels play a role in potassium channel activity, and these channels can be found in the spiral ganglion. These cells misfiring may alter activity in the brainstem?

 

@Utdmad89, ah right, a troll with fuck all to contribute except the funny button.

A change in the action potentials that trigger a failure in the upstream inhibitory circuit is what makes most sense to me. Rauschecker suggested a schematic for that network in his 2010 paper. What I've tried to do is build an example that would function within a solid-state circuit but also translate into a biological model. I just need to sketch up some illustrations and then upload it.

 

He seems to be a grifter.

 

There is no mystery as to why not all noise-induced hearing loss leads to tinnitus.

First of all, let's think about noise. Noise exposure has highly heterogeneous effects on cochlear sensory cells, non-sensory cells, and primary cochlear neurons. The heterogeneous effect of the noise damage itself on cochlear pathology is further amplified by the fact that exposed ears are at various states of vulnerability depending on their accumulated insults from prior exposure, age, circadian cycle etc.

Second, let's think about hearing loss. Hearing loss (i.e., elevated thresholds measured with a pure tone audiogram) has very little to say about any of the latent pathology mentioned above. Cochlear neural degeneration is the most common - though by no means the only - precipitator of tinnitus but it isn't measured by a pure tone audiogram.

Lastly, the proximal generator of tinnitus is in the brain. It is often linked to cochlear neural degeneration but can be elicited by factors that have nothing to do with cochlear neural degeneration (e.g., tapering benzodiazepines too rapidly).

When I said there isn't much debate about the generator of the tinnitus sound, I was referring to disinhibition and I stand by that statement. When I said that the precise mechanism is not known, I was referring to the fact that it is not yet clear what essential pattern of neural activity arising from disinhibition is essential for eliciting conscious awareness of a phantom sound. Not any pattern of elevated neural activity will elicit a conscious percept. The activity has to assume a particular form for it to be recognized by the brain as a sensory feature and not just random neural noise. That is why something as distant as noise exposure should never be expected to have a 1:1 mapping with whether or not a phantom sound is experienced.

Rauschecker's data on limbic recruitment were interesting but his model about frontal loops is overly complicated. There are far simpler explanations. Still, I agree with you that limbic recruitment is essential to explain many important aspects of tinnitus disorder that cannot be accounted for by the fairly well-established matter of disinhbition as the generator of the phantom percept.

Yes, I think you hit the nail on the head. Susan Shore's approach was based on a very specific model of auditory-trigeminal input timing. Then Neuromod used wildly different auditory-trigeminal timing (presumably as a control) but then observed the same basic effect as the very specific timing and called it a treatment arm instead. And now Neosensory is showing roughly comparable effects but the stimulator isn't even activating the trigeminal nerve, which wouldn't even recruit the same inhibitory pathway that was described in Shore's work. So, it's clear that it is working though it seems highly unlikely that it is working through the original spike timing-dependent plasticity model in the DCN that Susan proposed. But that's what makes it so exciting to study. Even if she wasn't exactly right on the precise mechanism, she was clearly right about the utility of combining sound and somatosensory stimulation in tinnitus modulation. What's out there now is just the first step; it seems likely that it can be greatly amplified and extended.

 

When you talk about the peaks in the DCN, are you referring to a similar aggravation of tinnitus via the trigeminal nerve with, for example, dysfunctions in the neck and jaw?

I mean that if TMJ problems worsen, the tinnitus (somatosensory) already present will also increase in volume?

 

There are a lot of papers which suggest DCN is at least in part responsible for tinnitus. Reducing hyperactivity in the DCN would seem the right direction for researchers.

 

I'll be the first, but it is very difficult to find an experienced surgeon who wants to do it. I cannot force someone to do it. Maybe if I identify as a trans half-deaf man, it will be easier, because this should be considered 'normal' these days.

Probably because there is abnormal activity in the auditory nerve.