Auditory Neuropathy — Neural and Synaptic Mechanisms

[Juan]

Auditory neuropathy — neural and synaptic mechanisms

Key Points

• Auditory neuropathy impairs speech comprehension severely, beyond the extent that would be expected on the basis of increased threshold of audibility
  
  
• Auditory neuropathy encompasses a range of disease mechanisms that typically disrupt the synaptic encoding and/or neural transmission of auditory information in the cochlea and auditory nerve
  
  
• Auditory synaptopathy, impaired sound encoding at the synapses between inner hair cells and spiral ganglion neurons, results from genetic defects or insults such as exposure to loud noise
  
  
• Advanced physiological and psychophysical testing combined with molecular genetic analysis facilitate diagnostics of auditory synaptopathy and neuropathy
  
  
• Although traditional hearing aids often do not provide substantial benefit for patients with auditory synaptopathy or neuropathy, cochlear implants can provide effective hearing rehabilitation depending on the site(s) of disorder

Abstract
Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they "can hear but cannot understand". This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function — resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca2+ influx, or synaptic vesicle exocytosis — leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

https://www.nature.com/articles/nrneurol.2016.10

 

[GBB]

Auditory neuropathy — neural and synaptic mechanisms

Key Points

• Auditory neuropathy impairs speech comprehension severely, beyond the extent that would be expected on the basis of increased threshold of audibility
  
  
• Auditory neuropathy encompasses a range of disease mechanisms that typically disrupt the synaptic encoding and/or neural transmission of auditory information in the cochlea and auditory nerve
  
  
• Auditory synaptopathy, impaired sound encoding at the synapses between inner hair cells and spiral ganglion neurons, results from genetic defects or insults such as exposure to loud noise
  
  
• Advanced physiological and psychophysical testing combined with molecular genetic analysis facilitate diagnostics of auditory synaptopathy and neuropathy
  
  
• Although traditional hearing aids often do not provide substantial benefit for patients with auditory synaptopathy or neuropathy, cochlear implants can provide effective hearing rehabilitation depending on the site(s) of disorder

Abstract
Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they "can hear but cannot understand". This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function — resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca2+ influx, or synaptic vesicle exocytosis — leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

https://www.nature.com/articles/nrneurol.2016.10

So presumably there is a third type of damage, to the auditory nerve itself, rather than to the hair cells or synapses. I haven't seen any drugs proposed to deal with neuropathy rather than synaptopathy.

 

[weab00]

So presumably there is a third type of damage, to the auditory nerve itself, rather than to the hair cells or synapses. I haven't seen any drugs proposed to deal with neuropathy rather than synaptopathy.

And so the plot thickens :|

 

[Juan]

So presumably there is a third type of damage, to the auditory nerve itself, rather than to the hair cells or synapses. I haven't seen any drugs proposed to deal with neuropathy rather than synaptopathy.

Often ENTs cannot point to the specific area damaged when patients with the same audiogram show very different performance on speech in noise tests.

 

[frpp]

I believe BDNF also helps in the the regeneration of peripheral nerves, so maybe OTO-413 has a chance of fixing that to. Honestly better imaging and tests need to be developed so doctors can actually see and pinpoint what's going on inside the ear, until then everything is a guess worse than throwing at a dartboard blind.

 

[tommyd87]

I believe BDNF also helps in the the regeneration of peripheral nerves, so maybe OTO-413 has a chance of fixing that to. Honestly better imaging and tests need to be developed so doctors can actually see and pinpoint what's going on inside the ear, until then everything is a guess worse than throwing at a dartboard blind.

I though that the nerves got treated through the BDNF use. The current standard of imaging is inept and as a result we will need to probably just throw everything at our treatment in order to achieve a good result. This isn't a bad thing though as I am absolutely positive I could use a hair cell, synapse, and inflammation treatments to deal with my issues too.

 

[serendipity1996]

So presumably there is a third type of damage, to the auditory nerve itself, rather than to the hair cells or synapses. I haven't seen any drugs proposed to deal with neuropathy rather than synaptopathy.

