Auditory System Flashcards
Congential Hearing Loss: General information
Consequences: poor language and behavioural developments, lower literacy and academic achievements
Genetic factors are thought to cause more than 50% of all incidents of congenital hearing loss in children
Currently >100 genes underpinning deafness
Other causes: intrauterine infectons, (German measles, cytomegalovirus, and HSV), prematurity, hypoxia, hyperbilirubinemia, maternal alcohol/drug use
Acquired Hearing Loss: Infection/Inflammation
- The spread of a bacterial or viral infection from the middle ear (otitis media)
- As a direct consequence of infection or tissue injury to the inner ear or hearing nerve
- Meningitis is also a source of inner ear inflammation and results from infection through the CSF
- The inner ear can rapidly mount an inflammatory response which can cause bystander tissue injury. This inflammatory response can damage delicate structures of the inner ear and cause permanent hearing loss. Macrophages and other immune cell release inflammatory cytokines
Most common causes of acquired hearing loss
- Presbyacusis
- Noise trauma
- Ototoxic drugs
Common features of hearing loss pathology
- Hair cells damaged and replaced by scar tissues
- A reduction in density of nerves
- Drugs & Age: Initial loss of basal cells and high frequencies. Noise: frequency-related damage
Effects of noise on the cochlea
Metabolic damange not mechanical unless acute impulse noise
- OHC - clashing of tectorial membrane and OHC causes damage at high noises. Cell death by apoptosis due to oxidative stress
- Spiral ligament - damange to spiral ligament type 4 fibrocytes which are important for recycling of K+. Atrophy of intermediate cells which secrete K+, reduction in endocochlear potential.
- IHC - excessive glutamate causes swelling of spiral ganglion neuron. More resistant to ROS but excessive glutamate causes damange.
- Pillar cells - acute exposure to impulse noise causes buckling and therefore results in collapsing of the organ of corti.
Glutamate excitotoxicity
Excessive release causes swelling of receptor due to water entry, can be repaired but continuous abuse causes entry of Ca2+ through NMDA channels which activates apoptotic and necrotic pathways leading to spiral ganglion neuron death. Generation of ROS and mitochondrial dysfunction
Inflammation from noise exposure
CD45+ inflammatory cells and macrophages and other cells invade through spiral ligament and cause damage.
Oxidative stress and noise-induced hearing loss
Oxidative stress in the cochlea may be a common factor for hearing loss from noise, aminoglycoside antibiotics, ototoxic anticancer drugs and aging.
Free radical are capable of breaking down lipid and protein molecules, damaging DNA and triggering cell death, all of which contribute to the loss of function after noise exposure.
How are ROS/free radicals formed as a result of noise?
During noise exposure, the electron transport chain of the mitochondira uses large amounts of oxygen, which can then create large amounts of superoxide as an unwanted byproduct.
The increased superoxide can then react with other molecules to generate higher levels of ROS in the cochlea
Examples of ROS
Oxygen based molecules that act as free radicals
* Superoxide (O2-)
* Hydroxyl radical
* Perioxynitrite radical (ONOO)
Readily capable of generating free radicals:
* Hydrogen perioxide
* Ozone
Equations of forming ROS
O2 -> to superoxide ions via an enzyme (NADPH oxidase…)
Superoxide can react with NO to form ONOO
Superoxide can form hydrogen peroxide through superoxide mutase and copper (II)
Hydrogen perioxide can undergo fenton reaction to produce hydroxyl free radical.
Hydrogen peroxide can react with catalase and Fe (II) to give water and O2
Apoptosis process - hair cell
Normal -> Cell shrinkage, membrane blebbing -> nuclear fragmentation, chromatin condensation, formation of apoptotic bodies
Necrotic process - hair cell
Normal -> cell swelling -> rupture of plasma membrane, post-lytic DNA fragmentation. Causes inflammatory reaction
Presbyacusis - General information
- A mixture of acquired auditory stresses, trauma and otological diseases superimposed upon an intrinsic, genetically controlled, ageing process
- The loss of hearing sensitivity begins at the highest frequency
- Untreated hearing impairment contributes to social isolation, depression, loss of self-esteem and cognitive decline
Characterised by:
* Reduced hearing sensitivity and speech understanding in noisy environments
* Slowed central processing of acoustic information
* Impaired localisation of sound sources in horizontal plane.
