Cross-species experiments reveal less recognized form of hearing loss may be prevalent

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It has long been known that hearing loss (for example, due to overexposure to noise and/or aging) can significantly limit the communication abilities of sufferers, especially in noisy listening environments such as restaurants, busy streets and sports venues. Hearing loss, which is clinically diagnosed as a reduced ability to detect (i.e. hear) quiet sounds, is conventionally thought to result from damage to the sensory cells (hair cells) of the cochlea (ear internal). While this type of sensory loss is certainly an important component of hearing loss, recent data from animal studies show that damage from noise exposure and aging can also affect the neural connections that carry information from inner ear to the brain. Strikingly, animal data show that this form of neural loss (aka cochlear synaptopathy) can occur permanently even when the sensory dysfunction is only temporary (i.e., no permanent loss of cells ciliates)! Additionally, animal data suggest that cochlear synaptopathy may occur in response to sound exposures of intensities common in many occupational and recreational settings, and at younger ages than would conventionally be expected to be lost. auditory sets in! This raises the possibility that certain familiar experiences, such as ringing and muffled perception temporarily Attending a loud rock concert or sporting event may not be as harmless as we once thought, and middle-aged people with clinically normal hearing could also have cochlear synaptopathy. Because neural loss without sensory loss cannot be detected with standard clinical audiometry, whether such damage occurs in humans is hotly debated. In our recent article by Communications Biology (Bharadwaj et al., 2022), we addressed this debate through coordinated experiments in at-risk human groups and a wild-type chinchilla model. Results from our animal and human laboratory studies, in addition to retrospective analyzes of human clinical data, suggest that cochlear neural damage is, in fact, widespread even in populations with clinically normal hearing!

Based on previous work, we have selected two non-invasive measurements/tests that can potentially reveal cochlear synaptopathy. First of all, we wanted to establish that these measures are indeed sensitive to cochlear neural lesions. To do this, we exposed a genetically heterogeneous (wild-type) cohort of chinchillas to moderate-level noise in a pre-post design. Exposure to octave band noise in this animal model causes temporary hearing loss (similar to after a rock concert), but long-lasting loss of cochlear synapses (as seen in the confocal images in Fig. 1, where the synapses under the inner hair cells are labeled as bright green dots). Quantitative analyzes of confocal imaging reveal cochlear synaptopathy in a wide cochlear region (1-10 kHz) following noise exposure.

Figure 1. Confocal imaging and quantification of cochlear nerve loss in chinchillas following exposure to moderate noise levels.

In this controlled chinchilla model of cochlear synaptopathy, we recorded our noninvasive tests. Specifically, we measured the strength of the broad-band middle ear muscle reflex (WB-MEMR), a feedback circuit in the auditory pathway that acts to provide some protection to the ear against loud sounds. We observed (see left panel of Fig. 2) a large sustained reduction (>50%) in WB-MEMR amplitudes (and increased thresholds, not shown here). We also observed reduced suprathreshold auditory brainstem response (ABR) amplitudes, but this effect was less robust than WB-MEMR reductions in chinchilla (not shown here). These data from chinchillas show that WB-MEMR is indeed a very sensitive measure of cochlear synaptopathy, even in the presence of many extraneous sources of variance between individual animals (e.g., due to genetic variability).

Figure 2. Broadband middle ear muscle reflex (WB-MEMR) measurements showing significant reductions after moderate noise exposure in chinchillas (left) and reduced strength in human groups at increased risk for synaptopathy (to the right).

With the sensitivity of noninvasive measurements confirmed in chinchillas, we used them to test whether cochlear synaptopathy occurs in humans. We studied three groups of human subjects with normal hearing (as measured by standard clinical audiometry) with varying age and noise exposure. Our young control group (YCtrl) had clinically normal hearing and limited noise exposure, our young exposed group (YExp) also had matching clinical hearing status but reported regular exposure to loud sounds (e.g., marching bands or shooting clubs), and our middle-aged (MA) group had clinically matched hearing but were 35-60 years old. Interestingly, our YExp and MA groups both showed reduced WB-MEMR and ABR amplitudes compared to the YCtrl group despite all groups having “normal” and matched hearing. hearing as measured audiologically (Fig. 2, right). Our results suggest a substantial degree of cochlear synaptopathy in middle-aged humans with normal hearing, similar to our chinchilla model and previous indications from human postmortem data. The exposed youth group on this hand showed signs of more subtle damage.

Finally, we also analyzed data from a large, publicly available repository of audiological measurements from the NHANES 2012 repository. From this large repository, we carefully sub-selected N = 1885 individuals who had clinically normal audiograms (15 dB HL or better at 8 kHz). Yet this big data analysis revealed a clear and steady decline in MEMR amplitude with age (see Fig. 3)! This analysis of a large independent public dataset, along with our additional measurements using clinical equipment (not shown here), corroborated the patterns revealed by our targeted cross-species experiments.

Figure 3. Analysis of a large public dataset showing a consistent decrease in middle ear muscle reflex strength with age despite clinically normal hearing.

Taken together, our results suggest that humans are susceptible to cochlear synaptopathy due to noise exposure, and in particular normal aging. Our data suggest that such damage may in fact be widespread even in people with good hearing status by current clinical criteria! Although not tested in this study, an additional implication is that such cochlear neural loss would likely also accompany conventionally recognized forms of hearing loss (i.e., in the search for noninvasive measurements that may reveal cochlear synaptopathy, our results also show that WB-MEMR shows promise The WB-MEMR test is likely to be available for wide clinical use in the near future and therefore the measurement may be appropriate for use in clinical trials of therapeutic drugs for restore cochlear neural connections, both for candidate selection and as an outcome measure. Finally, although this cochlear synaptopathy does not affect our ability to detect quiet sounds (i.e. it is reasonable to expect that this “hidden hearing loss” may contribute to suprathreshold perceptual deficits; that is to say, it perhaps contributes to the experience of being able to listen But no to understand speech in noisy environments. The The WB-MEMR test will also aid us in our efforts to understand if, how, and under what conditions, cochlear synaptopathy affects auditory perception and day-to-day communication.

The full article can be found at https://www.nature.com/articles/s42003-022-03691-4. Human and chinchilla data for this study can be obtained from https://github.com/haribharadwaj/CommunBiol_CrossSpecies_Synaptopathy and are permanently archived using Zenodo https://doi.org/10.5281/zenodo.6672827.

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