Rinri Therapeutics is working on this. And I am pretty sure that damage to the auditory nerve itself is far more unlikely in cases of NIHL than synaptopathy or hair-cell damage - I think @FGG has mentioned this before.

 

[FGG]

Rinri Therapeutics is working on this. And I am pretty sure that damage to the auditory nerve itself is far more unlikely in cases of NIHL than synaptopathy or hair-cell damage - I think @FGG has mentioned this before.

From everything I have read on this (including the link in this post), "auditory neuropathy" is typically used almost synonymously with "cochlear synaptopathy" because damage to the non synapse portion is rare. Other than direct surgical trauma or cancer (acoustic neuroma), damage is from things like demyelination disorders like MS or GBS.

In those cases, it would be extremely unlikely to only have auditory symptoms (but it's theoretically possible). There are genetic conditions that degrade the nerves, too (e.g., Charcot-Marie-Tooth disease).

True auditory nerve dysfunction, though uncommon, prevents people from being a good cochlear implant patient so there is a lot of research on this. Rinri Therapeutics seems to be the furthest on a treatment for auditory nerve repair, almost no one here will need it though imo.

It gets a little confusing though because a lot of these links refer to synapse damage as "nerve damage" which is technically correct since the synapse is part of the nerve but it makes it seem that there is a wider problem with "nerve damage" the way most people think of it.

 

[Frédéric]

Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold

Tinnitus is a common auditory disease worldwide; it is estimated that more than 10% of all individuals experience this hearing disorder during their lifetime. Tinnitus is sometimes accompanied by hearing loss. However, hearing loss is not acquired in some other tinnitus generations. In this study, we injected adult rats with salicylate sodium (SS) (200 mg/kg/day for 10 days) and found no significant hearing threshold changes at 2, 4, 8, 12, 14, 16, 20, or 24 kHz (all ). Tinnitus was confirmed in the treated rats via Behaviour Testing of Acoustic Startle Response (ASR) and Gap Prepulse Inhibition Test of Acoustic Startle Reflex (GPIAS). A immunostaining study showed that there is significant loss of anti-CtBP2 puncta (a marker of cochlear inner hair cell (HC) ribbon synapses) in treated animals in apical, middle, and basal turns (all ). The ABR wave I amplitudes were significantly reduced at 4, 8, 12, 14, 16, and 20 kHz (all ). No significant losses of outer HCs, inner HCs, or HC cilia were observed (all ). Thus, our study suggests that loss of cochlear inner HC ribbon synapse after SS exposure is a contributor to the development of tinnitus without changing hearing threshold.

Full article: https://www.hindawi.com/journals/np/2020/3949161/

 

[sssing]

A good clip explaining synapses. It's from Catherine Weisz who discovered the role of the type II afferent synapses in the cochlear. She was then a graduate student in Paul Fuchs lab.

 

[sssing]

From everything I have read on this (including the link in this post), "auditory neuropathy" is typically used almost synonymously with "cochlear synaptopathy" because damage to the non synapse portion is rare. Other than direct surgical trauma or cancer (acoustic neuroma), damage is from things like demyelination disorders like MS or GBS.

In those cases, it would be extremely unlikely to only have auditory symptoms (but it's theoretically possible). There are genetic conditions that degrade the nerves, too (e.g., Charcot-Marie-Tooth disease).

True auditory nerve dysfunction, though uncommon, prevents people from being a good cochlear implant patient so there is a lot of research on this. Rinri Therapeutics seems to be the furthest on a treatment for auditory nerve repair, almost no one here will need it though imo.

It gets a little confusing though because a lot of these links refer to synapse damage as "nerve damage" which is technically correct since the synapse is part of the nerve but it makes it seem that there is a wider problem with "nerve damage" the way most people think of it.

From what I saw in that video, correct me if I am wrong, synapses talk to neurons, and then the neurons talk to the nerve?

 

[FGG]

From what I saw in that video, correct me if I am wrong, synapses talk to neurons, and then the neurons talk to the nerve?

Synapses are the connections between neurons. And groups of neurons form nerves.