Uh Oh! Here Comes Noise-Induced Cochlear Synaptopathy …And It Just May Up-End Everything We Know About Hearing Conservation

Uh Oh! Here Comes Noise-Induced Cochlear Synaptopathy …And It Just May Up-End Everything We Know About Hearing Conservation

For several decades damage from noise-induced hearing loss has been monitored using threshold sensitivity measurements recorded on the conventional pure tone audiogram; and more recently, measuring damage to the delicate outer hair cells in the cochlea using otoacoustic emissions. However, new research into noise-induced cochlear synaptopathy — which by insideously causing auditory dys-synchrony places it squarely in the auditory neuropathy spectrum disorder (ANSD) “spectrum” — threatens to up-end everything we know about noise-induced hearing loss measurement and treatment due to the temporal resolution damage it silently causes to speech discrimination, while barely affecting threshold measurements. In an upcoming article, we’ll lay out how this new information affects the diagnostic tools the clinician uses, and the technologies recommended.

Noise-induced cochlear synaptopathy is the loss of neural firing synchrony causing loss of temporal resolution at the dorsal cochlear nucleus because of excitotoxic synaptic damage at the inner hair cell — spiral ganglion synapse, with subsequent gradual neural degeneration occurring, adversely affecting fine speech structure decoding hence speech perception, especially in noise.1 And Yes, this puts this form of noise-induced hearing damage squarely inside the ANSD “spectrum” (called until 2008 auditory neuropathy/dys-synchrony (AN/AD)).2 Now at this point, your eyeballs are probably starting to glaze over and you’re wondering what this all means.

Harvard Medical School professor Sharon G Kujawa writes in Putting the ‘Neural’ Back in Sensorineural Hearing Loss:1A, 1B

…Recent work in noise and aging, however, has revealed a much more insidious process that progressively interrupts [synaptic] communication between sensory hair cells and auditory neurons, ultimately leading to death of the neurons themselves. These neurodegenerative changes are likely very common, occurring even in ears with normal threshold sensitivity and a full complement of hair cells [Emphasis added]. As a result, they challenge our traditional approaches to diagnosis and management.

The inner hair cell–cochlear nerve fiber synapse is the primary conduit through which information about the acoustic environment is transmitted to the auditory nervous system. In ears that age normally—without noise exposure, for example—synapses are lost gradually throughout life. Such losses are seen in the cochlea long before the age-related decline of threshold sensitivity or hair cells.3

Figure 1 from Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment, by Tobias Moser, Friederike Predoehl, and Arnold Starr (2013) Hair cell ribbon synapse-molecules affected in genetic auditory synaptopathies: A: Physiology-based classification of sensorineural hearing loss. Defects or loss of outer hair cells (OHC) disrupt cochlear amplification, defects or loss of inner hair cells (IHC) or their synapses disrupt synaptic encoding of sound, defects or loss of spiral ganglion neurons (SGN) disrupt encoding and/or conduction of auditory information. Defects of cochlear electrolyte homeostasis or mechanoelectrical transduction cause global dysfunction. B: Normaski image of the mouse organ of Corti with hair bundles of IHCs and schematic representation of a patch-clamped IHC and one of its ribbon synapses. Inset: model of a normal mouse IHC ribbon synapse obtained from electron tomography.

Figure 1 from Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment, by Moser, Predoehl, and Starr. 7
Click to enlarge in a new window.

Noise produces similar, but immediate, synaptic losses and then accelerates aging, even for exposures that produce reversible threshold shifts and no hair cell loss.4, 5A, 5B

A good way of looking at what happens to the neural firing synchrony is to relate it to signal jitter;6A or a bit more closely, cyclic phase jitter,6B which is “rapid, repeated phase perturbations that result in the intermittent shortening or lengthening of signal elements,” which in the case of cochlear synaptopathy is lengthening only, as you can see in the grey arrows, which yield a lower and longer action potential (AP) on the electrocochleogram (ECochG), and hence ABR wave I:

