TinnitusFree · War on Tinnitus

Proposal for innovative
treatments for tinnitus.

Dirk De Ridder & Divya Adhia
Brai3n Clinic, Ghent, Belgium · Research Unit, University of Otago, New Zealand

This proposal is a high-risk, high-gain approach to finding a solution for tinnitus within a short time frame of three to five years, and every study in it is easy to roll out in tinnitus clinics if proven successful. The goal is to reduce and ideally abolish the sound itself, whereas most tinnitus studies attempt to reduce the suffering associated with it.

Time frame3 to 5 years
Programme14 studies
Strategymultimodal
Targetthe sound itself

Background

Tinnitus is generated
by the brain.

The brain is the generator of tinnitus, even when it is triggered from the ear.1

Tinnitus is not the consequence of a single brain area, the auditory cortex, going into overdrive, as was previously thought.2 It is better seen as an emergent property of dysfunctional interactions between multiple networks.3–5 One network generates the abnormal sound, the tinnitus itself. Other co-activated networks generate the suffering (anxiety, depression) and still others the disability, such as cognitive dysfunction (problems with memory, concentration and attention).

The condition rests on genetic and environmental risk factors. These induce epigenetic changes (changes in gene expression) and changes in the microbiome, which together create a pro-inflammatory state that turns transient tinnitus into chronic tinnitus, analogous to what has been proposed for chronic pain.6

Heuristic pathophysiological model of tinnitus
FigureHeuristic model: genetic and environmental risk factors act through epigenetics and the microbiome on neuroinflammation, which determines whether tinnitus becomes chronic.

Treatment development

A ‘war on tinnitus’:
multimodal and surprising.

The approach borrows from how a war is fought: use whatever relevant scientific information exists to build a strategy that is multimodal and surprising.

Surprising
Traditional evidence-based approaches have not produced a single FDA- or CE-approved tinnitus treatment after many years of research. A surprising approach is therefore essential.
Multimodal
Different ways of attacking the problem are combined, for example sound treatment with psychedelics, multi-target brain stimulation, anti-inflammatory approaches, or transcranial photobiomodulation combined with neuromodulation. This is analogous to a war fought by ground troops, air force and navy together.
Precedent
The same logic has proven highly successful against HIV/AIDS. By using four drugs that each act on a different mechanism, survival increased from 5 years with one drug to 20 years with two, 40 years with three, and a normal life expectancy with four.7
If positive
Effective studies are combined in a new study, increasing the multimodality. Running studies in neuromodulation, psychedelics, sound therapy and anti-inflammatory treatment in parallel raises the chance that the therapies can later be combined in a truly multimodal approach.
If below expectation

That would indicate distinct, currently unknown tinnitus subgroups. The next step is then more individualised studies, in which genome, microbiome and cytokines are determined for each person to create tailor-made treatments (see appendix).

This personal information supplements the individual brain state as measured by EEG or fMRI: brain stimulation adjusted to the EEG, medication to the genome, pre-, pro- or antibiotics to the microbiome, and anti-inflammatory drugs or food supplements to the cytokine profile. This is far more expensive and less practical to introduce on a large scale, but still feasible in a larger multidisciplinary tinnitus clinic.

The proposal

Fourteen studies aimed at
a common pathway.

Based on the idea that there may be a final pathophysiological pathway shared by all tinnitus patients, the programme proposes an objective diagnostic marker and thirteen novel treatment studies, following the multimodal war-on-tinnitus rationale.

From a strict scientific point of view this is suboptimal, and the authors acknowledge that fully. The underlying idea is that if something yields a large effect size, its mechanism of action can subsequently be unravelled in a more rigorous, traditional scientific way.

Diagnostics

Objective marker

  1. 01AI-based EEG signature of tinnitus
Focused ultrasound

Deep targets

  1. 02Caudate nucleus and insula
  2. 03Rewarding reconditioning, nucleus accumbens
  3. 04Disrewarding reconditioning, habenula
Electrical stimulation

Network disruption

  1. 05Tinnitus core disruption, grey noise
  2. 06Insula versus insula + core network
  3. 07Quadruple network stimulation
  4. 08Rebalancing stimulation
Photobiomodulation

Light therapy

  1. 09Photobiomodulation for tinnitus
  2. 10Photobiomodulation + quadruple network
MDMA-assisted

Plasticity windows

  1. 11Electrical stimulation + MDMA
  2. 12Sound treatment + MDMA
Anti-inflammatory

Inflammation

  1. 13Anti-inflammatory food supplements
  2. 14Anti-inflammatory medication

NoteThese are proposed research studies, to be carried out by clinicians and researchers under medical supervision. Nothing on this page is treatment advice, and none of the substances or dosages mentioned should be used outside a supervised study.

