TU Delft & Prof. Dirk De Ridder — Bimodal Stimulation Device for Treating Tinnitus

[Christiaan]

There was a university in the US that did trials on vagus nerve stimulation (implant) combined with sounds. The name was "MicroTransponder" back in 2011 or so.

The results showed not much success, otherwise they would have continued with that approach. I never heard again from any additional trials.

The TU Delft device is not very different except that it is not invasive. They will stimulate the vagus nerve by the outer ear and combine this with sounds. So, after almost more than 10 years, they try a similar method or theory even when the initial trials with MicroTransponder showed not much benefit. I personally doubt that the TU Delft device will be successful.

I wonder what is the crucial difference?

However, I will keep checking the progress here on Tinnitus Talk. Thanks for all your updates.

I made a post about this subject somewhere in this thread. Besides the non-invasive aspect of the TU Delft device, there are additional differences we can expect from it vis à vis VNS devices like MicroTransponder:

Dr. De Ridder has conducted many experiments with bimodal stimulation (pre-clinical and clinical), but the main difference with previous [VNS] devices is that they've now decided to use a different location of the vagus nerve (auricular branch of the vagus nerve instead of the left vagus nerve in the neck) for electrical stimulation. They've also chosen burst stimulation (intermittent) instead of tonic stimulation (continuous) and have decided to pair noise stimulation with tinnitus-matched sounds (instead of sound exposure excluding the tinnitus-matched frequency).

 

[BB23]

Serdijn then mentions that he has also tried the device once, but that he can't really comment on it other than that he felt that his stress response to his tinnitus appeared weakened.

So it's a habituation device?

 

[Christiaan]

So it's a habituation device?

It's not intended as a habituation device. Dr. De Ridder and Prof. Serdijn have mentioned in multiple articles and interviews that their main aim is to reduce tinnitus severity, not merely the annoyance per se. They hope to retrain the brain's fight-or-flight response to a rest-and-digest response, thereby stopping the generation of phantom sound perception.

This text is from the summary of the NRC article:

Dirk de Ridder, a professor of neurosurgery at the University of Otago in New Zealand, and Wouter Serdijn, a professor of bio-electronics at TU Delft, have collaborated to develop a device intended to treat tinnitus through a new method. Their device, humorously referred to as 'De broodtrommel' (The lunchbox) during the interview but officially called the Delft Tinnitus Device, aims to teach the brain that the sound heard by tinnitus patients is not significant, hoping this realization will lead the brain to stop generating the sound.

Concerning the rationale behind the rest and digest response:

Yet, the dual mechanism involved may theoretically even have a third component, which is that paring the tinnitus-matched sound to simultaneous vagus nerve stimulation may be effective in reducing the tinnitus loudness and distress via Pavlovian reconditioning. The parasympathetic nervous system, including its main component, the vagus nerve, have been called the "rest, digest and restore" system, in balance with the sympathetic "fight and flight" system.

When presenting a distressful tinnitus sound with simultaneous relaxing and mood improving vagus nerve stimulation, this may result in Pavlovian reduction of tinnitus intrusiveness via reduction of the tinnitus related distress network. This tinnitus-matched sound-paired VNS stimulation has not yet been performed in humans, however, it is not inconceivable that this may underlie the benefits noted in VNS in epilepsy patients, as the constant phantom sound may progressively become associated to the "rest and digest" vagus nerve stimulation. A study should be performed with tinnitus-matched sound paired vagus nerve stimulation, as the pairing is more obvious for the brain when the tinnitus matched sound is temporally also matched (fig. 3)

(Source)

Concerning Prof. Serdijn's remark:

In my view, we can't judge the effectiveness of a tinnitus treatment like the TU Delft device after just using it once, much like Dr. Shore's Auricle device demonstrates. These treatments rely on neuroplastic changes within the brain, which inherently take time. Dr. Shore's device shows us that for a real, meaningful reduction in tinnitus perception, consistent and long-term stimulation is crucial. It's about retraining our brain's auditory processing, and this process doesn't happen overnight. We need to give these treatments time to work, as the brain adapts and learns to process sounds differently, which could ultimately lead to a significant decrease in the severity of one's tinnitus.

 

[GregCA]

They hope to retrain the brain's fight-or-flight response to a rest-and-digest response, thereby stopping the generation of phantom sound perception.

So they don't expect their mechanism to actually lower the volume of tinnitus? They hope that something else will take care of that later? I'm curious what data points leads them to believe that this is a reasonable hypothesis.

I know, for example, that in my case (n=1), I do not have any fight-or-flight response like I used to have in the beginning of my tinnitus journey. However, my tinnitus hasn't changed: my brain has not decided to stop the generation of that phantom sound at all.