Figure 2 from Perspectives on Auditory Neuropathy: Disorders of Inner Hair Cell, Auditory Nerve, and Their Synapse: A representation of the patterns of activity of afferent auditory nerve fibers with synaptic connections to an inner hair cell. The onset of a transient stimulus is indicated by the vertical line below. The occurrence of fiber activity in a normally functioning system is represented by black arrows while fiber activity in an abnormal system is represented by gray arrows. The patterns of activity in the two conditions are shown below. The abnormalities of fiber activity that are represented include (a) variable delay in the latency of discharge and (b) absence of a response in 30%of the fibers. Note the short latency and synchrony of the population’s response when the system is normal and the delayed latency, temporal dispersion, and reduced amplitude of the population’s response when the system is abnormal. We suggest that the pattern of abnormality of activity would be similar whether the disorder were at inner hair cell, the synapse including neurotransmitter release, reuptake and binding to receptor sites, or in the nerve fibers. However, the extent of latency delay and variability as well as in the proportion of fibers that are activated would vary according to the type and extent of the pathological processes.

Figure 2 from Perspectives on Auditory Neuropathy: Disorders of Inner Hair Cell, Auditory Nerve, and Their Synapse:7 A representation of the patterns of activity of afferent auditory nerve fibers with synaptic connections to an inner hair cell. The onset of a transient stimulus is indicated by the vertical line below. The occurrence of fiber activity in a normally functioning system is represented by black arrows while fiber activity in an abnormal system is represented by gray arrows. The patterns of activity in the two conditions are shown below. The abnormalities of fiber activity that are represented include (a) variable delay in the latency of discharge and (b) absence of a response in 30%of the fibers. Note the short latency and synchrony of the population’s response when the system is normal and the delayed latency, temporal dispersion, and reduced amplitude of the population’s response when the system is abnormal. We suggest that the pattern of abnormality of activity would be similar whether the disorder were at inner hair cell, the synapse including neurotransmitter release, reuptake and binding to receptor sites, or in the nerve fibers. However, the extent of latency delay and variability as well as in the proportion of fibers that are activated would vary according to the type and extent of the pathological processes.

The questions for researchers to answer become:

  • What exactly does this noise-induced cyclic phase jitter sound like;
  • What is the demonstrable effect on speech perception in quiet and in noise;
  • And, how do we measure it?

On this last item, in private correspondence between your humble editor, Prof Kujawa, and our friend Prof Brian CJ Moore at Cambridge, synaptopathic damage that occurs not severe enough to appear on the pure tone audiogram may still be detected on the threshold equivalent noise (TEN) test, but only at a level of TEN thresholds elevated by maybe 5 dB; and importantly, below the 10 dB elevation to diagnose a cochlear dead zone.

Professor Kujawa sounds the alarm in her final 3 paragraphs:

These sobering findings have important implications for public health. One question is, once an ear has been exposed to noise, can the noise insult influence future changes in the ear and hearing, such as those that accrue with age?

Traditionally, the focus has been on thresholds, and an absence of delayed threshold shifts after exposure has been taken as evidence that noise effects will not occur later. Recent work using powerful new tools provides clear evidence that delayed effects can happen, though.

The current goal of federal noise exposure guidelines aims to protect against permanent threshold shifts, assuming that reversible threshold shifts are associated with cochlear recovery and a safe exposure. Accumulating evidence suggests that this assumption is unwarranted.

In order to clarify what damage occurs where and the effects, we have taken Figure 1A from Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment 7 and annotated it:

For more on the “nuts and bolts” please see Perspectives on Auditory Neuropathy: Disorders of Inner Hair Cell, Auditory Nerve, and Their Synapse.7

Also, from Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment:8

Abstract/Objective: To review new insights into the pathophysiology of sensorineural hearing impairment. Specifically, we address defects of the ribbon synapses between inner hair cells and spiral ganglion neurons that cause auditory synaptopathy.

Noise-Induced and Age-Related Hearing Loss
Recent findings indicate that cochlear synaptic mechanisms may contribute to these 2 most common forms of hearing impairment. Changes in synapse number and structure have been implied in noise-induced and age-dependent hearing loss. Interestingly, a human association study suggests polymorphisms in the gene coding for the metabotropic glutamate receptor mGluR7 to contribute to susceptibility for age-dependent hearing loss. Excitotoxic synaptic and neural damage is a key candidate mechanism for noise-induced and age-dependent hearing loss (Fig. 5A). It may result from excessive presynaptic release of glutamate, which has long been discussed for noise-induced hearing loss (see below) and has recently been implied for a human progressive hearing loss caused by mutations in the gene GIPC3. Susceptibility to excitotoxic damage could also arise from abnormally high numbers or sensitivity of postsynaptic glutamate receptors, alterations of efferent innervation and from interference with glutamate uptake, 5  but the relevance of these mechanisms for human disease has not yet been demonstrated.

