Frequency Therapeutics — Hearing Loss Regeneration

Congratulations, you just made the worst comment on this thread. Your comment singlehandedly killed any credibility this thread had.

 

Why would your leg grow back if you cure your hearing?

 

I don't know if there's a special term for this, but there are cause-effect relationships involving distinct events, which is what you are describing, and there are cause-effect relationships that are continuous or ongoing.

 

Referring to proximal versus ultimate cause?

At any rate, correlation does not imply causation. So the story goes, we in fact cannot say with precision that smoking cigarettes causes lung cancer, but we have extremely strong correlative evidence of a relationship between smoking and lung cancer. Not causative... merely correlative, like the example of a person whose tinnitus improved while using hearing aid.

 

Hell yes. That's the power of regenerative medicine, and the reason we are all here

 

If hearing aids actually cured hearing instead of just overcompensating for lost hearing, this would be a more valid point.

 

I felt pretty bad when I saw the news about the failed trail, but I was doing well at the time. I had a bad spike after a motorcycle journey recently, so am back on the forum, getting by on promises of future glory.

Things look better than when I last looked for tinnitus treatment. I hope that FREQ can pull through with hearing regeneration!

 

Getting back to the discussion at hand: the problem I have with the idea of hearing restoration completely eradicating tinnitus is that there's no evidence that it will disrupt the network effect that a tinnitus brain usually develops. I think it will be better perceived with hearing aids and cochlear implants because you are improving the signal-to-noise ratio. Just the same as if you use earplugs; your tinnitus is going to rocket in volume for the reverse reason.

Most research indicates that tinnitus is generated by the brain when hearing loss occurs. Numerous imaging studies show this network effect, or centralisation, as some call it. Fatima Husain is a well-known researcher, and her work shows that there are key differences in the emotional centres of the brain of those with tinnitus compared with controls. There's also been observed differences in the white matter of the brain of those with chronic tinnitus. These are physical differences. The precuneus may also be involved in how tinnitus is perceived. Again, imaging studies have shown that it acts differently in tinnitus brains compared to non-tinnitus brains.

The precuneus is connected to the dorsal attention network and the default mode network which both do completely opposite jobs. The dorsal attention network is active when we are engaged and concentrating on something whereas the default mode network is active when our mind is at rest. When one network is active the other is switched off. The precuneus may be a possible marker. I believe the idea is that some tinnitus brains may struggle to switch off and are always at attention. This could be correlated to tinnitus patients’ lack of concentration and inability to sleep.

In that study, we compared a group of patients with mild tinnitus who had developed tinnitus recently, having had their percept for > 6 months but less than one year, to another group of patients with mild tinnitus that had their tinnitus for > one year. We examined three resting-state networks (the DMN, dorsal attention, and auditory networks) and the only significant result was found in the DMN; patients with long-term tinnitus had decreased connectivity between seed regions and the precuneus when compared to the recent-onset group. This finding echoes the results found by Schmidt et al. (2013), which compared the same long-term group from Carpenter-Thompson et al. (2015) to control groups without tinnitus, and suggests that this disruption to the DMN is not immediate but occurs over time in patients.

In the current study, we examined an additional tinnitus characteristic's effect on resting-state connectivity: tinnitus severity. Tinnitus severity in resting-state studies has been variable, ranging from mild to catastrophic (Husain and Schmidt, 2014); it could therefore help to explain the differing results. The existing literature seems to suggest that tinnitus severity has a significant impact on the resting state.​

There's also an impact on the resting state:

Results: Data were included from nine resting-state neuroimaging studies that reported a total of 51 distinct foci. The meta-analysis identified consistent regions of increased resting-state brain activity in tinnitus patients relative to controls that included, bilaterally, the insula, middle temporal gyrus (MTG), inferior frontal gyrus (IFG), parahippocampal gyrus, cerebellum posterior lobe and right superior frontal gyrus. Moreover, decreased brain activity was only observed in the left cuneus and right thalamus.​

Resting-State Brain Abnormalities in Chronic Subjective Tinnitus: A Meta-Analysis

There's a stack of research indicating other areas of the brain's involvement, particularly emotional memory. The caudate nucleus, which is involved with learning, memory, reward, motivation, emotion, and romantic interaction, etc, is also linked in many studies. I find this deep brain stimulation study quite interesting:

Results: Acute tinnitus loudness reduction was observed at 5 caudate locations, 4 positioned at the body and 1 at the head of the caudate nucleus in normalized Montreal Neurological Institute space. The remaining 15 electrical stimulation interrogations of the caudate head failed to reduce tinnitus loudness. Compared to the caudate head, the body subdivision had stronger functional connectivity to the auditory cortex on fMRI (p < 0.05).

