Predicting synapse counts in living humans by combining computational models with auditory physiology

Abstract

Aging, noise exposure, and ototoxic medications lead to cochlear synapse loss in animal models. As cochlear function is highly conserved across mammalian species, synaptopathy likely occurs in humans as well. Synaptopathy is predicted to result in perceptual deficits including tinnitus, hyperacusis, and difficulty understanding speechin-noise. The lack of a method for diagnosing synaptopathy in living humans hinders studies designed to determine if noise-induced synaptopathy occurs in humans, identify the perceptual consequences of synaptopathy, or test potential drug treatments. Several physiological measures are sensitive to synaptopathy in animal models including auditory brainstem response (ABR) wave I amplitude. However, it is unclear how to translate these measures to synaptopathy diagnosis in humans. This work demonstrates how a human computational model of the auditory periphery, which can predict ABR waveforms and distortion product otoacoustic emissions (DPOAEs), can be used to predict synaptic loss in individual human participants based on their measured DPOAE levels and ABR wave I amplitudes. Lower predicted synapse numbers were associated with advancing age, higher noise exposure history, increased likelihood of tinnitus, and poorer speech-in-noise perception. These findings demonstrate the utility of this modeling approach in predicting synapse counts from physiological data in individual human subjects.

The Relative and Combined Effects of Noise Exposure and Aging on Auditory Peripheral Neural Deafferentation: A Narrative Review

“…The effect of excessive noise exposure on the amplitude of wave I of young normal-hearing human adults has been inconclusive. Some studies have reported that a smaller amplitude of wave I of the ABR is associated with high noise exposure in young subjects (Stamper and Johnson, 2015a,b;Liberman et al, 2016;Bramhall et al, 2017Bramhall et al, , 2021Valderrama et al, 2018;Buran et al, 2022), while several other studies failed to document such an effect (Grinn et al, 2017;Grose et al, 2017;Prendergast et al, 2017aPrendergast et al, , 2018Skoe and Tufts, 2018;Couth et al, 2020). Table 3 shows a summary of studies that investigated the effect of noise exposure on ABR wave I amplitude in humans.…”

“…After controlling for audiometric threshold loss, ABR wave I amplitude was found to decrease by about 17.8% per decade. Buran et al ( 2022 ) provided a re-analysis of the Bramhall et al ( 2017 ) data ( n = 64; age range: 19–35; summarized in Table 3 ). After the potential confounds of sex and OHC function (as reflected by distortion product otoacoustic emission levels) were accounted for, ABR wave I amplitude measured at 110 dB peSPL was found to decrease by about 6.1% per decade.…”

“…The computational modeling found that OHC loss even slightly increased ABR wave 1 amplitude for stimulus levels above 90 dB peSPL (Verhulst et al, 2018a ). Moreover, Buran et al ( 2022 ) also showed that accounting for cochlear gain loss (based on pure tone thresholds or distortion product otoacoustic emissions) in a computational modeling algorithm had a small effect on synapse predictions generated by the model from the ABR wave I amplitude measurements.…”

Model-based hearing-enhancement strategies for cochlear synaptopathy pathologies

“…Listeners with higher degrees of CS (and hence smaller unprocessed EFR markers) may be those who benefitted less from CS-compensating processing, however this was not clear from the results of our statistical analysis. To this end, diagnostic assessments of the individual degree of CS in each participant [58, 59] could help to explain the individual performance differences between participants with more certainty.…”

“…These markers included envelope-following responses (EFRs), amplitude-modulation (AM) detection sensitivity, and SI in terms of speech reception thresholds (SRTs) and word recognitions scores (WRSs). Because a direct quantification of CS relies on post-mortem imaging of the temporal bone [7, 57], we focussed on older listeners who had been shown to be affected by CS through non-invasive electroencephalographic (EEG) techniques [14, 58, 59].…”