Diagnostics · Focused ultrasound

Measure it objectively,
then reach deep targets.

01

Objective marker for tinnitus

Background
Tinnitus is an entirely subjective symptom. It cannot be diagnosed objectively the way blood pressure is measured to diagnose hypertension. Because tinnitus is generated in the brain, it should in theory be possible to diagnose it objectively from an EEG, which records brain activity. This requires recognising a specific tinnitus pattern in the brain in a purely data-driven way, and the best tool for that is advanced AI such as large language models or agentic AI. The idea is to treat the EEG as a language, which makes it possible to translate an EEG into the presence, loudness and suffering of tinnitus.
Goal
Find a brain signature that (1) diagnoses tinnitus, and (2) rates the loudness of the tinnitus from 1 to 10 as well as the associated suffering from 1 to 10.
Study
Hire a postdoctoral researcher specialised in AI to work with a very large EEG database of more than 3,000 EEGs with associated clinical data (from Prof. Jae-Jin Song, Seoul, Korea), which can be compared with smaller databases from Belgium and Germany.
LLM agent architecture for EEG-based tinnitus diagnosis
FigureAn LLM agent reasons over Korean, Belgian and German EEG databases and reports whether tinnitus is present, its loudness and its suffering, each on a scale of 1 to 10.
02

Transcranial pulsed ultrasound stimulation of the caudate nucleus and insula

Background
A case report describes a stroke in the left caudate nucleus that resulted in near-total silencing of tinnitus.8 The caudate nucleus is involved in retrieving learned associations from memory. It has been targeted with deep brain implants for tinnitus, with variable success.9 In tinnitus it is more densely connected to the auditory cortex, the nucleus accumbens and the dorsolateral prefrontal cortex. It lies deep in the brain and cannot be reached directly by electrical or magnetic stimulation.
Goal
Disrupt the tinnitus network with transcranial focused ultrasound aimed at the caudate nucleus, passing through the pgACC, dACC and insula. This should disrupt the major players in the tinnitus network.
Study
Treat 20 patients with transcranial ultrasound, three sessions a week for three weeks (nine sessions), using the Neurolith transcranial focused ultrasound system (Storz Medical), compared with placebo stimulation.
Neurolith transcranial ultrasound set-up
FigureNeuronavigated treatment set-up.
Ultrasound focus in the brain
FigureTranscranial pulsed ultrasound reaching deep structures.
03

Rewarding reconditioning stimulation of the nucleus accumbens with transcranial focused ultrasound

Background
Reconditioning stimulation is a novel concept. In theory it should be possible to recondition the brain by pairing external stimuli with stimulation of the reward system, thereby rewarding certain stimuli and withholding reward from others.
Goal
By pairing non-tinnitus frequencies with rewarding stimulation of the nucleus accumbens, the salience of non-tinnitus sounds increases. By not rewarding the tinnitus-matched frequencies, their relative salience decreases. The tinnitus sounds are not rewarded and the non-tinnitus sounds are. In rats this approach is capable of reducing tinnitus.10
Study
Target the nucleus accumbens while presenting non-tinnitus sounds, and do not stimulate while presenting tinnitus-matched sounds. This can be done with the neuronavigated Neurolith device (Storz Medical) in 10 patients, compared with placebo stimulation.
Rewarding stimulation in nucleus accumbens paired with non-tinnitus sounds
FigureAll non-tinnitus sounds paired with rewarding stimulation of the nucleus accumbens.
04

Disrewarding reconditioning stimulation of the habenula with transcranial focused ultrasound

Background
The same reconditioning principle as in study 03: pairing external stimuli with stimulation of the reward system makes it possible to reward certain stimuli and withhold reward from others.
Goal
Disrewarding stimulation of the habenula, paired with tinnitus-matched frequencies, can in theory remove the salience of the tinnitus tone.
Study
Target the habenula while presenting tinnitus-matched sounds, and do not stimulate while presenting non-tinnitus sounds. This can be done with the neuronavigated Neurolith device (Storz Medical) in 10 patients, compared with placebo stimulation.
Disrewarding stimulation in habenula paired with tinnitus-matched sounds
FigureAll tinnitus-matched sounds paired with disrewarding stimulation of the habenula.