Conclusions: Acute tinnitus loudness reduction was more readily achieved by electrical stimulation of the caudate nucleus body. Compared to the caudate head, the caudate body has stronger functional connectivity to the auditory cortex. These first-in-human findings provide insight into the functional anatomy of caudate nucleus subdivisions and may inform future target selection in a basal ganglia-centric neuromodulation approach to treat medically refractory tinnitus.​

Human caudate nucleus subdivisions in tinnitus modulation

I think once tinnitus is centralised, there are too many neural networks involved for hearing restoration to eliminate it. My opinion is that something else will be needed to disrupt the network. However, as I stated at the beginning, I think restoring one's hearing will always work to improve the signal-to-noise ratio. It should always improve the perception to some degree.

We need to figure out is what is causing the maladaptive plasticity and find ways to reverse it.

EDIT:

I was in a bit of a rush writing the above as I had to get my daughter ready for nursery. I want to add further detail by adding more relevant information. I've highlighted parts in bold, but you should read it all because it would make for an interesting debate.

Tinnitus is a common auditory perceptual disorder whose neural substrates are under intense debate. One physiologically based model posits the dorsal striatum to play a key role in gating auditory phantoms to perceptual awareness. Here, we directly test this model along with the roles of auditory and auditory-limbic networks in tinnitus non-invasively by comparing resting-state fMRI functional connectivity patterns in chronic tinnitus patients against matched control subjects without hearing loss. We assess resting-state functional connectivity of the caudate dorsal striatum (area LC), caudate head (CH), nucleus accumbens (NA), and primary auditory cortex (A1) to determine patterns of abnormal connectivity. In chronic tinnitus, increases in ipsilateral striatal–auditory cortical connectivity are found consistently only in area LC. Other patterns of increased connectivity are as follows: (1) right striatal area LC, A1, CH, and NA with parietal cortex, (2) left and right CHs with dorsal pre-frontal cortex, (3) NA and A1 with cerebellum, hippocampus, visual and ventral pre-frontal cortex. Those findings provide further support for a striatal gating model of tinnitus, where dysfunctionally permissive area LC enables auditory phantoms to reach perceptual awareness.

A recent development is the striatal gating model (Larson and Cheung, 2012), which hypothesizes the caudate nucleus to act as a gating mechanism for tinnitus awareness. The striatal gating model is physiologically based, motivated by electrical stimulation experiments in dorsal striatal area LC, located at the junction of the head and body of the caudate nucleus, on awake and interactive humans. Direct stimulation of area LC during deep brain stimulation (DBS) surgery in movement disorders patients with comorbid chronic tinnitus modulates auditory phantom loudness (Cheung and Larson, 2010) and triggers auditory phantom percepts in HL patients without tinnitus (Larson and Cheung, 2012). Furthermore, vascular infarction of area LC results in enduring tinnitus loudness suppression (Larson and Cheung, 2013). According to this model, dysfunctional corticostriatal connections between the dorsal striatum and auditory cortex act as a pathway for auditory phantom representations to reach perceptual awareness. The normally restrictive dorsal striatum becomes pathologically permissive in chronic tinnitus. Although the physiological mechanisms are not clear, it has been proposed that alteration in the balance of excitation and inhibition either within the caudate or in its connections to auditory cortex modulates this permissiveness (Calabresi et al., 2000; Goubard et al., 2011)​

Increased striatal functional connectivity with auditory cortex in tinnitus

This is from an article, with Winfried Schlee, that caught my attention many years ago:

It’s not just the auditory cortex that is affected when people get tinnitus. Neuroscientists, using increasingly sophisticated brain scans, are finding that changes ripple out across the entire brain. Winfried Schlee of the University of Konstanz in Germany and his colleagues have been making some of the most detailed studies of tinnitus ever, using a method called magnetoencephalography (MEG, for short). They take advantage of the fact that every time neurons send each other signals, their electric current creates a tiny magnetic field. MEG allows scientists to detect such changing patterns of activity in the brain 100 times per second.

Schlee and his colleagues find widespread differences in the brains of people with tinnitus and those without it. A network of regions in the brains of people with tinnitus tend to fire their neurons in sync. Schlee has determined that his tinnitus-stricken subjects have a more synchronized pattern of signals coming out of regions in the front and the back of the brain. (For brain anatomy junkies, they are the dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex in the front; in the back, they are the precuneus and posterior cingulate cortex.) Schlee and his colleagues also discovered a more strongly synchronized flow of signals coming into the temporal cortex — a region that includes the auditory cortex — in people with tinnitus.