Age-related Cochlear Pathology
Loss of OHC and spiral ganglion neurons
Stria Vascularis - highest impact mainly vascular impact leading to atrophy of SV and decreased secretion of K+
Classification of Presbyacusis
Sensory (outer hair loss)
Neural (neuronal cell loss)
Metabolic (strial atrophy)
Mixed and indeterminate
Sensory presbyacusis related to accumulated environmental noise toxicity, whilst the strial pattern has a high heritability index.
Cochlear aging: animal studies
- Gerbils raised in quiet have just as much or more hearing loss with age than group of noise-related animals - strongly suggesting genetic
- Degeneration of the stria vasularis (marginal and intermediate cells) is the most prominent element
- A loss of Na+,K+ ATPase results in reduced postassium secretion and decline in endocochlear potential (EP)
- Degeneration of the stria vascularis and the resultant decline in EP has given rise to the dead battery theory of presbyacusis
Animal models of presbyacusis
C57BL/6 mouse, early onset hearing loss, ARHL locus (ahl) that contributes to hearing loss in the C57BL/6 mouse has been mapped to chromosome 10. Carries a specific mutation in the cadherin 23 gene, which encodes a component of the hair cell tip-link.
CBA/CaJ mouse, late onset hearing loss. Carries the ahl-resistance gene.
Fisher 344 albino rat - model of sensory ARHL
Mongolian gerbil - model of strial ARHL
Mechanisms of Presbyacusis
Genetic and environment factors
* Reduction of vascularisation in the stria vascularis
* Collagen damage - especially in spiral ligament fibrocytes which affects K+ cycling.
* Cumulative noise exposure - causes repeated oxidative stress causing massive apoptosis and necrosis. MtDNA damage which cant be repaired
* Oxidative stress and apoptosis
Ototoxicity
Two major classes of drugs can cause permanent hearing loss:
* Aminoglycoside antibiotics
* Platinum-based chemotherapeutic agens
Both damage the hair cells in the basal turn of the organ of Corti, spiral ganglion neurons and the lateral wall tissues resulting in functional deficits.
Aminoglycoside ototoxicity
Aminogylcoside antibiotics are used in treatment of TB and serious gram negative bacterial infections such as bacterial endocarditis, UTI and pneumonia.
AG enters and forms complex with Fe. Produces ROS. Activates JNK which leads to transcription of preapoptotic genes which put small holes in the mitochondria, leading to leakage of Cyt C and apoptosis
What type of cancer is cisplatin and carboplatin used to treat and what are complications?
- Testiciular
- Ovarian
- Bladder
- Head and Neck
- Lung
Complications: nephrotoxicity, neurotoxicity and ototoxicity
Cisplatin ototoxicity: General
- High incidence of hearing loss (up to 80%)
- Ototoxicity: tinnitus and bilateral frequency high frequency sensorineural hearing loss
- Involves the production of ROS and depletion of glutathione and antioxidant enzymes (SOD, catalase and glutathione perioxidase) in the cochlea
- Excessive ROS production activates primarily caspase-depedent apoptotic pathways
- Ototoxicity can be ameliorated by protective agents targeting oxidative stress and apoptosis.
Cisplatin Ototoxicity: Mechanism
CP form complex with monohydrated complex (MHC), activation of enzyme NOX-3. Production of ROS and activation of JNK. Transcription of proapoptotic genes. Mitochondira holes, cyt C and apoptosis.
Pharmacological interventions to reduce hearing loss
- Restoring the normal balance of free radical with antioxidants
- Reducing glutamate excitotoxicty with NMDA receptor antagonists
- Maintaining adequate cochlear blood floow during and after noise
- Supressing inflammation
- Inhibiting pathways to apoptotic cell death to preserve hair cells
Free Radical/Antioxidant balance in the cochlea
Increasing cochlear antioxidant supplies can be substantially prevent hair cell damage and hearing loss.