So as to not limit ourselves to n=1, there are lots of testimonials online (on Tinnitus Talk, but also elsewhere) from people describing habituation as "your tinnitus hasn't changed, you just don't worry about it anymore", and that seems to indicate that even if you get rid of the fight-or-flight response, your brain doesn't decide to stop generating tinnitus.

There may exist testimonials from people who say "I had horrible tinnitus, but I stopped worrying about it and it went away", but I have to say I haven't come across those, neither in the "anecdotal evidence" source that online fora provide, nor on more scientific sources such as PubMed. Certainly not from folks who have measurable hearing damage as result of auditory insults or disease.

 

[IYIiKe]

So they don't expect their mechanism to actually lower the volume of tinnitus? They hope that something else will take care of that later? I'm curious what data points leads them to believe that this is a reasonable hypothesis.

I know, for example, that in my case (n=1), I do not have any fight-or-flight response like I used to have in the beginning of my tinnitus journey. However, my tinnitus hasn't changed: my brain has not decided to stop the generation of that phantom sound at all.

So as to not limit ourselves to n=1, there are lots of testimonials online (on Tinnitus Talk, but also elsewhere) from people describing habituation as "your tinnitus hasn't changed, you just don't worry about it anymore", and that seems to indicate that even if you get rid of the fight-or-flight response, your brain doesn't decide to stop generating tinnitus.

There may exist testimonials from people who say "I had horrible tinnitus, but I stopped worrying about it and it went away", but I have to say I haven't come across those, neither in the "anecdotal evidence" source that online fora provide, nor on more scientific sources such as PubMed. Certainly not from folks who have measurable hearing damage as result of auditory insults or disease.

I have gotten the intimation that Dr. De Ridder doesn't believe firmly in bimodal neuromodulation based on his other talks. I was curious why this device because it mimics Dr. Shore's device. My guess is there is a sense a money train might be coming and they don't want to miss out. I think it most likely means they don't have data to support lowered tinnitus volume.

I am questioning cynically if this could be a way to discredit bimodal neuromodulation in advance of a future treatment yet to be announced.

 

[Fields]

Concerning Prof. Serdijn's remark:

In my view, we can't judge the effectiveness of a tinnitus treatment like the TU Delft device after just using it once, much like Dr. Shore's Auricle device demonstrates.

Ah, I didn't mean to pass any judgment concerning Prof. Serdijn's remark.

I just thought it was interesting that Dr. De Ridder felt the need to expand on having used the device, whereas Prof. Serdijn (who actually suffers from tinnitus) understandably answered with "no comment." The bit about a less severe stress response feels like it was added for the sake of the interview/article.

I'm curious to see where this goes. There actually already is a clinic in the Netherlands that offers pulsed radiofrequency of the auriculotemporal nerve. You can read their research on ResearchGate.

 

[BB23]

Funny.

I don't see this helping out with reactivity, hyperacusis, or noxacusis.

 

[Christiaan]

So they don't expect their mechanism to actually lower the volume of tinnitus? They hope that something else will take care of that later? I'm curious what data points leads them to believe that this is a reasonable hypothesis

Valid point. Dr. De Ridder suggests in this article that the mechanism of vagus nerve stimulation (VNS), especially when paired with sound, is expected to influence the perceived volume of tinnitus directly, rather than hoping for an indirect or later effect.

According to Dr. De Ridder, the subjective loudness perception (lateral pathway), distress (medial pathway) & the noise canceling system (descending pathway) are important factors in the manifestation of subjective tinnitus. He support the idea that VNS paired with sound stimulation can reduce the functional connectivity between those pathways in hopes of reducing tinnitus severity, annoyance and awareness. It does this by making certain parts of the brain communicate less with each other via bimodal stimulation. These parts are usually involved in how we perceive the loudness of tinnitus, how distressed it makes us feel and what makes us aware of external/internal stimuli.

Here you can find relevant information from the article concerning the data points that support this hypothesis:

Vagus nerve stimulation for tinnitus

Vagus nerve stimulation is a neuromodulation technique that exerts an effect on the brainstem and brain. Using functional imaging it has been shown that vagus stimulation modulates activity in the auditory system (including superior temporal gyrus, Heschl's gyrus, planum porale, and planum temporale) (Lehtimaki et al., 2013; Yakunina et al., 2018) and limbic system (amygdala) (Yakunina et al., 2018). Furthermore, the parahippocampus is also modulated by vagus nerve stimulation (Yakunina et al., 2018). All these areas are implicated in tinnitus (De Ridder and Vanneste, 2014; De Ridder et al., 2006; Maudoux et al., 2012; Song et al., 2012). In the brainstem the locus coeruleus and nucleus tractus solitarius are modulated as well, which are connected to the dorsal cochlear nucleus (Kaltenbach, 2006).