When Schlee compared people who suffer a lot of distress from tinnitus with those who are not much bothered by it, he found that the more distress people felt, the stronger the flow of signals out of the front and back of the brain and into the temporal cortex. This pattern suggests that the network Schlee discovered is important for the full experience of tinnitus. Tinnitus, in other words, extends beyond the ear, beyond a hearing-specialized part of the brain, beyond even any single piece of neural real estate. It is a disease of networks that span the brain.

Clearly the auditory cortex is just an early stop on the journey that sound takes from the outside world to our awareness. Some neurons in the auditory cortex extend branches down to the brain stem, where they link to a pair of regions called the caudate nucleus and putamen. Those regions may be important for processing the signals in several ways, such as categorizing sounds.

Once signals travel from the ear to the auditory cortex, caudate, and putamen, they eventually make their way to regions of the brain that carry out more sophisticated sound information processing: connecting the sounds with memories, interpreting their meaning, giving them emotional significance. It is precisely these regions that Schlee and his colleagues noted were behaving strangely in people with tinnitus. He argues that it is only when signals reach this large-scale network that we become conscious of sounds, and it is only at this stage that tinnitus starts to cause people real torment. Schlee’s results suggest that the higher regions of the brain send their own feedback to the auditory cortex, amplifying its false signals. Schlee’s model of tinnitus and consciousness could explain some curious observations. Even in bad cases of tinnitus, people can become unaware of the phantom sound if they are distracted. It may be that distractions deprive the errant signals from the auditory cortex of the attention they need to cause real distress. What’s more, some of the most effective treatments for tinnitus appear to work by altering the behavior of the front of the brain.​

I found this part very interesting:

As a young man, Lowry spent a summer working on a farm with a noisy tractor. The experience left him with partial hearing loss and a high-pitched ringing in his ears that plagued him for 40 years. Then at age 63, Lowry suffered a mild stroke. A CT scan and an MRI revealed that the stroke had damaged his caudate and putamen. But the stroke also brought a pleasant surprise. Lowry was completely cured of his tinnitus, without any further hearing loss.​

The Brain: "Ringing in the Ears" Actually Goes Much Deeper Than That

 

Anyone watch the presentation this morning? Can anyone give a summary? Anything new?

 

@Ed209, very interesting stuff.

I've flagged my interest in participating in an MEG based study ”trying to objectively diagnose tinnitus and see how changes in different parts of the brain can be a cause of the perceived sound”. It will hopefully start in the beginning of next year.

The more research the better! Feels like we have a long way to go. So let's step it up! I don't want to wait until I get a stroke that might has the change to stop the tinnitus.

And please can we get rid of the hearing loss and sometimes ”crawling” feeling in my ear? It's so sad that the ear doesn't heal from such things I think. Or maybe it's just take long enough time... Since this tinnitus crap started I have more of a hard time feeling sorry for people when they have an illness that are temporary. Soon five months and still going... What if you had an illness that lasted forever?

Sorry, I just still have a hard time comprehending that this is my reality going forward.

 

This is really cool, Star. Keep us posted.

What I find intriguing is that electrical stimulation of the caudate has shown to reduce tinnitus loudness, or at least modulate the volume, and the person who ended up with a damaged caudate via a stroke was completely cured.

For anyone who’s interested, here's a detailed case report of what happened, including the guy’s audiograms and brain scans:

https://www.researchgate.net/publication/8468432_An_Absence_of_Tinnitus

 

It is a shame that in my country there is no research in which I can participate and help with the research. I don't know why there is nothing that puts the research across all countries... they would have much more results.

 

Here's a cool graphic from a recent publication by Thanos Tzounopoulos:



What’s the buzz? The neuroscience and the treatment of tinnitus

 

Magnificent discussion Ed & Friends.

I'm of the view that these up-front arguments even when (or very often when) there is some struggle & strife, it can lead to new ways of looking at things. Just like brainstorming.

The cause of tinnitus vs the location of tinnitus.

Most people agree that in many cases it starts off with hearing damage. Inner hair cells? Outer hair cells? Stereocilia? Synapses anyone? But the process develops as the brain (and location?) changes.

Maybe the people on this board should differentiate more strongly between acute (recent onset) tinnitus and chronic (greater than 6 months? 12 months?) tinnitus. This usually is a big part of the picture.

