Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects

Abstract

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.

Binaural Processing Deficits Due to Synaptopathy and Myelin Defects

“…This outcome is in agreement with both experimental studies on animal models ( Kujawa and Liberman, 2009 ; Sergeyenko et al, 2013 ; Wan and Corfas, 2017 ) and our computational study of SGN fibers suggesting that myelin defects in SGN fibers or loss of IHC-SGN synapses cause a drop in cumulative SGN activity ( Budak et al, 2021 ). Decreased SGN activity leads to smaller numbers of input spikes to the cochlear nucleus, thus significantly decreasing spike rates of SBCs, GBCs and finally MSO cells as well ( Figures 2A–C ).…”

“…We prescribed SGN myelinopathy levels (see also Budak et al, 2021 ) by varying the length of the initial unmyelinated segment L u , such that 0% variation represents a homogeneous population of SGN fibers whose L u is 10 μm (putative control condition), whereas 100% variation stands for a heterogeneous SGN population where L u ’s vary between 10 and 20 μm.…”

“… Cochlear nucleus circuit model containing spiral ganglion neurons (SGNs), spherical bushy cells (SBCs), globular bushy cells (GBCs), and medial superior olives (MSOs) of both sides. Sound stimuli trigger release events at inner hair cell (IHC)-SGN synapses that stimulate SGN fibers as described in Budak et al (2021) . SGNs then relay the signal to the ipsilateral SBCs and GBCs in the cochlear nucleus.…”

“…To test this hypothesis, we constructed a network model of binaural auditory processing from the periphery to the MSO. We employed the computational model from Budak et al (2021) to simulate the response of SGN fibers to sound stimuli under conditions simulating either myelin defects at SGN heminodes or synapse loss at inner hair cell (IHC)-SGN synapses, since animal studies suggested that myelinopathy in the SGN heminodes ( Wan and Corfas, 2017 ) and synaptopathy at IHC-SGN synapses ( Kujawa and Liberman, 2009 ; Furman et al, 2013 ; Sergeyenko et al, 2013 ; Viana et al, 2015 ; Gleich et al, 2016 ; Valero et al, 2017 ) result in HHL. We additionally simulated the activity of SBC and GBC populations, and their projections to MSO populations.…”

Intracranial lateralization bias observed in the presence of symmetrical hearing thresholds

“…and an imbalanced perception of diotic suprathreshold stimuli. One could even speculate that the biases represent asymmetric presentations of “hidden” hearing loss ( Budak et al , 2021 ).…”