(...)

Thus, the application of vagus nerve stimulation in tinnitus intuitively makes sense, as it modulates brain areas involved in the emotional, auditory and mood components of tinnitus (Elgoyhen et al., 2015; Langguth et al., 2013).

Yet, vagus nerve stimulation can also be paired with external stimuli, driving neuroplasticity by resetting dysfunctional circuits through cortical map expansion. This provides a form of replication with variation that supports a Darwinian mechanism to select the most behaviorally useful circuits (Kilgard, 2012).

How does sound paired VNS exert its clinical benefit?

Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization (Engineer et al., 2011). Repeatedly pairing tones with brief pulses of vagus nerve stimulation (Borland et al., 2016, 2018; Loerwald et al., 2018) completely eliminates the physiological and behavioral correlates of tinnitus in noise-exposed rats (Engineer et al., 2011). (...) Pairing tones with VNS reduces neural synchronization in a rat model of tinnitus (Engineer et al., 2011).

Thus, the hypothesis is that pairing sounds with VNS can result in a desynchronization of highly correlated activity within human auditory cortex. This is confirmed in EEG analysis, which demonstrates that gamma band activity, itself correlated to tinnitus loudness perception (De Ridder et al., 2015a; van der Loo et al., 2009), is decreased after sound paired VNS.

Sound paired with VNS reduces the functional connectivity between the dorsal anterior cingulate cortex and the auditory cortex in the theta frequency band. Sound paired with VNS also reduces functional connectivity between the descending noise canceling pathway hubs of the subgenual anterior cingulate cortex and parahippocampus. Furthermore, it has been shown that the subgenual anterior cingulate cortex and parahippocampus form a general aversive network (Moulton et al., 2011), which is confirmed in tinnitus (Vanneste et al., 2013).

Clinically, this reduction in functional connectivity is expected to dissociate the normally present correlation between subjective loudness perception (lateral pathway) and distress (medial pathway), because the decreased communication between the pathways decreases the salience, encoded by the medial pathway (Seeley et al., 2007), from the tinnitus sound. The decreased functional connectivity with the parahippocampus and subgenual anterior cingulate cortex permits the noise canceling system to function more effectively, and thus decrease the loudness and percentage of the time the tinnitus is present [descending pathway] (Song, 2015). As expected, sound paired vagus nerve stimulation indeed seems to dissociate the normally present correlation between subjective loudness perception and distress (Vanneste et al., 2017).

Vagus nerve stimulation and tinnitus

(...)

Of the 20 pre-operative epilepsy patients with tinnitus, all patients continued to have tinnitus post-operatively. Four (20%) noted no changes in VAS of tinnitus loudness while 16 (80%) improved with at least a one-point decrease. The mean difference between pre- and 1 year post-operative VAS of loudness was 2.05, which was statistically significant (Tyler et al., 2017).


These results suggest the possibility that VNS may reduce tinnitus severity via two distinct mechanisms. VNS triggers release of neuromodulators including norepinephrine, acetylcholine and serotonin, which desynchronizes the cortex and improves mood. When paired with specific events VNS also drives long lasting neural plasticity, which can restore function in animal models of tinnitus, stroke, spinal cord injury and peripheral nerve damage (Ganzer et al., 2018). It is possible that the targeted plasticity produced by pairing VNS with particular events also benefits from non-specific actions, including effects on mood (Elger et al., 2000).

(Source)

Several pathways involved in manifestation tinnitus

(Source)

I have gotten the intimation that Dr. De Ridder doesn't believe firmly in bimodal neuromodulation based on his other talks. I was curious why this device because it mimics Dr. Shore's device. My guess is there is a sense a money train might be coming and they don't want to miss out. I think it most likely means they don't have data to support lowered tinnitus volume.

I am questioning cynically if this could be a way to discredit bimodal neuromodulation in advance of a future treatment yet to be announced.

Dr. De Ridder has been conducting extensive research on VNS for tinnitus, with and without sound stimulation, since at least 2014:

De Ridder, D., Vanneste, S., Engineer, N.D., Kilgard, M.P., 2014a. Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series. Neuromodulation 17, 170–179.

Concerning your remark on Dr. De Ridder's view on VNS with/without sound stimulation:

Vagus nerve stimulation is a promising new tool for the treatment of chronic tinnitus.

Current protocols [pairing VNS with non-tinnitus sounds] produce a clinically significant but moderate improvement in tinnitus distress and a modest benefit in tinnitus loudness perception.