In a previous post, on causality I made the philosophical analogy of Lee Harvey Oswald being the cause of the Kennedy assassination. But extracting Oswald is not going to bring back JFK.

I guess that may be the reason that Frequency Therapeutics regrowing hair cells and synapses (regenerative medicine) has attracted so many supporters and so much emotion on here. You're kind of doing a reset of the entire thingie. Also the stock value might be another reason people get emotional and angry

And lastly, life is so much more fun if you have some little thing to raise your hopes -- something to look forward to. Some people set their hopes on a tinnitus cure. Well Hey! Some people put their hopes on ummmm Red Sox or Gophers.

 

Don't be put off by proponents of the old "stuck in the brain" theories and other variations like DDR.

Their arguments aren't all wrong, but if tinnitus is caused by hearing loss, reestablishing hearing input should have a positive influence on tinnitus, this is the principle behind most cases of tinnitus.

DDR talks a lot but I still don't know what concrete and reproducible he offers; have I missed something?

Dr. Shore's science has the merit of being consistent and studied. I have a very specific case of tinnitus, and my symptoms fully correspond to her theory and more generally to the theory that tinnitus is reversible.

The cerebral plasticity implies that you can evolve badly, but also evolve well. Maybe hearing regeneration will need to be accompanied by neuromodulation / KV7 openers, that's a possibility. But hearing regeneration will have a significant effect in "standard" cases of tinnitus.

 

It's a metaphor.

I can tell you this in another way; cancer. A woman who has cancer and loses a breast because of it, even if she is 100% cured of cancer, her breast does not grow back. Loss of the breast is directly related to cancer. If you still don't understand this, I give up, believe what you want.

 

Yea, that's a good point. I think long-term chronic tinnitus is less likely to correct itself with hearing restoration alone, but I think a case could be made for it stopping acute tinnitus from becoming chronic.

 

Bro, are you ok?

 

I've got a metaphor for you all every time this "tinnitus origins" debate comes up... but first my thoughts on the matter. As it relates to tinnitus as a chronic symptom following hearing loss - related events (acute or gradual), which seems to be associated with many of the members on this site; it really seems reasonable that reversing the underlying cause (the damage to the cochlea) should cause a downstream improvement in the tinnitus sensation in the brain. (Remember: Neuroplasticity).

My opinion: It seems like there's a ton of time and resources "invested" in looking at the brain and associated nervous system to understand what is happening when "ears start ringing." And frankly, for the most part, the observations are looking at it in a one-way direction: the damage worsens over time and so does the tinnitus. So, more resources need to go into repairing the underlying cause (hearing loss, TMJ, etc). There's not a lot of research, if any, only anecdotes on sites like this, that indicate that as hearing recovers, the tinnitus experience also seems to resolve to some extent.

Now, back to the metaphor. The nail = hearing damage.

It's Not About The Nail

 

If it's all in the brain how come my tinnitus gets dramatically louder before a rainstorm? Do you expect me to believe my brain re-wires itself prior to the rainstorm, then re-wires itself back the way it was a day or so after the rain is gone?

 

The scientific world used to focus almost entirely on the ears when it came to tinnitus. It's only relatively recently that the brain became more of a focal point as our understanding improved. That's where the science led. Not everyone experiences ringing ears; for some, it's quite literally a ringing brain/head. I have both.

It's a valid point, however, to believe that by fixing the cochlea we could eliminate the tinnitus for some. I don't think it would help with chronic cases because there's too much evidence showing that eventually other parts of the brain take over and feed the auditory cortex, and the fact we perceive the sound also means that our higher consciousness is picking the signal up. There has to be something different going on in the brains of those with chronic cases because hearing loss alone cannot explain why it happens for some, but not for the majority.

It's interesting that tinnitus can be induced in those who don't have it via deep brain stimulation to the caudate body, and can be lowered and modulated in those who do have it. I think the network effect is so vast that it would be very difficult to fix chronic cases with hearing restoration alone. I understand what you are saying, though, that by repairing one of the primary sources it could induce some plasticity and return normal functioning to the brain. We won't truly know until we are capable of doing such things, and I don't think the data on cochlear implants is compelling enough.

Not entirely sure how to interpret this.

 

Your entire existence is in the brain.

For many, tinnitus fluctuates quite dramatically from day to day and hour to hour. I think this can be better explained via mechanisms of the brain rather than the idea that damage is simultaneously occurring in the ear whilst not occurring some moments later.

What would your explanation be as to why yours gets worse before a rainstorm? What do you think is happening?