Transcranial electrical stimulation

If the network falls apart,
the tinnitus should disappear.

Four studies use the 32-channel Neuroelectrics stimulator, which can stimulate whole networks at once based on computer simulations of current flow in a standard head model.

05

Tinnitus core disruption by transcranial grey noise stimulation

Background
A tinnitus core network (posterior cingulate cortex, parahippocampus, auditory cortex) has been described by comparing the brain networks of people with hearing loss without tinnitus and people with the same hearing loss who do have tinnitus.11
Goal
Disrupt the tinnitus network with electrical noise stimulation. Because tinnitus is an emergent property of a ‘tinnitus network’, the tinnitus should disappear if that network falls apart.
Study
Treat 20 patients with noise stimulation versus placebo, three sessions a week for three weeks (nine sessions), using the Neuroelectrics 32-channel stimulator for network stimulation (see the upper right of the figure below).
Expected outcome
Reduction or disappearance of tinnitus.
Brain networks in hearing loss with and without tinnitus
FigureDecreased auditory input without tinnitus (A) and with development of tinnitus (B).
Neuroelectrics active montage and simulated current flow
FigureActive montage of the 32-channel stimulator and simulated current flow.
06

Transcranial electrical insula stimulation versus insula + tinnitus core network stimulation

Background
The insula is part of the salience network, which assesses behavioural relevance. It signals to the rest of the brain that the tinnitus is salient, that is, behaviourally relevant12 (left figure; lIns = left insula). The insula is also part of the chronic tinnitus network13 (right figure).
Goal
Stop the insula from sending information to the tinnitus network, and compare this with disrupting the insula together with the rest of the chronic tinnitus network: insula + DLPFC + parahippocampus + auditory cortex (right figure).
Study
Treat 20 patients, 10 in each group, with noise stimulation from the 32-channel Neuroelectrics stimulator to disrupt the pathological connections (see study 05).
Expected outcome
Reduction or disappearance of tinnitus.
Insula connectivity in tinnitus
LeftThe left insula signals salience to the network.
Chronic tinnitus network: insula, DLPF, A1, A2, parahippocampus
RightThe chronic tinnitus network.
07

Quadruple network stimulation

Background

A sound activates the auditory cortex in conscious patients and also in unconscious ones.14 For a sound to become conscious, the auditory cortex must be connected to consciousness-enabling networks:15 the default mode network (DMN), which integrates the tinnitus into the self, and the central executive network (CEN).16 The sound only persists if the brain deems it salient: a sound is perceived when the salience network (SN) is co-activated.17 These three networks form the triple network, involved in almost all brain disorders studied so far.18

Integrating the core tinnitus network into the triple network model means targeting a quadruple network: the triple network plus the auditory cortex.4 The authors have developed a triple network stimulator that normalises activity and communication within and between the three networks (not yet published), which can be extended to the auditory cortex for quadruple network stimulation.

Goal
Disrupt the quadruple network, that is, the connections between the DMN, SN, CEN and auditory cortex.
Study
Treat 20 patients versus placebo with the 32-channel Neuroelectrics transcranial electrical stimulator, three sessions a week for three weeks.
Expected outcome
Reduction or disappearance of tinnitus.
Quadruple network: triple network plus auditory cortex
FigureThe quadruple network: the triple network extended with the auditory cortex.
08

Transcranial rebalancing electrical stimulation

Background
It has been proposed that tinnitus results from the balance between two tinnitus-provoking networks (the lateral sound pathway and the medial suffering pathway) and one tinnitus-suppressing network, the noise-cancelling network.5
Goal
Restore the balance by suppressing the two tinnitus-provoking networks and activating the noise-cancelling network, analogous to what has been shown in pain.6
Study
Rebalance the three networks with the 32-channel network stimulator, using inhibitory cathodal stimulation of the two activating networks and excitatory anodal stimulation of the noise-cancelling network.
Expected outcome
Reduction or disappearance of tinnitus.
Lateral, medial and descending pathways
FigureLateral sound pathway, medial suffering pathway and descending noise-cancelling pathway.

Photobiomodulation · MDMA-assisted

Energise the brain,
then open a window for change.