Excitotoxic synaptic damage due to excessive presynaptic release of glutamate has long been indicated to contribute to noise-induced hearing loss. Immunohistochemical quantification of ribbon synapse number has now been used to establish the loss of ribbon synapses during noise exposures. Strikingly, even noise exposures that caused only temporary threshold loss were accompanied by a permanent loss of approximately 50% of the hair cell synapses and subsequent slow degeneration of spiral ganglion neurons in the high frequency region of the cochlea (Fig. 5C, D, F, G). The morphologic damage was reflected by a reduced spiral ganglion compound action potential. Measured as Jewett wave I of the auditory brainstem responses, a permanent reduction was found (Fig. 5E), despite full recovery of the physiologic threshold (Fig. 5B). One possible hypothesis explaining this discrepancy of functional findings is that the noise-induced insult hits the low-sensitivity spiral ganglion neurons, which signal loud sounds, but spares the high-sensitivity neurons, which are responsible for sound perception near threshold. This hypothesis can well explain the finding of poor speech recognition in noisy background. Not surprisingly synaptic insult occurs also during noise exposures that cause a permanent threshold increase.5

FIGURE 5: Excitotoxic irreversible loss of IHC ribbon synapses during noise-induced temporary threshold loss. A, Cartoon illustrating excitotoxic synaptic insult: loud noise induces excessive presynaptic glutamate release that causes overexcitation and massive sodium influx into the postsynaptic terminal of the SGN. The ensuing osmotic load causes swelling and finally disruption of the terminal. Work by Kujawa and Liberman (2009) in animals suggests that the SGN do not re-establish synaptic connections with IHCs after the insult and are finally lost. B, Induction and recovery of ABR threshold loss following a 100 dB octave band noise for 2 h. C, Irreversible loss of half of the synaptic ribbons in high-frequency IHCs in the same mice, despite threshold recovery after 2 weeks. D, Representative projections of confocal images of the immunolabeled IHC ribbons in control and noise-exposed mice: reduction of ribbon number. Long-term percentage reduction of (E) the amplitude of ABR wave 1 reflecting the loss of synchronously firing SGN, (F) ribbon synapse number in high frequency IHCs and (G) SGN somata: simultaneous loss of synapses and synchronously firing neurons, delayed physical loss of SGN. (B-G) were taken with permission from Kujawa and Liberman, J Neurosci 2009.

FIGURE 5: Excitotoxic irreversible loss of IHC ribbon synapses during noise-induced temporary threshold loss. A, Cartoon illustrating excitotoxic synaptic insult: loud noise induces excessive presynaptic glutamate release that causes overexcitation and massive sodium influx into the postsynaptic terminal of the SGN. The ensuing osmotic load causes swelling and finally disruption of the terminal. Work by Kujawa and Liberman (2009) in animals suggests that the SGN do not re-establish synaptic connections with IHCs after the insult and are finally lost. B, Induction and recovery of ABR threshold loss following a 100 dB octave band noise for 2 h. C, Irreversible loss of half of the synaptic ribbons in high-frequency IHCs in the same mice, despite threshold recovery after 2 weeks. D, Representative projections of confocal images of the immunolabeled IHC ribbons in control and noise-exposed mice: reduction of ribbon number. Long-term percentage reduction of (E) the amplitude of ABR wave 1 reflecting the loss of synchronously firing SGN, (F) ribbon synapse number in high frequency IHCs and (G) SGN somata: simultaneous loss of synapses and synchronously firing neurons, delayed physical loss of SGN. (B-G) were taken with permission from Kujawa and Liberman, J Neurosci 2009.