 

@Cernuto, I have the same thoughts about somatic tinnitus. Jumping up and down, stretching or clamping my jaw all radically change the pitch and loudness of the noise in my head. It would sure seem like there is something physical going on.

 

I don't know but I highly doubt my brain is re-wiring itself due to changes in the atmosphere.

 

To me the fact that we have accounts of cochlear implant users being able to eliminate their tinnitus by turning them on and their tinnitus comes back when they turn them off is a big pointer.

My own theory is that for noise-induced tinnitus it is the ears and lack of input. I mean something is definitely still going on with my ears after a year on from my worsening. They still hurt almost everyday and I can't bear noises that normal people have no issue with, that's not just in my brain, there is something physical going on.

But back to the point. Cochlear implants are the closest thing we have at the moment to seeing the impact of restoring the hearing signal. And we have numerous accounts and articles that report cochlear implants changing tinnitus. As these are the only real accounts so far we have, it must be a big clue as to where the problem lies.

If I break my arm the brain feels the pain until my arm is fixed, if I have a bad tooth my brain feels the pain till my tooth is sorted, anything that you have when it heals you don't have the pain anymore. Tinnitus to me is like any other chronic pain, the body can't heal and so you have the pain, we can't heal the ears so have the tinnitus.

But don't get me wrong, I am glad that different options are being researched. Surely if you throw enough mud at the wall something will stick, and I don't care what I have to ingest, inject, stick on me, which part of body I got to electrocute, I will do anything if it works.

But I guess we are just all going round in circles with the same topics every time we come here as no one knows... no one in the world knows and we are just desperate for anything at all. Wish I could just get on and not be bothered by this.

 

Somatic tinnitus can be modulated and created by electrically stimulating nerves. Moller and Rollins found that tinnitus could be modulated by stimulating the median nerve in the wrist, for example. There's a lot of nerves in the head and neck, and this is why problems like cervical injuries and TMD can cause tinnitus.

A lot of people can change their tinnitus by simply opening their jaws or moving their eyes (or by doing various other bodily movements). This is an effect of the interaction between two different signal pathways. The brain is constantly forming new connections between neurons based on our experiences, and when new skills are learned. For dramatic changes to take place (that will lead to long-term changes in our behaviour, for example), I believe it takes a matter of weeks to months.

 

But then you can have chronic pain where there is no longer a physical injury present, or where there were no injuries to begin with. It can become widespread across the entire body in cases like fibromyalgia. Chronic pain, fibromyalgia, phantom limb syndrome, visual snow, and tinnitus, etc, all share similar qualities; there's some kind of maladaptive problem in the brain.

But this still doesn't explain why so many people with hearing loss, hidden or otherwise, do not have tinnitus. The data regarding the effect cochlear implants have on tinnitus is inconsistent and inconclusive, in my opinion. How can a questionnaire differentiate if the improvements are signal-to-noise based, or physiological?

Those who are eligible for cochlear implants are profoundly deaf, so one should expect some degree of improvement when you have a higher signal coming in. Try, for example, putting in some earplugs and then listening to your tinnitus. When you remove them, does your tinnitus improve? If a profoundly deaf person has mild tinnitus, it's going to sound loud. If you improve the input signal there's a chance you could effectively eliminate it, so that it's no longer noticeable.

How can we differentiate the reason for the improvement without an objective measure to go by?

I do believe that restoring hearing can work, but my opinion is that there's likely to be a timeframe for its success, but who knows?

 

There's also a theory about inflammation that could be the explanation for this too, if I'm not mistaken.

 

What I've long suspected Cernuto, it's all in the clouds.

........................................................................................

 

But we don't yet have the possibility to grow a limb back maybe if limbs could be grown back, people with phantom limb syndrome might be cured of that too. I know there have now been some successful limb transplants and some studies have shown that this resolved PLP. Maybe it can be the same with our ears.

"Our program has transplanted nine hands in eight recipients over the last 15 years. Prior to surgery, six of our recipients reported a history of significant phantom limb pain (PLP)--a form of neuropathic pain that is experienced as arising from the absent limb. Up to 85% of amputees experience moderate to severe PLP, which can adversely impact health and quality of life (Jensen et al 1985). Further, evidence-based treatments are lacking (Weeks et al 2010), and there is no FDA-approved pharmacological intervention (Zanni & Wick, 2008). Remarkably, all six patients experienced complete resolution of PLP or discomfort post-transplant."

Abrogation of Phantom Limb Pain Following Hand Transplantation.