Although the potential to use neural plasticity to reduce or eliminate the neural drivers of ongoing tinnitus is exciting, much work is needed to understand the neural basis of tinnitus more completely and to develop tailored therapies to address the suffering caused by this heterogeneous condition.

Whether pairing of the vagus stimulation with non-tinnitus or tinnitus-matched sounds is essential is still to be determined. Current evidence for paired or unpaired vagus nerve stimulation in the setting of tinnitus is insufficient for FDA approval.

(Source)

See my response to @GregCA about the data concerning lowered tinnitus volume.

 

[DeanD]

I don't see this helping out with reactivity, hyperacusis, or noxacusis.

Perhaps reactivity and hyperacusis is where it works best.

I had a neurologist appointment who did deduce (theory mind) that reactiveness is a neuroplastic change in the brain as a response to auditory changes.

This response continues until, one would assume, neuroplastic changes again to reverse the trigger.

Personally my reactivity appears to be 'echos'. If I come from a call it sounds like a thousand voices as a tinnitus tone, all repeating over each other. A long car drive and I'll hear more hissing. Rain on the roof and the reactivity becomes high pitch. The brain could could be stuck in an auditory feedback loop for a period time.

All tinnitus and hyperacusis theories are speculative, no one knows, but if neuroplasticity changes really have set in causing reactivity, perhaps - just perhaps - bimodal stimulation could reverse that brain change for the better.

 

[HighleyTall]

They have no clue. I see a lot of question marks in Figure 3 on the ends of the diagram.

 

[Nick47]

De Ridder, D., Vanneste, S., Engineer, N.D., Kilgard, M.P., 2014a. Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series. Neuromodulation 17, 170–179.

So this is the paper.

Again, as per Dr. De Ridder style, the full article is behind a paywall.

Weaknesses:

• Small group
• No placebo

Strengths:

• Used TFI and Minimum Masking Level (MML)

Again, being just the abstract, there is little information on the methods, little discussion, and no information or data to view on what the changes in TFI and MML were. What were the profiles of the patients? What were the inclusion/exclusion criteria?

Just like the other papers he has been the lead author on, this was barebones. His or Sven Vanneste's paper on Cyclobenzaprine was just the same.

 

[annV]

Again, as per Dr. De Ridder style, the full article is behind a paywall.

Again, as per my style, the full article is attached.

 

[Christiaan]

They have no clue. I see a lot of question marks in Figure 3 on the ends of the diagram.

View attachment 56477

You could read the paper to understand the reason for the question mark placed after 'tinnitus loudness' & 'Pavlovian reconditioning'. The word 'may' is pivotal here, since the pairing of tinnitus-matched sound with VNS has not yet been tested in humans. However, there are indications that this approach could aid in reducing tinnitus loudness, based on the outcomes of VNS treatments paired with non-tinnitus sound stimulation.

With the upcoming trial of the TU Delft device, researchers aim to determine whether adjusting parameters could optimize the effects of reducing tinnitus loudness.

Text from paper (concerning fig. 3):

Yet, the dual mechanism involved may theoretically even have a third component, which is that paring the tinnitus-matched sound to simultaneous vagus nerve stimulation may be effective in reducing the tinnitus loudness and distress via Pavlovian reconditioning. The parasympathetic nervous system, including its main component, the vagus nerve, have been called the "rest, digest and restore" system, in balance with the sympathetic "fight and flight" system. When presenting a distressful tinnitus sound with simultaneous relaxing and mood improving vagus nerve stimulation, this may result in Pavlovian reduction of tinnitus intrusiveness via reduction of the tinnitus related distress network. This tinnitus-matched sound-paired VNS stimulation has not yet been performed in humans, however, it is not inconceivable that this may underlie the benefits noted in VNS in epilepsy patients, as the constant phantom sound may progressively become associated to the "rest and digest" vagus nerve stimulation. A study should be performed with tinnitus-matched sound paired vagus nerve stimulation, as the pairing is more obvious for the brain when the tinnitus matched sound is temporally also matched (Fig. 3)

(Source)

 

[Nick47]

Thanks @annV.

So a mean decrease of 14 dB for all participants, for those on medication 4.9 dB, and out of the 5 that were on no medication, a permanent mean decrease of 29 dB.

A very small sample size and no placebo. Given the invasive nature, I can understand why.

If that type of result can be achieved with 100 participants, it's a winner.

 

[ImmortalWombat]

Any update on TU Delft & Dr. Dirk de Ridder's research?

 

[Nick47]

Any update on TU Delft & Dr. Dirk de Ridder's research?

The last I heard, the results will be announced in November. You can sign up for the Q&A through Tinnitus Quest, as it will be held with Dr. Dirk De Ridder in October.