09

Photobiomodulation for tinnitus

Background

Photobiomodulation applies laser or LED light to the brain at wavelengths between 780 nm and 2500 nm, which is known to penetrate the skull,19 as its use in functional imaging (fNIRS) shows. Its mechanism of action is the activation of mitochondria.20 This generates more energy and also has strong anti-inflammatory effects.21

Chronic tinnitus is associated with low-grade neuroinflammation along the auditory pathway, from the cochlea to the auditory cortex.22 Transotic and transcranial photobiomodulation can therefore target the inflammation in the cochlea and in the auditory cortex respectively.

Study
Treat 20 patients with the Neuronic LIGHT 1070 nm photobiomodulation device in a delayed-start design. In 10 patients transcranial and transotic photobiomodulation (tPBM + toPBM) start immediately; in the other 10 the first nine sessions are placebo, followed by nine sessions of real stimulation.
Expected outcome
If toPBM + tPBM can reduce inflammation, the tinnitus should be reduced.
Light delivery approaches for photobiomodulation
FigureLight delivery approaches for photobiomodulation.
Neuronic LIGHT photobiomodulation helmet
FigureNeuronic LIGHT 1070 nm device.
10

Photobiomodulation combined with quadruple network stimulation

Background
Photobiomodulation (see study 09) generates more energy (ATP) in the mitochondria.20 Transcranial light stimulation has been shown to improve cognitive function.23
Goal
Based on the triple network model of cognitive function, extended by the authors to the quadruple network,4 adding photobiomodulation should enhance the benefit of quadruple network treatment. This applies especially to patients with cognitive problems caused by exhaustion from chronic, tinnitus-related stress. Such exhaustion can lead to atrophy of the stress network (the salience network).24 In patients with anxiety and depression the insula is indeed atrophic,25 as a result of excitotoxicity (exhaustion).
Study
Treat 20 patients with severe tinnitus and cognitive dysfunction using the Neuronic LIGHT 1070 nm device: 10 receive photobiomodulation before quadruple network stimulation, 10 receive quadruple network stimulation with placebo photobiomodulation.
Expected outcome
Patients who might not respond to quadruple network stimulation because their brain is exhausted (chronic fatigue) may benefit from the combined approach.
11

Transcranial electrical stimulation combined with MDMA

Background
Psychedelics transiently increase communication (connectivity) between many areas of the brain,26 which explains the ego dissolution and blissful state. MDMA can also reopen the critical period,27 a period after birth marked by increased neuroplasticity, the brain’s capacity to adapt. This is used successfully in post-traumatic stress disorder (PTSD).28
Goal
Use MDMA to increase neuroplasticity, the malleability of the brain, followed by quadruple network normalisation to restore connectivity to its state before the tinnitus.
Study
Treat 20 patients: quadruple network neurostimulation with MDMA versus quadruple network stimulation without MDMA, using the 32-channel Neuroelectrics stimulator.
Expected outcome
Reduction or disappearance of tinnitus.
Quadruple network stimulation plus MDMA
FigureQuadruple network stimulation combined with MDMA.
12

Sound treatment combined with MDMA

Background
In severe tinnitus the phantom sound is accompanied by suffering (anxiety, depression), sleep problems and disability (problems with memory, concentration and attention).29 As noted in study 11, MDMA is used successfully in combination with exposure therapy for PTSD. Under MDMA, in a safe environment, exposure to the trauma is perceived as non-salient, and the trauma is therefore extinguished from memory as a horrible memory.
Goal
When the tinnitus becomes irrelevant because of the blissful state while tinnitus tones are presented, the brain should suppress the irrelevant tinnitus, in the same way we stop feeling our clothes because they are irrelevant.
Study
Present tinnitus tones under 125 mg of MDMA in three sessions, once a week.
Expected outcome
Reduction or disappearance of tinnitus, or habituation to it so that it is no longer bothersome.
Tinnitus-matched sounds presented under MDMA
FigureAll tinnitus-matched sounds presented under MDMA.

Anti-inflammatory approaches

Stop the inflammation that
makes tinnitus chronic.

Chronic tinnitus is associated with low-grade neuroinflammation along the auditory pathway, from the cochlea to the auditory cortex.22

13

Treatment of tinnitus with anti-inflammatory food supplements

Background

The two most relevant pro-inflammatory cytokines, expressed at every level of the auditory pathway, are TNF-α and IL-1β.

Acute tinnitus becomes chronic when it arises during a pro-inflammatory state,22 as in stress. Under stress the hypothalamus may become inflamed,30 which alters the interaction between the nervous system, the endocrine (hormonal) system and the immune system.31 This shifts the balance between the sympathetic and parasympathetic systems, resulting in a persistent pro-inflammatory state and the chronification of acute pathology.

