damage, regeneration and repair of the auditory and vestibular systems

What is the global and UK prevalence of hearing loss?

466 million people worldwide.

In the UK, 11 million (second most common disability), with over 6 million having sensorineural hearing loss.

What is Significance of dizziness and vertigo in the UK?

Major contributors to mobility disabilities (most common UK disability).

80% of unexplained elderly falls due to vestibular dysfunction, costing NHS £1 billion/year.

Top GP visit reason for over-50s.

Degrees of hearing loss by decibel (dB) ranges?

Mild: 25-40 dB

Moderate: 40-55 dB

Moderate-to-Severe: 55-70 dB

Severe: 70-90 dB

Profound: ≥90 dB

How is an audiogram used to assess hearing loss?

Plots frequency (x-axis) vs. hearing loss (y-axis, dB). 0 dB = normal hearing.

Moderate loss due to outer hair cell (OHC) damage; profound loss due to inner hair cell (IHC) damage.

Three types of hearing loss?

1. Conductive: External/middle ear.

2. Sensorineural: Inner ear, auditory nerve, or central processing.

3. Mixed: Both conductive and sensorineural.

Causes of conductive hearing loss?

Ear canal blockage (e.g., earwax), infections, foreign objects, eardrum perforation, or loss of pinna (outer ear) amplification.

Causes of sensorineural hearing loss?

Aging (presbycusis), noise exposure, ototoxic drugs, tumors, or central auditory processing damage

Causes of mixed hearing loss?

Genetics, trauma, or infections affecting both conductive and sensorineural pathways

How to diagnose hearing loss types?

Tuning fork tests distinguish conductive vs. sensorineural loss.

Role of outer hair cells (OHCs) in hearing?

Provide ~40 dB amplification, less innervated, more prone to damage due to more basilar membrane (BM) movement.

Role of inner hair cells (IHCs) in hearing?

Transmit 95% of auditory information to the brain via auditory nerve.

Damage causes severe/profound loss.

What are tip links and their role in hearing loss?

Connect stereocilia to ion channels.

Excessive BM movement (noise, drugs, aging) breaks tip links, disrupting mechanotransduction

What is noise-induced hearing loss (NIHL)?

High-intensity noise (>85 dB) causes excessive BM movement, damaging hair cells, leading to temporary or permanent loss

OSHA guidelines for noise exposure?

Exposure time decreases rapidly above 85 dB.

Hearing protection mandatory in workplaces with noise >85 dB.

How does the decibel scale work?

Logarithmic: 20 dB increase = 10x louder sound intensity.

What is a temporary threshold shift (TTS) in NIHL?

Reversible hearing loss after noise exposure, measurable by audiogram.

What is a permanent threshold shift (PTS) in NIHL?

Irreversible hearing loss, often underlying TTS, due to permanent hair cell or nerve damage

What are the structural changes in mild noise trauma?

Supporting cells buckle, OHCs lose tectorial membrane contact, stereocilia damaged.

What are the changes in higher sound pressure level (SPL) noise trauma?

Stereocilia fracture at rootlets, tip links break, losing mechanotransduction much more long term damage

what are the changes in severe noise trauma?

Cell membrane disruption, rupture of reticular lamina and Reissner's membrane, extensive cochlear damage.

how does tonotopic organization relate to NIHL?

Damage to specific BM regions causes frequency-specific loss (base = high frequencies, apex = low frequencies).

What is hidden hearing loss?

Difficulty hearing in noise due to synaptopathy (loss of auditory nerve fibre synapses with IHCS), despite a normal audiogram.

This is due to the waveform nature of the auditory system, the whole wave may function but there may be underlying damage to the first wave (from the ear to the ANF)

How was hidden hearing loss shown in mice?

Studies showed "temporary" loss on audiograms but permanent damage in auditory brainstem response (ABR) wave 1 (cochlea to auditory nerve).

What is age-related hearing loss (ARHL, presbycusis)?

Progressive, bilateral, symmetrical sensorineural loss, affecting ~25% of 65-75-year-olds, >70% of over-75s.

Social and health impacts of ARHL?

Linked to depression, increased dementia risk, one of four leading chronic conditions in the elderly.

Causes of ARHL?

Insults (noise, ototoxins, smoking, poor diet), genetic predisposition, chronic conditions (e.g., heart disease, diabetes).

How does hair cell loss contribute to ARHL?

OHC loss: ~40 dB loss (reduced amplification, frequency discrimination). IHC loss: permanent loss (no brain communication).

Why is speech recognition impaired in ARHL?

High-frequency consonants (e.g., "f," "s," "ch") lost first, especially in noise, making words like "fat" vs. "sat" hard to distinguish.

Four pathological subtypes of ARHL (Schuknecht)?

