Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects

Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans. Author summary Hidden hearing loss (HHL) is an auditory disorder caused by noise exposure, aging or peripheral neuropathy. It is named 'hidden' because it does not affect hearing thresholds, but deficits are observed in sound-evoked auditory nerve activity. Studies on animal models suggest two possible pathogenic mechanisms for HHL: (1) loss of synapses between inner hair cells and auditory nerve fibers, and (2) disruption of auditory-nerve myelin. In this study, we constructed a computational model of sound-evoked auditory nerve fiber activity to understand how each of these mechanisms affects nerve compound action potentials. We show that disruption of auditory-nerve myelin desynchronizes sound-evoked auditory neuron spiking, decreasing the amplitude and increasing the latency of the compound action potential. In addition, elongation of the initial axon segment may cause spike generation failure leading to decreased spiking probability. In contrast, synapse loss only decreases the probability of firing, thus reducing the compound action potential amplitude without disturbing its latency. This model, which accurately represents in vivo findings on HHL in the first stages of auditory processing, can be useful to analyze the consequences of synaptopathy and myelinopathy on downstream sound processing and perceptual deficits.

Automated summary

Hidden hearing loss (HHL) is an auditory disorder characterized by deficits in sound-evoked auditory nerve activity, despite normal hearing thresholds, caused by mechanisms such as loss of IHC synapses or disruption of auditory-nerve myelin. Computational models have shown that disruptions in myelinization desynchronize auditory neuron spiking, whereas synapse loss decreases firing probability, ultimately leading to reduced auditory nerve activity and perceptual deficits.