Goal

1. Block overproduction of IL-1β and TNF-α with a cocktail of food supplements that inhibits the activity of both cytokines. The cocktail consists of curcumin 500 mg + piperine 10 mg, omega-3 500 mg, quercetin 500 mg, resveratrol 500 mg, boswellia 500 mg, standardised reishi extract 500 mg, green tea extract 500 mg and vitamin D 1000 IU.

2. Stop hypothalamic inflammation to normalise the interaction between the brain, the immune system and the endocrine system. The yellow dahlia flower contains three substances that together create an anti-inflammatory effect capable of completely abolishing hypothalamic inflammation in animals.32

Study
Comparative study of one month of Dahlia4™ plus the anti-inflammatory cocktail versus placebo in 20 patients with chronic tinnitus.
Expected outcome
Reduction or disappearance of tinnitus, or habituation to it so that it is no longer bothersome.
Neuroinflammation in tinnitus meta-analysis
FigureNeuroinflammation along the auditory pathway in tinnitus: meta-analysis.
Interaction of nervous, endocrine and immune systems
FigureStress, the hypothalamus and the nervous, endocrine and immune systems.
14

Treatment of tinnitus with anti-inflammatory medication

Background
The neuroinflammation in chronic tinnitus may be mediated by the cytokine interferon, as interferon induces tinnitus in about 50% of patients.33 Anifrolumab blocks type I interferon and, for about 50%, TNF-α, but not IL-1β.
Goal
Stop inflammation of the auditory pathway, and with it the chronification of tinnitus, using interferon-blocking medication.
Study
Open-label study of three months of the interferon blocker anifrolumab (300 mg once a month) in 10 patients. If only a partial effect is obtained, an IL-1β antagonist (anakinra, canakinumab, rilonacept) could be added. The study needs to be done in hospital, in collaboration with an immunologist.
Expected outcome
Reduction or disappearance of tinnitus, or habituation to it so that it is no longer bothersome.
Mechanism of anifrolumab on type I interferon signallingAnifrolumab vial
FigureAnifrolumab blocks the type I interferon receptor, reducing JAK/STAT activation.

Appendix

Towards personalised
multimodal treatment.

Based on the heuristic pathophysiological model, further studies can be proposed. They become relevant if the programme reveals distinct tinnitus subgroups.

01 · Genetics

Correct for the individual genome.

Individual genomes can be analysed to see which genes are not optimal, and treatment can correct for them. If a genome shows a polymorphism in the dopamine D2 receptor gene, a dopamine D2 agonist can be given; if the SLC6A4 gene is abnormal, sertraline or MDMA can be given. If multiple genes show polymorphisms, a pharmacological cocktail can be tailored to them.

This extends to genes coding for enzymes that break down medication. If such an enzyme breaks a drug down faster, a higher dose of a potentially beneficial drug can be proposed; if the enzyme is deficient, lower doses or alternative drugs may be given.

02 · Microbiome

Restore microbial balance.

The microbiome is the community of commensal, symbiotic and pathogenic microorganisms within a body space or other environment. Individual microbiomes can be analysed to see whether they lack diversity or are dominated by one strain. The microbiome secretes chemicals that influence brain function directly or indirectly, and may be involved in generating tinnitus, especially in patients with autism spectrum disorder. Deviations can be countered with probiotics, antibiotics or faecal transplants.

03 · Cytokines

Match the immune profile.

Based on the individual immune response, as shown by cytokine analysis, a cocktail of medication or food supplements can be given to counter the person’s neuroinflammatory state.

04 · Epigenetics

Read the epigenetic tags.

Epigenetic tags mark certain genes to increase or decrease their expression. Epigenetic tagging caused by environmental factors can therefore mimic risk genes. Given an epigenome analysis, the pharmacological approach can be adjusted to the epigenetic profile, as with genetic risk genes. More general epigenetic modifiers such as valproate can also be proposed.

05 · Toxicology

Screen for heavy metals and toxins.

A toxicology screening for heavy metals and other toxins can be performed. Toxins such as chromium, cadmium or manganese, if detected, can be treated with chelators.

Principle

Measure, then treat per level.

Each level of the model, from genes and environment through epigenetics and microbiome to neuroinflammation and brain networks, has its own measurement and its own treatment. Combined, they form a truly personalised multimodal approach.

Heuristic model annotated with measurement and treatment per level
FigureThe heuristic model annotated with what to measure and how to treat at each level.

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