Antioxidant levels can be increaed in two ways:
1. Application of exogenous antioxidant molecules locally or systemically into the body
2. Endogenously by using sound conditioning
Examples of antioxidants
Antioxidants are molecules that scavenge ROS and convert them to less dangerous molecules
Mammals maintain complex system of multiple types of antioxidants such as glutathione, vitamins A, C and E, magnesium as well as enzymes such as catalase, superoxide dismutase and various peroxidases
Effects of Sound conditioning in animals
Conditioned animals with previous exposure to low noise for long periods of time resulted in mich higher antioxidant levels
Experimental therapies: Hair cell regeneration
Gene transfer technology
Replacement of hair cells by stem cells
Atoh1/GFP+ cells show morphological and molecular correlates of innervation and synaptogeneis.
Hereditary Hearing Loss (HHL)
Accounts for about 50% of congenital hearing loss
Over 100 genes underlying HHL
50% of these genes related to sensory hair cells
HHL classification according to the mode of transmission
Autosomal dominant
Autosomal recessive
X-chromosome-linked
DFNB9 Deafness
Inner hair cell synaptopathy
An auditory neuropathy defined as a hearing loss characterised by the absence of auditory brainstem responses with preserved function of the outer hair cells.
Due to a defect in synaptic protein otoferlin expressed in the inner hair cells.
Otoferlin knockout mice key to understanding DFNB9 pathogenesis
Otoferlin - Ca2+ sensor role
It is a presynaptic protein which otoferlin acts as a calcium-sensitive scaffolding protein, localizing SNARE proteins proximal to the calcium channel so as to synchronize calcium influx with membrane fusion. It forms complex with ribbons allowing docking and therefore release
Otoferlin triggers synaptic vesicle-plasma membrane fusion at the IHC ribbon synapse. Degeneration process of the IHC active zone and some afferent neurones likely to take place in DFNB patients. Early cochlear implants expected to be of major help because it bypasses synpase.
Usher syndrome: General information
- USH is a monogenic sensory disability (autosomal recessive transmission)
- Causes sensorineural hearing loss, retinitis pigmentosa and balance problems
- 3-6% of all children who are deaf and another 3-6% of children who are hard-of-hearing have Usher syndrome
- Juvenile age of onset, diffrential degree of hearing loss and balance problems, night blindess and decrease of visual acuity, starts off with periphery moves centrally later.
- Three clinical subtypes; USH I,II and III
- Types 1 and 2 are the most common and account for approximately 90-95% of all causes of children with USH
Further information about Usher subtypes
Diagnosis of Usher syndrome
- Because USH affecs hearing, balance and vision diagnosis includes the evaluation of all three senses
- Eye evaluation: visual field test, retinal examination and electroretinogram (ERG)
- Hearing evaluation: audiometry
- An electronystagmogram (ENG) measures involuntary eye movements that could signifiy and a balance problem
- Early diagnosis of Usher syndrome is very important
Usher syndrome: human and mouse causative genes and encoded proteins
Most of them target sensory hair cells
Hair bundle anomalies appear in the foetus around the time of maturation (USH I and USH II)
The photoreceptors in the retina also affected
Usher Type III: hair cells
not fused upright
downwards fused
damaged cuticular plate
Treatment for Usher syndrome
- Currently, there is no cure for Usher snydrome
- The best strategy involves early identification so that educational programs can begin as soon as possible
- Treatment will include hearing aids, cochlear implants, orientation and independent living trains
- High dose of vitamin A may slow the progression of retinitis pigmentosa
Gap junction defects
- Gap junctions play a key role in K+ cyclking in the cochlea and maintenance of the endocochlear potential (EP)
- Cx26 and Cx30 the main connexins of the cochlear gap junctions forming two major cellular networks: epithelial and connective
- Mutation in connexin 26 (Cx26 or GJB2) and Cx30 (GJB6) the major cause of congenital hearing loss
- Mutations in connexins 29,31 and 32 also cause deafness
Gap junction cellular networks in the cochlea
Connective tissue gap junction system
* Fibrocytes (SL)
* Strial basal and intermediate cells
* Limbal fibrocytes
