Appendix II. Summary of studies of hidden hearing loss and cochlear synaptopathy involving humans.

Author(s) (year) Study Design	Question	Participant characteristics	Noise protocol	Test protocol	Outcome
Bramhall et al (2017) 23	Are higher lifetime noise exposure histories in young adults with normal pure-tone thresholds associated with lower ABR wave I amplitudes?	19–35 years of age Pure-tone thresholds of ≤20 dB HL from 0.25–8 kHz 29 veterans 35 nonveterans Assigned to one of four groups based on reported noise exposure and veteran status 11 veterans with high noise exposure 7 veterans with low noise exposure	Questionnaire: Lifetime Exposure of Noise and Solvents Questionnaire (LENS-Q) Interview	ABR Stimulus type : tone burst at 1, 3, 4, and 6 kHz Stimulus amplitude : @ 1 kHz—70, 80, 90, 100, 110 dB p-peSPL @4 kHz—60, 70, 80, 90, 100, 110 dB p-peSPL @ 6 kHz—110 dB p-peSPL Stimulus rate : 11.1 Hz Stimulus polarity : alternating Repetitions : 1,024 presentations for two replications Stimulus duration : rise/fall time of 0.5 ms with Blackman envelope; 4 ms for 1 kHz; 2.5 ms for 3 kHz; 2 ms for 4 kHz; 1.5 ms for 6 kHz Electrode montage : tiptrode ear canal and high forehead High frequency audiometry (HFA) 9–16 kHz OAE ER-10 B+ probe microphone; EMAV software Frequency ratio f 1 /f 2  = 1.2; L 1  = 55 dB SPL; L 2  = 65	ABR: Wave I amplitude reduced in group with higher reported noise exposure; decrease in amplitude of 29% in veteran high noise group compared with nonveterans control group
Guest et al (2017) 24	Is tinnitus along with a normal audiogram (TNA) associated with greater lifetime noise exposure? Is TNA associated with ABR effects consistent with CS? Is TNA associated with temporal coding deficits consistent with CS?	25.7 ± 1.3 years of age for tinnitus group; 25.5 ± 1.3 years of age for control group Pure-tone thresholds of 0.25–8 kHz, normal middle ear pressure and compliance 20 subjects in tinnitus group; 20 subjects in control group No history of head trauma, middle ear surgery, neurologic disorder, and ototoxic exposure	Interview	ABR Stimulus type : high-pass filtered click Stimulus amplitude : 102 dB peSPL Stimulus rate : 7.05 Hz Repetitions : 7,040 per ear Transducer : ER3A insert Electrode montage : Cz and ipsilateral mastoid EFR Stimulus type : transposed tones with a 4-kHz carrier and 0.1-Hz modulator Stimulus duration : 400 ms plus 15 ms onset and offset ramps S/N : 20-dB broadband RMS Modulation depth and polarity : 0 dB and −6 dB re:100% modulation; two polarities Repetitions : 630 Interstimulus interval: 400 ms	ABR: no association evident between noise exposure and amplitude of wave I; no association between noise exposure and wave I/V ratio Tinnitus was not associated with reduced ABR wave I amplitude between groups EFR: no association between noise exposure and EFR amplitude at shallow modulation depth
Liberman et al (2016) 16	Are ECochG, OAE, HFA, and speech perception sensitive to differences in groups of high-risk versus low-risk noise exposure?	18–41 years of age, native English speakers, pure-tone thresholds of <20 dB HL at 0.25–8 kHz 22 subjects in high-risk group 12 subjects in low-risk group No history of ear or hearing problems, or neurologic disorders	Self-report via questionnaire	Degraded speech recognition: Stimulus: NU-6, 50 word lists Condition: in quiet, ipsilateral S/N +5 dB, ipsilateral S/N 0 dB Stimulus: Time compressed Condition: 45 or 65% both with 0.3 second reverberation added ECochG: Stimulus type : 100 μs clicks Stimulus amplitude : 94.5 dB nHL stimulus and 55 dB nHL contralateral masking Stimulus polarity : alternating Stimulus rate : 9.1 or 40.1 Hz Repetitions : up to 2 k Filter : 0.01–3 kHz bandpass filter Artifact reject : enabled Transducer : ER3A earphones Electrode montage : horizontal with forehead ground Impedance : N/R; between electrodes were <2 k ohms HFA: 9–16 kHz using Circumaural HDA200 high-frequency headset OAE: DPOAE; amplitude versus frequency sweeps; frequency ratio f 1 /f 2  = 1.2; L 1 =65 dB SPL, L 2  = 55 dB SPL; frequencies from 0.5–12 kHz	Degraded speech recognition (speech in noise, time compressed, time compressed with reverberation); performance was significantly worse in the high-risk group HFA thresholds were significantly worse for high-risk group ECochG SP/AP ratio high-risk nearly twice low-risk group OAE amplitudes were not significantly different between groups
Mehraei et al (2017) 26	Does auditory nerve fiber deafferentation increase forward masking thresholds and does forward masking increase wave V latency?	20–30 years of age; pure-tone thresholds of 0.25–8 kHz < 20 dB HL	None	Forward masking ABR: Masker stimulus type : 100 ms long broadband noise Probe stimulus type : flat-spectrum, broadband chirp (0.08–20 kHz) Masker stimulus amplitude : 35 and 70 dB SPL Probe stimulus amplitude : 90 dB peSPL Stimulus polarity : not stated Stimulus rate : 2 Hz Repetitions : 1.5 k trials per stimulus condition Filter : 0.1–2 kHz Artifact reject : not stated Transducer : not stated Electrode montage : 5 channel: Pz, Cz, Fz, M1, M2 Impedance : not stated MPI : 20, 40, 201 ms Forward masking behavioral experiment: Masker stimulus amplitude : 35 and 70 dB SPL Probe stimulus: flat-spectrum, broadband chirp (0.08–20 kHz) Offset of masker to onset of probe (MPI ): 20, 40, 72, 132, 168, 201 ms Measure : chirp threshold in quiet and for each condition	Masked ABR may be a useful tool in identifying cochlear synaptopathy
Mehraei et al (2016) 19	Does noise affect latency of ABR wave V? Does the effect of noise on wave V latency predict perceptual temporal sensitivity?	20–40 years of age; pure-tone thresholds of ≤ 15 dB HL 0.25–8 kHz	None for human (see animal table for animal data from this study)	ABR wave I and V Stimulus type : 80 μs click Stimulus amplitude : 50–90 dB peSPL in 10 dB steps (wave V) and 60–100 dB peSPL (wave I) Stimulus polarity : alternating Stimulus rate : 10 Hz Repetitions : 3 k Filter : bandpass 0.1–2 kHz Artifact reject : N/R Transducer : ER-1 insert phones Electrode montage : Ear canal, Cz, Fz Impedance : N/R ABR masked Stimulus type : 80 μs click Stimulus amplitude : 80 dB peSPL with broadband noise varying from 42–82 dB SPL in 1-dB steps Stimulus polarity : alternating Stimulus rate : 10 Hz Repetitions : 3,000 Filter : bandpass 0.1–2 kHz Artifact reject : N/R Transducer : ER-10C earphones Electrode montage : Ear canal, Cz, Fz Impedance : N/R Interaural time difference detection: transposed tone; carrier frequency either 2 or 4 kHz; modulation frequency of 50 Hz Carrier phase same for both ears; ITDD applied to the 50 Hz envelope OAE Click-evoked; bandpass filtered 0.25–6 kHz; growth function; f 2 /f 1  = 1.2	ABR: Wave V latency decreased with intensity increase; wave V latency in background noise increased with increase in intensity Perceptual temporal sensitivity can be predicted by wave V latency (accounting for effects of noise) No correlation between wave V latency shift and OAE results