1. Sensory: OHC/IHC loss → high-frequency loss.

2. Strial: Stria vascularis thinning → broad, moderate loss.

3. Neural: Auditory nerve fiber loss → broad, severe loss.

4. Mechanical: Affects cochlear mechanics.

What is ototoxicity?

Pharmacological reaction damaging inner ear or auditory nerve, causing cochleotoxicity (hearing loss) or vestibulotoxicity (balance issues).

Signs and symptoms of ototoxicity?

Tinnitus, unilateral/bilateral hearing loss, dizziness, vertigo, oscillopsia (visual instability).

Common ototoxic drugs and their effects?

1. Aminoglycosides (e.g., gentamicin): Permanent high-frequency SNHL, vestibulopathy.

2. Cisplatin: Permanent high-frequency SNHL. 3. Loop diuretics: Sudden SNHL (transient/permanent).

4. Anti-inflammatories (e.g., ibuprofen): Reversible loss.

5. Antimalarials (e.g., quinine): Reversible loss.

Factors increasing ototoxicity risk?

Dose/duration, infusion speed, renal function, concomitant ototoxins, age, pre-existing hearing loss, mitochondrial gene mutations.

How do ototoxins enter the cochlea?

Via stria vascularis capillaries, cleared into endolymph through ion channels/transporters.

How do aminoglycosides cause ototoxicity?

Enter via MET channels, apical cation channels, TRPA1, or endocytosis.

Damage mitochondria → ROS → caspase activation → apoptosis.

How does cisplatin cause ototoxicity?

Enters via membrane diffusion, MET channels, or cation channels.

Causes OHC death → high-frequency SNHL via ROS, inflammation, apoptosis, autophagy, necroptosis.

Difference between necrosis and apoptosis in hair cell death?

Necrosis: Passive, cell swells, membrane ruptures, causes inflammation, uncontrolled cell death

Apoptosis: Active, cell shrinks, DNA fragments, minimal inflammation, pharmaceutical target, controlled by cell cell death

Hair cell death in ototoxicity vs. noise-induced damage?

Ototoxicity: Primarily apoptosis.

Noise-induced: Both apoptosis and necrosis.

Current hearing restoration treatments?

1. Hearing aids: Amplify signal and noise, less effective in noise

.

2. Cochlear implants: Bypass damaged hair cells, effective in children.

3. Auditory brainstem implants: Used when auditory nerve absent.

Why is hair cell regeneration promising?

Non-mammalian vertebrates (e.g., birds, fish) regenerate hair cells, inspiring human research.

How do cold-blooded animals regenerate hair cells?

Add hair cells throughout life via ongoing production.

How do birds regenerate hair cells in the basilar papilla?

No ongoing production but regenerate post-trauma (e.g., 1.5 kHz, 120 dB, 48 hrs), restoring auditory function.

Why don't mammalian cochleae regenerate hair cells?

No regeneration in adult cochlea; permanent SNHL.

Immature cochlea has capacity, lost post-hearing onset.

Regeneration capacity in mammalian vestibular system?

Limited regeneration via phenotypic conversion (not mitosis), but vestibular function poorly characterized.

Three mechanisms of hair cell regeneration?

1. Regeneration via division: Supporting cells divide.

2. Phenotypic conversion: Supporting cells convert to hair cells.

3. Repair: Damaged hair cells (e.g., tip links) repair.

How to test cell cycle entry in regeneration studies?

Markers (e.g., BrdU) detect DNA synthesis in S-phase, indicating supporting cell division.

How was phenotypic conversion demonstrated?

New markers showed hair cell regeneration without cell cycle entry, via supporting cell conversion.

Evidence of tip link repair?

Chick studies showed tip link repair within 24 hours post-drug damage, restoring MET channel function (dye uptake).

How are hair bundles repaired in surviving hair cells?

Bundle-less hair cells regrow bundles, or new bundles grow alongside damaged ones, aiding recovery without proliferation.

Three approaches to human hair cell regeneration?

1. Gene therapy: Induce Atoh1 expression.

2. Pharmacological therapy: Manipulate Notch-Delta signaling.

3. Stem cells: Replace hair cells with pluripotent/multipotent cells.

How does gene therapy target hair cell regeneration?

Uses Atoh1 (master transcription factor for hair cell fate). Overexpression induces ectopic hair cells; absence prevents formation.

How does pharmacological therapy promote regeneration?

Gamma-secretase inhibitors (GSIs) inhibit Notch signaling → reduce Hes genes → increase Atoh1 → promote supporting cell-to-hair cell conversion.

How are stem cells used for regeneration?

Pluripotent (embryonic) or multipotent (adult) stem cells replace hair cells. 3D inner ear organoids mimic developmental pathways to create sensory epithelia.

Challenges of cell replacement therapies in the cochlea?

1. Cochlea inaccessibility.

2. Complex tissue with multiple cell types.

3. Difficulty integrating new cells into compact epithelium.

4. Damage to cochlear homeostasis affecting new cell survival.