The epithelial cell gap junction system
* Root cells
* Supporting cells
* Interdental cells
Cx26 defect
- Causative gene for DFNB1 and DFNA3 (a rare dominant form of deafness
- Mutations in Cx26 highly prevalent in caucasian population and account for 30-50% of non-syndromic congenital hearing loss
- A variety of mutations found to be responsible for DFNB1 (35delG point mutation most common)
- Testing Cx26 point mutations is a priority in the molecular diagnosis
- Cx26 and Cx30 located close together on the same chromosome, hence combined point mutations/deletions possible
- Mouse models available
Conditional Cx26 knockout mice
- Affects only epithelial gap junction network in the cochlea
- Moderate hearing impairment
- A significant decrease in endolymphatic K+ concentration
- EP reduced by more than 50%
- Apoptosis in the organ of Corti from P14 onwards
- The absence of Cx26 in the epithelial gap junction network results in a local increase in extracellular K+ concentration in the basal region of hair cells that might be toxic
- Cx30 which co-localises with Cx26 in cochlear gap junctions is not able to compensate for the lack of Cx26.b
Cx30 knockout mice
- Display severe to profound hearing loss
- From P13 onwards show complete lack of EP even before any histological alterations
- Substantial cell death affecting both hair cells and supporting cells
- Hearing function rescued in transgenic mice overexpressing Cx26 on a Cx30 – back ground.
- There seems to be a quantitative rather than qualitative requirement for Cx30 .
Diagnosis of hearing loss caused by mutations in the Cx26 gene
- Hearing loss found at birth or in early childhood
- Hearing loss mild,moderate, severe or profound
- Hearing loss without any other medical problem (non-syndromic_
- Hearing loss without obvious cause
Testing for Cx26 mutations:
* Identify the cause of hearing loss
* Excluse a syndromic form of hearing loss
* Predict the prognosis of hearing loss
Vestibular disorders: General information
- Symptoms can result from a peripheral or central vestibular disorder
- Common symptoms: dizziness, vertigo and disequillibrium
- The main causes of vertigo are benign paroxysmal positional vertigo, Menieres disease, vestibular neuritis and labyrinthitis
Meniere’s disease: General information
Defined by the association of four symptoms
* Vertigo attacks
* Fluctuating hearing loss
* Tinnitus
* Auricular plenitude sensation (fulness in the ear)
Other symptoms include
* Diarrhea
* Headaches
* Pain or discomfort in the abdomen
* Nausea and vomiting
* Nystagmus (uncontrollable eye movments)
Meniere’s disease: Pathophysiology
Distention of membranous labyrith by the endolym known as endolymphatic hydrops
Meniere’s disease: Animal studies
- Obliteration of the endolymphatic sac in the guinea pig consistently produces endolymphatic hydrops
- The findings shows cytochemical and ultrastructural lesions affecting the fibrocytes within the spiral ligmanet, hair cells and cochlear neurons.
- These changes occured before the develpoment of hydrops.
- Type 1 and 2 fibrocytes of the spiral ligmanet are the most severely affected cochlear cells
- Type 1 fibrocytes before hydrops showed increased immunostainings for the NAK2Cl cotransporter, decreased immunostaining for C-Jun-N-terminal kinase (JNK)
- NKCC1 is involved in regulation of cellular volume in response to osmotic stress
- Changes reflect compensatory mechanisms for regulation of cell volume
- JNK is known to be a critical player in many forms of cellular stress responses. The decrease in staining for JNK indicates that the fibrocytes are under stress.
Tympanometry
- Air pressure is varied positive and negative relative to atmospheric and effects of air presure changes on how sound is transmitted through middle ear is measured
- Tympanogram is graphic represenation of how sound travels through middle ear as a function of ear canal pressure
- When ear drum is working well: little to no reflection
- When ear drum not working well: lot of reflection
- Also measures space: if ear drum perforated then lots of space
Components of an acoustic immitance instrument
- Sound source that generates a low frequency (usually 226 or 660 Hz) pure tone
- Microphone that measures the reflected sound wave
- Air pump and manometer which varies the air pressure within the ear canal
Compliance curve: Type Ad
Floppy, dislocation of middle ear bones?