Prendergast et al (2017) 28	Is cochlear synaptopathy prevalent in young adults with normal hearing and is it measurable by suprathreshold electrophysiologic measures?	18–36 years of age; pure-tone thresholds of ≤ 25 dB HL 0.25–8 kHz	Structured interview	ABR Stimulus type : 100 μs diotic clicks high-pass filtered at 1.5 kHz Stimulus amplitude : 80 and 100 dB peSPL Stimulus polarity : alternating Stimulus rate : 11.1 Hz Repetitions : 7,480 Filter : no online filtering Artifact reject : no online rejection criteria set Transducer : ER3A inserts Electrode montage : C7, Fz, M1, M2 Impedance : N/R FFR Stimulus type : 4 tones presented simultaneously with low frequency tone (.24 to .285 kHz) transposed to 4 kHz; 220 ms in duration including 10 ms ramps Stimulus amplitude : 80 dB SPL Stimulus polarity : alternating Stimulus rate : Interstimulus interval randomly selected within 85–95 ms range Repetitions : 4,000 (2,000 per polarity) Filter : no online filtering Artifact reject : no online rejection criteria set Transducer : ER3A inserts Electrode montage : Fz, C7 Impedance : N/R HFA 16 kHz using Sennheiser HAD-200 circumaural headphones OAE Transient evoked; six frequencies in range of 1.5–4 kHz in .5 kHz steps using narrow band clicks presented at 83 dB peSPL	ABR: No evidence of ABR or FFR changes based on reported noise exposure in young adults; 16 kHz thresholds increased with noise exposure for females, but not males Total recovery of DPOAEs suggested recovery of outer hair cell function
Stuermer et al (2015) 27	Can AS/AN be differentiated from SNHL by differences in threshold, latency, or amplitude ratio between AP and SP?	Age 6 months to 11 years; moderate to profound hearing loss; 10 with absent or severely abnormal ABRs with preserved CMs (cochlear microphonics); OAEs detected in 6 of these participants 10 with elevated ABR thresholds, but clearly detectable ABR waveforms with no signs of asynchrony; absent OAEs	N/A	ECochG State of arousal : anesthetized Stimulus type : 2 kHz tone burst 2 ms rise fall time with 6 ms duration Stimulus amplitude : 10–20 dB above individual threshold level between 70 and 102 dB nHL Stimulus polarity : condensation and rarefaction Stimulus rate : 21.3 Hz Repetitions : 500 Filter : bandpass 0.15–3 kHz Artifact reject : N/R Transducer : ER-2A inserts Electrode montage : promontory Impedance : N/R	Significant differences in CM, SP thresholds were lower than CAP thresholds in AS/AN patients; CM, SP thresholds were comparable to CAP thresholds in SNHL patients
Verhulst et al (2016) 25	Does a functional model designed to predict the slope of ABR wave V latency–intensity function and amplitude intensity function compare with measured latency–intensity function and amplitude–intensity function measured from 30 participants with normal or high-frequency sloping audiograms?	12 listeners with normal hearing; 18 listeners with high-frequency sloping audiograms	N/A	ABR Stimulus type : 100 μs clicks Stimulus amplitude : 70, 80, 90, and 100 dB peSPL Stimulus polarity : condensation Stimulus rate : 33.3 Hz Repetitions : 7,000 Filter : bandpass 0.7–1.5 kHz Artifact reject : N/R Transducer : ER-2 inserts Electrode montage : Cz, earlobes Impedance : N/R OAE Distortion product threshold at 4 kHz; frequency ratio f 1 /f 2  = 1.2 over a ⅓ octave range around 4 kHz; growth function	Latency–intensity function and amplitude–intensity function may help differentiate CS from other sensorineural loss

Abbreviations: ABR, auditory brainstem response; DPOAE, distortion product otoacoustic emissions; ECochG, electrocochleograpy; EFR, envelope following response; FFR, frequency following response; HFA, high frequency audiometry; ITDD, interaural time difference detection; N/A, not applicable; NR, not reported; OAE, otoacoustic emission; TEOAE, transient evoked otoacoustic emissions.