Current research aims to understand the presynaptic and postsynaptic changes that occur during noise damage. Moreover, studies explore the reasons why excitotoxic synapse loss is not followed by de novo synapse formation during the weeks after the insult when the disconnected inner hair cells and spiral ganglion neurons are still present. The extent, irreversibility, and functional consequences of excitotoxic synapse loss had not yet appreciated and now require studies of the relevance of this disease mechanism for human noise-induced hearing loss. If comparable to the animal findings, which is likely the case, noise exposure is much more dangerous than we have assumed. We will then have to acknowledge that noise induces synapse and progressive neuron loss and thereby impairs speech reception in noisy environments. We will need to revise noise exposure guidelines, diagnostic procedures and clinical evaluation of occupational hearing loss. In summary, excitotoxic synaptic damage is likely a disease mechanism of noise induced and possibly also of age-dependent hearing loss.

To cap it off, authors Predoehl, Moser, and Starr conclude on the first page:

Abstract/Conclusion: Hair cell ribbon synapses are highly specialized to enable indefatigable sound encoding with utmost temporal precision. Their dysfunctions, which we term auditory synaptopathies, impair audibility of sounds to varying degrees but commonly affect neural encoding of acoustic temporal cues essential for speech comprehension. Clinical features of auditory synaptopathies are similar to those accompanying auditory neuropathy, a group of genetic and acquired disorders of spiral ganglion neurons. Genetic auditory synaptopathies include alterations of glutamate loading of synaptic vesicles, synaptic Ca influx or synaptic vesicle turnover. Acquired synaptopathies include noise-induced hearing loss because of excitotoxic synaptic damage and subsequent gradual neural degeneration. [Emphasis added] Alterations of ribbon synapses likely also contribute to age-related hearing loss.

Last Minute Addendum:

Jolene OHSU

Click the picture to see Jolene Ohsu‘s important contribution to hearing conservation education

Connecting The Dots: As our loyal readers know well, we at The Hearing Blog are Big Fans of FM assistive listening systems. [Balance of this section deleted June 14, 2015.]

References:

  1. A: Putting the ‘Neural’ Back in Sensorineural Hearing Loss, by Sharon G Kujawa PhD; The Hearing Journal: November 2014 – Volume 67 – Issue 11 – p 8; doi: 10.1097/01.HJ.0000457006.94307.97 | Mirror copy
    B: AudiologyOnline recorded course #25214: Putting the ‘Neural’ Back in Sensorineural: Cochlear Neurodegeneration in Noise and Aging, presented in partnership with American Auditory Society;
  2. Management of Individuals with Auditory Neuropathy Spectrum Disorder, by Charles Berlin PhD (2008; Lake Como Conference proceedings. | Mirror copy
  3. Age-Related Cochlear Synaptopathy: An Early-Onset Contributor to Auditory Functional Decline, by Yevgeniya Sergeyenko, Kumud Lal, M Charles Liberman, and Sharon G Kujawa; The Journal of Neuroscience, 21 August 2013, 33(34): 13686-13694; doi: 10.1523/JNEUROSCI.1783-13.2013. | Mirror copy
  4. Acceleration of Age-Related Hearing Loss by Early Noise Exposure: Evidence of a Misspent Youth, by Sharon G Kujawa, and  M Charles Liberman; The Journal of Neuroscience, 15 February 2006; 26(7): 2115-2123; doi: 10.1523/JNEUROSCI.4985-05.2006 | Mirror copy
  5. A: Adding Insult to Injury: Cochlear Nerve Degeneration after “Temporary” Noise-Induced Hearing Loss, by Sharon G Kujawa, and  M Charles Liberman; The Journal of Neuroscience, 11 November 2009,  29(45): 14077-14085; doi: 10.1523/JNEUROSCI.2845-09.2009 | Mirror copy of article
    B: Mirror copy of Supplemental Data
  6. A: Definition of jitter
    B: Definition of phase jitter
  7. Perspectives on Auditory Neuropathy: Disorders of Inner Hair Cell, Auditory Nerve, and Their Synapse, by Arnold Starr, Fan-Gang Zeng, H J Michalewski, and Tobias Moser (2008) | Mirror copy
  8. Review of Hair Cell Synapse Defects in Sensorineural Hearing Impairment, by Tobias Moser, Friederike Predoehl, and Arnold Starr (2013) | Mirror copy

Bootnotes:

 

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About the author

Dan Schwartz

Electrical Engineer, via Georgia Tech

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