Compliance curve: Type A
Normal
Compliance curve: Type B
Fluid behind tympanic membrane so cannot move
Compliance curve: Type C
Negative pressure - pulling in from middle ear
Can result from cold
Precursor to type B curve
Compliance curve: Type As
Something to do with middle ear bones. Otosclerosis. Cochlea become occified. Often seen in pregnant woman due to hormonal changes
Audiogram curve: Sloping Audiogram
Most common: lose high frequency hearing loss, aging or noise exposure. “Speech banana”
Audiogram curve: Cookie-Bite Audiogram
Congenital hearing loss
Audiogram curve: Flat Audiogram
Uncommon
Audiogram curve: Reverse-Slope Audiogram
Meniere’s disease - balance problems, hearing fluctuates
Audiogram curve: Tent-shaped Audiogram
Opposite of Cookie-Bite Audiogram
Audiogram curve: Corner Audiogram
Progressive congenital hearing loss, candidate for bionic ear or cochlea implant.
Three types of Hearing Loss
Conductive hearing loss, sensorineural hearing loss, mixed hearing loss
Conductive hearing loss
Bone conduction better than air conduction
Sensorineural hearing loss
Bone conduction = air conduction
Mixed hearing hearing loss
Decrease bone and air conduction
Mixed hearing loss
Decrease bone and air conduction
Sensorineural hearing impairment resulsts in:
Hearing impairment: not simply a loss of sensitivty of the cochlea but strongly altered signal processing capabilities
Components:
* loss of audibility
* loss of frequency resolution - lose OHC tuning
* loss of compressive signal processing due to loss of outer hair cells
Psychoacoustics
Broadened auditory filters - inability to resolve sounds
Loudness growth - recruitment, compression of range
Perceptual consequences of hearing loss
- Highly specialised mechanisms for signal analysis are strongly degraded
- Mechanisms for separating sounds are missing
- Speech intelligibility especially in noise is degraded
How does a cochlea implant work?
- External speech processor captures sound and converts it to digital signals
- Processor sends digitial signals to internal implants
- Internal implant turns signals into electrical energy, sending it to an array inside the cochlea
- Electrodes stimulate hearing nerve, bypassing damaged hair cells and the brain perceives signals, you hear sound.
Tinnitus definition
Perception of sound when there is no sound, theres no sound waving coming into the ear
Objective tinnitus
Sound is coming from the body, clicking from palate, blood flow, eustachian tube etc
Tinnitus disorder
Perception of sound has an impact on person’s daily life
Male with tinnitus: associations
Hearing loss
Females with tinnitus: associations
Hearing loss, Insomnia, Dizziness & Vertigo (hormones)
65+ with tinnitus: associations
Memory problems, dizziness & vertigo, hearing loss, insomnia, vision problems
Neural differences after general hearing loss
Cochlear nucleus and inferior colliculus increase in intensity after hearing loss
Current treatments to tinnitus
Counselling - remove fear aound tinnitus, lifestyle changes, attention control, sensory management, perceptual training, adaptation
Hearing aids - reducing contrast of background noise, hearing loss like being put into a soundproof room so becomes detrimental
Masking - play another nicer sound
Tinnitus: Emerging treatments
OTO-313
NMDA receptor antagonists
Brain stimulation - retraining with a patterened sound. Vagus and Tragus nerve have an impact on plasticity so hopefully can change underlying representation of tinnitus.
Tactile trigeminal nerve stimulation through tongue
Somatosensory stimulation through stimulation of nerves in neck
Tinnitus: On going research
Metabolomics: Correlate metabolic changes with clinical characteristics of tinnitus and/or tinnitus-related distress. Identify tinnitus-causing metabolic networks. Develop personalized treatment targeting affected networks.
Tinnitus: Precision Sound Therapy
Patient undergoes a clinic-based psycoacoustic and psychometric hearing and tinnitus assesment. An customized profule using AI is established using the clinician dashboard and fitting algorithms according to the patient’s needs and tinnitus assesment. Therapy is download to user’s smartphone.
AI can predict who will and won’t respond based on EEG.
